Journal articles: '100=aacr2 700=aacr2'

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Hoffe, Sarah E., Dae Won Kim, James Costello, Mokenge Peter Malafa, Todd Anthony Aguilera, Muhammad Shaalan Beg, Parag Parikh, et al. "GRECO-2: A randomized, phase 2 study of stereotactic body radiation therapy (SBRT) in combination with GC4711 in the treatment of unresectable or borderline resectable nonmetastatic pancreatic cancer (PC)." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): TPS4175. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.tps4175.

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TPS4175 Background: While systemic treatment of PC has improved, rates of surgical resection - considered optimum treatment - remain low. Patients with un-resectable or borderline PC still have poor outcomes, with both toxicity and disease progression during induction chemotherapy limiting the number eligible for surgery. SBRT practice to enhance margin negative resection or to provide local control, if inoperable after neoadjuvant therapy, has shifted to higher dose delivery (Mellon 2015, Colbert 2018), but timing and appropriate patient selection are under constant debate. SBRT delivery over 50Gy exhibits superior cell killing compared to conventionally fractionated RT but carries potential GI toxicity risk (Zhong 2017). GC4711 is a selective superoxide dismutase mimetic that converts superoxide to hydrogen peroxide. As radiation response modifiers, dismutase mimetics have the potential to increase tumor control without compromising radiation safety (Sishc, AACR 2019). GC4711 consistently augmented tumor control by SBRT in PC experimental xenograft mouse models. In a pilot phase 1/2 trial (GC4419-101), subjects with locally advanced PC were randomized to receive SBRT plus either the selective dismutase mimetic GC4419 or placebo. This pilot trial has demonstrated acceptable safety with SBRT (5 × 10-11Gy), as well as apparent improvements in survival, surgical resection, locoregional control, and time to distant metastases. Altogether, these data support the hypothesis that GC4711 may improve tumor outcomes and the benefit-risk ratio of 5-fraction SBRT delivering 50Gy by improving efficacy without increasing GI-toxicity. Methods: GRECO-2 is a phase 2, multicenter, randomized, double-blind, placebo-controlled study to determine the effect on overall survival of adding GC4711 to SBRT following 4 months of chemotherapy in subjects with un-resectable or borderline non-metastatic PC. Approximately 160 subjects will be enrolled at over 20 sites to receive GC4711 100 mg or placebo IV given as IV infusion over 15 min, prior to each of 5 SBRT fractions of 10Gy). Subjects judged operable will be explored within 8 weeks after SBRT. All subjects will complete 2 additional months of adjuvant chemotherapy. Primary end point is overall survival and secondary endpoints address resection rates, local and distant disease progression, and safety, while exploratory studies include ctDNA, tumor exome/transcriptome sequencing, and immune profiling, patient-reported symptoms (PRO-CTCAE), CA19.9 normalization, and radiomics. Colbert L, Rebueno N, Moningi S et al Advances in Radiation Oncology (2018) 3, 693-700 Mellon EA, Hoffe SE, Springett GM, et al Acta Oncologica, 2015;54:7 Zhong J, Patel K, Switchenko J, et al. Cancer. 2017 Sep 15;123(18):3486-3493. Sishc BJ, Saha D, Story MD. AACR PADC 2019 C52. Clinical trial information: NCT04698915.

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Cai, Weisong, Fang Liu, Xuejiao Liu, Xiaojuan Wang, Chunyang Wang, Tonghui Ma, and Shu Li. "Abstract 5756: Next-generation sequencing (NGS) reveals different molecular profiles of pediatric sarcoma in children and adults." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5756. http://dx.doi.org/10.1158/1538-7445.am2022-5756.

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Abstract Background: Pediatric sarcomas represent approximately 12% of all pediatric cancers with over 100 subtypes. Although some molecular detection techniques can be used to assist the diagnosis and treatment of pediatric sarcoma, it still remains challenging due to overlapping morphological features and limited biopsy specimens. Here we performed next generation sequencing (NGS) to analyze the molecular profiles of pediatric and adult sarcomas in China. Methods: A total of 700 Chinese patients with sarcoma were collected. The tumor tissue and matching blood specimens were tested by the integrative DNA and RNA sequencing panel Onco Panscan plus࣪ at Genetronhealth. Results: Of the 700 sarcoma patients, there were 224 children (32%) and 476 adults (68%). Difference from the almost same ratio of men to women in adults, there were more males (n = 134) than females (n = 90) in children. Rhabdomyosarcoma was the most common soft tissue tumor in children, accounting for 24.1% (n = 54), followed by Ewing's sarcoma (9.8%, n = 22) and Osteosarcoma (8.5%, n = 34), while Angiosarcoma (3.8%, n = 18) and Fibrosarcoma (3.6%, n = 17) were the most common in adults. Based on mutation types, the frequent alterations were missense mutations (n = 326, 51.2%), fusions (n = 129, 20.3%) and copy number variants (n = 66, 10.4%) in children with a mean of 3 mutations per patient, and missense mutations (n = 1438, 66.8%), fusions (n = 221, 10.3%) and truncating mutations (n = 215, 10.0%) in adults with an average 5 mutations. TP53 (12.9%, n = 29), EWSR1 (8.9%, n = 20) and ALK mutations (6.7%, n = 15) were common in children, which was distinct from TP53 (29.4%, n = 140), NF1 (4.8%, n = 23), CTNNB1 (4.2%, n = 20) and RB1 (4.2%, n = 20) in adults. Based on NGS results, pathological subtypes could be confirmed in 40.2% (90/224) and 48.1% (229/476) of children and of adults sarcoma patients, respectively. In addition, we identified a total of 72 drug-targeted gene mutations in the 57 children patients, of which 35 (48.6%) gene mutations could be targeted by FDA-approved drugs. In adults, 256 drug-targeted gene mutations were detected and the proportion of actionable mutations was up to 78.9% (n = 202). Conclusion: The genomic landscape of pediatric sarcomas is different from that of adults. NGS aids in the subtype classification and clinical guidance of pediatric sarcomas, providing evidence for personalized treatments with clinical benefit. Citation Format: Weisong Cai, Fang Liu, Xuejiao Liu, Xiaojuan Wang, Chunyang Wang, Tonghui Ma, Shu Li. Next-generation sequencing (NGS) reveals different molecular profiles of pediatric sarcoma in children and adults [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5756.

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Gao, Feng, Xuejiao Liu, Xiaojuan Wang, Chunyang Wang, Tonghui Ma, and Changsheng Yang. "Abstract 5755: Mutation profiling of homologous recombination-related (HRR) genes in sarcoma patients." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5755. http://dx.doi.org/10.1158/1538-7445.am2022-5755.

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Abstract BACKGROUND: Homologous recombination deficiency (HRD) is associated with tumorigenesis. Therapy directed toward HRD has been approved in breast and ovarian cancer, however, whether there is a chance of benefit for patients with other cancers remains unknown. Herein, we investigated the mutation characteristics of homologous recombination-related (HRR) genes in Chinese patients with sarcoma to explore possible benefit opportunities for sarcoma patients. METHODS: The genetic landscape of HRR genes was assessed in 700 Chinese sarcoma patients with different subtypes including Rhabdomyosarcoma (RMS, n = 67), Liposarcoma (LPS, n = 58), Osteosarcoma (n = 34), Synovial sarcoma (n = 30), Leiomyosarcoma (n = 29), Ewing's sarcoma (EWS, n = 27), Angiosarcoma (n = 20), other rare (n = 375) and unknown subtypes (n = 60). Molecular profiles were performed by using next generation sequencing (NGS)-based Onco Panscan plus࣪ at Genetronhealth, a laboratory accredited by College of American Pathologists and Clinical Laboratory Improvement Amendments. RESULTS: Among the 700 patients, the overall mutation frequency of HRR genes was 19.0%. Correspond to specific subtypes, the mutation frequency of HRR genes were higher in Leiomyosarcoma (27.6%, 8/29), Angiosarcoma (25.0%, 5/20) and LPS (17.2%, 10/58) compared with RMS (14.9%, 10/67), Osteosarcoma (14.7%, 5/34), Synovial sarcoma (13.3%, 4/30) and EWS (3.7%, 1/27). ATRX was the most commonly mutated gene (5.1%, n = 36) and was preferentially identified in Leiomyosarcoma (10.3%) and Angiosarcoma. (10.0%), followed by ARID1A (3.1%, n = 22), ATM (2.1%, n = 15) and FANCA/C/D2/E/F/G/L (1.7%, n = 12). The median tumor mutational burden (TMB) was 2.35 in patients with HRD and 0.94 in patients without HRD. Although BRCA1 and BRCA2 mutations were less common overall (1.1% and 0.7%), a significant proportion of BRCA1 and BRCA2 mutations was found in Angiosarcoma, Liposarcoma and Leiomyosarcoma (5.0%, 3.4% and 3.4%, respectively). CONCLUSION: Our results reported the genetic landscape of HRR genes in Chinese sarcoma patients, providing a reference for the clinical application of PARP inhibitors. Citation Format: Feng Gao, Xuejiao Liu, Xiaojuan Wang, Chunyang Wang, Tonghui Ma, Changsheng Yang. Mutation profiling of homologous recombination-related (HRR) genes in sarcoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5755.

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Higgs, Alysha, Angelique Ryan, Jayanthi Ramprakash, Dana Ruminski Lowe, Yves Konigshofer, Catherine Huang, Andrew Anfora, Russell Garlick, and Bharathi Anekella. "Abstract 7030: Reference materials for analysis of DNA methylation in cell-free circulating tumor DNA." Cancer Research 84, no. 6_Supplement (March 22, 2024): 7030. http://dx.doi.org/10.1158/1538-7445.am2024-7030.

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Abstract Aberrant DNA methylation is associated with many cancers including breast, liver, bone, and colon and has been identified as a biomarker for early cancer screening. Liquid biopsies are beginning to screen for DNA methylation in cancer-derived DNA, but accurate assessment of methylation is not trivial, and methods like bisulfite sequencing can result in biased data. Reference materials for establishing the analytical validity of measurements of CpG methylation are not widely available. In order to prepare such reference materials, genomic DNA (gDNA) was extracted from the well characterized human reference cell line GM24385 and fragmented to a circulating tumor DNA (ctDNA)-like size distribution. This DNA was processed further to prepare CpG-methylated and unmethylated versions. The size distribution was determined by using the Bioanalyzer High Sensitivity DNA Kit (Agilent, Santa Clara, CA). Methylation status in the reference materials was confirmed by both digital PCR (dPCR) and NGS based methods. A digital PCR method was developed to analyze heterozygous single nucleotide polymorphisms (SNPs) using the Bio-Rad QX200™ Droplet Digital PCR (ddPCR) System. To determine methylation levels by NGS, the NEBNext™ Enzymatic Methyl-seq Kit was used (EM-seq). Paired-end sequencing of the libraries was performed on a NextSeq™ 2000 (Illumina, San Diego, CA). Data alignment to hg19 was done with the bwa-meth (Pedersen, BS., et al.) aligner, and assessment of methylation in the aligned data was done with MethylDackel (Ryan, D.). Each reference material had an average peak size of ~160 bp in length, similar to patient cfDNA. By dPCR, the unmethylated reference material had an average of 0.73% DNA methylation, while the methylated reference material had an average of 100.10% DNA methylation. Values can be above 100% by dPCR due to unequal representation of both alleles. By NGS, the unmethylated reference material had an average of 0.93 % CpG methylation, which was similar to the background of 1.13 % and 1.31 % for CHG and CHH methylation, respectively. The methylated reference material had an average of 93.95 % CpG methylation, with a background of 0.69 % and 0.74 % for CHG and CHH methylation, respectively. Because EM-seq relies on enzymatic protection and conversion steps, it may be that these reactions did not allow for full protection and full conversion, which led to values above 0 % for unmethylated and below 100 % for methylated materials. We have developed reference materials for the assessment of DNA methylation in ctDNA. One unmethylated and one methylated reference material was created. These reference materials can be mixed together to the level of methylation required to help aid in assay design, optimization, and validation. Citation Format: Alysha Higgs, Angelique Ryan, Jayanthi Ramprakash, Dana Ruminski Lowe, Yves Konigshofer, Catherine Huang, Andrew Anfora, Russell Garlick, Bharathi Anekella. Reference materials for analysis of DNA methylation in cell-free circulating tumor DNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7030.

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Champiat, Stephane, Martin Wermke, Johann de Bono, Aurelien Marabelle, Christiane Jungels, Cécile Vicier, Norbert Vey, et al. "Abstract CT188: ICT01, an anti-butyrophilin 3A targeted mAb activating g9d2 T cells, induces immune remodeling of the tumor microenvironment and clinical responses in combination with pembrolizumab in patients with advanced solid tumors who failed prior checkpoint inhibitor therapy: EVICTION Trial." Cancer Research 82, no. 12_Supplement (June 15, 2022): CT188. http://dx.doi.org/10.1158/1538-7445.am2022-ct188.

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Abstract Background: γ9δ2 T cells are part of the innate-like immune response to malignancies and have the ability to bridge to the adaptive immune response via cytokine release (e.g., IFNγ and TNFα). Butyrophilin 3A is a novel checkpoint molecule required to activate γ9δ2 T cells highly expressed on immune and malignant cells, and the target of a monoclonal antibody ICT01. ICT01 induces activation/migration of γ9δ2 T cells from the blood to induce immune remodeling of the tumor microenvironment at doses ≥700 μg being tested in the ongoing EVICTION clinical trial (NCT04243499) (AACR 2021, CT034). In vitro studies showed that ICT01 induces upregulation of PD-1 on γ9δ2 T cells and that the combination with pembrolizumab leads to enhanced cancer cell killing, providing scientific rationale for evaluating this combination. Methods: EVICTION is an ongoing Phase 1/2a, international, open-label trial with Group C assessing ICT01 (IV Q3W) plus pembrolizumab (200mg IV Q3W) in patients with bladder cancer, HNSCC, melanoma, or NSCLC who failed ≥1 CPI. Pharmacodynamic activity was monitored by immunophenotyping and cytokine level analysis. Tumor biopsies (baseline, Day 28) were used for immunohistochemistry of BTN3A and tumor-infiltrating lymphocytes, and gene expression profiling. Efficacy evaluations by i/RECIST 1.1 were conducted every 8 weeks. Results: Five Group C patient cohorts have been enrolled and treated with ICT01 doses of 700μg, 2mg, 7mg, 20mg or 75mg (n=30) plus pembrolizumab, with the 200mg ICT01 cohort enrolling currently. To date, no DLTs have been observed with the combination. First-dose fever and chills (Grade 1/2) were the most common AEs that increased in frequency up to 75mg (100%, n=6), without any increase in severity, and rarely recur with subsequent dosing. ICT01+pembrolizumab induced trafficking of >95% of circulating γ9δ2 T cells within 30 min post ICT01 (≥700 μg), which was sustained for 21 days at 75mg. Transient, dose-dependent increases in serum cytokines at 30 min (TNFα) or 4h (IFNγ) post-dose were correlated with baseline γ9δ2 T cell counts and returned to baseline by 24 hrs post dose. Baseline γ9δ2 T cell count also correlated with increases in tumor infiltration of γδ, CD3, and CD8 T cells, confirming the ability to remodel the TME, and the potential to select/enrich patients with higher baseline γ9δ2 T cell counts. Sixteen patients (9/16 pembro-experienced, 5/16 received >1 prior CPI) were efficacy-evaluable at ≥Week 8 by RECIST1.1 at ICT01 doses up to 20 mg, with an observed disease control rate of 44% including 3 confirmed PRs beyond 6 months: bladder (2mg), melanoma (2mg), NSCLC (7mg). The Ipi/Nivo-refractory melanoma patient with PR also achieving a CR on their non-target lesion brain metastasis at 6 months. Data from the 75 and 200mg cohorts will be presented. Conclusion: The immune remodeling of the TME by ICT01-activated γ9δ2 T cells is associated with clinical benefit in CPI-experienced patients when used in combination with pembrolizumab. The selection of patients with higher baseline γ9δ2 T cells may improve the response profile to this novel therapeutic combination in CPI-failure patients, which will be tested in the Phase 2a portion of EVICTION starting in Q2 2022. Citation Format: Stephane Champiat, Martin Wermke, Johann de Bono, Aurelien Marabelle, Christiane Jungels, Cécile Vicier, Norbert Vey, Catrin List, Katrin Wetzko, Leo Ruhnke, Elena Garralda, Vladimir Galvão de Aguiar, Patricia LoRusso, Nuria Kotecki, Aude De Gassart, Emmanuel Valentin, Patrick Brune, Marina Iché, Céline Leparquier, Daniel Olive, Paul Frohna. ICT01, an anti-butyrophilin 3A targeted mAb activating g9d2 T cells, induces immune remodeling of the tumor microenvironment and clinical responses in combination with pembrolizumab in patients with advanced solid tumors who failed prior checkpoint inhibitor therapy: EVICTION Trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT188.

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Myung, I. S., J. K. Choi, J. M. Wu, J. Y. Lee, H. L. Yoo, and H. S. Shim. "Bacterial Stripe of Hog Millet Caused by Acidovorax avenae subsp. avenae, a New Disease in Korea." Plant Disease 96, no. 8 (August 2012): 1222. http://dx.doi.org/10.1094/pdis-03-12-0320-pdn.

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In July 2011, bacterial stripe was observed on a commercial field of hog millet (Panicum miliaceum L.) in Chuncheon, Korea, with a disease incidence of 37% in the field. Symptoms on leaves included reddish-brown, long, narrow stripes that varied in length and were sharply delineated by uninfected adjacent vascular bundles. Eleven bacterial isolates (BC3107, BC3214 to BC3223) were recovered on trypticase soy agar from lesions surface sterilized in 70% ethanol for 1 min. The isolates, all obtained from different plants, were gram negative, oxidase positive, aerobic rods with two to four flagella. The isolates produced circular, cream-colored, nonfluorescent, butyrous colonies with entire margins on King's B medium. Using the Biolog Microbial Identification System, Version 4.2 (Biolog Inc., Hayward, CA), the isolates were identified as Acidovorax avenae subsp. avenae with Biolog similarity indices ranging from 0.52 to 0.72 after 24 hr. Characters for differentiating between Acidovorax spp. were tested according to Schaad et al. (2). The isolates were positive for gelatin liquefaction, nitrate reduction, lipase production, utilization of D-mannitol, sodium citrate, and alkaline in litmus milk. The isolates were negative for utilization of D-arabitol and did not amplify with PCR primer sets Aaaf5, Aaaf3/Aaar2, and Aacf2/Aacr2. Colonies were V–, V+, and V+ for utilization of D-fucose, maltose, and ethanol, respectively. Regions of the 16S rRNA (rrs) and the IGS were sequenced to aid in the identification of the isolates using reported PCR primer sets (1,4). A 1,426 bp fragment of the rrs region shared 100% similarity with all strains of A. avenae available in GenBank. Pathogenicity tests were separately performed for the 11 isolates in different greenhouses located in Suwon (National Academy of Agricultural Science), and Chuncheon (Gangwondo Agricultural Research and Extension Services) in Korea. Pathogenicity was confirmed by clip inoculation with sterilized scissors dipped into cell suspensions containing 105 CFU/ml on three 8-day-old leaves of hog millet (two plants per isolate), rice (Oryza sativa L. cv. Hopyeong), and sweet corn (Zea mays L. cv. Daehak) in a greenhouse maintained at 28 to 32°C and 90% relative humidity. The isolates induced similar symptoms as those originally observed on hog millet 5 days after inoculation. No symptoms were observed on the control plants (hog millet, rice, and sweet corn), which were clipped with scissors dipped in sterilized distilled water. The identity of bacteria reisolated from the stripes on inoculated leaves was confirmed by analyzing sequences of the 16S-23S rRNA intergenic spacer region (IGS) (1). On the basis of physiological, pathological, and sequence data, the isolates were identified as A. avenae subsp. avenae. To our knowledge, this is the first report of bacterial stripe of hog millet caused by A. avenae subsp. avenae in Korea. The spread of the bacterial disease is expected to have a significant economic impact on hog millet culture in the fields of Gangwon Province in Korea. Nucleotide sequence data reported are available under accession numbers JQ743877 to JQ743887 for rrs of BC 3207 and BC3214 to BC3223, and JQ743877 to JQ743887 for IGS of BC3207 and BC3214 to BC3223. References: (1) T. Barry et al. The PCR Methods Appl. 1:51, 1991. (2) N. W. Schaad et al. Syst, Appl. Microbiol. 31: 434, 2008. (3) K. Tamura et al. Mol. Biol. Evol. 28:2731, 2011. (4) W. G. Weisburg et al. J. Bacteriol. 173: 697, 1991.

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Zhao, Yu, and Lindsey Cambria. "Abstract 7009: Quantification of DNA methylation using methylation-sensitive restriction enzymes and digital PCR." Cancer Research 84, no. 6_Supplement (March 22, 2024): 7009. http://dx.doi.org/10.1158/1538-7445.am2024-7009.

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Abstract DNA methylation is a common epigenetic modification, characterized by the presence of the signature 5-methylcytosine without altering the sequence of DNA. The study of DNA methylation in mammals has gained significant attention due to its broad impact on numerous biological processes and its critical role in the onset and progression of many diseases, such as cancer and aging. Consequently, there is a pressing need for a rapid and precise method to assess methylation status. Currently, most approaches for quantifying DNA methylation rely on sodium bisulfite treatment. However, such approaches do not align with the uracil DNA glycosylase PCR system. In this study, we demonstrate the application of methylation-sensitive restriction enzymes (MSRE) and digital PCR to determine the methylation status of the Ras association domain family 1 isoform A (RASSF1A) in cancer cell lines. Digital PCR enables the precise detection and absolute quantification without the reliance on reference standards. We developed a multiplex digital PCR assay that includes the target gene RASSF1A, along with two reference genes for the purpose of monitoring digestion completion and correcting DNA input. Each sample of interest was measured both before and after a MSRE digestion. To ensure the quantification accuracy, we employed the commercially available CpGenome human methylated DNA standard with a known concentration from MilliporeSigma, treating it with and without a MSRE, and subsequently performing digital PCR experiments using Roche Digital LightCycler® IVD system with a Universal nanowell plate featuring 28,000 partitions. The expected concentrations lay within the 95% confidence interval, affirming the accurate quantification achieved through digital PCR. Next, we measured the fraction of methylated alleles in various lung cancer and breast cancer cell lines, as well as in healthy human gDNA. The methylation of RASSF1A promoter in healthy human gDNA is ~0.7%, while a broad range of methylation levels was observed in cancer cell lines, ranging from ~0.7% to ~100.2%. Notably, the influence of GC bias was identified in this study. To overcome this critical challenge, we optimized the usage of several high GC enhancers. The results demonstrated that the concentration of 5-7.5% DMSO, 7.5% glycerol, and commercially available OneTaq or Q5 GC enhancers from New England Biolabs were effectively incorporated into the Roche digital PCR system, thereby enhancing the accuracy of quantification from 30% to 100%. Together, we demonstrated a remarkable approach for DNA methylation analysis using Roche digital PCR system in combination with MSREs and suitable high GC enhancers. This study suggests a promising rapid, accurate and cost-effective tool to advance research in the field. *Data on file at Roche Diagnostics, Wilmington, MA, USA Citation Format: Yu Zhao, Lindsey Cambria. Quantification of DNA methylation using methylation-sensitive restriction enzymes and digital PCR [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7009.

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Day, Charles, Florina Grigore, Alyssa Langfald, David J. Daniels, James Robinson, and Edward Hinchcliffe. "Abstract 705: Inhibition of H3.3 S31 phosphorylation by the pediatric glioma driver mutation, H3.3 K27M, results in chromosomal instability, loss of p53 regulation, and tumorigenesis." Cancer Research 82, no. 12_Supplement (June 15, 2022): 705. http://dx.doi.org/10.1158/1538-7445.am2022-705.

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Abstract The heterozygous H3.3 K27M mutation is found in the majority of pediatric High-Grade Glioma’s (pHGG). H3.3 K27M is thought to promote tumor formation through altered epigenetic gene regulation. However, it is unclear if epigenetic reprogramming alone is sufficient for glioma formation. H3.3 contains a unique Serine at position 31 which is phosphorylated in early mitosis (where it functions in chromosome segregation) and again in late M/early G1 when a mitotic error has occurred (triggering p53 expression). We found that pHGG cell lines harboring H3.3 K27M have significantly reduced S31 phosphorylation as compared to both pHGG and non-transformed H3.3 WT cells. When compared to WT H3.3 in an in vitro kinase assay, H3.3 K27M exhibits an ~60% reduction in S31 phosphorylation by Chk1, the mitotic S31 kinase. In normal diploid cells, expression of K27M or non-phosphorylatable S31A mutant significantly increased chromosome missegregation. Yet expressing a phosphomimetic double mutant (K27M/S31E) did not significantly alter the rate of chromosome mis-segregation compared to WT. Furthermore, patient-derived pHGG lines harboring K27M have significantly higher rates of chromosome mis-segregation compared to an H3.3 WT pHGG line or H3.3 WT non-transformed human cells. We used CRISPR gene editing to remove the H3.3 K27M allele or replace it with WT H3.3. In both cases, loss of K27M elevated pS31 levels and reduced chromosome mis-segregations. Yet, when K27M was replaced with S31A, the mis-segregation rate remained similar to the parental K27M cells. In normal cells, chromosome missegregation stimulates p53-dependent cell cycle arrest in G1 to prevent the proliferation of aneuploid daughters. However, cells expressing H3.3 K27M or S31A failed to arrest following missegregation - despite having WT p53. To determine if the induction of chromosomal instability would alter tumor formation, we expressed H3.3 WT, K27M or S31A in combination with PDGFβ in a glioma mouse model. Expression of WT H3.3 failed to generate high-grade tumors. But 66% of mice expressing K27M and 93% of those expressing H3.3 S31A developed diffuse high-grade brain tumors by 100 days. Our results suggest that loss of phospho-S31 alone is oncogenic because H3.3 S31A-expressing cells are WT for K27me3. Our results demonstrate that H3.3 K27M inhibits Ser31 phosphorylation both in vitro and in vivo, leading to both chromosome missegregation and loss of subsequent G1 arrest - thus creating diffuse midline gliomas with both dynamic, complex karyotypes and epigenetic reprogramming. Citation Format: Charles Day, Florina Grigore, Alyssa Langfald, David J. Daniels, James Robinson, Edward Hinchcliffe. Inhibition of H3.3 S31 phosphorylation by the pediatric glioma driver mutation, H3.3 K27M, results in chromosomal instability, loss of p53 regulation, and tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 705.

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Jungles, Kassidy M., Zhuwen Wang, Caroline Bishop, Cydnee Wilson, Meilan Liu, Jadyn James, Michael Green, James M. Rae, Corey W. Speers, and Lori J. Pierce. "Abstract 708: Targeting aurora kinase B (AURKB) as a radiosensitizing strategy in syngeneic models of triple negative breast cancer (TNBC)." Cancer Research 84, no. 6_Supplement (March 22, 2024): 708. http://dx.doi.org/10.1158/1538-7445.am2024-708.

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Abstract Purpose: Triple negative breast cancer (TNBC) is an aggressive breast cancer (BC) subtype with few treatment options. Radiation therapy (RT) is a mainstay therapy for the treatment of BC, but local recurrence following RT therapy is common. Consequently, decreasing local recurrence in patients with TNBC is a critical clinical need. Prior work demonstrated that AURKB is overexpressed in TNBC, and over-expression correlates with poor prognosis. Here, we examined the effects of AURKB inhibition as a novel radiosensitizing strategy in syngeneic TNBC models. Methods: Cell viability assays were used to determine the half-maximal inhibitory concentrations (IC50) of the AURKB inhibitors Barasertib-HQPA and SP-96 72 hours post treatment. Clonogenic survival assays were used to assess the radiosensitivity of TNBC murine cell lines to AURKB inhibition. In these assays, AURKB inhibitors were delivered at sub-IC50 concentrations 24 hours prior to RT, and radiation enhancement ratios (rERs) were calculated. Immunofluorescent microscopy using DAPI stain assessed micronuclei. Propidium iodide staining to assess aneuploidy was completed via flow cytometry. To assess the radiosensitizing effects of AURKB inhibition in vivo, the 4T1 syngeneic TNBC cell line was injected bilaterally into Balb/c mice and treated with Barasertib and RT. Tumor volume was recorded twice weekly throughout the study. Results: Aurora kinase B inhibitors (500-750 nM Barasertib-HQPA, 100-200 nM SP-96) delivered 24 hours prior to radiation therapy induced radiosensitization in the murine TNBC cells 4T1 (rER: 1.24-1.56) and Py8119 (rER: 1.51-1.72). Mechanistically, combined AURKB inhibition and RT significantly increased micronuclei formation in 4T1 cells 24 hours after RT compared to vehicle control (p<0.0001). Furthermore, combined AURKB inhibition and RT induced aneuploidy in murine TNBC cell lines 24 hours after radiation therapy compared to vehicle control. Combined AURKB inhibition (Barasertib 25 mg/kg, IP) and RT (8 Gy RT in 1 fraction) significantly decreased tumor volume compared to mice that had received vehicle control (777 ± 61 mm3 vs 1623 ± 126 mm3; p <0.0001). Conclusion: AURKB inhibition induces radiosensitization in syngeneic models of TNBC and leads to increased micronuclei and aneuploidy, suggesting a mechanism of sensitization. These results suggest that AURKB is a potential radiosensitizing strategy for the treatment of triple negative disease. Ongoing studies are further refining the underlying mechanisms of AURKB inhibition and RT on the antitumoral immune response. Citation Format: Kassidy M. Jungles, Zhuwen Wang, Caroline Bishop, Cydnee Wilson, Meilan Liu, Jadyn James, Michael Green, James M. Rae, Corey W. Speers, Lori J. Pierce. Targeting aurora kinase B (AURKB) as a radiosensitizing strategy in syngeneic models of triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 708.

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Hu, Xichun, Jun Cao, Yue’e Teng, Hui-Ping Li, Lili Zhang, Quchang Ouyang, Weimin Xie, et al. "Abstract P4-01-43: PyrotInib in combination with Capecitabine for trasTUzumab-REsistant, HER2-positive advanced breast cancer (PICTURE): a multicenter phase 2 trial." Cancer Research 83, no. 5_Supplement (March 1, 2023): P4–01–43—P4–01–43. http://dx.doi.org/10.1158/1538-7445.sabcs22-p4-01-43.

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Abstract Background: Approximately 10% of patients with HER2-positive breast cancer have primary resistance to trastuzumab, leading to poor prognosis. Although several trials enrolled those hard-to-treat patients, there has been no strong evidence available for the clinical decision making. This multicenter phase 2 trial aimed to investigate the activity and safety of pyrotinib plus capecitabine only in those patients with trastuzumab-resistant, HER2-positive advanced breast cancer. Methods: Patients from 17 sites in China received pyrotinib 400 mg once a day and capecitabine 1000 mg/m2 twice a day on days 1-14 every 21 days until disease progression or intolerable toxicity. Based on the definitions used in prior clinical trials, primary trastuzumab resistance was defined as progression during trastuzumab treatment (Group 1) or within 12 months after completing trastuzumab treatment in the (neo)adjuvant setting (trastzuzumab should have been for ≥9 weeks, Group 2), or progression within 6 months after the initiation of trastuzumab treatment in the advanced setting (treatment should have been for ≥6 weeks, Group 3). The primary endpoint was progression-free survival (PFS). The study is registered with ClinicalTrials.gov, NCT04001621. Results: Between June 2019 and September 2021, a total of 100 patients enrolled; 35 (35.0%) patients had hormone receptor (HR)-positive disease, and 65 (65.0%) had HR-negative disease. Prior use of trastuzumab, pertuzumab and antibody-drug conjugate was reported in 100%, 21.0% and 2.0% of patients, respectively. By the data cutoff on July 10, 2022, the median follow-up duration was 23.4 months (95%CI, 20.5-25.6) with 66 PFS events documented. Median PFS was 11.8 months (95%CI, 8.4-15.1) in the overall population. Patients in Group 2 (n=49) had the longest median PFS of 17.8 months (95%CI, 13.8-not reached), which was significantly different from either 8.2 months (95%CI, 3.0-20.7; p = 0.001) in Group 1 (n=21) or 5.6 months (95%CI, 4.1-6.9; p < 0.001) in Group 3 (n=30). No significant difference in median PFS was observed in subgroup by HR status (HR-positive: 9.7 months [95%CI, 6.4-18.4]; HR-negative: 12.3 months [95%CI, 8.2-17.8]; p = 0.764). Objective response rate was 70.0% (95%CI, 60.0%-78.8%). Overall survival data was immature. The most common grade ≥3 treatment-emergent adverse events included diarrhea (24.0%), palmar-plantar erythrodysaesthesia syndrome (9.0%), neutrophil count decreased (7.0%), hypokalemia (5.0%), and decreased appetite (5.0%). No treatment-related deaths occurred. Conclusions: Pyrotinib plus capecitabine resulted in a promising PFS that crossed the pre-specified efficacy boundary in patients with HER2-positive advanced breast cancer who met the traditional definition of primary trastuzumab resistance. Patients in Group 2 had a significant longer PFS than those in either Group 1 or Group 3, highlighting the need to re-define primary trastuzumab resistance and to clarify efficacy of new anti-HER2 biologicals for each subpopulation. Citation Format: Xichun Hu, Jun Cao, Yue’e Teng, Hui-Ping Li, Lili Zhang, Quchang Ouyang, Weimin Xie, Yueyin Pan, Zhenchuan Song, Xiaoling Ling, Xiaohong Wu, Jingwei Xu, Li Li, Liping Ren, Hong Wang, Dongxian Zhou, Jing Luo. PyrotInib in combination with Capecitabine for trasTUzumab-REsistant, HER2-positive advanced breast cancer (PICTURE): a multicenter phase 2 trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-43.

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Moss, Rachel M., Kelsie L. Becklin, Lauren J. Mills, Branden S. Moriarity, Beau R. Webber, and Logan G. Spector. "Abstract 702: Interaction between genetic ancestry and EWS-FLI induced transcription in Ewing sarcoma tumorigenesis." Cancer Research 82, no. 12_Supplement (June 15, 2022): 702. http://dx.doi.org/10.1158/1538-7445.am2022-702.

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Abstract Ewing Sarcoma (ES) is a rare but deadly pediatric bone and soft tissue tumor, with little improvement in survival for decades despite knowing the driving fusion oncoprotein EWS-FLI1. EWS-FLI1 is notably toxic, acting as an aberrant transcription factor and leading to growth arrest and apoptosis in all but a few cell types. ES incidence in populations of European ancestry is nearly ten times that found in children with primarily African ancestry. To better understand how EWS-FLI1 transforms the transcriptome and the protective effect of the African genome, we leveraged this disparate genomic context to study ES tumorigenesis by introduction of EWS-FLI1 into cells derived from donors with a range of African ancestry followed by RNA sequencing (RNA-seq). Induced pluripotent stem cell (iPSC) lines with genome wide SNP genotyping data were obtained and local ancestry was assessed using RFMix to establish genetic ancestry. Two lines each of ~100% European and African ancestry and four lines with intermediate European/African admixture (45% to 90% African) were differentiated into neural crest cells (iNCC, a proposed cell-of-origin for ES) and transduced with a lentivirus expressing either a GFP reporter or a GFP-2A-EWS/FLI1 cassette. Interestingly, iNCC derived from European lines maintained a higher frequency of cells expressing GFP/EWS-FLI1 than the pure African lines, with admixed lines showing an intermediate frequency. RNA was extracted at 48- and 96-hour time points and sequenced for gene expression analysis. As expected, we identified pronounced changes to the transcriptional landscape in EWS-FLI1-induced cells compared to control with 13,578 differentially expressed genes (adjusted p-value < 0.05). More interestingly we identified 3,128 genes with ancestry-associated gene expression differences in response to EWS-FLI1 expression. Gene Set Enrichment Analysis (GSEA) using MSigDB 50 hallmark gene sets (v7.4) detected 24 significantly enriched gene sets with an inverse correlation with percent African ancestry, including those sets involved with oxidative phosphorylation, MYC v1 and v2, and MTORC1 signaling. To identify those expression changes that are key to ES tumorigenesis we are comparing the transcriptional profiles of our EWS-FLI1 expressing iNCC to ES tumors and ES cell lines as well as other models of ES derived from mesenchymal stem cells. Ongoing studies will include profiling of chromatin accessibility and EWS-FLI1 occupation for each ancestral iNCC line following EWS-FLI1 transduction to determine the early, ancestry-linked transitions that are permissive to oncogenic transformation. As EWS-FLI1 itself has proven elusive to direct targeting, studying its immediate downstream effects has the potential for establishing new druggable biologic pathways for treatment of ES. Citation Format: Rachel M. Moss, Kelsie L. Becklin, Lauren J. Mills, Branden S. Moriarity, Beau R. Webber, Logan G. Spector. Interaction between genetic ancestry and EWS-FLI induced transcription in Ewing sarcoma tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 702.

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Wainberg, Zev A., Shubham Pant, Colin D. Weekes, Muhammad Furqan, Pashtoon M. Kasi, Craig E. Devoe, Alexis D. Leal, et al. "Abstract C092: T cell responses and clinical outcomes in pancreatic and colorectal cancer patients with minimal residual disease in AMPLIFY-201, a phase 1 trial of a first-in-class amphiphile lymph node targeted mutant KRAS vaccine." Cancer Research 84, no. 2_Supplement (January 16, 2024): C092. http://dx.doi.org/10.1158/1538-7445.panca2023-c092.

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Abstract Background: Mutations in RAS occur in > 25% of solid tumors and > 90% of patients (pts) with PDAC and > 40% of pts with CRC. ELI-002 2P is a vaccine comprised of lymph-node targeted Amphiphile (Amph)-modified G12D and G12R mutant KRAS peptides together with an Amph-modified CpG oligonucleotide adjuvant designed to expand polyfunctional mutant KRAS-specific T cells. Interim phase 1 AMPLIFY-201 data (O’Reilly et al; ASCO, 2023, #2528) showed that adjuvant administration of ELI-002 was well-tolerated, with T cell responses in 87%, and tumor biomarker responses in 77% (a subset of 32% had ctDNA clearance). Here we report relapse free survival data and correlations between ELI-002 2P- induced T cell levels and outcomes in pts with PDAC and colorectal cancer (CRC) at high risk for relapse following locoregional treatment. Methods: Resected PDAC (n=20) and CRC (n=5) pts with tumors harboring KRAS G12D or G12R who had minimal residual disease positivity (MRD+) defined as elevated circulating tumor DNA (ctDNA) and/or serum tumor biomarker (CA19-9/CEA), received up to 6 priming doses and 4 booster doses separated by a 3-month rest period of subcutaneous ELI-002 2P vaccine monotherapy comprised of Amph-peptides (700 mcg each G12D/G12R), admixed with Amph-CpG-7909 at 0.1, 0.5, 2.5, 5.0 and 10.0 mg per cohort dose level. Primary endpoints included safety and recommended phase 2 dose (RP2D) of Amph-CPG-7909; secondary endpoints: biomarker reduction/clearance; exploratory endpoints: included relapse free survival (RFS) using immune Response Evaluation Criteria in Solid Tumors (iRECIST) and immunogenicity assessed by direct ex vivo Fluorospot and intracellular cytokine staining of peripheral blood mononuclear cells. Results: Direct ex vivo polyfunctional mKRAS-specific T cell responses to ELI-002 2P were observed in 20/23 (87%; 50% induced both CD4+ and CD8+ T cells, median 13-fold and mean 56-fold increase from baseline), with response in 9/9 (100%) pts treated at highest two dose levels including the 10 mg RP2D. Clinical efficacy correlated with T cell response in evaluable pts (n=22): median tumor biomarker reduction/clearance was -86.9% vs -4.5% in above vs below median T cell responders, respectively (p < 0.0124). At 25 weeks median follow-up, the median RFS was not reached compared to 17.1 weeks in above versus below median T cell responders (HR 0.11; 95% CI 0.027-0.446; p = 0.0108). The association of RFS with T cell response was not confounded by other baseline prognostic variables (including tumor stage, recovery from prior cytotoxic therapy as assessed by absolute neutrophil count, or immune system subsets such as %CD4+ or %CD8+of CD3+ lymphocytes). Conclusions: The association of ELI-002 2P vaccine T cell responses with clinical outcomes in a novel MRD+ trial design underscores the potential to reduce recurrence in the setting of microsatellite stable PDAC and CRC. A new phase 1/2 trial, AMPLIFY-7P (NCT05726864), is evaluating a new seven peptide (G12D, G12R, G12V, G12C, G12A, G12S, G13D) ELI-002 7P formulation. Citation Format: Zev A. Wainberg, Shubham Pant, Colin D. Weekes, Muhammad Furqan, Pashtoon M. Kasi, Craig E. Devoe, Alexis D. Leal, Vincent Chung, James R. Perry, Lochana Seenappa, Lisa K. McNeil, Esther Welkowsky, Peter C. DeMuth, Christopher M. Haqq, Eileen M. O'Reilly. T cell responses and clinical outcomes in pancreatic and colorectal cancer patients with minimal residual disease in AMPLIFY-201, a phase 1 trial of a first-in-class amphiphile lymph node targeted mutant KRAS vaccine [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C092.

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Peña-Ortiz, Tania Y., Umesh Narayan, Ana Velazquez Mañana, Linda Salgin, Catherine M. Pichardo, Sheila F. Castañeda, Humberto Parada, Linda C. Gallo, Gregory A. Talavera, and Margaret S. Pichardo. "Abstract C122: Demographic and lifestyle characteristics of cancer survivors in the NIH-All of Us Research Program." Cancer Epidemiology, Biomarkers & Prevention 32, no. 1_Supplement (January 1, 2023): C122. http://dx.doi.org/10.1158/1538-7755.disp22-c122.

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Abstract Background: Cancer is the second leading cause of morbidity and mortality in the United States (U.S.), and minoritized ethnic and racial groups are disproportionately affected. Non-Hispanic Black (NHB) adults have the highest death rate among racial and ethnic groups in the U.S. for most cancers, with 73,680 cancer deaths projected in 2022. For U.S. Hispanic/Latino adults, cancer is the leading cause of death, accounting for 20% of deaths. Compared to Non-Hispanic White (NHW) adults, Non-Hispanic Asian (NHA) adults have lower cancer rates; however, cancer-specific disparities in morbidity and mortality exist. The National Institutes of Health All of Us Research Program has one of the largest and most nationally representative samples of adults in terms of socioeconomic status, race and ethnicity, age, and geography. Our study aims to describe the prevalence of cancer among the racially and ethnically diverse cohort of adults enrolled in All of Us. Methods: The All of Us tier five data release includes data from a convenience sample of 323,351 adults recruited and enrolled between May 6, 2018, and April 1, 2021, across 340 sites in the U.S. Using self-reported questionnaire data at the time of study enrollment, we identified 22,676 cancer survivors and described cancer site/types and associated cancer lifestyle characteristics (i.e., demographics, co-morbidities, lifestyle behaviors) by race and ethnicity. Descriptive statistics were calculated using Student’s T and Chi-squared tests for continuous and categorical variables, respectively. Results: Among 323,351 All of Us participants, 7.0% (n = 22,676) self-reported a history of cancer at enrollment. Overall, 88.6% of cancer survivors self-identified as NHW, 3.5% as NHB, 3.4% as Hispanic/Latino, 1.0% as NHA, and 3.6% as other race or ethnicity. Among all survivors, the mean ± standard deviation age was 69 ± 10 years, 56.3% were female, 55.3% had a college education or higher, 31.0% had a household income of $75,000-$150,000, 98.0% were insured, 66.9% were unemployed, 67.0% were partnered, and 93.1% were born in the U.S. The most prevalent cancer was skin cancer (34.5%), followed by cancers of the breast (16.8%) and prostate (10.1%). Breast cancer was the most prevalent cancer among NHA (36.1%), NHB (27.1%), and Hispanics/Latinos (20.1%). Skin cancer was the most common cancer among NHW (37.2%). Among all survivors, 38.8% had hypertension, 39.0 % had high cholesterol, 1.0% had type 1 diabetes, 10.8% had type 2 diabetes, 10.0% had obesity, 38.6% were never smokers, and 70.5% had a family history of cancer. All sociodemographic and lifestyle factors differed statistically (p < 0.05) by race and ethnicity. Conclusion: Approximately seven percent of All of Us adults were cancer survivors, a number that exceeds rates previously reported by diverse, prospective cohorts. Cancer prevalence, as well as lifestyle characteristics, varied across racial and ethnic groups, with breast cancer being the most reported cancer for minoritized groups compared to skin cancer for NHW participants. Citation Format: Tania Y. Peña-Ortiz, Umesh Narayan, Ana Velazquez Mañana, Linda Salgin, Catherine M. Pichardo, Sheila F. Castañeda, Humberto Parada Jr., Linda C. Gallo, Gregory A. Talavera, Margaret S. Pichardo. Demographic and lifestyle characteristics of cancer survivors in the NIH-All of Us Research Program [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C122.

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Vaishampayan, Ulka, Darshana Patil, Wahida Rahman, Stephanie Patterson, Emilija Mitrikeska, and Joe Dib. "Abstract OT3-18-02: Clinical validation of “TriNetra™-Breast” test for breast cancer screening in a prospective, observational, case-cohort study." Cancer Research 83, no. 5_Supplement (March 1, 2023): OT3–18–02—OT3–18–02. http://dx.doi.org/10.1158/1538-7445.sabcs22-ot3-18-02.

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Abstract Introduction The Standard of Care for early detection of breast cancer in asymptomatic women is screening mammography, which has limitations such as radiation exposure and lower sensitivity to detect cancer in women with high breast density or invasive carcinomas. TriNetra™-Breast is a blood test for the detection of breast cancer associated circulating tumor cells in blood. Previously, this test has been used in a study for breast cancer detection in India, where it has shown a sensitivity of 92.5%. It has since been granted the United States Food and Drug Administration (USFDA) Breakthrough Device Designation, attesting its potential to provide for improved detection of breast cancer. This prospective, observational, case-cohort study will confirm the clinical performance characteristics of the technology in the US population. Patients and Methods The primary endpoint of this study will be to determine the sensitivity and specificity of the test for breast cancer screening, using mammography and histopathology confirmed diagnosis (when relevant) as the reference methods. Women ≥40 years, with no prior diagnosis of any cancer and undergoing screening mammography for breast cancer will be eligible for participation in this study. 700 women, representing the diverse ethnic US population, will be enrolled. Cohort A will have 500 women with BI-RADS score of 1, 2, or 3. Among these 500 participants, the age categories of 40-49 years, 50-74 years and >74 years will have 100, 300 and 100 women respectively. Cohort B will have 100 women with suspicion of DCIS (without a suspicion of simultaneous invasive carcinoma) and 50 women each with BI-RADS score of 4 or 5. These study population numbers will ensure optimal representation of in-situ carcinoma, malignant and benign cases. Blood samples will be collected from the enrolled women for TriNetra™-Breast, within sixty (60) days of the screening mammogram. If biopsy is indicated, sample collection will be required prior to the procedure. The lab investigators will be blinded to the clinical information of all participants, including mammography and histopathology results, while the participants and clinical investigators will be blinded to the TriNetra™-Breast test results. The results of TriNetra™-Breast will be compared with the results of mammography and/or histopathology for performance estimation of the test. Study participants will be followed for clinical outcomes for maximum duration of 2 years. Citation Format: Ulka Vaishampayan, Darshana Patil, Wahida Rahman, Stephanie Patterson, Emilija Mitrikeska, Joe Dib. Clinical validation of “TriNetra™-Breast” test for breast cancer screening in a prospective, observational, case-cohort study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-18-02.

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Ahn, Sarah, Subing Cao, Melissa A. Russo, and John S. Yi. "Abstract 703: Transient G1 cell cycle arrest with trilaciclib enhances the generation of polyfunctional CD4+ and CD8+ T cells." Cancer Research 83, no. 7_Supplement (April 4, 2023): 703. http://dx.doi.org/10.1158/1538-7445.am2023-703.

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Abstract When administered prior to chemotherapy, intravenous trilaciclib transiently arrests cyclin-dependent kinase 4/6-dependent cells in the G1 phase of the cell cycle, which has been shown to augment antitumor immunity. In an open-label, phase 2 trial in patients with metastatic triple-negative breast cancer (NCT02978716), administering trilaciclib prior to gemcitabine plus carboplatin improved overall survival, potentially through protection and direct activation of immune function. To determine the impact of trilaciclib on effector T-cell function, we conducted in vitro studies to assess the kinetics of cytotoxic function and generation of polyfunctional T cells. Peripheral blood mononuclear cells (PBMCs) or naïve CD4+ and CD8+ T cells were purified from 6 healthy human donors and activated with CD2/3/28 beads. On days 0, 1, and 3 post activation, 100 nM trilaciclib was added to the cells. To visualize phenotypic and functional changes, T cells that had been activated for 3, 7, or 14 days with or without trilaciclib were restimulated with phorbol myristate acetate (PMA) and ionomycin. Dimension-reduction analysis of flow cytometric data was used to identify polyfunctional subpopulations of CD4+ and CD8+ T cells. T-cell clusters with polyfunctional profiles were identified based on the coproduction of IFNγ, TNFα, and IL-2 cytokines. Subsets of polyfunctional clusters were defined according to other immune phenotypic profiles, including T-cell exhaustion (PD-1 and LAG-3), degranulation (granzyme B), proliferation (Ki-67), and transcription factors (TOX, TCF-1, and T-bet). For both CD4+ and CD8+ T cells, 3 polyfunctional subpopulations were identified based on differential expression of granzyme B, PD-1, and TOX. When CD4+ and CD8+ T cells were activated in the presence of trilaciclib and restimulated with PMA and ionomycin, there was an increase in the frequency of polyfunctional T-cell subsets producing granzyme B. This was compensated by a decrease in granzyme Blow polyfunctional cells, which was associated with increased PD-1high and TOXhigh expression. Clustering analysis of trilaciclib-treated PBMCs also revealed a reduction in proliferating CD8+ T cells with undetectable effector cytokine function based on a decrease in the frequency of CD8+ T cells expressing TOXhigh and Ki-67high. Transient G1 cell cycle arrest in T cells may limit T-cell hyperactivation, which has been shown to induce immunopathological responses. The increased generation of polyfunctional CD8+ T cells is associated with enhanced effector T-cell responses and memory T-cell differentiation. In combination with previous data showing increased differentiation of naïve T cells into memory T cells upon exposure to trilaciclib, these data support a beneficial role for trilaciclib in enhancing antitumor T-cell responses. Citation Format: Sarah Ahn, Subing Cao, Melissa A. Russo, John S. Yi. Transient G1 cell cycle arrest with trilaciclib enhances the generation of polyfunctional CD4+ and CD8+ T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 703.

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Chen, Ying-Yin, Chen-Wen Lin, Yenh-Chen Hsein, and Chung-Yu Chen. "Abstract 2264: Role of first-line immune checkpoint inhibitors monotherapy for oncogene-driven non-small cell lung cancer." Cancer Research 83, no. 7_Supplement (April 4, 2023): 2264. http://dx.doi.org/10.1158/1538-7445.am2023-2264.

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Abstract Though improvement of overall survival in non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs) was observed, their efficacy varies greatly among different immune and molecular profiles in tumors. Particularly, the clinical significance of ICIs for oncogene-driven NSCLC has been controversial. In this study, after excluding NSCLC patients harboring driven oncogenes as EGFR, ALK and ROS1 mutation, twenty NSCLC patents with higher Programmed cell death 1 ligand 1 (PD-L1) expression (PD-L1 ≧ 50%, immunohistochemical stained by SP263 or 22C3) were administered with Pembrolizumab alone as first-line immunotherapy. NSCLC patients with more higher PDL1 expression (PD-L1 ≧ 80%) had longer progression-free survival (PFS) PD-L1 ≧ 80% v.s. PD-L1 < 80%, PFS, median, 11.2 v.s 7.0 months, hazard ratio [HR]: 0.52, p = 0.03). 10 of them had other driven oncogenes (5 for KRAS, 3 for MET, 1 for BRAF and 1 for NRAS) were detected by next-generation sequencing (NGS) (Illumina iSeq 100 Sequencing System; AmpliSeq for Illumina Focus Panel). Patients harboring driven oncogene had shorter PFS by first-line immunotherapy as Pembrolizumab (With driven oncogene v.s. without, PFS, median, 4.2 v.s.10.8 months, HR: 2.76, p = 0.001). In conclusion, NGS analysis was recommended even the NSCLC patients with higher PD-L1 expression before immunnotherapy. First-line ICIs monotherapy should be cautious for oncogene-driven NSCLC patients. Citation Format: Ying-Yin Chen, Chen-Wen Lin, Yenh-Chen Hsein, Chung-Yu Chen. Role of first-line immune checkpoint inhibitors monotherapy for oncogene-driven non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2264.

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Gion, Maria, Patricia Cortez-Castedo, Isabel Blancas, Alfonso Cortés, Frederik Marmé, Salvador Blanch, Serafin Morales Murillo, et al. "Abstract PS16-02: Efficacy and safety of first-line atezolizumab + bevacizumab + paclitaxel in patients with advanced triple-negative breast cancer: the ATRACTIB phase 2 trial." Cancer Research 84, no. 9_Supplement (May 2, 2024): PS16–02—PS16–02. http://dx.doi.org/10.1158/1538-7445.sabcs23-ps16-02.

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Abstract BACKGROUND Triple-negative breast cancer (TNBC) is an aggressive tumor characterized by poor outcomes and new treatment strategies are urgently required. The programmed cell death-ligand 1 (PD-L1) antibody (Ab) atezolizumab (ATZ) combined with first-line (1L) nab-paclitaxel (nab-PTX) is approved in multiple countries for the treatment of PD-L1-positive patients (pts) with advanced TNBC (aTNBC) based on a significant improvement in progression-free survival (PFS) and a numerically higher and clinically meaningful median overall survival (OS). A synergism between antiangiogenic therapy and immunotherapy (IO)-based strategies has been observed preclinically and in different tumor types, but data in aTNBC is lacking. METHODS ATRACTIB (NCT04408118) is an international, open-label, single-arm, phase 2 trial evaluating the efficacy and safety of 1L ATZ + BVZ + PTX for pts with aTNBC, regardless of their tumors’ PD-L1 status. Adult pts with untreated, unresectable locally advanced/metastatic TNBC were included. Pts who had received (neo)adjuvant taxane-based chemotherapy (CT) and/or IO and/or an antiangiogenic agent had to have had a relapse with a disease-free interval beyond 12 months (mo). Pts received intravenous ATZ 840 mg + BVZ 10 mg/kg on days (D)1 and D15 + PTX 90 mg/m2 on D1, 8, and 15 of every 28-day cycle until disease progression, intolerable toxicity, death, or patient withdrawal. Tumor assessments were performed every 8 weeks for the first 12 mo and every 12 weeks thereafter. Baseline PD-L1 expression was centrally assessed using 22C3 (combined positive score [CPS]) and SP142 (expression on tumor-infiltrating immune cells [ICs]) Abs. The primary endpoint was investigator-assessed PFS by RECIST v.1.1. Key secondary endpoints included OS, objective response rate (ORR), clinical benefit rate (CBR), duration of response (DoR), and safety. Median PFS was analyzed with exponential maximum likelihood estimation (H0: ≤7.0 mo; HA: ≥9.5 mo). We estimated that enrolling 100 pts would provide 80% power at one-sided α nominal level of 5%, assuming a 10% drop-out rate. RESULTS Between October 2020 and May 2022, 100 female pts from 28 centers across 5 European countries were included. Median age was 55.0 years (32.0 - 84.0), 57.0% of pts had visceral disease, 46.0% had ≥3 metastatic sites, and 70.0% had received prior treatment for early BC (taxane-based CT in 87.1% of them). A total of 82 and 85 tumor samples out of 100 pts were available for PD-L1 assessment using 22C3 and SP142 assays, respectively. Most pts had PD-L1-negative tumors (87.8% with 22C3 [CPS < 10] and 97.6% with SP142 [expression on < 1% positive of ICs]). At data cutoff (15th September 2023), 23 pts were still on therapy. With a median follow-up of 16.7 mo (1.1 - 34.1), median PFS was 11.0 mo (95% CI, 9.0 - 13.2). OS data were immature at data cutoff, with 30 events. Estimated 18-month OS was 69.4% (95% CI, 58.4% - 78.1%). ORR was 63.0% (95% CI, 52.8% - 72.4%), CBR was 79.0% (95% CI, 69.7% - 86.5%), and median DoR was 10.0 mo (95% CI, 7.2 - 13.8). Regarding safety, the most common treatment-emergent adverse events (TEAEs) were peripheral neuropathy (68.0%) and fatigue (62.0%). Grade (G) 3/4 treatment-related TEAEs occurred in 47.0% of pts, mainly peripheral neuropathy (13.0%) and neutropenia (12.0%). Any-grade immune-related TEAEs, thrombosis or embolism, and bleeding occurred in 13.0% (5.0%; G≥3), 4.0% (1.0%; G≥3), and 10.0% (0.0%; G≥3) of pts, respectively. There were no drug-related deaths. CONCLUSIONS 1L ATZ + BVZ + PTX demonstrated encouraging anti-tumor activity in aTNBC pts, most of them presenting with PD-L1-negative tumors. Median PFS seems to be much higher compared with that previously reported with other IO-based regimens in a similar patient population. The safety profile was consistent with the known safety data of ATZ and BVZ combined with CT, without significant added toxicity. These results merit further research of this combination for PD-L1-negative aTNBC. Citation Format: Maria Gion, Patricia Cortez-Castedo, Isabel Blancas, Alfonso Cortés, Frederik Marmé, Salvador Blanch, Serafin Morales Murillo, Nieves Díaz, Isabel Calvo-Plaza, Sabela Recalde, Alejandro Martínez-Bueno, Manuel Ruiz-Borrego, Elisenda Llabres, María Teresa Taberner, Michelino de Laurentiis, José Ángel García-Sáenz, Jana Repkova, Antonio Antón, Joseph Gligorov, Susana de la Cruz, Oliver Hoffmann, Jacques Medioni, Melissa Phillips, Miguel Sampayo-Cordero, Daniel Alcalá-López, José Manuel Pérez-García, Antonio Llombart-Cussac, Javier Cortés. Efficacy and safety of first-line atezolizumab + bevacizumab + paclitaxel in patients with advanced triple-negative breast cancer: the ATRACTIB phase 2 trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS16-02.

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Leoni, Lorenzo M., Brian Crain, Brandi Bailey, Mimi Phillips, Heather Bendall, Qi Chao, Jack Reifert, Christina Niemeyer, and Gary Elliott. "Mechanism of Action and Safety of Second Generation Analogs of SDX-101 (R-Etodolac)." Blood 104, no. 11 (November 16, 2004): 3411. http://dx.doi.org/10.1182/blood.v104.11.3411.3411.

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Abstract SDX-101 (R-etodolac), which is currently being evaluated in clinical trials for treatment of chronic lymphocytic leukemia, down regulates the activity of the β-catenin pathway and inhibits the growth of non-Hodgkin’s Lymphoma Daudi tumor xenografts in vivo when dosed orally (AACR PROC 2004 Abs# 2061 and #4574). Initial co-immunoprecipitation experiments conducted on cell nuclear fractions identified a heteromeric nuclear protein complex containing β-catenin and PPAR-γ. Furthermore, we have demonstrated that SDX-101 treatment reduces nuclear β-catenin in the immunoprecipitated complex, indicating that this complex may represent a target of SDX-101 (AACR PROC 2004 Abs# 3672). We recently reported evaluation of novel structural analogs of SDX-101 and have shown that these analogs, whose structures were not disclosed, are 5–10 fold more potent in in vitro cytotoxicity assays than SDX-101 and that they are orally efficacious in vivo (NCI/EORTC 2004 Abs #383). Our current studies further characterize the mechanism of action and safety of these analogs and identify the structures of selected analogs. Novel functional assays were developed to test and compare SDX-101 and the analogs at 4 hours post-treatment, a time before appreciable loss of viability was detected. Best results were obtained using a functional assay co-transfecting a β-catenin-dependent reporter construct (TOPFLASH) and β-catenin and RXR expression vectors. The average IC50 of analogs in this β-catenin reporter system ranged from 50 to 160 μM. These values were approximately five- to ten- fold lower than the IC50 for SDX-101 (~700 μM). Similar results were obtained assessing the inhibition of PPAR-γ-mediated transcription, using a PPAR-dependent reporter and co-transfection with PPAR-γ and RXR expression vectors. The average IC50s of the analogs ranged from 50–150 μM in this functional assay, demonstrating an approximately 10-fold increase in potency of the analogs when compared to SDX-101 (~1000 μM). No effect was observed at the 4 hour time point using a constitutive SV40-based control reporter vector. These results suggest that the primary target for these compounds may be a nuclear complex containing β-catenin, PPAR-γ and RXR, supporting a hypothesis developed upon evaluation of earlier results generated with SDX-101. To evaluate the safety of two SDX-101 analogs in vivo, normal mice were administered each analog at 240, 120 and 60 mg/kg/d (M-F) for four weeks. Mortality, morbidity, clinical signs, hematology/chemistry were monitored. There were no mortalities, overt toxicities or abnormal observations at necropsy with either of the analogs at any of the tested dose levels. There was a transient body weight loss (<5%) and a mild dose-independent increase in platelets and a reversible decrease in total bilirubin. Results of the histopathological examination of critical organs are pending. These results suggest, when given at doses previously shown to be efficacious in a DAUDI murine lymphoma model, these analogs were well tolerated. In conclusion, these data demonstrate that the second generation analogs of SDX-101 display more potent in vitro and in vivo activity while retaining a mechanism of action similar to that of SDX-101.

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Park, Hyo-Hyun, Hye-Ran Kim, Jin Kyeong Choi, Jee Hyun Choi, JinHo Kang, Jinback Lim, Hyo Jung Lim, Jong Yeong Lee, Eunkyo Joung, and Hun Jung. "Abstract 709: AST-301, a pDNA-based therapeutic cancer vaccine encoding HER2 ICD, improves the efficacy of checkpoint blockade therapy in CD34+ humanized gastric cancer mouse model." Cancer Research 83, no. 7_Supplement (April 4, 2023): 709. http://dx.doi.org/10.1158/1538-7445.am2023-709.

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Abstract PD-1/PD-L1 play a crucial role in modulating immune response and promoting self-tolerance through activating apoptosis of antigen-specific T cells and suppressing apoptosis of regulatory T cells. Although immunotherapy to block this may provide a greater survival benefit for some patients, the therapeutic effect shown in clinical trials is limited by shortage of pre-existing CD8+ T cells infiltrating the tumor. AST-301 is a pDNA-based therapeutic cancer vaccine encoding HER2 ICD sequence. It was effective in eliciting HER2-specific T cells and antibody immunity in the majority of breast and ovarian cancer patients who completed the vaccine regimen and has proven safety as well as long-term immunological memory efficacy of T-cell immune by the phase 1 study (PN 109, NCT00436254). Our previous study has shown that AST-301 has anti-tumor effects by mediating NK cells in human HER2+ gastric cancer cell (NCI-N87) xenograft athymic mice. Here, we aimed to determine whether combined administration of AST-301 can enhance the anti-tumor effect of immune checkpoint inhibitor (ICI) using NCI-N87 xenograft humanized mouse. To confirm the tumor suppressive effect of pembrolizumab (anti-PD-1) treatment combined with AST-301 in the hu-CD34+ hematopoietic stem cell-engrafted NSG mice that formed tumors with NCI-N87, AST-301 (100 μg) and pembrolizumab (5 mg/kg) were administered into mice once a week for a total of 3 times and one booster doses of AST-301 was injected at week 4. Pembrolizumab low dose (5 mg/kg) test group administered with AST-301 had a relatively higher tumor growth inhibition (TGI) effect than the same concentration of Pembrolizumab alone group. TGI effect (%) of G2 (a combination of AST-301 and Pembrolizumab 5 mg/kg), G3 (Pembrolizumab 5 mg/kg), and G4 (Pembrolizumab 10 mg/kg) were 54%, 47%, and 78%, respectively. To evaluate the mechanism underlying the enhanced anti-tumor effect due to the combined administration of AST-301 and pembrolizumab, we measured the ratio of immune cells isolated from spleen and tumor in mice. in G2, the ratio of helper T cells and cytotoxic T cells in splenocytes higher than the vehicle-treated control group (G1), and the ratio of cytotoxic T cells infiltrated the tumor was also detected high in some subjects compared to those in all the other three groups. These results suggest that AST-301 can improve HER2+ gastric cancer treatment outcomes of immune checkpoint blockade therapy by inducing a robust cytotoxic CD8+ T cell response to tumor cells. Currently, we are ongoing study to prove the anti-tumor synergistic effects of the combination of AST-301 and various FDA-approved Antibody Drug Conjugates (ADCs). This effort is focused on narrowing the administration doses to low levels to resolve the safety issue of ADC or ICI, and it will strongly support the diverse applicability of the cancer therapeutic vaccine. Citation Format: Hyo-Hyun Park, Hye-Ran Kim, Jin Kyeong Choi, Jee Hyun Choi, JinHo Kang, Jinback Lim, Hyo Jung Lim, Jong Yeong Lee, Eunkyo Joung, Hun Jung. AST-301, a pDNA-based therapeutic cancer vaccine encoding HER2 ICD, improves the efficacy of checkpoint blockade therapy in CD34+ humanized gastric cancer mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 709.

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Zhang, Yang, Nan Ji, Gang Chen, Haiyang Wu, Yi Wang, Xiao’ou Li, Wei Xu, et al. "Abstract CT086: H3.3-K27M neoantigen vaccine elicits CD4+ and CD8+ T cells immunity and improved prognosis against diffuse intrinsic pontine glioma." Cancer Research 83, no. 8_Supplement (April 14, 2023): CT086. http://dx.doi.org/10.1158/1538-7445.am2023-ct086.

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Abstract Background: Diffuse intrinsic pontine glioma (DIPG) harboring H3.3-K27M mutation is a malignant pediatric brain tumor with a >90% mortality rate within two years of diagnosis. Aiming to improve therapeutic outcomes, we herein describe a neoantigen peptide vaccine against H3.3-K27M which effectively triggers both CD8+ and CD4+ T cell responses. Methods: A neoantigen vaccine was designed to trigger T cell immunity against DIPGs harboring the H3.3-K27M mutation. ENACTING (NCT04749641) was then initiated as an open-label, single center, two-armed phase 1 trial to assess T cell immune responses and vaccine safety. The vaccine was administered intramuscularly with poly-ICLC adjuvant until tumor progression or untolerated toxicity. PBMCs before and after each vaccine treatment were collected for TCR repertoire analysis and immune response assessment. Results: As of November 2022, 10 patients have been treated. No grade 3-4 treatment-related adverse events have been observed, with fever (80%) and injection site pain (60%) being the most common AEs. On a per patient basis, vaccines induce a landscape change of TCR repertoire in patients’ PBMC after 4-6 times of dosing, indicating multiple dosing is required to trigger extensive T cell responses. T cell responses against neoantigens were detected and H3.3-K27M mutation-specific CD4+ and two CD8+ clones were validated. Among 9 efficacy-assessable patients, the one-year overall survival rate was 71.4%. The mPFS has reached 11.7 months and increasing. One patient reached complete response. As this trial remains ongoing, subgroup analysis will be reported in the future. Conclusion: The H3.3-K27M neoantigen vaccine was well tolerated and elicited mutation-specific CD4+ and CD8+ T cell responses in patients. Initial results from this ongoing study suggest that, compared with other current immunotherapies against DIPG, H3.3-K27M peptide vaccination may provide superior patient outcomes, for both life qualities and survival outcomes. Table 1. Clinical efficacy and adverse events Efficacy Complete response (CR) 1 (11.1%) Partial response (PR) 0 (0) Stable disease (SD) 8 (88.9%) Progressive disease (PD) 0 (0) Disease control rate (DCR) 100% 12-month overall survival 71.4% Median progression-free survival (mPFS) 11.7 months (95% CI, 7.0-NR) Median overall survival (mOS) 15.7 months (95% CI, 10.0-NR) Treatment-Related Adverse Events All grades Grade 3 Grade 4 Fever 9 (90.0%) 0 0 Injection site pain 6 (60.0%) 0 0 Bloating 1 (10.0%) 0 0 Abdominal pain 1 (10.0%) 0 0 Vomiting 1 (10.0%) 0 0 Increased blood LDH 1 (10.0%) 0 0 Proteinuria 1 (10.0%) 0 0 Hypocalcemia 1 (10.0%) 0 0 Citation Format: Yang Zhang, Nan Ji, Gang Chen, Haiyang Wu, Yi Wang, Xiao’ou Li, Wei Xu, Ling Peng, Tian Li, Yi Wang, Li-Feng Zhang, Shengjun Sun, Xiaobing Zhao, Si Li, Peter Alexander, Liwei Zhang, Qi-Jing Li. H3.3-K27M neoantigen vaccine elicits CD4+ and CD8+ T cells immunity and improved prognosis against diffuse intrinsic pontine glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT086.

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Tezuka, Yuta, Kyoko Kawasaki, Yoshiki Sumitomo, Masato Saito, Akari Yao, and Munetoshi Ando. "Abstract 5310: KK2269, an epithelial cell adhesion molecule-targeted CD40 agonist, demonstrates antitumor effects in combination with standard therapies for NSCLC." Cancer Research 84, no. 6_Supplement (March 22, 2024): 5310. http://dx.doi.org/10.1158/1538-7445.am2024-5310.

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Abstract CD40 is a key molecule expressed on antigen presenting cells (APCs), whose signaling activates APCs and generates antitumor immune responses. Although CD40 agonists have been investigated in clinical trials, systemic toxicities have limited their full potential in providing adequate antitumor effects. To overcome this limitation, we developed KK2269, a bispecific antibody, using REGULGENT™ technology. KK2269 binds to CD40 and tumor-expressed epithelial cell adhesion molecule (EpCAM) to allow activation of CD40+ APCs only at EpCAM+ tumor sites, thus avoiding systemic toxicity. EpCAM is overexpressed in many types of epithelial cancers, including non-small cell lung cancer (NSCLC). KK2269 exerts synergistic antitumor activity and tumor-specific immune responses in combination with docetaxel, a common chemotherapy for NSCLC, in an EpCAM-expressing tumor mouse model. Hence, we aimed to evaluate KK2269 for the treatment of NSCLC. Docetaxel is used as a combination therapy with ramucirumab, an anti-VEGF receptor 2 (VEGFR2) antibody, for previously treated advanced NSCLC. In addition, many clinical studies are evaluating the add-on effects of PD-1/PD-L1 blockade combined with standard chemotherapies (including docetaxel) in NSCLC, which may become the standard of care for advanced NSCLC in the future. Therefore, we investigated the antitumor effect of KK2269 in combination with docetaxel + anti-mouse VEGFR2 (study 1) and with docetaxel + anti-mouse PD-1 (study 2) using a mouse EpCAM-expressing B16F10 tumor-bearing human CD40 transgenic mouse model. The prolongation of TTP5X (the day on which the tumor volume is observed to be ≥5-fold of that observed on day 0) was evaluated. In study 1, the median TTP5X (95% confidence interval [CI]) with the control, docetaxel + anti-VEGFR2, and triple combination (KK2269, docetaxel, anti-VEGFR2) was 10.0 days (7.0, 10.0), 26.0 days (17.0, 28.0), and 52.0 days (42.0, not calculable), respectively. The TTP5X was significantly prolonged with the triple combination compared with the control (p=0.000007, log-rank test) and docetaxel + anti-VEGFR2 (p=0.000004, log-rank test). In study 2, the median TTP5X (95% CI) was 7.0 days (not calculable), 9.0 days (6.0, 11.0), 16.0 days (7.0, 18.0), and 26.5 days (7.0, 32.0) with the control, KK2269, docetaxel + anti-PD-1, and triple combination (KK2269, docetaxel, anti-PD-1), respectively. TTP5X was significantly prolonged with the triple combination compared with the control, KK2269, and docetaxel + anti-PD-1 (p<0.0001, p=0.0003, and p=0.0023, respectively, log-rank test). Thus, a significant antitumor effect was demonstrated when KK2269 was added to the standard treatment of NSCLC (docetaxel + anti-VEGFR2 antibody) and to docetaxel + anti-PD-1 antibody. Our findings strongly suggest that KK2269 provides improved treatment options for patients with NSCLC. Citation Format: Yuta Tezuka, Kyoko Kawasaki, Yoshiki Sumitomo, Masato Saito, Akari Yao, Munetoshi Ando. KK2269, an epithelial cell adhesion molecule-targeted CD40 agonist, demonstrates antitumor effects in combination with standard therapies for NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5310.

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Liu, Qinran, Yiwen Zhang, Jane B. Vaselkiv, Lorelei A. Mucci, Edward L. Giovannucci, Elizabeth A. Platz, and Siobhan Sutcliffe. "Abstract 4203: A prospective study of birth weight and prostate cancer risk: extended analysis in the Health Professionals Follow-up Study." Cancer Research 83, no. 7_Supplement (April 4, 2023): 4203. http://dx.doi.org/10.1158/1538-7445.am2023-4203.

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Abstract Introduction: Birth weight, a potential marker of the in utero hormonal and growth factor milieu, has been associated with an increased risk of prostate cancer (PCa) in some, but not all, previous studies. It was also associated with a non-significantly greater risk of advanced stage PCa (relative risk [RR] = 1.37, 95% confidence interval [CI]: 0.61-3.05 for ≥10 lbs compared to 7.0-8.4 lbs, p-trend = 0.087) in our previous analysis in the Health Professionals Follow-up Study (HPFS). However, these suggestive findings were based on a relatively small number of advanced stage cases and short follow-up. We have now updated our previous analysis of birthweight and PCa risk in the HPFS with an additional 14 years of follow-up. Method: Birth weight was assessed by self-report on the 1994 follow-up questionnaire using pre-specified categories. PCa diagnoses were ascertained on each biennial follow-up questionnaire and confirmed by medical record review. Cox proportional hazards regression was used to evaluate the association between birth weight and PCa risk through 2016. Result: Of the 17,949 eligible men who reported their birth weight in 1994, 3,167 were subsequently diagnosed with PCa. With the exception of a suggestive positive trend between increasing birth weight and high-grade PCa (RRadj per pound: 1.06; 95% CI: 0.98-1.16; p-trend=0.15), no associations were observed between birth weight and risk of total, organ-confined, low-grade, advanced stage, lethal, or fatal PCa. Conclusion: Overall, no association was observed between birth weight and PCa risk and mortality in this large prospective cohort study of US male health professionals. Table 1. Associations between self-reported birth weight and prostate cancer in the Health Professionals Follow-up Study, 1994-2016 Birth weight (lbs) <5.5(<2,495 g) 5.5-6.9(2,495-3,174 g) 7.0-8.4(3,175-3,855 g) 8.5-9.9(3,856-4,535 g) ≥10.0(≥4,536 g) Per 1 lb (454g) increase Total prostate cancer Cases/person-years 125/17,019 518/80,053 1,931/297,495 396/60,445 197/22,993 HRa (95% CI) 0.98 (0.81-1.18) 0.86 (0.78-0.95) 1.00 0.85 (0.76-0.95) 0.98 (0.84-1.13) 1.01 (0.96-1.05) High-grade prostate cancer (Score 4+3 and higher) Cases/person-years 23/17,117 119/80,434 453/299,015 105/60,741 52/23,148 HRa (95% CI) 0.76 (0.50-1.16) 0.83 (0.68-1.03) 1.00 0.93 (0.75-1.16) 1.03 (0.76-1.39) 1.06 (0.98-1.16) Advanced stage prostate cancer (T3b+) at diagnosis Cases/person-years 4/17,135 29/80,516 109/299,370 25/60,811 12/23,195 HRa (95% CI) 0.53 (0.19-1.46) 0.91 (0.60-1.40) 1.00 0.98 (0.62-1.54) 1.02 (0.54-1.92) 1.08 (0.91-1.29) Lethal prostate cancer Cases/person-years 11/17,127 70/80,491 225/299,247 51/60,791 27/23,178 HRa (95% CI) 0.81 (0.43-1.50) 1.15 (0.86-1.52) 1.00 1.07 (0.78-1.47) 1.01 (0.66-1.54) 1.00 (0.89-1.13) Fatal prostate cancer Cases/person-years 10/17,551 59/82,316 197/307,363 43/62,246 23/23,996 HRa (95% CI) 0.88 (0.45-1.67) 1.17 (0.86-1.60) 1.00 1.11 (0.78-1.56) 1.03 (0.65-1.63) 1.00 (0.87-1.14) RR=relative risk; CI = confidence interval a Adjusted for age, calendar time, race, smoking status, family history of prostate cancer (yes or no), PSA testing in >50% of previous cycles (yes or no), physical activity, diabetes, diet (tomato sauce intake, coffee, and energy intake), alcohol intake, multivitamin use, vitamin E supplement use, and aspirin use. Citation Format: Qinran Liu, Yiwen Zhang, Jane B. Vaselkiv, Lorelei A. Mucci, Edward L. Giovannucci, Elizabeth A. Platz, Siobhan Sutcliffe. A prospective study of birth weight and prostate cancer risk: extended analysis in the Health Professionals Follow-up Study. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4203.

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DuPont, Michael, Anna Moshnikova, Marissa Iraca, Craig Klumpp, Hannah Visca, Dana Allababidi, Phoebe Pelzer, Donald Engelman, Oleg Andreev, and Yana Reshetnyak. "Abstract 6758: Eradication of tumors and development of immunity from pHLIP-targeted intracellular delivery of STINGa." Cancer Research 84, no. 6_Supplement (March 22, 2024): 6758. http://dx.doi.org/10.1158/1538-7445.am2024-6758.

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Abstract Activation of the stimulator of interferon genes (STING) pathway causes the release of factors that trigger the immune response in the tumor microenvironment (TME). Transient strong activation leads to immune activation and tumor suppression, while prolonged weak activation leads to immuno-suppression promoting tumor development. Reprogramming of M2-type tumor-associated macrophages (M2-TAMs) toward an M1 phenotype, suppression of cancer-associated fibroblasts (CAFs) and myeloid-derived suppressor cells (mMDSCs), as well as activation of dendritic cells (DCs) to train T-cells are advantageous, while the activation of STING pathway in T-cells is leads to their apoptosis. Thus, targeted delivery of STINGa to specific cells with TME to induce strong transient activation may be a key to therapy. We have developed a delivery approach that uses one or two pH Low Insertion Peptides (pHLIPs) that collaborate in the targeted intracellular delivery of a STINGa. STINGa were conjugated with pHLIPs via S-S cleavable self-immolating linkers. Biophysical studies were performed to ensure proper interactions of pHLIP-STINGa agents with membrane lipid bilayers. pHLIPs extend the lifetime of STINGa in the blood and target them to acidic cancer and stromal cells (CAFs), as well as M2-TAMs, mMDSCs and DCs within TME. The targeting results in selective cytokine activation in tumors with no systemic activation, which triggers the eradication of small (100 mm3) and large (400-700 mm3) CT26 tumors in mice after one or two doses of pHLIP-STINGa. The tumor stroma was destroyed, intratumoral hemorrhage developed, and the level of acidity within the TME was reduced. No tumors developed in mice re-challenged by an additional injection of cancer cells in a 90-day experiment. Thus, targeted delivery of STINGa to cancer cells, tumor stroma and TAMs induces activation of signaling, potentially resulting in the recruitment and infiltration of T- and NK-cells, which gain access to the tumor core. The cytotoxic activity of T- and NK-cells is not impaired by the acidic environment and immune memory is developed. The pHLIP technology may allow transformation of immuno-activating agents into more potent therapeutics, since pHLIP can target and deliver these agents to cancer cells, tumor stroma and myeloid cells. Citation Format: Michael DuPont, Anna Moshnikova, Marissa Iraca, Craig Klumpp, Hannah Visca, Dana Allababidi, Phoebe Pelzer, Donald Engelman, Oleg Andreev, Yana Reshetnyak. Eradication of tumors and development of immunity from pHLIP-targeted intracellular delivery of STINGa [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6758.

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Huang, Shiang-Fu, Huei-Tzu Chien, Chi-Kuan Young, Yun-Shien Lee, Chun-Ta Liao, Kai-Lun Cho, and Ching-Han Chen. "Abstract LB379: HLA-DQB1*05:02: An independent genetic marker for oral cavity squamous cell carcinoma susceptibility." Cancer Research 84, no. 7_Supplement (April 5, 2024): LB379. http://dx.doi.org/10.1158/1538-7445.am2024-lb379.

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Abstract Environmental exposure to carcinogens causes mucosal damage in the upper aerodigestive tract, which can lead to cancers. The genetic basis of head and neck cancer is controversial. To identify susceptibility genes in head and neck cancers, we enrolled patients with early-onset disease in Taiwan. This case-control study included 54 young male patients with oral squamous cell carcinoma (OSCC) who were treated between March 1996 and December 2016, as well as 2,400 healthy controls. A single-nucleotide polymorphism (SNP) array was used to determine genetic loci that increase susceptibility to OSCC. Sequencing-based typing (TBG Biotechnology Corp., Taipei, Taiwan) was used to determine the HLA-DQB1 genotype in another cohort of 147 OSCC patients. We analyzed the allele frequencies of 664,994 autosomal SNPs in the 54 OSCC cases. In a genome-wide association analysis, four SNPs within loci on chromosomes 6, 7, 9, and 12 were significantly different between OSCC patients and controls (corrected P < 1.0 × 10−6). HLA-DQB1 was closest to rs28451423 on chromosome 6. HLA-DQB1*05:02 in OSCC (18.5%) was significantly different from normal population (7.0%) (P = 0.009). The influence of disease onset was independently significant after adjusting cigarette smoking, alcohol drinking and areca-quid chewing (P = 0.015, OR: 3.922, 95% confidence interval: 1.311 - 11.734). Furthermore, HLA-DQB1*05:02 was associated with early-onset OSCC (P = 0.004). HLA-DQB1*05:02 is associated with OSCC independent of environmental exposures. HLA-DQB1*05:02 is also related with early onset of OSCC. It provides evidence of a genetic basis for OSCC. Citation Format: Shiang-Fu Huang, Huei-Tzu Chien, Chi-Kuan Young, Yun-Shien Lee, Chun-Ta Liao, Kai-Lun Cho, Ching-Han Chen. HLA-DQB1*05:02: An independent genetic marker for oral cavity squamous cell carcinoma susceptibility [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB379.

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Engelman, Donald M., Yana K. Reshetnyak, and Oleg A. Andreev. "Abstract 1804: Durable eradication of tumors by single injections of a pHLIP-STING agonist." Cancer Research 83, no. 7_Supplement (April 4, 2023): 1804. http://dx.doi.org/10.1158/1538-7445.am2023-1804.

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Abstract Purpose: pHLIPs (pH-Low Insertion Peptides) target cell surface acidity resulting from the metabolism of cells in a solid tumor. The acidity causes pHLIPs to insert as transmembrane helices, and attached cargoes can be delivered into targeted cells. STING agonists can trigger an immune response when they are inside cells. pHLIP targeted delivery of a STING agonist (STINGa) effectively triggers cytokine secretion to mobilize the immune system to eradicate tumors while avoiding side effects. Experimental Procedures: Constructs consisting of a pHLIP peptide (Var3) linked to a STINGa (diABZI) via a self-immolating linker were synthesized and characterized. Activation of the STING pathway by the agent was confirmed in cells. Small (100 mm3) and large (400-700 mm3) tumors were grown in female Balb/c mice following flank injections of CT26 colorectal cancer cells. Randomized groups of mice were injected i.p. or i.v. with pHLIP-STINGa made with L- or D- amino acid pHLIP peptides, STINGa alone, pHLIP alone or vehicle. Tumor size and body weight were then measured 3 times per week. The durability of the response to the agent was tested by a second injection of CT26 cells after 60 days. In separate experiments, the identities of targeted immune and stromal cells, the production of cytokines, the PK, tumor targeting and biodistribution were assessed. Results and Conclusions: pHLIP extends the lifetime of a STINGa in the blood 6-fold and delivers STINGa to acidic cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), myeloid derived suppressor cells (mMDSCs), and dendritic cells (DCs). The resulting activation of cytokines within the tumor microenvironment (TME) triggers the eradication of small and large CT26 tumors in mice after a single dose of pHLIP-STINGa. The tumor stroma was destroyed, intratumoral hemorrhage developed, and the TME pH increased, which is important for the efficient cytotoxic activity of immune cells. Further, no tumors developed in 20 out of 25 tumor-free mice re-challenged by an additional injection of cancer cells. The therapeutic effect on CT26 tumors was insignificant in nude mice lacking T-cells. Inhibition of MHC-I negative B16F10 melanoma tumor growth was also observed in Balb/c mice. Thus, targeted delivery of the STINGa to the tumor stroma and TAMs activates signaling, potentially resulting in the recruitment and infiltration of both T-cells and NK-cells, which gain access to the tumor core. The cytotoxic activity of immune cells is enhanced, and immune memory is developed. Citation Format: Donald M. Engelman, Yana K. Reshetnyak, Oleg A. Andreev. Durable eradication of tumors by single injections of a pHLIP-STING agonist [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1804.

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Summersgill, Robert J., Jesse M. Fox, Jennifer S. Dickey, Liam T. Cox, Cal D. Palumbo, Kenneth C. Valkenburg, Brian J. Caveney, Shakti Ramkissoon, and Jennifer B. Jackson. "Abstract 5020: Pre-analytical characterization of cell-free DNA to enable liquid biopsy for solid tumors." Cancer Research 84, no. 6_Supplement (March 22, 2024): 5020. http://dx.doi.org/10.1158/1538-7445.am2024-5020.

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Abstract Background: The integration of liquid biopsy in oncology has transformed clinical management of patients with cancer. Cell-free DNA (cfDNA) represents extracellular nucleic acid fragments shed during cellular apoptosis, necrosis, or secretion, and can be extracted from whole blood. PGDx elio plasma focus analyzes cfDNA to enable non-invasive genomic profiling with next-generation sequencing. In this study, we characterized the cfDNA fraction (%) and yield (ng) across multiple tumor types and stages. Methods: cfDNA fraction was obtained using automated electrophoresis (Agilent 4200 TapeStation System) to assess a region of 50-700 bp across 293 clinical plasma samples (tumor stages I - IV). The fraction of cfDNA to total DNA present was then calculated to determine overall cfDNA percentage. The overall DNA yield (ng) was quantified via Qubit fluorometer immediately following extraction from plasma and normalized to volume of plasma (ng of cfDNA/mL of plasma). In addition, data was evaluated from 100 clinical plasma cases with strict extraction conditions allowing for yield normalization to plasma volume. Sequencing metrics were evaluated for all clinical cases with a recommended input of 25 ng DNA using PGDx elio plasma focus. Results: Average cfDNA fraction for individual tumor types ranged from 78.0% - 91.4%, with a mean (n=293) of 84.8%. When examining the yield normalized cohort (n=206), the average yield was 23.4 ng of cfDNA/mL of plasma. cfDNA yield and fraction varied across tumor types and increased with cancer stage. Despite these differences, the majority of cases (99.7%) yielded sufficient cfDNA to proceed with PGDx elio plasma focus testing. No statistical differences in sequencing performance (variants reported and coverage for each tumor type) were observed and the PGDx elio plasma focus assay success rate was 97%. There was a slightly higher failure rate (17.6% (3/17)) for samples below 60% cfDNA, indicating that high amounts of contaminating genomic DNA from white blood cells may obscure the number of available cfDNA fragments for analysis. Conclusions: These data characterize pre-analytical factors that impact performance of PGDx elio plasma focus using cfDNA isolated from plasma of patients with solid tumors. We showed cfDNA yield and fraction varied across tumor types and increased with cancer stage. The overall success rate for testing was 97% while failed samples were associated with higher levels of genomic DNA contamination. Citation Format: Robert J. Summersgill, Jesse M. Fox, Jennifer S. Dickey, Liam T. Cox, Cal D. Palumbo, Kenneth C. Valkenburg, Brian J. Caveney, Shakti Ramkissoon, Jennifer B. Jackson. Pre-analytical characterization of cell-free DNA to enable liquid biopsy for solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5020.

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Shah, Punit, Richard Searfoss, Valerie Bussberg, Bennett Greenwood, Shraddha Karmacharya, Allison MacDonald, Kennedy Ofori-Mensa, et al. "Abstract 5319: Treatment of K562 leukemia cells with an experimental UBE2K modifier identifies multi-omic changes associated with altered oncogenic processes." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5319. http://dx.doi.org/10.1158/1538-7445.am2022-5319.

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Abstract Ubiquitination is a conserved post translation modification involving covalent attachment of ubiquitin protein and is known to regulate many biological processes, including proteasomal degradation. Three major families of enzymes are involved in the regulation of ubiquitination, including activating enzyme E1, Ubiquitin conjugating enzyme E2 and ubiquitin ligase E3. UBE2K is an E2 conjugating ligase that was identified as an anti-cancer drug target from the BERG Interrogative Biology® platform, an artificial intelligence multi-omics analytical method employing Bayesian algorithms. Herein, we used proteomics, lipidomics and metabolomics to investigate the impact of the treatment of UBE2K small molecule ligand (BRG0451) on K562 leukemia cells. K562 cells were treated with 30, 100 and 300 nM concentrations for 24 hours with BRG0451 or Paclitaxel or 0.1% DMSO (Control). Cells were pelleted and analyzed using a multi-omics approach. Proteomic analysis was performed using Thermo Q-Exactive+ LC MS/MS analysis. Lipidomic analysis was performed using SCIEX TripleTOF MS/MS ALL shotgun workflow and metabolomics was performed using 3 different platforms (High resolution RP-LC-MS, HILIC QqQ LC-MS/MS and GC-TOF MS). Unsupervised clustering and differential analysis were used to investigate the impact of the treatments. Proteomic analysis identified and quantified 6930 proteins from K562 cells using TMT labelling with offline 24 fractions and LC-MS/MS. Structural lipidomics analysis evaluated 1980 lipid molecular species and metabolomics analysis identified over 700 metabolites using GC-MS, LC-MS and LC-MS/MS. Multiomics and regression analysis for 30 nM BRG0451 treatment revealed no distinct pattern of omics variables. However, treatment on K562 cells with 300 nM treatment demonstrated 97 differentially expressed proteins compared to control. Pathway analysis revealed chromatin remodeling, and more specifically, regulation of chromatin silencing and localization to nucleolus as major pathways impacted by differentially expressed proteins. Similar pathways were impacted by Paclitaxel and Nocodazole treatment compared to control. Additionally, metabolomic and lipidomic differentials were observed with 300 nM BRG0451 treatment. Structural lipidomics revealed dose -dependent changes in triacylglycerols and cholesterol esters, glycolipid monounsaturated species, and glycolipid medium carbon chain subgroups. Dose dependent impact on amino acids metabolism, purine metabolism, and pyrimidine metabolism was observed with a high degree of similarity for compared drugs. Herein, we demonstrated the use of multi-omics technology in deconvoluting the impact of BRG0451 on independent biological pathways, revealing the intricate mechanisms targeting cell cycle as well as ubiquitin regulator components in a leukemia cell line. Citation Format: Punit Shah, Richard Searfoss, Valerie Bussberg, Bennett Greenwood, Shraddha Karmacharya, Allison MacDonald, Kennedy Ofori-Mensa, Vladimir Tolstikov, Pragalath Sundararajan, Maria-Dorothea Nastke, Eric M. Grund, Gregory M. Miller, Stephane Gesta, Rangaprasad Sarangarajan, Elder Granger, Niven R. Narain, Vivek K. Vishnudas, Michael A. Kiebish. Treatment of K562 leukemia cells with an experimental UBE2K modifier identifies multi-omic changes associated with altered oncogenic processes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5319.

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Chung, Ezra, Yong Sik Bong, Renxiang Chen, Michael Zhang, Steven Long, and Dong Shen. "Abstract 1368: Novel mRNA encoding anti-PD-L1 monoclonal antibodies for cancer immunotherapy." Cancer Research 84, no. 6_Supplement (March 22, 2024): 1368. http://dx.doi.org/10.1158/1538-7445.am2024-1368.

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Abstract The difficulties with antibody-based therapies stem from their steep costs, complex procedures, and contamination risks. We investigate the use of in vitro transcription (IVT) for mRNA production, presenting a novel approach to traditional antibody treatments by promoting internal protein or antibody synthesis. We aim to create innovative mRNA-based anti-PD-L1 antibodies with strong immunotherapeutic effectiveness. The study begins with mouse immunization and hybridoma generation. Immunizing mice with the glycosylated extracellular domain of PD-L1 produces mouse antibodies against human PD-L1. Hybridomas, derived from post-immunization splenocytes, yield monoclonal antibodies screened for PD-L1 binding affinity via flow cytometry. A neutralizing assay identifies 22 antibodies with similar IC50 values and shared binding epitopes. M1, chosen for glycospecificity, affinity, and neutralizing activity, undergoes additional evaluation for the expression and anti-tumor efficacy of mRNA-encoded antibodies. The expression of M1 and atezolizumab antibodies is facilitated through an mRNA-lipid nanoparticles (LNPs) delivery system. Following intravenous administration in mice, sustained serum levels of M1 (ranging from 100 to 700 μg/mL at 24 hours post-injection) are observed. Serum concentrations of M1 and atezolizumab antibody peak at the first timepoint (24 or 48 h) after mRNA-LNP injection, respectively, and then significantly decrease within the next 4 days, with a gradual decline over the next 2 weeks. Conversely, the serum concentrations of M1 or atezolizumab protein decline significantly 24 hours post-injection and consistently stay at a baseline level (t1/2 of 94 and 4 h for M1 mRNA-LNP and protein, respectively). This indicates that the injection of encoded mRNA in mice can stably and continuously express antibodies.Administering Atezolizumab mRNA-LNP through two intravenous injections leads to a significant decrease in MC38 tumor growth, exhibiting a dose-dependent effect (TGI% = 8.1, 43.1, and 62.8 for doses of 0.2, 0.6, and 1 mg/kg, respectively). A complete tumor regression was observed up to day 19 following injection with a 2 mg/kg dose of mRNA-LNP (TGI% = 90.8%). Remarkably, a 3 mg/kg dose of atezolizumab antibody demonstrates a similar reduction in tumor growth as 0.6 mg/kg of the mRNA-LNP formulation in this model. In conclusion, this research underscores the potential of LNP-formulated mRNA as a transformative approach, converting the human body into a site for the continuous, stable expression of antibodies, offering a promising alternative to traditional protein-based therapies for combating cancer. This innovative approach shows promise in overcoming the limitations associated with traditional antibody production and clinical utilization. Citation Format: Ezra Chung, Yong Sik Bong, Renxiang Chen, Michael Zhang, Steven Long, Dong Shen. Novel mRNA encoding anti-PD-L1 monoclonal antibodies for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1368.

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Huang, Jiajie, Haigang Gu, Janet Orton, Marina Sedova, Sophie Rozenzhak, Fiona Hyland, and Guang Liu. "Abstract 328: A comprehensive genomic profiling of myeloid malignancies demonstrates mutational spectrum of DNA variants, FLT3-ITDs, and gene fusions." Cancer Research 84, no. 6_Supplement (March 22, 2024): 328. http://dx.doi.org/10.1158/1538-7445.am2024-328.

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Abstract Introduction: Myeloid malignancies encompass diverse hematopoietic disorders, including acute myeloid leukemia (AML), myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), and juvenile myelomonocytic leukemia (JMML). We developed two assays to address the genetic complexity of myeloid malignancies, OncomineTM Myeloid Assay and OncomineTM Myeloid Assay GX v2, detecting mutations in 45 DNA genes and >30 fusion driver genes, including >700 fusion isoforms. Our panel includes genetic alterations such as FLT3-Internal Tandem Duplications (ITDs), IDH1/2, CEBPA, CALR, and TP53. Methods: Here we describe the genomic profiles of 8503 clinical research samples (including AML, MPN, MDS, CML, CMML, or JMML). A total of 4723 samples were run on the Ion GeneStudioTM S5 System and analyzed using the OncomineTM Myeloid Research workflow on Ion ReporterTM 5.18. A total of 3780 samples were run on the Ion TorrentTM Genexus Software 6.6 and analyzed using the OncomineTM Myeloid Assay GX v2. Results: On Genexus, the turnaround time (the time between starting the run and NGS data report) was 23-25 hours and the hands-on time was around 1 hour. The success rate of the samples was 100%. Frequency of relevant mutations and variant allele frequency by gene: Genes like TET2 (detected in 12.6% of samples), ASXL1 (9.3%), DNMT3A (7.8%), TP53 (7.5%) exhibited high mutation rates. 56.4% of samples had mutations, averaging 2.3 mutations per sample. Common co-occurring mutations included ASXL1-TET2 and SRSF2-TET2. Variant allele frequency varied greatly, e.g., ANKRD26 had a median VAF of 66%, while MYD88 had only 7%. Mutation spectrum of FLT3ITD variants: FLT3-ITD was observed in 3% of samples, with an average VAF of 0.32, featuring a multi-modal length with the highest peak at around 34 bp and maximum length at 151 bp. Mutation spectrums of fusions: 710 (8.4%) samples were fusion-positive with read counts ranging 21-113,000. ABL1 was the most common driver and BCR-ABL1 was the most common gene pair. Other common drivers included KMT2A, MYH11, RARA, and RUNX1. 17 distinct driver genes, 49 gene pairs, and 110 gene isoforms were observed, including rare fusions like ZMYM2-FGFR1 and KAT6A-CREBBP that are not detectable by traditional methods like qPCR (quantitative polymerase chain reaction) or FISH (fluorescence in-situ hybridization). Conclusions: The Oncomine Myeloid Assay is a fast, robust, and reproducible solution for comprehensive genomic profiling of myeloid malignancies. We describe the mutational spectrum of DNA variants and RNA fusions in a range of clinical research samples. (For research use only. Not for use in diagnostic procedures. © 2023 Thermo Fisher Scientific Inc. All rights reserved. All trademarks are the property of Thermo Fisher Scientific and its subsidiaries unless otherwise specified.) Citation Format: Jiajie Huang, Haigang Gu, Janet Orton, Marina Sedova, Sophie Rozenzhak, Fiona Hyland, Guang Liu. A comprehensive genomic profiling of myeloid malignancies demonstrates mutational spectrum of DNA variants, FLT3-ITDs, and gene fusions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 328.

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Raskin, Grigory, Vasily Kazey, Svetlana Gorbacheva, Aiyyna Nikiforova, Galina Statsenko, Elena Artamonova, Liubov Vladimirova, et al. "Abstract 3481: Pharmacokinetics of alofanib and biomarker analysis in patients with advanced gastric cancer: A phase 1b study." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3481. http://dx.doi.org/10.1158/1538-7445.am2022-3481.

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Abstract Alofanib is a potent, small molecule, allosteric inhibitor that binds to the non-active extracellular site of IIIc and IIIb FGFR2 isoforms. Phase 1b clinical study (RPT835GC1B) met its primary endpoints and recommended phase 2 dose was described early. Here, we present pharmacokinetics (PK) and results of biomarker analysis. Alofanib was administered daily intravenously for 5-days followed by a 2-day interval (rest). There were five dose levels using a 3 + 3 design. 21 patients have been enrolled in the study. Patients were Caucasian (100%), predominantly male (71%), 67% had 2 and more metastatic sites, including liver (43%) and bone (14.3%) metastases, 19% had ECOG PS 2, and were heavily pretreated (86% had previous 3 and more lines of therapy). The PK and biomarker analysis set included 18 patients. FGFR2 amplification was accessed by FISH with ZytoLight SPEC FGFR2/CEN 10 Dual Color Probe and FGFR2 expression was accessed by IHC with antibody 1G3 (Abcam (ab 5820). Table summarizes PK data. The geometric mean values of Cmax, AUC0-t, T1/2, Vd increased and CL, Kel decreased approximately dose-proportionally after single dosing, similar to previous preclinical studies. The decrease in the mean value of the Vd for a dose of 350 mg/m2 may be associated with a significant increase in AUC0-t. No correlations between PK values and objective response rate (n=2; 9.5%), progression-free (median 3.63 months (95% CI, 1.58 - 5.68) and overall (median 7.0 months (3.82 - 10.18) survival as well as in patients with liver metastases were found (all P>0.1). A positive FGFR2 IHC expression was observed in all tumor cells and a weak positive reaction in normal epithelium. FGFR2 amplification was confirmed by FISH in 1 (5.6%) patient.Alofanib PK in a gastric patient population is well characterized, supporting the use of a once-daily 350 mg/m2 dose. In further studies, the evaluation of FGFR2 amplification seems to be important. Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 50 mg/m2 100 mg/m2 165 mg/m2 250 mg/m2 350 mg/m2 Cmax, mcg/ml (CV%) 21.4 (32.3) 23.7 (18.4) 44.7 (15.5) 72.8 (64.3) 145.9 (42.7) AUC0-t, mcg*h/ml (CV%) 2.3 (31.9) 6.6 (14.2) 13.3 (49.9) 23.8 (8.7) 74.0 (57.5) Vd, ml/m2 (CV%) 4006.1 (28.3) 4907.5 (14.7) 5676.8 (26.6) 6686.7 (11) 3823.0 (63.8) CL, ml/h/m2 (SD) 19609.5 (7740) 14028.2 (1990) 11910.5 (8740) 10011.0 (827) 4183.0 (2420) Kel, 1/h (CV%) 4.9 (15.3) 2.9 (2.8) 2.1 (41.2) 1.5 (3.8) 1.1 (47.0) T1/2, h (SD) 0.1 (0.024) 0.2 (0.01) 0.3 (0.118) 0.5 (0.0171) 0.6 (0.293) Citation Format: Grigory Raskin, Vasily Kazey, Svetlana Gorbacheva, Aiyyna Nikiforova, Galina Statsenko, Elena Artamonova, Liubov Vladimirova, Natalia Besova, Anastasia Mochalova, Ivan Rykov, Vladimir Moiseyenko, Igor Utyashev, Sergei Iugai, Nadezhda Dragun, Dmitry Reznikov, Evgenia Gavrilova, Sergei Tjulandin, Ilya Tsimafeyeu. Pharmacokinetics of alofanib and biomarker analysis in patients with advanced gastric cancer: A phase 1b study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3481.

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Zheng, Jingtian, Evan Phillips, Yi-Chien Wu, Steve Seung-Young Lee, and Vytautas Bindokas. "Abstract 4707: LED photobleaching-based multiplex 3D microscopy of the tumor microenvironment." Cancer Research 83, no. 7_Supplement (April 4, 2023): 4707. http://dx.doi.org/10.1158/1538-7445.am2023-4707.

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Abstract Multiplexing in immunofluorescence imaging is important for the spatial profiling of cells and molecules in tumor tissue samples. Cyclic immunofluorescence (IF) methods using oxidants (e.g. hydrogen peroxide) and enzymes (e.g. DNase) localize a great number of cellular makers and proteins in a tissue section while repeating a process of IF staining, imaging, and fluorescence deactivation. However, the repeated use of chemicals and enzymes might cause artifacts in tissue and cell morphologies. Furthermore, these methods are restricted to thin tissue sections (~5 μm thick) which are inappropriate to provide comprehensive structural information on tissue samples. Although reconstruction of two-dimensional (2D) images from serial tissue sections can provide a certain volumetric tissue image, it takes a huge amount of time and effort. Here we introduce a three-dimensional (3D) multiplex IF imaging method using LED photobleaching. We built high-power LED illuminators with 100W warm (emission wavelength: 480-700 nm), green (430-520 nm), and red (600- 680 nm) LED chips, which can efficiently bleach a broad or selected wavelength of fluorescence signals in tissue samples. We integrated this LED photobleaching with the Transparent Tissue Tomography (T3) protocol and created a 3D cyclic IF method involving tissue macrosectioning (400 μm), three-color IF staining, D-fructose-based tissue clearing, 3D confocal fluorescence microscopy, LED photobleaching, tissue washing, and three-color IF staining for other biomarkers, and repeating the process. By applying this method to mouse mammary tumor tissues, we could perform 8-plex fluorescence microscopy for visualizing cell nuclei (DAPI), vascular (CD31, SMA) and structural (ER-TR7) cells, immune cells (CD3, CD8, CD45), and cancer cells (CK8) in the tumor macrosections in 3D at tissue and cellular resolution. To validate the method as an evaluation tool for immunotherapy, we treated the mouse mammary tumor with a STING agonist (DMAXX) intratumorally and collected the tumor tissue 1 day after the treatment, and processed it for the 3D cyclic IF protocol. The quantitative multiplex image data showed immune-driven-cancer eradication and high tumor infiltration of a large number of CD3+CD8+CD45+ cytotoxic T cells. We also examined that Red and Green LED illumination can selectively bleach fluorophores in tissues, which would be useful for patterning fluorescence in tissue as well as studying fluorescent drug-cell interaction in a tissue. In summary, this chemical and enzyme-free 3D cyclic IF imaging method will be a powerful tissue assay tool to provide comprehensive spatial information of tissue (tumor) samples including cell types, cellular and molecular location, and their 3D organization in a tissue sample. Citation Format: Jingtian Zheng, Evan Phillips, Yi-Chien Wu, Steve Seung-Young Lee, Vytautas Bindokas. LED photobleaching-based multiplex 3D microscopy of the tumor microenvironment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4707.

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Shen, Sherry, Johnny Allsop, Erica Salehi, Cara Anselmo, Stacie Corcoran, Jill Clayton, Andrea Smith, Melissa Emerzian, Mark Robson, and Neil Iyengar. "Abstract P1-09-05: Baseline dietary patterns among women with newly diagnosed early-stage breast cancer enrolled in the Optimal Living Program." Cancer Research 82, no. 4_Supplement (February 15, 2022): P1–09–05—P1–09–05. http://dx.doi.org/10.1158/1538-7445.sabcs21-p1-09-05.

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Abstract Background: Evidence-based recommendations support a dietary pattern rich in whole grains, fruits, and vegetables with limited consumption of added sugars to improve cancer risk and mortality. The Optimal Living Program (OLP) is a prospective multiparametric lifestyle intervention that engages early-stage breast cancer patients at the time of diagnosis in risk-stratified, personalized lifestyle management. Here, we report baseline dietary patterns among women enrolled in the OLP. Methods: Upon enrollment, patients complete a questionnaire that incorporates the National Cancer Institute (NCI) Dietary Screener Questionnaire (DSQ), which queries the consumption frequency of 26 food items over the past month. Based on standard NCI DSQ scoring procedures, we calculated total daily serving equivalents of all food items within a dietary factor group. This included: 1) total daily cup equivalents of fruit and vegetables from fruit, fruit juice, salad, potatoes, beans, other vegetables, tomato sauce, salsa, and pizza, 2) total daily ounce equivalents per day of whole grains from cereal, whole grain bread, popcorn, and whole grain rice, and 3) total daily teaspoon (tsp) equivalents of added sugars from cookies/cake/pie, doughnuts, ice cream, candy, cereals, and sugar-sweetened beverages including soda, fruit drinks, and sugar/honey in coffee/tea. Results: There were 100 patients enrolled in the OLP for whom baseline DSQ data were available. The median age at diagnosis was 58 and median BMI was 27.4 mg/m2. 69 patients were white (69.0%), 14 were Black (14.0%), and 7 were Asian (7.0%). 62 patients had stage I disease (62.0%), 22 patients had stage II disease (22.0%), and 15 patients had ductal carcinoma in situ (15.0%). 74 patients had hormone receptor-positive disease (74.0%), 3 had HER2-positive disease (3.0%), and 7 had triple-negative disease (7.0%). Daily frequency of consumption of dietary factor groups are shown in Table 1. Only 29 patients (29.0%) met the current dietary guideline of 4-5 cup equivalents of fruits and vegetables per day and no patients (0%) met the guideline of more than 3 ounce equivalents of whole grains per day. Added sugar intake ranged from 0 to 4.8 teaspoon equivalents per day. Conclusion: Most women in this cohort with newly diagnosed early-stage breast cancer did not consume the recommended daily intake of fruits, vegetables, and whole grains per the 2020-2025 Dietary Guidelines and the American Institute for Cancer Research. Our findings identify these dietary factors as important targets of intervention with personalized dietary guidance at the time of breast cancer diagnosis. Table 1.<1/day1 - 2/day2 - 3/day3 – 4/day>4/dayFruits and vegetables (cup equivalents)6 (6.0%)23 (23.0%)28 (28.0%)14 (14.0%)29 (29.0%)Whole grains (ounce equivalents)63 (63.0%)29 (29.0%)8 (8.0%)0 (0%)0 (0%)Added sugar (tsp equivalents)32 (32.0%)35 (35.0%)22 (22.0%)6 (6.0%)5 (5.0%)Sugar-sweetened beverages (tsp equivalents)62 (62.0%)21 (21.0%)15 (15.0%)2 (2.0%)0 (0%) Citation Format: Sherry Shen, Johnny Allsop, Erica Salehi, Cara Anselmo, Stacie Corcoran, Jill Clayton, Andrea Smith, Melissa Emerzian, Mark Robson, Neil Iyengar. Baseline dietary patterns among women with newly diagnosed early-stage breast cancer enrolled in the Optimal Living Program [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-09-05.

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Song, Kai, Oh Kyu Yoon, Luting Zhuo, Emon Elboudwarej, Biao Li, Jillian Boice, Yang Pan, See Phan, and Monica Motwani. "Abstract 4392: Expression landscape of trophoblast cell surface antigen 2 (Trop-2) in breast cancer." Cancer Research 83, no. 7_Supplement (April 4, 2023): 4392. http://dx.doi.org/10.1158/1538-7445.am2023-4392.

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Abstract Background: Antibody-drug conjugates (ADCs) are novel agents linking potent payloads to antibodies targeting antigen-expressing tumors. Sacituzumab govitecan (SG), a Trop-2-directed ADC, is approved for patients with metastatic triple-negative breast cancer (mTNBC) with ≥2 prior therapies (≥1 in metastatic setting). SG is also being investigated in other breast cancer subtypes, including hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer and in earlier lines of treatment. To understand the landscape of Trop-2 expression and potential clinical actionability of Trop-2 and other antigens, we evaluated RNA expression data in breast cancer from The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC). Methods: TCGA and METABRIC datasets were assessed for Trop-2, HER2, and programmed death ligand 1 (PD-L1) expression via processed RNA sequencing (RNA-seq) and microarray data of the corresponding genes TACSTD2, ERBB2, and CD274. Gene expression across clinical parameters was assessed via one-way ANOVA, t-test, or Spearman correlation. HER2 status was classified as HER2 immunohistochemistry (IHC) 0 or HER2-low (IHC1+, or IHC2+ and in situ hybridization-negative). Survival was estimated via Kaplan-Meier method. Neoadjuvant therapy datasets were assessed for effects of aromatase inhibitors on Trop-2 expression. Results: RNA-Seq data was available from 1030 and 2136 breast cancer patients in TCGA and METABRIC datasets, respectively. Most patients (96%) had high TACSTD2 expression (>100 transcripts per million [TPM]). TACSTD2 expression was comparable by breast cancer histology (median log2TPM 6.8-7.5), by disease stages I-IV (median log2TPM 7.0-7.5), or by subtypes (median log2TPM 7.1-7.3). TACSTD2 expression was not correlated with ERBB2 (Spearman rho=0.06) or CD274 (Spearman rho=-0.13) expression. No difference in TACSTD2 expression was noted between HER2 IHC0 or HER2-low subtypes. TACSTD2 expression was not associated with survival, though low tertile TACSTD2 groups had better prognosis in the basal subtype; treatments were heterogeneous. Changes in TACSTD2 gene expression were not observed post-aromatase inhibitors. Conclusions: While SG is approved for use in mTNBC, TACSTD2 is stably expressed across all breast cancer stages and subtypes, including HER2 IHC0 and HER2-low, and across all ranges of PD-L1 expression, suggesting a broad patient population may benefit from Trop-2-directed ADCs. Citation Format: Kai Song, Oh Kyu Yoon, Luting Zhuo, Emon Elboudwarej, Biao Li, Jillian Boice, Yang Pan, See Phan, Monica Motwani. Expression landscape of trophoblast cell surface antigen 2 (Trop-2) in breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4392.

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Rugo, Hope, Xianchen Liu, Benjamin Li, Lynn McRoy, Connie Chen, Rachel M. Layman, and Adam M. Brufsky. "Abstract P3-01-14: Real-world treatment patterns of Palbociclib plus an aromatase inhibitor or aromatase inhibitor alone for metastatic breast cancer in the Flatiron database." Cancer Research 83, no. 5_Supplement (March 1, 2023): P3–01–14—P3–01–14. http://dx.doi.org/10.1158/1538-7445.sabcs22-p3-01-14.

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Abstract Background: CDK4/6 inhibitor in combination with an aromatase inhibitor (AI) or fulvestrant as initial endocrine therapy are standard of care for patients with HR+/HER2– advanced/metastatic breast cancer (mBC). This analysis describes treatment patterns including dosing patterns and time to subsequent treatment in patients receiving first line Palbociclib (PB)+AI therapy compared to AI alone, for HR+/HER2– mBC in the US routine clinical setting. Methods: This was a retrospective analysis of Flatiron Health’s nationwide longitudinal electronic health records from over 280 cancer clinics representing more than 3 million actively treated cancer patients in the US. Between February 2015 and March 2020, 2888 postmenopausal mBC women and men aged ≥18 years started first-line PB+AI or AI therapy. Patients were followed from start of therapy to September 2020, death, or last visit, whichever came first. PB treatment patterns were captured as starting dose and dose adjustments from medical records during the observation period. Comparative time to subsequent therapy (TTNT) or chemotherapy (TTC) was defined as length of time from the start of treatment to next line of anticancer therapy/chemotherapy, death from any cause, last visit, or end of study, whichever came first. Cox proportional-hazards models were used to estimate the relative effectiveness of PB+AI vs AI. Stabilized inverse probability treatment weighting (sIPTW) and propensity score matching (PSM) statistical methods were used to balance of baseline demographics and clinical characteristics. Results: Of the 2888 eligible pts (1324 with PB+AI and 1564 with AI), median age was 70.0 years, 67.8% were white, 34.8% had de novo mBC, 29.4% had lung or liver involvement, 38.7% had bone-only disease. Median follow-up was 25.0 months in the PB+AI arm and 23.3 months in the AI alone arm. Of the 1342 patients receiving PB, therapy was started at 125 mg, 100 mg, and 75 mg/day in 83.8%, 10.9%, 3.6%, respectively (1.7% undocumented PB dose) with dose changes in 41.1%, 36.8%, 31.3% of patients in each starting dose category with dosing information. After sIPTW median TTNT was 18.4 months (95%CI: 16.3-20.3) in the PB +AI group and 8.3 months (95%CI: 7.2-10.0) in the AI group; HR=0.56 (95%CI: 0.51-0.62), p< 0.0001. After sIPTW median TTC was 37.4 months (95%CI: 33.7-40.7) PB+AI group and 29.2 months (95%CI: 26.8-33.5) in the AI group; HR=0.77 (95%CI: 0.69-0.86), p< 0.0001. Results for the PSM analyses were similar. The table presents full results in detail. Conclusions: These treatment patterns analyses in a heterogeneous mBC patients from real world US clinical practice, provide support for first line PB+AI treatment for HR+/HER2– mBC. The majority of patients initiated therapy at the 125 mg/daily dose (84%). Importantly, these analyses also report meaningful differences in the delay to next line of therapy and chemotherapy in the PB+AI compared to AI therapy arm. Table. Median time to next line of therapy or chemotherapy Citation Format: Hope Rugo, Xianchen Liu, Benjamin Li, Lynn McRoy, Connie Chen, Rachel M. Layman, Adam M. Brufsky. Real-world treatment patterns of Palbociclib plus an aromatase inhibitor or aromatase inhibitor alone for metastatic breast cancer in the Flatiron database [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-01-14.

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Liam, Chong Kin, Azura Rozila Ahmad, Te-Chun Hsia, Jianying Zhou, Dong-Wan Kim, Ross Andrew Soo, Ying Cheng, et al. "Abstract CT538: Tepotinib + gefitinib in patients with EGFR-mutant NSCLC with MET amplification: Final analysis of INSIGHT." Cancer Research 82, no. 12_Supplement (June 15, 2022): CT538. http://dx.doi.org/10.1158/1538-7445.am2022-ct538.

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Abstract Introduction: In the INSIGHT trial primary analysis (NCT01982955; median follow-up: 21.8 months), tepotinib (a potent, highly selective, once daily [QD] MET inhibitor) + gefitinib improved efficacy vs chemotherapy (CTX) in patients with EGFR-mutant NSCLC and resistance to anti-EGFR therapy due to MET amplification (Wu et al, Lancet Respir Med 2020). Here we report final analyses from INSIGHT (data cut-off: September 3, 2021; median follow-up: 57.5 months). Methods: Patients with EGFR-mutant (T790M-negative) NSCLC and anti-EGFR resistance, with MET gene copy number (GCN) ≥5 and/or MET:CEP7 ≥2 by FISH and/or MET IHC 2+/3+, were randomized to tepotinib 500 mg (450 mg active moiety) + gefitinib 250 mg QD or CTX. Primary endpoint was progression-free survival (PFS) per investigator. Preplanned analyses evaluated patients with MET amplification. Results: In the 19/55 randomized patients (34.5%) with MET amplification (GCN ≥5, n=18; MET:CEP7 ≥2, n=13; MET IHC 3+, n=17), median age was 60.4 years, 68.4% were never-smokers, and prior EGFR inhibitors were gefitinib (57.9%), afatinib (21.1%), erlotinib (10.5%) and icotinib (10.5%). Median duration of tepotinib + gefitinib was 11.3 months (range: 1.1-56.5), with treatment duration >1 year in 6 patients (31.6%) and >4 years in 3 patients (15.8%). Two patients continued treatment outside the study. Tepotinib + gefitinib improved PFS (hazard ratio [HR] 0.13; 95% confidence interval [CI] 0.04, 0.43), overall survival (HR 0.10; 95% CI 0.02, 0.36), objective response rate and duration of response vs CTX (Table). Treatment-related Grade ≥3 AEs occurred in 7 patients (58.3%) with tepotinib + gefitinib and 5 (71.4%) with CTX. Most common post-study therapies were kinase inhibitors (n=2 in the tepotinib + gefitinib arm; n=3 in the CTX arm). In patients with MET IHC 3+ (n=34; including 17 patients with MET amplification), tepotinib + gefitinib also markedly improved PFS (HR 0.35; 95% CI 0.17, 0.74) and OS (HR 0.44; 95% CI 0.23, 0.84) vs CTX. Conclusions: Tepotinib + gefitinib greatly improved PFS and OS vs CTX in patients with EGFR-mutant NSCLC with MET amplification. INSIGHT 2 is evaluating tepotinib + osimertinib in this setting. Table. Summary of efficacy and safety data in patients with MET amplification Endpoint Tepotinib + gefitinib (n=12) CTX (n=7) PFS Events, n (%) 7 (58) 7 (100) Median, months (90% CI) 16.6 (8.3, 22.1) 4.2 (1.4, 7.0) HR (90% CI) 0.13 (0.04, 0.43) OS* Events, n (%) 7 (58) 7 (100) Median, months (90% CI) 37.3 (21.1, 52.1) 13.1 (3.3, 22.6) HR (90% CI) 0.10 (0.02, 0.36) ORR n (%) [90% CI] 8 (66.7) [39.1, 87.7] 3 (42.9) [12.9, 77.5] OR (90% CI) 2.67 (0.37, 19.56) DOR Median, months (90% CI) 19.9 (7.0, NE) 2.8 (2.8, NE) Treatment-related Grade ≥3 AEs†, n (%) Amylase increased 4 (33.3) 0 Lipase increased 4 (33.3) 0 Anemia 0 2 (28.6) Neutrophil count decreased 0 2 (28.6) WBC count decreased 0 2 (28.6) *Post-study therapy included an EGFR inhibitor ± a MET inhibitor in two patients in each arm (tepotinib + gefitinib arm: osimertinib ± cabozantinib [n=1], gefitinib + cabozantinib [n=1]; CTX arm: erlotinib, afatinib, and osimertinib ± crizotinib [n=1], osimertinib [n=1]). Post-study CTX was received by one patient in the tepotinib + gefitinib arm and two patients in the CTX arm.†Reported in >20% of patients in either arm. AE, adverse event; CI, confidence interval; CTX, chemotherapy; DOR, duration of response; HR, hazard ratio; NE, not estimable; ORR, objective response rate; OR, odds ratio; OS, overall survival; PFS, progression-free survival; WBC, white blood cell. Citation Format: Chong Kin Liam, Azura Rozila Ahmad, Te-Chun Hsia, Jianying Zhou, Dong-Wan Kim, Ross Andrew Soo, Ying Cheng, Shun Lu, Sang Won Shin, James Chih-Hsin Yang, Yiping Zhang, Jun Zhao, Rolf Bruns, Andreas Johne, Yi-Long Wu. Tepotinib + gefitinib in patients with EGFR-mutant NSCLC with MET amplification: Final analysis of INSIGHT [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT538.

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Wang, Jie, Bella Guo, Xiang Zhang, Ximeng Zhao, Dongsheng Wang, Fei Sun, and Tonghui Ma. "Abstract 5875: Germline gene alterations in high grade and low grade gliomas: A multi-center, large scale study in China." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5875. http://dx.doi.org/10.1158/1538-7445.am2022-5875.

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Abstract Backgrounds: Germline gene alterations in gliomas play a significant role during malignant transformation of progenitor glial cells. Previous pan-caner studies suggested 6-10% of gliomas patients harboring germline gene mutations. However, these studies are limited to only known cancer predisposition genes and a small scale of gliomas patients. In this study, we performed a multi-canter, large scale study to investigate the contribution of germline gene alterations to LGG and HGG. Methods: Genomic DNA was extracted from white blood cells from 1006 LGG patients and 1578 HGG patients and was subjected to Next-generation sequencing with Onco PanScan. Pathogenic or likely pathogenic germline variants (PGVs) were identified in 150 putative cancer-predisposition genes according to ACGM guideline. Fisher’s exact test was used for the statistics analysis (two-sided). Results: We identified 54 PGVs in LGG patients and 112 PGVs in HGG patients which were located in 31 and 40 unique genes, respectively (Table 1). There was a significant difference between HGG and LGG in younger patients with germline gene mutations (A group, p < 0.001), while not in B and C group. The results indicated that the incidence rate of TP53 or MSH2 germline mutations in HGG patients was much higher than in LGG patient (p < 0.01), while a lower incidence rate of ERCC5 germline mutations was observed in HGG patients in comparison with LGG patients (p < 0.05). Conclusions: This study indicated a higher PGVs frequency in HGG than in LGG, especially in younger group. In addition, there is different contribution of germline gene alterations to risk the formation of LGG or HGG. It might aid in the early diagnosis of these patients and genetic counseling of their families. Informations of PGVs in LGG and HGG LGG HGG Numbers of mutation carriers Numbers of LGG Mutation rate Numbers of mutation carriers Numbers of HGG Mutation rate Age A: 0-30 years 14 a*** 292 4.1% 29 b*** 189 15.3% B: 31-55 years 30 554 5.4% 41 639 6.4% C: >55 years 10 160 6.3% 42 c*** 750 5.6% Total 54 1006 5.4% 112 1578 7.1% Gender Male 35 567 6.2% 65 935 7.0% Female 19 439 4.3% 50 643 7.8% Total 54 1006 5.4% 112 1578 7.1% Top ten of high mutation rate ERCC5*, MUTYH, BRCA2, CHEK2, WRN, PRSS1, MSH6, FANCD2, ERCC2, FANCA TP53**, MSH2**, BRCA2, NF1, RAD51D, MSH6, PRSS1, BUB1B, PDE11A, BLM Note: LGG 1, Low Grade Glioma; HGG 2, High Grade Glioma; aNumbers of mutation carriers in A group were statistical different in LGG and HGG patients; bNumbers of mutation carriers in A group and B group were statistical different in HGG patients; cNumbers of mutation carriers in A group and C group were statistical different in HGG patients; * p < 0.05; ** p < 0.01; *** p < 0.001 Citation Format: Jie Wang, Bella Guo, Xiang Zhang, Ximeng Zhao, Dongsheng Wang, Fei Sun, Tonghui Ma. Germline gene alterations in high grade and low grade gliomas: A multi-center, large scale study in China [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5875.

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Li, Cong, Yun Xu, Fangqi Liu, and Ye Xu. "Abstract 5773: A one-stop approach in diagnosing hereditary colorectal cancer: A prospective, proof-of-principle, single-center study." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5773. http://dx.doi.org/10.1158/1538-7445.am2022-5773.

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Abstract Background: Colorectal cancer (CRC) remains one of the most commonly diagnosed cancers and a leading cause of cancer-related deaths worldwide. Between 3 and 6% of all CRC cases are attributed to hereditary colorectal cancer (HCRC). It is important to distinguish CRCs that arise hereditarily from those that arise sporadically, because patients with HCRC and their relatives can benefit from intensive clinical management and surveillance. The detection of germline variants using tumor tissue and paired non-cancerous tissue/whole blood cells (WBC) (conventional method) is considered as the gold standard for germline confirmation, but which could introduce high cost and long turnaround time. In this work, we aimed to investigate the feasibility of diagnosing HCRC using only tumor next-generation sequencing data without normal tissue/WBC data. Methods: One-hundred patients with suspected HCRC were prospectively enrolled according to the clinical diagnosis. Both tumor tissue and paired WBC were collected from each patient. Capture-based targeted sequencing using a panel consisting of 41 cancer-related genes was performed on both tumor tissue and WBC sample. The germline variants were identified using conventional and ColonCore method, respectively. The sensitivity and positive predictive value (PPV) of ColonCore method in identifying germline alterations were calculated, when conventional method was used as a reference. Results: A total of 636 alterations were identified using ColonCore method, including 606 somatic alterations and 30 germline alterations. Among the somatic alterations detected from this panel, 599 single-nucleotide variants and 7 copy number variants were observed. The most frequently mutated genes were APC, TP53, and KRAS, occurring in 76%, 66%, and 46% of patients, respectively. For ColonCore analysis, 17, 9, 2, and 2 patients harbored germline pathogenic variants in DNA mismatch repair (MMR) genes, APC, MUTYH, and ATM, respectively. Compared to the conventional method, the sensitivity of ColonCore method in the diagnosis of HCRC achieved 88.5% with a PPV of 82.1%. Next, the diagnostic performance of ColonCore method in Lynch syndrome (LS) and familial adenomatous polyposis (FAP) was subsequently investigated. We found its sensitivity in the diagnosis of LS achieved 100% (with a PPV of 98.8%), which was obviously higher than that in the diagnosis of FAP (70.0% with a PPV of 63.6%). Twenty-three patients identified as having a microsatellite instability (MSI)-high tumor using ColonCore method were also identified as having an MMR-deficient (dMMR) tumor using immunohistochemistry staining analysis. Conclusions: Our study suggests that ColorCore method is a one-stop approach for detecting germline/somatic alterations and MSI/dMMR status for suspected HCRC. Furthermore, ColorCore method is a feasible and valid tool to diagnose HCRC, especially LS. Citation Format: Cong Li, Yun Xu, Fangqi Liu, Ye Xu. A one-stop approach in diagnosing hereditary colorectal cancer: A prospective, proof-of-principle, single-center study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5773.

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Ferreira-Gonzalez, Andrea, Gilbert C. Ko, Sreevalsa Appukkuttan, Brian Hocum, Sohul Shuvo, and Svetlana Babajanyan. "Abstract 1964: Racial and ethnic trends in next-generation sequencing (NGS) utilization among adult patients with selected advanced tumor types: a large commercial database analysis." Cancer Research 83, no. 7_Supplement (April 4, 2023): 1964. http://dx.doi.org/10.1158/1538-7445.am2023-1964.

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Abstract Introduction: NGS utilization has increased over the last decade, although opportunities for improvement remain. Evaluation of trends in NGS utilization between race/ethnic groups will provide a better understanding of potential populations that may not have equitable access to NGS testing. Methods: Optum Clinformatics® Data Mart administrative health claims data was utilized to conduct a retrospective cohort study among US adult patients with >2 diagnostic ICD-10 codes for metastatic non-small cell lung cancer (mNSCLC), metastatic colorectal cancer (mCRC), metastatic breast cancer (mBC), metastatic melanoma (mM), or primary central nervous system (CNS) tumors indexed between 1/1/2015 - 3/31/2021. NGS tests were identified using Current Procedural Terminology and Proprietary Laboratory Analyses codes. Outcomes by race and tumor type included time to first NGS test, prevalence of testing across study period and for key guideline/therapy timeframes. Data were summarized descriptively for analyses outcomes. Results: A total of 14,620 mNSCLC, 9,538 mCRC, 26,086 mBC, 1,740 mM, and 5,835 CNS patients met the inclusion criteria. Of these, 3.4% were Asian, 12.1% were Black, 9.4% were Hispanic, 70.0% were White and 5.1% were missing race data. NGS use increased for all races over the study period (Table 1). Median time to testing from diagnosis across tumors ranged from 1.1-1.8 months (mo) for Asian patients, 1.4-5.6 mo for Black, 1.4-5.1 mo for Hispanic, 1.2-7.2 mo for White and improved over key timeframes and overall study period. Conclusions: Within a similar access system, NGS testing rates for minorities in mNSCLC, mCRC, mBC, mM, and primary CNS tumors have increased between 2015 and 2021 and appear comparable to the White population. This analysis suggests equitable access to health insurance in a commercially insured population can lead to equal access to NGS testing between races. Table 1 NGS Testing Prevalence by Race and Key Timeframes Tumor Type/Race 1/1/2015 - 8/31/2016 (prior to key policy changes and larotrectinib approval) 9/1/2016 - 3/31/2018 (UnitedHealthcare expansion of NGS testing) 4/1/2018 - 11/25/2018 (Centers for Medicare & Medicaid Services recommending NGS use in diagnostics) 11/26/2018 - 6/30/2021 (Food and Drug Administration approval of larotrectinib) Mnsclc Asian 1.2% 1.4% 10.0% 21.1% Black 3.3% 1.4% 12.9% 15.5% Hispanic 2.9% 1.4% 9.3% 13.9% White 3.5% 6.7% 9.8% 16.5% mCRC Asian 1.4% 0.0% 11.9% 9.5% Black 2.5% 2.1% 4.0% 11.2% Hispanic 0.9% 1.1% 2.6% 7.8% White 1.5% 2.7% 3.9% 8.5% mBC Asian 0.5% 0.0% 3.0% 2.5% Black 0.1% 0.0% 1.4% 1.1% Hispanic 0.2% 0.2% 0.7% 2.1% White 0.1% 0.0% 1.0% 1.8% mM Asian 0.0% 0.0% 0.0% 20.0% Black 0.0% 0.0% 14.3% 21.4% Hispanic 0.0% 0.0% 0.0% 9.1% White 2.9% 3.0% 4.4% 11.1% Primary CNS Tumor Black 0.0% 0.0% 5.9% 5.7% Hispanic 0.6% 3.0% 1.9% 7.8% White 0.8% 1.3% 2.9% 6.4% Citation Format: Andrea Ferreira-Gonzalez, Gilbert C. Ko, Sreevalsa Appukkuttan, Brian Hocum, Sohul Shuvo, Svetlana Babajanyan. Racial and ethnic trends in next-generation sequencing (NGS) utilization among adult patients with selected advanced tumor types: a large commercial database analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1964.

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Kolberg, Hans-Christian, Carmen Röhm, Angrit Stachs, Florian Schütz, Jens-Uwe Blohmer, Sarah Wetzig, Steffi Hartmann, Jörg Heil, and Markus Hahn. "Abstract P2-14-01: MOLECULAR FLUORESCENCE-GUIDED SURGERY USING BEVA800 FOR THE ASSESSMENT OF TUMOR MARGINS DURING BREAST CONSERVING SURGERY OF PATIENTS WITH PRIMARY BREAST CANCER (MARGIN-II)." Cancer Research 83, no. 5_Supplement (March 1, 2023): P2–14–01—P2–14–01. http://dx.doi.org/10.1158/1538-7445.sabcs22-p2-14-01.

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Abstract Introduction: The goal of breast conserving surgery (BCS) for early breast cancer (EBC) is to remove the tumor in toto and preserving as much of the normal breast tissue as possible. In 20-50% of cases a re-excision is necessary because of involved margins. Repeat surgeries are not only a burden to patients physically but also psychologically and can delay recommended adjuvant therapies. Accurate determination of tumor margins during surgery is therefore a critical need. Breast cancer tissue produces significantly higher amounts of VEGF-A than healthy tissue. VEGF-A stimulates tumor angiogenesis and is therefore a target for molecular imaging techniques. The fluorescence imaging agent bevacizumab-IRDye800CW (Beva800) is a conjugate of bevacizumab and IRDye800CW and binds specifically to VEGF-A. Beva800 provides a potentially efficacious approach to imaging specimen and cavity margins during BCS. We are presenting a phase II study that combined Beva800 with the SurgVision Explorer Air camera for intraoperative margin assessment during BCS for EBC. Methods: MARGIN II is a multicenter open-label single arm prospective clinical trial aimed at evaluating Beva800 for assessment of tumor margins in women with EBC scheduled for BCS. The study was a within-patient comparison of positive tumor margin rates using BCS standard of care margin assessment compared to intraoperative assessment with 4.5 mg Beva800 and fluorescence imaging with the SurgVision Explorer Air camera. All patients received an i.-v. bolus injection of 4.5 mg of Beva800 three days before surgery. The fluorescent signal was visualized during surgery using NIR fluorescence imaging (700–1000 nm). Standard of care margin assessment was defined as visual inspection, palpation and, in cases of pre-operative wire marking, specimen sonography or mammography. Beva800 efficacy was determined as the number of patients in which a pathology-confirmed positive margin was identified by fluorescence-guided surgery using Beva800 but not by standard of care BCS. Results: 49 patients were included in 5 centers. 4 training cases were only included in the safety analysis, 45 patients were evaluable for the efficacy analysis. 8 patients (17.8%) had involved margins after standard of care BCS, 4 of which were detected by molecular fluorescence intraoperatively resulting in the reduction of patients with positive margins by 50% (95% CI: 15.7%, 84.3%). 4 patients (8.9%; 95% CI: 2.5%, 21.1%) needed a re-excision because of involved margins. In 27 patients (60.0%) the additional molecular fluorescence guided cavity shaving did not change the resection status from positive to negative (false positive). Adverse events were reported by 16 of 49 patients (32.7%), but only 3 (6.1%) were related to Beva800 (syncope, hot flush, hypertensive crisis). One patient experienced a treatment related SAE (hypertensive crisis). No anti-Beva800 antibodies were detected. Conclusion: In our analysis the rate of necessary second operations was reduced by 50% using Beva800 and the SurgVision Explorer Air camera. The safety analysis confirmed the positive safety profile of Beva800 found in previous studies. Molecular fluorescence-guided surgery may have the potential to change the practice of breast conserving surgery by reducing unnecessary re-excisions. Future studies will have to address the high false positive rates. Citation Format: Hans-Christian Kolberg, Carmen Röhm, Angrit Stachs, Florian Schütz, Jens-Uwe Blohmer, Sarah Wetzig, Steffi Hartmann, Jörg Heil, Markus Hahn. MOLECULAR FLUORESCENCE-GUIDED SURGERY USING BEVA800 FOR THE ASSESSMENT OF TUMOR MARGINS DURING BREAST CONSERVING SURGERY OF PATIENTS WITH PRIMARY BREAST CANCER (MARGIN-II) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-14-01.

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Lu, Shun, Qiming Wang, Lin Wu, Ligang Xing, Yintao Li, Liang Han, Xiaorong Dong, et al. "Abstract CT201: HS-10365, a highly potent and selective RET tyrosine kinase inhibitor, demonstrates robust activity in RET fusion positive NSCLC patients." Cancer Research 83, no. 8_Supplement (April 14, 2023): CT201. http://dx.doi.org/10.1158/1538-7445.am2023-ct201.

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Abstract Background: Activating RET alterations drive oncogenic signaling in lung, thyroid, and other solid tumors.Until recently, only two RET tyrosine kinase inhibitor (TKI), BLU-667 and LOXO-292, had received approval for advanced NSCLC by FDA and NMPA. And it still had an unmet clinical need in this therapy area.HS-10365 is a highly potent and selective tyrosine kinase inhibitor, and the preclinical studies have indicated its favorable safety and antitumor activity in RET-altered tumor models. Here, we conducted a phase I study to assess the safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of HS-10365 in RET-altered solid tumors. Methods: This study (NCT05207787) recruited patients (pts) with RET-altered advanced solid tumors, including RET fusion-positive (+) NSCLC, RET-mutated medullary thyroid carcinoma and so on. Pts were dosed orally in 21-day cycles. A rule-based accelerated titration combined with 3+3 dose-escalation scheme was used to determine the MTD as the primary endpoint. Secondary endpoints contained safety, PK parameters, ORR and DCR assessed by RECIST V1.1. Results: As of Dec.15th 2022, 31 RET fusion+ NSCLC pts with RET TKI-naïve were received HS-10365 at 6 doses (40 mg QD to 200 mg BID), including 25 previously received platinum-based chemotherapy pts and 6 treatment-naïve pts. Among all fusion variants, 15 pts had KIF5B, 14 pts had CCDC6, and 2 pts were others. Dose limiting toxicity occurred only in one pt. at 200 mg BID (grade 3 hypertension). The MTD was not been defined, and the 160mg BID was the potentially recommended phase II dose. The common (≥25%) TRAEs were AST increase, bilirubin increase, ALT increase, WBC decrease, PLT decrease, neutrophil decrease, serum creatinine increase, prolonged QT interval, hypoalbuminemia and anemia. No pts discontinued treatment owing to AEs. Efficacy data was available for 30 RET fusion+ NSCLC pts with 24 pretreated pts and 6 treatment naïve pts. The ORR was 70.0% (21/30, 95% CI 50.6%-85.3%), with 66.7% (16/24) in pretreated pts and 83.3% (5/6) in treatment naïve pts. Furthermore, the DCR was 96.7% (29/30, 95% CI 82.8%-99.9%), with 95.8% (23/24) in pretreated pts and 100% (6/6) in treatment naïve pts. The longest response time was more than 48 weeks. Meanwhile, 25 of 31 pts remained on treatment and responses were ongoing. Plasma exposure of HS-10365 increased proportionally following single dose and multiple doses. The mean plasma half-life of HS-10365 was 5~9 hours. Conclusions: HS-10365 showed a manageable safety profile and favorable PK properties. The promising antitumor activity with expectable response time was observed in RET fusion+ NSCLC pts, no matter with or without previous treatments. Citation Format: Shun Lu, Qiming Wang, Lin Wu, Ligang Xing, Yintao Li, Liang Han, Xiaorong Dong, Hongying Wei, Wen Xu, Chuan Li, Liuqing Yang, Qiong Wu. HS-10365, a highly potent and selective RET tyrosine kinase inhibitor, demonstrates robust activity in RET fusion positive NSCLC patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT201.

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Zhang, Qingyuan, Jingxuan Wang, Quchang Ouyang, Xiaojia Wang, Jingfen Wang, Lu Gan, Daren Lin, et al. "Abstract PO1-29-02: Two and a half years follow-up data of HER2-targeted bispecific antibody KN026 combined with docetaxel as first-line treatment for HER2-positive recurrent/metastatic breast cancer." Cancer Research 84, no. 9_Supplement (May 2, 2024): PO1–29–02—PO1–29–02. http://dx.doi.org/10.1158/1538-7445.sabcs23-po1-29-02.

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Abstract Background: KN026 is a novel bispecific HER2-targeted antibody. Fully humanized, IgG1-like antibody binds to two distinct HER2 epitopes, the same domains as trastuzumab and pertuzumab. Preliminary safety and efficacy results (data as of Aug 18, 2022) were presented at SABCs 2022(PD18-08), showed promising efficacy and tolerability. Herein, we update the 2.5-year follow-up results. Methods: Eligible subjects with recurrent/metastatic breast cancer, HER-2 positive and treatment-naive were enrolled. Subjects received KN026 30 mg/kg combined with docetaxel 75 mg/m2 Q3W until disease progression, unacceptable toxicity, or other reasons. The primary endpoints were ORR and DoR. The secondary endpoints included safety, PFS and OS. Results: As of data cut-off date (Sep 15, 2023), 57 subjects were enrolled, the median age was 52 years (min:30, max:67), 100% were female, and 91.2 % (52/57) were stage IV. There were 34 and 23 subjects with and without visceral metastasis, respectively. 48 subjects with high HER2 expression (IHC 3+), and the other 9 subjects with HER2 expression 2+ or 1+. The confirmed ORR within 55 evaluable subjects was 76.4% (42/55). The DoR was not reached yet with a median follow-up of 27.0 mons (95% CI: 26.28, 28.98). The median study follow-up was 30.6 mons (95% CI: 29.11, 31.77). The mPFS was 27.7 mons (95% CI:17.97, NE) and the mOS was not reached. The OS rates at 12m, 24m and 30m were 93.0% (95% CI: 82.37, 97.31), 84.2% (95% CI: 71.85, 91.45) and 78.5% (95% CI: 65.25, 87.21). The mPFS of subjects with or without visceral metastasis were 23.6 mons and not reached. The mPFS of subjects with or without brain metastasis were 13.7 mons and 28.1 mons, respectively. The mPFS of 48 subjects with high HER2 expression (3+) was 28.1 months. The incidence of KN026-related Grade≥3 TRAE was 43.9% (25/57), including neutrophil count decreased 24.6% (14/57), white blood cell count decreased 12.3% (7/57), hypokalaemia 7.0% (4/57), diarrhoea 3.5% (2/57) and others less than 2%. The incidence of serious adverse events related to KN026 was 12.3% (7/57). There was no KN026 -related death. Conclusions: KN026 in combination with docetaxel is well tolerated and has shown promising clinical benefit as 1L treatment for HER2-positive BC. After 2.5 years follow-up, mPFS was 27.7 mons and the 24-months OS rate was 84.2%, which is very promising. No new safety signals were observed. Robustness of efficacy and safety results will be further confirmed in an ongoing randomized phase 3 clinical trial with PTH as control. Citation Format: Qingyuan Zhang, Jingxuan Wang, Quchang Ouyang, Xiaojia Wang, Jingfen Wang, Lu Gan, Daren Lin, Zhong Ouyang, Ting Xu, Yilan Liu, Yuan Lv. Two and a half years follow-up data of HER2-targeted bispecific antibody KN026 combined with docetaxel as first-line treatment for HER2-positive recurrent/metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-29-02.

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Mitsuhashi, Toshiyuki, Sachiko Ogasawara, Masamichi Nakayama, Reiichiro Kondo, Jun Akiba, Kenta Murotani, Takeharu Ono, Fumihiko Sato, Hirohito Umeno, and Hirohisa Yano. "Abstract 6273: GGCT expression is a useful marker for the diagnosis of follicular thyroid carcinoma." Cancer Research 84, no. 6_Supplement (March 22, 2024): 6273. http://dx.doi.org/10.1158/1538-7445.am2024-6273.

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Abstract Background: Follicular thyroid carcinoma (FTC) and follicular adenoma (FA) have similar histological findings. FTC is distinct from FA based on the presence of capsular or vascular invasion in the tissues, but it is difficult to confirm the diagnosis in some cases. In this study, we aimed to establish useful molecular maker for differential diagnosis between FTC and FA. Methods: This study included FTC (n = 32), FA (n = 64), and follicular tumors of uncertain malignant potential (FT-UMP, n = 5). Invasive front tissue and tumor center tissue from 3 cases of FTC were collected using a laser microdissection system; RNA was extracted, followed by microarray analysis to examine molecules that were commonly highly expressed in the invasive front. Subsequently, immunohistochemical staining of gamma-glutamyl cyclotransferase (GGCT) was performed. For assessment of GGCT expression, the intensity of the nuclear staining was stratified using a four-tiered scale (0 to 3) and percentage of positive cells (0-100%) in the hotspot. Multiplying intensity score and percent of positive cells, an expression score ranging from 0 to 300 was calculated. The Ki-67 labeling index was examined in 20 cases of FTC, 25 cases of FA, and 4 cases of FT-UMP from the same cohort. We counted at least 2,000 tumor cells in the hot spot for the assessment of Ki-67 labeling index. Results: Microarray analysis revealed GGCT exhibited high expression levels at the invasive front of FTC. In immunohistochemical assessment, GGCT expression scores were significantly higher in FTC than in FA (118.5 ± 51.4 vs. 57.3 ± 34.7, p < 0.0001). The median Ki-67 labeling index were 3.9% (range 0.2 - 16.1) for FTC and 2.4% (range 0.3 - 7.0) for FA. FTC showed a higher Ki-67 index than FA (Wilcoxon rank sum test, p = 0.0444). With GGCT expression score, applying a cutoff value of 101.1, the distinction between FTC and FA resulted in a sensitivity of 68.8% and a specificity of 87.5% (AUC: 0.832). With Ki-67 labeling index, applying a cutoff value of 4.0%, the distinction between FTC and FA resulted in a sensitivity of 50.0% and a specificity of 80.0% (AUC: 0.677). The GGCT expression score was positively related with the Ki-67 labeling index in the FTC cases. (Spearman's ρ = 0.5293, p = 0.0164). There were no significant associations between GGCT expression scores and clinicopathological parameters, including age, gender, tumor diameter, pT stage, pN stage, pattern of capsular invasion, number of foci of vascular invasion, and the presence of distant metastasis. Conclusions: GGCT is a potential marker for differentiating FTC from FA. The GGCT expression of FTC may contribute to estimating the invasive activity and proliferative activity. Citation Format: Toshiyuki Mitsuhashi, Sachiko Ogasawara, Masamichi Nakayama, Reiichiro Kondo, Jun Akiba, Kenta Murotani, Takeharu Ono, Fumihiko Sato, Hirohito Umeno, Hirohisa Yano. GGCT expression is a useful marker for the diagnosis of follicular thyroid carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6273.

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Cristofanilli, Massimo, Namita Chittoria, Sima Ehsani, Hallgeir Rui, Milana Dolezal, Lisette Stork-Sloots, Femke de Snoo, Christopher Recknor, and Vandana Abramson. "Abstract P5-17-08: A phase Ib/II study of leronlimab combined with carboplatin in patients with CCR5+ metastatic triple-negative breast cancer (mTNBC)." Cancer Research 82, no. 4_Supplement (February 15, 2022): P5–17–08—P5–17–08. http://dx.doi.org/10.1158/1538-7445.sabcs21-p5-17-08.

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Abstract Background C-C Chemokine Ligand type-5 (CCR5) is overexpressed in >95% of TNBC and has been correlated with disease progression. Moreover, enhancement of DNA repair signaling by CCR5 activation may contribute to chemotherapy resistance. Therefore, blocking CCR5 may result in increased immune response against tumor cells and synergize with chemotherapy. Leronlimab (PRO 140) is a humanized monoclonal antibody to CCR5. Preclinical data showed leronlimab binds human CCR5, blocks CCR5-mediated signaling, and CCL5-induced breast cancer cell invasion. The therapeutic antibody leronlimab has been administered to over 800 healthy and HIV-1 infected individuals with good tolerance and without obvious dose-related toxicity, making it an ideal partner for chemotherapy combinations in TNBC. Methods In this ongoing phase 1B/2 study, patients with CCR5+ mTNBC with ≤2 line of therapy in the metastatic setting (no prior carboplatin) are treated with weekly subcutaneous leronlimab (3 dose levels, 3+3 dose escalation) and a fixed dose of carboplatin AUC 5 on day 1 with a 21-day dose-limiting toxicity (DLT) window, followed by expansion in 30 patients with CCR5+ mTNBC who are naïve to chemotherapy in the metastatic setting or who have failed first-line combination of chemotherapy (excluding carboplatin) and a checkpoint inhibitor in the metastatic setting. CCR5 positivity is centrally assessed by IHC and defined as >10% CCR5 staining in primary or metastatic tumor cells and/or high predominance of CCR5+ tumor-infiltrating leukocytes (TIL). Primary objectives are safety, tolerability, determination of maximum tolerated dose, and determination of the recommended phase 2 dose (RP2D). Results Fifteen patients had archived tumor tissue assessed for CCR5 expression, with 12 being CCR5 positive (median expression 20%, range 0 - 100%, and 7 out of 12 high CCR5+ TILs) . A total of ten patients (median age 51 years; median 2 prior therapies) have been enrolled at 3 dose levels (350, 525, and 700 mg). In the second cohort, 1 additional patient was inadvertently enrolled. All patients completed the DLT assessment period and no DLTs have been observed. Patients received between 3 and 27 doses of leronlimab with the number of cycles ranging from 1 to 9. Five patients remain on treatment. The most common treatment-emergent adverse events (TEAEs) by any grade were: fatigue (6/10), headache (4/10), constipation (3/10), and nausea (3/10). The following grade ≥3 TEAEs were reported: neutropenia, anemia, thrombocytopenia, hyponatremia, hypertension, diarrhea and headache. Serious Adverse Events were reported in 2 patients (grade 2 sepsis and grade 3 headache). The following leronlimab treatment related adverse events (TRAEs) occurred (all grade 1): injection site reaction in cohort 1, fatigue (n=2) and headache in cohort 2. Three carboplatin TRAEs ≥3 were reported in one patient in cohort 1: thrombocytopenia, anemia and leukopenia. Two out of seven patients eligible for response achieved a confirmed partial response, and 4 patients stable disease. Conclusions Leronlimab, in combination with carboplatin, has been well-tolerated in all 3 dose levels with early signs of anti-tumor activity in patients with CCR5+ mTNBC. The study is currently enrolling patients at the RP2D dose of leronlimab 700mg in combination with carboplatin AUC 5 in the phase 2 part of the trial. Clinical trial information: NCT03838367 Citation Format: Massimo Cristofanilli, Namita Chittoria, Sima Ehsani, Hallgeir Rui, Milana Dolezal, Lisette Stork-Sloots, Femke de Snoo, Christopher Recknor, Vandana Abramson. A phase Ib/II study of leronlimab combined with carboplatin in patients with CCR5+ metastatic triple-negative breast cancer (mTNBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-17-08.

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Schott, Anne F., Sara Hurvitz, Cynthia Ma, Erika Hamilton, Rita Nanda, George Zahrah, Natasha Hunter, et al. "Abstract GS3-03: GS3-03 ARV-471, a PROTAC® estrogen receptor (ER) degrader in advanced ER-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer: phase 2 expansion (VERITAC) of a phase 1/2 study." Cancer Research 83, no. 5_Supplement (March 1, 2023): GS3–03—GS3–03. http://dx.doi.org/10.1158/1538-7445.sabcs22-gs3-03.

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Abstract Background: ARV-471 is a selective, orally administered PROteolysis TArgeting Chimera (PROTAC®) protein degrader that targets wild-type and mutant ER. ARV-471 is being evaluated in patients with ER+/HER2- locally advanced or metastatic breast cancer in a first-in-human phase 1/2 study (NCT04072952). In the phase 1 dose escalation, ARV-471 monotherapy (dose range: 30–700 mg total daily dose) showed a manageable safety profile in patients who had previously received endocrine therapy and a cyclin-dependent kinase (CDK) 4/6 inhibitor. The clinical benefit rate (CBR; rate of confirmed complete or partial response or stable disease ≥24 weeks) was 40% (95% CI: 26–56) in 47 evaluable patients. The phase 2 expansion portion of the study (VERITAC) evaluated 2 doses of ARV-471.Methods: In VERITAC, ARV-471 monotherapy was administered at doses of 200 mg once daily (QD) or 500 mg QD to patients with ER+/HER2- locally advanced/metastatic breast cancer who had received ≥1 prior endocrine therapy for ≥6 months, ≥1 CDK4/6 inhibitor, and ≤1 chemotherapy regimen. The primary endpoint of CBR was evaluated in patients enrolled ≥24 weeks prior to the data cutoff. Results: As of June 6, 2022, 71 patients received ARV-471 (200 mg QD [n=35]; 500 mg QD [n=36]) in VERITAC. Across all treated patients, 69 (97.2%) were female and median age was 60 y (range: 41–86). Patients had received a median of 4 prior regimens in all settings (range: 1–10); 100% had prior CDK4/6 inhibitors, 78.9% had prior fulvestrant, and 73.2% had prior chemotherapy. ARV-471 was well tolerated at both doses, with most treatment-related adverse events (TRAEs) grade 1/2; the most common TRAEs were fatigue and nausea (Table). In all, 3 patients (1 in the 200 mg QD cohort and 2 in the 500 mg QD cohort) discontinued ARV-471 due to treatment-emergent adverse events (TEAEs); 3 patients had ARV-471 dose reductions due to TEAEs (all from 500 mg QD to 400 mg QD). CBR was 37.1% (95% CI: 21–55) in 35 evaluable patients treated at 200 mg QD and 38.9% (95% CI: 23–57) in 36 evaluable patients treated at 500 mg QD. CBR in evaluable patients with mutant ESR1 in the 200 mg QD (n=19) and 500 mg QD (n=22) cohorts was 47.4% (95% CI: 24–71) and 54.5% (95% CI: 32–76), respectively. Conclusions: In the phase 2 VERITAC expansion cohorts of patients with ER+/HER2- locally advanced/metastatic breast cancer and prior CDK4/6 inhibitor treatment, ARV-471 monotherapy showed evidence of clinical activity based on CBR, which was further enhanced in the subgroup with ESR1 mutations. The manageable AE profile observed in the phase 1 portion of the study was maintained during cohort expansion at doses of 200 mg QD and 500 mg QD. Additional analyses are ongoing.Table. TRAEs reported in ≥10% of patients overall aNo grade 3/4 TRAE occurred in >1 patient. AST=aspartate aminotransferase Citation Format: Anne F. Schott, Sara Hurvitz, Cynthia Ma, Erika Hamilton, Rita Nanda, George Zahrah, Natasha Hunter, Antoinette R. Tan, Melinda Telli, Jesus Anampa Mesias, Rinath Jeselsohn, Pamela Munster, Haolan Lu, Richard Gedrich, Cecile Mather, Janaki Parameswaran, Hyo S. Han. GS3-03 ARV-471, a PROTAC® estrogen receptor (ER) degrader in advanced ER-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer: phase 2 expansion (VERITAC) of a phase 1/2 study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS3-03.

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Dempster, Marcus, Matthew Wright, Daniela Cocco, Ayat Elsherif, Stephanie A. Valente, Hong Li, and Megan L. Kruse. "Abstract P1-08-13: Comparison of gene expression profiling results and clinical outcomes among patients with pleomorphic ILC and classic ILC." Cancer Research 82, no. 4_Supplement (February 15, 2022): P1–08–13—P1–08–13. http://dx.doi.org/10.1158/1538-7445.sabcs21-p1-08-13.

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Abstract Background Invasive lobular carcinoma (ILC) is the second most common histological subtype of breast cancer. Pleomorphic ILC (pILC) is a pathologically defined subtype of ILC that often presents at a higher stage compared to Classical ILC (cILC). pILC is traditionally thought to have poor outcomes compared with cILC. Utility and application of gene expression profiling, such as Oncotype Dx testing, for these patients is unknown. The purpose of this study is to compare Oncotype Dx recurrence scores, treatment patterns, and clinical outcomes for patients with cILC and pILC at our institution. Methods A retrospective analysis of a large institutional cancer database was performed to identify patients with ILC treated between 2004 and 2017. Patient and disease characteristics were collected, including subtype of ILC (classical vs pleomorphic), staging, treatment history, and presence of Oncotype Dx testing. Findings were analyzed for differences in clinical characteristics, Oncotype Dx results, progression free survival (PFS) and overall survival (OS) between patients who received endocrine therapy/chemotherapy (CET) versus endocrine therapy alone (ET) in both cILC and pILC groups. Results: 692 patients with ILC were identified with 100 (14.5%) categorized as pILC. The mean age at presentation was 62 for cILC and 60 for pILC. cILC was more frequently ER positive (98.5% vs. 94.0%, p=0.004). and less likely HER2 positive (7.0% vs 12.2%, p=0.07). pILC more commonly had more advanced tumor stage (Stages II-III 61% vs 41%, p<0.001) but lower nodal stage (N+ 48.5% vs 66%, p<0.001) 25% (25/100) of pILC patients had Oncotype Dx testing performed compared to 33% (198/592) of cILC patients. The majority of patients who had testing had T1cN0 or T2N0 disease (36% and 44% for pILC vs 34%, and 27% for cILC, respectively). A low risk recurrence score (0-10) accounted for 8% (2/25) of pILC cases and 18.2% (36/198) of cILC. Intermediate risk (11-25) accounted for 72% (18/25) of pILC and 73.2% (145/198) of cILC. High risk (26+) accounted for 20% (5/25) of pILC and 8.6% (17/198) of cILC. There was no statistically significant difference in Oncotype Dx recurrence score distribution between pILC and cILC (p=0.117). More patients with pILC received CET compared to cILC (62.0% vs 36.7%, p<0.001). Among pILC cases, 62% received CET and 34% received ET. There was no significant difference in RFS or OS between CET and ET among pILC cases (10-year RFS 74.7% (ET) vs. 76.6% (CET), p=0.52. 10-year OS 92.6% (ET) vs 78.0% (CET), p=0.40). Conclusions At our institution, patients with cILC more often had Oncotype Dx testing compared to those with pILC. Some of the difference may be related to more frequent HER2-positivity in pILC. When testing was done, pILC was twice as likely to have a high risk recurrence score compared to cILC, but this result was not statistically significant. Patients with pILC were more likely to receive CET than patients with cILC. There was no difference in survival between patients with pILC treated with CET versus those treated with ET alone although the sample size is small and this is worthy of further study in a larger population. These results suggest that gene expression testing may be underutilized in pILC. Citation Format: Marcus Dempster, Matthew Wright, Daniela Cocco, Ayat Elsherif, Stephanie A Valente, Hong Li, Megan L Kruse. Comparison of gene expression profiling results and clinical outcomes among patients with pleomorphic ILC and classic ILC [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-08-13.

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Tsoulos, Nikolaos, Konstantinos Agiannitopoulos, Georgia Pepe, Eirini Papadopoulou, Georgios N. Tsaousis, Despina Apostolopoulou, Angeliki Meintani, et al. "Abstract P2-09-10: Different CNVs account for 10.4% of pathogenic variants in 1418 patients referred for hereditary breast cancer testing." Cancer Research 82, no. 4_Supplement (February 15, 2022): P2–09–10—P2–09–10. http://dx.doi.org/10.1158/1538-7445.sabcs21-p2-09-10.

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Abstract Background: Breast cancer is the most frequently diagnosed cancer in women and about 10% of breast cancer cases are hereditary. BRCA1 and BRCA2 are the genes most frequently associated with Hereditary Breast Cancer, although there are numerous other genes, such as PALB2, CHEK2 and ATM, that require to be considered as well. Germline Copy Number Variation (CNV) is one mutation type that is an important contributor to hereditary breast cancer. Nowadays, next-generation sequencing (NGS) technologies has contributed to multi-gene panel analysis used in clinical practice. Methods: In total, 1418 individuals were tested for breast cancer predisposition, using a solution-based capture approach. Targeted NGS was performed with a panel of 36 genes. The capture-based approach allowed for computational analysis of CNVs from NGS data. Results: We investigate the performance of the CNV module of the commercial software suite SeqPilot (JSI Medical Systems) and the non-commercial tool panelcn.MOPS. Both algorithms are specifically developed for CNV analysis of sequencing data reporting 99-100% sensitivity and up to 100% specificity for the prediction of CNVs up to the level of a single gene exon. All CNVs detected with these algorithms were then verified experimentally using the MLPA technique as an orthogonal assay. At least one pathogenic/likely pathogenic variant was identified in 289 samples (20.4%). CNVs accounted for 10.4% (30/289), referring to the deletion of one or more exons of a gene. Interestingly, 50% of deletions were single exon and approximately 36% of CNVs were detected in genes other than BRCA1/2. In specific, of the 30 CNVs detected, 60% occurred in BRCA1, 3.3% in BRCA2, 20% in CHEK2, 6.7% in FANCA, 6.7% in PMS2, and 3.3% in ATM. The majority of CNVs in BRCA1 were deletions of exons 19, 22, and 22-23 whereas deletions of exons 9-10 were the most common deletions in CHEK2. Detailed information of all CNVs detected is provided in Table 1. Conclusions: Our results suggest that CNV analysis should not be restricted to BRCA1/2 due to the significant proportion of CNVs (36%) in additional breast cancer predisposition genes. Furthermore, in silico CNV detection tools provide a cost-effective and feasible methodology for the identification of CNVs from NGS experiments. This outlines the clinical utility of comprehensive genetic testing that includes full sequencing and CNV analysis in hereditary breast cancer facilitating personalized management decisions for patients. Table 1.Pathogenic Copy Number Variations (CNVs) identified in this studyGeneHGVS nomenclatureOther nomenclature# detectedATMNM_000051:c.(-30+1_-29-1)_(331+1_332-1)deldeletion of exons 2-41BRCA1NM_007294:c.(5467+1_5468-1)-(*1_?)deldeletion of exon 237BRCA1NM_007294:c.(5406+1_5407-1)_(*1_?)deldeletion of exons 23-245BRCA1NM_007294:c.(5193+1_5194-1)-(5277+1_5278-1)deldeletion of exon 196BRCA2NM_000059:c.(6841+1_6842-1)_(7007+1_7008-1)deldeletion of exons 12-131CHEK2NM_007194:c.(908+1_909-1)_(1095+1_1096-1)deldeletion of exons 9-104CHEK2NM_007194:c.(792+1_793-1)_(846+1_847-1)deletion of exon 72FANCANM_000135:c.(1626+1_1627-1)_ (2852+1_2853-1)deldeletion of exons 18-291FANCANM_000135:c.(893+1_894-1)_(1359+1_1360-1)deldeletion of exons 11-141PMS2NM_000535: c.(903+1_904-1)_(988+1_989-1)deldeletion of exon 91PMS2NM_000535:c.(705+1_706-1)_(2006+1_2007-1)deldeletion of exons 7-111 Citation Format: Nikolaos Tsoulos, Konstantinos Agiannitopoulos, Georgia Pepe, Eirini Papadopoulou, Georgios N Tsaousis, Despina Apostolopoulou, Angeliki Meintani, Vassileios Venizelos, Christos Markopoulos, Rodoniki Iosifidou, Sofia Karageorgopoulou, Christos Christodoulou, Ioannis Natsiopoulos, Konstantinos Papazisis, Maria Vasilaki-Antonatou, Eleftherios Kabletsas, Amanta Psyrri, Stylianos Giassas, Dimitrios Ziogas, Efthalia Lalla, Anna Koumarianou, Christos Papadimitriou, Vahit Ozmen, Sualp Tansan, Kerim Kaban, Tahsin Ozatlı, Dan Tudor Eniu, Angelica Chiorean, Alexandru Blidaru, George Nasioulas. Different CNVs account for 10.4% of pathogenic variants in 1418 patients referred for hereditary breast cancer testing [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-09-10.

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Aggarwal, Rahul, Antoine Italiano, Susan Domchek, Oscar Goodman, Sophie Postel-Vinay, Jesus Garcia-Donas, Tanya Dorff, et al. "Abstract CT222: Efficacy and safety of ceralasertib in the PLANETTE study in patients (pts) with ATM-altered advanced solid tumors (ASTs) or metastatic castration-resistant prostate cancer (mCRPC)." Cancer Research 84, no. 7_Supplement (April 5, 2024): CT222. http://dx.doi.org/10.1158/1538-7445.am2024-ct222.

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Abstract Background: Ceralasertib, a potent, selective ATR inhibitor, is synthetically lethal in ATM-deficient preclinical models. This Phase 2a study (NCT04564027) assessed ceralasertib monotherapy in previously treated pts with ATM-altered tumors. Methods: Adult pts had ASTs excluding NSCLC (Cohort [Co] A; data cutoff [DCO] Dec 21 2022) or mCRPC (Co B; DCO Apr 28 2023) and germline/somatic ATM pathogenic/likely pathogenic variants (PVs) by local assessment. ATM alterations were centrally confirmed by FMI F1CDx in tumor and/or FMI F1 liquid CDx in circulating tumor DNA, and/or by ATM protein deficiency by immunohistochemistry (cutoff ≤5%). Primary endpoints were objective response rate (ORR) in Co A and composite response rate (CRR) in Co B. Safety was a secondary endpoint. Results: The initial starting dose of 240 mg BID PO ceralasertib on Days 1-14 of a 28-day cycle was reduced to 160 mg BID due to hematologic toxicity. Results are reported for 30 pts in Co A and 15 pts in Co B with a starting dose of 160 mg BID. In Co A, the 28 pts with centrally confirmed ATM alterations (93.3% [28/30] with ATM PV and 36.7% [11/30] ATM-deficient) had an ORR of 7.1% (80% CI: 1.9, 17.9): 1 complete response in breast cancer (ongoing at 12 mos) and 1 partial response in endometrial cancer (ongoing at 9 mos), both ATM-deficient. In Co B, the 13 pts with centrally confirmed ATM alterations (73.3% [11/15] with ATM PV and 46.7% [7/15] ATM-deficient) had a CRR of 7.7% (80% CI: 0.8, 26.8): 1 pt with conversion of circulating tumor cell count from unfavorable to favorable (ongoing at 3 mos) with unknown ATM expression. The safety profile was manageable (Table). Steady-state ceralasertib plasma concentrations exceeded the IC90 for ~23 hrs/day. Conclusion: Responses to ceralasertib monotherapy were limited in ATM-altered tumors, despite reaching target plasma levels. Alternative pt selection and combination treatment strategies are being explored. TABLE 1: NAND Efficacy, safety of ceralasertib 160 mg BID on D1-14 of D28 cycle in pts with ATM-altered ASTs/mCRPC Cohort A: ASTs Cohort B: mCRPC Efficacy Response rate in pts with centrally confirmed ATM alterations, % (80% CI)* N=28 7.1 (1.9, 17.9)† N=13 7.7 (0.8, 26.8)‡ Response rate in pts with centrally confirmed ATM PVs, % (80% CI) N=28 7.1 (1.9, 17.9) N=11 9.1 (1.0, 31.0) Response rate in pts with centrally confirmed ATM-deficiency, % (80% CI) N=11 18.2 (4.9, 41.5) N=7 0.0 (0.0, 28.0) Safety, n (%) N=30 N=15 TEAEs 30 (100) 15 (100) Grade ≥3 TEAEs 15 (50.0) 8 (53.3) TRAEs 21 (70.0) 13 (86.7) Grade ≥3 TRAEs 6 (20.0) 5 (33.3) Serious TEAEs 4 (13.3) 4 (26.7) Serious TRAEs 2 (6.7) 1 (6.7) TEAEs leading to discontinuation 1 (3.3)§ 0 TEAEs leading to death 0 0 TEAEs (any grade) occurring in ≥20% of pts in either cohort, n (%) N=30 N=15 Nausea 13 (43.3) 8 (53.3) Abdominal pain 9 (30.0) 1 (6.7) Anemia 8 (26.7) 7 (46.7) Fatigue 8 (26.7) 5 (33.3) Asthenia 8 (26.7) 2 (13.3) Decreased appetite 7 (23.3) 3 (20.0) *Centrally confirmed ATM-altered patients were patients with either ATM PV confirmed by FMI F1CDx in tumor and/or by FMI F1 liquid CDx in circulating tumor DNA and/or ATM protein-deficient by immunohistochemistry assay at Ventana with cut-off ≤5%. Thus, ATM PV patients could also have ATM protein-deficiency. †Objective response by RECIST v1.1, in centrally confirmed ATM-altered patients. ‡Composite response: by RECIST v1.1 for soft tissue and visceral lesions and PCWG3 criteria for bone lesions; confirmed conversion of circulating tumor cell count from ≥5/7.5 mL blood to <5/7.5 mL; or confirmed prostate-specific antigen decline of >50%, in centrally confirmed ATM-altered patients. §Discontinuation due to decreased appetite classified as a serious adverse event. ASTs, advanced solid tumors; CI, confidence interval; mCRPC, metastatic castration-resistant prostate cancer; PV, pathogenic variant; pts, patients; TEAE, treatment-emergent adverse event; TRAE, treatment-related adverse event Citation Format: Rahul Aggarwal, Antoine Italiano, Susan Domchek, Oscar Goodman, Sophie Postel-Vinay, Jesus Garcia-Donas, Tanya Dorff, Zachery Reichert, Philippe Cassier, Neal Shore, Catherine Marshall, Graeme Parr, Itziar Irurzun-Arana, Neel Shah, Natalia Lukashchuk, Olga Murina, Daniel Slade, Bienvenu Loembé, Emma Dean, Elhan Sanai, Wassim Abida. Efficacy and safety of ceralasertib in the PLANETTE study in patients (pts) with ATM-altered advanced solid tumors (ASTs) or metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT222.

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Han, Baohui, Kai Li, Qiming Wang, Ying Cheng, Lei Yang, and Yueming Li. "Abstract CT200: Updated PFS & OS from the phase Ib study of TQB2450 alone/with Anlotinib in previously treated advanced non-small cell lung cancer." Cancer Research 83, no. 8_Supplement (April 14, 2023): CT200. http://dx.doi.org/10.1158/1538-7445.am2023-ct200.

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Abstract Background: At the interim analysis (data cutoff Oct 14, 2021) of this study (NCT03910127), TQB2450 plus anlotinb group significantly improved mPFS versus TQB2450 alone in chemotherapy treated patients with advanced NSCLC without driver gene alterations (6.9 months vs 2.7 months). We report an updated PFS, OS and safety results for this study. Method: This is a multicenter, randomized, double-blind, phase Ib study. Adult patients with histologically or cytologically-confirmed stage IIIB or IV NSCLC who had wild-type EGFR/ALK and at least one line of prior systemic therapy or being intolerable of chemotherapy were randomized 1:1:1 to receive TQB2450 1200 mg plus placebo, or anlotinib 10 or 12 mg. The primary end point was PFS and secondary endpoints included safety and OS. Results: Between July. 2019 and March. 2021, 101 pts were enrolled. 33 patients were randomly assigned to TQB2450 plus placebo and 68 patients to TQB2450 plus anlotinib. As of 19 September 2022, The median follow-up was 26.3 months. The median PFS (7.3 months, 95% CI 5.3-11.0) for TQB2450 plus anlotinib was significantly longer than that for TQB2450 plus placebo group (2.8 months, 95% CI 1.4-4.7) (HR 0.39, 95% CI 0.23-0.64; P=0.0001) (Table). In patients with PD-L1 ≥ 1%, the mPFS was 17.9 months (95% CI 5.8-31.1) in TQB2450 plus anlotinib 12 mg, which was numerically higher than that in TQB2450 plus anlotinib 10 mg. The median OS of patients with PD-L1 ≥ 1% for TQB2450 plus anlotinib 12 mg was numerically higher than that in TQB2450 plus anlotinib 10 mg (32.2 months vs 21.8 months). Grade 3 or higher TRAEs occurred in 50.0% of the patients in TQB2450 plus anlotinb and in 12.1% of those in TQB2450 plus placebo. Conclusions: In this updated analysis with longer follow-up, TQB2450 combined with anlotinib continues to demonstrate overall efficacy and manageable safety profiles in chemotherapy treated patients with advanced NSCLC without driver gene mutations. TQB2450 TQB2450+Anlotinib 10mg TQB2450+Anlotinib 12mg TQB2450+Anlotinib mPFS n 33 34 34 68 Censor, n (%) 7 (21.2) 9 (26.5) 8 (23.5) 17 (25.0) Median (95%CI) 2.8 (1.4-4.7) 7.0 (4.5-14.5) 8.7 (4.1-11.4) 7.3 (5.3-11.0) HR (95%CI) 0.37 (0.21-0.66) 0.40 (0.22-0.70) 0.39 (0.23-0.64) P value 0.0006 0.0001 mPFS (PD-L1≥1%) n 19 19 19 38 Censor, n (%) 3 (15.8) 6 (31.6) 7 (36.8) 13 (34.2) Median (95%CI) 2.1 (1.3-7.2) 7.0 (2.1-19.4) 17.9 (5.8-31.1) 8.6 (5.3-22.8) HR (95%CI) 0.35 (0.16-0.77) 0.29 (0.13-0.64) 0.32 (0.16-0.63) P value 0.0023 0.0006 mOS n 33 34 34 68 Censor, n (%) 12 (36.4) 14 (41.2) 12 (35.3) 26 (38.2) Median (95%CI) 15.3 (6.6-20.5) 20.6 (8.6-25.8) 14.7 (10.0-32.2) 17.9 (10.5-23.2) HR (95%CI) 0.78 (0.42-1.44) 0.84 (0.46-1.53) 0.81 (0.48-1.37) P value 0.7157 0.4329 mOS (PD-L1≥1%) n 19 19 19 38 Censor, n (%) 5 (26.3) 7 (36.8) 8 (42.1) 15 (39.5) Median (95%CI) 15.7 (7.8-21.0) 21.8 (7.1-NR) 32.2 (14.2-33.6) 21.8 (14.2-33.6) HR (95%CI) 0.72 (0.33-1.58) 0.63 (0.28-1.40) 0.67 (0.34-1.32) P value 0.4900 0.2479 Citation Format: Baohui Han, Kai Li, Qiming Wang, Ying Cheng, Lei Yang, Yueming Li. Updated PFS & OS from the phase Ib study of TQB2450 alone/with Anlotinib in previously treated advanced non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT200.

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Fan, Zhengfu, Jin Wang, Meiyu Fang, Johnston Patrick, Tun Han, David Sommerhalder, Jifang Gong, et al. "Abstract CT105: Preliminary results from the Phase I part of a first-in-human Phase I/II study of HH2853, an EZH1/2 inhibitor, in patients with relapsed/refractory non-Hodgkin lymphomas or advanced solid tumors." Cancer Research 83, no. 8_Supplement (April 14, 2023): CT105. http://dx.doi.org/10.1158/1538-7445.am2023-ct105.

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Abstract Background: The dysregulation of polycomb repressive complex 2 (PRC2) promotes tumorigenesis and progression. Two therapeutic agents targeting enhancer of zeste homolog (EZH) 2 or EZH1/2, the catalytic subunits of PRC2, have been approved in several cancer types. HH2853 is a novel selective EZH1/2 dual inhibitor, which has demonstrated superior anti-tumor efficacy to tazemetostat (EZH2 inhibitor approved by FDA) in various preclinical models. Methods: This is a first-in-human, open-label, multi-center, phase (Ph) I/II study of HH2853 in patients (pts) with relapsed/refractory (r/r) non-Hodgkin lymphomas (NHLs) or advanced solid tumors. HH2853 was administered orally twice daily (BID) on a continuous 28-day treatment cycle. Ph I consist of two parts: dose escalation part adopting accelerated titration followed by a Bayesian optimal interval design and dose extension part. Dose limiting toxicity (DLT) was evaluated during the 1st cycle in dose escalation. Safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary anti-tumor activity of HH2853 were explored in this Ph I study. Results: As of Oct 19, 2022, a total of 57 pts, including 50 pts with solid tumors and 7 pts with r/r follicular lymphoma (FL), were enrolled from 12 sites in China and the US. Twenty-five (43.9%) pts received ≥3 lines of prior systemic therapies. Six dose levels(50 mg, 100 mg, 200 mg, 400 mg, 600 mg and 800 mg)were evaluated. DLTs were observed in 2 of 8 DLT evaluable pts at 800 mg: one grade 3 platelet count decreased and one grade 3 diarrhea. A conclusive maximal tolerated dose was not reached. The most common treatment-related adverse events (TRAE) were diarrhea (45.6%), blood bilirubin increased (35.1%), white blood cell count (WBC) decreased (26.3%), platelet count decreased (26.3%), rash (24.6%) and anemia (22.8%). The most common ≥grade 3 TRAEs included anemia (8.8%), platelet count decreased (7.0%), WBC decreased (5.3%) and diarrhea (5.3%). TRAEs leading to dose interruption or reduction were reported in 17.5% and 8.8% pts respectively. No TRAE led to dose discontinuation or death. PK data indicated dose-related increase in exposure from 50 to 600 mg. PD data showed a significant inhibition (maximum reached >90%) of H3K27me3 in granulocytes and monocytes at 400-800 mg. Tumor responses were observed in 7 pts from 200 to 800 mg in multiple tumor types, including complete response in 1 patient with FL, partial response in 3 pts with epithelioid sarcoma, 2 pts with FL and 1 patient with malignant rhabdoid tumor of pancreas. Conclusions: This first-in-human study of HH2853 showed a manageable safety profile and promising anti-tumor activity in multiple tumor types, supporting further exploration in NHLs and solid tumors after recommended Ph II dose is determined.Clinical trial information: NCT04390737 Citation Format: Zhengfu Fan, Jin Wang, Meiyu Fang, Johnston Patrick, Tun Han, David Sommerhalder, Jifang Gong, Jilong Yang, Yun Yang, Javier Munoz, Yuqin Song, Zhiming Li, Xian'an Li, Qiuying Ma, Jinming Han, Lin Shen, Jun Zhu. Preliminary results from the Phase I part of a first-in-human Phase I/II study of HH2853, an EZH1/2 inhibitor, in patients with relapsed/refractory non-Hodgkin lymphomas or advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT105.

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Harel, Michal, Petros Christopoulos, Igor Puzanov, Jair Bar, Iris Kamer, Niels Reinmuth, Ina Koch, et al. "Abstract 1208: Plasma proteomics-based models for predicting therapeutic benefit and immune-related adverse events in non-small cell lung cancer patients treated with immunotherapy." Cancer Research 84, no. 6_Supplement (March 22, 2024): 1208. http://dx.doi.org/10.1158/1538-7445.am2024-1208.

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Abstract Background: Immune checkpoint inhibitors (ICIs) have significantly improved outcomes for patients with metastatic non-small cell lung cancer (NSCLC). However, clinical management is challenging. The PD-L1 biomarker does not optimally guide the choice between ICI monotherapy and combination ICI-chemotherapy, and there are currently no biomarkers to predict immune-related adverse events (irAEs). Here, we describe a versatile platform based on plasma proteomics and machine learning for generating predictive tools to support treatment decisions. Methods: Pre-treatment plasma samples were collected from 616 NSCLC patients receiving ICI-based therapy (NCT04056247). Clinical benefit (CB) data and irAEs were recorded. Proteomic profiling of plasma samples was performed using the SomaScan® assay, covering ~7000 proteins per sample. Proteins associated with Clinical Benefit (progression-free survival at 12 months) were classified as resistance-associated proteins (RAPs). Proteins associated with grade ≥3 irAEs occurring within the first 100 days of treatment were classified as toxicity-associated proteins (TAPs). RAPs and TAPs were integrated into two separate machine learning-based models, yielding CB and irAE probabilities, respectively. The CB model used a CB probability threshold to assign patients a PROphet-positive or PROphet-negative result. Bioinformatic analysis was performed on RAPs and TAPs. Results: CB and irAE models displayed strong predictive performance with a high correlation between predicted probability and observed CB or irAE rate (CB model: R2=0.98; p-value<0.0001; irAE model: R2= 0.92; p-value <0.0001). In the CB model, patients classified as PROphet-positive achieved significantly longer overall survival (OS) than PROphet-negative patients, with a median OS of 25.9 vs. 10.8 months (hazard ratio, HR = 0.51; p-value<0.001). Furthermore, patients with PD-L1 ≥50% tumors and a PROphet-negative result had significantly longer OS with ICI-chemotherapy in comparison to ICI monotherapy (HR=0.23, p-value = 0.0003), suggesting that combination therapy is preferable for such patients despite high PD-L1 levels. Bioinformatic analysis showed that RAPs related to immune regulation, angiogenesis, chemo-resistance, and other potential resistance mechanisms displayed higher expression levels in patients who did not benefit from treatment. Neutrophil- and inflammation-related proteins were significantly enriched in patients who experienced irAEs. Conclusions: We describe two machine-learning based predictive tools that may be used separately or in combination to inform treatment decisions based on the patient’s likelihood to benefit from ICI therapy and to develop serious irAEs. Our findings also provide biological insights related to treatment resistance and immune-related toxicity. Citation Format: Michal Harel, Petros Christopoulos, Igor Puzanov, Jair Bar, Iris Kamer, Niels Reinmuth, Ina Koch, Mor Moskovitz, Adva Levy-Barda, Alona Zer, Michal Lotem, David Farrugia, Rivka Katzenelson, Gillian Price, Abed Agbarya, Helen Cheley, Adam Hassani, Mahmoud Abu-Amna, Tom Geldart, Anirban Chatterjee, Andreas Polychronis, Maya Gottfried, Yanyan Lou, Tatiana Harkovsky, Alison Brewster, Ido Wolf, Ella Tepper, Ben Yellin, Itamar Sela, Coren Lahav, Yehonatan Elon, Raya Leibowitz, Adam P. Dicker, Young Kwang Chae, Ryan J. Sullivan, David Carbone, David Gandara, Jarushka Naidoo. Plasma proteomics-based models for predicting therapeutic benefit and immune-related adverse events in non-small cell lung cancer patients treated with immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1208.

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