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Treilleux, Isabelle, and Blandine Morellon-Mialhe. "Le cancer du sein de phénotype basal." Annales de Pathologie 29, no. 3 (June 2009): 180–86. http://dx.doi.org/10.1016/j.annpat.2009.04.001.
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Garcia de la Fuente, I., F. Jolicoeur, A. Robidoux, I. Gorska, D. Balicki, and L. Gaboury. "Caractérisation du cancer du sein de phénotype basal." Annales de Pathologie 26, no. 1 (February 2006): 69–70. http://dx.doi.org/10.1016/s0242-6498(06)70671-x.
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Vincent-Salomon, A., G. Macgrogan, E. Charaffe-Jauffret, J. Jacquemier, and L. Arnould. "Identification en pratique clinique des carcinomes basal-like du sein : des carcinomes « triple zéro/BRCA1-like »." Bulletin du Cancer 97, no. 3 (March 2010): 357–63. http://dx.doi.org/10.1684/bdc.2010.1062.
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Leidy, Jennifer, Ashraf Khan, and Dina Kandil. "Basal-Like Breast Cancer: Update on Clinicopathologic, Immunohistochemical, and Molecular Features." Archives of Pathology & Laboratory Medicine 138, no. 1 (January 1, 2014): 37–43. http://dx.doi.org/10.5858/arpa.2012-0439-ra.
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Context.—Basal-like breast carcinoma (BLBC) is a distinct molecular subtype of breast carcinoma identified through gene expression profiling studies. Objective.—To provide the clinical background, the histologic profile, and the immunohistochemical profile of these tumors and discuss the current knowledge of their molecular signature and their implications on targeted molecular therapy. Data Sources.—Data were obtained from review of the pertinent peer-reviewed literature. Conclusions.—Basal-like breast carcinomas are aggressive tumors with poor prognosis. Lack of targeted therapy makes their treatment a challenging task. Traditional chemotherapy is still associated with a high risk of relapse and death in a high percentage of patients. Platinum-based chemotherapy has been considered as a candidate for the treatment of BLBCs owing to their BRCA1 phenotype. Approximately 22% of patients treated with single-agent cisplatin show pathologic complete response, which is a comparable rate to that seen with nonplatinum agents. Antiangiogenic agents have been promising, but their currently demonstrated limited response is considered disappointing. Additionally, epidermal growth factor receptor was not shown to be a helpful target for BLBC. A recent study has shown that BLBC appears to be especially sensitive to MEK inhibitors, making it a promising therapeutic possibility. The list of new targets is still evolving and the “magic” therapeutic target is yet to be discovered.
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Liu, Ming, Julia Y. S. Tsang, Michelle Lee, Yun-Bi Ni, Siu-Ki Chan, Sai-Yin Cheung, Jintao Hu, Hong Hu, and Gary M. K. Tse. "CD147 expression is associated with poor overall survival in chemotherapy treated triple-negative breast cancer." Journal of Clinical Pathology 71, no. 11 (August 11, 2018): 1007–14. http://dx.doi.org/10.1136/jclinpath-2018-205342.
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AimsIn breast cancer models, the functional roles of CD147 in proliferation, invasion and treatment resistance have been widely reported. However, there are only a few studies examining the clinicopathological correlation and prognostic relevance of CD147 in breast cancer, especially in relation to breast cancer molecular subtypes.MethodsIn this study, we analysed CD147 expression in a large cohort of breast cancers, correlating with clinicopathological features and the expression of a comprehensive panel of biomarkers in triple-negative breast cancer (TNBC) and non-TNBC subsets. Its relationship with patients’ survival was also analysed.ResultsCD147 was expressed in 11.9%(140/1174) of all cases and in 23.8% (40/168) of TNBC. The expression was associated with tumour histological subtypes (p=0.01) and most commonly seen in carcinoma with medullary features (26.0%). CD147 expression correlated with high tumour grade, presence of necrosis and basal-like breast cancer (BLBC) subtype, high Ki67 and expression of some other basal markers and stem-like markers. CD147 expression was also associated with poor overall survival in chemotherapy treated patients with TNBC.ConclusionsCD147 is a putative marker in identifying TNBC or BLBC, and may be useful as a prognosis indicator for patients with TNBC or BLBC post chemotherapy.
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Kardos, Jordan, Jonathan J. Melquist, David D. Chism, Woonyoung Choi, Katherine Cockerill, Ravi Kumar Paluri, Kelvin A. Moses, et al. "Evaluation of basal and luminal subtypes of urothelial carcinoma in African American and non-African American patients." Journal of Clinical Oncology 33, no. 7_suppl (March 1, 2015): 305. http://dx.doi.org/10.1200/jco.2015.33.7_suppl.305.
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305 Background: African American (AA) patients with urothelial carcinoma (UC) have been known to have a worse prognosis even when corrected for variables such as tumor stage and grade. Analysis of gene expression of several malignancies has resulted in the discovery of molecular subtypes with well-defined intrinsic biology. Recent studies in high grade (HG), muscle-invasive UC have led to the identification of two intrinsic, molecular subsets termed “luminal” and “basal” with characteristics of stages of urothelial differentiation, and that remarkably reflect the luminal and basal-like molecular subtypes of breast cancer. Patients with basal-like UC have a significantly worse overall survival. Methods: A total of 215 HG muscle-invasive UC tumors from the MDACC (n=75) and TCGA (n=140) were used to make intrinsic subtype calls using gene expression profiling (MDACC: DASL [cDNA-mediated Annealing, Selection, extension, and Ligation] and TCGA: RNA seq). Basal and luminal subtype calls were derived using previously published subtype classifiers (Damrauer et. al. PNAS, 2014 and Choi et. al. Cancer Cell, 2014). Patients were classified into AA and non-AA (white, Hispanic, or Asian) based upon self-reported race. Results: In total there were 16 and 199 tumors from AA and non-AA patients respectively. In non-AA patients, the proportion of tumors that were classified as basal and luminal were approximately equal (93 and 106 respectively), while in AA patients, there was enrichment of basal tumors (12 basal and 4 luminal) (p=0.03735, Fisher’s exact test). Conclusions: AA patients are enriched in the basal molecular subtype of UC. Similar findings have been previously documented in AA women with breast cancer. The enrichment of basal UC in AAs suggests that a biological explanation may in part underlie the poor outcomes seen in AA patients. Future studies will explore the prognostic and predictive implications of basal subtype in AA patients with UC.
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Chukwuma, Uzoigwe J., Nzegwu M. Arinze, Onyishi N. Thaddeus, Ekwedigwe C. Kenneth, Edegbe O. Felix, Okani O. Chudi, Ajah O. Leonard, and Ekwedigwe I. Paul. "The Histological Subtypes of Breast Cancer Seen in a Tertiary Hospital in South-East, Nigeria." Global Journal of Health Science 12, no. 6 (April 20, 2020): 93. http://dx.doi.org/10.5539/gjhs.v12n6p93.
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INTRODUCTION: Breast cancer is a disease with heterogeneous nature that may have different prognosis and respond to therapy differently despite similarities in histological type, grade and stage. It is common among women in both developed and developing countries of the world.
MATERIALS AND METHODS: This study was a 2-year retrospective study involving a systematic analysis of all the formalin-fixed paraffin-embedded tissue blocks previously diagnosed as breast cancers. The study occurred at the Department of Morbid Anatomy, University of Nigeria Teaching Hospital, Enugu. We retrieved all the archived tissue blocks and subjected them to further ancillary testing using the immunohistochemistry monoclonal antibodies: (Oestrogen receptors (ER), Progesterone receptors (PR) and Her-2 neu antibodies).
RESULTS: Out of 417 cases of breast cancer analysed, four hundred and Ten (410) were females representing 98.3%, seven (7) were males representing 1.7%. The mean age of all subjects in this study was 45.1±10.2 SD (years). The age of patients ranged from20 to 70 years. The age group 31 to 40 years showed the highest number of cases, 133 (32.4%). The cases positive for ER were 157 (37.6%), while 260 (62.4%) were negative. The cases positive for PR were 144 (34.5%) and 273 (65.5%) were negative. Fifty-four cases (12.9%) were HER2-neu positive, 15 (3.6%) were equivocal and could not be further analysed due to lack of the facility to do Fluorescence in-situ hybridisation, and 348 (83.5%) were HER-neu negative. Phenotypic classification based on ER, PR, and Her2 immunohistochemistry showed 113 cases (27.1%) were Luminal A, 45 cases (10.8%) were Luminal B, 23 cases (5.5%) were Her2 Enriched, 236 cases (56.6%) were Basal-like/Triple-negative, and none (0%) was Normal-like.
CONCLUSION: In conclusion, this study shows that Basal-like/Triple-negative breast cancers are most common and are seen more in premenopausal women in Enugu.
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Mayer, Ingrid A., Rebecca Dent, Tira Tan, Peter Savas, and Sherene Loi. "Novel Targeted Agents and Immunotherapy in Breast Cancer." American Society of Clinical Oncology Educational Book, no. 37 (May 2017): 65–75. http://dx.doi.org/10.1200/edbk_175631.
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The treatment of breast cancer is generally determined according to breast cancer subtype: hormone receptor–positive (luminal), triple-negative (basal-like), and HER2-overexpressing breast cancer. Recent years have seen the development of exciting novel and potent therapeutics based on molecular pathways, immune modulation, and antibody conjugates. In this article, we cover new and emerging therapeutic areas and ongoing clinical trials that may result in further improvements in breast cancer outcomes.
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Gao, Yang, Elena B. Kabotyanski, Jonathan H. Shepherd, Elizabeth Villegas, Deanna Acosta, Clark Hamor, Tingting Sun, et al. "Tumor Suppressor PLK2 May Serve as a Biomarker in Triple-Negative Breast Cancer for Improved Response to PLK1 Therapeutics." Cancer Research Communications 1, no. 3 (December 2021): 178–93. http://dx.doi.org/10.1158/2767-9764.crc-21-0106.
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Polo-like kinase (PLK) family members play important roles in cell-cycle regulation. The founding member PLK1 is oncogenic and preclinically validated as a cancer therapeutic target. Paradoxically, frequent loss of chromosome 5q11–35, which includes PLK2, is observed in basal-like breast cancer. In this study, we found that PLK2 was tumor suppressive in breast cancer, preferentially in basal-like and triple-negative breast cancer (TNBC) subtypes. Knockdown of PLK1 rescued phenotypes induced by PLK2 loss both in vitro and in vivo. We also demonstrated that PLK2 directly interacted with PLK1 at prometaphase through the kinase but not the polo-box domains of PLK2, suggesting PLK2 functioned at least partially through the interaction with PLK1. Furthermore, an improved treatment response was seen in both Plk2-deleted/low mouse preclinical and patient-derived xenograft (PDX) TNBC models using the PLK1 inhibitor volasertib alone or in combination with carboplatin. Reexpression of PLK2 in an inducible PLK2-null mouse model reduced the therapeutic efficacy of volasertib. In summary, this study delineates the effects of chromosome 5q loss in TNBC that includes PLK2, the relationship between PLK2 and PLK1, and how this may render PLK2-deleted/low tumors more sensitive to PLK1 inhibition in combination with chemotherapy. Significance: The tumor-suppressive role of PLK2, and its relationship with oncogene PLK1, provide a mechanistic rationalization to use PLK1 inhibitors in combination with chemotherapy to treat PLK2-low/deleted tumors. TNBC, and other cancers with low PLK2 expression, are such candidates to leverage precision medicine to identify patients who might benefit from treatment with these inhibitors.
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Ladewig, Erik, Abbas Nazir, Christina Leslie, and Charles Sawyers. "Abstract 2048: Mutations in FOXA1 alter chromatin remodeling and cell fate in prostate organoids." Cancer Research 83, no. 7_Supplement (April 4, 2023): 2048. http://dx.doi.org/10.1158/1538-7445.am2023-2048.
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Abstract Genomic analysis of targeted patient tumor sequencing identified frequent mutations, 41% in prostate cancer (Li, et al., 2020) in the gene FOXA1, a developmentally important pioneer transcription factor (TF) in mammary and prostate tissues. Previous work by our group and others has shown that these FOXA1 mutations alter global chromatin accessibility and promote growth in prostate cells (Adams, 2019), but the underlying molecular details, including the identity of partner TFs, remain unclear. To address this topic, we generated mouse prostate organoids expressing Foxa1 alleles harboring three distinct classes of mutations: (i) overexpression of WT Foxa1 (reflecting focal gene amplification seen in tumors), (ii) a series of mutants within the Wing2region of the forkhead binding domain (FHBD) and (iii) a mutant bearing a stop codon after the FHBD to represent a series of C-terminal truncation mutants. We performed single nucleus multiome sequencing to obtain gene expression (snRNA-seq) and chromatin accessibility (snATAC-seq) readouts from the same individual nuclei. Whereas each Foxa1 mutant has distinct, often mutant-specific features, several themes emerge. These include alterations in the relative proportion of stem-like (L2) luminal cells vs secretory (L1) luminal cells as well as changes in luminal or basal gene signatures, increased androgen receptor signaling output, and enrichment for motifs of distinct classes of partner TFs. For example, cells expressing the truncation mutant show gain in the accessibility of Gata3 and Pou2f1 TF binding motifs, as well as enhanced numbers of L1-like luminal cells. Functional studies demonstrate that Pou2f1 is specifically required for the pro-luminal phenotype in cells expressing the truncation mutant whereas Gata3 plays a more general pro-luminal role. Correlations in motif accessibility and transcription factor expression across single cells further revealed a composite androgen receptor (AR)-FOXA1 motif enriched in the pro-luminal truncation mutant, while the canonical AR motif was enriched in pro-basal cell mutants. Finally, Foxa1 mutants cooperative with Trp53 and Pten loss in orthotopic prostate tumorigenicity assays, most strikingly manifest by reversion of the basal-like features characteristic of Trp53/Pten loss tumors to Ck8+ luminal adenocarcinoma histology, mirroring that seen in Foxa1-mutant human prostate cancer tumors in mice. Thus, mutant Foxa1 alleles cooperate with canonical prostate cancer tumor suppressors and alter the histologic phenotype of prostate cancers in mice through the activation of basal or luminal lineage differentiation programs. Citation Format: Erik Ladewig, Abbas Nazir, Christina Leslie, Charles Sawyers. Mutations in FOXA1 alter chromatin remodeling and cell fate in prostate organoids [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 2048.
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Jomaa, W., S. Ziadi, R. Ben Gacem, M. Hachana, S. Korbi, N. Baizig, and M. Trimeche. "Le cancer du sein de phénotype basal : prévalence et particularités anatomo-cliniques dans la région du centre tunisien." Annales de Pathologie 31, no. 5 (November 2011): S162. http://dx.doi.org/10.1016/j.annpat.2011.09.095.
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Araujo, Jhajaira M., Gabriel De la Cruz-Ku, Melanie Cornejo, Franco Doimi, Richard Dyer, Henry L. Gomez, and Joseph A. Pinto. "Prognostic Capability of TNBC 3-Gene Score among Triple-Negative Breast Cancer Subtypes." Cancers 14, no. 17 (September 1, 2022): 4286. http://dx.doi.org/10.3390/cancers14174286.
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Background: Triple-negative breast cancer (TNBC) is a complex and molecularly heterogeneous entity, with the poorest outcome compared with other breast cancer subtypes. Previously, we developed a TNBC 3-gene score with a significant prognostic capability. This study aims to test the 3-gene score in the different TNBC subtypes. Methods: Data from 204 TNBC patients treated with neoadjuvant chemotherapy were retrieved from public datasets and pooled (GSE25066, GSE58812, and GSE16446). After removing batch effects, cases were classified into Lehman’s TNBC subtypes and then the TNBC 3-gene score was used to evaluate the risk of distant recurrence in each subgroup. In addition, the association with tumor-infiltrating lymphocyte (TILs) levels was evaluated in a retrospective group of 72 TNBC cases. Results: The TNBC 3-gene score was able to discriminate patients with different risks within the pooled cohort (HR = 2.41 for high vs. low risk; 95%CI: 1.50–3.86). The score showed predictive capability in the immunomodulatory subtype (HR = 4.16; 95%CI: 1.63–10.60) and in the mesenchymal stem-like subtype (HR = 18.76; 95%CI: 1.68–208.97). In the basal-like 1, basal-like-2, and mesenchymal subtypes, the observed differential risk patterns showed no statistical significance. The score had poor predictive capability in the luminal androgen receptor subtype (p = 0.765). In addition, a low TNBC 3-gene score was related to a high level of TIL infiltration (p < 0.001). Conclusions: The TNBC 3-gene score is able to predict the risk of distant recurrence in TNBC patients, specifically in the immunomodulatory and mesenchymal stem-like subtype. Despite a small sample size in each subgroup, an improved prognostic capability was seen in TNBC subtypes with tumor-infiltrating components.
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Hamada, Akihiro, Yuki Kita, Di Wu, Mi Zhou, Sean Clark-Garvey, Andrew Gdowski, Michael Sturdivant, et al. "Abstract A016: NRF2 activation promotes a fitness disadvantage in normal urothelium and drives a basal-like phenotype." Clinical Cancer Research 30, no. 10_Supplement (May 17, 2024): A016. http://dx.doi.org/10.1158/1557-3265.bladder24-a016.
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Abstract Introduction: Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that plays a key role in protecting cells from oxidative stress. NRF2 is negatively controlled by Kelch-like ECH-associated protein 1 (KEAP1), which facilitates NRF2 ubiquitination and proteosomal degradation under homeostatic conditions. NRF2 activating mutations occur at a frequency of 5.9% in muscle-invasive bladder cancer (MIBC). However, the role of NRF2 in MIBC has not been fully understood. The aim of this study is to clarify how NRF2 affect to the normal epithelial cells and the tumor cells in bladder. Methods: We used genetically engineered mice (GEM) with a Cre inducible Nrf2 activating mutation (LSL-Nrf2-E79Q). To evaluate how Nrf2 affects the tumorigenesis process in vivo, the N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) was administered to Upk3a-CreERT2; LSL-Nrf2-E79Q/+ (UN) mice. We also established normal urothelial organoids and BBN tumor derived organoids from wild-type (WT) and Krt5-CreERT2; LSL-Nrf2-E79Q/+ (K5N) mice for ex vivo study. To induce overexpression of NRF2, we utilized KI696 (KEAP1-NRF2 inhibitor) as a pharmacological agent and performed NAD/NADH assay to quantify the reductive stress. Additionally, we performed single cell RNA sequencing (scRNA-seq) with WT, UN and K5N mice bladder to identify the effect of Nrf2E79Q on the normal epithelial cells. Results: In BBN induced tumor model in vivo, UN mice did not differ in time to tumor development from the control WT mice. Furthermore, UN tumors had lost the post-recombination allele of LSL-Nrf2-E79Q in genomic PCR, meaning cells expressing Nrf2E79Q are selected against during the process. In ex vivo study, KI696 induced reductive stress in both WT normal urothelial organoids and BBN tumor derived organoids, but inhibited cell proliferation only in normal urothelial organoids. In K5N organoids, Nrf2E79Q activation enhanced relative mRNA expression of a number of basal related genes. In addition to that, vehicle organoids in differentiation media showed phenotypic differentiation, whereas those treated with tamoxifen did not demonstrate phenotypic signs of differentiation suggesting Nrf2 activation promotes a basal-like phenotype. Furthermore, we annotated three clusters in mice bladder epithelial cells as luminal, intermediate and basal using scRNA-seq and looked at their proportion among WT, UN and K5N mice. We found that the percentage of luminal cells was decreased and intermediate and basal cells increased in both UN and K5N mice compared to WT mice. This indicated that Nrf2E79Q promotes disadvantage in luminal cells in UN mice, whereas it contributes to the increase in intermediate and basal cells in K5N mice. Conclusion: These results suggested that Nrf2E79Q promotes a fitness disadvantage in normal mice urothelium. Furthermore, Nrf2E79Q inhibits differentiation of K5N organoids and drives a basal-like phenotype in GEM models. Further investigation is needed to clarify the mechanism of NRF2 activating mutation contributing the tumorigenesis in bladder. Citation Format: Akihiro Hamada, Yuki Kita, Di Wu, Mi Zhou, Sean Clark-Garvey, Andrew Gdowski, Michael Sturdivant, Wolfgang Beckabir, Elliott Drew Toomer, Emily Kounlavong, Lucia Lim, Kathryn Gessner, Jeffrey Damrauer, William Kim. NRF2 activation promotes a fitness disadvantage in normal urothelium and drives a basal-like phenotype [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr A016.
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O'Kane, Grainne M., Sandra Fischer, Rob Denroche, Gun Ho Jang, Amy Zhang, Anna Dodd, Robert C. Grant, et al. "Integrative molecular profiling and response to chemotherapy on the COMPASS trial." Journal of Clinical Oncology 37, no. 4_suppl (February 1, 2019): 188. http://dx.doi.org/10.1200/jco.2019.37.4_suppl.188.
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188 Background: Predictive mutational and transcriptional features in advanced PDAC are needed for improved patient stratification and treatment selection. Methods: Patients (pts) on the COMPASS trial with advanced PDAC are prospectively recruited prior to first-line chemotherapy for WGS and RNAseq. Tumor tissue undergoes enrichment by laser capture microdissection with genomic analyses available within eight wks. Tumor responses and clinical outcomes in this maturing cohort were correlated with molecular characteristics. Results: 157 pts underwent a tumor biopsy between Dec 2015 and Jul 2018 with over 95% success in achieving results. 141 genomes have been reported in pts planned to receive chemotherapy; the median time from biopsy to report was 35.5 days. In the ITT population,118 pts are summarised for first-line response. The median age was 63 yrs (29-81), 55% were male, and 16% had locally advanced disease. 66 (56%) received modified FFX as first-line treatment. 25 (21%) tumors displayed the Moffitt basal-like RNA signature which associated with chemotherapy resistance, with tumor shrinkage mainly observed in the classical RNA subtype (p = 0.002). GATA6 expression (log10 scale) clearly separated Moffitt subgroups with classical tumors exhibiting high expression (p < 0.0001). GATA6 in situ hybridization strongly correlated with RNAseq, (r = 0.89, p < 0.001) with strong correlation also seen with GATA6 IHC. The median overall survival (OS) in the classical group was 8.5 mths vs. 6.6 mths in the basal-like group (HR 0.53, 95% CI 0.32-0.89 p = 0.015). In those treated with mFFX, median OS was 10.1mths in classical versus 6.6mths in the basal-like subtypes, (HR 0.32, 95% CI 0.16-0.63, p=0.001). 30% of pts had potentially actionable genetic alterations including BRAF variants (n = 4) and an NTRK3-EML4 fusion in KRAS WT tumors (8%). Signatures of homologous recombination deficiency (HRD) were found in seven pts; two additional pts with BRCA germline variants did not exhibit somatic HRD hallmarks. Conclusions: Subsets of pts with advanced PDAC have actionable variants including those with HRD signatures and patients with KRAS WT tumors. GATA6 is a putative predictive biomarker of transcriptomic subgroups which should be incorporated in clinical trials. Clinical trial information: NCT02750657.
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Van Swearingen, Amanda, Marissa Lee, Layne Rogers, Alexander Sibley, Pixu Shi, Xiaodi Qin, Michael Goodin, Kouros Owzar, and Carey Anders. "Abstract PO4-14-07: Genomic and immune profiling of breast cancer brain metastases." Cancer Research 84, no. 9_Supplement (May 2, 2024): PO4–14–07—PO4–14–07. http://dx.doi.org/10.1158/1538-7445.sabcs23-po4-14-07.
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Abstract BACKGROUND: Brain metastases (BrM) arising from breast cancer (BC) are an increasing consequence of advanced disease, with up to half of patients (pts) with metastatic HER2+ or triple negative breast cancer experiencing central nervous system (CNS) recurrence. The genomic alterations driving CNS recurrence, along with contribution of the immune microenvironment, particularly by BC subtype remains unclear. METHODS: We characterized BrM from a cohort of n=42 BC pts by sequencing whole-exome DNA and total RNA libraries from frozen (n=31) and FFPE (n=34) BCBrM, FFPE extracranial (ECT, n=12) and blood DNA (n=26) tissues from the Duke Brain Tumor Biorepository. Analyses conducted and planned include inference of PAM50 intrinsic subtypes, somatic mutations, copy number alterations, immune cell type decompositions by CIBERSORTx, differential RNA expression, driver analysis, and associations with clinical outcomes. RESULTS: PAM50 subtypes across 31 frozen BrM were 23% Luminal (Lum) A, 13% LumB, 33% HER2-enriched, 27% Basal-like, 3% Normal-like. For 34 FFPE BrM, 15% were LumA, 24% LumB, 33% HER2-enriched, 24% Basal-like, 3% Normal-like. Across 26 paired FFPE and frozen BrM, subtype discrepancy was seen in 23% (6) cases of which frozen to FFPE classification differed: 3 LumA to LumB, 1 LumB to LumA, 1 Normal to LumB, and 1 Basal to LumB. Among 10 paired FFPE BrM and ECT, subtype concordance was observed in 70%. Discordance was seen in 1 case each for ECT to BrM: LumB to HER2, LumB to LumA, Basal to Normal-like. WES demonstrated frequent copy number alterations (CNA) in clinically-relevant genes including TGFB1, NOTCH1, CDK4, and ERBB3, in both BrM and ECT. For pts with matched blood, ERBB3 CNA (gain and loss) were more commonly found in FFPE BrM (7/19, 37%) compared to ECT (1/8, 13%). Among BrM, the most frequently altered clinically-relevant genes included TP53 (~75%), PTEN, EGFR, RB1, PIK3CA, NF1 and ESR1 (all ≤15%); in ECT, TP53 (67%), BRCA2, FBXW7, and ATM (all ≤33%). PI3K pathway genes (e.g. PTEN, PIK3CA) alterations were exclusive to BrM. One pt’s ECT showed an ATM mutation that was not observed in the paired BrM. Conversely, BRAF and CCND2 mutations were observed in BrM, but not ECT for 1 pt each. Inferring the relative abundance of immune populations in frozen BrM illustrated that 23% were CD4+ resting memory T cells, 25% M2 tumor-permissive macrophages, 13% M0 macrophages; M1 tumor-inhibiting macrophages were only 2%. When comparing immune cell populations between FFPE BrM and ECT, ECT had more M1 macrophages (Chi-sq 4.23, P = 0.04), while other immune cell populations were of similar relative abundance. Immune cell fractions did not vary by subtype in BrM or ECT with one exception: M2 macrophages were lower in Basal compared to LumB tissues (frozen BrM: Chi-sq = 9.28, P = 0.05; FFPE BrM: Chi-sq = 4.61, P = 0.33; FFPE EC: Chi-sq = 9.78, P = 0.04). In n=8 pt-matched FFPE BrM/ECT, hallmark pathways upregulated in BrM included MYC and E2F targets and oxidative phosphorylation, while those with lower expression in BrM included epithelial-mesenchymal transition, interferon gamma response, and JAK-STAT signaling. CONCLUSION: This analysis showed moderate discrepancy in subtype call of BrM by tissue preparation (frozen vs. FFPE), with LumB classification showing the highest discrepancy, and more commonly called in FFPE tissues. Subtype concordance between ECT and BrM was relatively high. Analysis of CNA illustrated deletions and amplifications in targetable genes, notably ERBB3 preferentially in BrM compared to ECT. Mutational analysis identified targetable alterations exclusive to BrM; this knowledge could lead to BrM-targeted treatments. Inferred immune cell populations illustrated a tumor permissive microenvironment in BrM. Therapeutic strategies repolarizing macrophages toward a tumor-inhibiting phenotype in BrM are warranted. Analyses of associations between genomic data and clinical outcomes, as well as driver analyses, are ongoing. Citation Format: Amanda Van Swearingen, Marissa Lee, Layne Rogers, Alexander Sibley, Pixu Shi, Xiaodi Qin, Michael Goodin, Kouros Owzar, Carey Anders. Genomic and immune profiling of breast cancer brain metastases [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 PO4-14-07.
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Ivory, Joannie M., Naim Rashid, Paola Zagami, Charles M. Perou, Katherine Elizabeth Reeder-Hayes, and Lisa A. Carey. "Impact of race and age on intrinsic subtype distribution and treatment decisions in metastatic breast cancer: Preliminary analysis of HARMONY (LCCC1829)." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): 1055. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.1055.
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1055 Background: Gene expression profiling (GEP) is used to classify breast cancer (BC) into four intrinsic subtypes: Luminal A (LumA), Luminal B (LumB), HER2-Enriched, and Basal-like. Non-LumA subtypes are associated with poorer outcomes. Studies in early BC show that hormone receptor-positive (HR+)/HER2-negative (HER2-) tumors have a higher frequency of non-LumA subtypes in Black and younger (<50) women. Similarly, triple negative BC, which carries the poorest prognosis and is mostly Basal-like, are overrepresented in Black and younger women. These variations in intrinsic subtype contribute to outcomes disparities. The extent to which these racial and age differences in subtypes and mortality occur in metastatic breast cancer (MBC) is unknown. Methods: HARMONY (NCT03769415) is a prospective clinical trial in patients with newly diagnosed MBC. Bulk tumor GEP (PAM50 intrinsic subtyping) is performed on primary and metastatic tumors. A primary objective is to determine the extent and treatment implications of molecular discordance (defined a priori as treatment differences by intrinsic subtype compared to clinical subtype); other endpoints to be reported later include GEP comparisons between primary and metastatic samples. Here we examine differences in a) intrinsic subtype and b) treatment patterns in MBC by race and age. Results: At the time of analysis, the study had accrued 220 participants. Mean age was 58, 24% were Black women. Sixty-five percent had HR+/HER2- MBC, 14% HER2-positive, and 21% triple negative. Unlike in early BC, LumB exceeded LumA (LumA 27%, LumB 35%, HER2-Enriched 12%, Basal-like 25%). Similar to early BC, subtype varied by race and age with more non-LumA subtypes in young and Black women. Discordance between intrinsic and clinical subtype was seen in 24% of Black, 20% of White women, in 29% of younger and 18% of older women. Treatment patterns also differed by race and age, where a higher percentage of younger Black women received first-line chemotherapy compared to younger White women overall (45% vs. 10%, p=0.0025), and in HR+/HER2- disease (33% vs 8.7%, p=>0.05). No difference was seen in older women (24% vs 17%, p=0.44). Median progression free survival was worst in younger Black women compared to all other participants (5.4 vs 19.5 months, p=0.027), which may be driven by clinical subtype. Conclusions: Intrinsic subtype of tumors in a metastatic population has a different distribution by race and age than early BC, with more poor-prognosis non-LumA subtypes, and approximately 1 in 5 have discordance between clinical and molecular subtype, which may be therapeutically relevant. Clinical trial information: NCT03769415 . [Table: see text]
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Sangera-Grewal, Ravina, and Parbeer Singh Grewal. "Gorlin Syndrome Presentation and the Importance of Differential Diagnosis of Skin Cancer: A Case Report." Journal of Pharmacy & Pharmaceutical Sciences 21, no. 1s (September 7, 2018): 222s—224s. http://dx.doi.org/10.18433/jpps30150.
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In a busy community practice, clinical skin findings can often be misinterpreted. Skin cancers can sometimes mimic rashes like psoriasis, eczema or prurigo nodularis in both appearance and symptoms. Gorlin syndrome is one such genetic syndrome, characterized by the eruption of multiple and early onset basal cell carcinomas (BCCs), which can be mistaken for a rash. We describe a 68-year-old female who presented to the dermatology office with a previous history of over 30 BCCs that had been previously biopsied and/or surgically removed. However, the patient had been lost to follow up for several years and had not been seen by a skin specialist. In the interim, she had been misdiagnosed as having eczematous or psoriatic lesions by primary care providers. Patients with Gorlin syndrome are even harder to diagnose as their skin cancers often do not possess the classic features associated with a basal cell or squamous cell carcinoma. When in doubt, and especially if failing topical therapy, patients presenting with dermatological lesions should be properly referred to a specialist for further assessment and workup.
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Foldi, Julia, Emily Reisenbichler, Liuliu Pan, Krsitina Sorg, Sarah E. Church, and Lajos Pusztai. "Abstract P1-05-02: Intratumor molecular tumor heterogeneity in low ER-expressing primary breast tumors." Cancer Research 82, no. 4_Supplement (February 15, 2022): P1–05–02—P1–05–02. http://dx.doi.org/10.1158/1538-7445.sabcs21-p1-05-02.
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Abstract Background: Change in estrogen receptor (ER) status between primary breast cancer and distant recurrence are seen in the clinic in up to 15-20% of patients. This is difficult to reconcile with the current understanding of breast cancer molecular subtypes, the large-scale molecular differences between ER-positive (ER+) and ER-negative (ER-) cancers suggest different cellular origins, luminal versus basal breast epithelium, respectively. A potential explanation for ER status switch is the presence of mixed molecular subtypes at diagnosis. ER+ cancers with less than 100% positivity may be composed by both luminal and basal-like cancer cells, and a recurrence might arise from one subtype that survived adjuvant therapy. The goal of this study was to test if molecular subtype heterogeneity exists at diagnosis in less than 100% ER+ breast cancer using the NanoString GeoMx™ platform. Methods: GeoMx™ is a highly multiplexed assay that quantifies RNA expression from spatially discrete regions of interest (ROIs) within formalin fixed paraffin embedded (FFPE) tissue sections. We identified 4 cancers with 30-40% ER-positivity on routine immunohistochemistry (IHC) staining (clone SP1). Eight ROIs per case were selected to represent both ER-high and -low regions of the section using ER IHC (clone 1D5). Invasive tumor cells were defined as PanCK positive cells. 1,825 mRNA species were measured separately in each ROI. mRNA expression results (unique molecular index [UMI] counts) were quantile normalized and differential expression analyses for all genes, ESR1, ER-regulated gene set, and PAM50 gene set were performed between ROIs within the same cancer. We also assessed PAM50 subtypes of each cases on bulk RNA using NanoString BC360 panel. Results: Three of the 4 cases had heterogenous ER IHC (1D5) staining; the fourth case was uniformly ER-negative during ROI selection. For this last case, ROIs were selected based on PanCK staining from different locations in the cancer. Bulk PAM50 subtyping indicated 1 basal-like, 2 HER2-enriched (HER2-E), and 1 luminal (lum)A cancer. We also attempted ROI-level subtyping; however, Pearson correlations to the nearest centroid were low (<0.5) for all ROIs, possibly due to low expression of PAM50 genes or to the exploratory methodology used. There was substantial within cancer, between ROI, expression heterogeneity for many genes including ESR1 and sensitivity to endocrine therapy (SET) index genes. Conclusions: ER- and ER+ cells are intermixed which makes defining low and high ER regions challenging. We observed region to region variation in ESR1 and SET index gene expression. ROI-level PAM50 subtyping was unstable. The novel NanoString GeoMx™ DSP technology can be used to study intratumor molecular heterogeneity in regions of interest on FFPE breast cancer tissue sections. We found substantial region-to-region gene expression differences within tissue sections. Case ID1234ER IHC SP130%40%40%30%ER IHC 1D50%40%40%30%Bulk PAM50 SubtypeBasalHER2-ELumAHER2-EESR1 UMI average (range across ROIs)28.45 (22.4-34.6)64.9 (18.8-173)179.9 (114-245)34.8 (25.1-45.4)SET Index (genes positively correlated with ESR1) UMI average (range across ROIs)41.5 (39.1-44.8)120.1 (86.9-182.9)94.9 (72.9-118.4)143.5 (124.9-150.3)SET Index (genes negatively correlated with ESR1) UMI average (range across ROIs)57.6 (45-75.3)43.4 (38.8-52.6)33.7 (31.8-36.7)44.8 (41.4-50.6) Citation Format: Julia Foldi, Emily Reisenbichler, Liuliu Pan, Krsitina Sorg, Sarah E. Church, Lajos Pusztai. Intratumor molecular tumor heterogeneity in low ER-expressing primary breast tumors [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 P1-05-02.
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Emens, Leisha A., Leonard D. Goldstein, Peter Schmid, Hope S. Rugo, Sylvia Adams, Carlos H. Barrios, Andreas Schneeweiss, et al. "The tumor microenvironment (TME) and atezolizumab + nab-paclitaxel (A+nP) activity in metastatic triple-negative breast cancer (mTNBC): IMpassion130." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 1006. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.1006.
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1006 Background: IMpassion130 was the first randomized phase 3 study to show clinical benefit of cancer immunotherapy (CIT) in untreated PD-L1+ mTNBC. Enhanced A + nP efficacy vs placebo (P) + nP was seen in pts with a richer immune TME but was confined to PD-L1 IC+ pts (PD-L1–expressing immune cells on ≥1% of tumor area; Emens JNCI 2021). While TNBC molecular subtyping and CD8 localization are prognostic in early TNBC, it is unknown whether these features are associated with CIT benefit in mTNBC. This exploratory analysis aimed to identify TME components associated with A + nP efficacy in IMpassion130. Methods: IHC was used to assess PD-L1 status (VENTANA SP142) and immune phenotypes (inflamed/excluded/desert per CD8 stromal/intratumoral localization; Mariathasan Nature 2018). RNA-seq was used for molecular subtyping (Burstein CCR 2015) and pathway analyses (MSigDB Hallmark). Cox regression was used to compare PFS/OS between A + nP vs P + nP, adjusted for prior taxanes, liver mets. Results: Sample classification and PD-L1 distribution are shown (Table). Improved PFS with A + nP vs P + nP was seen in PD-L1 IC+ inflamed and excluded tumors, but improved OS was limited to PD-L1 IC+ inflamed tumors. PD-L1 IC+ basal-like immune activated (BLIA) and immune suppressed (BLIS) subgroups derived PFS benefit, but OS benefit was limited to PD-L1 IC+ BLIA subgroups. In PD-L1 IC+ pts, pathway analysis identified proliferation/DNA damage repair (basal-like tumor features) and angiogenesis/ER response (higher in luminal androgen receptor [LAR]/ mesenchymal [MES] tumors) were associated with improved and reduced PFS, respectively. Conclusions: PD-L1 IC+ immune-inflamed tumors and PD-L1 IC+ BLIA tumors show highest CIT sensitivity, and LAR tumors may be resistant to CIT. These data warrant further study and validation. Clinical trial information: NCT02425891 .[Table: see text]
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Snider, Jessica N., Robyn R. Young, Lee Steven Schwartzberg, Jeffrey Warren Allen, Yasir Ahmed Javed, Mohammad Jahanzeb, and Jasgit C. Sachdev. "Neoadjuvant bevacizumab with weekly nab-paclitaxel plus carboplatin followed by doxorubicin plus cyclophosphamide (AC) for triple-negative breast cancer." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): TPS1137. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.tps1137.
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TPS1137 Background: Triple negative breast cancer (TNBC) predominantly clusters with “basal like” subtype on genomic profiling. Over-expression of Secreted Protein Acidic and Rich in Cysteine (SPARC) has been observed in basal like breast cancer (Charaffe-Jaufrett et al. Oncogene 2006; 2273-84). Endothelial transcytosis of nab- paclitaxel occurs via albumin- gp60 receptor-caveolin 1 interaction. SPARC entraps the albumin resulting in higher intratumoral accumulation, which may explain the increased efficacy of nab-paclitaxel (Desai et al. Translational Oncology 2009; 59-63). Exploiting this mechanism and the dysfunctional BRCA mediated DNA repair in basal tumors, we hypothesize that nab-paclitaxel + the DNA damaging drug carboplatin would produce high response rates in TNBC. Adding bevacizumab may enhance efficacy by blocking angiogenesis. In TNBC, pathologic complete remission (pCR) to neo-adjuvant therapy correlates with better disease-free survival (DFS). We hypothesize that high pCR rates can be achieved for patients with TNBC with this combination translating to an improved DFS than seen historically. Methods: Patients with palpable and operable TNBC ≥ 2 cm are eligible for this single stage phase II trial. pCR (defined as the absence of invasive tumor cells) in the breast is the primary end point, while pCR in the breast + axillary nodes and pCR + near pCR (residual tumor < 5mm) in the breast are secondary end points. 57 evaluable patients are needed, assuming a pCR rate of 25% vs. 40% for the null and alternate hypotheses respectively. 34 patients have been accrued to date. Patients receive carboplatin AUC 6 day 1 and nab-paclitaxel 100mg/m2 days 1, 8 and 15 of a 28 day cycle for 4 cycles and then dose dense AC for 4 cycles. Bevacizumab is given at 10mg/kg Q 2 weeks with chemotherapy for the first 6 cycles. Surgery and radiation are per institutional standards. Bevacizumab is continued postoperatively to complete 1 year of treatment. A core biopsy for collection of fresh tumor tissue is required prior to the start of study treatment. Blood is collected at baseline, and after 4 and 8 cycles for biomarker analysis. Gene expression profiling will be undertaken for correlation with response.
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Bordonaro, Sebastiano, Massimiliano Berretta, Antonino Carmelo Tralongo, Silvia Clementi, Brigida Stanzione, and Paolo Tralongo. "The Real Impact of Target Therapy in Breast Cancer Patients: Between Hope and Reality." Current Cancer Drug Targets 18, no. 5 (May 22, 2018): 480–98. http://dx.doi.org/10.2174/1568009617666170209100322.
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Over the last 15 years, we have seen a huge expansion of the development of drugs directed against biomolecular targets within breast cancer cells. The over-expression of certain receptors (ER, PgR, HER-2, VEGF-R), as well as alteration of several intracellular signal transduction pathways (the PI3K-AKT-mTOR pathway, MEK-MAPK pathway, loss of PTEN, etc ...) has a great impact on the likelihood of recurrence and progression of the disease, influencing the natural history of breast cancer. The recent biomolecular classification of breast cancer (Luminal A / B, HER2- driven, Basal Like) allowed finally to identify specific treatments against molecular target to associate or not to traditional chemotherapy, and to use in relation to the prognosis of the disease. In the following paragraphs, we will set out the major targeted drug that have received indications in breast cancer, both in the localized and in advanced disease, referring to the specific target (hormonal receptors, HER2, VEGF, m-TOR, PARP etc ...).
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Verma, Rupesh, Suzita Hirachan, and Yogendra P. Singh. "Palliative Toilet Mastectomy for Advanced Breast Cancer in a University Hospital of Nepal." Journal of Institute of Medicine Nepal 42, no. 1 (April 30, 2020): 71. http://dx.doi.org/10.3126/jiom.v42i1.37447.
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Introduction In Nepal, half of the breast cancer patients presented in advanced stage III (IIIA 18%, IIIB 22%), and stage IV (10%). Delayed presentations are due to lack of awareness, reluctancy and poor accessibility to health care services often leads to local complications like sloughing of fungating breast lesions, secondary infection and bleeding. The aim of this study was to analyze the advanced breast cancer (ABC) patients who underwent palliative toilet mastectomy.
MethodsRetrospective review of all patients presenting with ABC who underwent palliative toilet mastectomy in the breast unit of Tribhuvan University Teaching Hospital Kathmandu, Nepal from January 2016 to December 2018, was done. The data included were demographic profile, histopathological and immunohistochemistry report, indication of surgery, adjuvant therapy, timing of surgery, and quality of life after surgery.
ResultsTotal number of breast carcinoma patients was 155 within the duration of 3 years. There were 7 (4.5%) cases of breast cancer treated with palliative toilet mastectomy with mean age of 57.9±12.7 years. The mean tumor size was 4.3±1.3cm. The indications of palliative mastectomy were fungation-2 (28.5%), bleeding-2 (28.5%), ulceration-1 (14.3%), malodorous discharge with secondary infection-1 (14.3%) and hemiplegic patient with infection in 1 (14.3%). Luminal A molecular subtype was seen in 1 out of 7 patients (14.3%) with basal like subtype in 6 out of 7 patients (85.7%). Lympho-vascular invasion were seen in 4 out of 7 (57.14%). One patient underwent bilateral palliative mastectomy for progressive disease and margins were positive for tumor and remaining six patients had tumor free margins.
ConclusionAdvanced breast cancers are treated with neoadjuvant therapy prior surgery but the delayed presentation of these with fungating, ulcerative, infective and bleeding lesions make the initial palliative toilet mastectomy a useful option.
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Verma, Rupesh, Suzita Hirachan, and Yogendra P. Singh. "Palliative Toilet Mastectomy for Advanced Breast Cancer in a University Hospital of Nepal." Journal of Institute of Medicine Nepal 42, no. 1 (April 30, 2020): 71. http://dx.doi.org/10.59779/jiomnepal.1091.
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Introduction: In Nepal, half of the breast cancer patients presented in advanced stage III (IIIA 18%, IIIB 22%), and stage IV (10%). Delayed presentations are due to lack of awareness, reluctancy and poor accessibility to health care services often leads to local complications like sloughing of fungating breast lesions, secondary infection and bleeding. The aim of this study was to analyze the advanced breast cancer (ABC) patients who underwent palliative toilet mastectomy. Methods: Retrospective review of all patients presenting with ABC who underwent palliative toilet mastectomy in the breast unit of Tribhuvan University Teaching Hospital Kathmandu, Nepal from January 2016 to December 2018, was done. The data included were demographic profile, histopathological and immunohistochemistry report, indication of surgery, adjuvant therapy, timing of surgery, and quality of life after surgery. Results: Total number of breast carcinoma patients was 155 within the duration of 3 years. There were 7 (4.5%) cases of breast cancer treated with palliative toilet mastectomy with mean age of 57.9±12.7 years. The mean tumor size was 4.3±1.3cm. The indications of palliative mastectomy were fungation-2 (28.5%), bleeding-2 (28.5%), ulceration-1 (14.3%), malodorous discharge with secondary infection-1 (14.3%) and hemiplegic patient with infection in 1 (14.3%). Luminal A molecular subtype was seen in 1 out of 7 patients (14.3%) with basal like subtype in 6 out of 7 patients (85.7%). Lympho-vascular invasion were seen in 4 out of 7 (57.14%). One patient underwent bilateral palliative mastectomy for progressive disease and margins were positive for tumor and remaining six patients had tumor free margins. Conclusion: Advanced breast cancers are treated with neoadjuvant therapy prior surgery but the delayed presentation of these with fungating, ulcerative, infective and bleeding lesions make the initial palliative toilet mastectomy a useful option.
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Zerdes, Ioannis, Alexios Matikas, John Lövrot, Emmanouil G. Sifakis, François Richard, Christos Sotiriou, George Z. Rassidakis, Jonas C. S. Bergh, Antonios Valachis, and Theodoros Foukakis. "PD-1 protein and gene expression in early breast cancer: Prognostic implications." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 545. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.545.
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545 Background: We have previously shown the prognostic value of PD-L1 protein and gene expression in early breast cancer (BC), however, the prognostic role of PD-1 expression remains unclear. Methods: The prognostic value of PD-1 in early BC was investigated using three different approaches: i) evaluation of PD-1 at the protein (IHC, immunohistochemistry in tissue microarrays) and mRNA levels in a retrospective patient cohort of 586 patients treated for early BC in Stockholm, Sweden between 1997-2005, ii) systematic review and trial-level meta-analysis of studies published in Medline, Embase, Cochrane Library and Web of Science Core Collection libraries on the prognostic value of PD-1 IHC expression, and iii) pooled analysis of transcriptomic data from 39 publicly available datasets for the prognostic capacity of PD-1 gene expression. Univariate and multivariable Cox regression models were used. Results: In the retrospective study cohort, PD-1 protein was significantly associated with biologically high-risk characteristics. PD-1 protein, but not gene expression, was correlated with improved overall survival (OS) (adjusted HR = 0.73, 95% CI 0.55 – 0.96, p = 0.023 and adjusted HR = 0.88, 95% CI 0.68 – 1.13, p = 0.307, respectively). In the trial-level meta-analysis, 4736 entries were initially identified and 15 studies, including our original cohort, fulfilled the predefined eligibility criteria. PD-1 IHC expression was not prognostic in unselected patients. However, a significant correlation to improved disease-free survival was seen within the triple-negative subtype (pooled multivariate HR = 0.57, 95% CI 0.29 – 0.90, p = 0.02). In the pooled gene expression analysis, PD-1 gene expression was associated with improved OS in the entire population (adjusted HR = 0.89, 95% CI 0.80 – 0.99, p = 0.025) and in basal-like (adjusted HR = 0.77, 95% CI 0.63 – 0.95, p = 0.014) tumors. Conclusions: PD-1 expression at the RNA and protein levels represent promising prognostic factors, especially in the triple-negative and basal-like subtypes. Standardization and further validation are needed prior to clinical implementation.
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Nishiyama, Yasuyuki, Reiki Nishimura, Tomofumi Osako, Yasuhiro Okumura, and Nobuyuki Arima. "Ki-67, p53, and clinical outcomes of patients with triple-negative breast cancer." Journal of Clinical Oncology 30, no. 27_suppl (September 20, 2012): 142. http://dx.doi.org/10.1200/jco.2012.30.27_suppl.142.
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142 Background: Triple-negative breast cancer (TNBC) tends to produce a poor prognosis because of aggressive tumor biology and lack of targeted agents. Breast cancer with a high Ki-67 value responds better to chemotherapy but is associated with lower relapse-free (RFS) and overall survival rates. The basal-like subtype overlaps with TNBC in approximately 70% to 80% of the cases, and the vast majority of basal-like subtypes have mutated p53. The aim of this study was to evaluate the clinical and prognostic significance of Ki-67 and p53 in patients with TNBC. Methods: We retrospectively reviewed 1,711 patients with pT1-3 invasive breast cancer diagnosed between 2001 and 2010. Of the 200 TNBC cases, 165 patients received adjuvant chemotherapy. Cases were classified as luminal (ER+ and/or PR+ and HER2-), HER2 disease (HER2+) and TNBC (ER-, PR- and HER2-) subtypes. Estrogen receptor (ER) and progesterone receptor (PR) positivity was defined as ≥10% positive tumor cells with nuclear staining. Ki-67 was classified into the following three groups: low (<20%), intermediate (20-50%) and high (≥50%), and the p53 high group was indicated by ≥50% staining. RFS was compared according to the level of Ki-67 and p53. Results: Patients with a high Ki-67 value were frequently seen in 53% of the cases with TNBC (luminal: 6% and HER2 disease: 25%, p<0.0001). The greatest proportion of patients in the low p53 group were the luminal type (luminal: 7%, HER2 disease: 49%, TNBC: 54%, p<0.0001). A high Ki-67 value was not associated with poor RFS in TNBC (p=0.2734). A high p53 expression was associated with poor RFS (p=0.024). TNBC with adjuvant chemotherapy and a high p53 expression tended to produce poor RFS (p=0.0516). Conclusions: TNBC with a high Ki-67 value was not associated with poor prognosis in this study. However, p53 status could be a significant prognostic factor in TNBC patients, especially in adjuvant chemotherapy cases.
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Goldstein, Bree G., Hann-Hsiang Chao, Yizeng Yang, Yuliya A. Yermolina, John W. Tobias, and Jonathan P. Katz. "Overexpression of Krüppel-like factor 5 in esophageal epithelia in vivo leads to increased proliferation in basal but not suprabasal cells." American Journal of Physiology-Gastrointestinal and Liver Physiology 292, no. 6 (June 2007): G1784—G1792. http://dx.doi.org/10.1152/ajpgi.00541.2006.
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Krüppel-like factor 5 ( Klf5; also called IKLF or BTEB2), a zinc-finger transcription factor with proproliferative and transforming properties in vitro, is expressed in proliferating cells of gastrointestinal tract epithelia, including in basal cells of the esophagus. Thus, Klf5 is an excellent candidate to regulate esophageal epithelial proliferation in vivo. Nonetheless, the function of Klf5 in esophageal epithelial homeostasis and tumorigenesis in vivo has not previously been determined. Here, we used the ED- L2 promoter of the Epstein-Barr virus to express Klf5 throughout esophageal epithelia. ED-L2/ Klf5 transgenic mice were born at the appropriate Mendelian ratio, survived to at least 1 yr of age, and showed no evidence of esophageal dysplasia or cancer. Staining for bromodeoxyuridine (BrdU) demonstrated increased proliferation in the basal layer of ED-L2/ Klf5 mice, but no proliferation was seen in suprabasal cells, despite ectopic expression of Klf5 in these cells. Notably, expression of the KLF family member Klf4, which binds the same DNA sequences as Klf5 and which inhibits proliferation and promotes differentiation, was not altered in ED-L2/ Klf5 transgenic mice. In primary esophageal keratinocytes that overexpressed Klf5, expression of Klf4 still inhibited proliferation and promoted differentiation, providing a possible mechanism for the persistence of keratinocyte differentiation in ED-L2/ Klf5 mice. To identify additional targets for Klf5 in esophageal epithelia, we performed functional genomic analyses and identified a total of 15 differentially expressed genes. In summary, while Klf5 positively regulates proliferation in basal cells, it is not sufficient to maintain proliferation in the esophageal epithelium.
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Liu, Sandy. "CK13 expression in prostate tumors of patients with bone metastases at diagnosis." Journal of Clinical Oncology 34, no. 2_suppl (January 10, 2016): 257. http://dx.doi.org/10.1200/jco.2016.34.2_suppl.257.
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257 CK13 Expression in Prostate Tumors of Patients with Bone Metastases at Diagnosis Sandy T. Liu, Radu Cadaneanu, Kevin Lai, Bao Zhang, Haibo Liu, Lihong Huo, Colette Galet, William Aronson, Matthew Rettig, Michael Lewis, Isla P. Garraway; University of California Los Angeles, Los Angeles, CA Background: Biomarkers of lethal prostate cancer (PCa) are needed for appropriate clinical management. Benign stem/progenitor (S/P) cells reside in the basal layer of prostatic ducts/acini and function as cells of origin for PCa. Aggressive tumor cells may co-opt properties of S/P cells, such as mechanisms of resistance to castration. Distinct prostate epithelial populations, including stem-like tubule-initiating cells (TIC), basal cells (BC), and luminal cells (LC) can be isolated from benign prostate tissue. In this study, gene expression analysis was performed on benign prostate to identify TIC markers that may persist in cancer. Methods: Microarray analysis was performed on Epcam+CD44-CD49fHi TIC, Epcam+CD44+CD49fHi BC, and Epcam+CD44-CD49fLoLC using Affymetrix Array. Data was analyzed using Partek Genomics and validated with RT-PCR. Immunohistochemistry (IHC) was performed on 1) prostate tissue microarray (TMA) from 332 prostatectomies 2) pretreatment tissue from stage M1 patients and 3) post-treatment prostate tissue. Results: Affymetrix identified increased cytokeratin 13 (CK13) expression in TIC relative to BC and LC. Rare CK13+ epithelia are seen in ducts/acini of benign prostate tissue. TMA IHC revealed CK13+ cancer cores in 9% of cases, and significantly correlated with recurrence (p = 0.031), progression to castration-resistance (p = 0.05), and metastases (p = 0.009). Biopsy tissue from hormone-naive patients with diffuse bone metastases displayed CK13+ tumors in primary and metastatic foci. Epithelial cells populating residual prostate glands following radiation and ADT also displayed CK13 expression. Conclusions: CK13+ tumors reflect a “stem-like” state, enabling survival in low-androgen conditions and interactions that support invasion/metastases. Further characterization of CK13+ PCa variants could lead to clinical trials investigating agents that may prevent/treat dissemination and progression.
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Rabe, Brian, Anna Lyubetskaya, Andrew Kavran, Yulong Bai, Andrew Fisher, Hannah Pliner, Alba Font-Tello, et al. "Abstract B081: In situ multi-modal characterization of pancreatic ductal adenocarcinoma reveals tumor cell identity as a defining factor of the surrounding microenvironment." Cancer Research 84, no. 17_Supplement_2 (September 15, 2024): B081. http://dx.doi.org/10.1158/1538-7445.pancreatic24-b081.
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Abstract Pancreatic Ductal Adenocarcinoma (PDAC) is heterogeneous with low tumor purity, prominent microenvironment and complex architecture, which preclude identification of shared tumor intrinsic biology within and across patients. We overcame these challenges by applying complementary spatial omics approaches – providing necessary resolution and context – to primary untreated PDAC tumors from 39 patients capturing 341,949 low-bulk and 531,718 single-cell spatial transcriptomes. Of these, 59,403 low-bulk profiles and 205,665 single-cells represented tumor cells. We leveraged this data to build on prior reports of tumor cell subtypes in PDAC. We identify 5 distinct malignant subtypes, excluding ductal-like and intraepithelial neoplasia cells, that span the classical-to-basal spectrum. One tumor subtype is highly proliferative and enriched for the DNA synthesis-condensation-mitosis transcriptional network suggesting this subset disproportionately contribute to tumor growth. Strikingly, the spectrum of tumor cell subtypes was present within all patients, suggesting that subtype-based treatment stratification may need refinement. We find that each subtype has its own distinct regulators and histology. The classical subtype has extensive cell intrinsic regulation, higher cell density and lower extracellular matrix content. In contrast, the basal subtype phenotype results from a combination of cell intrinsic and tumor microenvironment (TME) interactions, wherein the basal subtype has a lower cell density, is surrounded by activated stroma and dense collagen matrix, and is poised for hypoxic adaptation. We derive the composition of cellular neighborhoods providing an explanation for the complex architecture seen in PDAC. Tumor cell neighborhoods stratified based on which side of the classical-to-basal spectrum they fell. For example, cells towards the classical-side of the spectrum had more homogenous tumor neighborhoods that generally lacked intermediate and basal tumor cells. In contrast, cells towards the basal-side of the spectrum were likely to contain classical neighbors. More broadly, neighborhoods along this continuum also contained different proportions of immune and stromal cells, cell densities, collagen deposition, and TME adaptation. These observations support a model where tumor subtypes exist within disparate niches. Lastly, our atlas unifies the catalog of previously reported stromal cells (fibroblasts and stellate cells versus myofibroblastic and inflammatory cancer associated fibroblasts (CAF)) and describes a novel interferon stimulated gene (ISG) resistance signature (ISG.RS) fibroblast. We map the location of these various stromal cells relative to tumor subtypes. For example, myofibroblast CAFs and ISG.RS fibroblasts are enriched near the basal tumor subtype whereas inflammatory CAF abundance increases with distance away from tumor cells. In sum, our atlas provides a lens for stratifying tumor complexity in a cancer cell centric manner and provides a path for testing therapeutic hypothesis in the right cell subtype and context. Citation Format: Brian Rabe, Anna Lyubetskaya, Andrew Kavran, Yulong Bai, Andrew Fisher, Hannah Pliner, Alba Font-Tello, Anne Lewin, Ruifeng Hu, Alexandre P Alloy, Yelena Cheng, Chao Dai, Yunfan Fan, Constance Brett, Todd Brett, Lauren Giampapa, Soeren Stahlschmidt, Fayaz Seifuddin, Steven Vasquez Grinnell, Daniel Carrera, Carlos Rios, Tom Lila, Pradeep Kar, Abhishek Shukla, Rachael Bashford Rogers, Lara Heij, Mike Mason, Ryan Golhar, Isaac Neuhaus, Enas Abu Shah, Shivan Sivakumar, Jimena Trillo Tinoco, Benjamin J Chen, Konstantinos J Mavrakis, Eugene Drokhlyansky. In situ multi-modal characterization of pancreatic ductal adenocarcinoma reveals tumor cell identity as a defining factor of the surrounding microenvironment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B081.
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Rajagopal, Padma, Sonya Reid, Run Fan, Lindsay Venton, Anne Weidner, Mya Roberson, Susan Vadaparampil, et al. "Abstract PO1-15-04: Young Black Women With Triple-Negative Breast Cancer Molecular Subtypes: Population-Specific Patterns and Batch Effect Considerations." Cancer Research 84, no. 9_Supplement (May 2, 2024): PO1–15–04—PO1–15–04. http://dx.doi.org/10.1158/1538-7445.sabcs23-po1-15-04.
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Abstract Introduction: While triple-negative breast cancer (TNBC) molecular subtypes have been associated with biological differences and clinical outcomes, studies have overwhelmingly been conducted in populations of European or Asian ancestry. Data collected across diverse populations is required to better leverage clinical directions from translational studies in TNBC. Through females recruited through the Black Women: Etiology and Survival of Triple-Negative Breast Cancers (BEST) study, we sought to characterize subtypes and explore associations. Methods: Our study included Black women diagnosed with early-stage (I-III) invasive TNBC at < = age 50 from 2005 to 2016, with recruitment from Florida and Tennessee state cancer registries. Germline DNA, tumor RNA, clinical outcomes, and risk factor data were collected. TNBC status in the BEST study was based on immunohistochemistry from pathology reports, cancer registry data, and self-reported data. Analyses on banked tumor samples, extracted at multiple time points, were conducted through PAM50 (Nanostring) and whole-transcriptome RNA-seq. TNBC subtype was assessed using TNBCtype-4 (Lehmann et al. 2016). Sources of batch effect were evaluated using PCA and corrected via limma. Genetic ancestry based on OncoArray or MEGA genotyping data was inferred using 1000Genomes continental reference samples. Immune cell characterization was performed via CIBERSORT and ESTIMATE. Statistical significance in comparing differences across subtypes was assessed via Chi-square test. Kaplan-Meier estimates and log-rank test were used for survival analysis. Results: RNA-seq from 114 self-reported Black females with TNBC was analyzed. TNBC subtype distribution in the BEST study cohort included 31.6% basal-like 1 (BL1), 28.9% basal-like 2 (BL2), 16.7% luminal androgen receptor (LAR), and 21.9% mesenchymal (M). While results were largely consistent with prior studies in patients of European or East Asian ancestry, a higher percentage of BL2 subtype was observed (28.9% vs. 21.0%, p=0.053). Based on PAM50 subtyping, 100% of tumors with BL1 and M were basal, whereas 68.8% of LAR and 86.7% of BL2 subtypes were basal. Tumors without subtype decreased from 9.8% to 1.1% after batch correcting for location at which RNA was extracted (Moffitt vs. Vanderbilt) and time between RNA banking and sequencing. All TNBC subtypes in this population demonstrated monocyte/activated dendritic cell predominance, with no significant subtype-specific associations with immune cell patterns. A lower relative proportion of M subtype was found in tumors from BRCA1/2 carriers, but this was not statistically significant due to the small number of carriers (8% vs. 18%; p=0.22). With a median follow-up time of 9 years, there was no significant difference in 10-year overall survival by TNBC subtype (p=0.18). However, patients with M subtype appeared to have worse survival relative to other subtypes combined (p=0.036). Conclusion: Our study is among the largest to date that interrogates TNBC subtypes and associated molecular/clinical data in self-reported Black females with invasive breast cancer. Our findings suggest that established TNBC subtyping can be applied in patients of African ancestry. Furthermore, data to correct for lab-based confounders remains critical; in this study, it enabled us to use many samples that could not be subtyped initially. Several population-specific patterns were observed, including no difference in 10-year overall survival across TNBC subtypes (consistent with prior data), but worse initial outcomes in M subtype; a preliminary association between BRCA1/2 carriers and non-M subtypes (in contrast to prior data); and no significant difference in immune cell distributions (in contrast to prior data mainly from patients of European ancestry). Studies of associations between TNBC subtypes, additional clinical data, and treatment data (type and response rates) are ongoing. Citation Format: Padma Rajagopal, Sonya Reid, Run Fan, Lindsay Venton, Anne Weidner, Mya Roberson, Susan Vadaparampil, Xuefeng Wang, Sean Yoder, Marilin Rosa, Jibril Hirbo, Jennifer Whisenant, Jennifer Pietenpol, Fei Ye, Tuya Pal, Brian Lehmann. Young Black Women With Triple-Negative Breast Cancer Molecular Subtypes: Population-Specific Patterns and Batch Effect Considerations [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 PO1-15-04.
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Huggins-Puhalla, Shannon Leigh, Jan Hendrik Beumer, Leonard Joseph Appleman, Hussein Abdul-Hassan Tawbi, Ronald G. Stoller, Yan Lin, Brian Kiesel, et al. "A phase I study of chronically dosed, single-agent veliparib (ABT-888) in patients (pts) with either BRCA 1/2-mutated cancer (BRCA+), platinum-refractory ovarian cancer, or basal-like breast cancer (BRCA-wt)." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 3054. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.3054.
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3054 Background: Veliparib (ABT-888) is an oral, potent inhibitor of PARP 1/2. Preclinically, PARP inhibitors have activity in tumors with defective homologous recombination (HR), particularly those that are BRCA+. Reduced levels of BRCA expression have been observed in ovarian cancer and basal-like breast cancer, which share genotypic and phenotypic similarities with BRCA+ cancers. We postulated that these tumors types may be similarly sensitive to single-agent PARP inhibition. This study sought to establish the maximum tolerated dose (MTD), dose limiting toxicities (DLT), pharmacokinetic and pharmocodynamic properties, and preliminary efficacy of chronically-dosed veliparib. Methods: A 3+3 dose escalation phase I trial was performed. Nine dose levels (DL) were planned, and dose escalation started at 50 mg BID to a maximum of 500 mg BID. Veliparib was administered orally continuously on a 28 day cycle. Results: 63 pts have been enrolled to date. Thirty-eight were BRCA+ (20 ovary, 12 breast, 2 pancreas, and one each - prostate, peritoneal, fallopian tube, endometrial); 25 BRCA-wt. (21 breast, 4 ovarian). DLTs occurred at the following dose levels: BRCA+: gr. 2 thrombocytopenia at 50 mg BID; BRCA+: gr.3 Nausea/vomiting at 400 mg BID; BRCA-wt: gr 2 seizure at 400 mg BID. The MTD has not been determined and 500 mg BID is presently enrolling. Notable toxicities have included low-grade fatigue and nausea. PK was linear and non-saturable with t ½ of 5 h. The number of cycles administered ranged from 1- 15, median 2. In BRCA+ pts, there were 2 partial responses (breast, ovarian) and 10 pts had evidence of prolonged SD ≥ 4 months. In BRCA-wt pts, there was 1 PR (breast) and 7 pts with SD≥ 4 months. Correlative studies, including assessment of PAR inhibition and BRCA methylation status, are ongoing. Conclusions: Veliparib is tolerable on a continuous oral dosing schedule with evidence of anti-tumor activity seen in BRCA+ and BRCA-wt tumors. A mandatory biopsy expansion cohort is planned at the recommended phase II dose, which will allow further insights regarding efficacy and mechanisms of resistance to PARP inhibition.
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Glynn, Sharon A., Dibyangana Bhattacharyya, Shauna Lambe, Emma Kerr, Simon McDade, Faizan H. Khan, Eoin Dervan, Feng Wang-Johanning, Sean Hynes, and Grace Callagy. "Abstract P3-06-05: Human endogenous retrovirus-K (HERV-K) is aberrantly expressed in triple negative breast cancer (TNBC) and associated with increased distant metastasis: Impact of HERV-K knockdown on gene expression patterns and invasive potential of mesenchymal TNBC." Cancer Research 82, no. 4_Supplement (February 15, 2022): P3–06–05—P3–06–05. http://dx.doi.org/10.1158/1538-7445.sabcs21-p3-06-05.
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Abstract Background: Human endogenous retrovirus K (HERV-K) belongs to a family of endogenous retroviruses that are present in our genome with similarities to present day exogenous retroviruses. HERV-K, like other endogenous retroviruses, is transmitted vertically in a Mendelian fashion through the human genome. This virus can express several proteins but our knowledge of HERV-K expression in human cancers is mainly limited to the envelope (Env) protein. Elevated HERV-K env protein expression has been shown in breast cancer both in in vitro and in vivo studies. Previous work from this laboratory has shown increased HERV-K expression in blood is predictive of a prostate cancer diagnosis. Aims & Experimental Approach: This project aimed to decipher whether individual HERV-K proteins (Env and Gag) display differential association with histological type, molecular subtype and patient outcomes in an Irish cohort of triple negative breast cancer patients (n=177). Additionally we aimed to assess the impact of HERV-K targeting shRNA mediated knockdown on TNBC characteristics including cell migration, invasion and proliferative capacity in 2D and 3D cell culture models. RNA seq and bioinformatics analysis was performed to identify key molecular processes regulated by HERV-K in TNBC. Results: HERV-K Env expression showed a trend towards an association with poor survival in TNBC (Log rank test, p=0.105), while HERV-K Gag was not found to be associated with survival. HERV-K Env positive metastatic patients had an increased involvement of the bone and lungs compared to HERV-K Env negative patients, while HERV-K gag positive patients showed reduced liver metastasis involvement. Knockdown of HERV-K in TNBC cell lines MDA-MB-231 and MDA-MB-468 reduced their proliferative, migratory and invasive potential. Preliminary screens using a cancer drug target array shows significantly reduced expression of HDAC4, a regulator of cell growth and the anti-apoptotic protein. GSEA analysis of RNAseq data from MDA-MB-231 HERV-K shRNA knockdown demonstrated enrichment for genes associated with both the Charafe downregulated in Luminal A versus Mesenchymal gene signature (p= 5.14x10-133), and the Charafe downregulated in Luminal A versus Basal gene signature (p= 7.03x10-110), indicating that HERV-K may play an important role in mesenchymal and basal phenotype TNBC. Additionally pathway analysis points toward a role in the regulation of many different pathways and cellular process, including focal adhesion (p= 9.77x10-7), cellular senescence (p= 7.63x10-7) and viral signalling pathways (p= 6.86x10-14). Discussion: Reduced rates of migration, invasion and proliferation in HERV-K knockdowns points towards the essential role of HERV-K in tumorigenesis and metastasis. HERV-K knockdown also modulated key gene expression signatures traditionally associated with the basal and mesenchymal phenotypes in breast cancer. Taken together, our findings indicate that HERV-K may be a useful molecular target for the treatment of TNBC. Citation Format: Sharon A Glynn, Dibyangana Bhattacharyya, Shauna Lambe, Emma Kerr, Simon McDade, Faizan H Khan, Eoin Dervan, Feng Wang-Johanning, Sean Hynes, Grace Callagy. Human endogenous retrovirus-K (HERV-K) is aberrantly expressed in triple negative breast cancer (TNBC) and associated with increased distant metastasis: Impact of HERV-K knockdown on gene expression patterns and invasive potential of mesenchymal TNBC [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 P3-06-05.
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Rusanen, Peter, Emilia Marttila, Sajeen Bahadur Amatya, Jaana Hagström, Johanna Uittamo, Justus Reunanen, Riina Rautemaa-Richardson, and Tuula Salo. "Expression of Toll-like receptors in oral squamous cell carcinoma." PLOS ONE 19, no. 4 (April 9, 2024): e0300437. http://dx.doi.org/10.1371/journal.pone.0300437.
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Almost 380,000 new cases of oral cancer were reported worldwide in 2020. Oral squamous cell carcinoma (OSCC) accounts for 90% of all types of oral cancers. Emerging studies have shown association of Toll-like receptors (TLRs) in carcinogenesis. The present study aimed to investigate the expression levels and tissue localization of TRL1 to TRL10 and NF-κB between OSCC and healthy oral mucosa, as well as effect of Candida colonization in TRL expression in OSCC. Full thickness biopsies and microbial samples from 30 newly diagnosed primary OSCC patients and 26 health controls were collected. The expression of TLR1 to TLR10 and NF-κB was analyzed by immunohistochemistry. Microbial samples were collected from oral mucosa to detect Candida. OSCC epithelium showed lower staining intensity of TRL1, TRL2 TRL5, and TRL8 as compared to healthy controls. Similarly, staining intensity of TRL3, TRL4, TRL7, and TRL8 were significantly decreased in basement membrane (BM) zone. Likewise, OSCC endothelium showed lower staining intensity of TLR4, TLR7 and TLR8. Expression of NF-κB was significantly stronger in normal healthy tissue compared to OSCC sample. Positive correlation was found between the expression of NF-κB, TRL9 and TRL10 in basal layer of the infiltrative zone OSCC samples (P = 0.04 and P = 0.002, respectively). Significant increase in TRL4 was seen in BM zone of sample colonized with Candida (P = 0.01). According to the limited number of samples, our data indicates downregulation of TLRs and NF-κB in OSCC, and upregulation of TLR4 expression with presence of Candida.
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Saillard, Charlie, Flore Delecourt, Benoit Schmauch, Olivier Moindrot, Magali Svrcek, Armelle Bardier-Dupas, Jean Francois Emile, et al. "Identification of pancreatic adenocarcinoma molecular subtypes on histology slides using deep learning models." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 4141. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.4141.
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4141 Background: Pancreatic adenocarcinoma (PAC) is predicted to be the second cause of death by cancer in 2030 and its prognosis has seen little improvement in the last decades. PAC is a very heterogeneous tumor with preeminent stroma and multiple histological aspects. Omic studies confirmed its molecular heterogeneity, possibly one of the main factors explaining the failure of most clinical trials. Two and three transcriptomic subtypes of tumor cells and stroma respectively, were described with major prognostic and predictive implications. The tumor subtypes, Basal-like and Classical, have been shown by several groups to be predictive of the response to first line chemotherapy. As of today, these subtypes can only be defined by RNA profiling which is limited by the quantity and quality of the samples (formalin fixation and low cellularity) as well as by the analytical delay that may restrict its application in routine care. In addition, tumors may harbor a mixture of several subtypes limiting their interpretation using bulk transcriptomic approaches and thereby their clinical use. Here, we propose a multistep approach using deep learning models to predict tumor components and their molecular subtypes on routine histological preparations. Methods: 728 whole-slide digitized histological slides corresponding to 350 consecutive resected PAC from four centers with clinical and transcriptomic data were assembled and used as a discovery set. PAC from TCGA (n = 134) was used as a validation set. Tumor regions from slides of the discovery set were annotated to train a multistep deep learning model that first recognizes tumor tissue and then predicts tumor and stroma cells molecular subtypes assessed by the published PurIST algorithm. Results: The tumor detection model was very efficient (AUC = 0.98 in the TCGA validation cohort). In the discovery set, the Basal-like/Classical classification performance of the model by cross validation was 0.79 (AUC) and reached 0.86 when restricted to samples with a high-confidence RNA-defined molecular subtype.Subtypes defined by the model were independently associated with overall survival in multivariate analysis (HR = 2.56 [1.87 - 3.49], pval < 0.001), and association was higher relatively to PurIST RNA subtypes (HR = 1.60 [1.17 - 2.19] pval < 0.001). In the validation cohort, the model had an overall AUC of 0.82, and 0.89 in the subset of “subtype-pure” tumors. In addition to demonstrating the value of histology-based deep learning models for tumor subtyping in PAC, these results also show the limit of molecular-based subtyping in highly heterogeneous samples. Conclusions: This study provides the first PAC subtyping tool usable worldwide in clinical practice, finally opening the possibility of patient molecular stratification in routine care and clinical trials.
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Barry, Rory, Jennifer Boggs, Máirín McMenamin, and Rupert Barry. "P009 Cylindrocarcinoma: a rare entity." British Journal of Dermatology 191, Supplement_1 (June 28, 2024): i18—i19. http://dx.doi.org/10.1093/bjd/ljae090.036.
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Abstract A 73-year-old man was referred from a secondary hospital to the dermatology department with a 2-year history of a biopsy-reported recurrent basal cell carcinoma on the left nasal ala. Full-skin examination revealed a solitary 20 × 11-mm, slightly tender, pink-coloured nodule. His past medical history was significant for multiple nonmelanoma skin cancers and colon cancer. No regular medications were prescribed. Mohs micrographic surgery was performed, with two layers required for margin clearance. The Mohs debulk described a carcinoma with features suggestive of a cylindrocarcinoma with necrosis and a high mitotic rate. On immunohistochemical profiling, tumour cells were strongly positive for S0X10, p63 and p53; had multifocal moderate positive staining for S100; had membranous staining for BerEP4; and were focally positive for CD117. Tumour cells were negative for epithelial membrane antigen, calponin, smooth muscle actin, keratin 20, chromogranin, GATA3 and p16. A PET-CT scan was performed, which ruled out any metastatic disease. No clinical recurrence has been observed 8 months after excision. Cylindromas are benign adnexal neoplasms, usually arising on the head and neck. Malignant transformation of these tumours has been reported only rarely, with fewer than 50 cases in the literature. A female predominance has been noted in both benign and malignant cylindromas. Nineteen cases of metastatic disease have been described, typically in the high-grade form of this malignant tumour, with spread to local lymph nodes or distant viscera. Histopathologically, cylindrocarcinomas may show a salivary gland-type basal cell adenocarcinoma-like pattern. Depending on the grade of the tumour, basaloid cells vary in size and degree of nuclear pleomorphism, and are surrounded by a hyaline eosinophilic sheath. Loss of the hyaline sheath network in a jigsaw pattern can be recognized by partial or complete loss of periodic acid–Schiff positivity in malignant cases. Focal to extensive tumour necrosis is frequently seen. Lymphovascular or perineural invasion is not typically identified. The similar clinical characteristics of cylindrocarcinomas to basal cell carcinomas prompt an important differential diagnosis for dermatology clinicians to be aware of, given the metastatic potential. The rapid growth over 2 years in our case is atypical for basal cell carcinomas and more in keeping with cylindrocarcinomas, as documented in previous case reports of this rare tumour. This case also highlights the merits of reviewing histology slides from the original referring centre when performing Mohs micrographic surgery.
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Jones, H. E., L. Goddard, J. M. W. Gee, S. Hiscox, M. Rubini, D. Barrow, J. M. Knowlden, S. Williams, A. E. Wakeling, and R. I. Nicholson. "Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells." Endocrine-Related Cancer 11, no. 4 (December 2004): 793–814. http://dx.doi.org/10.1677/erc.1.00799.
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De novo and acquired resistance to the anti-tumour drug gefitinib (ZD1839; Iressa), a specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) has been reported. We have determined whether signalling through the IGF-I receptor (IGF-1R) pathway plays a role in the gefitinib-acquired resistance phenotype. Continuous exposure of EGFR-positive MCF-7-derived tamoxifen resistant breast cancer cells (TAM-R) to 1 μM gefitinib resulted in a sustained growth inhibition (90%) for 4 months before the surviving cells resumed proliferation. A stable gefitinib-resistant subline (TAM/TKI-R) was established after a further 2 months and this showed no detectable basal phosphorylated EGFR activity. Compared with the parental TAM-R cells, the TAM/ TKI-R cells demonstrated (a) elevated levels of activated IGF-1R, AKT and protein kinase C (PKC)δ, (b) an increased sensitivity to growth inhibition by the IGF-1R TKI AG1024 and (c) an increased migratory capacity that was reduced by AG1024 treatment. Similarly, the EGFR-positive androgen-independent human prostate cancer cell line DU145 was also continuously challenged with 1 μM gefitinib and, although substantial growth inhibition (60%) was seen initially, a gefitinib-resistant variant (DU145/TKI-R) developed after 3 months. Like their breast cancer counterparts, the DU145/TKI-R cells showed increases in the levels of components of the IGF-1R signalling pathway and an elevated sensitivity to growth inhibition by AG1024 compared with the parent DU145 cell line. Additionally, DU145/TKI-R cell migration was also decreased by this inhibitor. We have therefore concluded that in breast and prostate cancer cells acquired resistance to gefitinib is associated with increased signalling via the IGF-1R pathway, which also plays a role in the invasive capacity of the gefitinib-resistant phenotype.
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Vaklavas, Christos, Vandana Gupta Abramson, Nancy U. Lin, Minetta C. Liu, Hope S. Rugo, Rita Nanda, Anna Maria Storniolo, et al. "TBCRC 019: An open label, randomized, phase II trial of nanoparticle albumin-bound paclitaxel (nab-PAC) with or without the anti-death receptor 5 (DR5) monoclonal antibody tigatuzumab (TIG) in patients with metastatic triple negative breast cancer (TNBC)." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 1052. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.1052.
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1052 Background: TIG, an agonistic anti-DR5 monoclonal antibody, triggers apoptosis in DR5+ human tumor cells without the aid of crosslinking. TIG has shown strong in vitro and in vivo activity against basal-like breast cancer cells that is enhanced by chemotherapy like paclitaxel. Methods: Randomized 2:1 phase II trial of nab-PAC with/without TIG in TNBC patients. Patients stratified by prior exposure to chemotherapy in the metastatic setting. Patients received nab-PAC weekly x 3 and TIG every other week, every 28 days. Primary endpoint was overall response rate (ORR). Secondary objectives were safety, progression free survival (PFS), TIG immunogenicity, and PK. Biopsies and circulating tumor cells were collected. The trial was not powered to compare arms but allowed early stopping for futility and was sized to estimate ORR with 95% CI. Results: 64 patients enrolled, 60 treated; 39 in the combination arm and 21 in the nab-PAC arm. Of the 39 in the combination arm, there were 2 CR, 9 PR (1 near CR, 96% tumor reduction), 11 SD and 17 PD; ORR 28% (95% CI 14%-42%). Of the 21 in the single agent arm, there were no CR, 8 PR, 4 SD and 9 PD; ORR 38% (95% CI 17%-59%). Higher ORRs were seen in the chemotherapy naïve patients (58% vs. 15% combination and 42% vs. 35% single agent). 2 patients with CR, 1 near CR, and 1 PR in the combination arm are still on therapy (602+, 531+, 466+, 460+ days). PFS was similar in both groups (3.6 months); higher in chemotherapy naïve patients. Combination was well tolerated (most toxicities grade 1/2); the most common AEs were fatigue, alopecia, peripheral sensory neuropathy, anemia, neutropenia, nausea, thrombocytopenia, anorexia, diarrhea, and vomiting. No grade 4 or 5 toxicity. No apparent added toxicity with TIG was seen. Conclusions: Combination therapy with nab-PAC + TIG was well tolerated, without apparent improvement in ORR relative to nab-PAC alone; however, 4 subjects treated as first-line had prolonged clinical benefit with the combination, and correlative studies will investigate markers that might predict clinical outcome (Next-Gen genomic analysis). Clinical trial information: F101004001.
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Iwase, H., Y. Yamamoto, J. Kurebayashi, H. Tsuda, T. Ota, M. Kurosumi, K. Miyamoto, and T. Iwase. "Clinicopathologic and prognostic features of triple-negative breast cancer analyzed in registration data of the Japanese Breast Cancer Society, 11705 cases." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e22122-e22122. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e22122.
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e22122 Background: Triple-negative (TN) breast cancers which are negative for ER, PgR, and HER2 by immunohistochemistry are associated with a poor prognosis. To clarify the characteristics of TN tumors, the data of the registration committee of the Japanese Breast Cancer Society were analyzed with respect to clinicopathologic factors, response to neoadjuvant chemotherapy (NAC) and prognosis. Methods: Of 14,748 cases that were registered in 2004, 11,705 cases (79.4%) were examined for ER, PgR, and HER2 status, which was based on local institute. In the 2,331 cases of all registered cases, the prognosis and details of the treatment were analyzed with 47.8 months as median follow-up period. In 184 cases (7.9%), NAC was mainly performed using anthracycline and taxane based chemotherapy. Results: Luminal A type with positive for ER and/or PgR and negative for HER2 was most prevalent (53.8%), followed by TN type (15.5%). TN cancers were diagnosed at a slightly advanced stage and more of the cases had lymph node metastases compared to other types. Mucinous or tubular carcinoma was frequently seen in the Luminal A type. Squamous cell, spindle cell carcinoma, or metaplastic carcinoma with bone/cartilage metaplasia was found in only TN type. The HER2 type and TN type had statistically worse outcome compared to Luminal type in DFS and OS (P<.0001 and P<.0001, respectively). Pathological response rate of NAC, including grade 2 and 3, was higher in TN tumor as 51.5 % (22/53) than in Luminal A tumor as 16.7% (12/72). Responders in TN tumors have a better prognosis than non-responder (P=.0016), but this tendency was not recognized in non-TN tumors (P=.15). Conclusions: The ratio of the TN tumors in Japan was 15–6%. Central reviews of immunohistochemistry, such as ER, PgR, HER2, CK5/6, EGFR etc, will be confirmed in this cohort, for TN tumors are similar to basal-like tumors discriminated by gene- profiling. [Table: see text]
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Gamal, Sameh, Nefertiti A. El-Nikhely, Hesham Nematallah, and Hesham M. Saeed. "Abstract 4317: The role of autophagy in triple negative breast cancer." Cancer Research 84, no. 6_Supplement (March 22, 2024): 4317. http://dx.doi.org/10.1158/1538-7445.am2024-4317.
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Abstract Breast cancer (BC) remains a global health concern, being the most common cancer amongst women in the world, and the second-leading cause of cancer related death. Triple-negative breast cancer (TNBC) represents a challenging frontier in oncology, characterized by its aggressiveness and its unique molecular profile devoid of the known receptors. Its elusiveness lies in the inherent heterogeneity within its subtypes, contributing to diverse clinical behaviours and treatment responses. TNBC has also shown elevated basal autophagy level as a pro-survival mechanism to make up for the increased nutrients demand mandated by the high K-RAS signalling. To tackle such tumour, we chose an autophagy blocker in addition to multi-kinase inhibitor. The combination index calculated for the proposed drugs has shown promising results in reduction of cell viability more than each drug separately. Selectivity index proved the safety of our doses on normal fibroblast cells in contrast to two breast cancer cell lines (MDA-MB 231 & MCF7). To further complement the findings, cell cycle arrest was witnessed at S phase which lead to apoptosis seen by flowcytometry and other expression analysis studies. Finally, Imaging studies and expression analysis on protein level have documented the apoptotic effects rendered by autophagy inhibition.Research endeavours continue to unravel the intricate landscape of TNBC, seeking novel avenues for targeted treatments, immunotherapies, and personalized medicine, aiming to transform the paradigm of care for those affected by this enigmatic form of breast cancer. As evident from the results, our combination has also managed to reduce the cells migration effectively which reflects that it can be initiated with aggressive metastatic tumours like TNBC. Citation Format: Sameh Gamal, Nefertiti A. El-Nikhely, Hesham Nematallah, Hesham M. Saeed. The role of autophagy in triple negative breast cancer [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 4317.
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Turner, Nicholas, Jorge Reis-Filho, Matthew Goetz, Christine Desmedt, Sarat Chandarlapaty, Hironobu Sasano, Carlos Arteaga, et al. "Abstract GS03-06: Genomic and transcriptomic profiling of primary tumors from patients with HR+, HER2-, node-positive, high-risk early breast cancer in the monarchE trial." Cancer Research 84, no. 9_Supplement (May 2, 2024): GS03–06—GS03–06. http://dx.doi.org/10.1158/1538-7445.sabcs23-gs03-06.
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Abstract Background Two years of adjuvant abemaciclib combined with endocrine therapy (ET) resulted in significant and clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in patients (pts) with HR+, HER2-, node-positive, high-risk early breast cancer in the monarchE trial (NCT03155997). Abemaciclib benefit was sustained beyond the completion of treatment (tx) with deepening magnitude of absolute benefit in IDFS and DRFS at 5 years. Here, we evaluate comprehensive molecular profiling of archived primary tumor tissue and association with clinical outcomes. Methods For biomarker analysis, a proportionally stratified random sampling case-cohort design was utilized to include all patients who experienced an IDFS event at a pre-specified interim analysis with a median follow up of 54 months. A cohort of 895 pts (189 with IDFS event) in the abemaciclib + ET arm was matched 1:1 with 903 pts (270 with IDFS event) in the ET arm. Baseline primary tumor samples underwent exome-capture RNA sequencing (RNAseq; n=1324, 23% intent-to-treat (ITT) population) and paired tumor-normal (germline blood samples) whole-exome sequencing (WES; n=1234, 22% ITT population). Expression-based intrinsic subtypes (i.e., luminal A (LumA), luminal B (LumB), HER2-enriched (HER2E), basal- and normal-like) were characterized using the Absolute Intrinsic Molecular Subtyping model. The 21-gene expression signature score (Oncotype DX test) was inferred from RNAseq; samples were categorized into lower (0-25) and high (26-100) risk groups. To investigate associations of biomarkers with abemaciclib benefit, WES genomic events including oncogenic and hotspot mutations by OncoKB, and copy number events, of incidence >9% were pre-selected. Results The biomarker subset of monarchE was reflective of the ITT population. A total of 1190 tumors (abemaciclib+ET n= 605; ET alone n=585) yielded adequate RNAseq results. Intrinsic subtype distribution was consistent across tx arms (Table A). Low tumor purity limited assessment of the normal-like subtype. The 4-year IDFS benefit of abemaciclib was consistent across all subtypes. LumA cancers had the lowest risk of recurrence while HER2E and basal-like subtypes had the highest. Inferred 21-gene expression signature score showed similar benefits from abemaciclib in both lower and high-risk groups (Table B). A total of 1173 tumors yielded adequate WES results (abemaciclib+ET n=580; ET alone n=593). Consistent abemaciclib benefit was observed across the most frequently altered genes (Table C). In exploratory analysis, lower benefit from abemaciclib was seen in the subset of focal-high level MYC amplified tumors (n=176, HR 1.30, 95% CI, 0.77, 2.20) compared to MYC non-amplified tumors (n=997, HR 0.62, 95% CI, 0.47, 0.80, nominal interaction p=0.014). The treatment benefit of abemaciclib was observed across all subpopulations of altered genes based on gene expression data. Conclusions Adjuvant abemaciclib+ET maintained IDFS benefit compared to ET alone across all molecular subtypes as measured by RNAseq. Benefit was consistent across most altered genes assessed by WES, except for the subset of tumors with MYC amplification. Additional research is necessary to confirm these findings. Table. Citation Format: Nicholas Turner, Jorge Reis-Filho, Matthew Goetz, Christine Desmedt, Sarat Chandarlapaty, Hironobu Sasano, Carlos Arteaga, Sherene Loi, Stephanie Graff, Deli Liu, Vanessa Rodrik-Outmezguine, Anthony Sireci, Cynthia Sandoval Rubenstein, Helen Won, Lacey M. Litchfield, Maria Munoz, Stephen Johnston. Genomic and transcriptomic profiling of primary tumors from patients with HR+, HER2-, node-positive, high-risk early breast cancer in the monarchE 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 GS03-06.
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Reyes, Giovanna Merchand, Ramasamy Santhanam, Frank H. Robledo Avila, Christoph Weigel, Juan D. Ruiz Rosado, Xiaokui Mo, Santiago Partida Sanchez, et al. "Abstract LB050: Targeting cells in the microenvironment as a novel therapeutic strategy for chronic lymphocytic leukemia." Cancer Research 82, no. 12_Supplement (June 15, 2022): LB050. http://dx.doi.org/10.1158/1538-7445.am2022-lb050.
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Abstract Chronic lymphocytic leukemia (CLL) is a disease that affects the elderly, characterized by the accumulation of mature B cells in the bloodstream. With an estimation incidence of 21,250 new cases diagnosed and 4,320 deaths for 2021, CLL is still considered a non-curable disease despite the wide therapeutic alternatives. CLL, like other malignant diseases, involves the activity of different cells in the microenvironment that support the leukemic cells by providing survival signals, even in presence of therapeutic agents. Among these cells, nurse-like cells (NLC) are of great importance. NLCs are M2-like macrophages known to be developed from blood monocytes, which need close contact with CLL cells for both their differentiation and their protective function. They provide multiple survival signals to CLL cells, and protect them against agents like the BTK inhibitor ibrutinib. Despite their relevance, little research has been done to elucidate the program that drives NLC differentiation. Here, we addressed this question by looking at the DNA methylation signatures before and after NLC differentiation. We found that NLC differentiation produced a marked DNA hypomethylation when compared to freshly isolated monocytes, characterized by the enrichment in AP-1 transcription binding sites. AP-1 is known to be regulated by MAP kinases, so we decided to chemically inhibit these pathways and found that specific MEK inhibition lead to reduced numbers of NLCs in vitro. Further studies showed that indeed NLCs have an activated MEK signaling as seen by the basal phosphorylation of ERK in vitro by confocal microscopy. We then used the adoptive transfer Eµ-TCL1 mice model to seek the effect of MEK inhibition in vivo. By treating the mice with trametinib, an FDA-approved MEK inhibitor, we found an increase in mouse survival when compared with the vehicle control. In addition, we observed a reduced number of monocyte/macrophage populations, especially in those expressing EGR2, a known M2 marker, suggesting that MEK inhibition causes a disruption in CLL-supportive macrophages both in vitro and in vivo. In conclusion, we observed that NLC differentiation strongly depends on the MEK signaling pathway, and that its inhibition leads to reduced myeloid supportive cells for CLL cells, followed by a reduced leukemic progression and increased CLL survival in vivo. Thus, we propose that MEK inhibition could be a potential therapeutic alternative for CLL. Further research is ongoing to determine how MEK signaling is activated during NLC differentiation. Citation Format: Giovanna Merchand Reyes, Ramasamy Santhanam, Frank H. Robledo Avila, Christoph Weigel, Juan D. Ruiz Rosado, Xiaokui Mo, Santiago Partida Sanchez, Jennifer A. Woyach, Christopher C. Oakes, Susheela Tridandapani, Jonathan P. Butchar. Targeting cells in the microenvironment as a novel therapeutic strategy for chronic lymphocytic leukemia [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 LB050.
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Ciruelos, Eva, Tomás Pascual, Mafalda Oliveira, Santiago Escrivá-de-Romaní, Sonia Pernas, Laia Paré, Barbara Adamo, et al. "Abstract PD8-03: Palbociclib and trastuzumab for HER2-positive metastatic breast cancer (SOLTI-1303 PATRICIA): Final results from cohort A and B, prospective, open-label, multicenter phase II study." Cancer Research 82, no. 4_Supplement (February 15, 2022): PD8–03—PD8–03. http://dx.doi.org/10.1158/1538-7445.sabcs21-pd8-03.
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Abstract Background: CDK4/6 inhibition combined with anti-HER2 therapy is currently being explored in HER2-positive (HER2+) breast cancer (BC). Here, we report the final efficacy and genomic analysis of cohort A and B of the PATRICIA phase II trial evaluating palbociclib in combination with trastuzumab in advanced HER2+ BC. Methods: PATRICIA is a prospective, open-label, multicenter phase II trial. Patients had received 2-4 prior lines of anti-HER2-based regimens. Treatment consisted of palbociclib 200 mg daily for 2 weeks and 1 week off plus trastuzumab. The study was based on a Simon two-stage design comprising three cohorts: estrogen receptor (ER)-negative (cohort A), ER-positive (cohort B1), and ER-positive with letrozole (cohort B2). Patients with ER-positive tumors were randomized to cohorts B1 or B2. Primary endpoint was progression-free survival (PFS) rate at 6 months (PFS6). Secondary objectives included PFS, overall survival (OS) and the association of the research-based PAM50 intrinsic subtyping with PFS and OS. PAM50 was performed from FFPE samples using the nCounter platform. For each sample we calculated the PAM50 signature scores (Basal-like, HER2-E, Luminal A and B, Normal-like), CES, ROR-Subtype, ROR-proliferation and the proliferation signature score. Multivariable Cox regression analyses evaluating PAM50 subtypes, age, performance status, treatment line, type of biopsy, and ER status. Results: Seventy-one patients were recruited (n = 15 in cohort A and 28 in each cohort B). Median follow-up was 42.3 months (IQR 34.7-54.8). The PFS6 rate in cohorts A, B1, and B2 was 33.3% (5/15), 42.8% (12/28), and 46.4% (13/28), respectively. Median PFS was 4.2 months (95% CI 0.7-6.7) in cohort A, 6.0 months (95% CI 4.0-10.6) in cohort B1 and 5.1 months (95% CI 3.7-9.1) in cohort B2. Regarding PAM50, 59 (83.1%) tumors samples (42.4% metastasis) were profiled. 49.2% of the tumor samples were identified as HER2-E, followed by Luminal B (22.0%), Luminal A (16.9%), normal-like (10.2%), and Basal-like (1.7%). Luminal disease defined by PAM50 was independently associated with longer PFS compared with non-luminal disease (10.6 vs. 4.2 months median PFS; adjusted hazard ratio [HR] = 0.34; P = 0.007). Median OS was 21.8 months (95% CI 13.8-32.2) in cohort A, 28.0 months (95% CI 14.2-48.8) in cohort B1 and 34.3 months (95% CI 20.6-47.6) in cohort B2. Luminal disease defined by PAM50 was not independently associated with OS compared with non-luminal disease (34.3 vs. 26.1 months; adjusted HR = 0.753; P = 0.365). Among the 9 PAM50 signatures, expression of 3 signatures were found significantly associated with OS: CES (HR = 0.50; p=0.021), Luminal A score (HR=0.33; p=0.022) and ROR-S (HR=1.018; p=0.027). Conclusion: Our analysis shows that the promising PFS previously reported in trastuzumab pretreated ER-positive/HER2+ advanced breast cancer with a PAM50 Luminal A or B subtype were maintained after a median of >3 years of follow-up. A longer OS was seen in patients with luminal tumors, but results were not statistically significant and could have been influenced by the low sample size. Cohort C of PATRICIA is currently randomizing patients with HR-positive/HER2+, PAM50 Luminal A or B tumors to palbociclib and endocrine therapy plus trastuzumab or treatment of physician’s choice (NCT02448420). Acknowledgements: This study is sponsored by SOLTI and financially supported by Pfizer Citation Format: Eva Ciruelos, Tomás Pascual, Mafalda Oliveira, Santiago Escrivá-de-Romaní, Sonia Pernas, Laia Paré, Barbara Adamo, Eduardo Martínez, Javier Cortés, Antonia Perelló, Maria Galan, Mireia Melé, Pablo Tolosa, Blanca González-Farré, Patricia Galván, Jordi Canes, Paolo Nuciforo, Xavier Gonzalez, Patricia Villagrasa, Aleix Prat. Palbociclib and trastuzumab for HER2-positive metastatic breast cancer (SOLTI-1303 PATRICIA): Final results from cohort A and B, prospective, open-label, multicenter phase II study [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 PD8-03.
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Bellmunt, Joaquim. "Stem-Like Signature Predicting Disease Progression in Early Stage Bladder Cancer. The Role of E2F3 and SOX4." Biomedicines 6, no. 3 (August 2, 2018): 85. http://dx.doi.org/10.3390/biomedicines6030085.
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The rapid development of the cancer stem cells (CSC) field, together with powerful genome-wide screening techniques, have provided the basis for the development of future alternative and reliable therapies aimed at targeting tumor-initiating cell populations. Urothelial bladder cancer stem cells (BCSCs) that were identified for the first time in 2009 are heterogenous and originate from multiple cell types; including urothelial stem cells and differentiated cell types—basal, intermediate stratum and umbrella cells Some studies hypothesize that BCSCs do not necessarily arise from normal stem cells but might derive from differentiated progenies following mutational insults and acquisition of tumorigenic properties. Conversely, there is data that normal bladder tissues can generate CSCs through mutations. Prognostic risk stratification by identification of predictive markers is of major importance in the management of urothelial cell carcinoma (UCC) patients. Several stem cell markers have been linked to recurrence or progression. The CD44v8-10 to standard CD44-ratio (total ratio of all CD44 alternative splicing isoforms) in urothelial cancer has been shown to be closely associated with tumor progression and aggressiveness. ALDH1, has also been reported to be associated with BCSCs and a worse prognosis in a large number of studies. UCC include low-grade and high-grade non-muscle invasive bladder cancer (NMIBC) and high-grade muscle invasive bladder cancer (MIBC). Important genetic defects characterize the distinct pathways in each one of the stages and probably grades. As an example, amplification of chromosome 6p22 is one of the most frequent changes seen in MIBC and might act as an early event in tumor progression. Interestingly, among NMIBC there is a much higher rate of amplification in high-grade NMIBC compared to low grade NMIBC. CDKAL1, E2F3 and SOX4 are highly expressed in patients with the chromosomal 6p22 amplification aside from other six well known genes (ID4, MBOAT1, LINC00340, PRL, and HDGFL1). Based on that, SOX4, E2F3 or 6q22.3 amplifications might represent potential targets in this tumor type. Focusing more in SOX4, it seems to exert its critical regulatory functions upstream of the Snail, Zeb, and Twist family of transcriptional inducers of EMT (epithelial–mesenchymal transition), but without directly affecting their expression as seen in several cell lines of the Cancer Cell Line Encyclopedia (CCLE) project. SOX4 gene expression correlates with advanced cancer stages and poor survival rate in bladder cancer, supporting a potential role as a regulator of the bladder CSC properties. SOX4 might serve as a biomarker of the aggressive phenotype, also underlying progression from NMIBC to MIBC. The amplicon in chromosome 6 contains SOX4 and E2F3 and is frequently found amplified in bladder cancer. These genes/amplicons might be a potential target for therapy. As an existing hypothesis is that chromatin deregulation through enhancers or super-enhancers might be the underlying mechanism responsible of this deregulation, a potential way to target these transcription factors could be through epigenetic modifiers.
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Basho, Reva K., Clinton Yam, Jason B. White, Li Zhao, Lei Huo, Elizabeth A. Mittendorf, Alastair Mark Thompson, et al. "Incidence of PI3K pathway alteration and response to neoadjuvant therapy (NAT) in triple negative breast cancer (TNBC) subtypes." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 561. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.561.
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561 Background: Limited cell line and human data suggest that TNBCs characterized as mesenchymal and luminal androgen receptor (LAR) commonly have alterations in the PI3K pathway. More data is needed to better characterize the role of the PI3K pathway across TNBC subtypes. Methods: Pre-treatment tumor biopsies were collected from operable TNBC patients (pts) enrolled on a clinical trial of genomically tailored NAT (ARTEMIS; NCT02276443). Tumors were categorized into 5 groups using the Pietenpol criteria: basal-like (BL) comprised of BL-1 and BL-2, mesenchymal and mesenchymal stem-like (M), immunomodulatory (IM), LAR, or unspecified (UNS). Using whole exome sequencing data, variants (single nucleotide polymorphisms and insertions/deletions) and copy number variations (CNVs) were identified in 32 genes known to activate the PI3K pathway. Results: Tumor subtyping and pathologic response to NAT was available in 127 pts (clinical stage I: 9; II: 84; III: 34). PI3K pathway alteration defined as a variant in one of the evaluated genes and/or deletion of PTEN was seen in 76 (60%) tumors. The most frequent alterations were: PTEN deletion (21%), PIK3CA variant (11%), and PIK3R1 variant (8%). PI3K alteration and residual cancer burden (RCB) rates across TNBC subtypes are shown in the table. There was a significant difference in pathologic complete response (pCR)/RCB 0 rate after NAT across TNBC subtypes (chi2 test; P = 0.02). There was a significant difference in the incidence of PI3K pathway alteration across TNBC subtypes (chi2 test; P < 0.01). Overall, the presence of PI3K alteration was not associated with pCR (Fisher exact test; P = 0.85). Pts with M tumors had a higher rate of substantial residual disease (RCB II-III) after NAT. Presence of PI3K pathway alteration was common in the M subtype and associated with RCB II-III (82% in PI3K-altered vs 33% in wild-type tumors; Fisher exact test; P = 0.02). Presence of PI3K pathway alteration was common but not associated with response in the LAR subtype. Conclusions: The incidence of PI3K pathway alteration varied by TNBC subtype but was not associated with pathologic response to NAT with the exception of increased substantial residual disease (RCB II-III) in the M subtype. [Table: see text]
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Johnson, Gary L., Keith D. Amos, James S. Duncan, Marty Whittle, Jon Zawistowki, Dan Goulet, Xiaping He, et al. "Kinome reprogramming response to MEK inhibition: A window-of-opportunity trial in triple-negative breast cancer (TNBC)." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 512. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.512.
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512 Background: Targeted therapy (Rx) in TNBC is challenging due to heterogeneity and cancer cell kinome “reprogramming” in response to targeted kinase inhibitors (Cell 149:307, 2012). In preclinical TNBC models specific kinases (e.g., DDR1/2, PDGFRbeta, VEGFR2, AXL) are activated in response to MEK inhibition. Our studies define unique kinome reprogramming in basal-like (BBC) versus claudin-low (CL). This study compared kinome profiles of TNBC pre- and post- MEK1/2 inhibition with GSK1120212 (trametinib, T) using multiplexed inhibitor beads coupled with mass spectrometry (MIB/MS). Methods: Eligible patients (pts) with untreated TNBC received T (initial dose 1.5mg/d raised after interim analysis of kinome effects to 2mg/d) for 7 days preceding breast surgery. Fresh tumor tissue was obtained before and after T. Kinase activation state was analyzed as post:pre(-)treatment ratio; molecular subtype was by gene expression analysis. Results: Kinome response profiling was completed in 7 of 9 pts by abstract submission. Toxicities included grade 2 (2pts) or grade 1 (1pt) rash, grade 1 diarrhea (1pt), and grade 1 nausea (1pt). Two of the 9 pts profiled did not have sufficient pre-treatment tumor for kinome analysis. Molecular subtypes included 6 BBC patients (one of which was CL after T), 2 CL patients (one of which was BBC after T), and 1 normal-like patient (which was BBC after T). MEK1/2 inhibition and kinase reprogramming was seen in 6 of the 7 tumors where both pre- and post T samples could be analyzed. The results show kinome reprogramming in response to MEK1/2 inhibition occurs in human tumors similar to preclinical modeling in TNBC cell lines and credentialed engineered mouse models; the kinase reprogramming pattern differed between BBC and CL. Conclusions: MEK1/2 inhibition upregulates and activates specific receptor tyrosine kinases in BBC that are different from CL.A subset of BBC and CL may have plasticity, changing their molecular subtype and kinome profile, and responding heterogeneously to MEK1/2 inhibition. Analysis of kinome reprogramming identifies upregulation of druggable targets for individual patients that suggest rational combinations with MEK inhibition in TNBC. Clinical trial information: NCT01467310.
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Bedi, Deepa, Rachel Martini, Melissa B. Davis, and Clayton Yates. "Abstract B101: Obesity mediates altered triple-negative breast cancer tumor biology in African American women independent of ancestry." Cancer Epidemiology, Biomarkers & Prevention 32, no. 12_Supplement (December 1, 2023): B101. http://dx.doi.org/10.1158/1538-7755.disp23-b101.
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Abstract African American (AA) breast cancer (BC) is associated with a higher incidence of aggressive BC phenotypes at younger age, higher grade of tumor as compared to BCs of age-matched patients of European American (EA). For AA women, there is a higher frequency of the more aggressive TNBC subtype and of the PAM50-molecular basal subtype. AA tumors are enriched for inflammatory and immune pathways, implicating inherited susceptibility associated with African ancestry. Obesity induces a state of low-grade inflammation. AA women tend to be more obese than EA and have elevated a inflammatory markers, including CRP, IL6, and IL1. Since inflammation related to obesity is a reflection of dysfunctional adipocyte biology, we used dataset GSE88837 to perform in silico analysis of gene expression changes in visceral adipose tissue for AAs and EAs. AA adipose tissue is more inflamed than EAs at the same level of obesity (BMI>30). There was a high expression of secreted mediators causing systemic inflammation, including heat shock protein 60 (HSPD1), CXCL1, S100A9, and SPP1. VEGFA, S100A9, and SPP, tumor-promoting angiogenic mediators, were higher in obese AAs than EAs. These data indicate that obesity enhances inflammation in visceral adipose tissue of AAs. We performed in silico analysis of dataset GSE78958, of 400 BC patients annotated for race, BMI, and hormone receptor expression. We analyzed BC patients for differential gene expression, PAM50 subtype, tumor stage and grade, based on race and BMI. AA women have a higher BMI (48.9%) than EA women (32.3%) and a higher percentage of poorly differentiated tumors (51.1%) than EAs (40.6%). AA women with BMI >30, had more basal-like tumors (34.8%) than EA women (19.3%). These analyses confirm that excess adiposity promotes the basal BC phenotype. With BMI >30 as a criterion for obesity, the GSE78958 dataset containing BCs for 96 AA and 200 EA patients was analyzed for differences in gene expression. DEGs showed upregulation of T cell exhaustion marker PTPN22 and LAIR2. The metastasis and proliferation promoting chemokines CXCL1, CCL2, CXC12, CXCR4, and S100A9 were higher in the BCs of obese AAs, than BCs of non-obese AAs. Stemness related genes, STAT1, SOX4, and KLF4, were higher in BCs of obese AAs. CD163-expressing M2 macrophages were higher in BCs of obese AAs. Our group showed that there was a considerable overlap of genes among African and AA cases, but there were some non-overlapping genes indicating that ancestry alone cannot explain the genetic diversity in the tumor phenotype of AA patients. The divergence was largely driven by an upregulated gene signature found among AAs and not seen among African patients. GSE78958 (obesity BC dataset) was mapped for ancestral correlation of altered genes in the AA BC dataset. Ancestry mapping showed an inverse correlation of HSPD1 with ancestry. Obesity upregulated HSPD1 in BCs of AAs as well as in AA adipose tissue and decreased the probability of survival for women of AA ethnicity, suggesting delineation of ancestry-specific and race-specific effects. Citation Format: Deepa Bedi, Rachel Martini, Melissa B. Davis, Clayton Yates. Obesity mediates altered triple-negative breast cancer tumor biology in African American women independent of ancestry [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B101.
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Sousa, Elisa Rodrigues, Eugenio Zoni, Mario Scarpa, Marta De Menna, Allen Abey Alexander, Simone De Brot, George N. Thalmann, and Marianna Kruithof-de Julio. "Abstract 22: A new transgenic mouse model to explore the role of Cripto signaling in lethal prostate cancer." Cancer Research 83, no. 7_Supplement (April 4, 2023): 22. http://dx.doi.org/10.1158/1538-7445.am2023-22.
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Abstract Introduction: Prostate cancer (PCa) at its early stages is treated with surgery or androgen-deprivation therapy, but PCa can turn castration resistant possibly due to pre-existing stem cell-like cells that reinitiate tumor growth and lead to metastasis. Given that human tumors express high levels of the oncofetal Cripto, our hypothesis is that Cripto might play a role in PCa initiation and progression, so we conditionally knock out Cripto in GEMMs models representative of early and late metastatic PCa to study its oncogenic potential. Methods: Conditional Cripto knock out (CRIPTOflox/flox) was performed on N (Nkx3.1CreERT2, R26 LSL-YFP/LSL-YFP), NP (Nkx3.1CreERT2; Ptenflox/flox, R26 LSL-YFP/LSL-YFP) and NPK (Nkx3.1CreERT2; Ptenflox/flox; KrasLSL-G12D/+, R26 LSL-YFP/LSL-YFP) to generate respectively NC, NPC and NPKC. Normal epithelium is mirrored by N animals, whereas first stage of the disease, high-grade prostatic intraepithelial neoplasia (PIN)/carcinoma lesions with local invasive epithelium, are seen in NP. The advanced stage of PCa with metastasis formation is developed in NPK. In vivo experiments presented the following workflow: 8-weeks old mice were castrated and induced one month later with 5 daily injections of tamoxifen, after 2.5 weeks animals were weekly treated with testosterone (10 weeks). Single cells were isolated from prostate tissue and the YFP+/− population recovered by FACS sorting and cultured as organoids. Results: Published PCa models N, NP and NPK were confirmed. The histopathological evaluation of newly generated NPC and NPKC shows presence of mPIN (100%, nNPC= 6, nNPKC=5), with a dominant cribriform morphology. NPKC presents invasive PCa with an extent dominant pattern of 100%. Invasive portions in NPKC present dense stroma forming whorl-like structures and occasional sheet-like accumulations of polygonal in stroma of regions with mPIN. Compared to the published models, NPC and NPKC feature a more reactive stroma with a mild/moderate inflammation. OrganoidsYFP+ recapitulate molecular prostate tissue features, expressing luminal and basal markers. Organoids’ morphology varies consistently: N and NC organoids present a more cystic morphology, with lower densities which is consistent with low-grade PIN phenotypes, whereas NP and NPK organoids are smaller and denser which mimics an oncogenic transformation. In general, NC, NPC and NPKC organoids present a higher percentage of hollow organoids compared to N, NP and NPK respectively. Conclusions: Histopathological evaluation of NPC and NPKC phenotype specifically, showed important stromal alterations suggesting that Cripto might play a role not only on the epithelial compartment as well as in the stroma. For this reason, studies on secreted Cripto inhibition with ALK4-Fc are on-going. Our finding support that organoids are an efficient in vitro model replicating different phenotypes seen in vivo. Citation Format: Elisa Rodrigues Sousa, Eugenio Zoni, Mario Scarpa, Marta De Menna, Allen Abey Alexander, Simone De Brot, George N. Thalmann, Marianna Kruithof-de Julio. A new transgenic mouse model to explore the role of Cripto signaling in lethal prostate 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 22.
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Sousa, Elisa Rodrigues, Eugenio Zoni, Mario Scarpa, Marta De Menna, Allen Abey Alexander, Simone De Brot, George N. Thalmann, and Marianna Kruithof-de Julio. "Abstract A044: Generation of a new mouse model to study the role of oncofetal Cripto in aggressive lethal prostate cancer." Cancer Research 83, no. 11_Supplement (June 2, 2023): A044. http://dx.doi.org/10.1158/1538-7445.prca2023-a044.
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Abstract Introduction: Early stages of prostate cancer (PCa) are commonly treated with surgery and androgen-deprivation therapy, but PCa can turn castration resistant due to pre-existing stem cell-like cells which might re-initiate tumor growth and lead to metastasis. Previously, it has been shown that human tumors express high levels of Cripto, an oncofetal protein, for this reason our hypothesis is that Cripto might play a role in PCa initiation and progression. We aim to study its oncogenic features in GEMMs models that are representative of early and late metastatic PCa. Methods: We performed conditional Cripto (CRIPTOflox/flox) knock out on N (Nkx3.1CreERT2, R26 LSL-YFP/LSL-YFP), NP (Nkx3.1CreERT2; Ptenflox/flox, R26 LSL-YFP/LSL-YFP) and NPK (Nkx3.1CreERT2; Ptenflox/flox; KrasLSL-G12D/+, R26 LSL-YFP/LSL-YFP) to generate respectively NC, NPC and NPKC. N animals mirror normal epithelium, whereas first stage of the disease, high-grade prostatic intraepithelial neoplasia (PIN)/carcinoma lesions with local invasive epithelium, are seen in NP. More advanced stage with invasive prostate adenocarcinoma with metastasis are developed in NPK. In vivo experiments’ workflow was the following: 8-weeks old mice were castrated and induced one month later with 5 daily injections of tamoxifen, after 2.5 weeks, animals were weekly treated with testosterone (10 weeks). Organoids were generated from YFP+/− single cell population recovered by FACS sorting. Results: Histopathological evaluation of newly generated NPC and NPKC showed presence of mPIN (100%, nNPC= 6, nNPKC=2), with a dominant cribriform morphology. NPKC additionally, features invasive PCa with an extent dominant pattern of 100%, showing portions with dense stroma forming whorl-like structures and occasional sheet-like accumulations of polygonal in stroma of regions with mPIN. In general, NPC and NPKC feature a more reactive stroma with a mild/moderate inflammation compared to the published models. OrganoidsYFP+ recapitulate molecular prostate tissue features, expressing luminal and basal markers. Organoids’ morphology varies consistently: N and NC are low in density and present a more cystic morphology, which is consistent with low-grade PIN phenotypes, whereas NP and NPK organoids are solid and denser which mimics an oncogenic transformation. In general, NC, NPC and NPKC organoids present a higher percentage of hollow organoids compared to N, NP and NPK respectively. Conclusions: NPC and NPKC phenotype specifically, showed important stromal alterations suggesting that Cripto might play a role not only on the epithelial compartment as well as in the stroma. For this reason, studies on secreted Cripto inhibition with ALK4-Fc are on-going. Our results show that organoids are an efficient in vitro model replicating different phenotypes seen in vivo. Citation Format: Elisa Rodrigues Sousa, Eugenio Zoni, Mario Scarpa, Marta De Menna, Allen Abey Alexander, Simone De Brot, George N. Thalmann, Marianna Kruithof-de Julio. Generation of a new mouse model to study the role of oncofetal Cripto in aggressive lethal prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A044.
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Guramare, Maria, Syed Ashar Javed, Christian Kirkup, Dinkar Juyal, Jacqueline Brosnan-Cashman, Victoria Mountain, Ryan Leung, et al. "Abstract PO3-07-04: Prediction of PAM50 molecular subtypes from H&E-stained breast cancer specimens using tumor microenvironment features and additive multiple instance learning models." Cancer Research 84, no. 9_Supplement (May 2, 2024): PO3–07–04—PO3–07–04. http://dx.doi.org/10.1158/1538-7445.sabcs23-po3-07-04.
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Abstract Background: PAM50, a 50-gene signature, classifies breast cancers into one of five subtypes (basal, luminal A, luminal B, HER2-enriched, and normal-like), revealing information about underlying tumor biology, and has emerged as a key prognostic indicator influencing treatment decisions. There is growing interest in bridging the gap between expression-based metrics and histopathology, where immunohistochemistry (IHC) and sequencing-based approaches have been proposed for this purpose. However, hematoxylin and eosin (H&E)-stained slides are ubiquitously utilized by pathologists for cancer diagnosis, while IHC and sequencing-based approaches require additional tissue and specialized processing and/or analysis. Here, we describe a computer vision-based approach to predict PAM50 classification using H&E-stained whole slide images (WSIs). Methods: We obtained expression-based PAM50 subtype labels and corresponding H&E-stained WSIs for 961 breast carcinomas from the TCGA BRCA cohort. We used two separate machine learning (ML) approaches to predict PAM50 subtypes from WSIs. In the first approach, we deployed previously trained PathExplore models to extract quantitative human-interpretable features (HIFs) that summarize the TME. We subsequently trained random forest classification models on these HIFs to predict PAM50 subtypes. For the second approach, we developed additive multiple instance learning (aMIL) models. Additionally, we explored the effects of PAM50 subtype labeling and aggregation strategies beyond the 5-class approach. Our 3-class approach combines Luminal A and B, as seen in IHC efforts to increase agreement with PAM50 assays, while excluding Normal, a category containing few and heterogeneous samples. We also performed binary classification for each subtype in the 3-class model (e.g. luminal vs. other). Slides were split into training (60%), validation (20%), and test (20%) sets, stratified by PAM50 labels, and model performance was assessed using the area under the receiver operator curve (AUROC) metric on the held-out test set, using a one vs. rest approach for multi-class models. To establish a baseline for PAM50 prediction, we developed random forest classification models using only clinical covariates (tumor stage, histologic grade, histological subtype, and BRCA1/2 status). Results: We compared the performance of our two ML models (HIF and aMIL) to that of the baseline model, and we report the AUROC values in Table 1. These models both performed well in predicting Basal, Luminal A, Luminal B, and Luminal (A+B), while the model performance was less strong for predictions of the HER2 and Normal classifications. The three-class model showed improved performance of predicting Luminal classifications relative to the five-class model that separates Luminal A and B. Although simplifying classification problems to a binary use case typically provides improved performance, this phenomenon was not observed for any of the PAM50 subtypes. Conclusions: These results demonstrate that AI-powered digital pathology can accurately and reproducibly perform molecular-based classification tasks, such as predicting PAM50 classifications, using WSIs, suggesting a more efficient path toward clinically relevant breast cancer characterization. Table 1. Performance of all models in predicting PAM50 molecular subtypes. AUROC values are shown. Shaded cells represent the best test-set performance for each class (row). Citation Format: Maria Guramare, Syed Ashar Javed, Christian Kirkup, Dinkar Juyal, Jacqueline Brosnan-Cashman, Victoria Mountain, Ryan Leung, Bahar Rahsepar, John Abel, Amaro Taylor-Weiner, Jake Conway. Prediction of PAM50 molecular subtypes from H&E-stained breast cancer specimens using tumor microenvironment features and additive multiple instance learning models [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 PO3-07-04.
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André, Fabrice, Regula Deurloo, Aditi Qamra, David Cameron, Joseph Gligorov, Andreas Schneeweiss, Carlos Barrios, et al. "Abstract PD10-05: Activity of atezolizumab (atezo) plus paclitaxel (pac) in metastatic triple-negative breast cancer (mTNBC) according to Burstein molecular subtype: Analysis of the IMpassion131 trial." Cancer Research 82, no. 4_Supplement (February 15, 2022): PD10–05—PD10–05. http://dx.doi.org/10.1158/1538-7445.sabcs21-pd10-05.
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Abstract Background: In contrast to the IMpassion130 trial evaluating atezo + nab-pac [Schmid, NEJM 2018], the randomized phase 3 IMpassion131 trial (NCT03125902) did not demonstrate significantly improved progression-free survival (PFS; primary endpoint) and showed no improvement in overall survival (OS; secondary endpoint) with the addition of atezo to pac as first-line therapy for mTNBC in either the PD-L1+ or the intention-to-treat (ITT) population [Miles, Ann Oncol 2021]. In IMpassion130, enhanced PFS and OS improvement with atezo + nab-pac were seen in the basal-like immune-activated (BLIA) subtype, whereas potential resistance to atezo + nab-pac was observed in the luminal androgen receptor (LAR) subtype [Emens, ASCO 2021]. LAR may be more prevalent in Asian populations [Ding, Oncotarget 2019], which represented one-third of patients enrolled in IMpassion131 and could have influenced the overall result. PFS outcomes were numerically worse in Asian vs non-Asian subgroups in IMpassion131 [Miles, Ann Oncol 2021]. To investigate potential reasons for observing different effects in IMpassion130 and IMpassion131, we explored the prevalence and impact on clinical outcomes of TNBC molecular subtypes and race in IMpassion131. Patients and Methods: Patients with mTNBC (no prior systemic therapy or ≥12 months since [neo]adjuvant chemotherapy) were randomized 2:1 to atezolizumab 840 mg or placebo (days 1, 15), both with paclitaxel 90 mg/m2 (days 1, 8, 15), every 28 days until disease progression or unacceptable toxicity, stratified by tumor PD-L1 status, prior taxane, liver metastases, and geographic region. Molecular subtypes according to Burstein classification were determined by RNA sequencing (Illumina TruSeq RNA Access) of baseline tumor samples. Prevalence of Burstein molecular subtypes [Burstein, Clin Cancer Res 2015] was assessed in Asian (of whom 69% were enrolled in China) and non-Asian populations; clinical outcomes were assessed according to molecular subtype and race using Cox proportional hazards analysis. All analyses were performed using the final data cut-off (Sep 4, 2020; median follow-up duration: 14.4 months). Results: The biomarker-evaluable population (BEP; n=471) was representative of the ITT population (n=651) with respect to baseline characteristics and PFS hazard ratio (HR; 0.75 [95% CI 0.61-0.92] vs 0.81 [95% CI 0.68-0.96], respectively). Distribution of molecular subtypes in the BEP was: 30% BLIA, 41% basal-like immune suppressed (BLIS), 24% LAR, 5% mesenchymal (MES), similar to IMpassion130. Among the BLIA samples, 82% were PD-L1+ and 18% PD-L1-; corresponding percentages were 41% vs 59% for BLIS, 31% vs 69% for LAR, and 32% vs 68% for MES. Compared with non-Asian patients, the Asian subgroup (n=117) included more LAR (31% vs 22%) and fewer MES (1% vs 6%) samples; this was particularly pronounced in the cohort enrolled in China (n=79; 37% LAR, 0% MES). PFS was improved with atezo + pac in the BLIA subtype (HR 0.66, 95% CI 0.45-0.97). None of the Burstein subgroups derived OS benefit from atezo + pac. Findings were similar irrespective of PD-L1 status. Direction of effect for PFS and OS favored the placebo + pac arm in the LAR Asian subgroup (n=30). Conclusion: In these exploratory analyses, the distribution of molecular subtypes and enhanced effect of atezo + pac in the BLIA subtype are consistent with findings from IMpassion130. The lack of improved efficacy with the combination of atezo + pac in the IMpassion131 trial cannot be explained by overrepresentation of a Burstein subtype less sensitive to atezo in the trial population. Citation Format: Fabrice André, Regula Deurloo, Aditi Qamra, David Cameron, Joseph Gligorov, Andreas Schneeweiss, Carlos Barrios, Binghe Xu, Ching-Wei Chang, Luciana Molinero, Shilpen Patel, Andrea Liptrot, Leilani Morales, David Miles, Joyce O’Shaughnessy. Activity of atezolizumab (atezo) plus paclitaxel (pac) in metastatic triple-negative breast cancer (mTNBC) according to Burstein molecular subtype: Analysis of the IMpassion131 trial [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 PD10-05.
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Jones, S. F., R. B. Cohen, E. C. Dees, Y. Lee, J. A. Papas, M. R. Cooper, K. M. Galvin, and H. A. Burris. "Phase I clinical trial of MLN8054, a selective inhibitor of Aurora A kinase." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 3577. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.3577.
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3577 Background: MLN8054 is a small molecule inhibitor of Aurora A kinase, with > 150-fold greater potency against this enzyme than the structurally related but functionally distinct Aurora B kinase. Because of its structural similarity to benzodiazepines, MLN8054 binds to the gamma-aminobutryic acid alpha 1 benzodiazepine (GABAA a1 BZD) receptor and in preclinical studies caused benzodiazepine-like CNS effects. Methods: MLN8054 was given as capsule by mouth for 7 consecutive days, repeated every 21 days. Cohorts of 3- 6 patients (pts) were enrolled to successively increasing doses until dose-limiting toxicity was seen in = 2 pts at a given dose level. Serial blood samples were collected to estimate PK; skin biopsies were obtained before and 6 hours after the first dose to assess inhibition of Aurora A kinase in basal epithelial cells. Results: 22 pts were enrolled to evaluate single daily doses of 5, 10, 20, 30 and 40 mg/day. MLN8054 was in general rapidly absorbed, displayed dose-proportionate exposure, and had a mean elimination half-life of 35 hours. The ratio of peak to trough plasma concentrations was approximately 5. Reversible grade 2 somnolence was first seen in 3 patients treated at 20 mg/day, and 2/4 patients treated at 40 mg/day experienced reversible grade 3 somnolence. In order to reduce the sedative effects of MLN8054, 16 additional pts were enrolled to doses of 25, 35, 45 and 55 mg/day given as divided doses on a QID schedule. Two of 4 pts treated at the 55 mg/day dose experienced reversible grade 3 somnolence, establishing 45 mg/day as the maximum tolerated total daily dose on a QID schedule. No myelosuppression or mucosal toxicity was seen at any dose with either schedule. Immunohistochemical analysis of skin biopsies from pts treated with once daily dosing did not demonstrate accumulation of cells in mitosis. Three pts with metastatic colorectal cancer treated with single daily doses of MLN8054 received = 8 cycles of treatment. Conclusions: The study is now escalating divided daily dosing of MLN8054 with the co-administration of methylphenidate. Post-treatment skin biopsies are now obtained on Day 7. Duration of treatment will be extended to 14 days, since steady-state concentrations of MLN8054 require 5–7 days of dosing, and because the effects of Aurora A kinase inhibition are duration-dependent. No significant financial relationships to disclose.