Journal articles on the topic 'NSCLCs'
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1
Awad, Mark M., Geoffrey R. Oxnard, David M. Jackman, Daniel O. Savukoski, Dimity Hall, Priyanka Shivdasani, Jennifer C. Heng, et al. "MET Exon 14 Mutations in Non–Small-Cell Lung Cancer Are Associated With Advanced Age and Stage-Dependent MET Genomic Amplification and c-Met Overexpression." Journal of Clinical Oncology 34, no. 7 (March 1, 2016): 721–30. http://dx.doi.org/10.1200/jco.2015.63.4600.
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Purpose Non–small-cell lung cancers (NSCLCs) harboring mutations in MET exon 14 and its flanking introns may respond to c-Met inhibitors. We sought to describe the clinical, pathologic, and genomic characteristics of patients with cancer with MET exon 14 mutations. Patients and Methods We interrogated next-generation sequencing results from 6,376 cancers to identify those harboring MET exon 14 mutations. Clinical characteristics of MET exon 14 mutated NSCLCs were compared with those of NSCLCs with activating mutations in KRAS and EGFR. Co-occurring genomic mutations and copy number alterations were identified. c-Met immunohistochemistry and real-time polymerase chain reaction to detect exon 14 skipping were performed where sufficient tissue was available. Results MET exon 14 mutations were identified in 28 of 933 nonsquamous NSCLCs (3.0%) and were not seen in other cancer types in this study. Patients with MET exon 14–mutated NSCLC were significantly older (median age, 72.5 years) than patients with EGFR-mutant (median age, 61 years; P < .001) or KRAS-mutant NSCLC (median age, 65 years; P < .001). Among patients with MET exon 14 mutations, 68% were women, and 36% were never-smokers. Stage IV MET exon 14–mutated NSCLCs were significantly more likely to have concurrent MET genomic amplification (mean ratio of MET to chromosome 7, 4.3) and strong c-Met immunohistochemical expression (mean H score, 253) than stage IA to IIIB MET exon 14–mutated NSCLCs (mean ratio of MET to chromosome 7, 1.4; P = .007; mean H score, 155; P = .002) and stage IV MET exon 14–wild-type NSCLCs (mean ratio of MET to chromosome 7, 1.2; P < .001; mean H score, 142; P < .001). A patient whose lung cancer harbored a MET exon 14 mutation with concurrent genomic amplification of the mutated MET allele experienced a major partial response to the c-Met inhibitor crizotinib. Conclusion MET exon 14 mutations represent a clinically unique molecular subtype of NSCLC. Prospective clinical trials with c-Met inhibitors will be necessary to validate MET exon 14 mutations as an important therapeutic target in NSCLC.
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Maitra, Radhashree, Parth Malik, and Tapan Kumar Mukherjee. "Targeting Estrogens and Various Estrogen-Related Receptors against Non-Small Cell Lung Cancers: A Perspective." Cancers 14, no. 1 (December 24, 2021): 80. http://dx.doi.org/10.3390/cancers14010080.
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Non-small cell lung cancers (NSCLCs) account for ~85% of lung cancer cases worldwide. Mammalian lungs are exposed to both endogenous and exogenous estrogens. The expression of estrogen receptors (ERs) in lung cancer cells has evoked the necessity to evaluate the role of estrogens in the disease progression. Estrogens, specifically 17β-estradiol, promote maturation of several tissue types including lungs. Recent epidemiologic data indicate that women have a higher risk of lung adenocarcinoma, a type of NSCLC, when compared to men, independent of smoking status. Besides ERs, pulmonary tissues both in healthy physiology and in NSCLCs also express G-protein-coupled ERs (GPERs), epidermal growth factor receptor (EGFRs), estrogen-related receptors (ERRs) and orphan nuclear receptors. Premenopausal females between the ages of 15 and 50 years synthesize a large contingent of estrogens and are at a greater risk of developing NSCLCs. Estrogen—ER/GPER/EGFR/ERR—mediated activation of various cell signaling molecules regulates NSCLC cell proliferation, survival and apoptosis. This article sheds light on the most recent achievements in the elucidation of sequential biochemical events in estrogen-activated cell signaling pathways involved in NSCLC severity with insight into the mechanism of regulation by ERs/GPERs/EGFRs/ERRs. It further discusses the success of anti-estrogen therapies against NSCLCs.
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Farago, Anna F., Martin S. Taylor, Robert C. Doebele, Viola W. Zhu, Shivaani Kummar, Alexander I. Spira, Theresa A. Boyle, et al. "Clinicopathologic Features of Non–Small-Cell Lung Cancer Harboring an NTRK Gene Fusion." JCO Precision Oncology, no. 2 (November 2018): 1–12. http://dx.doi.org/10.1200/po.18.00037.
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Purpose Gene rearrangements that involve NTRK1/2/3 can generate fusion oncoproteins that contain the kinase domains of TRKA/B/C, respectively. These fusions are rare in non–small-cell lung cancer (NSCLC), with frequency previously estimated to be < 1%. Inhibition of TRK signaling has led to dramatic responses across tumor types with NTRK fusions. Despite the potential benefit of identifying these fusions, the clinicopathologic features of NTRK fusion-positive NSCLCs are not well characterized. Methods We compiled a database of patients with NSCLCs that harbor NTRK fusions. We characterized clinical, molecular, and histologic features with central review of histology. Results We identified 11 patients with NSCLCs that harbor NTRK gene fusions verified by next-generation sequencing and with available clinical and pathologic data. Fusions involved NTRK1 (n = 7) and NTRK3 (n = 4), with five and two distinct fusion partners, respectively. Fifty-five percent of cohort patients were male with a median age at diagnosis of 47.6 years (range, 25.3 to 86.0 years) and a median smoking history of 0 pack-years (range, 0 to 58 pack-years). Seventy-three percent of patients had metastatic disease at diagnosis. No concurrent alterations in KRAS, EGFR, ALK, ROS1, or other known oncogenic drivers were identified. Nine patients had adenocarcinoma, including two with invasive mucinous adenocarcinoma and one with adenocarcinoma with neuroendocrine features; one had squamous cell carcinoma; and one had neuroendocrine carcinoma. By collating data on 4,872 consecutively screened, unique patients with NSCLC, we estimate a frequency of NTRK fusions in NSCLC of 0.23% (95% CI, 0.11% to 0.40%). Conclusion NTRK fusions occur in NSCLCs across sexes, ages, smoking histories, and histologies. Given the potent clinical activity of TRK inhibitors, we advocate that all NSCLCs be screened for NTRK fusions by using a multiplexed next-generation sequencing–based fusion assay.
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Nowinska, Jablonska, Pawelczyk, Piotrowska, Partynska, Gomulkiewicz, Ciesielska, et al. "Expression of Irisin/FNDC5 in Cancer Cells and Stromal Fibroblasts of Non-small Cell Lung Cancer." Cancers 11, no. 10 (October 11, 2019): 1538. http://dx.doi.org/10.3390/cancers11101538.
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Background: Recent in vitro studies have indicated that irisin inhibits proliferation, migration and epithelial-mesenchymal transition. Irisin expression has not been studied in tumour tissues of non-small cell lung cancer (NSCLC) patients yet. The aim of the study was to determine the irisin expression in NSCLCs in comparison to the clinicopathological factors and expression of TTF-1, p63 and Ki-67. Material and methods: Tissue microarrays with 729 NSCLC and 140 non-malignant lung tissue (NMLT) were used to perform immunohistochemical reactions. Laser Capture Microdissection (LCM) was used to collect cancer and stromal cells from NSCLCs. FNDC5 expression was tested for LCM samples, 75 NSCLCs and 25 NMLTs with the RT-PCR technique. Western-blot, immunofluorescence reaction and RT-PCR assays were performed on lung cancer cell lines. Results: Irisin expression was observed in NSCLC cancer cells and stromal fibroblasts. In cancer cells, irisin expression was decreased in higher grades (G) of malignancy, tumour size (T) and according to lymph node metastasis. In stromal cells, irisin expression was increased in higher G and advanced T. A shorter overall survival was observed in patients with higher irisin expression in NSCLC stromal cells. Conclusions: Irisin expression in stromal fibroblasts may influence cancer cell proliferation and may be a prognostic factor for survival in NSCLC.
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Yan, Dan, H. Shelton Earp, Deborah DeRyckere, and Douglas K. Graham. "Targeting MERTK and AXL in EGFR Mutant Non-Small Cell Lung Cancer." Cancers 13, no. 22 (November 11, 2021): 5639. http://dx.doi.org/10.3390/cancers13225639.
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MERTK and AXL are members of the TAM family of receptor tyrosine kinases and are abnormally expressed in 69% and 93% of non-small cell lung cancers (NSCLCs), respectively. Expression of MERTK and/or AXL provides a survival advantage for NSCLC cells and correlates with lymph node metastasis, drug resistance, and disease progression in patients with NSCLC. The TAM receptors on host tumor infiltrating cells also play important roles in the immunosuppressive tumor microenvironment. Thus, MERTK and AXL are attractive biologic targets for NSCLC treatment. Here, we will review physiologic and oncologic roles for MERTK and AXL with an emphasis on the potential to target these kinases in NSCLCs with activating EGFR mutations.
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Landre, Thierry, Gregoire Justeau, Jean-baptiste Assié, Kader Chouahnia, Chérifa Taleb, Christos Chouaid, and Boris Duchemann. "Anti PD-(L)1 in KRAS mutant advanced nsclcs: A meta-analysis of randomized controlled trials." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 9025. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.9025.
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9025 Background: KRAS comprise the most frequently found oncogene driver mutation in non-small cell lung cancer (NSCLC), accounting for 20-25% of these patients. Single-agent Anti PD-(L)1 clinical efficacy against KRAS mutant NSCLC is a topic of debate. Methods: This meta-analysis examined randomized-trial data comparing first-or second line Anti PD-(L)1 +/- chemotherapy (CT) vs CT alone for KRAS mutant advanced NSCLCs. Outcome measures included overall survival (OS) and progression-free survival (PFS). Analyses were computed using the Cochrane method of collaboration for meta-analyses, with Review Manager software (RevMan version 5.3; Oxford, UK). Results: We analyzed 3 trials in first line (IMPOWER-150, KEYNOTE-189 and KEYNOTE-042), as well as 3 trials in second line (OAK, POPLAR and CHECKMATE-057) including 1313 NSCLCs (386 KRAS mutant and 927 KRAS wild-type tumor). Anti PD-(L)1 +/- CT was significantly associated (hazard ratio [95% confidence interval]) with prolonged OS (0.59 [0.49-0.72]; p < 0.00001) and PFS (0.58 [0.43-0.78]; p = 0.0003) compared to CT alone in KRAS mutant NSCLCs. Survival benefits occured in both first and second line. Survival benefits observed in KRAS wild-type NSCLCs were (0.87 [0.76-0.99]; p = 0.03) and (0.79 [0.56-1.11]; p = 0.17) respectively. OS benefit in KRAS mutant was significantly superior compared to OS benefit in KRAS wild-type (p = 0,001). Conclusions: Anti PD-(L)1 (+/- CT) appears superior to CT alone both for mutant and wild-type KRAS in advanced NSCLCs for OS and PFS with higher magnitude of benefit in KRAS mutated group for OS.
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Liu, Jia-Chun, Suresh Narva, Kang Zhou, and Wen Zhang. "A Review on the Antitumor Activity of Various Nitrogenous-based Heterocyclic Compounds as NSCLC Inhibitors." Mini-Reviews in Medicinal Chemistry 19, no. 18 (November 29, 2019): 1517–30. http://dx.doi.org/10.2174/1389557519666190312152358.
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At present, cancers have been causing deadly fears to humans and previously unpredictable losses to health. Especially, lung cancer is one of the most common causes of cancer-related mortality accounting for approximately 15% of all cancer cases worldwide. While Non-Small Cell Lung Carcinomas (NSCLCs) makes up to 80% of lung cancer cases. The patient compliance has been weakening because of serious drug resistance and adverse drug effects. Therefore, there is an urgent need for the development of novel structural agents to inhibit NSCLCs. Nitrogen-containing heterocyclic compounds exhibit wide range of biological properties, especially antitumor activity. We reviewed some deadly defects of clinical medicines for the lung cancer therapy and importance of nitrogen based heterocyclic derivatives against NSCLCs. Nitrogen heterocycles exhibit significant antitumor activity against NSCLCs. Nitrogen heterocyclic hybrids could be developed as multi-target-directed NSCLC inhibitors and it is believed that the review is significant for rational designs and new ideas in the development of nitrogen heterocyclic-based drugs.
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Wang, Hsiang-Sheng, Chien-Ying Liu, Sheng-Chi Hsu, Shih-Chiang Huang, Tsai-Hsien Hung, Kwai-Fong Ng, and Tse-Ching Chen. "A Single-Institute Experience with C-ros Oncogene 1 Translocation in Non-Small Cell Lung Cancers in Taiwan." International Journal of Molecular Sciences 23, no. 10 (May 21, 2022): 5789. http://dx.doi.org/10.3390/ijms23105789.
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(1) Background: The C-ros oncogene 1 (ROS1) gene translocation is an important biomarker for selecting patients for crizotinib-targeted therapy. The aim of this study was to understand the incidence, diagnostic algorithm, clinical course and objective response to crizotinib in ROS1 translocated lung non-small cell lung cancers (NSCLCs) in Taiwan. (2) Methods: First, we retrospectively studied the ROS1 status in 100 NSCLC samples using break-apart fluorescent in situ hybridization (FISH) and immunohistochemical (IHC) staining to establish a diagnostic algorithm. Then, we performed routine ROS1 IHC tests in 479 NSCLCs, as crizotinib was available from 2018 in Taiwan. We analyzed the objective response rate and the survival impact of crizotinib. (3) Results: Four ROS1 translocations were clustered in epidermal growth factor receptor (EGFR) wild-type adenocarcinomas but not in cases with EGFR mutations. Strong ROS1 expression was positively correlated with ROS1 translocation (p < 0.001). NSCLCs with ROS1 translocation had a poor prognosis compared to those without ROS1 translocation (p = 0.004) in the pre-crizotinib stage. Twenty NSCLCs were detected with ROS1 translocation in 479 wild-type EGFR specimens from 2018. Therefore, the incidence of ROS1 translocation is approximately 4.18% in EGFR wild-type NSCLCs. In these 20 ROS1 translocation cases, 19 patients received crizotinib treatment, with an objective response rate (ORR) of 78.95% (confidence interval = 69.34% to 88.56%), including 1 complete response, 14 partial responses, 3 stable cases and 1 progressive case. Overall survival and progression-free survival were better in the 19 ROS1-translocated NSCLCs of the prospective group with crizotinib treatment than the four ROS1-translocated NSCLCs of the retrospective group without crizotinib treatment. (4) Conclusions: ROS1-translocated NSCLCs had a poor prognosis and could have a beneficial outcome with crizotinib.
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Gasparini, Pierluigi, Luciano Cascione, Lorenza Landi, Stefania Carasi, Francesca Lovat, Carmelo Tibaldi, Greta Alì, et al. "microRNA classifiers are powerful diagnostic/prognostic tools in ALK-, EGFR-, and KRAS-driven lung cancers." Proceedings of the National Academy of Sciences 112, no. 48 (November 16, 2015): 14924–29. http://dx.doi.org/10.1073/pnas.1520329112.
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microRNAs (miRNAs) can act as oncosuppressors or oncogenes, induce chemoresistance or chemosensitivity, and are major posttranscriptional gene regulators. Anaplastic lymphoma kinase (ALK), EGF receptor (EGFR), and V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) are major drivers of non-small cell lung cancer (NSCLC). The aim of this study was to assess the miRNA profiles of NSCLCs driven by translocated ALK, mutant EGFR, or mutant KRAS to find driver-specific diagnostic and prognostic miRNA signatures. A total of 85 formalin-fixed, paraffin-embedded samples were considered: 67 primary NSCLCs and 18 matched normal lung tissues. Of the 67 primary NSCLCs, 17 were echinoderm microtubule-associated protein-like 4–ALK translocated (ALK+) lung cancers; the remaining 50 were not (ALK−). Of the 50 ALK− primary NSCLCs, 24 were EGFR and KRAS mutation-negative (i.e., WT; triple negative); 11 were mutant EGFR (EGFR+), and 15 were mutant KRAS (KRAS+). We developed a diagnostic classifier that shows how miR-1253, miR-504, and miR-26a-5p expression levels can classify NSCLCs as ALK-translocated, mutant EGFR, or mutant KRAS versus mutation-free. We also generated a prognostic classifier based on miR-769-5p and Let-7d-5p expression levels that can predict overall survival. This classifier showed better performance than the commonly used classifiers based on mutational status. Although it has several limitations, this study shows that miRNA signatures and classifiers have great potential as powerful, cost-effective next-generation tools to improve and complement current genetic tests. Further studies of these miRNAs can help define their roles in NSCLC biology and in identifying best-performing chemotherapy regimens.
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Serresi, Michela, Bjorn Siteur, Danielle Hulsman, Carlos Company, Matthias J. Schmitt, Cor Lieftink, Ben Morris, et al. "Ezh2 inhibition in Kras-driven lung cancer amplifies inflammation and associated vulnerabilities." Journal of Experimental Medicine 215, no. 12 (November 28, 2018): 3115–35. http://dx.doi.org/10.1084/jem.20180801.
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Kras-driven non–small-cell lung cancers (NSCLCs) are a leading cause of death with limited therapeutic options. Many NSCLCs exhibit high levels of Ezh2, the enzymatic subunit of polycomb repressive complex 2 (PRC2). We tested Ezh2 inhibitors as single agents or before chemotherapy in mice with orthotopic Kras-driven NSCLC grafts, which homogeneously express Ezh2. These tumors display sensitivity to EZH2 inhibition by GSK126 but also amplify an inflammatory program involving signaling through NF-κB and genes residing in PRC2-regulated chromatin. During this process, tumor cells overcome GSK126 antiproliferative effects. We identified oncogenes that may mediate progression through an in vivo RNAi screen aimed at targets of PRC2/NF-κB. An in vitro compound screening linked GSK126-driven inflammation and therapeutic vulnerability in human cells to regulation of RNA synthesis and proteostasis. Interestingly, GSK126-treated NSCLCs in vivo also showed an enhanced response to a combination of nimesulide and bortezomib. Thus, Ezh2 inhibition may restrict cell proliferation and promote defined adaptive responses. Targeting these responses potentially improves outcomes in Kras-driven NSCLCs.
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Passaro, Antonio, Ilaria Attili, Alessandra Rappa, Davide Vacirca, Alberto Ranghiero, Caterina Fumagalli, Juliana Guarize, et al. "Genomic Characterization of Concurrent Alterations in Non-Small Cell Lung Cancer (NSCLC) Harboring Actionable Mutations." Cancers 13, no. 9 (April 30, 2021): 2172. http://dx.doi.org/10.3390/cancers13092172.
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An increasing number of driver genomic alterations with potential targeted treatments have been identified in non-small cell lung cancer (NSCLC). Much less is known about the incidence and different distribution of concurrent alterations, as identified by comprehensive genomic profiling in oncogene-addicted NSCLCs. Genomic data from advanced NSCLC consecutively analyzed using a broad next-generation sequencing panel were retrospectively collected. Tumors harboring at least one main actionable gene alteration were categorized according to the presence/absence of concurrent genomic aberrations, to evaluate different patterns among the main oncogene-addicted NSCLCs. Three-hundred-nine actionable gene alterations were identified in 284 advanced NSCLC patients during the study period. Twenty-five tumor samples (8%) displayed concurrent alterations in actionable genes. Co-occurrences involving any pathogenic variant or copy number variation (CNV) were identified in 82.8% of cases. Overall, statistically significant differences in the number of concurrent alterations, and the distribution of TP53, STK11, cyclines and receptor tyrosin kinase (RTK) aberrations were observed across the eight actionable gene groups. NGS analyses of oncogene-addicted NSCLCs showed a different distribution and pattern of co-alteration profiles. Further investigations are needed to evaluate the prognostic and treatment-related impact of these concurrent alterations, hooked to the main gene aberrations.
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Hellmann, Matthew David, Francisco Sanchez-Vega, Konnor La, Hira Rizvi, Darragh Halpenny, Andrew Plodkowski, Niamh Long, et al. "Molecular determinants of response and resistance to anti-PD-(L)1 blockade in patients with NSCLC profiled with targeted next-generation sequencing (NGS)." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 9015. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.9015.
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9015 Background: Anti-PD-(L)1 therapy has revolutionized treatment for patients (pts) with NSCLC. We previously reported that non-synonymous tumor mutation burden (TMB) by whole exome sequencing associates with immunotherapy benefit. Targeted NGS is increasingly routine in clinical practice and may be a useful tool for predicting benefit to anti-PD-(L)1 blockade. Methods: Pts had advanced NSCLC treated with anti-PD-(L)1 (+/- aCTLA-4) therapy and profiling by hybrid-capture NGS of 341-468 genes (MSK-IMPACT). Efficacy assessed by RECIST v1.1; durable clinical benefit (DCB) defined as PR or SD > 6mo. TMB and copy number alteration burden (“fraction of genome altered”, FGA) were normalized by size of genome covered. Comparisons were also made to a cohort of all NSCLCs profiled by MSK-IMPACT (n = 1679). Results: Of 437 evaluable pts treated with anti-PD-(L)1, 197 (45%) had NGS profiling, of whom 30% had DCB. TMB was higher in those with DCB vs no DCB (mean 10.2 vs 7.1 SNV/MB, p = 0.02) and compared to all NSCLCs ( < 0.0001). DCB was more common and PFS was longer in pts with > vs < 85th percentile TMB of all NSCLCs (Odds ratio 2.3, 95% CI 1.1-4.9, p = 0.03; HR = 0.59, p = 0.004), but were similar when dichotomized at the 50th or 75th percentile. FGA was higher in pts with no DCB compared to all NSCLCs (p = 0.02). Molecular signatures related to deficient homologous-recombination-based DNA repair and smoking were more common in DCB vs no DCB (p = 0.042, p = 0.058) and vs all NSCLCs (p = 0.026, p = 0.01). Compared to all NSCLCs profiled by NGS, alterations in STK11and EGFRwere enriched in no DCB (p = 0.0008, p = 0.02). Alterations in JAK2and CD274(PD-L1) were uncommon (2.1%, 1.6%) but exclusively associated with no DCB. For a subset (n = 52) of these cases also profiled by whole exome sequencing, comparison with targeted NGS will be presented. Conclusions: In pts with NSCLC, targeted NGS profiling is a routinely available tool that can provide insight into predicting benefit with anti-PD-(L)1 therapy. Increased TMB associates with clinical benefit. Increased copy number alterations (FGA) and alterations in genes including STK11, JAK2, and CD274 may associate with resistance to anti-PD-(L)1 therapy.
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Skrzypski, Marcin Tomasz, Amelia Szymanowska-Narloch, Ewa Jassem, Michał Marczyk, Joanna Polanska, Wojciech Biernat, Witold Rzyman, Agnieszka Maciejewska, Ryszard Pawlowski, and Jacek Jassem. "Prognostic value of NK and T-lymphocytes markers in operable non-small cell lung cancer (NSCLC)." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 11556. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.11556.
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11556 Background: Therapies aimed at activation of T and NK cells are developed to expand NSCLC treatments options. It is conceivable that markers of ‘immune ignorant’, ‘immune excluding’ or ‘inflamed’ tumor phenotypes could be prognostic or predictive of benefit from specific immune-targeting therapies. Aim: To assess the prognostic value of expression of T and NK cells mRNA markers and immune-related genes in early stage NSCLC. Methods: qRT-PCR was used to assess 48 mRNAs levels in frozen cancer tissue sections and matched normal lung parenchyma from 56 surgically treated stage I-IIIA NSCLC patients. The mRNA expression (normalized vs. 4 reference genes) was compared between the groups that did (44%) or did not relapse, as well as clinicopathological features (33% never-smokers, 75% lung adenocarcinoma). Results: Low expression of FAS-L (p.adj. = 0.048) , TIGIT and LAG3 was correlated with shorter distant metastasis free survival (DMFS) (p < 0.04). Expression of PD-1 (p = 0.024) and CTLA4 (p = 0.04) was significantly lower in relapsed vs. non-relapsed NSCLCs, whereas there was no difference for PDL-1 and PDL-2. Expression of NK activation markers: NCR3 and NCR1, but not NCR3-ligand 1 was significantly lower in relapsed vs. not relapsed NSCLCs. Other NK cell markers: CD96 and NKG2D were expressed at lower levels (p = 0.02) in relapsed vs. not relapsed NSCLCs, whereas there was no difference for NKG2C and NKG2A. Expression of CXCR3 was lower in relapsed NSCLCs (p = 0.03), however, the expression of its ligands (chemoattractants for lymphocytes) - CXCL9, CXCL10 or CXCL11 or endothelin receptor type B was not different according to metastatic status. GITR and FOXP3 expression was significantly higher in cancers vs. normal lung parenchyma (p.adj. < 0.003). There were no differences in expression according to gender, smoking or NSCLC histological types. Conclusions: Non-inflamed NSCLC phenotype is associated with higher risk of dissemination after primary resection. Neoplastic tissue is characterized by higher level of immune tolerance in comparison to normal lung tissue.
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Kaplan, Benjamin G., Richard S. Huang, Lucas Dennis, Lee A. Albacker, Garrett M. Frampton, Ethan S. Sokol, and Smruthy Sivakumar. "Abstract 753: Comprehensive genomic profiling (CGP) reveals site-specific enrichment of immunotherapy biomarkers and targetable alterations in non-small cell lung cancer (NSCLC) metastasis." Cancer Research 82, no. 12_Supplement (June 15, 2022): 753. http://dx.doi.org/10.1158/1538-7445.am2022-753.
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Abstract Introduction NSCLCs are frequently identified at a later stage, with 30-40% of cases presenting with metastasis at the time of diagnosis. Metastatic progression is a major cause of cancer death, thereby making it critical to understand the genomic differences across metastatic sites and their associated treatment implications. Methods CGP was performed on 64,062 NSCLCs for all classes of alterations in at least 324 genes (Foundation Medicine, Inc.). The cohort comprised 59% lung (LB), 25% metastatic site (MB) and 17% regional/distant lymph node (LN) biopsies. A subset of 386 patients with matched LB/MB samples were examined. Tumor mutational burden (TMB) was determined on 0.8-1.1 Mb and PD-L1 IHC (DAKO 22C3) was evaluated in a subset of cases. Results MB NSCLCs comprised liver (23%), brain (23%), bone (15%), soft tissue (14%), adrenal gland (8%) and other rare sites (e.g., spine, head&neck, kidney). MB NSCLCs had elevated TMB compared to LB NSCLCs (median 7.8 v 6.3 mut/Mb; P < 10-4), most notably in brain (11.3 mut/Mb), adrenal gland (10.4 mut/Mb) and kidney (9.2 mut/Mb) MB, whereas TMB in liver MB was similar to LB (6.3 mut/Mb). Heterogeneity in PD-L1 expression (≥50%) was also observed, with higher rates in head&neck (42%), adrenal gland (40%), LN (39%), and soft tissue (35%) compared to LB (30%; all P < 0.05). Clinically informative alterations and known NSCLC drivers exhibited site-specific patterns. EGFR alterations differed by sites with the highest rates in omentum (40% v 15% LB), bone (20%) and liver (18%). Fusions in ALK, RET and ROS1 were more common in MB NSCLCs relative to LB, while MET exon 14 skipping alterations were rarer in MB NSCLCs. Liver MB had fewer KRAS alterations (21% v 31% LB, P<10-4), while brain MB had elevated rates of KRAS, KEAP and STK11 alterations (37% v 31%, 16% v 9%, 23% v 15%, respectively, P<10-4). A repertoire of genes with potential role in metastatic spread (e.g., SMARCA4, RICTOR, PIK3CG), were identified to be enriched in specific MB NSCLCs. Of note, MB NSCLCs also presented with significantly higher rates of aneuploidy across the genome. 386 patients with longitudinal LB/MB samples were available (median collection time difference = 474 days). Concordance, defined by percent positive agreement (PPA) of alterations with LB, varied by site and was highest in bone and brain MB. While truncal, driver events were often shared, short variants in PIK3CA, ARID1A and copy number alterations in MYC, RICTOR, MET and CDKN2A/2B were frequently acquired in MB. TMB was elevated in MB compared to LB in 204 cases, though only 39 patients transitioned from TMB <10 to TMB ≥10 mut/Mb status. Conclusions NSCLC metastases exhibit heterogeneity in clinically actionable alterations and immunotherapy biomarkers (PD-L1, TMB). Site-specific alterations may have clinical implications and inform the biology of metastatic progression. Citation Format: Benjamin G. Kaplan, Richard S. Huang, Lucas Dennis, Lee A. Albacker, Garrett M. Frampton, Ethan S. Sokol, Smruthy Sivakumar. Comprehensive genomic profiling (CGP) reveals site-specific enrichment of immunotherapy biomarkers and targetable alterations in non-small cell lung cancer (NSCLC) metastasis [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 753.
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Lypova, Nadiia, Susan M. Dougherty, Lilibeth Lanceta, Jason Chesney, and Yoannis Imbert-Fernandez. "PFKFB3 Inhibition Impairs Erlotinib-Induced Autophagy in NSCLCs." Cells 10, no. 7 (July 3, 2021): 1679. http://dx.doi.org/10.3390/cells10071679.
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Tyrosine kinase inhibitors (TKIs) targeting the kinase domain of the epidermal growth factor receptor (EGFR), such as erlotinib, have dramatically improved clinical outcomes of patients with EGFR-driven non-small cell lung carcinomas (NSCLCs). However, intrinsic or acquired resistance remains a clinical barrier to the success of FDA-approved EGFR TKIs. Multiple mechanisms of resistance have been identified, including the activation of prosurvival autophagy. We have previously shown that the expression and activity of PFKFB3—a known driver of glycolysis—is associated with resistance to erlotinib and that PFKFB3 inhibition improves the response of NSCLC cells to erlotinib. This study focuses on investigating the role of PFKFB3 in regulating erlotinib-driven autophagy to escape resistance to erlotinib. We evaluated the consequence of pharmacological inhibition of PFKFB3 on erlotinib-driven autophagy in NSCLC cells with different mutation statuses. Here, we identify PFKFB3 as a mediator of erlotinib-induced autophagy in NSCLCs. We demonstrate that PFKFB3 inhibition sensitizes NCSLCs to erlotinib via impairing autophagy flux. In summary, our studies uncovered a novel crosstalk between PFKFB3 and EGFR that regulates erlotinib-induced autophagy, thus contributing to erlotinib sensitivity in NSCLCs.
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Ricciuti, Biagio, Kathryn Cecilia Arbour, Joao Victor Machado Alessi, Navin Mahadevan, James Lindsay, Rileen Sinha, Natalie I. Vokes, et al. "Association of a very high tumor mutational load with increased CD8+ and PD-1+ T-cell infiltration and improved clinical outcomes to PD-(L)1 blockade across different PD-L1 expression levels in non-small cell lung cancer." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 9018. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.9018.
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9018 Background: Although high TMB correlates with improved outcomes to immune checkpoint inhibitors (ICI) in patients (pts) with non-small cell lung cancer (NSCLC), an optimal TMB cutoff to discriminate cancers most likely to respond to ICI has not been identified. Whether TMB impacts outcomes to ICI in different PD-L1 levels subgroups is also unclear. Methods: Unbiased recursive partitioning (URP) was used to identify an optimal TMB cutoff for objective response rate (ORR) in two independent cohorts of pts with NSCLC treated with ICI at DFCI and MSKCC. TCGA was interrogated to find differences in tumor immune cell subsets according to the TMB cutoff identified. Multiplexed immunofluorescence (IF) for CD8, PD-1, PD-L1, Foxp3, and CK7 was also performed on NSCLC samples at the DFCI. Results: In the DFCI (N=686) and MSKCC (N=672) cohorts, URP found an optimal TMB cutoff for ORR at 19 mutations/megabase (mut/Mb), corresponding to the ̃90th percentile in each cohort. Median progression-free (PFS) and overall survival (OS) were significantly longer in NSCLCs with TMB ≥19 mut/Mb vs <19 mut/Mb, in both cohorts (Table). After harmonizing TMB between DFCI OncoPanel and MSK-IMPACT NGS platforms, URP confirmed an optimal TMB cutoff for ORR at the 90th percentile in the combined cohort, which also associated with longer PFS/OS to ICI (Table). A TMB ≥90th percentile correlated with longer PFS/OS to ICI among NSCLCs with PD-L1 levels ≥50% and 1-49%, and longer PFS among those with PD-L1 <1% (Table). Cell subset transcriptome analysis from the TCGA showed higher proportions of CD8+ T cells (P=0.02) and M1 macrophages (P<0.01) among NSCLCs with a TMB ≥ vs <90th percentile. IF confirmed increased CD8+, CD8+ PD1+ T-cell infiltration (P<0.01), and increased CD8+/Foxp3+ ratio in NSCLC with very high TMB Conclusions: A very high TMB is associated with better outcomes to ICI and a distinct immunophenotype in NSCLC. Rational integration of TMB and PD-L1 expression may identify NSCLCs most likely to respond to ICI.[Table: see text]
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Ohashi, Kadoaki, Lecia V. Sequist, Martin Sos, Xi Chen, Charles M. Rudin, Teresa Moran, Maria E. Arcila, et al. "Characteristics of NSCLCs harboring NRAS mutations." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 7532. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.7532.
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7532 Background: We sought to determine the frequency and clinical characteristics of patients with non-small cell lung cancers (NSCLCs) harboring NRAS mutations. We used preclinical models to identify targeted therapies likely to be of benefit against NRAS mutant lung cancer cells. Methods: We reviewed data in the Catalogue of Somatic Mutations in Cancer (COSMIC) and clinical history from patients with NSCLC whose tumors underwent systematic screening for driver mutations including NRAS. Patient characteristics examined included age, gender, race, smoking history, disease stage, treatment history, and overall survival (OS). 6 NSCLC cell lines with NRAS mutations were screened for sensitivity against multiple targeted agents. Gene expression was profiled using Affymetrix U133A arrays in 5 NRAS mutant NSCLC cell lines, 8 with EGFR mutations and 17 with KRAS mutations. Results: Among 4524 patients with NSCLC tested, NRAS mutations were present in 29 (0.64%). The types of substitutions found were Q61H/K/L/R and G12A/C/D/R/S, with NRAS Q61L the most common (n=14; 48%). One tumor had a concurrent KRAS mutation. 83% had adenocarcinoma histology, with no significant differences in gender. While 90% of patients were former or current smokers, smoking-related G:C>T:A transversions were significantly less frequent in NRAS than in KRAS-mutant NSCLC (KRAS: 66%, NRAS: 13%, p<0.05). Systemic chemotherapy showed limited efficacy in 7 patients with metastatic disease (median OS 7 mos). 5 of 6 NRAS mutant lung cancer cell lines were sensitive to the MEK inhibitors, AZD6244 and GSK1120212, while other targeted agents (against EGFR, ALK, MET, IGF-1R, PIK3CA, BRAF) were minimally effective. Gene expression profiles of NRAS mutant cell lines were distinct from those with KRAS or EGFR mutations. Conclusions: NRAS mutations define a distinct subset of NSCLCs (~1%) with potential sensitivity to MEK inhibitors. While NRAS gene mutations are more common in current/former smokers, the types of mutations are not those classically associated with smoking.
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Rocco, Danilo, Ciro Battiloro, Luigi Della Gravara, and Cesare Gridelli. "Advanced Non-Small Cell Lung Cancer with Activating Epidermal Growth Factor Receptor Mutation: First Line Treatment and Beyond." Reviews on Recent Clinical Trials 14, no. 2 (May 31, 2019): 120–28. http://dx.doi.org/10.2174/1574887114666181205155211.
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Background:Lung cancer is the leading cause of cancer mortality, being responsible for more than 1.6 million deaths each year worldwide and non-small-cell lung cancer (NSCLC) accounts for approximately 85% of lung cancers; moreover, 10 to 15% of all NSCLCs harbor EGFR (epidermal growth factor receptor) activating mutations, being suitable for EGFR-Tyrosine Kinase Inhibitors (TKI) molecular targeted therapy. However, EGFR+ NSCLCs gain acquired resistance to these agents, representing one of the key challenges for modern precision oncology.Objective:herefore, this paper aims to provide an extensive state of the art review, alongside with hints about future perspectives.Conclusion:To date, in the light of the data from the FLAURA study, osimertinib represents the best first-line option in NSCLC patients with EGFR activating mutations; EGFR-TKI plus chemotherapy combination therapies, even though interesting, must still be considered investigational.
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Nambirajan, Aruna, Varsha Singh, Nishu Bhardwaj, Saurabh Mittal, Sunil Kumar, and Deepali Jain. "SMARCA4/BRG1–Deficient Non–Small Cell Lung Carcinomas: A Case Series and Review of the Literature." Archives of Pathology & Laboratory Medicine 145, no. 1 (April 9, 2020): 90–98. http://dx.doi.org/10.5858/arpa.2019-0633-oa.
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Context.— Somatic mutations in SMARCA4 (SWI/SNF–related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4) gene and/or BRG1 (Brahma-related gene 1) loss identifies a subset of non–small cell lung carcinomas (NSCLCs) lacking alterations in EGFR (epidermal growth factor receptor), ALK (anaplastic lymphoma kinase), and ROS1 (ROS proto-oncogene 1) genes. Preliminary observations suggest responsiveness to immunotherapy and targeted therapies. Objective.— To study BRG1 loss in NSCLCs and elucidate the clinicopathologic profile of such SMARCA4-deficient NSCLCs. Design.— Non–small cell lung carcinomas diagnosed during 6 years were subject to immunohistochemistry for BRG1 and BRM (Brahma). Tumors with BRG1 loss were stained with antibodies against thyroid transcription factor 1 (TTF-1), p40, cytokeratins, hepatocyte paraffin 1 (Hep Par 1), Sal-like protein 4 (SALL4), CD34, SRY-box 2 (SOX2), chromogranin, synaptophysin, p53, integrase interactor 1, ALK, and ROS1. EGFR mutation testing was performed by polymerase chain reaction–based method. Results.— Among 100 NSCLCs tested, 4 cases (4%) showed BRG1 loss. The histology ranged from solid adenocarcinomas (n = 1) to large cell/poorly differentiated carcinomas (n = 3) with clear cell cytology in 2 cases. All showed loss/reduction of BRM with variable cytokeratin and SALL4 expression, and were negative for TTF-1, p40, Hep Par 1, ALK, ROS1, and EGFR mutations. CD34 and SOX2 were negative in all 4 cases. Isolated BRM loss was common (21%), distributed across all NSCLC subtypes including squamous cell carcinomas and a hepatoid adenocarcinoma. Conclusions.— BRG1 loss occurs in a subset of TTF-1/p40–negative poorly differentiated NSCLCs. Identification and follow-up will clarify the prognosis, diagnostic criteria, and potential for therapeutic personalization.
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Rocha, Pedro, Jiexin Zhang, Raquel Laza-Briviesca, Alberto Cruz-Bermúdez, Katsuhiro Yoshimura, Carmen Behrens, Apar Pataer, et al. "Abstract 6152: Distinct immune gene programs associated with host tumor immunity, neoadjuvant chemotherapy and chemoimmunotherapy in resectable NSCLC." Cancer Research 82, no. 12_Supplement (June 15, 2022): 6152. http://dx.doi.org/10.1158/1538-7445.am2022-6152.
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Abstract Background: Our understanding of the immunopathology of early-stage NSCLC is still limited. While neoadjuvant immunotherapeutic strategies have recently shown anti-tumor effects in resectable NSCLC, their mechanisms remain inadequately understood. Here, we explore immune programs that inform of tumor immunity and response to neoadjuvant chemotherapy and chemoimmunotherapy in localized NSCLC. Methods: Targeted immune gene sequencing using the HTG Precision Immuno-Oncology panel was performed in localized NSCLCs from three cohorts based on treatment: naïve (n=190), neoadjuvant chemotherapy (n=38) and neoadjuvant chemoimmunotherapy (n=21). Three tumor immune microenvironment (TIME) phenotypes (inflamed, cold, excluded) were derived based on CD8+ T cell infiltration. Signatures of immune cell abundance and immune genes were statistically compared based on tumoral PD-L1 expression, immune phenotypes, associated with pathological response, and were cross-compared across the three cohorts. Results: PD-L1 positive tumors exhibited increased signature scores for various lymphoid and myeloid cell subsets (both, p<0.05). TIME phenotypes exhibited disparate frequencies by stage, PD-L1 expression, and mutational burden. Inflamed NSCLCs displayed overall significantly heightened levels of immune signatures with the excluded group representing an intermediate state. A signature of cytotoxic T cells was associated with favorable survival in neoadjuvant chemotherapy-treated NSCLCs (p<0.05). Major pathological response to chemoimmunotherapy was positively associated with CD8 T cells (p<0.05) and Th1 cells were significantly reduced post-chemoimmunotherapy (p<0.001). Among the three cohorts, chemoimmunotherapy-treated NSCLCs exhibited highest scores for various immune cell subsets including T effector and B cells (both, p<0.05). Conclusions: Our findings highlight immune gene programs that may underlie host tumor immunity and response to neoadjuvant chemotherapy and chemoimmunotherapy in early-stage NSCLC. Citation Format: Pedro Rocha, Jiexin Zhang, Raquel Laza-Briviesca, Alberto Cruz-Bermúdez, Katsuhiro Yoshimura, Carmen Behrens, Apar Pataer, Edwin Parra-Cuentas, Cara Haymaker, Junya Fujimoto, Stephen Swisher, John Heymach, Don L. Gibbons, J Jack Lee, Boris Sepesi, Tina Cascone, Luisa M. Solis, Mariano Provencio, Ignacio I. Wistuba, Humam Kadara. Distinct immune gene programs associated with host tumor immunity, neoadjuvant chemotherapy and chemoimmunotherapy in resectable NSCLC [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 6152.
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Chandra, Raghav, Josiah Flaming, Aiden Nguyen, Michael Peyton, Amit Das, Boning Gao, Steven Horrigan, Rolf Brekken, and John Minna. "919 Tegavivint reduces the immunosuppressive macrophage phenotype in a preclinical co-culture model of the non-small cell lung cancer tumor microenvironment." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A964. http://dx.doi.org/10.1136/jitc-2021-sitc2021.919.
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BackgroundActivation of the Wnt/ß-catenin pathway in non-small cell lung cancer (NSCLC) is associated with tumor growth and metastasis. Activation of this pathway in tumor cells may also modulate the immune tumor microenvironment (TME) by polarizing macrophages into an immunosuppressive M2-like phenotype. We tested whether treatment of co-cultures of human NSCLC cells, cancer-associated fibroblasts (CAFs) and macrophages with Tegavivint (Iterion Therapeutics), a novel compound that targets TBL1 to inhibit ß-catenin function that is in early-phase clinical trials, altered the phenotype of mouse macrophages in vitro.MethodsOur prior work testing a large panel of patient-derived NSCLC lines in co-cultures of CAFs and mouse bone marrow-derived macrophages (BMDMs) demonstrated that individual NSCLC lines reproducibly generated several macrophage phenotypes, one of which was immunosuppressive (high expression of Arginase-1). We prepared co-cultures of NSCLC cells (H1666 and H2009) (70%), human CAFs (25%) and mouse BMDMs (5%) and demonstrated conversion to the macrophage high Arginase-1 immunosuppressive phenotype by monitoring quantitative expression of mouse genes with qRT-PCR. Expression of ß-catenin protein relative to GAPDH by Western blot was determined before and after treatment with Tegavivint (10 and 20 nM). Co-cultures were treated with Tegavivint (10 nM) for 48 and 72 hours and qRT-PCR for mouse macrophage-specific genes reflecting an immunosuppressive M2-like or an inflammatory, immunostimulatory M1-like phenotype (Arginase-1 and iNos, respectively) was performed. Positive controls consisted of stimulation of macrophages with IL-4 and LPS (to generate M2-like and M1-like phenotypes, respectively). Cytotoxicity assays (MTS and crystal violet) to determine the IC50 of Tegavivint were performed on NSCLC and macrophage cells.ResultsTegavivint IC50 values for NSCLCs were 17–40 nM. At 10 nM, Tegavivint had no cytotoxic effect on macrophages. Treatment with Tegavivint decreased NSCLC expression of ß-catenin by ~30–40%. When co-cultures of NSCLCs, human CAFs, and mouse BMDMs were treated with 10 nM Tegavivint, we found that macrophage expression of Arginase-1 was significantly inhibited at 48 and 72 hours of treatment (figure 1).Abstract 919 Figure 1Tegavivint reduces Arginase-1 mRNA expression from macrophages co-cultured with CAFs and H1666 (A) and H2009 (B) patient-derived NSCLC cell lines after 72-hour treatment. *: p<0.05, ****: p<0.0001.ConclusionsTegavivint, at pharmacologically achievable doses and concentrations that have little or no cytotoxic effect on NSCLCs or macrophages, decreases tumor cell ß-catenin expression, and reduces the immunosuppressive macrophage phenotype (reduced macrophage Arginase-1 expression) induced by co-cultures of patient-derived NSCLCs and CAFs. These preclinical data set the stage for future clinical translation of Tegavivint as a NSCLC therapeutic in combination with immunotherapy approaches.AcknowledgementsSupported by P50 CA070907 and Physician-Scientist Institutional Award from the Burroughs Wellcome Fund (TARDIS Fellowship)
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Chang, Jia-Ming, Kam-Hong Kam, Wen-Ying Chao, Pei-Wen Zhao, Shu-Hsin Chen, Hui-Chen Chung, Yi-Zhen Li, Jin-Yi Wu, and Ying-Ray Lee. "Berberine Derivatives Suppress Cellular Proliferation and Tumorigenesis In Vitro in Human Non-Small-Cell Lung Cancer Cells." International Journal of Molecular Sciences 21, no. 12 (June 13, 2020): 4218. http://dx.doi.org/10.3390/ijms21124218.
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Lung cancer is the leading cause of death in the world, and the most common type of lung cancer is non-small-cell lung cancer (NSCLC), accounting for 85% of lung cancer. Patients with NSCLC, when detected, are mostly in a metastatic stage, and over half of patients diagnosed with NSCLC die within one year after diagnosis; the 5-year survival rate is 24%. However, in patients with metastatic NSCLC, the 5-year survival rate is 6%. Therefore, development of a new therapeutic agent or strategy is urgent for NSCLCs. Berberine has been illustrated to be a therapeutic agent of NSCLC. In the present study, we synthesized six derivatives of berberine, and the anti-NSCLC activity of these agents was examined. Some of them exert increasing proliferation inhibition comparing with berberine. Further studies demonstrated that two of the most effective agents, 9-O-decylberberrubine bromide (B6) and 9-O-dodecylberberrubine bromide (B7), performed cell cycle regulation, in-vitro tumorigenesis inhibition and autophagic flux blocking, but not induction of cellular apoptosis in NSCLC cells. Moreover, B6 and B7 were determined to be green fluorescent and could be penetrated and localized in cellular mitochondria. Herein, B6 and B7, the berberine derivatives we synthesized, revealed better anti-NSCLC activity with berberine and may be used as therapeutic candidates for the treatment of NSCLCs.
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Alessi, Joao Victor Machado, Carolyn Glass, Biagio Ricciuti, Liam F. Spurr, Lynette M. Sholl, and Mark M. Awad. "Clinicopathologic characteristics and immunotherapy outcomes in SMARCA4-mutant (mut) non-small cell lung cancer (NSCLC)." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 9577. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.9577.
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9577 Background: The catalytic unit of the SWI/SNF chromatin remodeling complex is encoded by the SMARCA4 gene, which is mutated in ~10% of NSCLCs. We sought to characterize the clinicopathologic characteristics and outcomes to immune checkpoint inhibition in SMARCA4-mutant NSCLC. Methods: We collected clinicopathologic and genomic data from patients with NSCLC that had undergone targeted next generation sequencing (NGS) by OncoPanel at the Dana-Farber Cancer Institute. SMARCA4 frameshift, nonsense, and splice-site mutations were considered pathogenic, as were missense mutations if predicted to be pathogenic by Mutation Assessor and Polyphen-2. Clinical outcomes to immune checkpoint inhibition among SMARCA4-mutant NSCLCs were retrospectively assessed. Results: Of 2690 patients with NSCLC, 8% (N = 211) harbored SMARCA4 mutations. Clinicopathological characteristics were balanced between SMARCA4 mut and SMARCA4 wild-type (wt) in terms of age, histology, and PD-L1 expression. We observed a male predominance (P = 0.03), greater use of tobacco (P < 0.001), a higher tumor mutational burden (TMB) (P < 0.001), a higher prevalence of advanced disease (P < 0.001), and a lower prevalence of concurrent targetable driver mutations (P < 0.001) in SMARCA4mut vs SMARCA4wt NSCLCs. Among 513 patients with nonsquamous NSCLC who received immune checkpoint inhibitors, 11% (N = 57) harbored SMARCA4 mutations. From the start of immunotherapy, we observed no difference in overall response rate (ORR 21.5% vs 19.3%; P = 0.3), median progression free survival (mPFS 3.2 months vs 2.1 months; P = 0.4), or median overall survival (mOS 12.0 months vs 8.2 months; P = 0.09) in SMARCA4wt vs SMARCA4mut NSCLC, respectively. However, among KRASmut NSCLC, a concurrent SMARCA4 mut conferred a significantly lower ORR (23.1% vs 0.0%; P = 0.02), a significantly shorter mPFS (4.8 months vs 1.7 month; HR: 0.31 [95% CI: 0.15-0.61]; P < 0.001), and a significantly shorter mOS (15.6 months vs 2.7 months; HR: 0.25 [95%CI: 0.12-0.49]; P < 0.001). The deleterious effect of SMARCA4 mut on immunotherapy outcomes in KRAS mut NSCLC was maintained when controlling for concurrent STK11 mut. Conclusions: SMARCA4 mutations define a genomic subset of NSCLC with unique clinicopathologic characteristics, and confer worse outcomes to immunotherapy in KRAS mut NSCLC.
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Gutierrez, Catherine, Biagio Ricciuti, Joao Victor Machado Alessi, Federica Pecci, Adriana Paula de Castro Barrichello, Victor R. Vaz, Lynette M. Sholl, and Mark M. Awad. "Impact of STK11 copy loss on clinical outcomes to PD-(L)1 blockade in non–small cell lung cancer." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): 9059. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.9059.
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9059 Background: STK11 is among the most commonly altered genes in non-squamous lung cancers. While STK11 mutation is associated with diminished efficacy of immune checkpoint inhibition (ICI), particularly in KRAS mutated tumors, it is not known whether STK11 copy deletion influences outcomes to ICI. Methods: Patients with advanced non-squamous non-small cell lung cancer (NSCLC) treated with ICI whose tumors underwent genomic profiling were included. Clinical outcomes to ICI were analyzed according to KRAS mutation and STK11 deletions. STK11 copy number variations (CNVs) were determined using an internal informatic pipeline. Kaplan-Meier methodology was used to estimate event-time distributions. Results: Of 559 patients with non-squamous NSCLCs (Nsq-NSCLC), 40.4% (N = 226) had a KRAS mutation ( KRASmut), 18.4% (N = 103) had an oncogenic STK11 mutation ( STK11mut), and 22.5% had either single (N = 123), or bi-allelic (N = 3) deletion ( STK11del). Given that 32.5% of STK11del cases had a concurrent oncogenic STK11 mutation in our cohort, to isolate the impact of STK11del on ICI outcomes we excluded samples with STK11mut from this analysis. In all comers with NSCLC, STK11del had no impact on objective response rate (22.2% versus 23.8%, P = 0.8), progression-free (PFS, HR 0.90, P = 0.30), and overall survival (OS, HR 0.96, P = 0.79) to ICI. When we examined the impact of STK11del on clinical outcomes to PD-(L)1 blockade among KRASmut cases we found that STK11del was associated with a numerically lower ORR (13.3% versus 30.0%, P = 0.12), and a significantly shorter PFS (HR 0.57, P = 0.018) compared to cases without STK11del. No difference in OS were observed between these groups (HR 0.77, P = 0.39). Among KRASwt NSCLCs, STK11del cases had a similar ORR (22.6% versus 22.9%, P = 0.99), PFS (HR 0.92, P = 0.63), and OS (HR 1.18, P = 0.32) to PD-(L)1 inhibition compared to cases without STK11del. Among KRASmut but not KRASwt NSCLCs, cases with STK11del had significantly lower PD-L1 expression compared to those without STK11 deletions (27.5% versus 70%, P = 0.01). Conclusions: STK11 deletion is associated with low response rate and short progression-free survival among KRAS mutant NSCLCs. Future analyses will incorporate additional cases to increase sample size and immunopathologic findings to assess impact of mono and bi-allelic deletion on protein expression.
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Gutierrez, Catherine, Biagio Ricciuti, Joao Victor Machado Alessi, Federica Pecci, Adriana Paula de Castro Barrichello, Victor R. Vaz, Lynette M. Sholl, and Mark M. Awad. "Impact of STK11 copy loss on clinical outcomes to PD-(L)1 blockade in non–small cell lung cancer." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): 9059. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.9059.
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9059 Background: STK11 is among the most commonly altered genes in non-squamous lung cancers. While STK11 mutation is associated with diminished efficacy of immune checkpoint inhibition (ICI), particularly in KRAS mutated tumors, it is not known whether STK11 copy deletion influences outcomes to ICI. Methods: Patients with advanced non-squamous non-small cell lung cancer (NSCLC) treated with ICI whose tumors underwent genomic profiling were included. Clinical outcomes to ICI were analyzed according to KRAS mutation and STK11 deletions. STK11 copy number variations (CNVs) were determined using an internal informatic pipeline. Kaplan-Meier methodology was used to estimate event-time distributions. Results: Of 559 patients with non-squamous NSCLCs (Nsq-NSCLC), 40.4% (N = 226) had a KRAS mutation ( KRASmut), 18.4% (N = 103) had an oncogenic STK11 mutation ( STK11mut), and 22.5% had either single (N = 123), or bi-allelic (N = 3) deletion ( STK11del). Given that 32.5% of STK11del cases had a concurrent oncogenic STK11 mutation in our cohort, to isolate the impact of STK11del on ICI outcomes we excluded samples with STK11mut from this analysis. In all comers with NSCLC, STK11del had no impact on objective response rate (22.2% versus 23.8%, P = 0.8), progression-free (PFS, HR 0.90, P = 0.30), and overall survival (OS, HR 0.96, P = 0.79) to ICI. When we examined the impact of STK11del on clinical outcomes to PD-(L)1 blockade among KRASmut cases we found that STK11del was associated with a numerically lower ORR (13.3% versus 30.0%, P = 0.12), and a significantly shorter PFS (HR 0.57, P = 0.018) compared to cases without STK11del. No difference in OS were observed between these groups (HR 0.77, P = 0.39). Among KRASwt NSCLCs, STK11del cases had a similar ORR (22.6% versus 22.9%, P = 0.99), PFS (HR 0.92, P = 0.63), and OS (HR 1.18, P = 0.32) to PD-(L)1 inhibition compared to cases without STK11del. Among KRASmut but not KRASwt NSCLCs, cases with STK11del had significantly lower PD-L1 expression compared to those without STK11 deletions (27.5% versus 70%, P = 0.01). Conclusions: STK11 deletion is associated with low response rate and short progression-free survival among KRAS mutant NSCLCs. Future analyses will incorporate additional cases to increase sample size and immunopathologic findings to assess impact of mono and bi-allelic deletion on protein expression.
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Bhattacharya, Raka, Jeanne Kowalski, Allison R. Larson, Malcolm Brock, and Rhoda M. Alani. "Id1 Promotes Tumor Cell Migration in Nonsmall Cell Lung Cancers." Journal of Oncology 2010 (2010): 1–8. http://dx.doi.org/10.1155/2010/856105.
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Id1, which belongs to the Id family of helix-loop-helix transcription factors has been most associated with tumor progression and metastatsis; however, its significance in lung cancers has not been extensively explored. Here we seek to evaluate the expression of Id1 in a pilot study of nonsmall-cell lung cancers (NSCLCs) and determine its diagnostic and functional significance in these tumors. Paired normal and malignant lung tissues as well as a panel of NSCLC primary tumors and cell lines were evaluated for Id1 expression using Western blotting and quantitative RT-PCR. Functional assays were performed to evaluate the role of Id1 in tumor cell growth, migration and progression. We find Id1 expression is upregulated in squamous cell carcinoma when compared to adenocarcinoma of the lung and that expression of Id1 versus the normal control is variable in NSCLCs. We also note that Id1 expression in NSCLC cells is largely growth factor dependant and constitutive expression of Id1 in NSCLC cells significantly increases tumor cell migration without affecting cell proliferation. We conclude that Id1, as a mediator of tumor cell migration, may be an indicator of aggressive potential in nonsmall-cell lung cancers.
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Gristina, Valerio, Maria La Mantia, Federica Iacono, Antonio Galvano, Antonio Russo, and Viviana Bazan. "The Emerging Therapeutic Landscape of ALK Inhibitors in Non-Small Cell Lung Cancer." Pharmaceuticals 13, no. 12 (December 18, 2020): 474. http://dx.doi.org/10.3390/ph13120474.
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The treatment of metastatic non-small cell lung cancer (NSCLC) has undergone a paradigm shift over the last decade. Better molecular characterization of the disease has led to the rapid improvement of personalized medicine and the prompt delivery of targeted therapies to patients with NSCLC. The discovery of the EML4-ALK fusion gene in a limited subset of patients affected by NSCLC and the subsequent clinical development of crizotinib in 2011 has been an impressive milestone in lung cancer research. Unfortunately, acquired resistances regularly develop, hence disease progression occurs. Afterward, modern tyrosine kinase inhibitors (TKIs), such as ceritinib, alectinib, brigatinib, and lorlatinib, have been approved by the Food and Drug Administration (FDA) for the management of anaplastic lymphoma kinase (ALK)-positive NSCLCs. Several compounds are currently under investigation to achieve the optimal strategy of therapy. Additionally, the results of ongoing clinical trials with novel-generation TKI will provide more evidence on the best sequence in the treatment of ALK-positive NSCLC patients. In this review, we provide a comprehensive overview of the state-of-the-art targeted therapy options in ALK-positive NSCLCs. Resistance, potential therapeutic strategies to overcome drug resistance, and future perspectives for this subset of patients are critically analyzed and summarized.
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Pawelczyk, Konrad, Aleksandra Piotrowska, Urszula Ciesielska, Karolina Jablonska, Natalia Gletzel-Plucinska, Jedrzej Grzegrzolka, Marzenna Podhorska-Okolow, Piotr Dziegiel, and Katarzyna Nowinska. "Role of PD-L1 Expression in Non-Small Cell Lung Cancer and Their Prognostic Significance according to Clinicopathological Factors and Diagnostic Markers." International Journal of Molecular Sciences 20, no. 4 (February 14, 2019): 824. http://dx.doi.org/10.3390/ijms20040824.
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Background: The latest immunotherapy, used in the treatment of non-small cell lung cancer (NSCLC), uses monoclonal antibodies directed against programmed death ligand 1 (PD-L1) to inhibit its interaction with the PD-1 receptor. Elevated levels of PD-L1 expression were observed on NSCLC cells. The association between PD-L1 expression and clinicopathological features is still unclear. Therefore, we examined this relationship and also compare PD-L1 expression levels with Ki-67, p63 and TTF-1. Methods: 866 samples of NSCLCs were used to prepare tissue microarrays (TMAs) on which immunohistochemical (IHC) reactions were performed. Changes in the level of CD274 (PD-L1) gene expression in 62 NSCLC tumors were tested in relation to 14 normal lung tissues by real-time PCR reactions (RT-PCR). Results: PD-L1 expression was observed in 32.6% of NSCLCs. PD-L1 expression was increased in higher malignancy grades (G) (p < 0.0001) and in higher lymph node status (pN) (p = 0.0428). The patients with low PD-L1 expression had longer overall survival compared to the group with high expression (p = 0.0332) in adenocarcinoma (AC) only. Conclusions: PD-L1 expression seems to be associated with increased tumor proliferation and aggressiveness as well as shorter patient survival in NSCLC, predominantly in the AC group.
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Honma, Rio, Ichiro Kinoshita, Eiji Miyoshi, Utano Tomaru, Yoshihiro Matsuno, Yasushi Shimizu, Satoshi Takeuchi, Kichizo Kaga, Naoyuki Taniguchi, and Hirotoshi Akita. "Prognostic significance of α1,6-fucosyltransferase (α1,6-FT) in non-small cell lung cancers (NSCLCs)." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 7550. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.7550.
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7550 Background: Lung cancer is one of the leading causes of cancer death throughout the world. A more sophisticated understanding of the pathogenesis and biology of NSCLCs could provide useful information for predicting clinical outcome and individualizing treatment. α1,6-FT is the only one enzyme responsible for the core α1,6-fucosylation of N-glycans of glycoproteins, including EGF receptor, TGF-β1 receptor, and integrin α3β1. Methods: α1,6-FT expression was studied by immunohistochemistry in a cohort of 129 surgically resected NSCLCs, classified categorically based on the proportion of positively stained cancer cells (high, > 20%; or low, < 20%), and analyzed statistically in relation to various characteristics, including histology, survival and prognosis. Results: High and low expression of α1,6-FT was found in 67 and 62 of 129 NSCLCs, respectively. Multivariate logistic regression analysis revealed a significant association between high α1,6-FT expression and non-squamous cell carcinoma (mostly adenocarcinoma), as compared with squamous cell carcinomas (odds ratio, 3.51; p = 0.008). Patients with tumors having high α1,6-FT expression had significantly shorter survival time than patients with tumors having low expression in potentially curatively resected NSCLCs (p = 0.03) and adenocarcinomas (p = 0.009), as well as in pStage I NSCLCs (p = 0.03) by the log-rank test. Surprisingly, in pStage I adenocarcinomas, 12 of 23 patients with tumors having high α1,6-FT expression died of lung cancer, although none of 15 patients with tumors having low expression died of lung cancer. High α1,6-FT expression was a significant and independent unfavorable prognostic factor in potentially curatively resected NSCLCs (hazard ratio, 1.81; p = 0.047) and adenocarcinomas (hazard ratio 2.39; p = 0.006) and in pStage I NSCLCs (hazard ratio 2.55; p = 0.03) by Cox’s proportional hazards model analysis. Conclusions: These results suggest that α1,6-FT may play a pivotal role for the biological characteristics of NSCLCs. α1,6-FT expression is associated with histology of NSCLCs, and may be a new prognostic marker for overall NSCLCs and adenocarcinomas.
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Pyo, Jung-Soo, and Nae Yu Kim. "Clinicopathological Impact of the Spread through Air Space in Non-Small Cell Lung Cancer: A Meta-Analysis." Diagnostics 12, no. 5 (April 28, 2022): 1112. http://dx.doi.org/10.3390/diagnostics12051112.
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This study aimed to elucidate the clinicopathological significance of spread through air space (STAS) in non-small cell lung cancer (NSCLC) through a meta-analysis. Using 47 eligible studies, we obtained the estimated rates of STAS in various histological subtypes of NSCLC and compared the clinicopathological characteristics and prognosis between NSCLC with and without STAS. The estimated STAS rate was 0.368 (95% confidence interval [CI], 0.336–0.0.401) in patients with NSCLC. Furthermore, the STAS rates for squamous cell carcinoma and adenocarcinoma were 0.338 (95% CI, 0.273–0.411) and 0.374 (95% CI, 0.340–0.409), respectively. Among the histological subtypes of adenocarcinoma, micropapillary-predominant tumors had the highest rate of STAS (0.719; 95% CI, 0.652–0.778). The STAS rates of solid- and papillary-predominant adenocarcinoma were 0.567 (95% CI, 0.478–0.652) and 0.446 (95% CI, 0.392–0.501), respectively. NSCLCs with STAS showed a higher visceral pleural, venous, and lymphatic invasion than those without STAS. In addition, anaplastic lymphoma kinase mutations and ROS1 rearrangements were significantly more frequent in NSCLCs with STAS than in those without STAS. The presence of STAS was significantly correlated with worse overall and recurrence-free survival (hazard ratio, 2.119; 95% CI, 1.811–2.480 and 2.372; 95% CI, 2.018–2.788, respectively). Taken together, the presence of STAS is useful in predicting the clinicopathological significance and prognosis of patients with NSCLC.
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Borzi, Cristina, Giulia Galli, Monica Ganzinelli, Diego Signorelli, Claudio Vernieri, Marina Garassino, Gabriella Sozzi, and Massimo Moro. "Beyond LKB1 Mutations in Non-Small Cell Lung Cancer: Defining LKB1less Phenotype to Optimize Patient Selection and Treatment." Pharmaceuticals 13, no. 11 (November 13, 2020): 385. http://dx.doi.org/10.3390/ph13110385.
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LKB1 is frequently mutated in non-small cell lung cancer (NSCLC). LKB1-mutated NSCLCs often have a dismal prognosis and receive lower benefit from the currently available therapies. LKB1 acts as a cell emergency brake in low-energy conditions, by modulating the activity of crucial anabolic enzymes. Thus, loss of LKB1 activity leads to the enhancement of tumor cell proliferation also under conditions of energy shortage. This unrestrained growth may be exploited as an Achilles heel in NSCLC, i.e., by inhibiting mitochondrial respiration. Recently, clinical trials have started to investigate the efficacy of metabolism-based treatments in NSCLCs. To date, enrollment of patients within these trials is based on LKB1 loss of function status, defined by mutation in the gene or by complete absence of immunohistochemical staining. However, LKB1 impairment could be the consequence of epigenetic regulations that partially or completely abrogate protein expression. These epigenetic regulations result in LKB1 wild-type tumors with aggressiveness and vulnerabilities similar to those of LKB1-mutated ones. In this review, we introduced the definition of the “LKB1less phenotype”, and we summarized all currently known features linked to this status, in order to optimize selection and treatment of NSCLC patients with impaired LKB1 function.
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Lin, Yu-Shun, Yen-Chu Chen, Tzu-En Chen, Mei-Ling Cheng, Ke-Shiuan Lynn, Pramod Shah, Jin-Shing Chen, and Rwei-Fen S. Huang. "Probing Folate-Responsive and Stage-Sensitive Metabolomics and Transcriptional Co-Expression Network Markers to Predict Prognosis of Non-Small Cell Lung Cancer Patients." Nutrients 15, no. 1 (December 20, 2022): 3. http://dx.doi.org/10.3390/nu15010003.
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Tumour metabolomics and transcriptomics co-expression network as related to biological folate alteration and cancer malignancy remains unexplored in human non-small cell lung cancers (NSCLC). To probe the diagnostic biomarkers, tumour and pair lung tissue samples (n = 56) from 97 NSCLC patients were profiled for ultra-performance liquid chromatography tandem mass spectrometry (UPLC/MS/MS)-analysed metabolomics, targeted transcriptionomics, and clinical folate traits. Weighted Gene Co-expression Network Analysis (WGCNA) was performed. Tumour lactate was identified as the top VIP marker to predict advance NSCLC (AUC = 0.765, Sig = 0.017, CI 0.58–0.95). Low folate (LF)-tumours vs. adjacent lungs displayed higher glycolytic index of lactate and glutamine-associated amino acids in enriched biological pathways of amino sugar and glutathione metabolism specific to advance NSCLCs. WGCNA classified the green module for hub serine-navigated glutamine metabolites inversely associated with tumour and RBC folate, which module metabolites co-expressed with a predominant up-regulation of LF-responsive metabolic genes in glucose transport (GLUT1), de no serine synthesis (PHGDH, PSPH, and PSAT1), folate cycle (SHMT1/2 and PCFR), and down-regulation in glutaminolysis (SLC1A5, SLC7A5, GLS, and GLUD1). The LF-responsive WGCNA markers predicted poor survival rates in lung cancer patients, which could aid in optimizing folate intervention for better prognosis of NSCLCs susceptible to folate malnutrition.
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Fumagalli, Caterina, Chiara Catania, Alberto Ranghiero, Carlo Bosi, Giuseppe Viale, Filippo de Marinis, Massimo Barberis, and Elena Guerini-Rocco. "Molecular Profile of Advanced Non-Small Cell Lung Cancers in Octogenarians: The Door to Precision Medicine in Elderly Patients." Journal of Clinical Medicine 8, no. 1 (January 18, 2019): 112. http://dx.doi.org/10.3390/jcm8010112.
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Background: There is a pressing need to expand the evidence base in geriatric lung oncology. Most non-small cell lung cancers (NSCLCs) are diagnosed in the elderly, with approximately 15% of cases affecting octogenarians. Treatment-related decisions are challenging in this population, and the role of biologically driven therapies is still underrated. Methods: A single-institution cohort of 76 NSCLCs from octogenarian patients was submitted to molecular analysis using a next-generation sequencing (NGS) multigene panel, fluorescence in situ hybridization (FISH) analyses, and immunohistochemistry for PD-L1 assessment. Treatment and clinical outcome data were available for 33 patients. Results: Most cases (n = 66, 87%) harbored at least one genomic alteration. EGFR and KRAS mutations were detected in 18 (24%) and 20 (26%) patients, respectively. No ALK alterations were found, but in two patients ROS1 translocation was identified. Of 22 cases tested, 17 were positive for PD-L1 staining. Octogenarian patients who received tyrosine kinase inhibitors (TKIs) based on molecular analysis showed clinical benefits, with long progression-free survival as expected in TKI-treated younger cohorts. Conclusions: This study highlights the utility of molecular profiling in all advanced-stage NSCLCs, regardless of the age at diagnosis, to drive personalized treatment. The prevalence of druggable alterations and the clinical benefits obtained by biologically-driven therapies in octogenarians were comparable to those of the younger NSCLC population.
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Tuononen, Katja, Virinder Kaur Sarhadi, Aino Wirtanen, Mikko Rönty, Kaisa Salmenkivi, Aija Knuuttila, Satu Remes, et al. "Targeted Resequencing RevealsALKFusions in Non-Small Cell Lung Carcinomas Detected by FISH, Immunohistochemistry, and Real-Time RT-PCR: A Comparison of Four Methods." BioMed Research International 2013 (2013): 1–9. http://dx.doi.org/10.1155/2013/757490.
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Anaplastic lymphoma receptor tyrosine kinase (ALK) gene rearrangements occur in a subgroup of non-small cell lung carcinomas (NSCLCs). The identification of these rearrangements is important for guiding treatment decisions. The aim of our study was to screenALKgene fusions in NSCLCs and to compare the results detected by targeted resequencing with results detected by commonly used methods, including fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), and real-time reverse transcription-PCR (RT-PCR). Furthermore, we aimed to ascertain the potential of targeted resequencing in detection ofALK-rearranged lung carcinomas. We assessedALKfusion status for 95 formalin-fixed paraffin-embedded tumor tissue specimens from 87 patients with NSCLC by FISH and real-time RT-PCR, for 57 specimens from 56 patients by targeted resequencing, and for 14 specimens from 14 patients by IHC. All methods were performed successfully on formalin-fixed paraffin-embedded tumor tissue material. We detectedALKfusion in 5.7% (5 out of 87) of patients examined. The results obtained from resequencing correlated significantly with those from FISH, real-time RT-PCR, and IHC. Targeted resequencing proved to be a promising method forALKgene fusion detection in NSCLC. Means to reduce the material and turnaround time required for analysis are, however, needed.
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Farago, Anna F., Martin S. Taylor, Robert Charles Doebele, Alexander I. Spira, Theresa A. Boyle, Eric B. Haura, Roxana S. Azimi, Alice Tsang Shaw, Mari Mino-Kenudson, and Alexander E. Drilon. "Clinicopathologic features of non-small cell lung cancer (NSCLC) harboring an NTRK gene fusion." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 11580. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.11580.
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11580 Background: Gene fusions involving NTRK1/2/3 can generate oncoproteins containing the kinase domains of TRKA/B/C, respectively. Inhibition of TRK signaling has led to dramatic responses across tumor types with NTRK fusions. An estimated 0.1 – 1% of NSCLCs harbor NTRK fusions. To date, clinical and radiographic responses to TRK inhibitors have been reported for 2 NTRK fusion-positive NSCLCs (Farago et al., 2015; Hong et al., 2016). Despite the potential benefit of identifying these fusions, the clinicopathologic features of NTRK fusion NSCLCs are not well characterized. Methods: Physicians across multiple institutions contributed deidentified cases to an NTRK fusion NSCLC database. A central pathologist (M.M.) reviewed tumor histology in cases with available tissue. Results: 10 NSCLC cases with NTRK gene fusions were identified. Of these, TRK kinase domain-containing potentially activating fusions were verified by next-generation sequencing (NGS) in 7, forming the study cohort. Fusions involved NTRK1 (6) and NTRK3 (1) with 6 different partners. Four (57%) patients were male. Median age at diagnosis was 47.6 years (range 27.9 – 86.0). The average smoking pack year history was 8.9 (range 0 to 30). Five (71%) presented with metastatic disease. No concurrent alterations in KRAS, EGFR, ALK, ROS1, or other known drivers were identified in the study cohort cases. On pathologic review of 4 cases, all were adenocarcinoma, including 2 invasive mucinous adenocarcinomas and 1 adenocarcinoma with neuroendocrine features. Of the 3 remaining non-study cohort cases, 1 was a non-kinase domain-containing NTRK1 fusion with a concurrent KRAS G12C mutation, 1 was an NTRK2 intragenic deletion disrupting the exon 18 3’ splice site, and 1 was an NTRK1 alteration detected by FISH but not verified by NGS and with a concurrent HER2 L755P mutation. Conclusions: NTRK fusions occur in both men and women across wide ranges in age and smoking history. We therefore suggest that all NSCLC adenocarcinomas without other oncogenic driver alterations be screened for NTRK fusions. Notably, not all NTRK alterations are activating, requiring validation of the specific position of the fusion.
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Tamiya, Yutaro, Shingo Matsumoto, Takaya Ikeda, Kiyotaka Yoh, Terufumi Kato, Kazumi Nishino, Masahiro Kodani, et al. "Clinico-pathological and genomic features of NRAS- or HRAS-mutated non-small cell lung cancer (NSCLC) identified in large-scale genomic screening project (LC-SCRUM-Asia)." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 9054. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.9054.
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9054 Background: RAS ( KRAS, NRAS and HRAS) is a targetable oncogene family in several cancers, including NSCLC, and the clinical development of various RAS-targeted therapies are ongoing. However, the clinical relevance of uncommon RAS mutations, such as NRAS and HRAS mutations, in NSCLC patients (pts) remains unclear. Methods: In a large-scale genomic screening project (LC-SCRUM-Asia), we have prospectively analyzed lung cancer pts for genomic alterations by a targeted next-generation sequencing (NGS) system, Oncomine Comprehensive Assay. We evaluated clinico-pathological and genomic characteristics in NRAS- or HRAS-mutated NSCLC pts comparing with those in KRAS-mutated pts based on the LC-SCRUM-Asia database. Results: Since March 2015 to December 2020, 9131 NSCLC pts were enrolled in the LC-SCRUM-Asia, and 8374 of them (92%) were successfully analyzed by NGS. The RAS mutation frequencies were 1134 KRAS (14%), 50 NRAS (0.6%), and 15 HRAS (0.2%). The most frequent variant of NRAS and HRAS mutations was Q61X (78%) and G13X (80%), respectively, whereas that of KRAS was G12X (84%). Patient characteristics were summarized in Table. Male was significantly frequent in NRAS- than in KRAS-group (p=0.03), and smokers were frequent in all the three groups (overall, 79%). The majority of NRAS (70%) and KRAS mutations (89%) were detected in adenocarcinoma (Ad), whereas 60% of HRAS mutations were in squamous cell carcinoma (Sq). Tumor mutation burden (TMB) was significantly higher in NRAS-mutated tumors than in KRAS-mutated tumors (p=0.03). Concomitant TP53 mutations were significantly frequent in HRAS-mutated pts than in KRAS-mutated pts (53% vs. 30%, p=0.05), and STK11 mutations were also tended to be frequent in HRAS-mutated pts than in KRAS-mutated pts (20 vs. 7%, p=0.10). Therapeutic efficacy of PD-1/PD-L1 inhibitors was not different among the three groups in the current follow-up data, but HRAS-mutated tumors did not respond to PD-1/PD-L1 inhibitors (response rate, 0%; median PFS, 1.6 months). Conclusions: NRAS- or HRAS-mutated NSCLCs were different from KRAS-mutated NSCLCs in clinico-pathological and genomic profiles. In particular, the immunotherapies were not effective for HRAS-mutated NSCLCs.[Table: see text]
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Costa, Daniel Botelho, Hiroyuki Yasuda, Natasha J. Sng, Wee-Lee Yeo, Lorena Lobo de Figueiredo-Pontes, Daniel G. Tenen, and Susumu Kobayashi. "Sensitivity to EGFR inhibitors based on location of EGFR exon 20 insertion mutations within the tyrosine kinase domain of EGFR." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 7523. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.7523.
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7523 Background: Epidermal growth factor receptor (EGFR) mutations (M) define an important subgroup of non-small-cell lung cancer (NSCLC). Most patients whose tumors harbor exon 19 deletions or L858R EGFR M have responses to reversible ATP-mimetic EGFR tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib. Exon 20 insertion M comprise ~5% of EGFR M, occur at the N-lobe of EGFR after its C-helix (AA M766), and nearly all NSCLCs with EGFR exon 20 insertion M display lack of responses to EGFR TKIs (Yasuda H. Lancet Oncol 2011). Methods: We have 1) compiled genotype-clinical outcomes of EGFR exon 20 insertion M NSCLCs to EGFR TKIs, 2) generated a comprehensive panel of exon 20 EGFR M constructs using site-directed mutagenesis and introduced them into Ba/F3 cells for in vitro analysis, and 3) compared NSCLC cell lines with EGFR M to a novel malignant pleural effusion-derived cell line. Results: The disease control rate of gefitinib or erlotinib was significantly higher in EGFR exon 20 insertion M located within the C-helix (3/3,100%) when compared to M following the C-helix (1/14, 7%; p=0.00059). The NSCLC with EGFR-A763_Y764insFQEA (located within the C-helix of EGFR) achieved a partial response to erlotinib that lasted 18 months. Most other exon 20 insertion M-positive NSCLCs did not respond (p=0.07). Eight representative exon 20 insertion M were studied (including EGFR-A763_Y764insFQEA, Y764_S765insHH, A767_V769dupASV, D770_N771insNPG, H773_V774insH). All, but A763_Y764insFQEA, were resistant to micromolar concentrations (C) of EGFR TKIs. Ba/F3 cells with EGFR-A763_Y764insFQEA underwent apoptosis upon exposure to nanomolar C of erlotinib. A patient-derived cell line with EGFR-A763_Y764insFQEA had phosphorylated EGFR, ERK and AKT inhibited by nanomolar C of erlotinib. Conclusions: Not all EGFR exon 20 insertion mutations are resistant to EGFR TKIs, and in specific EGFR-A763_Y764insFQEA is an EGFR TKI-sensitive M. This finding has clinical implications for the care of the 10,000 cases of EGFR exon 20 insertion M NSCLC diagnosed yearly and points towards the need to define the molecular mechanisms that underlie differential responses to EGFR TKIs.
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Césaire, Mathieu, Juliette Montanari, Hubert Curcio, Delphine Lerouge, Radj Gervais, Pierre Demontrond, Jacques Balosso, and François Chevalier. "Radioresistance of Non-Small Cell Lung Cancers and Therapeutic Perspectives." Cancers 14, no. 12 (June 8, 2022): 2829. http://dx.doi.org/10.3390/cancers14122829.
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Survival in unresectable locally advanced stage non-small cell lung cancer (NSCLC) patients remains poor despite chemoradiotherapy. Recently, adjuvant immunotherapy improved survival for these patients but we are still far from curing most of the patients with only a 57% survival remaining at 3 years. This poor survival is due to the resistance to chemoradiotherapy, local relapses, and distant relapses. Several biological mechanisms have been found to be involved in the chemoradioresistance such as cancer stem cells, cancer mutation status, or the immune system. New drugs to overcome this radioresistance in NSCLCs have been investigated such as radiosensitizer treatments or immunotherapies. Different modalities of radiotherapy have also been investigated to improve efficacity such as dose escalation or proton irradiations. In this review, we focused on biological mechanisms such as the cancer stem cells, the cancer mutations, the antitumor immune response in the first part, then we explored some strategies to overcome this radioresistance in stage III NSCLCs with new drugs or radiotherapy modalities.
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Eren, Bulent, Mehmet Sar, Buge Oz, and Fazilet H. Oner Dincbas. "MMP-2, TIMP-2 and CD44v6 Expression in Non-small-cell Lung Carcinomas." Annals of the Academy of Medicine, Singapore 37, no. 1 (January 15, 2008): 32–39. http://dx.doi.org/10.47102/annals-acadmedsg.v37n1p32.
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Introduction: Factors that emerge as crucial participants in tumour invasion and metastases are matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinase (TIMP) inhibitors and cellular adhesion molecules (CD44 and similar molecules). They play important roles in tumour invasion and metastasis in non-small-cell lung carcinomas (NSCLCs). Materials and Methods: The study was performed using the data of 33 patients. MMP-2 from the metalloproteinase family, TIMP-2 from the metalloproteinase inhibitor family and the adhesion molecule CD44v6 expression were investigated immunohistochemically to search their role in the metastasis and the clinical outcome of the patients with NSCLCs. Results: Twenty-three tumours (70%) were squamous cell carcinoma (SCC), 9 (27%) were adenocarcinoma (AC), and 1 (3%) was large cell carcinoma (LCC). MMP-2 and TIMP-2 were expressed in high rates in NSCLC but CD44v6 expression was about 50%. Lymphatic invasion was less frequent in TIMP-2-positive patients and this difference was statistically significant (P = 0.005). There was a statistically significant difference between SCCs and ACs with respect to CD44v6 tumoral expression (P = 0.004). Also, there was a negative correlation between lymphatic invasion and the extent of CD44v6; lymphatic invasion was significantly less in CD44v6-positive cases (P = 0.013). Conclusion: We found that TIMP-2 and CD44v6 can decrease the lymphatic invasion in NSCLCs. Also there was observed histiotype-related pattern of CD44v6 variant expression in SCCs. Key words: Immunohistochemistry, Metastasis, Pulmonary neoplasms
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Bang, Heejin, Mi-Sook Lee, Minjung Sung, Juyoung Choi, Sungbin An, Seok-Hyung Kim, Seung Eun Lee, and Yoon-La Choi. "NTRK Fusions in 1113 Solid Tumors in a Single Institution." Diagnostics 12, no. 6 (June 13, 2022): 1450. http://dx.doi.org/10.3390/diagnostics12061450.
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Most NTRK fusions occur at very low frequencies in various common cancers. Recent recommendations on NTRK testing recommend immunohistochemistry (IHC) as the initial test for tumor types with a low frequency of NTRK fusions. This study investigated the accuracy of an IHC assay to detect NTRK fusions and characterize the clinicopathological and molecular features of NTRK-rearranged tumors. This retrospective study was conducted on 1113 solid tumor samples known to harbor no oncogenic driver alterations, including 510 non-small cell lung cancers (NSCLC), 503 colorectal cancers (CRC), and 79 inflammatory myofibroblastic tumors (IMT). Additionally, 21 ALK expression-positive cases were included. TRK expression was evaluated using a pan-Trk IHC assay, and positive cases were validated using NGS. TRK expression was observed in three NSCLCs (0.6%), six CRCs (1.2%), and six IMTs (6%). NTRK fusions were finally detected in two NSCLCs (0.4%), six CRCs (1.2%), and one IMT (1%). In NSCLC and CRC, the majority of NTRK fusions were readily discernible due to diffuse moderate-to-strong cytoplasmic staining on pan-Trk IHC. In IMT, focal weak nuclear staining indicated the presence of NTRK fusion. Therefore, the utility of pan-Trk IHC should be assessed considering that the difference in performance depends on tumor type.
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Watanabe, Satoshi, Kazuko Sakai, Naoya Matsumoto, Jun Koshio, Akira Ishida, Tetsuya Abe, Daisuke Ishikawa, et al. "Phase II Trial of the Combination of Alectinib with Bevacizumab in Alectinib Refractory ALK-Positive Nonsquamous Non-Small-Cell Lung Cancer (NLCTG1501)." Cancers 15, no. 1 (December 29, 2022): 204. http://dx.doi.org/10.3390/cancers15010204.
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Anaplastic lymphoma kinase (ALK)-positive lung cancer is a rare cancer that occurs in approximately 5% of non-small-cell lung cancer (NSCLCs) patients. Despite the excellent efficacy of ALK-tyrosine kinase inhibitor in ALK-positive NSCLCs, most patients experience resistance. We conducted a phase II study to investigate the combination of alectinib with bevacizumab in ALK-positive NSCLC patients after failure of alectinib. In this study, ALK-positive nonsquamous NSCLC patients previously treated with alectinib received bevacizumab 15 mg/kg on day 1 every 3 weeks and alectinib 600 mg/day until disease progression. The primary endpoints were progression-free survival (PFS) and the safety of alectinib and bevacizumab. The secondary endpoints included overall survival (OS) and correlation of circulating tumor DNA and plasma proteins with PFS. Of the 12 patients treated, the median PFS was 3.1 months (95% CI 1.2–16.1), and the median OS was 24.1 months (95% CI 8.3-not estimable). The EML4-ALK fusion gene in circulating tumor DNA was significantly correlated with shorter PFS (1.2 months vs. 11.4 months, HR 5.2, p = 0.0153). Two patients experienced grade 3 adverse events; however, none of the patients required dose reduction. Although the primary endpoint was not met, alectinib combined with bevacizumab showed clinical efficacy in ALK-positive patients.
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Kim, Jin Seuk, Haengbung Lee, Hojoong Kim, Young Mog Shim, Joungho Han, Joobae Park, and Duk-Hwan Kim. "Promoter Methylation of Retinoic Acid Receptor Beta 2 and the Development of Second Primary Lung Cancers in Non–Small-Cell Lung Cancer." Journal of Clinical Oncology 22, no. 17 (September 1, 2004): 3443–50. http://dx.doi.org/10.1200/jco.2004.11.135.
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PurposeTo investigate whether the promoter hypermethylation of retinoic acid receptor beta 2 (RARβ2) is associated with the development of second primary lung cancers (SPLCs) differentially according to smoking status in primary non–small-cell lung cancer (NSCLC).Patients and MethodsWe retrospectively analyzed the relationship between RARβ2 methylation and the SPLC development in a total of 342 NSCLCs. The methylation status of RARβ2 was determined by using methylation-specific polymerase chain reaction. The difference in the time to SPLC development was analyzed by using the log-rank test and the Cox proportional hazards model. The median follow-up was 4.1 years.ResultsSPLCs developed in 19 (5.6%) of the 342 NSCLCs, and overall incidence rate of SPLC development was 1.54 per 100 patient-years. SPLCs did not occur in 39 patients who had not smoked. After controlling for possible confounding factors, the hazard of failure for former smokers with RARβ2 hypermethylation was about 2.87 (95% CI, 0.92 to 13.64; P = .08) times higher compared to those without RARβ2 methylation. However, for current smokers, hypermethylation of the RARβ2 was found to have a protective effect against the SPLC development (hazard ratio = 0.23; 95% CI, 0.11 to 0.87; P = .03).ConclusionHypermethylation of RARβ2 promoter had a differential effect on the development of SPLCs in NSCLC, and this was dependent on smoking status. Our study suggests that a combination of retinoids and/or a demethylating agent may be effective in the prevention of SPLCs in never-smokers and former smokers with NSCLC.
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Ricciuti, Biagio, Joao Victor Alessi, Xinan Wang, Arrien A. Bertram, Victor R. Vaz, Mizuki Nishino, James Lindsay, et al. "Abstract 2143: Clinicopathologic, genomic and immunophenotypic landscape of ATM mutations in non-small cell lung cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2143. http://dx.doi.org/10.1158/1538-7445.am2022-2143.
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Abstract Introduction: Defective DNA damage repair machinery is a hallmark of cancer, resulting in increased mutation rates and genomic instability. In non-small cell lung cancer (NSCLC), ATM is mutated in ~10% of cases, representing the most commonly mutated DNA damage and repair gene. However, the clinicopathologic, genomic, and immunophenotypic correlates of ATM mutations in NSCLC are unknown. The impact of ATM mutation on clinical outcomes to PD-(L)1 blockade is also unclear. Methods: Clinicopathologic and genomic data were collected from 3592 patients (pts) with NSCLC who had consented to correlative studies at the Dana-Farber Cancer Institute (DFCI), and whose tumors underwent genomic profiling (OncoPanel). Multiplexed immunofluorescence (mIF) for CD8, PD1, PD-L1, FOXP3, and CK AE1/AE3 was performed on a subset of 416 NSCLC samples to examine tumor-infiltrating immune cells. ATM immunohistochemistry (IHC) was also performed on 184 ATM mutated NSCLCs with available tissue. ATM mutated (ATMMUT) tumors were defined as harboring loss-of-function mutations (nonsense, frameshift, splice site, known deleterious missense mutations). Missense mutation of unknown significance were excluded, unless deemed to affect protein function in silico. Tumors lacking ATM mutations or harboring benign ATM alterations were defined as ATM wild type (ATMWT). Results: A total of 399 deleterious ATM mutations were identified in 10.2% (365/3592) of samples; 138 (34.6%) mutations were truncating (nonsense, frameshift, and splice site mutations); the remaining 261 (65.4%) were missense mutations. Truncating mutations were significantly more likely to result in ATM loss by IHC compared to missense mutations (71.4% vs 28.9%, P<0.01) When we examined the genomic profiles of tumors with versus without deleterious ATM mutations, we found that ATMMUT NSCLCs were significantly enriched with KRAS, STK11, RBM10, and KDM5C co-mutations (P<0.01), while co-mutations in EGFR, CDKN2A and TP53 were nearly mutually exclusive (P<0.01). Among ATMMUT NSCLCs, those with ATM loss by IHC were significantly enriched with KRAS and STK11 co-mutations, while those with retained ATM expression were enriched with TP53 co-mutations (P<0.01). Pts with ATMMUT NSCLCs had similar outcomes to PD-(L)1 inhibition +/- chemotherapy, compared to ATMWT cases, and similar immune cell subsets infiltration (P>0.05). Pts with deleterious mutations in ATM and TP53 (ATMMUT/TP53MUT) had increased response rates to chemo-immunotherapy compared to those with ATMMUT/TP53WT, ATMWT/TP53MUT, or ATMWT/TP53WT genotypes (70% vs 56.2% vs 35.7% vs 27.4%, respectively, P=0.01), as well as increased tumor-stroma interface CD8+ T cells (P<0.01) and higher PD-L1 expression by mIF on tumor (P<0.01) and immune cells (P<0.01). Conclusion: Deleterious ATM mutations defined a subset of NSCLC with unique clinicopathologic, genomic, and immunophenotypic features. Citation Format: Biagio Ricciuti, Joao Victor Alessi, Xinan Wang, Arrien A. Bertram, Victor R. Vaz, Mizuki Nishino, James Lindsay, Kristen D. Felt, Bijaya Sharma, Lynette M. Sholl, Rodig Scott, Mark M. Awad, Michael L. Cheng. Clinicopathologic, genomic and immunophenotypic landscape of ATM mutations in non-small cell lung cancer [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 2143.
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Nehme, Eliana, Zahraa Rahal, Ansam Sinjab, Athar Khalil, Hassan Chami, Georges Nemer, and Humam Kadara. "Epigenetic Suppression of the T-box Subfamily 2 (TBX2) in Human Non-Small Cell Lung Cancer." International Journal of Molecular Sciences 20, no. 5 (March 7, 2019): 1159. http://dx.doi.org/10.3390/ijms20051159.
Full textAbstract:
(1) The TBX2 subfamily of transcription factors (TBXs 2, 3, 4 and 5) are markedly down-regulated in human non-small cell lung cancer (NSCLC) and exert tumor suppressor effects in lung malignancy. Yet, mechanisms underlying suppressed expression of the TBX2 subfamily in NSCLC are elusive. Here, we interrogated probable epigenetic mechanisms in suppressed expression of the TBX2 subfamily in human NSCLC. (2) TBX2 subfamily gene expression and methylation levels in NSCLC and normal lung tissues were surveyed using publicly available RNA-sequence and genome-wide methylation datasets. Methylation β-values of the four genes were statistically compared between NSCLCs and normal lung tissues, correlated with gene expression levels, and interrogated with clinicopathological variables. Expression and methylation levels of TBXs were quantified in NSCLC cells using real-time PCR and methylation-specific PCR assays, respectively. Effects of the DNA methyltransferase inhibitor 5-azacytidine (Aza) on TBX2 subfamily expression were assessed in NSCLC cells. Impact of TBX2 subfamily expression on Aza-treated cells was evaluated by RNA interference. (3) All four TBXs were significantly hypermethylated in NSCLCs relative to normal lung tissues (p < 0.05). Methylation β-values of the genes, with exception of TBX2, were significantly inversely correlated with corresponding mRNA expression levels (p < 0.05). We found no statistically significant differences in hypermethylation levels of the TBX2 subfamily by clinicopathological features including stage and tobacco history. Expression levels of the TBX genes were overall suppressed in NSCLC cells relative to normal alveolar cells. Members of the subfamily were significantly hypermethylated in all tested NSCLC cell lines relative to normal alveolar cells. Treatment with Aza induced the expression of the TBX2 subfamily concomitant with NSCLC cell growth inhibition. Further, simultaneous knockdown of the four TBX genes markedly reduced anti-growth effects of Aza in NSCLC cells. (4) Our study sheds light on new epigenetic profiles in the molecular pathogenesis of human NSCLC.
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Che, Nanying, Ziguang Xu, Yujie Dong, Peng Cheng, Yun Gao, Yang Yu, Shijun Fu, Min Gao, and Lingfei Kong. "Identification of MET Exon 14 skipping by targeted RNA-based next-generation sequencing in Chinese Patients with NSCLC." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e20018-e20018. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e20018.
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e20018 Background: MET (mesenchymal-epithelial transition) exon14 skipping mutations have been reported to represent a clinically unique molecular subtype of NSCLC. The prevalence rates of MET exon 14 skipping in lung adenocarcinoma are quite different, from 0.9% to 4.0% in Asian populations. Since some somatic variants not covering the MET exon 14 splice sites might also induce MET exon 14 skipping, we believed that RNA-based sequencing is the most accurate method to detected exon 14 skipping. Methods: A total of 951 NSCLC patients from two hospitals were enrolled in this study. We detected MET exon14 skipping using both targeted DNA- and RNA-based next generation sequencing and elucidated the driver gene mutation profile of Chinese NSCLC patients. Results: The overall estimated prevalence of MET exon 14 skipping was approximately 1.8% (14 of 772) in adenocarcinomas and 1.7 % (16/951) in NSCLCs. Furthermore, we compared the detection rate of MET exon 14 skipping from different specimen source, including surgical resection, percutaneous transthoracic needle biopsy (PTNB) and transbronchial lung biopsy (TBLB). Notably, the detection rate of MET exon 14 skipping from surgical resection specimen is 2.3% in NSCLCs and 2.0% in adenocarcinomas, respectively. MET exon 14 skipping was identified in 7.1% of EGFR/KRAS/ALK/ROS1/RET negative adenocarcinomas (13 of 196). In addition, PD-L1 trended to be highly expressed in NSCLC patients harboring MET exon 14 skipping (55.6% vs 17.3%, p = 0.022). Conclusions: In this study, the prevalence of MET exon14 skipping in lung adenocarcinomas in East Asian population was very close to that of West population using RNA-based NGS. The NSCLC patients with Met exon 14 skipping tended to be older than patients with other oncogenic driver mutations, such as EGFR, ALK, ROS1. In addition, PD-L1 trended to be highly expressed in NSCLC patients with MET exon 14 skipping.
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Choudhury, Noura J., Jaime Laurel Schneider, Tejas Patil, Viola Weijia Zhu, Debra A. Goldman, Soo-Ryum Yang, Christina Falcon, et al. "Response to immune checkpoint inhibition as monotherapy or in combination with chemotherapy in metastatic ROS1-rearranged lung cancers." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 9049. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.9049.
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9049 Background: ROS1 fusions are oncogenic drivers in various cancers types, including 1-3% of non-small cell lung cancers (NSCLCs). Immunotherapy approvals for NSCLC include ROS1-rearranged carcinomas, but the activity of immune checkpoint inhibition (ICI) as monotherapy or in combination with chemotherapy (chemo-ICI) therapy, as well as the immunophenotypic characteristics of these tumors, have not been described in a large data set. Methods: In this multi-institutional study, patients with ROS1-rearranged NSCLC were identified retrospectively. Tumor PD-L1 expression and tumor mutational burden (TMB) were assessed as part of routine clinical care. In patients who received ICI monotherapy or chemo-ICI in the metastatic setting, time to treatment discontinuation (TTD) and objective response rate (ORR; RECIST v. 1.1) were calculated. TTD was assessed with Kaplan-Meier methods; patients remaining on treatment were censored at last follow up. Results: 184 patients with ROS1-rearranged NSCLC were identified. Among 146 PD-L1 evaluable cases, PD-L1 expression was < 1% in 60 (41%), 1-49% in 35 (24%) and ≥50% in 51 (35%) tumors. Ninety-two of 100 (92%) TMB-evaluable tumors had < 10 mutations/megabase (mut/Mb). TMB was significantly lower for ROS1-rearranged NSCLCs (n = 97) vs. ROS1-wild type tumors (n = 5,380) evaluated with next-generation sequencing using MSK-IMPACT (median 2.6 vs. 5.9 mut/Mb, p < 0.001). Twenty-eight patients received ICI monotherapy and 11 patients received chemo-ICI. The median TTD was 2.1 months (95% CI: 1.0-4.2; n = 28) for single-agent ICI therapy and 10 months (95% CI: 4.7-14.1; n = 11) for chemo-ICI therapy. The ORR was 13% (2/16 RECIST-evaluable; 95% CI: 2-38%) for ICI monotherapy and 83% (5/6 RECIST-evaluable; 95% CI: 36-100%) for chemo-ICI therapy. There was no difference in PD-L1 tumor expression (p = 0.9) or TMB (p = 0.8) between responders and non-responders and no correlation between PD-L1 tumor expression (rho = 0.16, p = 0.6) or TMB (rho = 0.03, p = 0.9) and maximum change in sum of target lesions. Conclusions: Most ROS1-rearranged NSCLCs have low or no PD-L1 expression and low TMB. The activity of checkpoint inhibitor monotherapy is disappointing in ROS1-driven NSCLC. In contrast, combination chemoimmunotherapy can achieve clinically meaningful activity.
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Nishio, M., F. Ohyanagi, A. Horikike, Y. Ishikawa, Y. Satoh, S. Okumura, K. Nakagawa, K. Nishio, and T. Horai. "Serum levels of administered gefitinib correlate with the time to treatment failure in non small cell lung cancer patients." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 17027. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.17027.
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17027 Background: Gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, has been shown to have clinical activity against non-small cell lung cancer (NSCLC). The aim of the present study was to clarify the relationship between serum gefitinib levels and clinical efficacy in patients with advanced NSCLCs. Methods and Results: Sera from 89 cases (51 men and 38 women) were obtained after 2 weeks gefitinib (250 mg/day) monotherapy. The average gefitinib level was 429.4 ± 214.8 ng/ml (mean ± SD) with 17-fold variability observed. No significant variation was observed with reference to gender, smoking history or performance status. There was no direct link between gefitinib level and tumor response, but a significant positive correlation was evident with time to treatment failure in 44 patients receiving gefitinib for more than 3 months (R = 0.365, P = 0.0144). Conclusions: These results suggested that a dose response may exist for time treatment failure in the patients who benefit from gefitinib. Dose modification in accordance with the serum gefitinib level may thus improve the efficacy of gefitinib for NSCLCs. [Table: see text]
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Takano, Atsushi, Yusuke Nakamura, and Yataro Daigo. "Identification of LASEP3 as a new serological and prognostic biomarker for lung and various type of cancer." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e13565-e13565. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e13565.
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e13565 Background: Identification of early cancer detection and prognostic biomarkers is urgently required to improve clinical outcome. Methods: We have screened cancer biomarkers using a strategy as follows; i)To identify up-regulated genes in non-small cell lung cancers (NSCLCs) using the cDNA microarray representing 27,648 genes and 120 lung cancers, ii) To verify the candidate genes for their no or low expression in 23 normal tissues by northern-blot analysis, iii)To validate clinicopathological significance of their protein expression by tissue microarray consisting of 259 lung cancers, iv) To verify whether they are essential for the growth of cancer cells by siRNA assay, and v) To measure their serum protein levels by ELISA in patients with various type of cancers. Results: We identified LASEP3 (Lung cancer Associated Serum Protein 3) encoding secreted protein as a candidate. Immunohistochemical analysis showed that LASEP3 was frequently over-expressed in various histological types of lung cancers; positive staining of LASEP3 was observed in 198 (54.8%) of 361 NSCLCs. In addition, a high level of LASEP3 expression was associated with poor prognosis of patients with NSCLC (p=0.0183 by log-rank test). Serum LASEP3 levels were higher in NSCLC patients than in healthy volunteers. The proportion of serum LASEP3-positive cases was 160 (61.8%) of 259 NSCLCs; 131 (63.6%) of 206 ADCs and 29 (54.7%) of 53 SCCs, while 6 (5.5%) of 109 healthy volunteers were falsely diagnosed. Serum LASEP3 levels were significantly higher in breast and colon cancer patients than in healthy volunteers, and tissue LASEP3 protein was overexpressed in breast and colon cancer tissues. Furthermore, treatment of lung cancer cells with siRNAs against LASEP3 suppressed its expression and resulted in growth suppression of cancer cells. Induction of exogenous expression of LASEP3 promoted cell mobility in vitro. We found a 50-kDa receptor (LASEPR) which interacts with LASEP3 on cancer cell surface, suggesting that LASEP3 is an autocrine/paracrine growth factor. Conclusions: LASEP3 is a potential target for the development of diagnostic and prognostic biomarkers for lung and various types of cancers
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Lin, Emily Pei-Ying, Ching-Yao Yang, Ching-Wen Lin, Bo-Tsang Huang, Wei-Yun Lai, Yi-Ting Tseng, and Pan-Chyr Yang. "Priming PD-L1 expression by chemotherapeutic agents in non-small cell lung cancers." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e20087-e20087. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e20087.
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e20087 Background: Immunotherapy targeting PD-1/PD-L1 axis has yielded fruitful results in non-small cell lung cancers (NSCLCs). Evidences showed that treatment responses are likely correlated with tumor PD-L1 expression levels, which is especially true in the first line setting. Results from Keynote-021 suggested that pembrolizumab plus platinum-pemetrexed doublet came out with better overall response rate and progression free survival as compared to chemotherapy alone even in the PD-L1 low-expression group. Nevertheless, grade III and IV toxicities were much frequently observed in the combinational arm. The aim of the current study is to investigate the effect of chemotherapeutics on PD-L1 priming in NSCLCs so as to provide a better option in the chemo-immunotherapy combinational setting. Methods: NSCLC cell lines CL1-5, CL141, and H1299 were treated with a platinum-based drug (cisplatin), microtubule-targeted agents (paclitaxel or vinorelbine), or antimetabolites (pemetrexed or gemcitabine) for 24 to 72 hrs. The concentration of each drug selected for experiments was stepping-down titrated from the IC50s, with the maximum concentration allowed being 10 μM. The priming effects of chemotherapeutics on PD-L1 expression were evaluated with RT-qPCR, Immunoblotting and FACSCalibur flow cytometer. The functionality of the induced PD-L1 was examined by the T cell cytotoxic assay and the IL-2 production ability, done with co-cultured systems containing chemo-primed tumor cells and activated T cells. Results: The results showed that pemetrexed or gemcitabine, but not cisplatin, paclitaxel or vinorelbine, effectively induced PD-L1 expression at concentrations below the IC50s. Membranous distribution of the induced PD-L1 was observed. Addition of anti-PD-L1 blocking antibody in the co-cultured system increased T cell cytotoxic ability and promoted IL-2 production, implicating the biological functionality of the induced PD-L1. Conclusions: The data suggested that pemetrexed or gemcitabine effectively primed the expression of biologically functional PD-L1 in NSCLC cells. The results implicate that pemetrexed or gemcitabine alone may be a good combinational candidate for PD-L1-targeted therapy in NSCLCs.
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Alessi, Joao Victor, Biagio Ricciuti, Yvonne Lin-Liu, Hersh Gupta, Xinan Wang, Giuseppe Lamberti, Gonzalo Recondo, et al. "67 Cancer aneuploidy is associated with a distinct tumor immune microenvironment and impacts outcomes to immune checkpoint inhibition in nonsquamous non-small cell lung cancer." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A74—A75. http://dx.doi.org/10.1136/jitc-2021-sitc2021.067.
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BackgroundCancer aneuploidy, an unbalanced number of chromosomes, is associated with somatic mutation rate, expression of proliferative genes, and altered immune signaling. Whether aneuploidy correlates with a distinct tumor immunophenotype or impacts clinical outcomes to immune checkpoint inhibitors (ICIs) in NSCLC is unclear.MethodsAmong nonsquamous NSCLCs which underwent targeted next-generation sequencing, we retrospectively quantified aneuploidy using the fraction of chromosomal arm alterations (FAA), defined as the number of aneuploid chromosome arms divided by the number of chromosome arms assessed. An unbiased recursive partitioning algorithm was used to investigate an FAA level which best discriminated responders from non-responders to ICIs. Multiplexed immunofluorescence to quantify CD8, FOXP3, and PD-1-positive cell counts, as well as PD-L1 expression was performed on a separate cohort of nonsquamous NSCLCs to determine differences in tumor immune cells subsets according to FAA levels.ResultsAmong 1426 nonsquamous NSCLCs identified, FAA increased along with the increase of pathologic stage, and was highest among tumors harboring EGFR mutations and RET fusions, and lowest among those with KRAS, BRAF, and MET mutations. FAA inversely correlated with PD-L1 expression levels, and positively correlated with tumor mutational burden (TMB) (figure 1A-D). Among 281 NSCLCs treated with ICIs, the median FAA was significantly lower among patients with a partial response to ICI compared to those with stable or progressive disease (0.11 vs 0.21, P=0.006). A fractional aneuploidy level of 0.06 (representing the lowest quartile of FAA) was identified as an optimal cutpoint to discriminate responders from non-responders to ICI. Compared to pts with an FAA >0.06 (N=212), pts with FAA ≤0.06 (N=69) had a significantly higher ORR (42.0% vs 19.3%, P<0.001), longer median progression-free survival (mPFS 6.8 vs 3.2 months, HR: 0.64, P=0.004), and longer median overall survival (mOS 24.8 vs 13.8 months, HR: 0.65, P=0.012) with ICIs (figure 2). After adjusting for performance status, PD-L1 expression, TMB, and line of treatment, FAA retained a significant association with improved PFS (HR: 0.66, P=0.018) and OS (HR: 0.66, P=0.041) to immunotherapy. FAA had no impact on clinical outcomes among pts who received first-line platinum doublet chemotherapy without ICI (figure 3). Among 239 nonsquamous NSCLCs profiled by multiplex immunofluorescence, cancers with a low FAA (≤25th percentile) were significantly enriched in CD8+ T cells and had a higher CD8+ to FOXP3+ ratio compared to those with high FAA (>25th percentile) (figure 4).Abstract 67 Figure 1(A) Median fraction of chromosomal alterations (FAA) are shown for stages I, II, III, and IV NSCLCs. (B) Tumors with negative (<1%), low (1–49%), and high PD-L1 tumor proportion score (TPS) (≥50%) expression. (C) Pearson’s correlation coefficient between FAA and tumor mutational burden (TMB). (D) Median FAA distribution across a set of 8 targetable driver mutations (ALK, BRAF, EGFR, HER2, KRAS, MET, RET and ROS1) and none identified alteration.Abstract 67 Figure 2(A) Objective response rate, (B) progression-free survival, and (C) overall survival, in patients with a fraction of chromosomal arm alterations (FAA) ≤0.06 versus >0.06 in the immunotherapy-cohort.Abstract 67 Figure 3(A) Objective response rate and (B) progression-free survival (PFS) in patients with a fraction of chromosomal arm alterations (FAA) ≤0.06 versus >0.06 in the chemotherapy-cohort.Abstract 67 Figure 4(A) CD8+, (B) PD-1+, (C) PD-1+ CD8+ (D), FOXP3+ cells/mm2, and (E) PD-L1 distribution in nonsquamous NSCLCs with an fraction of arm-level altered (FAA) low (≤25th percentile) versus high (>25th percentile). (F) CD8+ to FOXP3+ ratio in tumors with FAA low versus FAA high.ConclusionsNonsquamous NSCLCs with low aneuploidy have a distinct immune microenvironment and more favorable outcomes to ICIs.