BRCA mutations detected by tumour next-generation sequencing in non-small cell lung cancer: impact on response to therapy and disease course

Introduction

Deleterious germline mutations in the BRCA1 and BRCA2 tumour-suppressor genes have long been implicated in the majority of hereditary breast and ovarian cancers (1). Individuals harbouring germline BRCA mutations are also at increased risk for pancreatic and prostate cancer, with a higher risk amongst BRCA2 carriers (2-5). In these cancers, insight into the role of BRCA status has paved the way for genetic counselling programs, risk-reducing interventions (e.g., prophylactic bilateral salpingo-oophorectomy), and the development of therapeutic strategies. A heightened response to platinum-based therapy is a hallmark of BRCA-mutated breast and ovarian cancers, owing to their inherent inability to efficiently repair intra-stand DNA crosslinks induced by platinum agents (6). Alongside platinum-based therapy, poly (ADP-ribose) polymerase (PARP) inhibition is another important treatment strategy, currently approved as subsequent-line therapy for BRCA-mutated breast, ovarian and prostate cancers, and as maintenance therapy for ovarian and pancreatic cancer patients who have responded favourably to platinum-based chemotherapy (7-11).

In a recent pan-cancer analysis of 234,145 tumour samples by Sokol and colleagues, BRCA1/2 alterations were observed in 3% of non-BRCA1/2 associated cancers, suggesting a potentially broader landscape for BRCA-targeted therapy than is currently available (12). However, the phenotypic implications of BRCA status in these cancer types remains poorly defined.

For non-small cell lung cancer (NSCLC) patients, molecular profiling through next-generation sequencing (NGS) for the purpose of identifying targetable driver mutations (i.e., EGFR, ALK, ROS1, MET, KRAS, BRAF, NTRK) is considered the standard of care (13). Still, there is only limited data regarding the role of BRCA status as a prognostic and predictive biomarker in this setting. Tian et al. assessed the prevalence and distribution of pathogenic or likely pathogenic germline variants in 1764 Chinese patients with lung cancer (14). Pathogenicity was determined based on American College of Medical Genetics and Genomics (ACMG) guidelines. In this cohort, BRCA2 was the most common site of germline mutation, with a prevalence of 0.79%, while BRCA1 was the third-most common site, with a prevalence of 0.34%. Clinico-pathologic features of the BRCA1/2 subgroup were not assessed.

More recently, the molecular profile of pulmonary tumours from 379 patients participating in the ongoing SAFIR02-Lung Trial was published (15). BRCA1/2 mutations were identified in 5.3% of the cohort, with confirmed pathogenic variants identified in 2.1% of enrolled patients, of which 75% were somatic. Notably, the overall response rate (ORR) to platinum-based chemotherapy amongst the eight patients with pathogenic BRCA (either somatic or germline) was low (13%). This, together with a low concordance between BRCA pathogenicity and the patients’ homologous recombination deficiency (HRD) score (a genomic instability score calculated based on copy number variations) lead the authors to doubt the predictive role of BRCA status in NSCLC.

In this study, we aimed to shed further light on the role of tumour BRCA mutation status in NSCLC by evaluating its impact not only on platinum-sensitivity, but on tumour response to chemo-immunotherapy, immunotherapy-only and platinum-based chemo-radiation regimens. We also sought to directly compare the clinico-pathological features and treatment response profile of patients with BRCA-mutated tumours against BRCA-wildtype counterparts. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-594/rc).

Methods

Study population

Cases were selected retrospectively. The study population consisted of all consecutive patients treated for stage III–IV NSCLC at the Rabin Medical Centre (RMC), for whom NGS was performed between January 2015 and August 2020 (Figure S1). This initial cohort was used for the purposes of genetic analyses. Treatments were assigned according to National Comprehensive Cancer Network (NCCN) guidelines: metastatic patients were treated with systemic therapy (chemotherapy, chemotherapy & immunotherapy combinations, or targeted oral therapy); stage III patients were treated with chemoradiation. Electronic medical records (EMR) were available for 396 (89%) out of the initial 445-patient cohort. This sub-cohort was used for the purposes of additional clinical analyses.

NGS

Commercial NGS was conducted in patients with advanced disease (stage III–IV) for the purpose of identifying targetable driver mutations. Sequencing was performed via one of two methods: tissue-based sequencing using FFPE samples (Foundation One^©, TempusXT^©, MyPG^©, Genesort^©), or liquid ctDNA-based sequencing (FoundationACT^©, Foundation One Liquid^©, Guardant360^©).

Molecular characterization of tumour samples

Programmed death-ligand 1 (PD-L1) expression level in lung tumour samples was measured using the Dako PD-L1 immunohistochemistry (IHC) 22C3 pharmDx assay (16). Expression levels were reported as tumour proportion score (TPS) and classified as either negative (<1%), low-positive (1–49%) or positive (≥50%).

Variant classification

For the purpose of classifying BRCA variants by their pathogenic potential, we employed the scheme detailed in the Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer, which includes the following categories: “variants of strong clinical significance”, “variants of potential clinical significance”, “variants of unknown clinical significance” and “benign or likely benign variants” (17).

For each BRCA variant, we performed search queries in both the Varsome and Clinvar databases (18,19). A consensus-based approach was used wherein only variants classified as having strong clinical significance or potential clinical significance in both databases were considered as such for downstream analysis. We termed these variants pBRCA (pathogenic/likely pathogenic).

Germline BRCA status was not evaluated in the study. Therefore, we were not able to reliably categorize any of the pBRCA mutations identified by NGS as being either a manifestation of a background germline BRCA mutation, or of purely somatic origin.

Curation of clinical data

Data were extracted from patients’ EMR and includes the following: demographic details, smoking history, personal and family history of malignancy, tumour histology, disease stage and Eastern Cooperative Oncology Group (ECOG) score at presentation, tumour histology & level of differentiation, thyroid transcription factor-1 (TTF-1) status and PD-L1 status.

Clinical endpoints

The study’s clinical endpoints included the prevalence of pathogenic or non-pathogenic BRCA mutations identified by NGS, response to platinum-based chemotherapy, response to treatment with chemotherapy & immunotherapy combinations, response to immunotherapy treatment, response to targeted oral therapy treatments, median progression-free-survival, and median overall survival (OS).

Response to various lines of systemic treatment was assessed and categorized as complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD), adapted from RECIST 1.1. Progression-free-survival (PFS) was defined as the time interval from treatment initiation to disease progression or death. OS was defined as the time interval between diagnosis and death.

Statistical analysis

All statistical analyses were performed using IBM^© SPSS^© software version 25. A chi-square test of independence was performed to examine the relation between BRCA mutation status and various categorical clinico-pathologic variables. Frequencies are expressed as percentages. An independent samples t-test was used to examine the relationship between BRCA mutation status and various continuous clinico-pathologic variables. Results are expressed as mean ± standard deviation (SD). A log rank test was run to determine if there were differences in the survival distribution by BRCA mutation status, stratified by the treatment modality administered (platinum-based chemotherapy/chemoradiation, chemo-immunotherapy or immunotherapy). A Cox regression model was used to quantify the hazard ratio (HR) for disease progression under various treatment modalities, based on BRCA mutation status. P values of <0.05 were considered statistically significant.

Ethics

The study was approved by the Rabin Medical Center Institutional Review Board (IRB) (0391-14-RMC), and was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Written consent for the usage of NGS data, as well as demographics & disease characteristics for the purpose of research and/or publication, was provided by all participants.

Results

BRCA mutation status detected by tumour NGS

Of 445 reports included, 239 (53.7%) were from formalin-fixed paraffin-embedded (FFPE) samples and 184 (41.3%) were circulating tumour DNA (ctDNA)-based. For an additional 22 (5%) reports, there was no documentation of the sample source. Out of 445 patients in our cohort, 109 (24.5%) had a BRCA1/2 variant, whereas in 336 (75.5%) no BRCA variants were reported (wtBRCA) (Figure S2). Of patients with a BRCA variant, 86 (78.9%) had a single variant, 16 (14.7%) had two different variants, 4 (3.7%) had three different variants and 3 (2.8%) had four different variants.

Amongst BRCA-mutated tumours, 25 had a confirmed pathogenic/likely pathogenic variant (pBRCA), which constitutes 5.6% of the entire study cohort (25/445), while 14/25 of pBRCA mutations were in BRCA2 and 11/25 were in BRCA1. Notably, in 12 (48%) patients, the pathogenic variant was a well-established BRCA founder mutation, which might potentially reflect a germline origin. However, germline status was not routinely performed in the study, therefore none of the cases could be reliably classified as germline.

Demographics and disease characteristics

Three hundred and ninety-six out of 445 patients (89%) had EMR data available for analysis. Based on EMR data, demographic and disease characteristics were compared between pBRCA (n=24) and wtBRCA (n=292) patients (Table 1). The cumulative amount of smoking pack-years was lower in the pBRCA group [mean 42.6 (29.2) vs. 25.7 (24.0) pack years in the wtBRCA and pBRCA groups, respectively; P=0.024]. All other demographic and disease characteristics did not differ significantly between the groups.

Co-occurring driver mutations

Of the 25 patients with a pBRCA mutation identified by NGS, 15 (60%) had a co-occurring alteration in at least one of the established NSCLC driver genes (EGFR, KRAS, ALK, BRAF, MET, ERBB2 or ROS1), including 13 patients with a characteristic driver mutation. Notably, 3 pBRCA patients had no identifiable driver mutation, and no history of smoking, suggesting a possible oncogenic role for BRCA in these patients.

Patient-level specifics for pBRCA patients, including co-occurring alterations, gender, smoking history, response to treatment (to either platinum-based therapy or single-agent immunotherapy) and PD-L1 expression levels, are shown in Table 2.

Disease control rate under platinum-based therapy

In total, 239 patients were treated with platinum-based therapy in the frontline setting for stage 3–4 disease (chemotherapy, chemo-radiation, or chemo-immunotherapy), including 175 wtBRCA patients and 17 pBRCA patients. In the pBRCA group, 10 patients were treated with chemotherapy/chemo-radiation, and 7 patients received a chemo-immunotherapy combination.

Overall disease control rates (PR, CR or SD) under the various platinum-based regimens, according to BRCA mutation status, are shown in Table 3. Disease control rates did not differ significantly between the wtBRCA and pBRCA groups.

PFS with platinum-based therapy

Mean time for the study cohort was 27 months. In a log-rank analysis, median PFS was significantly prolonged for pBRCA patients (n=15) compared with wtBRCA patients (n=129) treated with platinum-based therapy [10 (2.2) vs. 4.6 (0.3) months; P=0.002; Figure 1].

Figure 1 PFS with platinum-based therapy. wtBRCA, wild type BRCA; pBRCA, pathogenic/likely pathogenic BRCA; PFS, progression-free survival.

In a further breakdown by specific platinum-based regimens, median PFS was significantly prolonged for pBRCA (n=7) compared with wtBRCA (n=30) patients on chemo-immunotherapy [11.1 (3.7) vs. 4.4 (0.9) months; P=0.014; Figure 2]. Congruently, a univariate cox regression model showed that pBRCA status was associated with prolonged PFS under first-line chemo-immunotherapy (HR =0.279; P=0.021, 95% CI: 0.094–0.825).

Figure 2 PFS with frontline chemo-immunotherapy. wtBRCA, wild type BRCA; pBRCA, pathogenic/likely pathogenic BRCA; PFS, progression-free survival.

Finally, median PFS with first-line platinum-based chemotherapy/chemo-radiation was prolonged for the pBRCA group (n=8) compared with wtBRCA (n=99), albeit not to a statistically-significant degree [8.3 (2.8) vs. 4.7 (0.5) months; P=0.062; Figure 3].

Figure 3 PFS with frontline chemotherapy/chemoradiation. wtBRCA, wild type BRCA; pBRCA, pathogenic/likely pathogenic BRCA; PFS, progression-free survival.

Response rate with single-agent immunotherapy

Eight patients with pBRCA mutated NSCLC were treated with single agent immune-checkpoint inhibition (one in the first-line setting and seven in the second-line setting). Four of them derived clinical benefit (one patient achieved CR, one patient achieved PR and two patients exhibited SD) (Table 2).

OS

A Log- Rank analysis was performed in order to assess the association between BRCA mutation status and OS, as calculated from the time of being diagnosed with advanced disease (stage 3–4). Median OS did not differ significantly between the wtBRCA (n=266) and pBRCA (n=21) groups [21 (1.39) vs. 24.2 (3.1) months for wtBRCA and pBRCA, respectively; P=0.837; Figure S3].

Discussion

This study extends the limited literature concerning BRCA status in NSCLC.

The proportion of lung cancer tumour samples in our cohort harbouring a pathogenic BRCA mutation was 5.6%, which is higher than previously-reported rates, including in the SAFIR02-Lung trial (2.1%), and in a study by Jordan and colleagues comprising 860 metastatic lung adenocarcinoma patients (1.3%) (15,20).

Differences in the reported pBRCA prevalence rates might be due to variability in the way variants were classified as pathogenic: in our study, variants were stratified based on expert panel consensus in the Clinvar and Varsome^© databases; Jordan et al. employed a four-tier system based on the level of evidence suggesting the variant in question might be targetable by standard or investigational therapies; lastly, in the SAFIR02-Lung trial variants were classified by a molecular geneticist as pathogenic, being of unknown pathogenicity or probably non-pathogenic based on an undisclosed classification scheme. Another putative factor is the high prevalence of germline pBRCA variants among Ashkenazi Jews (AJ), which are over-represented in this study (21,22). Indeed, in a comparable series of 248 Israeli patients with NSCLC from 2019, the rate of pathogenic germline BRCA mutation was 4.8%, which is closer to our own reporting (23). In both cohorts, the rate of pBRCA was higher than the background BRCA carrier frequency amongst AJs, which is estimated at maximally 2.5% (24).

For a detailed comparison of previous studies reporting on BRCA mutation carrier frequency amongst NSCLC patients, either somatic or germline (Table S1) (14-15,20,23,25).

Notably, 40% (n=1,025) of pBRCA tumours we identified did not have a co-occurring NSCLC driver mutation, hinting at a potentially significant role for BRCA loss in oncogenesis in these patients. This might be especially relevant in the 3 patients out of the 10 who have no prior history of smoking (Table 2).

In a direct comparison of wtBRCA and pBRCA patients, we found that BRCA positivity was associated with a longer PFS with platinum-based therapy as a whole, an effect which seems to be driven primarily by a favourable PFS under chemotherapy-immunotherapy regimens. While the median PFS for pBRCA patients treated with chemo-immunotherapy in our study was prolonged (11.1 months), even compared with the chemo-immunotherapy arm in the KEYNOTE-189 trial (8.8 months) (26), the number of patients who received chemo-immunotherapy in our study (n=7) is too small to draw a robust conclusion (24). Further research is warranted in order to establish the role of BRCA positivity as a determinant of response in this setting.

On the molecular level, there is mechanistic rationale for BRCA-deficient tumours to display a heightened sensitivity to immunotherapy. In these tumours, BRCA-mediated effects on the tumour-immune microenvironment, including increased neo-antigen load and the enrichment of distinct immune-cell subpopulations, result in greater immunogenicity (27,28). In the clinical setting, however, the extent of real-life efficacy of immunotherapy in BRCA-mutated tumours is variable. In breast cancer (BC), for example, it is likely dependent upon additional molecular underpinnings such as hormone receptor subtypes, loss of heterozygosity (LOH) and homologous-recombination deficiency (HRD) score (29). This is made evident by the reported ORR with single-agent immunotherapy for triple-negative BC, the most common hormonal classification in BRCA-mutated breast cancers, which is generally less than 20% (30-32). Similarly, in our study the ORR with single-agent immunotherapy in the pBRCA group was 25% (2/8).

This study has several limitations. First, small sample sizes in each of the analysed treatment arms warrant caution when interpreting our findings, especially with regards to the efficacy of chemotherapy-immunotherapy combinations for pBRCA patients. Secondly, unaccounted-for imbalances between the pBRCA and wtBRCA groups might have contributed to the observed differences in PFS. This is especially true with regards to established predictive markers for immunotherapy response; there was a higher proportion of PD-L1 low-positive/positive patients in the pBRCA group compared with the wtBRCA group, albeit not to a statistically significant degree, while data regarding tumour mutational burden (TMB) in each of the groups is unfortunately lacking.

An additional limitation stems from the fact that prior to 2021, NGS in Israel was an out-of-pocket expense; as such, the study population excludes patients of lower socio-economic background and is therefore selective. In addition, response to treatment evaluation, as well as the genomic analyses, were de-centralized to several different oncology clinics and multiple commercial panels. On the other hand, variant pathogenicity was carefully determined in a centralized fashion by two of the authors: a medical geneticist (YG) and a medical oncologist (RT), using two separate and equally-validated databases. Since we relied on commercial tumour-directed NGS panels, we were unable to define the rate of germline BRCA mutations in this cohort.

Notwithstanding the above limitations, our findings do suggest that pulmonary tumours harbouring pathogenic BRCA mutations can represent a specific subtype of NSCLC, in which platinum-based therapy as a whole, and chemo-immunotherapy combinations in particular, is an effective strategy. Future subgroup analyses in large prospective trials can help better define this tumour subtype.

Conclusions

Our data suggests that pBRCA-mutated tumors may represent a distinct subtype of NSCLC. In a subset of these tumours, no additional driver mutations are identified, hinting at a potentially significant role for BRCA impairment in oncogenesis. The therapeutic yield of specifically targeting BRCA in this subset of patients remains to be validated through further prospective research.

Acknowledgments

The abstract has been presented at ESMO virtual scientific meeting 2020 (abstract 1351P).

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-594/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-594/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-594/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-594/coif). DAG has received institutional research funding from BMS, Merck and Janssen, and consulting fees from Vivio Health. He has also held an unpaid advisory and leadership role at Optimal Cancer Care Alliance. He holds personal stock at Viviohealth and TailorMed. ED has received institutional research funding from Astra Zeneca, and consulting/speaking fees from Roche, Astra Zeneca, Pfizer, Merck Sharpe & Dohme, Bristol Myers Squibb, Novartis, Takeda, Sanofi, Merck Serono, Medison Pharma, and Janssen Israel. She has also received support for attending meetings and/or travel from Merck Serono and Medison Pharma. In addition, ED participated in data safety monitoring boards at Roche, Astra Zeneca, Pfizer, Merck Sharpe & Dohme, Bristol Myers Squibb, Novartis, Takeda, Sanofi, Merck Serono, Medison Pharma, and Janssen Israel. ED also has occupied a chair position at the Israeli Society for Clinical Oncology and Radiotherapy (ISCORT), is an ESMO faculty member, and an IASLC mesothelioma committee member. NP has received advisory fees & honorarium from, and has performed research with AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, FoundationMedicine, Gaurdant³⁶⁰, Merk, MSD Novartis, NovellusDx, Pfizer, Roche, and Takeda. He has also received support for attending meetings and/travel from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, FoundationMedicine, Gaurdant360, Merk, MSD, Novartis, NovellusDx, Pfizer, Roche, Takeda. AZ has received consulting fees from AstraZeneca, Oncohost, Steba MSD, Takeda Nixio and Medison. She has also received payments for lectures from BMS, Novartis, Takeda, MSD, Pfizer and Roche. In addition, AZ received support for attending meetings and/or statements from Janssen, has participated on a data safety monitoring board at Beyond Cancer, and holds stock/stock options at Nixio. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was approved by the Rabin Medical Center Institutional Review Board (IRB) (0391-14-RMC), and was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Written consent for the usage of NGS data, as well as demographics & disease characteristics for the purpose of research and/or publication, was provided by all participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Gershoni-Baruch R, Dagan E, Fried G, et al. Significantly lower rates of BRCA1/BRCA2 founder mutations in Ashkenazi women with sporadic compared with familial early onset breast cancer. Eur J Cancer 2000;36:983-6. [Crossref] [PubMed]
2. Hahn SA, Greenhalf B, Ellis I, et al. BRCA2 germline mutations in familial pancreatic carcinoma. J Natl Cancer Inst 2003;95:214-21. [Crossref] [PubMed]
3. Hankey BF, Feuer EJ, Clegg LX, et al. Cancer surveillance series: interpreting trends in prostate cancer--part I: Evidence of the effects of screening in recent prostate cancer incidence, mortality, and survival rates. J Natl Cancer Inst 1999;91:1017-24. [Crossref] [PubMed]
4. Leongamornlert D, Mahmud N, Tymrakiewicz M, et al. Germline BRCA1 mutations increase prostate cancer risk. Br J Cancer 2012;106:1697-701. [Crossref] [PubMed]
5. Lynch HT, Deters CA, Snyder CL, et al. BRCA1 and pancreatic cancer: pedigree findings and their causal relationships. Cancer Genet Cytogenet 2005;158:119-25. [Crossref] [PubMed]
6. Mylavarapu S, Das A, Roy M. Role of BRCA Mutations in the Modulation of Response to Platinum Therapy. Front Oncol 2018;8:16. [Crossref] [PubMed]
7. Robson M, Im SA, Senkus E, et al. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med 2017;377:523-33. [Crossref] [PubMed]
8. Matulonis UA, Penson RT, Domchek SM, et al. Olaparib monotherapy in patients with advanced relapsed ovarian cancer and a germline BRCA1/2 mutation: a multistudy analysis of response rates and safety. Ann Oncol 2016;27:1013-9. [Crossref] [PubMed]
9. Mateo J, Carreira S, Sandhu S, et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. N Engl J Med 2015;373:1697-708. [Crossref] [PubMed]
10. Golan T, Hammel P, Reni M, et al. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. N Engl J Med 2019;381:317-27. [Crossref] [PubMed]
11. Moore K, Colombo N, Scambia G, et al. Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N Engl J Med 2018;379:2495-505. [Crossref] [PubMed]
12. Sokol ES, Pavlick D, Khiabanian H, et al. Pan-Cancer Analysis of BRCA1 and BRCA2 Genomic Alterations and Their Association With Genomic Instability as Measured by Genome-Wide Loss of Heterozygosity. JCO Precis Oncol 2020;4:442-65. [Crossref] [PubMed]
13. Lindeman NI, Cagle PT, Beasley MB, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Mol Diagn 2013;15:415-53. [Crossref] [PubMed]
14. Tian P, Cheng X, Zhao Z, et al. Spectrum of Pathogenic Germline Mutations in Chinese Lung Cancer Patients through Next-Generation Sequencing. Pathol Oncol Res 2020;26:109-14. [Crossref] [PubMed]
15. Remon J, Besse B, Leary A, et al. Somatic and Germline BRCA 1 and 2 Mutations in Advanced NSCLC From the SAFIR02-Lung Trial. JTO Clin Res Rep 2020;1:100068. [Crossref] [PubMed]
16. Roach C, Zhang N, Corigliano E, et al. Development of a Companion Diagnostic PD-L1 Immunohistochemistry Assay for Pembrolizumab Therapy in Non-Small-cell Lung Cancer. Appl Immunohistochem Mol Morphol 2016;24:392-7. [Crossref] [PubMed]
17. Li MM, Datto M, Duncavage EJ, et al. Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: A Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. J Mol Diagn 2017;19:4-23. [Crossref] [PubMed]
18. Available online: https://varsome.com/
19. Available online: https://www.ncbi.nlm.nih.gov/clinvar/
20. Jordan EJ, Kim HR, Arcila ME, et al. Prospective Comprehensive Molecular Characterization of Lung Adenocarcinomas for Efficient Patient Matching to Approved and Emerging Therapies. Cancer Discov 2017;7:596-609. [Crossref] [PubMed]
21. Lewin-Epstein N, Cohen Y. Ethnic origin and identity in the Jewish population of Israel. J Ethn Migr Stud 2019;45:2118-37. [Crossref]
22. Laitman Y, Vaisman Y, Feldman D, et al. Rates of risk-reducing surgery in Israeli BRCA1 and BRCA2 mutation carriers. Clin Genet 2014;85:68-71. [Crossref] [PubMed]
23. Kadouri L, Rottenberg Y, Zick A, et al. Homologous recombination in lung cancer, germline and somatic mutations, clinical and phenotype characterization. Lung Cancer 2019;137:48-51. [Crossref] [PubMed]
24. Warner E, Foulkes W, Goodwin P, et al. Prevalence and penetrance of BRCA1 and BRCA2 gene mutations in unselected Ashkenazi Jewish women with breast cancer. J Natl Cancer Inst 1999;91:1241-7. [Crossref] [PubMed]
25. Hu X, Yang D, Li Y, et al. Prevalence and clinical significance of pathogenic germline BRCA1/2 mutations in Chinese non-small cell lung cancer patients. Cancer Biol Med 2019;16:556-64. [Crossref] [PubMed]
26. Gadgeel S, Rodríguez-Abreu D, Speranza G, et al. Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol 2020;38:1505-17. [Crossref] [PubMed]
27. Samstein RM, Krishna C, Ma X, et al. Mutations in BRCA1 and BRCA2 differentially affect the tumor microenvironment and response to checkpoint blockade immunotherapy. Nat Cancer 2021;1:1188-203. [Crossref] [PubMed]
28. Strickland KC, Howitt BE, Shukla SA, et al. Association and prognostic significance of BRCA1/2-mutation status with neoantigen load, number of tumor-infiltrating lymphocytes and expression of PD-1/PD-L1 in high grade serous ovarian cancer. Oncotarget 2016;7:13587-98. [Crossref] [PubMed]
29. Kraya AA, Maxwell KN, Wubbenhorst B, et al. Genomic Signatures Predict the Immunogenicity of BRCA-Deficient Breast Cancer. Clin Cancer Res 2019;25:4363-74. [Crossref] [PubMed]
30. Nanda R, Chow LQ, Dees EC, et al. Pembrolizumab in Patients With Advanced Triple-Negative Breast Cancer: Phase Ib KEYNOTE-012 Study. J Clin Oncol 2016;34:2460-7. [Crossref] [PubMed]
31. Adams S, Schmid P, Rugo HS, et al. Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: cohort A of the phase II KEYNOTE-086 study. Ann Oncol 2019;30:397-404. [Crossref] [PubMed]
32. Dirix LY, Takacs I, Jerusalem G, et al. Avelumab, an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase 1b JAVELIN Solid Tumor study. Breast Cancer Res Treat 2018;167:671-86. [Crossref] [PubMed]