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BACKGROUND: Breast cancer (BC) is the most common cancer and the second leading cause of cancer-related deaths worldwide. Mutations in tumor suppressor genes BRCA1 and BRCA2 are the most common cause of hereditary breast and ovarian cancer. Additionally, carriers of germline BRCA1/2 mutations also have an elevated risk of other malignancies. Identification of mutations within these genes is essential for determining early cancer detection and risk-reducing strategies in carriers and establishing a therapeutic approach in breast cancer patients. The aims of this study were to evaluate the prevalence and spectrumof germline BRCA1 and BRCA2 variants in peruvian breast cancer patients. METHODS: Patients with HER2Neu negative BC referred to ONCOGENOMICS laboratory from 2019 to2021 to assessed poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor treatment were included in the study. Blood samples were collected to assess the status of germline BRCA1 and BRCA2. Next Generation Sequencing (NGS) was performed using the Ampliseq for Illumina BRCA panel and run on the Illumina MiSeq. The Human Genome Variation Society (HGVS) nomenclature guidelines (http://varnomen.hgvs.org/) were used to annotate identified variants and the ClinVar database (www.ncbi.nlm.nih.gov/clinvar/) was used to determine the clinical significance of all reported variants. Current American College of Medical Genetics (ACMG) guidelines were also used for further classification. RESULTS: A total of 155 HER2Neu negative BC cases were evaluated. Median age at BRCA1/2 evaluation was 51 (23-82) years, 78.1% (121) were negative HR status (triple-negative BC, TNBC); 21.9% (34) were positive HR status; 33.5% (52) were clinical stage III and 66.5% (103) were clinical stage IV. Most patients were from Lima-Callao (65.8%) followed by patients from the coast (23.9%), highlands (9%) and rainforest(1.3%). Only 18.7% of patients were from public health centers. The prevalence of pathogenic (P) and likely pathogenic (LP) variants in BRCA1/2 was 13.5% (21) (13 in BRCA1 and 8 in BRCA2). The pathogenic variant in BRCA1 c.2105dupT (p.Leu702Phefs*10) was found in 3 cases (2 Lima-Callao and 1 coast). All variants identified in BRCA1 were in TNBC. In BRCA2, half of pathogenic variants were found in TNBC. The prevalence of variants of uncertain significance (VUS) was 6.4% (10). In BRCA2, we identified 7 VUS and the variant c.5465A>T (p.Asn1822Ile) was found in 3 cases with positive HR status. Only one VUS was found in BRCA1. CONCLUSION: BRCA1 and BRCA2 germline mutations were identified in 13.5% of peruvian HER2Neu negative BC patients. A higher rate of P/LP variants was found in BRCA1. TNBC patients demostrated a higher prevalence in BRCA1 variants. Citation Format: Joseph A Pinto, Yomali Ferreyra, Alicia M Cock-Rada, Franco Doimi, Jhoysi Casas, Jhajaira Araujo, Gina Rosas, Leny Bravo, Carolina Belmar-López. Landscape of germline BRCA1 and BRCA2 mutations in breast cancer in Peru [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-12-24.

Introduction: In a previous work we found differences in immune gene sets enrichment in NSCLC between genders, regardless their smoking status, where women had higher expression of gene sets associated with immune processes. Based in this fact, we hypothesize fewer benefits from immune checkpoint inhibitors in women patients compared than men patients. Objectives: Evaluate the benefit (in terms of progression-free survival) of women patients from immune checkpoint inhibitors nivolumab and pembrolizumab in published randomized phase III trials. Methods: We evaluated by meta-analysis four randomized phase III studies, two of prembrolizumab (Herbst et al., 2015 and Reck et al., 2016) and two of nivolumab (Borghaei et al., 2015 and Brahmer et al., 2015). We analyzed TCGA data for lung adenocarcinoma to evaluate differences in the expression of PDCD1, CD274 genes (encoding for PD-1 and PD-L1, respectively). Results: For all studies, it was observed an overall HR=0.79 (CI95%:0.71-0.87;P Conclusion: Although there are not differences between genders in the expression of PDCD1 and CD274 genes , such as is previously described for expression for PD-1 and PDL-1 proteins, in our meta-analysis we shown that women have modest benefit from anti immune checkpoint inhibitors. Blockade of PD1 and PD-L1 is a promising therapy in lung cancer; however, a better stratification of patients should be done. Meta-analysis of four phase III randomized studiesStudyAll patientsMenWomenWeightHazard Ratio IV, Fixed, 95% CIWeightHazard Ratio IV, Fixed, 95% CIWeightIV, Fixed, 95% CIReck et al., 201610.6%0.50 [0.37, 0.68]10.4%0.39 [0.26, 0.581]8.0%0.71[0.40, 1.26Brahmer et al., 201513.7%0.63 [0.48, 0.8217.8%0.63 [0.46, 0.86]11.2%0.75[0.46, 1.22]Borghaei et al., 201530.3%0.91 [0.76, 1.0926.6%0.81 [0.63, 1.04]37.8%1.02[0.78, 1.33]Herbst et al., 201545.40.85 [0.73, 0.98]45.2%0.78 [0.64, 0.95]43.0%1.04[0.81, 1.33]Total (95% Cl)100.0%0.79 [0.71, 0.87]100.0%0.71 [0.62, 0.80100.0%0.97[0.82, 1.14]Heterogeneity: Chi2=14.73,df=3 (P=0.002); I2= 80% Test for overall effect: Z= 4.73 (P Citation Format: Joseph A. Pinto, Luis A. Mas, Carlos S. Vallejos, Jhajaira Araujo, Leny Bravo, Alfredo Aguilar, Zaida Morante, Denisse Bretel, Henry L. Gomez, Christian Rolfo. Decrease of benefit from immune checkpoint inhibitors in women with non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2614. doi:10.1158/1538-7445.AM2017-2614