Abstract P4-05-08: Genomic landscape of breast cancer occurring in elderly individuals
Authors: Pier Selenica, Fresia Pareja, Audree Tadros, Lorenzo Ferrando, David N Brown, Hong Zhang, Pedram Razavi, Diana Mandelker, Mark E Robson, Sarat Chandarlapaty, Britta Weigelt, Jorge S Reis-Filho
Journal: Cancer Research (2020)

Abstract Introduction: There is evidence to suggest that the biology of breast cancer (BC) might vary according to age, as BCs in elderly patients might be associated with accumulation of DNA damage and BCs in younger individuals might be enriched for genetic alterations affecting cancer predisposition genes. Whether the genetic landscape of BC in elderly individuals differs is yet to be determined. Here, we sought to describe the spectrum of somatic genetic alterations and mutational signatures in BC according to age. Materials and Methods: We conducted a re-analysis of two cohorts of BC: i) MSK-IMPACT targeted sequencing cohort (primary, n=918; metastatic, n=1,000) and ii) whole-exome sequencing data of primary BCs from The Cancer Genome Atlas (TCGA) BC study (n=1087). BCs of younger (&amp;lt;65 years old) and elderly individuals (≥ 65 years old) were compared, matched by estrogen receptor (ER)/HER2 status at a 2:1 ratio (MSK-IMPACT) or a 1:1 ratio (TCGA). Somatic single nucleotide variants and copy number alterations (CNAs) were determined using a validated bioinformatics pipeline, and mutational signatures were defined using DeconstructSigs and SigMA. Two-tailed Fisher’s exact test was performed. Results: Primary BCs in elderly and younger patients, matched by ER/HER2 status, from the MSK-IMPACT (n=220 and n=440) and TCGA (n=290, each) cohorts, and metastatic BCs from elderly (n=98) and younger (n=196) patients from the MSK-IMPACT cohort, matched by ER/HER2 status, were compared. In both cohorts of primary BCs, PIK3CA, TP53 and CDH1 were the most frequently mutated genes. Compared to younger patients, primary BCs in elderly patients from the MSK-IMPACT cohort displayed a lower frequency of mutations in TP53 (23% vs 34%, P&amp;lt;0.01), AKT1 (2% vs 6%, P&amp;lt;0.05) and MAP2K4 (0.4% vs 4%, P&amp;lt;0.01). In the TCGA cohort, somatic mutations in AKT1 were found to be less frequent in elderly than in younger patients (1% vs 5%, P&amp;lt;0.05), whereas NF1 (2% vs 6%, P&amp;lt;0.05) mutations were more frequent in elderly than in younger patients with primary BCs. Our analyses of BC metastases subjected to MSK-IMPACT revealed that elderly patients harbored a higher frequency of mutations in NCOR1 (11% vs 4%, P&amp;lt;0.05) and RUNX1 (9% vs 2%, P&amp;lt;0.05) than younger patients. The frequency of bi-allelic inactivation of homologous recombination DNA repair deficiency (HRD) genes (i.e. BRCA1, BRCA2, PALB2, RAD51C and RAD51D) in primary BCs of elderly and younger individuals in the TCGA cohort was 2% and 5%, respectively. No differences in the frequency of CNAs were observed between the two groups. The most frequent mutational signatures found in primary BCs of elderly and younger patients were aging, APOBEC and HRD in the MSK-IMPACT cohort, and aging, APOBEC and HRD in primary BCs of the TCGA cohort, with APOBEC being enriched in younger patients compared to elderly patients. The most frequent mutational signatures in metastatic BCs in elderly and younger individuals of the MSK-IMPACT cohort were APOBEC followed by aging and HRD. Conclusion: Our findings show that BCs in elderly patients harbor a lower frequency of somatic mutations in TP53, AKT1 and MAP2K4 than younger individuals. In contrast, BCs in elderly patients more frequently harbor somatic mutations in the transcription factors RUNX1 and NCOR1. Bi-allelic alterations affecting HRD-related genes was numerically more frequent in younger than in older patients. As expected, BCs in elderly patients show a numerically higher incidence of the aging signature, whereas primary BCs affecting younger patients displayed a higher frequency of the APOBEC signature than primary BCs from elderly individuals. Citation Format: Pier Selenica, Fresia Pareja, Audree Tadros, Lorenzo Ferrando, David N Brown, Hong Zhang, Pedram Razavi, Diana Mandelker, Mark E Robson, Sarat Chandarlapaty, Britta Weigelt, Jorge S Reis-Filho. Genomic landscape of breast cancer occurring in elderly individuals [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-05-08.