Abstract GS4-08: Comprehensive genomic profiling of patients with breast cancer identifies germline-somatic interactions mediating therapy resistance

Abstract

Background: Germline genetic alterations are established mediators of breast carcinogenesis, often giving rise to specific forms of genomic instability. BRCA1/2 pathogenic variants (PVs) are emblematic of this phenomenon through their induction of homologous recombination deficiency. While specific patterns of genomic instability may sensitize cancers to therapies such as PARP inhibitors (PARPi) or platinum chemotherapy, their implications for lineage-directed therapies such as endocrine therapy (ET) or CDK4/6 inhibitors (CDK4/6i) are unknown. Herein, we systematically investigated the patterns of association of germline alterations with specific somatic alterations and explored the resulting effect on clinical outcomes. Methods: Patients who underwent germline and matched tumor tissue sequencing utilizing MSK-IMPACT from April 2014 to May 2021 and had available germline analysis results were included. The final analysis presented at SABCS will include 6000 tumors from 5,150 patients, anonymized according to established institutional IRB guidelines to allow for germline analysis on the full cohort. We analyzed genomic data to inform the full spectrum of somatic and germline mutations, ploidy, and allele-specific copy number to determine loss of heterozygosity (LOH). We performed gene- and pathway-level enrichment analyses between somatic variants and germline PVs. Univariable and multivariable Cox proportional hazards models were constructed to assess the association of therapy-specific progression-free survival (PFS) with select germline PVs and germline-somatic interactions. Results: The preliminary analysis includes 2,798 tumors from 2,242 patients with germline and somatic sequencing results. The most frequent germline PVs were: BRCA2 (n = 81), BRCA1 (n = 67), CHEK2 (n = 57), ATM (n = 32), PALB2 (n = 19). The cohort robustly confirmed previously established relationships such as mutual exclusivity of gATM and TP53 variants (OR 0.10, 95% CI 0.032 - 0.33, q = 0.005). Alterations of TP53 were seen in 83% (56/67) of gBRCA1 patients; however, this did not achieve significance when adjusted for receptor subtype (OR 3.90, 95% CI 1.34-11.38, q = 0.15). The size of the cohort allowed discovery of several novel relationships. For instance, gBRCA2 loss was associated with alterations in TGF-B pathway components (OR 3.58, 95% CI 1.70 - 7.56, q = 0.002), potentially relevant to metastatic disease progression. PIK3CA mutations were significantly less prevalent in both gBRCA2 (OR 0.52, 95% CI 0.31 - 0.87, q = 0.063) and gBRCA1 PVs (OR 0.21, 95% CI 0.085 - 0.51, q = 0.014). Our analysis uncovered a strong association between gBRCA2 and somatic RB1 pathogenic alterations (OR 3.58, 95% CI 1.70 - 7.56, q = 0.011), with most variants (80%) encountered in metastatic gBRCA2 tumors. Given the essential role of RB1 in CDK4/6i response, we investigated the effect of BRCA2 status on clinical efficacy of CDK4/6i-ET. Strikingly, gBRCA2 PVs were significantly associated with inferior PFS (HR 2.17, 95% CI 1.46-3.22, p < 0.001) on first line treatment with CDK4/6i-ET. We posited the enrichment of somatic RB1 loss as a potential mechanism of resistance to CDK4/6i. Given the proximity of RB1 to BRCA2 on chromosome 13, we hypothesized that co-LOH of BRCA2 and RB1 predisposes the cancer cells to bi-allelic loss under therapeutic pressure of CDK4/6i. Indeed, 18/26 gBRCA2 (69.2%) tumors evaluable for allele-specific copy number had evidence of RB1 LOH. Discussion: Analysis of germline-somatic interactions yielded novel associations relevant to breast cancer progression and treatment resistance. Among these, we demonstrated BRCA2 carriers to have inferior outcomes to first line CDK4/6i-ET with potential implications for optimal first line therapy and sequencing of CDK4/6i vs PARPi in this patient population. Citation Format: Anton Safonov, Chai Bandlamudi, Paulino Tallón de Lara, Emanuela Ferraro, Fatemeh Derakhshan, Marie Will, Mark Donoghue, Pier Selenica, Joshua Drago, Ezra Rosen, Carlos dos Anjos, Elaine Walsh, Elizabeth A Comen, Mehnaj Ahmed, Barbara Acevedo, Ahmet Zehir, Michael F Berger, David Solit, Larry Norton, Ronglai Shen, Zsofia Stadler, Simon Powell, Jorge S Reis-Filho, Sarat Chandarlapaty, Mark Robson, Pedram Razavi. Comprehensive genomic profiling of patients with breast cancer identifies germline-somatic interactions mediating therapy resistance [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 GS4-08.

Genomic Markers of CDK 4/6 Inhibitor Resistance in Hormone Receptor Positive Metastatic Breast Cancer

“…DNA repair defect (DRD) gene mutations may confer resistance to CDK4/6i. Safonov et al recently reported gBRCA2 mutation in association with significantly inferior PFS (HR 2.17, 95% CI 1.46-3.22, p < 0.001) for 1st-line treatment with CDK4/6 I [47]. No significant association between PALB2 mutation and PFS with CDK4/6i was identified in this study.…”

PARP Inhibitors for Breast Cancer Treatment

“…Retrospective analyses showed that outcomes with CDK4/6 inhibitors may be poorer in carriers of gBRCA1/2 variants compared with wild-type patients . In cases of gBRCA2 variants, this might be due to the co-occurrence of BRCA2 loss of heterozygosity and loss of RB1, a gene located in proximity to BRCA2 on chromosome 13, in which loss is a well-known mechanism of resistance to CDK4/6 inhibitors . Furthermore, gBRCA -associated tumors are more often nonluminal compared with sporadic ER-positive tumors .…”

Update Breast Cancer 2022 Part 6 – Advanced-Stage Breast Cancer

“…At this conference, data were presented showing that a germline mutation in BRCA2 had an unfavorable effect on the prognosis for patients treated with a CDK4/6 inhibitor. Compared to patients with the wild-type genotype, patients with a mutation had a higher risk of progression (HR = 2.32; 95% CI: 1.38 – 3.91) 28 .…”

“…Dort wurden Daten präsentiert, dass bei Patientinnen, die mit einem CDK4/6-Inhibitor behandelt werden, eine Keimbahnmutation in BRCA2 einen ungünstigen prognostischen Effekt hat. Verglichen mit Patientinnen mit einem Wildtyp-Genotyp hatten Patientinnen mit einer Mutation ein höheres Risiko für einen Progress (HR = 2,32; 95 %-KI: 1,38-3,91) [28].…”