The following article features coverage from the 2021 San Antonio Breast Cancer Symposium. Click here to read more of MPR‘s conference coverage.

 

An analysis of germline-somatic interactions in breast cancer tumors revealed novel associations relevant to the disease’s progression and treatment resistance.

For example, the study presented at the 2021 San Antonio Breast Cancer Symposium (SABCS) showed that carriers of the BRCA2 mutation had inferior outcomes to treatment with first-line CDK4/6 inhibitors plus endocrine therapy.

This could have implications for the optimal first-line therapy in these patients and for sequencing of CDK4/6 inhibitors, explained Anton Safonov, MD, of Memorial Sloan Kettering Cancer Center, who presented the study results.

“Germline mutations in susceptibility genes predispose to tumor development and confer sensitivity to targeted therapy,” Dr Safonov said. “Recent pan-cancer studies have investigated the relationship between germline variants and general somatic drivers in genes other than those containing the pathogenic variant.”

The purpose of this study was to investigate how germline-somatic interactions were associated with clinical outcomes to both lineage-directed and targeted therapy.

The study included samples from 4640 patients who underwent germline and matched tumor tissue sequencing using MSK-IMPACT from April 2014 to May 2021.

The most common germline pathogenic variants were BRCA2, BRCA1, CHEK2, ATM, and PALB2. During his presentation, Dr Safonov focused on BRCA1 (122 patients) and BRCA2 (101 patients).

Results confirmed previously established relationships such as mutual exclusivity of germline ATM and TP53 variants. Alterations in TP53 were seen in 83% of germline BRCA1 patients; however, this did not achieve significance when adjusted for receptor subtype.

Germline BRCA2 was associated with a distinct somatic aberration profile compared with wild-type.The most enriched somatic genes were variation in RB1, AGO2 and MYC, respectively. The RB1 enrichment was specific to BRCA2, Dr Safonov said, and was not seen with BRCA1.

Given that RB1 is a well-established mechanism of CDK4/6 resistance, Dr Safonov and colleagues investigated the effect of BRCA2 status on the efficacy of CDK4/6 inhibitors in combination with endocrine therapy.

Patients with germline BRCA2 mutations were found to have relatively worse outcomes with endocrine therapy and CDK4/6 in first-line setting and all lines of therapy.

This finding is rather provocative, Dr Safonov said. “It further raises the question of whether hormone receptor positive patients with BRCA2 be treated with CDK4/6 inhibitors in the front-line setting as a standard or should PARP inhibitors be considered in this setting instead?” Dr Safonov said.

Studies are ongoing to understand the exact mechanism of this association.

Reference

Safonov A, Bandlamudi C, Tallon de Lara P, et al. Comprehensive genomic profiling of patients with breast cancer identifies germline-somatic interactions mediating therapy resistance. Presented at SABCS 2021; December 7-10, 2021; San Antonio, TX. Abstract GS4-08.

This article originally appeared on Cancer Therapy Advisor