BRCA2 linked to inferior outcome to treatment with CDK4 / 6 inhibitors plus endocrine therapy

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

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

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


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

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

The study included samples from 4,640 patients who underwent germ line and corresponding 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).

The results confirmed previously established relationships such as the mutual exclusivity of the germline AT M and TP53 variants. Changes in TP53 were observed in 83% of germ lines BRCA1 the patients; however, this did not reach significance when adjusted for the receptor subtype.

Germ line BRCA2 was associated with a distinct somatic aberration pattern compared to the wild type. The most enriched somatic genes were the variation of RB1, AGO2 and MYC, respectively. the RB1 the enrichment was specific to BRCA2, said Dr Safonov, and has not been seen with BRCA1.

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

Germline patients BRCA2 the mutations were found to have relatively worse results with endocrine therapy and CDK4 / 6 as part of the first line and all lines of therapy.

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

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

Read more about Cancer therapy advisor coverage of SABCS 2021 by visiting the conference page.

Reference

Safonov A, Bandlamudi C, Tallon de Lara P, et al. Comprehensive genomic profiling of breast cancer patients identifies germline-somatic interactions that mediate resistance to treatment. Presented at SABCS 2021; December 7-10, 2021; San Antonio, Texas. Summary GS4-08.

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