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

An analysis of germline-somatic interactions in breast-cancer tumours revealed novel associations relevant to the disease’s progression and treatment resistance. For example, carriers of the BRCA2 mutation had inferior outcomes to treatment with first-line CDK4/6 inhibitors plus endocrine therapy.

Germline genetic alterations are established mediators of breast carcinogenesis, often giving rise to specific forms of genomic instability. BRCA1/2 pathogenic variants are representative of this phenomenon through their induction of homologous recombination deficiency. While specific patterns of genomic instability may sensitise cancers to therapies such as Poly(ADP-ribose) polymerase inhibitors (PARPi) or platinum chemotherapy, their implications for lineage-directed therapies, such as endocrine therapy or CDK4/6 inhibitors , are unknown. Therefore, Dr Anton Safonov (Memorial Sloan-Kettering Cancer Center, NY, USA) and colleagues systematically investigated the patterns of association of germline alterations with specific somatic alterations and explored the resulting effect on clinical outcomes. The study included samples from 4,640 patients who underwent germline and matched tumour-tissue sequencing. Dr Safonov presented the results [1].

The most common germline pathogenic variants were BRCA2, BRCA1, CHEK2, ATM, and PALB2. 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 (OR 3.90; 95% CI 1.34–11.38; Q=0.15).

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

Given that RB1 is a well-established mechanism of CDK4/6 resistance, the effect of BRCA2 status on the efficacy of CDK4/6 inhibitors in combination with endocrine therapy was investigated. Patients with germline BRCA2 mutations were found to have relatively worse progression-free survival with endocrine therapy and CDK4/6 in first line and subsequent lines of therapy (HR 2.17; 95% CI 1.46–3.22; P<0.001).

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

1. Safonov A, et al. Comprehensive genomic profiling of patients with breast cancer identifies germline-somatic interactions mediating therapy resistance. GS4-08, SABCS 2021 Virtual Meeting, 7–10 December.

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Posted on 31 January, 2022