<i>BRCA1/2</i> and Other Predisposition Genes in High-Risk Hormone Receptor+/Human Epidermal Growth Factor Receptor 2- Breast Cancer Treated With Endocrine Therapy With or Without Palbociclib: A Secondary PENELOPE-B Study Analysis.

Abstract

The PENELOPE-B trial (ClinicalTrials.gov identifier: NCT01864746) recruited patients with hormone receptor+/human epidermal growth factor receptor 2- early breast cancer without a pathological complete response after taxane-containing neoadjuvant chemotherapy and at a high risk of relapse. Patients were randomly assigned (1:1) to receive 13 cycles of palbociclib once daily or placebo on days 1-21 in a 28-day cycle in addition to endocrine therapy (ET). PENELOPE-B did not show improved invasive disease-free survival (iDFS) after adding palbociclib to ET. This retrospective analysis investigated the impact of germline pathogenic variant (PV) status of <i>BRCA1/2</i> and non-<i>BRCA1/2</i> cancer predisposition genes on the outcomes of PENELOPE-B trial patients. In total, 445 patients were sampled following a case-cohort design and 442 were analyzed for germline PVs. Statistical analyses were performed for time-to-event end points (iDFS, distant disease-free survival [DDFS], and overall survival [OS]). Of the 442 patients, 42 carried PVs in any cancer predisposition gene; 15 carried <i>BRCA1/2</i> PVs. Irrespective of the treatment arms, PV status was not a prognostic factor. Regarding the treatment arms in <i>BRCA1/2</i> PV carriers, numerically better 3-year outcomes were observed in the palbociclib arm (iDFS, 95%; DDFS, 95%; OS, 100%) than in the placebo arm (iDFS, 72.8%; DDFS, 72.8%; OS, 87.5%; hazard ratios palbociclib <i>v</i> placebo 0.349 [iDFS] and 0.562 [DDFS], not calculated for OS, too few events). In patients without <i>BRCA1/2</i> PVs, the differences in 3-year outcomes were negligible. PVs in non-<i>BRCA1/2</i> cancer predisposition genes did not influence the efficacy of palbociclib, although gene-specific effects could not be excluded. Patients with <i>BRCA1/2</i> PVs had numerically better outcomes after palbociclib. However, the number of <i>BRCA1/2</i> carriers was small. Larger randomized clinical trials should consider the PV status to further evaluate whether <i>BRCA1/2</i> PV carriers benefit from cyclin-dependent kinase 4 and 6 inhibitor treatment.