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.

Purpose: 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 and non- cancer predisposition genes on the outcomes of PENELOPE-B trial patients.

Methods: 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]).

Results: Of the 442 patients, 42 carried PVs in any cancer predisposition gene; 15 carried PVs. Irrespective of the treatment arms, PV status was not a prognostic factor. Regarding the treatment arms in 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 placebo 0.349 [iDFS] and 0.562 [DDFS], not calculated for OS, too few events). In patients without PVs, the differences in 3-year outcomes were negligible. PVs in non- cancer predisposition genes did not influence the efficacy of palbociclib, although gene-specific effects could not be excluded.

Conclusion: Patients with PVs had numerically better outcomes after palbociclib. However, the number of carriers was small. Larger randomized clinical trials should consider the PV status to further evaluate whether PV carriers benefit from cyclin-dependent kinase 4 and 6 inhibitor treatment.