BRCA1/2 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.
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ICR Authors
Authors
Hahnen, E
Hauke, J
Gelmon, K
Marmé, F
Ernst, C
Martin, M
Untch, M
Bonnefoi, H
Knudsen, E
Im, S-A
DeMichele, A
Van't Veer, L
Kim, S-B
Bear, H
McCarthy, N
Rhiem, K
Turner, N
Witkiewicz, A
Rojo, F
Filipits, M
Martin, L-A
Fasching, PA
Schem, C
Becker, K
García-Sáenz, JA
Kelly, CM
Reimer, T
Toi, M
Rugo, HS
Denkert, C
Gnant, M
Makris, A
Liu, Y
Valota, O
Felder, B
Weber, K
Nekljudova, V
Loibl, S
Hauke, J
Gelmon, K
Marmé, F
Ernst, C
Martin, M
Untch, M
Bonnefoi, H
Knudsen, E
Im, S-A
DeMichele, A
Van't Veer, L
Kim, S-B
Bear, H
McCarthy, N
Rhiem, K
Turner, N
Witkiewicz, A
Rojo, F
Filipits, M
Martin, L-A
Fasching, PA
Schem, C
Becker, K
García-Sáenz, JA
Kelly, CM
Reimer, T
Toi, M
Rugo, HS
Denkert, C
Gnant, M
Makris, A
Liu, Y
Valota, O
Felder, B
Weber, K
Nekljudova, V
Loibl, S
Document Type
Journal Article
Date
2025-04-01
Date Accepted
2025-03-03
Abstract
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 BRCA1/2 and non-BRCA1/2 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 BRCA1/2 PVs. Irrespective of the treatment arms, PV status was not a prognostic factor. Regarding the treatment arms in BRCA1/2 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 v placebo 0.349 [iDFS] and 0.562 [DDFS], not calculated for OS, too few events). In patients without BRCA1/2 PVs, the differences in 3-year outcomes were negligible. PVs in non-BRCA1/2 cancer predisposition genes did not influence the efficacy of palbociclib, although gene-specific effects could not be excluded. CONCLUSION: Patients with BRCA1/2 PVs had numerically better outcomes after palbociclib. However, the number of BRCA1/2 carriers was small. Larger randomized clinical trials should consider the PV status to further evaluate whether BRCA1/2 PV carriers benefit from cyclin-dependent kinase 4 and 6 inhibitor treatment.
Citation
JCO Precision Oncology, 2025, 9 (9), pp. e2400742 -
Source Title
JCO Precision Oncology
Publisher
LIPPINCOTT WILLIAMS & WILKINS
ISSN
2473-4284
eISSN
2473-4284
Collections
Research Team
Molecular Oncology