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

Hahnen E, Hauke J, Gelmon K, Marmé F, Ernst C, Martin M, Untch M, Bonnefoi H, Knudsen E, Im SA, Demichele A, Van'T Veer L, Kim SB, Bear H, McCarthy N, Rhiem K, Turner N, Witkiewicz A, Rojo F, Filipits M, Martin LA, Fasching P, 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 (2025)

Publication Language: English

Publication Type: Journal article

Publication year: 2025

Journal

Book Volume: 9

Article Number: e2400742

DOI: 10.1200/PO-24-00742

Abstract

PURPOSEThe 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.METHODSIn 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]).RESULTSOf 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.CONCLUSIONPatients 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.

Authors with CRIS profile

Involved external institutions

Virginia Commonwealth University (VCU) United States (USA) (US) University of Queensland Australia (AU) Universitätsklinikum Köln Germany (DE) HELIOS Kliniken Germany (DE) The Institute of Cancer Research (ICR) United Kingdom (GB) Roswell Park Cancer Institute United States (USA) (US) Hospital Universitario Fundación Jiménez Díaz Spain (ES) Medizinische Universität Wien Austria (AT) GBG Forschungs GmbH (German Breast Group) Germany (DE) St. James's Hospital Ireland (IE) Université de Bordeaux France (FR) Seoul National University (SNU) / 서울대학교 Korea, Republic of (KR) Penn Medicine United States (USA) (US) Mammazentrum Hamburg MVZ GbR Germany (DE) Universität zu Köln Germany (DE) Hospital Clínico San Carlos Spain (ES) Universität Rostock Germany (DE) UCSF Helen Diller Family Comprehensive Cancer Center United States (USA) (US) Philipps-Universität Marburg Germany (DE) East and North Hertfordshire NHS Trust United Kingdom (GB) Cardiovascular Research Foundation United States (USA) (US) British Columbia Cancer Agency Canada (CA) Universitätsklinikum Mannheim Germany (DE) Universidad Complutense de Madrid (UCM) Spain (ES) University of California San Francisco (UCSF) United States (USA) (US) Asan Medical Center / 서울아산병원 Korea, Republic of (KR) Breast Cancer Now Toby Robins Research Centre United Kingdom (GB) Kyoto University / 京都大学 Kyōto daigaku Japan (JP)

How to cite

APA:

Hahnen, E., Hauke, J., Gelmon, K., Marmé, F., Ernst, C., Martin, M.,... Loibl, S. (2025). 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. JCO Precision Oncology, 9. https://doi.org/10.1200/PO-24-00742

MLA:

Hahnen, Eric, et al. "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." JCO Precision Oncology 9 (2025).

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