Dynamics of molecular heterogeneity in high-risk luminal breast cancer—From intrinsic to adaptive subtyping

Denkert C, Rachakonda S, Karn T, Weber K, Martin M, Marmé F, Untch M, Bonnefoi H, Kim SB, Seiler S, Bear HD, Witkiewicz AK, Im SA, DeMichele A, Pehl A, van't Veer L, McCarthy N, Stiewe T, Jank P, Gelmon KA, García-Sáenz JA, Westhoff CC, Kelly CM, Reimer T, Felder B, Olivé MM, Knudsen ES, Turner N, Rojo F, Schmitt WD, Fasching P, Teply-Szymanski J, Zhang Z, Toi M, Rugo HS, Gnant M, Makris A, Holtschmidt J, Nekljudova V, Loibl S (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Book Volume: 43

Pages Range: 232-247.e4

Journal Issue: 2

DOI: 10.1016/j.ccell.2025.01.002

Abstract

We evaluate therapy-induced molecular heterogeneity in longitudinal samples from high-risk, hormone-receptor positive/HER2-negative breast cancer patients with residual tumor after neoadjuvant chemotherapy from the Penelope-B trial (NCT01864746; EudraCT 2013-001040-62). Intrinsic subtypes are prognostic in pre-therapeutic (Tx) samples (n = 629, p < 0.0001) and post-Tx residual tumors (n = 782, p < 0.0001). After neoadjuvant chemotherapy, a shift of intrinsic subtypes is observed from pre-Tx luminal (Lum) B to post-Tx LumA, with reverse transition back to LumB in metastases. In a combined analysis of 540 paired pre-Tx and post-Tx samples, we identify five adaptive clusters (AC-1–5) based on transcriptomic changes before and after neoadjuvant chemotherapy. These AC-subtypes are prognostic beyond classical intrinsic subtyping, categorizing patients into groups with excellent prognosis (AC-1 and AC-2), poor prognosis (AC-3 and AC-4), and very poor prognosis (AC-5, enriched for basal-like subtype). Our analysis provides a basis for an extended molecular classification of breast cancer patients and improved identification of high-risk patient populations.

Authors with CRIS profile

Involved external institutions

Philipps-Universität Marburg Germany (DE) GBG Forschungs GmbH (German Breast Group) Germany (DE) Goethe-Universität Frankfurt am Main Germany (DE) Universidad Complutense de Madrid (UCM) Spain (ES) Universitätsklinikum Mannheim Germany (DE) HELIOS Kliniken Germany (DE) Université de Bordeaux France (FR) Asan Medical Center / 서울아산병원 Korea, Republic of (KR) Virginia Commonwealth University (VCU) United States (USA) (US) Roswell Park Cancer Institute United States (USA) (US) University of California San Francisco (UCSF) United States (USA) (US) University of Queensland Australia (AU) British Columbia Cancer Agency Canada (CA) Hospital Clínico San Carlos Spain (ES) Mater Private Hospital / Ospidéal Príobháideach an Mater Ireland (IE) Universität Rostock Germany (DE) Medizinische Universität Wien Austria (AT) Seoul National University (SNU) / 서울대학교 Korea, Republic of (KR) Penn Medicine United States (USA) (US) Hospital Universitari Sant Joan de Reus Spain (ES) The Institute of Cancer Research (ICR) United Kingdom (GB) Cardiovascular Research Foundation United States (USA) (US) Kyoto University / 京都大学 Kyōto daigaku Japan (JP) UCSF Helen Diller Family Comprehensive Cancer Center United States (USA) (US) East and North Hertfordshire NHS Trust United Kingdom (GB) Spanish Breast Cancer Group / Grupo Español de Investigación en Cáncer de Mama (GEICAM) Spain (ES) Charité - Universitätsmedizin Berlin Germany (DE)

How to cite

APA:

Denkert, C., Rachakonda, S., Karn, T., Weber, K., Martin, M., Marmé, F.,... Loibl, S. (2025). Dynamics of molecular heterogeneity in high-risk luminal breast cancer—From intrinsic to adaptive subtyping. Cancer Cell, 43(2), 232-247.e4. https://doi.org/10.1016/j.ccell.2025.01.002

MLA:

Denkert, Carsten, et al. "Dynamics of molecular heterogeneity in high-risk luminal breast cancer—From intrinsic to adaptive subtyping." Cancer Cell 43.2 (2025): 232-247.e4.

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