Dynamics of molecular heterogeneity in high-risk luminal breast cancer—From intrinsic to adaptive subtyping
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
- Angela M. DeMichele (ORCID: https://orcid.org/0000-0003-1297-4251)
- Nicole McCarthy (ORCID: https://orcid.org/0000-0001-7394-8909)
- Wolfgang Schmitt (ORCID: https://orcid.org/0000-0002-7870-138X)
- Johannes Holtschmidt (ORCID: https://orcid.org/0000-0002-2723-1154)
- Frederik Marmé (ORCID: https://orcid.org/0000-0002-6591-3367)
- Sabine Seiler (ORCID: https://orcid.org/0000-0002-8539-033X)
- Julia Teply‐Szymanski (ORCID: https://orcid.org/0000-0002-3880-1968)
- Federico Rojo (ORCID: https://orcid.org/0000-0001-9989-0290)
- M. Untch
- Thomas Karn (ORCID: https://orcid.org/0000-0002-3264-6573)
- Paul Jank (ORCID: https://orcid.org/0000-0001-7076-0476)
- Michael Gnant (ORCID: https://orcid.org/0000-0003-1002-2118)
- Erik S. Knudsen (ORCID: https://orcid.org/0000-0002-5130-5969)
- Carsten Denkert (ORCID: https://orcid.org/0000-0002-2249-0982)
- Agnieszka Katarzyna Witkiewicz (ORCID: https://orcid.org/0000-0003-4538-1145)
- Andreas Makris (ORCID: https://orcid.org/0000-0002-2003-1088)
- Christina C. Westhoff (ORCID: https://orcid.org/0000-0002-6812-3563)
- Karsten E. Weber (ORCID: https://orcid.org/0000-0003-0001-2135)
- Sungbae Kim (ORCID: https://orcid.org/0009-0009-4155-4679)
- Toralf Reimer (ORCID: https://orcid.org/0000-0003-3014-370X)
- Hervé Bonnefoi (ORCID: https://orcid.org/0000-0003-4293-9748)
- Valentina Nekljudova (ORCID: https://orcid.org/0000-0002-2801-7387)
- Thorsten Stiewe (ORCID: https://orcid.org/0000-0003-0134-7826)
- Harry D. Bear (ORCID: https://orcid.org/0000-0002-7632-9019)
- Karen A. Gelmon (ORCID: https://orcid.org/0000-0003-4111-2757)
- Zhe Zhang (ORCID: https://orcid.org/0009-0009-7615-6865)
- Catherine M. Kelly (ORCID: https://orcid.org/0000-0001-8355-6714)
- Nicholas Turner (ORCID: https://orcid.org/0000-0003-0650-4894)
- Bärbel Felder (ORCID: https://orcid.org/0009-0001-0072-0097)
- Mireia Melé (ORCID: https://orcid.org/0000-0002-3408-8018)
- Sivaramakrishna Rachakonda
- Hope S. Rugo (ORCID: https://orcid.org/0000-0001-6710-4814)
- Anika Pehl
- Miguel Martín (ORCID: https://orcid.org/0000-0003-2053-1039)
- José A. García-Sáenz
- Peter A. Fasching
- Masakazu Toi
- S. Loibl
- Laura van’t Veer
- Seock Ah Im
Institutions
- Goethe University Frankfurt (DE)
- Ulsan College (KR)
- Roswell Park Comprehensive Cancer Center (US)
- Institute of Cancer Research (GB)
- Université de Bordeaux (FR)
- Inserm (FR)
- Philipps University of Marburg (DE)
- The University of Queensland (AU)
- University of California, San Francisco (US)
- Pfizer (United States) (US)
- Virginia Commonwealth University (US)
- Kyoto University (JP)
- Heidelberg University (DE)
- Asan Medical Center (KR)
- University Hospital Heidelberg (DE)
- Seoul National University Hospital (KR)
- Hospital General Universitario Gregorio Marañón (ES)
- Hospital Clínico San Carlos (ES)
- Tokyo Metropolitan Komagome Hospital (JP)
- Humboldt-Universität zu Berlin (DE)
- University of Ulsan (KR)
- Universitätsklinikum Erlangen (DE)
- Comprehensive Cancer Center Vienna (AT)
- Arbeitsgemeinschaft Gynäkologische Onkologie Studiengruppe (DE)
- Cancer Trials Australia (AU)
- University of Miami Health System (US)
- Cancer Trials Ireland (IE)
- Mount Vernon Cancer Centre (GB)
- Royal Marsden Hospital (GB)
- Penn Center for AIDS Research (US)
- Hospital Universitario Fundación Jiménez Díaz (ES)
- German Breast group (DE)
- Institut Bergonié (FR)
- Helios Kliniken (DE)
- University of Pennsylvania Health System (US)
- Hospital Universitari Sant Joan de Reus (ES)
- Comprehensive Cancer Center Erlangen (DE)
- Helios Hospital Berlin-Buch (DE)
- University Medical Centre Mannheim (DE)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
- GEICAM – Spanish Breast Cancer Group (ES)
- UCSF Helen Diller Family Comprehensive Cancer Center (US)
- Abramson Cancer Center (US)
- BoRdeaux Institute of onCology (FR)
- University of Rostock (DE)
- Freie Universität Berlin (DE)
- Medical University of Vienna (AT)
- Charité - Universitätsmedizin Berlin (DE)
Publication Details
- Journal
- Cancer Cell
- Published
- 2025-02-01
- DOI
- https://doi.org/10.1016/j.ccell.2025.01.002
- Citations
- 19
- Primary Topic
- Breast Cancer Treatment Studies
- Type
- article
- Field-Weighted Citation Impact
- 17.79
Funders
- Bundesministerium für Forschung und Technologie
- Deutsche Krebshilfe