Circulating genomic landscape following cyclin-dependent kinase 4/6 inhibitors exposure in HR + /HER2− metastatic breast cancer: a retrospective multi-institutional Consortium analysis
Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) plus endocrine therapy (ET) are the mainstay of treatment for hormone receptor positive, HER2 negative (HR + /HER2-) metastatic breast cancer (MBC). However, disease progression is inevitable and unveiling resistance mechanisms is crucial to guide post-CDK4/6i therapeutic strategies. In this study, we retrospectively analyzed a real-world, multi-institutional cohort of patients with HR + /HER2- MBC characterized by circulating tumor DNA (ctDNA) through next-generation sequencing (NGS) before starting second-line treatment. Among 93 patients previously treated with CDK4/6i, PIK3CA (37.6%), ESR1 (46.2%) and TP53 (31.2%) were the most altered genes. Comparing with a CDK4/6i plus ET naïve control cohort, ESR1 (p < 0.001) was significantly associated with first-line exposure. In multivariable analyses, PTEN alterations were independently associated with shorter progression free survival (PFS) (p = 0.008) and overall survival (OS) (p = 0.006), while TP53 (p = 0.031), CCDN1 (p = 0.003) and the ET second-line clinician's choice (p = 0.011) impacted the OS. Moreover, a low-mutant allele frequency was correlated to longer PFS (p = 0.017) and OS (p = 0.038). These findings highlight the prognostic relevance of specific molecular alterations and support the role of genomic profiling in guiding second-line treatment decisions after CDK4/6i therapy. Prospective validation is warranted to confirm the clinical utility of this approach in HR + /HER2 - MBC.
Authors
- Eleni Andreopoulou
- Arielle J. Medford (ORCID: https://orcid.org/0000-0002-0829-183X)
- Eleonora Nicolò (ORCID: https://orcid.org/0000-0001-5042-6550)
- Marla Lipsyc-Sharf (ORCID: https://orcid.org/0000-0002-4071-6383)
- Emilio Bria (ORCID: https://orcid.org/0000-0002-2333-704X)
- Massimo Cristofanilli (ORCID: https://orcid.org/0000-0002-4194-7175)
- Aditya Bardia (ORCID: https://orcid.org/0000-0003-4885-1157)
- Mara Serena Serafini (ORCID: https://orcid.org/0000-0001-9192-9170)
- Letizia Pontolillo (ORCID: https://orcid.org/0009-0006-3363-8512)
- Judy J. Wang (ORCID: https://orcid.org/0000-0003-4905-6593)
- Lorenzo Gerratana (ORCID: https://orcid.org/0000-0002-8313-4834)
- Laura Muñoz-Arcos (ORCID: https://orcid.org/0000-0002-0229-9056)
- Charles S. Dai (ORCID: https://orcid.org/0000-0003-2615-3286)
- Andrew A. Davis
- Caterina Gianni (ORCID: https://orcid.org/0000-0001-9496-6719)
- Elisabetta Molteni (ORCID: https://orcid.org/0009-0005-1979-5020)
- Emily Podany (ORCID: https://orcid.org/0000-0002-9700-3616)
- Carolina Reduzzi (ORCID: https://orcid.org/0000-0003-0514-0152)
- X. Cynthia
- Marko Velimirovic (ORCID: https://orcid.org/0000-0002-1406-9469)
- Katherine Clifton (ORCID: https://orcid.org/0000-0001-8623-995X)
- Surbhi Warrior (ORCID: https://orcid.org/0000-0002-5817-7752)
- Diana Giannarelli (ORCID: https://orcid.org/0000-0002-6085-1195)
- Nadia Bayou
Institutions
- Università Cattolica del Sacro Cuore (IT)
- Northwestern University (US)
- University of Udine (IT)
- Cleveland Clinic (US)
- Harvard University (US)
- University of California, Los Angeles (US)
- Washington University in St. Louis (US)
- Cornell University (US)
- Agostino Gemelli University Polyclinic (IT)
- Massachusetts General Hospital (US)
- Centro di Riferimento Oncologico (IT)
- Weill Cornell Medicine (US)
- Tunis El Manar University (TN)
Publication Details
- Journal
- npj Breast Cancer
- Published
- 2025-08-16
- DOI
- https://doi.org/10.1038/s41523-025-00802-2
- Primary Topic
- Advanced Breast Cancer Therapies
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- American Association for Cancer Research
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- Sanofi
- Gilead Sciences
- Myriad Genetics
- Celltrion
- Natera
- Ministero della Salute
- Associazione Italiana per la Ricerca sul Cancro
- Genentech
- Daiichi Sankyo Europe