Circulating genomic landscape following cyclin-dependent kinase 4/6 inhibitors exposure in HR + /HER2− metastatic breast cancer: a retrospective multi-institutional Consortium analysis
Abstract 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...
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Nature Portfolio
2025-08-01
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| Series: | npj Breast Cancer |
| Online Access: | https://doi.org/10.1038/s41523-025-00802-2 |
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| author | Letizia Pontolillo Andrew A. Davis Lorenzo Gerratana Arielle J. Medford Judy Wang Eleonora Nicolo’ Katherine Clifton Marko Velimirovic Surbhi Warrior Emily Podany Eleni Andreopoulou Mara Serena Serafini Laura Munoz-Arcos Elisabetta Molteni Marla Lipsyc-Sharf Caterina Gianni Nadia Bayou Charles S. Dai Diana Giannarelli Emilio Bria Cynthia X. Ma Aditya Bardia Carolina Reduzzi Massimo Cristofanilli |
| author_facet | Letizia Pontolillo Andrew A. Davis Lorenzo Gerratana Arielle J. Medford Judy Wang Eleonora Nicolo’ Katherine Clifton Marko Velimirovic Surbhi Warrior Emily Podany Eleni Andreopoulou Mara Serena Serafini Laura Munoz-Arcos Elisabetta Molteni Marla Lipsyc-Sharf Caterina Gianni Nadia Bayou Charles S. Dai Diana Giannarelli Emilio Bria Cynthia X. Ma Aditya Bardia Carolina Reduzzi Massimo Cristofanilli |
| author_sort | Letizia Pontolillo |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-b9e09a8016fe4cffaae4c390b6dd8b91 |
| institution | Kabale University |
| issn | 2374-4677 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Breast Cancer |
| spelling | doaj-art-b9e09a8016fe4cffaae4c390b6dd8b912025-08-20T04:03:17ZengNature Portfolionpj Breast Cancer2374-46772025-08-0111111010.1038/s41523-025-00802-2Circulating genomic landscape following cyclin-dependent kinase 4/6 inhibitors exposure in HR + /HER2− metastatic breast cancer: a retrospective multi-institutional Consortium analysisLetizia Pontolillo0Andrew A. Davis1Lorenzo Gerratana2Arielle J. Medford3Judy Wang4Eleonora Nicolo’5Katherine Clifton6Marko Velimirovic7Surbhi Warrior8Emily Podany9Eleni Andreopoulou10Mara Serena Serafini11Laura Munoz-Arcos12Elisabetta Molteni13Marla Lipsyc-Sharf14Caterina Gianni15Nadia Bayou16Charles S. Dai17Diana Giannarelli18Emilio Bria19Cynthia X. Ma20Aditya Bardia21Carolina Reduzzi22Massimo Cristofanilli23Division of Hematology-Oncology, Weill Cornell MedicineDivision of Oncology, Department of Medicine, Washington University School of MedicineDepartment of Medical Oncology, CRO Aviano National Cancer Institute, IRCCSMassachusetts General Hospital Cancer Center, Harvard Medical SchoolDivision of Hematology-Oncology, Weill Cornell MedicineDivision of Hematology-Oncology, Weill Cornell MedicineDivision of Oncology, Department of Medicine, Washington University School of MedicineTaussig Cancer Institute, Cleveland Clinic FoundationRobert H. Lurie Comprehensive Cancer Center of Northwestern UniversityDivision of Oncology, Department of Medicine, Washington University School of MedicineDivision of Hematology-Oncology, Weill Cornell MedicineDivision of Hematology-Oncology, Weill Cornell MedicineDivision of Hematology-Oncology, Weill Cornell MedicineDivision of Hematology-Oncology, Weill Cornell MedicineDavid Geffen School of Medicine at UCLAMedical Oncology, Breast & GYN Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”Division of Hematology-Oncology, Weill Cornell MedicineMassachusetts General Hospital Cancer Center, Harvard Medical SchoolFacility of Epidemiology and Biostatistics, Fondazione Policlinico Universitario A. Gemelli IRCCSDepartment of Translational Medicine and Surgery, Università Cattolica del Sacro CuoreDivision of Oncology, Department of Medicine, Washington University School of MedicineMassachusetts General Hospital Cancer Center, Harvard Medical SchoolDivision of Hematology-Oncology, Weill Cornell MedicineDivision of Hematology-Oncology, Weill Cornell MedicineAbstract 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.https://doi.org/10.1038/s41523-025-00802-2 |
| spellingShingle | Letizia Pontolillo Andrew A. Davis Lorenzo Gerratana Arielle J. Medford Judy Wang Eleonora Nicolo’ Katherine Clifton Marko Velimirovic Surbhi Warrior Emily Podany Eleni Andreopoulou Mara Serena Serafini Laura Munoz-Arcos Elisabetta Molteni Marla Lipsyc-Sharf Caterina Gianni Nadia Bayou Charles S. Dai Diana Giannarelli Emilio Bria Cynthia X. Ma Aditya Bardia Carolina Reduzzi Massimo Cristofanilli Circulating genomic landscape following cyclin-dependent kinase 4/6 inhibitors exposure in HR + /HER2− metastatic breast cancer: a retrospective multi-institutional Consortium analysis npj Breast Cancer |
| title | Circulating genomic landscape following cyclin-dependent kinase 4/6 inhibitors exposure in HR + /HER2− metastatic breast cancer: a retrospective multi-institutional Consortium analysis |
| title_full | Circulating genomic landscape following cyclin-dependent kinase 4/6 inhibitors exposure in HR + /HER2− metastatic breast cancer: a retrospective multi-institutional Consortium analysis |
| title_fullStr | Circulating genomic landscape following cyclin-dependent kinase 4/6 inhibitors exposure in HR + /HER2− metastatic breast cancer: a retrospective multi-institutional Consortium analysis |
| title_full_unstemmed | Circulating genomic landscape following cyclin-dependent kinase 4/6 inhibitors exposure in HR + /HER2− metastatic breast cancer: a retrospective multi-institutional Consortium analysis |
| title_short | Circulating genomic landscape following cyclin-dependent kinase 4/6 inhibitors exposure in HR + /HER2− metastatic breast cancer: a retrospective multi-institutional Consortium analysis |
| title_sort | circulating genomic landscape following cyclin dependent kinase 4 6 inhibitors exposure in hr her2 metastatic breast cancer a retrospective multi institutional consortium analysis |
| url | https://doi.org/10.1038/s41523-025-00802-2 |
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