A Gene Panel Associated With Abemaciclib Utility in ESR1-Mutated Breast Cancer After Prior Cyclin-Dependent Kinase 4/6-Inhibitor Progression
Year: 2023
Type: article
Study design: Observational Study
Abstract: PURPOSE For patients with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) metastatic breast cancer (MBC), first-line treatment is endocrine therapy (ET) plus cyclin-dependent kinase 4/6 inhibition (CDK4/6i). After disease progression, which often comes with ESR1 resistance mutations (ESR1-MUT), which therapies to use next and for which patients are open questions. An active area of exploration is treatment with further CDK4/6i, particularly abemaciclib, which has distinct pharmacokinetic and pharmacodynamic properties compared with the other approved CDK4/6 inhibitors, palbociclib and ribociclib. We investigated a gene panel to prognosticate abemaciclib susceptibility in patients with ESR1-MUT MBC after palbociclib progression. METHODS We examined a multicenter retrospective cohort of patients with ESR1-MUT MBC who received abemaciclib after disease progression on ET plus palbociclib. We generated a panel of CDK4/6i resistance genes and compared abemaciclib progression-free survival (PFS) in patients without versus with mutations in this panel (CDKi-R[–] v CDKi-R[+]). We studied how ESR1-MUT and CDKi-R mutations affect abemaciclib sensitivity of immortalized breast cancer cells and patient-derived circulating tumor cell lines in culture. RESULTS In ESR1-MUT MBC with disease progression on ET plus palbociclib, the median PFS was 7.0 months for CDKi-R(–) (n = 17) versus 3.5 months for CDKi-R(+) (n = 11), with a hazard ratio of 2.8 ( P = .03). In vitro, CDKi-R alterations but not ESR1-MUT induced abemaciclib resistance in immortalized breast cancer cells and were associated with resistance in circulating tumor cells. CONCLUSION For ESR1-MUT MBC with resistance to ET and palbociclib, PFS on abemaciclib is longer for patients with CDKi-R(–) than CDKi-R(+). Although a small and retrospective data set, this is the first demonstration of a genomic panel associated with abemaciclib sensitivity in the postpalbociclib setting. Future directions include testing and improving this panel in additional data sets, to guide therapy selection for patients with HR+/HER2– MBC.
Source: JCO Precision Oncology
DOI: 10.1200/po.22.00532
Authors: Jamie O. Brett, Taronish D. Dubash, Gabriela N. Johnson, Andrzej Niemierko, Veronica Mariotti, Leslie S.L. Kim, Jing Xi, Apurva Pandey, Siobhan Dunne, Azadeh Nasrazadani, Maxwell R. Lloyd, Avinash Kambadakone, Laura M. Spring, Douglas S. Micalizzi, Maristela L. Onozato, Dante Che, Utthara Nayar, Adam Brufsky, Kevin Kalinsky, Cynthia X. Ma, Joyce O'Shaughnessy, Hyo S. Han, Anthony J. Iafrate, Lianne Y. Ryan, Dejan Juric, Beverly Moy, Leif W. Ellisen, Shyamala Maheswaran, Nikhil Wagle, Daniel A. Haber, Aditya Bardia, Seth A. Wander
Institutions: Harvard University, Massachusetts General Hospital, Dana-Farber Cancer Institute, Moffitt Cancer Center, Bristol-Myers Squibb (United States), Baylor University Medical Center, Washington University in St. Louis, University of Pittsburgh Medical Center, The University of Texas MD Anderson Cancer Center, Beth Israel Deaconess Medical Center, Columbia University Irving Medical Center, Winship Cancer Institute, Howard Hughes Medical Institute
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Howard Hughes Medical Institute, Breast Cancer Research Foundation, Breast Cancer Alliance, Eli Lilly and Company, Pfizer, AstraZeneca, Gilead Sciences, Dana-Farber/Harvard Cancer Center, Terri Brodeur Breast Cancer Foundation, National Comprehensive Cancer Network, MEI Pharma, Puma Biotechnology, G1 Therapeutics, EQRx, National Institutes of Health, Genentech, Novartis Institutes for BioMedical Research, National Cancer Institute, Daiichi Sankyo Europe
OpenAlex ID: W4368347286