A Gene Panel Associated With Abemaciclib Utility in ESR1 -Mutated Breast Cancer After Prior Cyclin-Dependent Kinase 4/6-Inhibitor Progression.

Autor:	Brett JO; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA.; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA., Dubash TD; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA., Johnson GN; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA., Niemierko A; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA., Mariotti V; Moffitt Cancer Center, Tampa, FL.; Bristol Myers Squibb, New York, NY., Kim LSL; Baylor University Medical Center Charles A. Sammons Cancer Center, Texas Oncology, Dallas, TX., Xi J; Division of Oncology, Washington University School of Medicine, St Louis, MO., Pandey A; Division of Hematology/Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA., Dunne S; Baylor University Medical Center Charles A. Sammons Cancer Center, Texas Oncology, Dallas, TX., Nasrazadani A; Division of Hematology/Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA.; Department of Breast Medical Oncology, MD Anderson Cancer Center, Houston, TX., Lloyd MR; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.; Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA., Kambadakone A; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA., Spring LM; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA., Micalizzi DS; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA., Onozato ML; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA., Che D; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA., Nayar U; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA., Brufsky A; Division of Hematology/Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA., Kalinsky K; Department of Medicine, Columbia University Irving Medical Center, New York, NY.; Emory University Winship Cancer Institute, Atlanta, GA., Ma CX; Division of Oncology, Washington University School of Medicine, St Louis, MO., O'Shaughnessy J; Baylor University Medical Center Charles A. Sammons Cancer Center, Texas Oncology, Dallas, TX., Han HS; Moffitt Cancer Center, Tampa, FL., Iafrate AJ; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA., Ryan LY; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA., Juric D; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA., Moy B; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA., Ellisen LW; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA., Maheswaran S; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA., Wagle N; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA., Haber DA; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA.; Howard Hughes Medical Institute, Chevy Chase, MD., Bardia A; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA., Wander SA; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA.; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
Jazyk:	angličtina
Zdroj:	JCO precision oncology [JCO Precis Oncol] 2023 May; Vol. 7, pp. e2200532.
DOI:	10.1200/PO.22.00532
Abstrakt:	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.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu