| Autor: |
Brett, Jamie O., Dubash, Taronish D., Johnson, Gabriela N., Niemierko, Andrzej, Mariotti, Veronica, Kim, Leslie S.L., Xi, Jing, Pandey, Apurva, Dunne, Siobhan, Nasrazadani, Azadeh, Lloyd, Maxwell R., Kambadakone, Avinash, Spring, Laura M., Micalizzi, Douglas S., Onozato, Maristela L., Che, Dante, Nayar, Utthara, Brufsky, Adam, Kalinsky, Kevin, Ma, Cynthia X. |
| Předmět: |
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| Zdroj: |
JCO Precision Oncology; 5/4/2023, Vol. 7, p1-14, 14p |
| 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. ESR1, and other genetic changes, may help predict CDK4/6 inhibitor benefit after prior progression in breast cancer. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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