CDK4/6 Inhibitors Overcome Endocrine ESR1 Mutation-Related Resistance in Metastatic Breast Cancer Patients
by
, and
Stefania Crucitta
1,†, 
Martina Ruglioni
1,†,
Giulia Lorenzini
2,
Irene Bargagna
2,
Giovanna Irene Luculli
1,
Irene Albanese
2,
Diana Bilancio
2,
Francesca Patanè
2,
Andrea Fontana
2,
Romano Danesi
1,* and
Marzia Del Re
1 1
Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
2
Unit of Medical Oncology, Department of Translational Research and New Technologies in Medicine, University of Pisa, 56126 Pisa, Italy
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cancers 2023, 15(4), 1306; https://doi.org/10.3390/cancers15041306
Submission received: 15 December 2022
/
Revised: 2 February 2023
/
Accepted: 9 February 2023
/
Published: 18 February 2023
(This article belongs to the Special Issue Precision Medicine in Breast Cancer Treatment)
Simple Summary
The present study investigates the clinical benefit of CDK4/6i in ESR1 mutant HR+ mBC patients treated with a CDK4/6i as first- or second-line therapy. Plasma was collected at baseline prior to CDK4/6i plus hormone therapy, and ESR1 mutation was analyzed in circulating free DNA by a ddPCR. This study demonstrates that the ESR1 mutations detected in liquid biopsy is an independent predictive factor of clinical recurrence in the adjuvant setting. No difference in progression-free survival (PFS) was observed in the presence or absence of ESR1 mutations in patients treated with CDK4/6i as first-line treatment. The results suggest that CDK4/6i can overcome ESR1-dependent resistance.
Abstract
ESR1 mutations contribute to endocrine resistance and occur in a high percentage of hormone-receptor-positive (HR+) metastatic breast cancer (mBC) cases. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) changed the treatment landscape of HR+ mBC, as they are able to overcome estrogen resistance. The present retrospective study investigates the clinical benefit of CDK4/6i in ESR1 mutant HR+ mBC patients treated with a CDK4/6i as first- or second-line therapy. Plasma was collected at baseline prior to CDK4/6i plus hormone therapy as a first- or second-line treatment. Circulating free DNA (cfDNA) was extracted from plasma, and ESR1 mutation analysis was performed on a ddPCR. Statistical analyses were performed to investigate the predictive power of ESR1 mutations and any association with clinical factors. A total of 42 patients with mBC treated with CDK4/6i plus endocrine therapy as first- (n = 35) or second-line (n = 7) were enrolled. Twenty-eight patients received hormonal therapy (AI or tamoxifen) in the adjuvant setting. ESR1 mutation status in blood was associated with shorter median disease-free survival (DFS) (30 vs. 110 months; p = 0.006). Multivariate analysis confirmed ESR1 mutations as independent factors of resistance in adjuvant hormone therapy. On the contrary, no difference in progression-free survival (PFS) was observed in the presence or absence of an ESR1 mutation in patients treated with CDK4/6i as first-line treatment (p = 0.29). No statistically significant correlation between the best response to CDK4/6i and ESR1 mutation was found (p = 0.46). This study indicates that the ESR1 mutation detected in cfDNA is an independent predictive factor of clinical recurrence in the adjuvant setting and that CDK4/6i can overcome ESR1-dependent resistance.
Keywords:
ESR1 mutation; liquid biopsy; ctDNA; metastatic breast cancer; CDK4/6 inhibitor
