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. 2023 Feb 18;15(4):1306.
doi: 10.3390/cancers15041306.

CDK4/6 Inhibitors Overcome Endocrine ESR1 Mutation-Related Resistance in Metastatic Breast Cancer Patients

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 , Marzia Del Re  1
Affiliations

CDK4/6 Inhibitors Overcome Endocrine ESR1 Mutation-Related Resistance in Metastatic Breast Cancer Patients

Stefania Crucitta et al. Cancers (Basel). .

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: CDK4/6 inhibitor; ESR1 mutation; ctDNA; liquid biopsy; metastatic breast cancer.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Incidence of ESR1 mutations and their association with the type of hormonal therapy received. AI: aromatase inhibitor.
Figure 2
Figure 2
Disease-free survival (A) of breast cancer patients treated with adjuvant hormonal therapy. Univariate Cox regression analysis (B) of the impact of ESR1 mutational status and patients’ clinical characteristics on DFS. * p < 0.05.
Figure 3
Figure 3
Overall survival of mBC patients treated with CDK4/6i (A) and progression-free survival of first-line CDK4/6i-treated patients (B) according to ESR1 mutational status.
Figure 4
Figure 4
Incidence of ESR1 mutations and their association with best response of patients in the overall population.
See this image and copyright information in PMC

References

    1. Testa U., Castelli G., Pelosi E. Breast Cancer: A Molecularly Heterogenous Disease Needing Subtype-Specific Treatments. Med. Sci. 2020;8:18. doi: 10.3390/medsci8010018. - DOI - PMC - PubMed
    1. Rozeboom B., Dey N., De P. ER+ metastatic breast cancer: Past, present, and a prescription for an apoptosis-targeted future. Am. J. Cancer Res. 2019;9:2821–2831. - PMC - PubMed
    1. Jeselsohn R., Buchwalter G., De Angelis C., Brown M., Schiff R. ESR1 mutations-a mechanism for acquired endocrine resistance in breast cancer. Nat. Rev. Clin. Oncol. 2015;12:573–583. doi: 10.1038/nrclinonc.2015.117. - DOI - PMC - PubMed
    1. Dustin D., Gu G., Fuqua S.A.W. ESR1 mutations in breast cancer. Cancer. 2019;125:3714–3728. doi: 10.1002/cncr.32345. - DOI - PMC - PubMed
    1. Toy W., Shen Y., Won H., Green B., Sakr R.A., Will M., Li Z., Gala K., Fanning S., King T.A., et al. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat. Genet. 2013;45:1439–1445. doi: 10.1038/ng.2822. - DOI - PMC - PubMed