Dataset Information

Distinct mechanisms of resistance to fulvestrant treatment dictate level of ER independence and selective response to CDK inhibitors in metastatic breast cancer.

ABSTRACT:

Background

Resistance to endocrine treatment in metastatic breast cancer is a major clinical challenge. Clinical tools to predict both drug resistance and possible treatment combination approaches to overcome it are lacking. This unmet need is mainly due to the heterogeneity underlying both the mechanisms involved in resistance development and breast cancer itself.

Methods

To study the complexity of the mechanisms involved in the resistance to the selective estrogen receptor degrader (SERD) fulvestrant, we performed comprehensive biomarker analyses using several in vitro models that recapitulate the heterogeneity of developed resistance. We further corroborated our findings in tissue samples from patients treated with fulvestrant.

Results

We found that different in vitro models of fulvestrant resistance show variable stability in their phenotypes, which corresponded with distinct genomic alterations. Notably, the studied models presented adaptation at different cell cycle nodes to facilitate progression through the cell cycle and responded differently to CDK inhibitors. Cyclin E2 overexpression was identified as a biomarker of a persistent fulvestrant-resistant phenotype. Comparison of pre- and post-treatment paired tumor biopsies from patients treated with fulvestrant revealed an upregulation of cyclin E2 upon development of resistance. Moreover, overexpression of this cyclin was found to be a prognostic factor determining resistance to fulvestrant and shorter progression-free survival.

Conclusions

These data highlight the complexity of estrogen receptor positive breast cancer and suggest that the development of diverse resistance mechanisms dictate levels of ER independence and potentially cross-resistance to CDK inhibitors.

SUBMITTER: Kaminska K

PROVIDER: S-EPMC7893923 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Publications

Distinct mechanisms of resistance to fulvestrant treatment dictate level of ER independence and selective response to CDK inhibitors in metastatic breast cancer.

Kaminska Kamila K Akrap Nina N Staaf Johan J Alves Carla L CL Ehinger Anna A Ebbesson Anna A Hedenfalk Ingrid I Beumers Lukas L Veerla Srinivas S Harbst Katja K Ehmsen Sidse S Borgquist Signe S Borg Åke Å Pérez-Fidalgo Alejandro A Ditzel Henrik J HJ Bosch Ana A Honeth Gabriella G

Breast cancer research : BCR 20210218 1

<h4>Background</h4>Resistance to endocrine treatment in metastatic breast cancer is a major clinical challenge. Clinical tools to predict both drug resistance and possible treatment combination approaches to overcome it are lacking. This unmet need is mainly due to the heterogeneity underlying both the mechanisms involved in resistance development and breast cancer itself.<h4>Methods</h4>To study the complexity of the mechanisms involved in the resistance to the selective estrogen receptor degra ...[more]

PMID: 33602273

Similar Datasets

Project description:BackgroundThe aromatase inhibitor anastrozole inhibits estrogen synthesis. Fulvestrant binds and accelerates degradation of estrogen receptors. We hypothesized that these two agents in combination might be more effective than anastrozole alone in patients with hormone-receptor (HR)-positive metastatic breast cancer.MethodsPostmenopausal women with previously untreated metastatic disease were randomly assigned, in a 1:1 ratio, to receive either 1 mg of anastrozole orally every day (group 1), with crossover to fulvestrant alone strongly encouraged if the disease progressed, or anastrozole and fulvestrant in combination (group 2). Patients were stratified according to prior or no prior receipt of adjuvant tamoxifen therapy. Fulvestrant was administered intramuscularly at a dose of 500 mg on day 1 and 250 mg on days 14 and 28 and monthly thereafter. The primary end point was progression-free survival, with overall survival designated as a prespecified secondary outcome.ResultsThe median progression-free survival was 13.5 months in group 1 and 15.0 months in group 2 (hazard ratio for progression or death with combination therapy, 0.80; 95% confidence interval [CI], 0.68 to 0.94; P=0.007 by the log-rank test). The combination therapy was generally more effective than anastrozole alone in all subgroups, with no significant interactions. Overall survival was also longer with combination therapy (median, 41.3 months in group 1 and 47.7 months in group 2; hazard ratio for death, 0.81; 95% CI, 0.65 to 1.00; P=0.05 by the log-rank test), despite the fact that 41% of the patients in group 1 crossed over to fulvestrant after progression. Three deaths that were possibly associated with treatment occurred in group 2. The rates of grade 3 to 5 toxic effects did not differ significantly between the two groups.ConclusionsThe combination of anastrozole and fulvestrant was superior to anastrozole alone or sequential anastrozole and fulvestrant for the treatment of HR-positive metastatic breast cancer, despite the use of a dose of fulvestrant that was below the current standard. (Funded by the National Cancer Institute and AstraZeneca; SWOG ClinicalTrials.gov number, NCT00075764.).

Dataset Information

Distinct mechanisms of resistance to fulvestrant treatment dictate level of ER independence and selective response to CDK inhibitors in metastatic breast cancer.

Background

Methods

Results

Conclusions

Publications

Distinct mechanisms of resistance to fulvestrant treatment dictate level of ER independence and selective response to CDK inhibitors in metastatic breast cancer.

Similar Datasets

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