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Published on: August 1, 2018
ESR1 testing on FFPE samples from metastatic lesions in HR + /HER2- breast cancer after progression on CDK4/6
Konstantinos Venetis1, Giulia Cursano1,2, Roberta Scafetta3
1Division of Pathology, European Institute of Oncology IRCCS, Milan, Italy.
Abstract:
Mutations in ESR1 play a critical role in resistance to endocrine therapy (ET) in hormone receptor-positive (HR +)/HER2- metastatic breast cancer (MBC). Testing for ESR1 mutations is essential for guiding treatment with novel oral selective estrogen receptor degraders (SERDs) like elacestrant or camizestrant. While most studies have utilized liquid biopsy (LB) for mutation detection, the role of formalin-fixed paraffin-embedded (FFPE) tissue biopsy in this context remains unclear. In this study, we analyzed a cohort of HR + /HER2- MBC patients who experienced resistance to ET and CDK4/6 inhibitors. Next-generation sequencing (NGS) was performed on FFPE biopsy samples obtained from metastatic sites at the time of disease progression. ESR1 mutations were detected in 24 out of 38 patients (63.2%), with p.D538G identified in 10 patients (45.5%) and p.Y537S in 6 patients (27.2%) as the most frequent alterations. One patient exhibited dual ESR1 mutations, and a recurrent ESR1-CCDC170 gene fusion was identified, underscoring the diversity and potential interplay of genetic alterations driving resistance in HR + /HER2- MBC. Notably, lung metastases were significantly more common in ESR1 mutant cases (8/24, 33.3%) compared to wild-type cases (1/14, 7.1%), while liver metastases showed no difference between mutant (12/24, 50.0%) and wild-type groups (7/14, 50.0%). Co-mutations in actionable pathways, particularly PIK3CA, were observed in n = 10 ESR1 mutant tumors (41.6%), highlighting their contribution to resistance mechanisms and posing significant challenges for treatment selection, as these alterations may necessitate combination therapies to effectively target multiple resistance pathways. This study presents new insights into the prevalence and clinical significance of ESR1 mutations in HR + /HER2- MBC, highlighting the potential utility of FFPE biopsy samples as a viable alternative or complementary approach to LB for mutation detection, particularly in resource-limited settings where access to ctDNA analysis may be constrained.
Insights
ESR1 mutations are common in endocrine therapy-resistant breast cancer, detectable via FFPE tissue biopsies. These mutations, often co-occurring with PIK3CA alterations, inform treatment strategies for metastatic breast cancer.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Endocrine therapy (ET) resistance in hormone receptor-positive (HR+)/HER2- metastatic breast cancer (MBC) is often driven by ESR1 mutations.
- Accurate detection of ESR1 mutations is crucial for guiding treatment with novel agents like selective estrogen receptor degraders (SERDs).
- While liquid biopsy (LB) is common, the utility of formalin-fixed paraffin-embedded (FFPE) tissue biopsy for ESR1 mutation detection in this setting is less understood.
Purpose of the Study:
- To investigate the prevalence and clinical significance of ESR1 mutations in HR+/HER2- MBC patients resistant to ET and CDK4/6 inhibitors.
- To evaluate the effectiveness of FFPE tissue biopsy using next-generation sequencing (NGS) for detecting ESR1 mutations.
- To explore the association of ESR1 mutations with metastatic site patterns and co-occurring actionable mutations.
Main Methods:
- Analysis of FFPE biopsy samples from HR+/HER2- MBC patients at disease progression after ET and CDK4/6 inhibitor treatment.
- Next-generation sequencing (NGS) performed on metastatic site FFPE biopsies.
- Detection and characterization of ESR1 mutations, including specific variants and gene fusions.
- Correlation of mutation status with clinical data, including metastatic site and co-mutations.
Main Results:
- ESR1 mutations were detected in 63.2% (24/38) of patients.
- The most frequent ESR1 mutations were p.D538G (45.5%) and p.Y537S (27.2%).
- A recurrent ESR1-CCDC170 gene fusion was identified, and 41.6% of ESR1-mutant tumors harbored co-mutations, notably PIK3CA.
- ESR1 mutant cases showed a higher incidence of lung metastases (33.3%) compared to wild-type cases (7.1%).
Conclusions:
- FFPE tissue biopsy is a viable method for detecting ESR1 mutations in HR+/HER2- MBC, offering an alternative to liquid biopsy, especially in resource-limited settings.
- The high prevalence of ESR1 mutations and co-occurring alterations like PIK3CA underscores their role in therapeutic resistance.
- Understanding these genetic drivers is essential for optimizing treatment strategies and potentially developing combination therapies for advanced breast cancer.
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