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Clinical and Genomic Characteristics of Patients with Hormone Receptor-Positive, Human Epidermal Growth Factor
Xi Rao1, Yongmei Chen1, Julie Beyrer1
1Eli Lilly and Company, Indianapolis, Indiana.
Purpose:
We explored the clinical and genomic characteristics of hormone receptor-positive (HR+), HER2-negative (HER2-) metastatic breast cancer (MBC) after progression on cyclin-dependent kinase 4 and 6 inhibitors (CDK4 and 6i) ± endocrine therapy (ET) to understand potential resistance mechanisms that may aid in identifying treatment options.
Experimental Design:
Patients in the United States with HR+, HER2- MBC had tumor biopsies collected from a metastatic site during routine care following progression on a CDK4 and 6i ± ET (CohortPost) or prior to initiating CDK4 and 6i treatment (CohortPre) and analyzed using a targeted mutation panel and RNA-sequencing. Clinical and genomic characteristics were described.
Results:
The mean age at MBC diagnosis was 59 years in CohortPre (n = 133) and 56 years in CohortPost (n = 223); 14% and 45% of patients had prior chemotherapy/ET, and 35% and 26% had de novo stage IV MBC, respectively. The most common biopsy site was liver (CohortPre, 23%; CohortPost, 56%). CohortPost had significantly higher tumor mutational burden (TMB; median 3.16 vs. 1.67 Mut/Mb, P < 0.0001), ESR1 alteration frequency (mutations: 37% vs. 10%, FDR < 0.0001; fusions: 9% vs. 2%, P = 0.0176), and higher copy-number amplification of genes on chr12q15, including MDM2, FRS2, and YEATS4 versus patients in the CohortPre group. In addition, CDK4 copy-number gain on chr12q13 was significantly higher in CohortPost versus CohortPre (27% vs. 11%, P = 0.0005).
Conclusions:
Distinct mechanisms potentially associated with resistance to CDK4 and 6i ± ET, including alterations in ESR1 and amplification of chr12q15 and CDK4 copy-number gain, were identified.
Insights
Genomic analysis of hormone receptor-positive, HER2-negative metastatic breast cancer revealed distinct resistance mechanisms to CDK4/6 inhibitors. Findings include increased ESR1 alterations and specific gene amplifications, guiding future treatment strategies.
Area of Science:
- Oncology
- Genomics
- Translational Research
Background:
- Hormone receptor-positive (HR+), HER2-negative (HER2-) metastatic breast cancer (MBC) is a significant clinical challenge.
- Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) have improved outcomes, but resistance eventually develops.
Purpose of the Study:
- To investigate the clinical and genomic characteristics of HR+, HER2- MBC after progression on CDK4/6i ± ET.
- To identify potential resistance mechanisms to CDK4/6i ± ET.
- To inform the selection of subsequent treatment options.
Main Methods:
- Retrospective analysis of tumor biopsies from HR+, HER2- MBC patients in the United States.
- Biopsies were collected pre-initiation (CohortPre) and post-progression (CohortPost) on CDK4/6i ± ET.
- Genomic analysis included targeted mutation panels and RNA-sequencing.
Main Results:
- CohortPost patients (n=223) were younger at diagnosis and had more prior therapies than CohortPre (n=133).
- Higher tumor mutational burden (TMB), ESR1 alterations (mutations and fusions), and copy-number amplifications (chr12q15 genes, CDK4) were observed in CohortPost.
- Liver was a more common biopsy site in CohortPost.
Conclusions:
- Specific genomic alterations, including ESR1 alterations and chr12q15/CDK4 copy-number gains, are associated with resistance to CDK4/6i ± ET.
- These findings provide insights into resistance mechanisms and potential therapeutic targets.
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