Inactivating NF1 Mutations Are Enriched in Advanced Breast Cancer and Contribute to Endocrine Therapy Resistance.

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Advanced breast cancer (ABC) molecular evolution under treatment pressure can lead to drug resistance and disease progression.
• Limited molecular characterization of ABC compared to early-stage disease necessitates further investigation.

Purpose of the Study:

• To identify potentially targetable mutations in advanced breast cancer through prospective molecular profiling.
• To understand the acquisition of mutations in advanced breast cancer and their clinical implications.

Main Methods:

• Prospective molecular characterization of 210 advanced breast cancer (ABC) patient samples using a 41-gene targeted panel.
• Circulating tumor DNA (ctDNA) analysis from blood samples at disease progression, with matched primary tumor analysis in a subset of patients.

Main Results:

• Enrichment of targetable mutations in *HER2*, *AKT1*, and *NF1* in ABC compared to primary tumors.
• *NF1* mutations were frequently acquired in ABC and associated with endocrine therapy resistance via ER-dependent and -independent mechanisms.
• Loss of *NF1* promoted ER-independent cyclin D1 expression, targetable with CDK4/6 inhibitors *in vitro*. Patients with baseline ctDNA *NF1* mutations showed good outcomes with palbociclib and fulvestrant.

Conclusions:

• Identification of multiple therapeutic opportunities for advanced breast cancer.
• Highlighting the previously underappreciated acquisition of *NF1* mutations in advanced breast cancer and their clinical relevance.