Inactivating NF1 mutations are enriched in advanced breast cancer and contribute to endocrine therapy resistance

Alex Pearson, Paula Z Proszek, Javier Pascual, Charlotte Fribbens, Monee K Shamsher, Belinda Kingston, Ben O'Leary, Maria Teresa Herrera-Abreu, Rosalind J Cutts, Isaac Garcia-Murillas, Hannah Bye, Brian A Walker, David Gonzalez De Castro, Lina Yuan, Sabri Jamal, Michael Hubank, Elena López-Knowles, Eugene F Schuster, Mitch Dowsett, Peter OsinAshutosh Nerurkar, Marina Parton, Alicia Fc Okines, Stephen R D Johnston, Alistair Ring, Nicholas C Turner

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)

Abstract

PURPOSE: Advanced breast cancer (ABC) has not been subjected to the same degree of molecular scrutiny as early primary cancer. Breast cancer evolves with time and under the selective pressure of treatment, with the potential to acquire mutations with resistance to treatment and disease progression. To identify potentially targetable mutations in advanced breast cancer, we performed prospective molecular characterisation of a cohort of patients with ABC.

EXPERIMENTAL DESIGN: Biopsies from patients with advanced breast cancer were sequenced with a 50 gene targeted panel in the Advanced Breast Cancer Biopsy (ABC-Bio) study. Blood samples were collected at disease progression for circulating tumour DNA (ctDNA) analysis, along with matched primary tumour to assess for acquisition in ABC in a subset of patients.

RESULTS: We sequenced 210 ABC samples, demonstrating enrichment compared to primary disease for potentially targetable mutations in HER2 (in 6.19% of samples), AKT1 (7.14%) and NF1 (8.10%). Of these enriched mutations, we show that NF1 mutations were frequently acquired in ABC, not present in the original primary disease. In ER positive cancer cell-line models, loss of NF1 resulted in endocrine therapy resistance, through both ER dependent and independent mechanisms. NF1 loss promoted ER-independent cyclin D1 expression, which could be therapeutically targeted with CDK4/6 inhibitors in vitro Patients with NF1 mutations detected in baseline circulating tumour DNA had a good outcome on the CDK4/6 inhibitor palbociclib and fulvestrant.

CONCLUSIONS: Our research identifies multiple therapeutic opportunities for advanced breast cancer and identifies the previously underappreciated acquisition of NF1 mutations.

Original languageEnglish
JournalClinical Cancer Research
Early online date07 Oct 2019
DOIs
Publication statusEarly online date - 07 Oct 2019

Bibliographical note

Copyright ©2019, American Association for Cancer Research.

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