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

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 identi...

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Bibliographic Details
Published in:Clinical cancer research 2020-02, Vol.26 (3), p.608-622
Main Authors: Pearson, Alex, Proszek, Paula, Pascual, Javier, Fribbens, Charlotte, Shamsher, Monee K, Kingston, Belinda, O'Leary, Ben, Herrera-Abreu, Maria T, Cutts, Rosalind J, Garcia-Murillas, Isaac, Bye, Hannah, Walker, Brian A, Gonzalez De Castro, David, Yuan, Lina, Jamal, Sabri, Hubank, Mike, Lopez-Knowles, Elena, Schuster, Eugene F, Dowsett, Mitch, Osin, Peter, Nerurkar, Ashutosh, Parton, Marina, Okines, Alicia F C, Johnston, Stephen R D, Ring, Alistair, Turner, Nicholas C
Format: Article
Language:English
Subjects:
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Breast Neoplasms - drug therapy
Breast Neoplasms - genetics
Breast Neoplasms - pathology
Cell Line, Tumor
Cyclin D1 - antagonists & inhibitors
Cyclin D1 - metabolism
Drug Resistance, Neoplasm - genetics
Female
Fulvestrant - administration & dosage
High-Throughput Nucleotide Sequencing
Humans
Middle Aged
Mutation
Neurofibromin 1 - genetics
Piperazines - administration & dosage
Prospective Studies
Pyridines - administration & dosage
Treatment Outcome
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Summary: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 characterization of a cohort of patients with ABC. Biopsies from patients with advanced breast cancer were sequenced with a 41 genes targeted panel in the ABC Biopsy (ABC-Bio) study. Blood samples were collected at disease progression for circulating tumor DNA (ctDNA) analysis, along with matched primary tumor to assess for acquisition in ABC in a subset of patients. We sequenced 210 ABC samples, demonstrating enrichment compared with primary disease for potentially targetable mutations in (in 6.19% of samples), (7.14%), and (8.10%). Of these enriched mutations, we show that mutations were frequently acquired in ABC, not present in the original primary disease. In ER-positive cancer cell line models, loss of 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 . Patients with mutations detected in baseline circulating tumor DNA had a good outcome on the CDK4/6 inhibitor palbociclib and fulvestrant. Our research identifies multiple therapeutic opportunities for advanced breast cancer and identifies the previously underappreciated acquisition of mutations.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.ccr-18-4044