Inactivating NF1 Mutations Are Enriched in Advanced Breast Cancer and Contribute to Endocrine Therapy Resistance.
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Authors
Pearson, A
Proszek, P
Pascual, J
Fribbens, C
Shamsher, MK
Kingston, B
O'Leary, B
Herrera-Abreu, MT
Cutts, RJ
Garcia-Murillas, I
Bye, H
Walker, BA
Gonzalez De Castro, D
Yuan, L
Jamal, S
Hubank, M
Lopez-Knowles, E
Schuster, EF
Dowsett, M
Osin, P
Nerurkar, A
Parton, M
Okines, AFC
Johnston, SRD
Ring, A
Turner, NC
Proszek, P
Pascual, J
Fribbens, C
Shamsher, MK
Kingston, B
O'Leary, B
Herrera-Abreu, MT
Cutts, RJ
Garcia-Murillas, I
Bye, H
Walker, BA
Gonzalez De Castro, D
Yuan, L
Jamal, S
Hubank, M
Lopez-Knowles, E
Schuster, EF
Dowsett, M
Osin, P
Nerurkar, A
Parton, M
Okines, AFC
Johnston, SRD
Ring, A
Turner, NC
Document Type
Journal Article
Date
2020-02-01
Date Accepted
2019-10-02
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 characterization of a cohort of patients with ABC. EXPERIMENTAL DESIGN: 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. RESULTS: We sequenced 210 ABC samples, demonstrating enrichment compared with 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 tumor 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.
Citation
Clinical cancer research : an official journal of the American Association for Cancer Research, 2020, 26 (3), pp. 608 - 622
Source Title
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
1078-0432
eISSN
1557-3265
Collections
Research Team
Endocrine Therapy Resistance
Molecular Oncology
Endocrinology
Translational Genomics
Molecular Oncology
Endocrinology
Translational Genomics