title: TumorBRCA1Reversion Mutation Arising during Neoadjuvant Platinum-Based Chemotherapy in Triple-Negative Breast Cancer Is Associated with Therapy Resistance.
abstract: Purpose:In germlineBRCA1orBRCA2(BRCA1/2) mutation carriers, restoration of tumorBRCA1/2function by a secondary mutation is recognized as a mechanism of resistance to platinum and PARP inhibitors, primarily in ovarian cancer. We evaluated this mechanism of resistance in newly diagnosed patients withBRCA1/2-mutant breast cancer with poor response to neoadjuvant platinum-based therapy.Experimental Design:PrECOG 0105 was a phase II neoadjuvant study of gemcitabine, carboplatin, and iniparib in patients with stage I-IIIA triple-negative orBRCA1/2mutation-associated breast cancer (n= 80). All patients underwent comprehensiveBRCA1/2genotyping. For mutation carriers with moderate or extensive residual disease after neoadjuvant therapy,BRCA1/2status was resequenced in the residual surgical breast tumor tissue.Results:Nineteen patients had a deleterious germlineBRCA1/2mutation, and four had moderate residual disease at surgery.BRCA1/2sequencing of residual tissue was performed on three patients. These patients hadBRCA11479delAG, 3374insGA, and W1712X mutations, respectively, with LOH at these loci in the pretreatment tumors. In the first case, a newBRCA1mutation was detected in the residual disease. This resulted in a 14-amino acid deletion and restoration of theBRCA1reading frame. A local relapse biopsy 4 months later revealed the identical reversion mutation, and the patient subsequently died from metastatic breast cancer.Conclusions:We report aBRCA1reversion mutation in a patient newly diagnosed with triple-negative breast cancer that developed over 18 weeks of platinum-based neoadjuvant therapy. This was associated with poor therapy response, early relapse, and death.Clin Cancer Res; 23(13); 3365-70. ©2017 AACR.
authors.affiliation: Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Anosheh
authors.initials: A
authors.lastname: Afghahi
authors.affiliation: Myriad Genetics, Inc., Salt Lake City, Utah.
authors.forename: Kirsten M
authors.initials: KM
authors.lastname: Timms
authors.affiliation: Department of Medicine, University, Hospitals Case Medical Center, Cleveland, Ohio.
authors.forename: Shaveta
authors.initials: S
authors.lastname: Vinayak
authors.affiliation: Department of Medicine, Stanford, University School of Medicine, Stanford, California.
authors.forename: Kristin C
authors.initials: KC
authors.lastname: Jensen
authors.affiliation: Department of Medicine, Stanford, University School of Medicine, Stanford, California.
authors.forename: Allison W
authors.initials: AW
authors.lastname: Kurian
authors.affiliation: National Comprehensive Cancer Network, Fort Washington, Pennsylvania.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Carlson
authors.affiliation: Department of Medicine, Stanford, University School of Medicine, Stanford, California.
authors.forename: Pei-Jen
authors.initials: PJ
authors.lastname: Chang
authors.affiliation: Department of Medicine, University of Washington School of Medicine, Seattle, Washington.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Schackmann
authors.affiliation: Grail, Inc., Menlo Park, California.
authors.forename: Anne-Renee
authors.initials: AR
authors.lastname: Hartman
authors.affiliation: Department of Medicine, Stanford, University School of Medicine, Stanford, California.
authors.forename: James M
authors.initials: JM
authors.lastname: Ford
authors.affiliation: Department of Medicine, Stanford, University School of Medicine, Stanford, California. mtelli@stanford.edu.
authors.forename: Melinda L
authors.initials: ML
authors.lastname: Telli
mesh_terms: D000368:Aged; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D020360:Neoadjuvant Therapy / Q000009:adverse effects; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010984:Platinum / Q000008:administration & dosage / Q000009:adverse effects; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D010984:Platinum; D016190:Carboplatin