884PD - Next generation sequencing of BRCA1/2 in high grade ovarian tumors expands BRCA defects beyond germline mutations

Date 28 September 2014
Event ESMO 2014
Session Gynaecological cancers
Topics Ovarian Cancer
Pathology/Molecular Biology
Translational Research
Presenter Melinda Yates
Citation Annals of Oncology (2014) 25 (suppl_4): iv305-iv326. 10.1093/annonc/mdu338
Authors M. Yates1, K. Timms2, M. Daniels1, B. Batte1, K. Ring1, C. Neff2, J. Potter2, S. Chau2, J. Chen2, D. Williams2, M. Perry2, B. Morris2, A. Gutin2, Y. Amin1, M. Munsell1, K.M. Schmeler1, J. Lanchbury2, K. Lu1
  • 1Gynecologic Oncology & Reproductive Medicine, University of Texas MD Anderson Cancer Center, 77030 - HOUSTON/US
  • 2Research Division, Myriad Genetics, Inc., Salt Lake City/US

Abstract

Aim

Germline BRCA1/2 mutation screening is critical in ovarian cancer patients to identify a subset of women who might benefit from PARP inhibitors. A recent clinical study suggests that women with either germline or somatic BRCA1/2 mutations may benefit from PARP inhibitors1. Tumor mutation screening could expand the number of ovarian cancer patients that might consider PARP inhibitor treatment2.

Methods

Previously untreated high grade epithelial ovarian cancer patients were prospectively enrolled between January 2011 and December 2013 in accordance with IRB protocol. Patients were offered germline and tumor BRCA1/2 mutation screening. Germline mutation screening was performed on DNA from blood via custom amplicon assay and next generation sequencing. DNA from FFPE tumor samples was sequenced using custom hybridization enrichment and next generation sequencing. Variants and large rearrangements were identified and classified according to established criteria.

Results

263 patients were enrolled and germline testing was completed. Germline mutation analysis revealed 39 deleterious mutations (15% mutation rate, 25 BRCA1 and 14 BRCA2 mutations). Somatic tumor analysis has been completed for 88 patients receiving upfront surgical treatment (out of 123 total upfront surgery patients). 14 (16%) had germline deleterious mutations and all 14 mutations were independently identified in the tumor, giving 100% concordance between the assays. An additional 8 (9%) deleterious somatic mutations were identified, representing an overall BRCA1/2 mutation rate of 25%. One somatic BRCA2 mutation was observed in a patient with a previously identified germline BRCA2 mutation.

Conclusions

Data from this prospective cohort support previously reported frequencies of BRCA1/2 deleterious mutations in high grade epithelial ovarian tumors2. Next generation sequencing assays on blood and tumor DNA were 100% concordant. Tumor sequencing identified additional BRCA1/2 defects. Further molecular profiling and clinical follow-up is ongoing to evaluate outcomes in these subgroups of ovarian cancer patients with BRCA1/2 defects. References 1. Ledermann et al, 2013 ASCO Annual Meeting 2. Hennessy et al, 2010 JCO 28:3570-6.

Disclosure

K. Timms, C. Neff, J. Potter, S. Chau, J. Chen, D. Williams, M. Perry, B. Morris, A. Gutin and J. Lanchbury: is an employee and stockholder of Myriad Genetics, Inc.; K. Lu: Participating MD Anderson researchers do not receive funds from Myriad Genetics, Inc.All other authors have declared no conflicts of interest.