Somatic mutations in BRCA1 and BRCA2 could expand the number of patients that benefit from poly (ADP ribose) polymerase inhibitors in ovarian cancer

Bryan T.J. Hennessy, Kirsten M. Timms, Mark S. Carey, Alexander Gutin, Larissa A. Meyer, Darl D. Flake, Victor Abkevich, Jennifer Potter, Dmitry Pruss, Pat Glenn, Yang Li, Jie Li, Ana Maria Gonzalez-Angulo, Karen Smith McCune, Maurie Markman, Russell R. Broaddus, Jerry S. Lanchbury, Karen H. Lu, Gordon B. Mills

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    218 Scopus citations

    Abstract

    Purpose: The prevalence of BRCA1/2 mutations in germline DNA from unselected ovarian cancer patients is 11% to 15.3%. It is important to determine the frequency of somatic BRCA1/2 changes, given the sensitivity of BRCA-mutated cancers to poly (ADP ribose) polymerase-1 (PARP1) inhibitors and platinum analogs. Patients and Methods: In 235 unselected ovarian cancers, BRCA1/2 was sequenced in 235, assessed by copy number analysis in 95, and tiling arrays in 65. 113 tumors were sequenced for TP53. BRCA1/2 transcript levels were assessed by quantitative polymerase chain reaction in 220. When available for tumors with BRCA1/2 mutations, germline DNA was sequenced. Results: Forty-four mutations (19%) in BRCA1 (n = 31)/BRCA2 (n = 13) were detected, including one homozygous BRCA1 intragenic deletion. BRCA1/2 mutations were particularly common (23%) in high-grade serous cancers. In 28 patients with available germline DNA, nine (42.9%) of 21 and two (28.6%) of seven BRCA1 and BRCA2 mutations were demonstrated to be somatic, respectively. Five mutations not previously identified in germline DNA were more commonly somatic than germline (four of 11 v one of 17; P = .062). There was a positive association between BRCA1 and TP53 mutations (P = .012). BRCA1/2 mutations were associated with improved progression-free survival (PFS) after platinum-based chemotherapy in univariate (P = .032; hazard ratio [HR] = 0.65; 95% CI, 0.43 to 0.98) and multivariate (P = .019) analyses. BRCA1/2 deficiency, defined as BRCA1/2 mutations or expression loss (in 24 [13.3%] BRCA1/2-wild-type cancers), was present in 67 ovarian cancers (30%) and was also significantly associated with PFS in univariate (P = .026; HR = 0.67; 95% CI, 0.47 to 0.96) and multivariate (P = .008) analyses. Conclusion: BRCA1/2 somatic and germline mutations and expression loss are sufficiently common in ovarian cancer to warrant assessment for prediction of benefit in clinical trials of PARP1 inhibitors.

    Original languageEnglish (US)
    Pages (from-to)3570-3576
    Number of pages7
    JournalJournal of Clinical Oncology
    Volume28
    Issue number22
    DOIs
    StatePublished - Aug 1 2010

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    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

    Cite this

    Hennessy, B. T. J., Timms, K. M., Carey, M. S., Gutin, A., Meyer, L. A., Flake, D. D., Abkevich, V., Potter, J., Pruss, D., Glenn, P., Li, Y., Li, J., Gonzalez-Angulo, A. M., McCune, K. S., Markman, M., Broaddus, R. R., Lanchbury, J. S., Lu, K. H., & Mills, G. B. (2010). Somatic mutations in BRCA1 and BRCA2 could expand the number of patients that benefit from poly (ADP ribose) polymerase inhibitors in ovarian cancer. Journal of Clinical Oncology, 28(22), 3570-3576. https://doi.org/10.1200/JCO.2009.27.2997