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 Mills

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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
Externally publishedYes

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Ovarian Neoplasms
Mutation
Germ-Line Mutation
DNA
Neoplasms
Platinum
Disease-Free Survival
Poly(ADP-ribose) Polymerase Inhibitors
Clinical Trials
Drug Therapy
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Somatic mutations in BRCA1 and BRCA2 could expand the number of patients that benefit from poly (ADP ribose) polymerase inhibitors in ovarian cancer. / Hennessy, Bryan T.J.; Timms, Kirsten M.; Carey, Mark S.; Gutin, Alexander; Meyer, Larissa A.; Flake, Darl D.; Abkevich, Victor; Potter, Jennifer; Pruss, Dmitry; Glenn, Pat; Li, Yang; Li, Jie; Gonzalez-Angulo, Ana Maria; McCune, Karen Smith; Markman, Maurie; Broaddus, Russell R.; Lanchbury, Jerry S.; Lu, Karen H.; Mills, Gordon.

In: Journal of Clinical Oncology, Vol. 28, No. 22, 01.08.2010, p. 3570-3576.

Research output: Contribution to journalArticle

Hennessy, BTJ, Timms, KM, Carey, MS, Gutin, A, Meyer, LA, Flake, DD, Abkevich, V, Potter, J, Pruss, D, Glenn, P, Li, Y, Li, J, Gonzalez-Angulo, AM, McCune, KS, Markman, M, Broaddus, RR, Lanchbury, JS, Lu, KH & Mills, G 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, vol. 28, no. 22, pp. 3570-3576. https://doi.org/10.1200/JCO.2009.27.2997
Hennessy, Bryan T.J. ; Timms, Kirsten M. ; Carey, Mark S. ; Gutin, Alexander ; Meyer, Larissa A. ; Flake, Darl D. ; Abkevich, Victor ; Potter, Jennifer ; Pruss, Dmitry ; Glenn, Pat ; Li, Yang ; Li, Jie ; Gonzalez-Angulo, Ana Maria ; McCune, Karen Smith ; Markman, Maurie ; Broaddus, Russell R. ; Lanchbury, Jerry S. ; Lu, Karen H. ; Mills, Gordon. / Somatic mutations in BRCA1 and BRCA2 could expand the number of patients that benefit from poly (ADP ribose) polymerase inhibitors in ovarian cancer. In: Journal of Clinical Oncology. 2010 ; Vol. 28, No. 22. pp. 3570-3576.
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title = "Somatic mutations in BRCA1 and BRCA2 could expand the number of patients that benefit from poly (ADP ribose) polymerase inhibitors in ovarian cancer",
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.",
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TY - JOUR

T1 - Somatic mutations in BRCA1 and BRCA2 could expand the number of patients that benefit from poly (ADP ribose) polymerase inhibitors in ovarian cancer

AU - Hennessy, Bryan T.J.

AU - Timms, Kirsten M.

AU - Carey, Mark S.

AU - Gutin, Alexander

AU - Meyer, Larissa A.

AU - Flake, Darl D.

AU - Abkevich, Victor

AU - Potter, Jennifer

AU - Pruss, Dmitry

AU - Glenn, Pat

AU - Li, Yang

AU - Li, Jie

AU - Gonzalez-Angulo, Ana Maria

AU - McCune, Karen Smith

AU - Markman, Maurie

AU - Broaddus, Russell R.

AU - Lanchbury, Jerry S.

AU - Lu, Karen H.

AU - Mills, Gordon

PY - 2010/8/1

Y1 - 2010/8/1

N2 - 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.

AB - 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.

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