Ovarian Cancer Research Today is a free monthly online journal that collates and summarizes the latest research about Ovarian Cancer, including details on symptoms, causes, treatment, information.

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

Hennessy BT, 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 GB

Department of Gynecology Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA. bryanhennessy74@gmail.com

PURPOSE: The prevalence of BRCA(1/2) mutations in germline DNA from unselected ovarian cancer patients is 11% to 15.3%. It is important to determine the frequency of somatic BRCA(1/2) 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, BRCA(1/2) was sequenced in 235, assessed by copy number analysis in 95, and tiling arrays in 65. 113 tumors were sequenced for TP53. BRCA(1/2) transcript levels were assessed by quantitative polymerase chain reaction in 220. When available for tumors with BRCA(1/2) 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. BRCA(1/2) 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). BRCA(1/2) 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. BRCA(1/2) deficiency, defined as BRCA(1/2) mutations or expression loss (in 24 [13.3%] BRCA(1/2)-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: BRCA(1/2) 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.

Published 30 July 2010 in J Clin Oncol, 28(22): 3570-6.
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Articles on Ovarian Cancer published 30 July 2010:

Gene expression profile of BRCAness that correlates with responsiveness to chemotherapy and with outcome in patients with epithelial ovarian cancer.   J Clin Oncol, 28(22): 3555-61.

PURPOSE: To define a gene expression profile of BRCAness that correlates with chemotherapy response and outcome in epithelial ovarian cancer (EOC). METHODS: A publicly available microarray data set including 61 patients with EOC with either sporadic disease or BRCA(1/2) germline mutations was used for development of the BRCAness profile. Correlation with platinum responsiveness was assessed in platinum-sensitive and platinum-resistant tumor biopsy specimens from six patients with BRCA germline ... [Abstract] [Full-text]

Articles on Ovarian Cancer published 28 July 2010:

Prevalence of lymph node metastasis in primary mucinous carcinoma of the ovary.   Obstet Gynecol, 116(2): 269-73.

OBJECTIVE: To estimate the prevalence of lymph node involvement in women with primary mucinous ovarian carcinomas. METHODS: A retrospective study was performed of patients with primary mucinous ovarian carcinomas evaluated at a single institution between 1985 and 2007. A gynecologic oncology pathologist evaluated all cases. Patients with tumors of low malignant potential and mucinous carcinomas metastatic to the ovary from other primary sites were excluded. RESULTS: Patients with primary ... [Abstract] [Full-text]

Endometrial giant cell carcinoma: a case series and review of the spectrum of endometrial neoplasms containing giant cells.   Am J Surg Pathol, 34(8): 1132-8.

Poorly differentiated endometrial carcinomas of specific type include the rarely reported endometrial carcinoma with a malignant giant cell component [endometrial giant cell carcinoma (GCC)]. Since the initial description in 1991, there has only been 1 subsequent case report of this entity. We report another 5 cases. The patients ranged in age from 53 to 83 years, presenting with vaginal bleeding, anemia, or a pelvic mass. Four of the 5 tumors contained areas of endometrial adenocarcinoma of ... [Abstract] [Full-text]

Articles on Ovarian Cancer published 27 July 2010:

Osteopontin is a new target molecule for ovarian clear cell carcinoma therapy.   Cancer Sci, 101(8): 1828-33.

Recent studies have demonstrated overexpression of osteopontin (OPN) in ovarian clear cell carcinoma. Here, we revealed the role of OPN in invasiveness in ovarian clear cell carcinoma. We used immunofluorescence analysis to detect OPN in a total of 160 patient-derived specimens. Ovarian clear cell carcinoma cell lines, RMG-1 and TOV-21G, were used to monitor changes in OPN and integrin levels, and cell invasiveness following treatment with OPN, simvastatin, and transfection with siRNA. ... [Abstract] [Full-text]

Articles on Ovarian Cancer published 26 July 2010:

Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial.   Lancet, 376(9737): 245-51.

BACKGROUND: Olaparib is a novel, orally active poly(ADP-ribose) polymerase (PARP) inhibitor that induces synthetic lethality in homozygous BRCA-deficient cells. We aimed to assess the efficacy and safety of olaparib for treatment of advanced ovarian cancer in patients with BRCA1 or BRCA2 mutations. METHODS: In this international, multicentre, phase 2 study, we enrolled two sequential cohorts of women (aged >or=18 years) with confirmed genetic BRCA1 or BRCA2 mutations, and recurrent, ... [Abstract] [Full-text]

Articles on Ovarian Cancer published 15 July 2010:

Activation of checkpoint kinase 2 by 3,3'-diindolylmethane is required for causing G2/M cell cycle arrest in human ovarian cancer cells.   Mol Pharmacol, 78(2): 297-309.

We evaluated the effect of 3,3'-diindolylmethane (DIM) in ovarian cancer cells. DIM treatment inhibited the growth of SKOV-3, TOV-21G, and OVCAR-3 ovarian cancer cells in both a dose- and time-dependent manner with effective concentrations ranging from 40 to 100 muM. Growth-inhibitory effects of DIM were mediated by cell cycle arrest in G(2)/M phase in all the three cell lines. G(2)/M arrest was associated with DNA damage as indicated by phosphorylation of H(2)A.X at Ser139 and activation of ... [Abstract] [Full-text]

Articles on Ovarian Cancer published 14 July 2010:

Detection of inherited mutations for breast and ovarian cancer using genomic capture and massively parallel sequencing.   Proc Natl Acad Sci U S A, 107(28): 12629-33.

Inherited loss-of-function mutations in the tumor suppressor genes BRCA1, BRCA2, and multiple other genes predispose to high risks of breast and/or ovarian cancer. Cancer-associated inherited mutations in these genes are collectively quite common, but individually rare or even private. Genetic testing for BRCA1 and BRCA2 mutations has become an integral part of clinical practice, but testing is generally limited to these two genes and to women with severe family histories of breast or ovarian ... [Abstract] [Full-text]

Articles on Ovarian Cancer published 12 July 2010:

Histopathological prognostic factors predicting para-aortic lymph node metastasis in patients with endometrioid uterine cancer.   Gynecol Oncol, 118(2): 151-4.

INTRODUCTION: The purpose of this study was to determine histopathological factors for para-aortic lymph node (PALN) metastasis in patients with endometrioid uterine cancer. METHODS: A total of 355 patients (Stage I, n=269; II, n=24; and III, n=62) (FIGO 2009) underwent primary radical surgery including complete systematic pelvic lymph node (PLN) and PALN dissection in Tohoku Gynecologic Cancer Unit (TGCU) between 1993 and 2004. Logistic regression analysis was used to determine the independent ... [Abstract] [Full-text]

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