Article

Rubin, S.C. et al. Clinical and pathological features of ovarian cancer in women with germ-line mutations of BRCA1. N. Engl. J. Med. 335, 1413-1416

Creighton University, Omaha, Nebraska, United States
New England Journal of Medicine (Impact Factor: 54.42). 12/1996; 335(19):1413-6. DOI: 10.1056/NEJM199611073351901
Source: PubMed

ABSTRACT We tested the hypothesis that ovarian cancers associated with germ-line mutations of BRCA1 have distinct clinical and pathological features as compared with sporadic ovarian cancers.
We reviewed clinical and pathological data on patients with primary epithelial ovarian cancer found to have germ-line mutations of BRCA1. Survival among patients with advanced-stage cancer and such mutations was compared with that in control patients matched stage, grade, and histologic subtype of the tumors. A combination of single-strand conformation and sequencing analyses was used to examine the 22 coding exons and intronic splice-donor and splice-acceptor regions of BRCA1 for mutations in pathological specimens. Alternatively, some patients were known to be obligate carriers of the mutant BRCA1 gene because of their parental relationships with documented mutant-gene carriers.
We identified 53 patients with germ-line mutations of BRCA1. The average age at diagnosis was 48 years (range, 28 to 78). Histologic examination in 43 of the 53 patients showed serous adenocarcinoma. Thirty-seven tumors were of grade 3, 11 were of grade 2, 2 were of grade 1, and 3 were of low malignant potential. In 38 patients, the tumors were of stage III; 9 patients (including those with tumors of low malignant potential) had stage I disease, 5 had stage IV, and 1 had stage II. As of June 1996, with a median follow-up among survivors of 71 months from diagnosis, 20 patients had died of ovarian cancer, 27 had no evidence of the disease, 4 were alive with the disease, and 2 had died of other diseases. Actuarial median survival for the 43 patients with and advanced-stage disease was 77 months, as compared with 29 months for the matched controls (P<0.001).
As compared with sporadic ovarian cancers, cancers associated with BRCA1 mutation appear to have a significantly more favorable clinical course.

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    • "Our findings have important clinical implications. In both breast and ovarian cancers, patients with BRCA mutations are known to have a better clinical outcome [2] [3]. This has been presumed to be due to increased sensitivity to chemotherapy. "
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    • "Our findings have important clinical implications. In both breast and ovarian cancers, patients with BRCA mutations are known to have a better clinical outcome [2] [3]. This has been presumed to be due to increased sensitivity to chemotherapy. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In ovarian cancer, loss of BRCA gene expression in tumors is associated with improved response to chemotherapy and increased survival. A means to pharmacologically downregulate BRCA gene expression could improve the outcomes of patients with BRCA wild-type tumors. We report that vascular endothelial growth factor receptor 3 (VEGFR3) inhibition in ovarian cancer cells is associated with decreased levels of both BRCA1 and BRCA2. Inhibition of VEGFR3 in ovarian tumor cells was associated with growth arrest. CD133+ ovarian cancer stemlike cells were preferentially susceptible to VEGFR3-mediated growth inhibition. VEGFR3 inhibition–mediated down-regulation of BRCA gene expression reversed chemotherapy resistance and restored chemosensitivity in resistant cell lines in which a BRCA2 mutation had reverted to wild type. Finally, we demonstrate that tumor-associated macrophages are a primary source of VEGF-C in the tumor microenvironment. Our studies suggest that VEGFR3 inhibition may be a pharmacologic means to downregulate BRCA genes and improve the outcomes of patients with BRCA wild-type tumors.
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    • "Many BRCA1 gene mutations characterized familial occurrence and the presence of specific mutations are much more frequent in certain isolated populations and ethnic groups compared to the general population [6]. Rubin et al. reported that carriers of mutations in the BRCA1 gene appear to have a significantly more favorable clinical course [7]. In opposite, Johannsson et al. suggested that the survival for carriers of BRCA1 mutation is similar or worse compared to the patients with breast and ovarian cancer in general [8]. "
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