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BRCA Mutations Associated with Improved Survival in Patients with Ovarian Cancer
Abstract & Commentary
Synopsis: Approximately 10% of invasive ovarian carcinomas are due to genetic predisposition and are associated with inherited mutations in either the BRCA1 or BRCA2 gene. In certain ethnic groups, such as Ashkenazi Jewish women, the frequency of these gene mutations are approximately 2%, and these women have a 16-44% lifetime risk of developing ovarian cancer. In the current report, histological and biological features of ovarian cancer occurring in Jewish women were compared in the context of the presence or absence of BRCA mutations. Women heterozygous for BRCA1 but not BRCA2 presented with ovarian cancer at a younger age. Histological features were comparable, but when matched for stage, those with BRCA mutations were more responsive to chemotherapy, and survival was significantly better.
Source: Cass I, et al. Cancer. 2003;97:2187-2195.
BRCA mutations occur with increased frequency in certain ethnic groups. The purpose of the study by Cass and colleagues from Cedars-Sinai Medical Center, UCLA, was to determine the clinical characteristics, treatment response, and frequency of p53 overexpression in Ashkenazi Jewish women with BRCA-associated hereditary ovarian cancer compared to non-BRCA-associated (sporadic) ovarian cancer.
There were 71 Jewish patients with epithelial ovarian cancer, and each was tested for the 3 BRCA founder mutations. Clinical and histopathological data were reviewed retrospectively. In vitro chemoresistance was analyzed in 32 patients, and mutations of the p53 were determined by examining for increased expression of p53 using immunohistochemistry.
Thirty-four of 71 Jewish patients with epithelial ovarian cancer (48%) had germline BRCA mutations, including 22 BRCA1 and 12 BRCA2 mutations. BRCA heterozygotes were younger, compared to Jewish ovarian cancer patients without BRCA mutations (50 years vs 59 years; P = .01). BRCA1 heterozygotes were younger than BRCA2 (48 years vs 57 years; P = .01). Histopathological tumor features were similar in those that occurred sporadically compared with those associated with BRCA mutations. BRCA heterozygotes had higher response rates to primary cytoreductive chemotherapy regimens. BRCA heterozygotes with advanced-stage disease had improved survival compared with patients with similarly staged sporadic ovarian cancer (91 months vs 54 months; P = .046) and a longer disease-free interval (49 months vs 19 months; P = .16).
Thus, BRCA1 heterozygotes developed ovarian cancer at a younger age compared with BRCA2 heterozygotes or those without BRCA mutation. BRCA heterozygotes had a better response to platinum-based chemotherapy regimens and better overall survival.
Comment by William B. Ershler, MD
That ovarian cancer patients with BRCA mutations had improved survival when compared to those without mutation has been previously observed,1,2 but some have speculated that this was related to earlier stage at diagnosis or less malignant histological variants. However, in the current series, there were no significant histological differences among those with BRCA-associated or sporadic ovarian carcinomas, and there were sufficient number of patients included that survival by stage could be determined. The data indicate that tumors that developed in BRCA heterozygotes were more chemosensitive in vitro, more chemoresponsive in vivo, and were associated with a longer survival time when compared to sporadic variants.
The mechanism that would account for this seemingly counter-intuitive observation has yet to be determined, but the hypothesis proposed by Cass et al seems reasonable. BRCA1 and 2 are considered tumor suppressor genes that regulate cellular proliferation and DNA repair by maintaining chromosomal integrity.3,4 Cass et al speculate that the absence of BRCA renders tumor cells more sensitive to the chemotherapy-induced cytotoxicity due to the impaired DNA repair capacity.
The findings reported confirm earlier observations that Jewish BRCA mutation carriers develop ovarian carcinoma at a younger age. It is apparent from the current series that this observation (earlier age of disease onset) is true for BRCA1 and not BRCA2 carriers. This finding has significant implications for counseling mutation carriers with regard to the timing of preventative measures, such as prophylactic oophorectomy, as those with BRCA1 mutations will develop ovarian cancer 5-10 years younger than those with BRCA2 mutations or than those who develop ovarian cancer sporadically. The added information with regard to enhanced chemosensitivity in those with BRCA mutations will need additional research for both confirmation and to elucidate mechanisms.
Dr. Ershler, INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC.
1. Rubin SC, et al. N Engl J Med. 1996;335:1413-1416.
2. Ben David Y, et al. J Clin Oncol. 2002;20:463-466.
3. Hartman AR, Ford JM. Nat Genet. 2002;32:180-184.
4. Yang H, et al. Science. 2002;297:1837-1848.