Improved survival in women with BRCA‐associated ovarian carcinoma

Abstract

BACKGROUND The objective of this study was to determine the clinical characteristics, treatment response, and frequency of p53 overexpression in Ashkenazi Jewish women with hereditary ovarian carcinoma. METHODS Seventy‐one Jewish women with epithelial ovarian carcinoma (EOC) were tested for the three BRCA founder mutations using single‐strand conformation polymorphism analysis, heteroduplex analysis, and protein truncation testing. Clinical and histopathologic data were reviewed retrospectively. In vitro chemoresistance was analyzed in 32 patients. Mutations of p53 were studied using immunohistochemical detection of p53 overexpression. RESULTS Thirty‐four of 71 Jewish patients with EOC (48%) had germline BRCA mutations (BRCA heterozygotes), including 22 BRCA1 mutations and 12 BRCA2 mutations. BRCA heterozygotes were younger compared with Jewish patients who had EOC without mutations (sporadic carcinoma; 50 years vs. 59 years, respectively; P = 0.01). BRCA1 heterozygotes were younger compared with BRCA2 heterozygotes (48 years vs. 57 years, respectively; P = 0.01). Histopathologic tumor features were similar; however, tumors with low malignant potential were seen only in women with sporadic carcinoma. Both groups had equivalent rates of surgical cytoreduction and similar median follow‐up (72 months). BRCA heterozygotes had higher response rates to primary therapy compared with patients who had sporadic disease (P = 0.01). In vitro chemoresistance predicted tumor response to platinum chemotherapy correctly in BRCA heterozygotes (P = 0.0096). BRCA heterozygotes with advance‐stage disease had improved survival compared with patients who had advanced stage sporadic carcinoma (91 months vs. 54 months, respectively; P = 0.046) and had a longer disease free interval (49 months vs. 19 months, respectively; P = 0.16). p53 overexpression was common in BRCA heterozygotes (80%). CONCLUSIONS BRCA1 heterozygotes developed EOC at a younger age compared with BRCA2 heterozygotes and women who had sporadic ovarian carcinoma. BRCA heterozygotes had a better response to platinum chemotherapy compared with women who had sporadic disease, which may have contributed to their improved prognosis. Cancer 2003;97:2187–95. © 2003 American Cancer Society. DOI 10.1002/cncr.11310

The E3 ubiquitin ligase EDD is an adverse prognostic factor for serous epithelial ovarian cancer and modulates cisplatin resistance in vitro

“…For example, patients with non-functional (mutated) BRCA1 or BRCA2, associated with hereditary breast and ovarian cancer, respond better to platinum chemotherapy owing to an increased sensitivity to DNA damage-induced cell death (Cass et al, 2003). Reintroduction of BRCA1 into cells lacking functional BRCA1 enhances resistance to both radiation and paclitaxel (Zhou et al, 2003), and cells with higher than normal levels of BRCA1 protein are resistant to killing with platinum drugs (Husain et al, 1998).…”

Gene expression profiling of primary cultures of ovarian epithelial cells identifies novel molecular classifiers of ovarian cancer

“…In the context of tumour suppressors involved in ovarian cancer, much attention has focused on the role of BRCA and p53. Whereas p53 mutation appears to be frequent (Marks et al, 1991;Okamoto et al, 1991), BRCA mutation occurs in less than 10% in all diagnosed cases (Ford et al, 1994;Cass et al, 2003) and represents a small minority of ovarian cancers. Here, we identified ST-5/HTS1 as a tumour suppressor gene downregulated in the majority of ovarian primary cultures derived from malignant tumours.…”

Variants in Notch signalling pathway genes, PSEN1 and MAML2, predict overall survival in Chinese patients with epithelial ovarian cancer

“…In addition to clinical and demographic factors, molecular biomarkers could be promising prognostic or predictive factors for EOC. For example, molecular epidemiological studies have demonstrated that the altered expression levels of BRCA1 and BRCA2 as a result of mutations are associated with individual variation of clinical outcomes of EOC patients 4, 5. The genomewide association study (GWAS) approach has also been used to identify susceptibility loci associated with clinical outcomes in European EOC patients 6.…”