European Journal of Obstetrics & Gynecology and Reproductive Biology
Survival analysis in familial ovarian cancer, a case control study
Introduction
Epithelial ovarian cancer ranks as the fourth most frequent cancer among women in the Western world. In The Netherlands, the age-standardised incidence rate is 14.9 per 100,000 women per year and 1029 deaths occurred in 1993 [1]. Survival rates for ovarian cancer have improved slightly since the refinement of surgical methods and the introduction of novel chemotherapeutic agents, such as cisplatin [2], taxol [3] and possibly topotecan [4]. However, the survival benefit appears to be limited to women under 65 years, while mortality rates for older women continue to increase [1]. The overall 5-year survival has remained fairly stable since 1985 and stands at 32% [5]. In the Western world, cancer of the ovary remains the most lethal of all female genital malignancies [6].
Several prognostic factors have been shown to correlate independently with survival. Clinical prognostic factors include: age, stage, residual disease after debulking surgery, volume of ascites and performance status [7]. Histopathological prognostic factors include histological subtype and tumour grade [8], [9]. In addition, several genetic prognostic factors, including aneuploidy or increased DNA content [10], [11] and overexpression of certain oncogenes and tumour suppressor genes, such as HER-2/neu [12] and p53 [13], have been shown to correlate with a poor prognosis.
An estimated 5–10% of all ovarian cancer cases are due to an autosomal dominant susceptibility factor with high penetrance. Mutations in the BRCA1 or BRCA2 genes have been found to be responsible for the vast majority of these hereditary cases [14], [15]. Surprisingly, mutations in these genes appear to play only a very limited role in sporadic ovarian cancer [16], [17]. Apart from this genetic difference, there is accumulating evidence that hereditary ovarian cancers have clinical characteristics that differ from their sporadic counterparts. Hereditary ovarian cancer appears to develop in patients with a lower mean age at onset and certain histological subtypes are likely to be over-represented [18]. Rubin et al. [19] demonstrated better long-term survival for patients with advanced BRCA1-related ovarian cancer. If survival is better for hereditary cases than for sporadic cases, this may have important clinical implications as far as prevention and treatment are concerned.
To address the issue of survival from epithelial ovarian cancer in relation to a strong family history of ovarian cancer and/or a germline mutation in BRCA1 or BRCA2, we studied 44 cases of familial ovarian cancer and 176 age- and stage-matched controls obtained from a cancer registry.
Section snippets
Subjects
By means of pedigree analysis, we retrospectively identified 102 families which had been referred to the Family Cancer Clinic at the University Hospital Vrije Universiteit in Amsterdam for counselling on hereditary breast and ovarian cancers. In total 31 families with a confirmed diagnosis of epithelial ovarian cancer in either two or more first-degree relatives or one relative with ovarian cancer and at least one other first-degree relative with breast cancer were included in this study.
Results
Germline mutations were detected in 16 of 29 families tested. In total 13 families (containing 20 patients from the study group) harboured BRCA1 mutations. Three families (three patients) harboured a BRCA2 germline mutation. Results are summarised in Table 1.
The clinical characteristics of patients from the study group and control group are shown in Table 2.
At the time of last follow-up, 14 (32%) patients from the study group were still alive after a mean follow-up of 47 months (range 6–186
Comments
Our study detected differences in survival between familial ovarian cancer cases and cancer registry controls, even when matched for age and stage and correction for other known prognostic factors. We found a survival benefit up to 5 years after diagnosis for familial cases. However, the difference in survival between hereditary ovarian cancer patients and BRCA1 and BRCA2 negative sporadic ovarian cancer patients may be greater than this. In our study, patients from the cancer registry control
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Improved survival in non-Ashkenazi Jewish ovarian cancer patients with BRCA1 and BRCA2 gene mutations
2011, Gynecologic OncologyCitation Excerpt :Studies outside of the Jewish population have been inconclusive. These studies have either been small; based on high-risk families [15–17] or tumor registries lacking in relevant clinical information (Table 1) [18]. Thus, there is conflicting data regarding the impact of BRCA mutations on survival in ovarian, fallopian tube and primary peritoneal cancer patients in women who are not of Ashkenazi Jewish heritage [15,18].
Hereditary breast and ovarian cancer due to mutations in BRCA1 and BRCA2
2010, Genetics in MedicineCitation Excerpt :Two small population-based studies in Sweden (n = 38) and a Canadian study (n = 44) found no differences in survival between women with BRCA1 mutations with ovarian cancer and controls.9,77 A short-term improvement seen in a case-control study from the Netherlands did not persist after 5 years,10 and a case-control study at the University of Iowa also failed to find a survival advantage for women with BRCA1 mutations with ovarian cancer.11 However, data suggesting a survival advantage for BRCA1/2 mutation carriers are growing.
Hereditary ovarian carcinoma: Heterogeneity, molecular genetics, pathology, and management
2009, Molecular OncologyCitation Excerpt :All the same, it bears noting that a subsequent study by the Cambridge group, which selected carriers confined to the Ashkenazi Jewish mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2, found that ovarian cancer patients who carried one or another of these mutations had a survival advantage over noncarriers, though the difference did not reach significance (Ramus et al., 2001). On the other hand, 3 relatively small studies of ovarian cancer patients, selected because their families had strong family histories for breast and/or ovarian cancer or they were presumed carriers of either germline or sporadic BRCA1 mutations or they were carriers of 1675delA or 1135insA founder mutations in BRCA1 without regard to ethnicity, found no significant differences in the survival of these patients compared with ovarian cancer patients who were not considered to bear increased hereditary risk (Buller et al., 2002; Kringen et al., 2005; Zweemer et al., 2001). Pursuant to those observations, 4 further studies in which ovarian cancer patients were selected because they carried an Ashkenazi mutation found significant survival advantages among carriers compared with ovarian cancer patients who were not mutation carriers.
One in 10 ovarian cancer patients carry germ line BRCA1 or BRCA2 mutations: Results of a prospective study in Southern Sweden
2004, European Journal of CancerCitation Excerpt :The BRCA mutation carriers in our study did not differ from non-carriers with respect to disease stage, which confirms previous observations [7,33,34]. A longer disease-free survival has been demonstrated by some investigators for patients with BRCA-associated invasive ovarian carcinomas compared with the sporadic cases [7,34,35]. However, other investigations have not demonstrated any survival advantage for BRCA1 mutation carriers [36].
Association of BRCA1/2 mutations with prognosis and surgical cytoreduction outcomes in ovarian cancer patients: An updated meta-analysis
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