Survival analysis in familial ovarian cancer, a case control study

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Abstract

Objective: familial ovarian cancer patients have been found to differ from sporadic cases, clinically as well as in the molecular make-up of the tumour. Here, a case control study is performed to analyse potential differences in survival. Study design: 31 families with a strong history of ovarian and/or breast cancer presenting to a family cancer clinic 44 ovarian cancer patients were included. Each patient was matched for age and stage with controls from a cancer registry. Survival rates and the effect of several prognostic factors were analysed. Results: median survival in the study group differed significantly from controls. A survival benefit for familial cases was maintained up to 5 years after diagnosis. Long-term survival was equally poor in both groups. Conclusion: the difference in survival between familial ovarian cancer cases and matched controls may reflect differences in biological behaviour. This may have important implications for the management and prevention of familial ovarian cancer.

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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