ScienceWeek

MEDICAL BIOLOGY: ON CANCER OF THE OVARY

The following points are made by Stephen A. Cannistra (New Engl. J. Med. 2004 351:2519):

1) Epithelial cancer of the ovary is a relatively uncommon gynecologic cancer in the US, with approximately 25,580 new cases and 16,090 deaths anticipated in 2004.[1] Most patients present with advanced disease, which is managed with surgical resection followed by platinum-based chemotherapy. During the past decade, advances in chemotherapy have resulted in improved survival and in more effective treatment of relapsed disease. In addition, a better understanding of genetic risk factors has permitted a tailored approach to preventive strategies, such as bilateral salpingo-oophorectomy in selected women.

2) Epithelial cancer of the ovary derives from malignant transformation of the epithelium of the ovarian surface, which is contiguous with the peritoneal mesothelium. The median age of patients with ovarian cancer is 60 years, and the average lifetime risk for women is about 1 in 70. A strong family history of ovarian or breast cancer is the most important risk factor, although an identifiable genetic predisposition is present in only approximately 5 percent of affected women. Nulliparity is associated with an increased risk of ovarian cancer, whereas oral contraceptive use, pregnancy, and lactation are associated with a reduced risk.[1,2] Taken together, these observations suggest that repeated stimulation of the epithelium of the ovarian surface, which occurs in the nulliparous state as a result of uninterrupted ovulation, may predispose the epithelium to malignant transformation. Although early reports suggested that fertility drugs might increase the risk of ovarian cancer, subsequent studies that adjusted for parity and the duration of infertility have not confirmed these results.[3,4,5] Women who have undergone tubal ligation appear to be at lower risk than those who have not, although the mechanism is unclear.

3) A strong family history of breast cancer, ovarian cancer, or both -- sometimes occurring at an early age and in the same woman -- may be related to the presence of an inherited mutation in one of two genes, known as BRCA1 and BRCA2. The BRCA1 and BRCA2 genes are located on chromosomes 17q and 13q, respectively, and their gene products are involved in DNA repair. Because a mutated allele for the BRCA1 or BRCA2 gene may be inherited from either parent, it is important to obtain a complete family history during risk assessment.

4) Certain ethnic groups, such as Ashkenazi Jews, have an increased probability of harboring germ-line BRCA1 or BRCA2 mutations. The three most common mutations that occur in healthy Ashkenazi Jewish women are the 185delAG mutation in BRCA1, the 5382insC mutation in BRCA1, and the 6174delT mutation in BRCA2, with a collective prevalence of approximately 2.5 percent. Among Ashkenazi Jewish women with a known diagnosis of ovarian cancer, however, the frequency of such mutations has been reported to be as high as 26 to 41 percent. Women with a germ-line mutation in BRCA1 are reported to have a lifetime risk of ovarian cancer that ranges from 16 to 44 percent, and a lifetime risk of breast cancer that ranges from 56 to 87 percent. Ovarian cancer may develop at an earlier age in women with germ-line BRCA1 mutations than in those with the sporadic form of the disease, although it is important to recognize that ovarian cancer may occur at any age in mutation carriers.

5) Like BRCA1, the BRCA2 protein is localized in the nucleus and is involved in DNA repair through its association with the protein RAD51. Women with germ-line mutations in BRCA2 have a lifetime risk of breast cancer that is similar to that for carriers of the BRCA1 mutation, and their lifetime risk of ovarian cancer is approximately 10 percent. Men with BRCA1 or BRCA2 mutations are at risk for male breast cancer and may also have an increased risk for developing pancreatic cancer, as compared with men who do not have the mutation. The natural history of ovarian cancer that develops in the setting of BRCA1 or BRCA2 germ-line mutations appears to be characterized by a more indolent course than that of sporadic disease.

References (abridged):

1. Schildkraut JM, Thompson WD. Familial ovarian cancer: a population-based case-control study. Am J Epidemiol 1988;128:456-466

2. Whittemore AS. Characteristics relating to ovarian cancer risk: implications for prevention and detection. Gynecol Oncol 1994;55:S15-S19

3. Rossing MA, Daling JR, Weiss NS, Moore DE, Self SG. Ovarian tumors in a cohort of infertile women. N Engl J Med 1994;331:771-776

4. Venn A, Watson L, Lumley J, Giles G, King C, Healy D. Breast and ovarian cancer incidence after infertility and in vitro fertilisation. Lancet 1995;346:995-1000

5. Ness RB, Cramer DW, Goodman MT, et al. Infertility, fertility drugs, and ovarian cancer: a pooled analysis of case-control studies. Am J Epidemiol 2002;155:217-224

New Engl. J. Med. http://www.nejm.org

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