Ovarian Cancer Risk Factors by Histologic Subtype: An Analysis From the Ovarian Cancer Cohort Consortium

Abstract

An understanding of the etiologic heterogeneity of ovarian cancer is important for improving prevention, early detection, and therapeutic approaches. We evaluated 14 hormonal, reproductive, and lifestyle factors by histologic subtype in the Ovarian Cancer Cohort Consortium (OC3).Patients and Methods Among 1.3 million women from 21 studies, 5,584 invasive epithelial ovarian cancers were identified (3,378 serous, 606 endometrioid, 331 mucinous, 269 clear cell, 1,000 other). By using competingrisks Cox proportional hazards regression stratified by study and birth year and adjusted for age, parity, and oral contraceptive use, we assessed associations for all invasive cancers by histology. Heterogeneity was evaluated by likelihood ratio test. ResultsMost risk factors exhibited significant heterogeneity by histology. Higher parity was most strongly associated with endometrioid (relative risk [RR] per birth, 0.78; 95% CI, 0.74 to 0.83) and clear cell (RR, 0.68; 95% CI, 0.61 to 0.76) carcinomas (P value for heterogeneity [P-het] , .001). Similarly, age at menopause, endometriosis, and tubal ligation were only associated with endometrioid and clear cell tumors (P-het # .01). Family history of breast cancer (P-het = .008) had modest heterogeneity. Smoking was associated with an increased risk of mucinous (RR per 20 pack-years, 1.26; 95% CI, 1.08 to 1.46) but a decreased risk of clear cell (RR, 0.72; 95% CI, 0.55 to 0.94) tumors (P-het = .004). Unsupervised clustering by risk factors separated endometrioid, clear cell, and low-grade serous carcinomas from high-grade serous and mucinous carcinomas. ConclusionThe heterogeneous associations of risk factors with ovarian cancer subtypes emphasize the importance of conducting etiologic studies by ovarian cancer subtypes. Most established risk factors were more strongly associated with nonserous carcinomas, which demonstrate challenges for risk prediction of serous cancers, the most fatal subtype.

Challenges and Opportunities in Studying the Epidemiology of Ovarian Cancer Subtypes

“…Table 1 provides a summary of results from the Ovarian Cancer Association Consortium (OCAC) [43–46], the Ovarian Cancer Cohort Consortium (OC3) [47], the Collaborative Group on Epidemiological Studies of Ovarian Cancer [48–52], and the Million Women’s Study [53]. Because these are generally based on earlier histotype definitions, many of the studies were not able to present results separately by LGSC and HGSC.…”

Ovarian Cancer Prevention in High-risk Women

“…A genetic predisposition to breast or ovarian cancer is the most important known risk for the development of ovarian cancer and 18-24% of ovarian carcinomas may arise in conjunction with a hereditary predisposition (9-14). Germline genetic mutations are far more common amongst Type II ovarian cancers, while endometriosis and hormonal factors predispose to Type I ovarian malignancies, (8, 12, 15). Interactions between environmental, hormonal and genetic factors are likely to impact ovarian cancer risk in an individual patient, but an understanding of the interplay and hierarchy of risk factors is rudimentary at this time.…”

“…A protective effective of progesterone in ovarian cancer prevention has been suggested both by animal models as well as the observation of a protective effect from progesterone only oral contraceptive pills (46). Parity, use of oral contraceptives (OCP), and lactation have all been described as protective factors while infertility may increase the risk of developing ovarian carcinoma (15, 47, 48). …”

“…A 40% risk reduction has been demonstrated after a woman's first birth and an 80% reduction was seen in those women with greater than 5 pregnancies(49). Parity is most protective against the development of endometrioid ovarian cancer (15, 50). …”

Large ovarian cancer screening trial shows modest mortality reduction, but does not justify population-based ovarian cancer screening

“…Most cancers are detected at advanced stages when therapeutic options are limited. Epithelial ovarian cancers are heterogeneous with respect to cell of origin, molecular pathways, morphological appearance, risk factor associations and survival 1 2. High-grade serous carcinomas are most common and have the worst prognosis.…”