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

Abstract

Purpose: 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 competing-risks 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.

Results: Most 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.

Conclusion: The 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.

Fig 1.

Unsupervised hierarchical clustering of ovarian cancer histologic subtypes by their associations with risk factors. Unsupervised hierarchical clustering of the (A) four subtypes and (B) that includes the serous subtype divided into well-, moderately, and poorly differentiated carcinomas by using β-estimates, complete linkage, and an uncentered correlation similarity metric. The categories used in the cluster analysis were ever versus never parous, ever versus never oral contraceptive (OC) use, ever versus never tubal ligation, ever versus never endometriosis, age at menarche > 15 v ≤ 11 years, age at menopause < 40 versus 50 to 55 years, ever versus never menopausal hormone therapy use, ever versus never hysterectomy, family history of breast cancer (yes v no), family history of ovarian cancer (yes v no), body mass index (BMI) > 35 versus 20 to 25 kg/m², height (per 5-cm increase), and ever versus never smoking. The color scale shows the range of β-values for each exposure.