A large, prospective analysis showed that risk factors for ovarian cancer demonstrate substantial heterogeneity in their associations with histologic subtypes of the disease. The heterogeneity has implications for prevention and risk prediction in ovarian cancer.
“Most ovarian cancers are detected at a late stage and have a poor prognosis,” wrote study authors led by Nicolas Wentzensen, MD, PhD, of the National Cancer Institute in Bethesda, Maryland, adding that two large trials failed to show any reduction in mortality with available screening techniques. “An understanding of the etiologic heterogeneity of ovarian cancer is critical for development of new prevention strategies.”
The new study evaluated associations of 14 key risk factors with invasive epithelial ovarian cancer risk both overall and by histologic subtype, based on data from the Ovarian Cancer Cohort Consortium (OC3). It included 5,584 cases, from more than 1.3 million women in 21 clinical trial cohorts. The results were published online ahead of print in the Journal of Clinical Oncology.
Most cases of ovarian cancer were serous (73.7%) histology, followed by endometrioid (13.2%), mucinous (7.2%), and clear cell (5.9%).
Parous women had a reduced risk of all subtypes compared with nulliparous women; the strongest association was seen in clear cell carcinomas, with a relative risk (RR) of 0.35 (95% CI, 0.27–0.47), and serous cancers had the least risk reduction with an RR of 0.81 (95% CI, 0.73–0.90). There was significant heterogeneity by subtype (P value for heterogeneity [Phet] < .001), and similar patterns were seen for number of children (with more children, risk decreased).
Age at menopause was significantly associated with risk of endometrial and clear cell carcinomas, but not with serous or mucinous tumors (Phet = .009). Tubal ligation was associated with reduced risk of endometrioid and clear cell histology but not the others (Phet < .001), and hysterectomy was associated with only clear cell carcinomas (Phet = .006). Oral contraceptive use was associated with reduced risk of all ovarian cancers, though the association was only significant for serous and clear cell carcinomas.
Non-hormonal or reproductive risk factors also showed heterogeneity in their associations with risk. First-degree family history of breast or ovarian cancer showed significant associations with increased risk of serous tumors, while a family history of breast cancer was associated with endometrioid carcinomas. Ever smoking was associated with an increased risk of mucinous carcinomas, but no other histologic subtype.
“The substantial heterogeneity of individual risk factor associations across ovarian cancer subtypes supports that subtypes are indeed different diseases and underscores the importance of evaluating risk factors and biomarkers by ovarian cancer subtypes,” the authors wrote. They suggested exploring potential risk factors specifically for high-grade serous cancers, which showed the weakest associations for the established risk factors.
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