Invasive ovarian cancer risk: understanding the role of the menstrual cycle

From the Harris Group, Public Health Sciences Division

Ovarian cancer is the tenth most common form of cancer among women in the United States, but it accounts for more deaths than any other cancer of the female reproductive system. If detected early, the 5-year survival rate is greater than 90%; however, a majority of ovarian cancer cases are diagnosed at a late stage. Thus, better understanding of ovarian cancer risk factors may have a significant public health impact. Researchers in the Public Health Sciences Division recently published a paper in Cancer Epidemiology, Biomarkers & Prevention of a study that carefully assessed the relationship between ovarian cancer risk and certain characteristics of the menstrual cycle.

Ovarian cancer is a highly heterogeneous disease; of the three main ovarian cancer types, epithelial is the most common, accounting for approximately 90% of all cases diagnosed. Within the epithelial category, there are several different histotypes that differ biologically and pathologically. Several previous epidemiological studies revealed that endocrine and reproductive factors, including characteristics of the menstrual cycle, are associated with ovarian cancer risk. Polycystic ovary syndrome (PCOS) is a hormonal imbalance disorder of unknown etiology that is characterized by the presence of ovarian cysts, irregular or infrequent menstrual cycles, and hyperandrogenism. PCOS and its hallmark symptom oligomenorrhea (infrequent menstrual cycling) have been associated with ovarian cancer risk but the current body of evidence presents mixed results, with some studies showing decreased risk and others reporting increased risk or no association. Assistant Member Dr. Holly Harris, who led the current study, described limitations of the previous work, “Previous studies examining this association have been small and few examined the association by histologic subtype.” Harris also emphasized that the heterogeneous nature of ovarian cancer must be taken into account, “examination of potential risk factor associations by histologic subtype is critical.”

Harris and colleagues undertook the current study to address these limitations and clarify the relationship between PCOS, menstrual cycle characteristics, and ovarian cancer risk by taking advantage of data available from the Ovarian Cancer Association Consortium (OCAC), an international group of investigators of ovarian cancer case-control studies. The large study population (14 studies, 16,594 ovarian cancer cases, and 17,718 controls) and associated data from the OCAC were a major strength of the study and allowed for “the pooling of the largest group of case-control studies ever assembled with data on PCOS and menstrual cycle characteristics to examine the association between PCOS and oligomenorrhea, and ovarian cancer risk by histologic subtype,” said Harris. The authors analyzed self-reported data on PCOS history, menstrual irregularity, and menstrual cycle length and calculated the association with invasive ovarian cancer and by individual ovarian cancer histotypes.

Graphical display of association between menstrual cycle length and invasive ovarian cancer risk
Association between menstrual cycle length >35 days and invasive ovarian cancer risk in 12 study sites in the Ovarian Cancer Association Consortium (OCAC). Overall, increased menstrual cycle length was associated with a 30% decrease in risk (blue diamond) as compared to women with menstrual cycle length <35 days. Results are presented as odds ratio and 95% confidence interval. Image by Maggie Burhans

In the overall analyses, the authors found that menstrual cycle irregularity or increased length were significantly associated with reduced risk of invasive ovarian cancer while the association with history of PCOS was not significant. An irregular menstrual cycle was associated with a decrease in risk by 17% as compared to regular menstrual cycles. The effect of menstrual cycles >35 days was even greater, with an overall reduction of invasive ovarian cancer risk by 30% as compared to menstrual cycles <35 days (see Figure). However, when the associations were analyzed by histotype, risk varied substantially. For example, irregular menstrual cycles were associated with an increased risk of borderline serous and borderline mucinous cancer but with a decreased risk of three invasive histotypes, including high grade serous, endometrioid, and clear cell. Other invasive histotypes were not significantly associated with cycle irregularity. In addition, menstrual cycle length >35 days was associated with reduced risk for borderline mucinous but not for borderline serous. Increased cycle length was also associated with reduced risk of three of five invasive histotypes including low grade serous, high grade serous, and mucinous.

As summarized by Harris, “Previously, smaller studies reported an increased risk of ovarian cancer among women with PCOS or irregular periods, but our research indicates that this may not be a higher risk group for most invasive ovarian cancer subtypes. Both menstrual cycle length >35 days and menstrual cycle irregularity, which are defining characteristics of PCOS, were associated with a decreased risk of invasive ovarian cancer.”

While the results from this large study have contributed to our understanding of the relationship between PCOS and characteristics of the menstrual cycle and risk of ovarian cancer by histotype, whether these associations have a causal foundation is not well defined. Harris and colleagues plan to address this gap in future work. When asked about the direction of this research going forward, Harris indicated that they will incorporate genetic-based analyses of single nucleotide polymorphisms (SNPs) into their work, stating that “The next steps for our research is to use Mendelian randomization using SNPs associated with PCOS as an instrumental variable to examine the association between PCOS and ovarian cancer.” The use of this approach will allow them to gain insight into “whether there is a causal relationship between PCOS and ovarian cancer subtypes,” says Harris.

Also contributing to this research from the Fred Hutch was Dr. Mary Anne Rossing.

This research was supported by the National Cancer Institute.

Harris HR, Babic A, Webb PM, Nagle CM, Jordan SJ, Risch HA, Rossing MA, Doherty JA, Goodman MT, Modugno F, Ness RB, Moysich KB, Kjaer SK, Hogdall E, Jensen A, Schildkraut JM, Berchuck A, Cramer DW, Bandera EV, Wentzensen N, Kotsopoulos J, Narod SA, Phelan CM, McLaughlin JR, Anton-Culver H, Ziogas A, Pearce CL, Wu AH, Terry KL. Polycystic ovary syndrome, oligomenorrhea, and risk of ovarian cancer histotypes: Evidence from the Ovarian Cancer Association Consortium. Cancer Epidemiology, Biomarkers and Prevention. 2017. doi: 10.1158/1055-9965.EPI-17-0655.