Though oral contraceptives (OCPs) have been available for approximately 60 years and have consistently been associated with a lower risk for subsequent ovarian and endometrial cancer across studies, data on the time-dependent, long-term correlations between OCP use and breast, ovarian, and endometrial cancer have been limited. This is partly due to the need for long-term follow-up to evaluate lifetime, OCP-related cancer risk in women who began taking OCPs early in their reproductive years, considering that the risk for breast, ovarian, and endometrial cancer peaks later in life. However, new data from an observational study of 256,661 women have demonstrated that OCPs can effectively lower a woman’s lifetime risk of developing both endometrial and ovarian cancer up to 30 to 35 years after OCP discontinuation.

Findings from the study, conducted by Karlsson et al, demonstrated a lower risk for ovarian and endometrial cancer among women who used OCPs at any point vs those who never did. Compared with individuals who never used OCPs, the odds ratio (OR) for ovarian cancer for former users was 0.72 (95% CI, 0.65-0.81; P <.001). When “never users” were contrasted with “former users” in an analysis of endometrial cancer risk, the OR was 0.68 (95% CI, 0.62-0.75; P <.001). Long-term contraceptive use (≥20 years) “was associated with substantially lower odds of ovarian [OR, 0.60; 95% CI, 0.48-0.75) and endometrial cancers [OR, 0.36; 95% CI, 0.28-0.45],” the study authors stated. By contrast with data from previous assessments of the association between OCP use and endometrial cancer, the results from this study suggest a longer empirical induction period for endometrial cancer, specifically.

Breast cancer, on the other hand, “appeared to occur in association with discontinuation of OCP use,” according to Karlsson et al, who observed an increased propensity for breast cancer development in those who stopped using OCPs. Notably, this heightened risk for breast cancer did not endure for more than 2 years after OCP discontinuation (HR, 1.55; 95% CI, 1.06-2.28). Although increased odds for breast cancer development were seen in women when follow-up was limited to those aged 55 years, this association did not apply for the full timespan.

Overall, lifetime breast cancer risk did not appear to be affected by OCP use, indicating that the association between OCP use and breast cancer is time- and age-dependent. No significant trend with duration of OCP use was seen for breast cancer.


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The retrospective study included 210,443 women who had used or were still using OCPs at the time of the evaluation (“ever users”), and 46,218 women who had never used OCPs (“never users”). The study population encompassed women from the UK Biobank (UKB) cohort who were born between 1939 and 1970 and had not been diagnosed with cancer at the time of OCP initiation. In the OCP user subset, the median patient age was 56 years; among those who had not used OCPs, the median patient age was 63 years. Of the 185,110 women with covariate data available for OCP duration analysis, the average duration was 10.7 years.

The hypothesis for why OCPs can offer long-term protection against endometrial and ovarian cancers, but not breast cancer, is because of the difference in how these cancers manifest, according to one of the study’s authors, Åsa Johansson. “The initiation of ovarian and endometrial cancers is linked to ovulation,” which OCPs directly prevent, said Johansson, an assistant professor of immunology, genetics, and pathology at Uppsala University. “It is plausible that the main effect of OCPs is to increase the growth rate of the breast tumor, and therefore, the [increased risk] effect can only be seen for a short period of time after the discontinuation of OCPs.”

Over the years, studies with narrower subject pools have asked similar questions about OCPs and cancer risk, but have yielded conflicting results. There are several reasons for this, but one of the hardest variables to pin down and adjust for in such studies is the fact that OCPs keep changing. The OCP pill first approved in the 1960s is dramatically different from the pill of 2021 in terms of chemical compounds and recommended dose, and OCPs that include both estrogen and progestin can be broken down into approximately 4 different generations based on their type of progesterone. Therefore, it is important not to extrapolate the findings of this study onto clinical outcomes for young women who are starting to take OCPs today. This current limitation, however, is only fueling future research for the Uppsala team.

“In our study, we did not even have information on the active compounds in the pills used by the women. However, we are now designing a follow up study where we will get access to the actual brand name, and active compounds of the OCPs,” Johansson said. “We hope that within a few years, will have results that are more useful for choosing the correct type of OCPs for different patients.”

Reference

Karlsson T, Johansson T, Höglund J, Ek WE, Johansson Å. Time-dependent effects of oral contraceptive use on breast, ovarian and endometrial cancers. Cancer Res. doi:10.1158/0008-5472.CAN-20-2476