Background
Oral contraceptive use has been associated with a higher breast cancer risk; however,
evidence for the associations between different oral contraceptive formulations and
breast cancer risk, especially by disease subtype, is limited.
Objective
This study aimed to evaluate the associations between oral contraceptive use by formulation
and breast cancer risk by disease subtype.
Study Design
This prospective cohort study included 113,187 women from the Nurses’ Health Study
II with recalled information on oral contraceptive usage from 13 years of age to baseline
(1989) and updated data on usage until 2009 collected via biennial questionnaires.
A total of 5799 breast cancer cases were identified until the end of 2017. Multivariable
Cox proportional hazards models estimated hazard ratios and 95% confidence intervals
for the associations between oral contraceptive use and breast cancer risk overall
and by estrogen and progesterone receptor and human epidermal growth factor receptor
2 status. Oral contraceptive use was evaluated by status of use (current, former,
and never), duration of and time since last use independently and cross-classified,
and formulation (ie, estrogen and progestin type).
Results
Current oral contraceptive use was associated with a higher risk for invasive breast
cancer (hazard ratio, 1.31; 95% confidence interval, 1.09–1.58) when compared with
never use, with stronger associations observed for longer durations of current use
(>5 years: hazard ratio, 1.56; 95% confidence interval, 1.23–1.99; ≤5 years: hazard
ratio, 1.19; 95% confidence interval, 0.95–1.49). Among former users with >5 years
since cessation, the risk was similar to that of never users (eg, >5 to 10 years since
cessation: hazard ratio, 0.99; 95% confidence interval, 0.88–1.11). Associations did
not differ significantly by tumor subtype. In analyses by formulation, current use
of formulations containing levonorgestrel in triphasic (hazard ratio, 2.83; 95% confidence
interval, 1.98–4.03) and extended cycle regimens (hazard ratio, 3.49; 95% confidence
interval, 1.28–9.53) and norgestrel in monophasic regimens (hazard ratio, 1.91; 95%
confidence interval, 1.19–3.06), all combined with ethinyl estradiol, was associated
with a higher breast cancer risk when compared with never oral contraceptive use.
No association was observed for current use of the other progestin types evaluated
(norethindrone, norethindrone acetate, ethynodiol diacetate, desogestrel, norgestimate,
and drospirenone), however, sample sizes were relatively small for some of the subgroups,
limiting these analyses.
Conclusion
Current oral contraceptive use was associated with a higher risk for invasive breast
cancer regardless of disease subtype, however, the risk in former users was comparable
with never users 5 years after cessation. In analyses by progestin type, associations
were observed for select formulations containing levonorgestrel and norgestrel. Assessment
of the associations for newer progestin types (desogestrel, norgestimate, drospirenone)
was limited by sample size, and further research on more recently introduced progestins
is warranted.
Key words
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Article Info
Publication History
Published online: December 15, 2021
Accepted:
December 8,
2021
Received in revised form:
November 30,
2021
Received:
September 14,
2021
Footnotes
N.A.B., R.K., and R.T.F. report no potential conflict of interest. A.L.S. reports receiving grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development , National Institutes of Health (NIH), and funding support from the Marriott Family Foundations. A.H.E., B.R., R.M.T., and S.S.T. report receiving grants from the National Cancer Institute , NIH, while the study was being conducted.
This project received funding from the NIH (under grant numbers R01 CA50385 and U01 CA176726) and the Breast Cancer Research Foundation . The funding sources had no role in the design, analysis, and reporting of the study. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Cite this article as: Burchardt NA, Eliassen AH, Shafrir AL, et al. Oral contraceptive use by formulation and breast cancer risk by subtype in the Nurses’ Health Study II: a prospective cohort study. Am J Obstet Gynecol 2022;226:821.e1-26.
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