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Breast Cancer Risk 'Similar' for Progesterone and Combined Contraceptives

A new analysis involving almost 10,000 women has shown that the added risk of breast cancer occurring under the age of 50 in association with oral contraceptive use was of similar magnitude regardless of whether a woman was taking a combined hormone pill or a progestogen-only preparation, in whatever form. 

Researchers from the study, published in PLOS Medicine, said: "This study provides important new evidence that current or recent use of progestogen-only contraceptives is associated with a slight increase in breast cancer risk, which does not appear to vary by mode of delivery, and is similar in magnitude to that associated with combined hormonal contraceptives."

Progestogen-Only Used Almost as Often as Combined Pills

The new research, from the Nuffield Department of Population Health at the University of Oxford, confirms previous studies showing the increase in breast cancer risk associated with the combined contraceptive pill, which declines in the years after stopping use. Until now, there have been limited data about the effect of progestogen-only contraceptives, even though their use has increased substantially in recent years. In 2020 there were almost as many prescriptions issued for oral progestogen-only contraceptives in England as for combined oral contraceptives.

At a briefing to the Science Media Centre, co-author Gillian Reeves, professor of statistical epidemiology and director of the Cancer Epidemiology Unit at Oxford Population Health, explained that whilst a slightly (20%) increased risk of breast cancer in current and recent users of oral contraceptives was known from a large meta-analysis in 1996, the risk seemed to decline once women stopped taking them.

However at that time, combined oral contraceptives were by far the most common type. The risks for progestogen-only contraceptives were "rather equivocal", because at that time not many women actually used them – so when the team tried to estimate the relative risk, the confidence intervals were "very wide". There was not enough evidence to be able to say reliably what was the risk of progestogen-only contraceptives. "And that was why we need to do this particular piece of research."

For their study the team assessed data from the Clinical Practice Research Datalink (CPRD) on 9498 women who had developed incident invasive breast cancer between age 20 and 49, diagnosed between 1996 and 2017. Their prospectively collected contraceptive histories were compared with those of 18,171 closely matched control women without breast cancer in a nested case-control study. 

Overall, 44% of the cases and 39% of control women had a prescription for a hormonal contraceptive an average of 3 years before diagnosis, around half of whom had last been prescribed a progestogen-only contraceptive. 

Conditional logistic regression was used to calculate odds ratios (ORs) for breast cancer by the hormonal contraceptive type last prescribed, controlled for age, GP practice, body mass index, number of recorded births, time since last birth, and alcohol intake.

Odds of Breast Cancer Similar Between Contraceptive Types

They reported that the odds of breast cancer were similarly and significantly raised, regardless of whether the contraceptive used was a combined oral preparation (OR=1.23, 95% CI 1.14 to 1.32, P<0.001), a progestogen-only oral preparation (OR= 1.26, 95% CI 1.16 to 1.37, P<0.001), an injected progestogen (OR= 1.25, 95% CI 1.07 to 1.45, P=0.004), or a progestogen releasing intra-uterine device (OR=1.32, 95% CI 1.17 to 1.49, P<0.001).

The increased risk declined after stopping use, so whereas with a last prescription within the previous year it was raised by 33% (OR=1.33, 95% CI 1.23 to 1.44), this dropped to 17% (OR=1.17, 95% CI 1.07 to 1.29) for last prescriptions 1-4 years ago, and to 15%, (OR=1.15, 95% CI 1.04 to 1.28) where a contraceptive had been last prescribed 5 or more years ago.

The researchers also searched MEDLINE and Embase and used fixed effects meta-analyses to combine the CPRD results with those from 12 previous observational studies (which included women from a wider age range) published between 01 January 1995 and 01 November 2022, to estimate absolute excess risks. 

'More Relevant' to Talk About Absolute Risk

This yielded significantly raised relative risks (RRs) for current or recent use of all forms of progestogen-only contraceptives: oral RR 1.29 (95% CI 1.21 to 1.37, heterogeneity χ25=6.7, P=0.2); injected RR 1.18 (95% CI 1.07 to 1.30, heterogeneity χ28=22.5, P=0.004); implanted RR 1.28 (95% CI 1.08 to 1.51, heterogeneity χ23=7.3, P=0.06), and intrauterine devices (IUD)s RR 1.21 (95% CI 1.14 to 1.28, heterogeneity χ24=7.9, P=0.1).

However, Prof Reeves told the SMC, rather than relative risks, in terms of public health messages, it's often more relevant to talk about absolute risk – "a 25% increase on a very low background risk of breast cancer is not going to cause much of an increase in absolute risk". Therefore, they estimated what the excess risk of breast cancer would be over a 15-year period after starting oral contraceptive use, given different patterns of use.

The team's results showed that after 5 years use of either oral combined or any form of progestogen-only contraceptive, the associated 15-year absolute excess incidence of breast cancer in high-income countries was estimated at 8 cases per 100,000 users at age 16-20 years and 265 cases per 100,000 users at age 35-39 years.

Absolute Risk Not Much Increased

So, Prof Reeves explained, by age 30, in nonusers of hormonal contraceptives, the absolute risk of breast cancer is about 0.8%, and this becomes 0.9% in women who use them. As women get older, their background risk increases – but again, "it doesn't amount to much of an increase". So, for example, in women who use contraceptives from age 25-29, over the 15 years after stopping, the risk rises from 0.5% in non-users to 0.57% in users. For women taking the drugs from age 35-39, the equivalent risk rises from 2.0% to 2.2%.

The researchers cautioned that, although their findings provided evidence about the short-term associations between hormonal contraceptives and breast cancer risk, they did not reveal longer-term associations, or the impact of total duration of contraceptive use on breast cancer.

Lead author Kirstin Pirie, a statistical programmer at Oxford Population Health, said: "The findings suggest that current or recent use of all types of progestogen-only contraceptives is associated with a slight increase in breast cancer risk, similar to that associated with use of combined oral contraceptives. Given that a person's underlying risk of developing breast cancer increases with advancing age, the absolute excess risk of breast cancer associated with either type of oral contraceptive will be smaller in women who use it at younger ages. These excess risks must, however, be viewed in the context of the well-established benefits of contraceptive use in women's reproductive years.”

Results 'Reassuring'

Commenting to the Science Media Centre, Professor Stephen Duffy of the Centre for Prevention, Detection and Diagnosis at Queen Mary University of London, said: "These results confirm those of the Collaborative Group on Hormonal Factors in Breast Cancer in the twentieth century, that oral contraceptives are associated with a small but significant increase in risk of breast cancer.

"In addition, they show that progestogen-only contraceptives have similar effects to those of combined contraceptives. At the time of the Collaborative Group meta-analysis, there was very little data on progestogen-only contraceptives and breast cancer. This study also confirms the reduction in the effect with increasing time since stopping using oral contraceptives. Ten years after stopping there was no excess risk associated with oral contraceptive use. The results are reassuring in that the effect is modest. The Collaborative Group in the past found that the enhanced risk was mainly in less severe disease."

Funding for the study was provided by the Cancer Epidemiology Unit by Cancer Research UK and the Medical Research Council. The authors declared no competing interests.