Underlying Breast Cancer Risk and Menopausal Hormone Therapy

Richard J. Santen; Daniel F. Heitjan; Anne Gompel; Mary Ann Lumsden; JoAnn V. Pinkerton; Susan R. Davis; Cynthia A. Stuenkel


J Clin Endocrinol Metab. 2020;105(6) 

In This Article

Abstract and Introduction


The recent Collaborative Group on Hormonal Factors in Breast Cancer (CGHFBC) publication calculated the attributable risk of breast cancer from use of estrogen alone and estrogen plus a synthetic progestogen for less than 5 to 15 or more years of use. This CGHFB report calculated attributable risk based on their findings of relative risk from pooled data from 58 studies. Notably, neither the CGHFBC nor other previous studies have examined the effect of underlying risk of breast cancer on attributable risk. This omission prompted us to determine the magnitude of the effect of underlying risk on attributable risk in this perspective. Meaningful communication of the potential risk of menopausal hormonal therapy requires providing women with the estimated risk above their existing underlying risk (ie, attributable risk). Therefore, we have estimated attributable risks from the data published by the CGHFBC, taking into account varying degrees of underlying risk. Based on the Endocrine Society Guideline on Menopausal Hormone Therapy (MHT), we divided groups into 3 categories of risk: low (1.5%), intermediate (3.0%), and high (6.0%) underlying risk of breast cancer over 5 years. In women taking estrogen plus a synthetic progestogen for 5 to 9 years, the attributable risks of MHT increased from 12, to 42, to 85 additional women per 1000 in the low-, intermediate-, and high-risk groups, respectively. The attributable risks for estrogen alone were lower but also increased based on underlying risk. Notably, the attributable risks were amplified with duration of MHT use, which increased both relative risk and breast cancer incidence.


The Endocrine Society Guidelines for use of menopausal hormone therapy (MHT) recommend that the underlying risk of breast cancer be considered in making individual patient recommendations (Because the terms underlying risk, attributable risk, relative risk, and excess risk have specific definitions which are not clearly understood by many, the authors have included a detailed discussion of these terms and their practical meaning in the appendix) (Table 1).[1,2] However, neither the Endocrine Society guidelines nor other previous publications have calculated the magnitude of the effect of underlying risk of breast cancer on attributable risk.[3–7] As a current example, the Collaborative Group on Hormonal Factors in Breast Cancer (CGHFBC) recently published a large review that summarized relative (RR) and attributable risks of breast cancer based on observational data from 58 studies but did not consider underlying risk.[8] The attributable risk in the CGHFBC study was based on comparing the incidence of breast cancer in patients using MHT with that of controls but underlying risk was not used in these calculations. This omission makes it impossible to know how to apply those risks to a specific patient trying to decide to take hormone therapy for relief of menopausal symptoms.

This perspective emphasizes the importance of underlying risk by calculating the magnitude of its effect on attributable risk of developing breast cancer. A key, underappreciated principle that prompted this perspective is that the RR of breast cancer associated with MHT use does not differ based on underlying risk of breast cancer. This issue was examined in a Women's Health Initiative (WHI) trial report.[9] that examined the RR of MHT in women as a function of underlying risk and specifically risks of 1.25%, 1.25 to 1.75%, and more than 1.75% over 5 years.[9] Notably, the RRs of 1.19 (95% CI 0.88–1.63), 1.20 (95% CI 1.00–1.69), and 1.25 (95% CI 0.99–1.69) did not differ among these respective underlying risk groups.

The new analysis in this perspective modeled data in subsets of women at low, intermediate, and high risk of developing breast cancer. We found that the level of underlying risk, although not affecting RR, does markedly influence the attributable risk, which is what patients and clinicians need to know. As an example, when comparing women at low, intermediate, and high underlying risks of breast cancer and taking estrogen plus synthetic progestogen (E + SP) (The CGHFBC study included patients primarily using synthetic progestogens (SP) and only a very small number taking progesterone. For this reason, the term SP is used) for 7.5 years, the attributable risks at 7.5 years increased from 12, to 42, to 85 additional women per 1000, respectively. Our analyses also indicated that women in the low-risk category taking MHT for less than 5 years have a relatively low attributable risk compared to women in higher-risk groups. These data indicate clinicians should inform patients that MHT is safer from a breast cancer perspective in women at low underlying risk of breast cancer. Our analyses reported here provide strong support for the recommendations in the Endocrine Society Clinical Practice Guideline to consider underlying risk in making recommendations to patients.[2]

The CGHFBC study, although not examining underlying risk, reported several clinically important points applicable to this perspective. Both forms of MHT, E, and E + SP (but not vaginal estrogen), increased risk as a function of duration of use with the attributable risk rising with use from less than 5 years to 15 or more years. Two factors resulted in this amplification of risk: i) the increased incidence of breast cancer over time in women not taking MHT, and ii) the increased RR with duration of use of MHT. Specifically, the RR for E + SP increased from 1.20 (95% CI 1.01–1.43) for less than 1 year; to 1.60 (95% CI 1.52–1.69) for 1 to 4 years; to 1.97 (95% CI 1.90–2.04) for 5 to 9 years; to 2.26 (95% CI 2.16–2.36) for 10 to 14 years; and to 2.51 (95% CI 2.35–2.68) for 15 or more years.[8] The same phenomenon was observed for E but with lesser magnitude, with an RR increasing from 1.17 (95% CI 1.10–1.26) for 1 to 4 years to 1.58 (95% CI 1.51–1.66) with 15 or more years of use.[8] The CGHFBC study applied these RR data to calculate the attributable risk. From these data, the extrapolated attributable risk for E + SP when starting at age 50 years and continuing for 10 years was 29 excess cancers per 1000 women calculated from the 6.3% incidence with no MHT and 9.2% with E + SP at the 10-year interval.[8] However, the CGHFBC data were taken from women of average underlying risk; thus, they would likely overestimate attributable risk for women in the lowest underlying risk category and conversely underestimate risk in women at the highest underlying risk.

To provide a more in-depth analysis of the CGHFBC data, 2 important questions were addressed in this perspective: i) What was the magnitude of the effect of the underlying risk of breast cancer on the attributable risk imparted by MHT? and ii) Was the safety of MHT greater in women at low underlying risk of breast cancer? The answers to these questions are critically important when discussing the initiation of MHT in postmenopausal women.