Menopause Live - IMS Updates

Date of release: 23 March, 2009

Postmenopausal hormone use and breast cancer risk

In a recently published investigation [1], Calle and colleagues selected a large cohort of postmenopausal US women (n = 67,754) from the 97,786 female participants of the prospective study Cancer Prevention Study II Nutrition Cohort. This cohort was established in 1982 by the American Cancer Society. Women aged 50–74 years were mailed self-administered questionnaires from 1992, with follow-up questionnaires being sent in 1997, 1999, 2001 and 2003. The follow-up period ended in June 2005, with an 89% response rate.

Of the respondents, 47.6% were never-users of hormone replacement therapy (HRT), 21.2% current estrogen-only users, 13% were current estrogen + progestogen users, 14.6% were former estrogen-only users and 3.6% were former estrogen + progestogen users. The incidence rates of breast cancer were significantly higher among current users of estrogen + progestogen compared with never-users for both ductal (relative risk (RR) 1.75; 95% confidence interval (CI) 1.53–2.01) and lobular cancer (RR 2.07; 95% CI 1.62–2.77). Risk increased within 2–3 years of usage and attenuated after this. Estrogen-only use was not associated with an overall increased risk of ductal carcinoma except in lean women (body mass index < 25 kg/m2) and in cancers diagnosed at the distant metastasis stage. The timing of mammographic screening was controlled for in the analysis.


Being a questionnaire survey, this ‘study’ suffers from the same limitations as the Million Women Survey (MWS) [2]. The main limitation is that there may have been a responder bias with potentially higher-risk women having returned their questionnaires. Although the cases of breast cancer were verified from the cancer registry/notes, there was no verification of the type/duration of HRT. The exclusion of women with HRT use of less than 1 year (n = 2823) and those with unknown type/duration of HRT (n = 7255) will have also biased the data towards increased risk. There is no analysis provided of risk associated with different types of estrogen and progestogen.
Despite the limitations of this study, it is interesting that the trend towards a lower risk of breast cancer with estrogen-alone therapy has been detected in this study as it has been in the previous studies such as the MWS (UK) [2], Women’s Health Initiative (WHI, USA) [3,4] and E3N–EPIC (France) [5]. This provides further evidence that estrogen-alone therapy is relatively neutral on the breast, with the small increase in risk being associated with estrogen + progestogen combinations. Unlike the WHI study, the increase in risk in this study was found to occur from year 3 onwards; this may reflect the demographics of the WHI population, particularly with regards to the high body mass index (mean of 30 kg/m2). Once again, it is unfortunate that there are no data on breast cancer risk by dose and subtype of estrogen and progestogen. Although the limited data provided by the MWS stated no difference with HRT subtypes (with erroneous mention of ethinylestradiol), the EPIC cohort did show a difference in risk according to progestogen subtype. 
All these studies represent practice primarily from the last decade. More recently, the dose of both estrogen and progestogen has been reduced and different (potentially safer) regimens have been instituted. Whilst it is not entirely clear whether dose and subtype of HRT will have a significant influence on breast cancer risk, one hopes that cohorts such as this are re-analyzed in 5–10 years time to determine whether change in practice is reflected in a reduction/neutralization of the small risk.


Nick Panay
Queen Charlottes & Chelsea Hospital, London, UK


  1. Calle EE, Feigelson HS, Hildebrand JS, Teras LR, Thun MJ, Rodriguez C. Postmenopausal hormone use and breast cancer associations differ by hormone regimen and histological subtypes. Cancer 2009;115:936-45. Published March 1, 2009.

  2. Beral V; Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2003;362:419-27.

  3. Writing Group for the Womens Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Womens Health Initiative randomized controlled trial. JAMA 2002;288:321-33.

  4. The Womens Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Womens Health Initiative randomized controlled trial. JAMA 2004;291:1701-12.

  5. Fournier A, Fabre A, Mesrine S, Boutron-Ruault MC, Berrino F, Clavel-Chapelon F. Use of different postmenopausal hormone therapies and risk of histology- and hormone receptor-defined invasive breast cancer. J Clin Oncol 2008;26:1260-8.