Menopause Live - IMS Updates

Date of release: 30 May, 2011

Breast cancer risk and the interval between menopause and starting HT

In the January issue of the Journal of the National Cancer Institute, Valerie Beral and co-workers report an update on the association between use of hormone therapy (HT) and breast cancer risk in the Million Women Study cohort [1]. After extended follow-up, more postmenopausal women (1,129,025 vs. 828,923) and more incident breast cancers (15,759 vs. 7140) were included in the new analysis than in the previous report from 2003 [2]. As before, a greater risk for current users of estrogen + progestogen (E+P) therapy than for estrogen-only therapy was found: relative risk (RR) 1.96, 95% confidence interval (CI) 1.90–2.02, average duration of use 6.8 years; RR 1.38, 95% CI 1.32–1.44, average duration of use 8.0 years, respectively. The updated data still point to an excessive risk in users of tibolone (RR 1.38, 95% CI 1.25–1.52, average duration of use 7.0 years). There was a rapid decline in risk after cessation of therapy: for 2 up to 14 years after discontinuation of use, the risk was similar to that in never-users (RR 0.99, 95% CI 0.93–1.05).


The main focus in this new analysis was on the influence of timing on breast cancer risk for the different treatment regimens. Relative risks were found to be higher if therapy was started before or soon after menopause than in the case of a longer gap (p < 0.001). Among current users of estrogen-only therapy, there was little or no increase in risk if use began 5 years or more after menopause (RR 1.05, 95% CI 0.89–1.24), whereas risk was increased if use began before or within 5 years after menopause (RR 1.43, 95% CI 1.35–1.51). A similar pattern was seen for users of E+P (RR 1.53, 95% CI 1.38–1.70 vs. RR 2.04, 95% CI 1.95–2.14). Figures for tibolone showed a similar tendency but did not reach statistical significance. A total of 6267 women diagnosed with breast cancer had started treatment with either estrogen-only therapy or E+P therapy and only 515 of those did so more than 5 years after menopause. The average time between menopause and start of HT in this subgroup was 10.3 years for estrogen-only therapy and 9.3 years for E+P therapy. 


The authors conclude that there was substantial heterogeneity in breast cancer  risk among current users of HT. Risks were greater for E+P than for estrogen-only use and if treatment started at around the time of menopause than later.


Some of the findings in the present report confirm what is already well known, e.g. that E+P poses a greater risk for breast cancer than estrogen-alone and that risk increases with duration of treatment. However, this extended follow-up and new analysis of the database also indicate that the interval between menopause and start of HT may have a modifying effect on breast cancer risk.
There is growing evidence that a ‘gap time’ between menopause and start of therapy is a biologically important factor for breast cancer risk. The findings here are in agreement with a previous re-analysis of the WHI data by Prentice and colleagues [3] and with reports from the large French E3N observational study [4]. In the WHI, women starting estrogen-only therapy more than 5 years after menopause (long gap time) had a significant reduction in breast cancer risk (RR 0.58, 95% CI 0.36–0.93). Such risk reduction was not seen in women starting it immediately after menopause (RR 1.12, 95% CI 0.39–3.21). Similarly, in the E3N cohort, when treatment with both estrogen-only or in combination with progestogen started after a short time gap, it was associated with a higher risk than after a longer time gap.
The biological mechanisms behind the apparent association of breast cancer risk and the gap time are incompletely understood but some possible explanations are discussed in the recently published, meticulous and extensive document by the Endocrine Society entitled ‘Scientific Statement on Postmenopausal Hormone Therapy’ [5]. This paper is recommended for reading for everyone with an interest in the field. One tentative explanation of a reduced breast cancer risk in long gap-time patients could be estrogen-induced apoptosis. Breast cancer cells deprived of estrogen in long-term cell cultures (analogous to a long gap time) seem to adapt and to become sensitized to pro-apoptotic effects of estrogen. A proportion of women starting HT may harbor a ‘reservoir’ of occult and undetected tumors. Hormones and, in particular, progestogens may activate stem cells and promote growth of such lesions and allow clinical detection [4–6]. A pro-apoptotic effect of estrogen could reduce the cell content of occult pre-existing tumors and reduce the rate of clinical cancer detection later. HT started within a short gap time to menopause might also delay age-related lobular involution. This involution is associated with a decreased breast cancer risk and has been found to accelerate at around 50 years of age [7]. It could be that treatment close to menopause would allow a reservoir of breast cells to remain active and hormone-sensitive. In contrast, a later start of therapy would give time for involution and inactivation of such lesions.
The Million Women cohort is a very large and important database. The estimated risk figures for different treatments from this material tend to be somewhat higher than in other similar studies, e.g. the equally large General Practitioners Research Database [8]. Over the years, some questions about possible confounding have been raised [9,10]. Women were invited to enroll when they were scheduled for mammography and those on HT, with anxiety of/or already aware of breast lumps could have been most motivated to participate. The finding of an increased risk for users of tibolone is in conflict with both the General Practitioners Research Database [8] and data from randomized clinical trials [5,11]. However, the main new finding in the present report seems well established. The timing of initiation of HT relative to that of menopause appears to be an important modifier of associated risk of breast cancer. Further work is needed to elucidate the biological mechanisms behind this phenomenon.


Bo von Schoultz
Professor Emeritus, Department of Obstetrics and Gynecology, Karolinska Hospital, Stockholm, Sweden


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

  3. Prentice RL, Chlebowski RT, Stefanick ML, et al. Conjugated equine estrogens and breast cancer risk in the Womens Health Initiative clinical trial and observational study. Am J Epidemiol 2008;167:1407-15.

  4. Fournier A, Mesrine S, Boutron-Ruault MC, et al. Estrogen-progestagen menopausal hormone therapy and breast cancer: does delay from menopause onset to treatment initiation influence risk? J Clin Oncol 2009;27:5138-43.

  5. Santen RJ, Allred DC, Ardoin SP, et al. Postmenopausal hormone therapy: an Endocrine Society scientific statement. J Clin Endocrinol Metab 2010;95(Suppl 1):S1-66.

  6. Horwitz KB, Sartorius CA. Progestins in hormone replacement therapies reactivate cancer stem cells in women with preexisting breast cancers: a hypothesis. J Clin Endocrinol Metab 2008;93:3295-8.

  7. Milanese TR, Hartmann LC, Sellers TA, et al. Age-related lobular involution and risk of breast cancer. J Natl Cancer Inst 2006;98:1600-7.

  8. Opatrny L, DellAniello S, Assoulines S, et al. Hormone replacement therapy use and variations in the risk of breast cancer. BJOG 2008;115:169-75.

  9. Shapiro S. The Million Woman Study: potential biases do not allow uncritical acceptance of the data. Climacteric 2004;7:3-7.

  10. Nelson HD, Fu R, Griffin JC, et al. Systemic review: comparative effectiveness of medications to reduce risk of breast cancer. Ann Intern Med 2009;151:703-15.

  11. Cummings SR, Ettinger B, Delmas PD, et al. The effects of tibolone in older postmenopausal women. N Engl J Med 2008;359:697-708.