28 October, 2013
"In conclusion, there are now several studies showing no increase in the risk of breast cancer in obese women. This study is also consistent with a previous large one and both show that HRT does not increase breast cancer risk in women with low breast density."
Hou and colleagues have addressed the question of different levels of risk of breast cancer under hormone replacement therapy (HRT) according to race, body mass index (BMI) and breast density . Using 1,642,824 screening mammograms, they analyzed 9300 breast cancer cases in postmenopausal women ≥ 45 years from the Breast Cancer Surveillance Consortium (BCSC), a longitudinal registry of mammography screening in the United States.
The aim was to investigate whether low- and high-risk groups could be identified. The BCSC was established in 1994 and collected participant characteristics (age group, mammographic breast density, race/ethnicity, BMI, HRT use, and diagnosis of cancer) at the time of each mammography screening examination. Breast density data were collected from the technician and radiologist at the time of mammography. Among the postmenopausal women, 44.4% reported being HRT users, 41.6% reported being HRT non-users, and the status of 14.0% was unknown.
Data on the duration of HRT use were not available and many data for risk factors were missing. Thus imputation (the process of replacing missing data with substituted values) was used to calculate the risks. The associations between HRT use and breast cancer risk were mostly positive in women aged 50 years and older, yet there was no statistically significant association for younger women aged 45–49 years.
The association was positive in non-Hispanic whites (odds ratio (OR) 1.21; 95% confidence interval (CI) 1.14–1.28), Asian/Pacific Islanders (OR 1.58; 95% CI 1.18–2.11), and Hispanics (OR 1.35; 95% CI 1.09–1.67), but not in non-Hispanic blacks (OR 0.91; 95% CI 0.72–1.14). HRT was more strongly associated with breast cancer risk in leaner women than overweight women or obese women. Furthermore, mostly high breast density (heterogeneously dense and extremely dense) was associated with an increase in breast cancer risk. The association between HRT use and breast cancer risk was strongest for underweight/normal weight women who had extremely dense breasts (adjusted OR 1.49; 95% CI 1.21–1.83).
Overweight and obese women with less dense breasts had no increased risk of breast cancer with HRT (adjusted OR 0.96–1.03). Overweight women with higher breast density had a significant increased risk. This was not the case for the obese women.
This study investigated BMI and breast density together regarding their effect modification on HRT and breast cancer risk. It was shown in several observational studies (including the Million Women Study  and the reanalysis from the Collaborative Group on Hormonal Factors in Breast Cancer ) that obese women had no further increase in the risk of breast cancer with HRT. It is usually believed that obese women are less sensitive to the exogenous source of circulating hormones introduced by HRT because they already produce hormones through aromatization. In most obese women, more fat accumulates in their breasts.
It can thus be considered that obese women with dense breasts should be more at risk than leaner women with dense breasts. This is not what is shown in the current study. It is the second study following that by Kerlikowske and colleagues  which demonstrates that HRT is not associated with an increased risk for breast cancer in women with low breast density. These observations suggest that stratifying the indications for HRT on populations at lower risk should help to decrease the risk of breast cancer attributable to HRT. The question of no increased risk in black women requires further investigation.
This study has some limitations which preclude definitive conclusions: only 12.0% of the observations included all the variables. The duration and types of HRT were not known. In the WHI trial, breast cancer risk and BMI interacted only in the estrogen-alone users. Black women are usually more often overweight/obese and hysterectomized and thus using estrogen-alone therapy.
In conclusion, there are now several studies showing no increase in the risk of breast cancer in obese women. This study is also consistent with a previous large one and both show that HRT does not increase breast cancer risk in women with low breast density.
Unité de Gynécologie-Endocrinienne, APHP, Port Royal Cochin Hospital and University Paris Descartes, France
1. Hou N, Hong S, Wang W, Olopade OI, Dignam JJ, Huo D. Hormone replacement therapy and breast cancer: heterogeneous risks by race, weight, and breast density. J Natl Cancer Inst 2013 Sept 3. Epub ahead of print
2. Beral V; Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2003;362:419–27.
3. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 1997;350:1047–59.
4. Kerlikowske K, Cook AJ, Buist DS, et al. Breast cancer risk by breast density, menopause, and postmenopausal hormone therapy use. J Clin Oncol 2010;28:3830–7.