Postmenopausal Hormone Therapy and the Risk of Breast Cancer
Postmenopausal Hormone Therapy and the Risk of Breast Cancer
Abstract & Commentary
Chen and colleagues from the University of Washington in Seattle conducted a case-control study of primary invasive breast cancer and postmenopausal hormone therapy. In this study, 705 cases were matched with 692 randomly selected age-matched controls. Hormone use was ascertained largely through a pharmacy database, but also by the means of a questionnaire. Current use was defined as at least 2 prescriptions during the 6 months prior to the diagnosis of breast cancer. Specific hormone products were not identified.
Chen et al concluded that "recent" long-term use of post-menopausal hormone therapy is associated with an increased risk of breast cancer, with a greater effect on lobular cancer. The risk of lobular breast cancer was greater with the current use of combination estrogen-progestin therapy (OR, 3.91; CI, 2.05-7.44). The difference between a sequential regimen and a continuous regimen was not statistically significant (Chen CL et al. JAMA. 2002;287:734-741).
Comment by Leon Speroff, MD
This case-control study was performed about as well as can be done and must be added to the list of positive reports on this subject in the last 2 years. Let’s first address some criticisms of the study, and then decide how this report should influence clinical practice.
The cases in this study were not identical when compared with the controls. They differed in a greater prevalence of a positive family history of breast cancer, a greater use of mammography, and more of the cases were nulliparous. Chen et al report that they adjusted for family history and mammography, as well as parity. However, there was no adjustment for the number of pregnancies (remember that the younger a woman is with a full-term pregnancy and the more pregnancies she has, the more protected she is against breast cancer). There was also no adjustment for alcohol intake and level of education (the information was not available)—known risk factors for breast cancer. Confounding variables such as these can influence results when the differences observed are not great. The strength of the associations reported in this study is consistently weak (odds ratios less than 2.0) except for the increased odds ratios for lobular cancer. But here the conclusions are based on small numbers. The 3- to 4-fold increased risks associated with recent long-term use of estrogen only were based on 8 cases, and that with long-term use of estrogen and progestin, 17 cases.
There were several observations that deserve special attention. There was no significant increase in the risk of breast cancer in past users of hormone therapy. The significant increase in risk was observed in estrogen receptor-positive tumors, not in receptor-negative tumors. The associations observed were greater with lobular breast cancer, known to be a more hormonally sensitive cancer. And the increased risk was significant only with localized cancers, not with metastatic cancers. These observations are consistent with the possibility that those studies finding an increased risk of breast cancer associated with postmenopausal hormone therapy are detecting effects of hormone exposure on pre-existing tumors. This is also consistent with the recent uniform reports that breast cancers detected in women who are using postmenopausal hormone therapy are better differentiated, lower grade, lower stage diseases; hence, they are associated with better outcomes, and surveillance/detection bias is not the only explanation for better survival.1-6 Lower grade tumors are present even when there is no difference in the prevalence of mammography comparing hormone users and nonusers, or when the data are adjusted for the method of detection.5-8 These biologic differences imply that hormone treatment promotes the growth of a malignant locus already in place, and it presents clinically with a more favorable biology. This conclusion is consistent with the fact that virtually all the positive studies find that any increase in risk disappears within 5 years of discontinuing hormone therapy, and tumors occur at an earlier stage and a younger age in women using hormone therapy.
Chen et al translate their numbers into estimates of attributable risks. They state that the increased risk of lobular cancer would increase the incidence from 23 per 100,000 women per year to 70, and because most breast cancer is ductal cancer (85% of the cases) the increase would be from 230 per 100,000 women per year to 349. Sometimes it is clinically helpful to present statistical ratios into actual numbers, but I am concerned about it here. This is an estimate based upon selected odds ratios in this study that might reflect confounding influences or the earlier detection of pre-existing tumors. To share these numbers with patients would inappropriately grant them a firmness they don’t deserve, and it would unnecessarily frighten patients.
Chen et al are guilty of a practice that I call "selective reporting." They point out that their results are consistent with previous studies and the collaborative re-analysis of the world’s date, but they unfairly neglect to mention the studies that did not find an increase in the risk of breast cancer with postmenopausal hormone therapy, including recent reports.9,10 There are more than 60 case-control and cohort studies in the literature, and the results are not uniform, but in fact negative results outnumber the positive reports.11
The conclusions in this new report are biologically plausible and the link with duration of use gives strength to the observations. However, where the case numbers are reasonably large the odds ratios are weak, and where the odds ratios are large, the case numbers are small. So, are we seeing a small increase in the risk of breast cancer associated with postmenopausal hormone therapy or are we seeing the effect of hormone exposure on pre-existing tumors? We don’t know the answer, an answer that can only be provided by a large, randomized clinical trial. Hopefully, the answer will emerge from the Women’s Health Initiative in 2006 and the European WISDOM trial in 2011. Until then, another case-control study and another report from a cohort study will bring no further clarity to this issue.
I think it is appropriate to point out to patients that we have more than 60 studies with no uniform, consistent conclusion—an indication that the association is either due to confounding problems or it is a small one. It is also time to bring the message to our patients, that users of postmenopausal hormone therapy who develop breast cancer have a reduced risk of dying of breast cancer, because their tumors are better differentiated, lower stage, lower grade disease.
Table
Risk of Breast Cancer Associated With Lifetime and Recent 5-Year HRT by Type of Breast Cancer
Cases ControlsOdds Ratio & CI
Current Use Estrogen Only (E-O) 132 111 1.17 (0.85-1.80) Current Use, E-P* 112 74 1.49 (1.04-2.12) Recent 5-Year UseE-O for 60 mos.
35 22 1.84 (1.04-3.27)Estrogen-Progestin for 57+ mos.
83 56 1.70 (1.15-2.50)Sequential E-P, 36+ mos.
58 40 1.82 (1.03-2.55)Continuous E-P, 20+ mos.
17 11 1.85 (0.81-4.21)
LOBULAR
Cases/Controls, OR (CI)
Cases/Controls, OR (CI) Current Use
E-O
21/111; 1.98 (1.04-3.78) 111/111; 1.08 (0.78-1.50)E-P
26/74; 3.91 (2.05-7.44) 86/74; 1.25 (0.86-1.61)Recent 5-Year Use
E-O, 60 mos.
8/22; 3.68 (1.46-9.25) 27/22; 1.60 (0.87-2.93)E-P, 57+ mos.
17/56; 3.07 (1.55-6.06) 65/56; 1.52 (1.01-2.29)Seq. E-P, 36+ mos.
10/40; 2.64 (1.14-8.08) 48/40; 1.49 (0.93-2.39)Cont. E-P, 11+ mos.
8/19; 6.07 (2.13-17.3) 18/19; 1.19 (0.58-2.43)* — Estrogen-Progestin
Points to be Made with Patients
- Some epidemiologic case-control and cohort studies conclude that long-term (5 or more years) of current use of postmenopausal hormone therapy is associated with a slight increase in the risk of breast cancer. This conclusion might be due to confounding biases, particularly detection/surveillance bias;
- All epidemiologic studies fail to find an increased risk of breast cancer associated with short-term (less than 5 years) use or past use of postmenopausal hormone therapy;
- The epidemiologic data do not agree that the addition of a progestin to the treatment regimen increases the risk observed in individual studies;
- The epidemiologic data indicate that a positive family history of breast cancer should not be a contraindication to the use of postmenopausal hormone therapy;
- Women who develop breast cancer while using postmenopausal hormone therapy have a reduced risk of dying from breast cancer. This is because of 2 factors: 1) increased surveillance and early detection; and 2) acceleration of tumor growth so that tumors appear at a less virulent and aggressive stage.
Dr. Speroff is Professor of Obstetrics and Gynecology, Oregon Health Sciences University, Portland.
References
1. Bonnier P, et al. Int J Cancer. 1998;79: 278-282.
2. LaCroix AZ, Burke W. Lancet. 1997;350: 1042-1043.
3. Holli K, et al. J Clin Oncol. 1998;16: 3115-120.
4. O’Connor IF, et al. J Clin Pathol. 1998; 51:935-938.
5. Bilimoria MM, et al. Ann Surg Oncol. 1999;6:200-207.
6. Cobleigh MA, et al. JAMA. 1999;281:1528-1530.
7. Schairer C, et al. J Natl Cancer Inst. 1999;91:264-270.
8. Jernström H, et al. Br J Cancer. 1999;80:1453-1458.
9. Persson I, et al. Cancer Causes Control. 1999;10: 253-260.
10. Moorman PG, et al. Am J Public Health. 2000;90: 966-971.
11. Bush TL, et al. Obstet Gynecol. 2001;98:498-508.
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