HABITS Redux
Abstract & Commentary
By Leon Speroff, MD, Editor, Professor of Obstetrics and Gynecology, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.
Synopsis: The Swedish HABITS trial reported after 4 years of follow-up about a two-fold increase in recurrent breast cancer in breast cancer survivors who used hormone therapy.
Source: Holmberg L, et al. J Natl Can Inst. 2008;100:475-482.
HABITS was a randomized but not placebo-controlled trial in which hormone therapy was compared to management without hormones in women with menopausal symptoms who had been previously treated for Stage I or Stage II breast cancer.1 Concomitant tamoxifen treatment was allowed in the HABITS patients but not aromatase inhibiters. Hormone therapy consisted of the variety of products and methods on the Swedish market, but not tibolone. Most of the treated women used products with the relatively high dose of 2 mg estradiol. After 2 years, the women were asked to stop hormone therapy. In the initial HABITS report, the reported hazard ratio for new breast cancer in the treated group was 1.8 (CI=1.03-3.1).2 In the current report, after 4 years of follow-up of 442 women, there were 39 cases of new breast cancer in women using hormone therapy compared with 17 in the non-treated group for a hazard ratio of 2.4 (CI=1.3-4.2).
Commentary
HABITS (Hormonal Replacement After Breast Cancer—Is It Safe) was initiated in May 1997, recruiting patients from multiple centers in Sweden. A similar trial was initiated in Stockholm. Because recruitment was slower than anticipated, the two trials agreed in February 2002 to pool their patients and to use a joint monitoring and safety committee. In October 2003 the safety committee recommended that the trial be discontinued because there were 26 women in the treated group with new breast cancers compared with 7 in the non-treated group. The HABITS trial was terminated in December 2003. Confronted with this outcome, the Stockholm investigators decided to cancel their trial as well even though the hazard ratio in the Stockholm patients was 0.82 (CI = 0.35-1.9).
The treated and non-treated groups of women in HABITS were not "pure," by this I mean that there were differences in characteristics and behaviors. More of the women in the treated group had hormone receptor-positive cancers (62.3%) compared with the non-treated group (54.5%). Eleven women in the treated group never received hormones; 43 in the non-treated group did receive hormones. There was a very wide range of exposure times, ranging from 0 to 80 months. About one-third of the women who received hormones changed products during the study. The method of analysis of the HABITS data was intent-to-treat, and thus the impact of these differences cannot be ascertained.
Analysis of the new breast cancers (either local recurrences or contralateral cancers) indicated statistically significant increases only in hormone receptor-positive cancers. However, when adjusted for use of hormone therapy before diagnosis of the original breast cancer, use of tamoxifen, and hormone receptor status, the hazard ratio was 2.2 with a CI of 1.0-5.1). By definition this is close, but not statistically significant. The authors flatly report this hazard ratio as statistically significant!! There were no differences in the rate of distant metastases or mortality comparing the two groups of patients.
Conclusions regarding the role of tamoxifen are impossible because the numbers are too small to allow this subgroup analysis. The authors also attempted to compare sequential estrogen-progestin regimens and estrogen-only treatment to continuous-combined preparations, but again the numbers were too small to allow meaningful conclusions (although the attempt found no differences in risk).
The Stockholm trial reported in 2005, after a median follow-up of 4.1 years, 11 new breast cancers in the treated arm and 13 new breast cancers in the non-treated arm.3 Why the difference between the Stockholm trial and HABITS? The HABITS investigators suggest that their patients had more node-positive disease, and thus "probably" had more women with subclinical disease that would be stimulated by hormone therapy. Another possibility was more protection with higher tamoxifen use in the Stockholm trial, although the HABITS trial could detect no impact of tamoxifen. The HABITS investigators believe that another possible explanation was the greater use of norethindrone and norethindrone acetate in HABITS compared with the use of medroxyprogesterone acetate in Stockholm. All of these explanations are speculations; the difference between the two trials remains and calls into question the reliability and accuracy of the data.
If we assume the HABITS data are accurate, the early and rapid increase and the preponderance of local events are consistent with an impact of hormone therapy on preexisting cancer tissue. The cancellation of HABITS and the Stockholm trials made it impossible for the English and Italian trials to continue recruitment in their trials, and they were also cancelled. Thus we have no on-going clinical trials of estrogen-progestin therapy in breast cancer survivors. In my view the data from the Swedish trials are confusing and not definitive. Although this report makes clinical decision-making more difficult, breast cancer survivors willing to accept an unknown risk deserve support if they wish to use hormone therapy.
I can't end this discussion without commenting on the editorial that accompanies the HABITS report. The editorial is written by Kathleen Pritchard from the Division of Medical Oncology, the Sunnybrook Odette Cancer Centre in Toronto.4 Here are some words and statements from the editorial. ". . . the HABITS trial suggests quite definitively that there is a statistically significantly increased risk of recurrence in women given HRT . . . the Stockholm study does not show as clear an effect. . . the harmful side effects of HRT have finally been clearly demonstrated. . . This trial, as well, has contradicted 30 years of dogma concerning the use of HRT. . . virtually all other dogma concerning the use of HRT in healthy women has been turned topsy-turvy. . . " There is not a single criticism of the HABITS study in the editorial.
My goodness, where has Pritchard been the last few years? She cites the Women's Health Initiative (WHI) results indicating an increase in dementia and an increase in coronary heart disease, and asks, "Could we have been more wrong?" Of course, by now we know that the only increase in dementia occurred in women 75 years of age and older, that coronary heart disease occurred only in women 70 years of age and older, that in fact the WHI agrees with 30 years of research when it is analyzed correctly. Pritchard goes on to say, "It seems ridiculous to continue to impute effects from observational studies when the conduct of a relatively small randomized controlled clinical trial could clearly provide a definitive answer to the question under study." I wish the late Trudy Bush was still here to remind Pritchard that every epidemiologic study is only one view of the truth and that it takes many studies to come close to seeing the truth. Pritchard's failure to recognize the limitations and problems within the available clinical trials is just as egregious as accepting a single observational study as the truth.
References
- Holmberg L, et al. On behalf of the HABITS Study Group, Increased risk of recurrence after hormone replacement therapy in breast cancer survivors. J Natl Cancer Inst. 2008;100:475-482.
- Anderson L, for the HABITS Steering and Data Monitoring Committees, HABITS (Hormonal Replacement Therapy After Breast Cancer—Is It Safe?), a randomized comparison: trial stopped. Lancet. 2004;363:453-455.
- von Schoulz E, Rutqvist LE. Stockholm Breast Cancer Study Group. Menopausal hormone therapy after breast cancer: the Stockholm Randomized Trial. J Natl Cancer Inst. 2005;97:533-535.
- Pritchard KI. Should observational studies be a thing of the past? J Natl Can Inst. 2008;100:451-452.
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