Stopping HABITS.

Sir—The medical community has given almost unquestioning credence to the results of randomised clinical trials. This reliance has led to a discounting of the results of observational studies, animal trials, and basic biological data. Like all forms of investigation, the randomised trial is limited by study design (eg, selection of patients before randomisation, selection of biologically meaningful endpoints), and by differential adherence to the study protocol. The HABITS trial (Feb 7, p 453) was designed to assess the efficacy of hormone therapy given to women after treatment of breast cancer. Hormone therapy after breast cancer is becoming an increasingly relevant problem as more women survive breast cancer; there are, however, important issues to be taken into account. Because of early diagnosis, women have less advanced disease. The use of hormones has different implications for women with treated limited cancers compared with those with advanced disease. Further, women are increasingly concerned about the risks and benefits of hormone therapy, specifically the risk of breast cancer. Limitations in the design and interpretation of the HABITS trial have bearing on this issue and deserve mention. There seem to be significant differences between the two study groups (one randomised to hormone replacement therapy [HRT] and the other to no hormone therapy). There was a 24% greater incidence of positive nodes in the group receiving HRT (26% vs 21%); nodal status is perhaps the most accurate prognosticator of recurrence. 16% more women in the HRT group than the no hormone group had oestrogen-receptor-positive tumours (56% vs 48%), which is certainly an indicator of the ability to respond to hormone therapy. There was also a 9% greater incidence of breast-preserving surgery in the HRT group (62% vs 57%), perhaps indicating more aggressive treatment of the non-HRT group and explaining the increased number of local recurrences. The Research letter and accompanying Commentary lack explanation of the basic biological principles that underlie carcinogenesis and tumour growth. It is a well established biological principle that sex steroids stimulate the breast. Also, breast cancers are indolent in nature; it is estimated that the duration from initial cancer cell to mammographically detectable lesion is at least 5 years. A 2·1-year study can only have detected pre-existing tumours that were present but not clinically evident at the onset of the trial. Does this represent an increase in breast cancer or increased detection of existent tumour? What was the role of the oestrogen in magnifying the already present differences mentioned above? The endpoints must be more biologically sound. The ultimate endpoint of interest is mortality, and it is not surprising that there were a greater number of breast cancer deaths in the non-HRT group (four vs three). Although not significant, this discrepancy illustrates the limitations of the study. We cannot conclude from the current data whether hormone therapy increases breast cancer occurrence or early detection. A 5–10-year study is required to obtain data on new cancer occurrence and to measure survival. Such a long-term prospective trial is impractical. This randomised trial included nodepositive women who most would not treat and more women with a poor prognosis in the HRT group, and did not find a difference in the appropriate endpoint: mortality. We must be careful not to accept blindly the results of randomised clinical trials as the final word. Any such results should be viewed in the context of previous scientific reports and rely on sound biological principles. *Hugh S Taylor, Frederick Naftolin