R. R. Love, D. L. DeMets, University of Wisconsin, Madison; D. C. Allred, Baylor College of Medicine, Waco, TX.
Correspondence to: Richard R. Love, M.D., M.S., Medical Oncology Section, Department of Medicine, University of Wisconsin School of Medicine, 610 Walnut St., 256 WARF, Madison, WI 53705 (e-mail: rrlove{at}facstaff.wisc.edu).
Although we appreciate Dr. Hortobagyis (1) editorial interest in our study (2), and in particular his call for a prospective randomized trial addressing the hypothesis we have proposed, that adjuvant luteal phase surgical oophorectomy is statistically significantly more effective than follicular phase oophorectomy, we believe he has mischaracterized the nature and results of our study.
We reported secondary analyses of data obtained prospectively in a trial designed to investigate the impact of adjuvant oophorectomy and tamoxifen in premenopausal women unselected for estrogen receptor status (2,3). In such circumstances, definitions of the particular variables and populations of interest are critical, and the values obtained from statistical significance testing must be considered nominal. The major analyses and four patient samples in our study included 80% of trial participants (and as noted in the last sentence of the "Results" section, an analysis including 86% of trial participants gave equivalent results) (2). It is not true, as stated by Hortobagyi (1), that the ". . . information about last menstrual period was considered reliable by the authors in only 79% of the patients enrolled in the original clinical trial." We reported in Fig. 1 of our paper (2) that we had data on the date of the last menstrual period for 700 of the 709 entered patients. We excluded 89 patients from the main analysis because, for these patients, the date of their last menstrual period applied to the cycle prior to their mastectomy before they entered the study, and with that last menstrual period date only and no cycle length data for individual patients, we could not reliably estimate the last menstrual period date before the ooophorectomy. The 46 additional patients excluded from the main study samples had reliable and interpretable last menstrual period data. It is also not true that the last menstrual period data were ". . . elicited initially only with the purpose of determining whether the patient was premenopausal." (1) because we planned to look at that very subject in our report. Thus, our results are not from an "unplanned, retrospective subset analysis" (1).
The four main study groups were defined by randomization and a prerandomization study variable (LMP [last menstrual period]), which should prevent them from selection bias and, as we would expect, by major prognostic criteria, these groups were statistically similar [see Table 1 in (2)].Contrary to the thrust of Hortobagyis further discussion regarding our definitions of follicular and luteal phase groups (1), our definitions actually biased against the results we found: very few women in the main samples, who were defined as being in the follicular phase (14 days from last menstrual period) could conceivably be in the luteal phase, whereas it is very likely that the luteal phase groups had many patients who were actually in the follicular phase or anovulatory.
Although we agree with Hortobagyi (1) that there have been no convincing data to date that hormone receptor-negative patients respond to hormonal therapy interventions, our inclusion of these types of patients in our analyses should again dilute and mask any oophorectomy benefit. Our inclusion of 80% (or 86%) of all participants in our trial in the main analyses is a strength of our approach, not a weakness, and belies the charge of "subset" analysis. In particular in this regard, we can assure Dr. Hortobagyi that our study sample did not suffer from "suboptimal estrogen receptor assessment" (3). Finally, data in a previous publication [see Table 1 in (2)], combined with the results of our multivariate analyses, give no hint of subtle confounding variables.
The direct implications of our results seem worthy of more words than we and Hortobagyi have used heretofore. Our findings suggest a broader hypothesis that in breast cancer, and perhaps in other solid tumors, manipulable host conditions at the time of primary surgery are critical in determining micrometastatic growth and death. Additionally, it would seem that our results suggest hypotheses for breast cancer prevention, screening, and diagnosis. Is prophylactic oophorectomy for breast cancer in BRCA mutation carriers more effective if done during in the luteal phase of the menstrual cycle (4,5)? Is mammography screening in premenopausal women associated with an excess of early deaths because women are often screened while in the follicular phase to get a better image (6)? Should postmenopausal women on combined hormone replacement therapy have suspicious breast changes biopsied during the time they are taking progesterone?
In the end, there is a whole wealth of data showing luteal/follicular phase differences in biologic parameters that offer the possibility that there is a biologic explanation for our findings (7), and we agree strongly with Hortobagyi (1) that we must pursue that and rigorous study of our hypothesis expeditiously.
REFERENCES
1 Hortobagyi GN. The influence of menstrual cycle phase on surgical treatment of primary breast cancer: have we made any progress over the past 13 years? J Natl Cancer Inst 2002;94:6413.
2 Love RR, Duc NB, Dinh NV, Shen TZ, Havighurst TC, Allred DC, et al. Mastectomy and oophorectomy by menstrual cycle phase in women with operable breast cancer. J Natl Cancer Inst 2002;94:6629.
3 Love RR, Duc NB, Allred DC, Binh NC, Dinh NV, Kha NN, et al. Oophorectomy and tamoxifen adjuvant therapy in premenopausal Vietnamese and Chinese women with operable breast cancer. J Clin Oncol 2002;20:255966.
4 Rebbeck TR, Lynch HT, Neuhausen SL, Narod SA, vant Veer L, Garber JE, et al. Prophylatic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 2002;346:161622.
5 Haber D. Prophylatic oophorectomy to reduce the risk of ovarian and breast cancer in carriers of BRCA mutations. N Engl J Med 2002;346:16602.
6 Retsky M, Demicheli R, Hrushesky W. Breast cancer screening for women aged 4049 years: screening may not be the benign process usually thought. J Natl Cancer Inst 2001;93:1572.
7 Hagen AA, Hrushesky WJ. Menstrual timing of breast cancer surgery. Am J Surg 1998;175:24561.[Medline]
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