The influence of menstrual cycle phase on surgical treatment of primary breast cancer: have we made any progress over the past 13 years?

The development and clinical course of breast cancer is modulated by a variety of endocrine influences. This observation led to the development of endocrine interventions, the first successful modality of targeted anticancer therapy. Today, it is widely recognized that endocrine interventions represent the most effective approaches to reducing the odds of recurrence and death for hormone-responsive primary breast cancer and for patients at risk for developing this disease (1–3). These accomplishments required the work of multiple laboratory-based and clinical investigators, the participation of tens of thousands of patients in prospective randomized trials, and the better part of the past three decades. During this time, a number of hypotheses were tested and, although several were proved with evidence, others were disproved, also with evidence. In 1989, Hrushesky et al. (4) proposed that the timing of surgical interventions for breast cancer had substantial influence on the outcome of such interventions. Specifically, they proposed that premenopausal patients with breast cancer who were operated on during the perimenstrual period of the menstrual cycle had higher disease-free and overall survival rates than did patients who were operated on during other phases of the cycle. This conclusion was based on a retrospective analysis of 41 patients. Subsequently, a number of reports addressed this hypothesis, reports that eventually became part of a meta-analysis (5). The results of these studies were, at best, heterogeneous. Some (6,7) supported the hypothesis described by Hrushesky et al. (4), some (8,9) found no influence of the phase of the menstrual cycle on outcome, and one (10) found the opposite results: that patients who received their surgical therapy during the follicular phase did better that those who received their surgical therapy during the luteal phase. Why such major differences in results? The most likely answer would point to differences in methodology. All studies designed to assess the efficacy of breast surgery in relation to the timing of the intervention during the menstrual cycle were retrospective. The phases of the menstrual cycle were determined arbitrarily on the basis of available information on the date of the last menstrual cycle before the surgical intervention. Even the definitions of follicular and luteal phases were made on the basis of different criteria in different institutions. Retrospective collection of data is fraught with inaccuracy, especially when the data being collected are not related to the primary objective of a clinical trial or research project. Furthermore, determining the timing of ovulation on the basis of the date of initiation of the previous menstrual cycle is notoriously inaccurate, as shown by a number of unwanted pregnancies resulting from avoiding intercourse during the periovulatory days as the major method of contraception. In fact, the follicular phase of the cycle is the less reliable or constant phase of the menstrual cycle, and assuming that ovulation will occur 15 days after the first day of menses often leads to major miscalculations. There are also statistical flaws when arbitrary definitions of the phases of the human menstrual cycle are adopted for analytical purposes. These have been eloquently reviewed by McGuire et al. (11) in an earlier issue of the Journal. Ten years ago, McGuire et al. (11) pointed to methodologic deficiencies of reports addressing the timing of breast surgical interventions during the menstrual cycle. Changing the definition of duration of a phase of the menstrual cycle by just a couple of days shifts substantial numbers of patients from the follicular to the luteal phase or vice versa. The only recognized and accurate method to identify the date of ovulation and therefore define the start and end of the follicular phase is by measuring plasma hormone levels. By such measurements, physicians would know whether the patient is in the follicular or the luteal phase of the menstrual cycle. Any other method leads to guessing—not a very reliable scientific method. The article by Love et al. (12) in this issue of the Journal adds fuel to this fire. In their article (12), the authors describe the results of a retrospective, unplanned analysis to determine whether the timing of surgery during the menstrual cycle influences outcome. One of the strengths of their work is that the analysis is based on a prospective randomized trial and, therefore, the treatments administered were prospectively determined and controlled. In addition, estrogen receptor assays were performed on the tumors of many of the patients, which helped to identify the group of patients most likely to be affected by this hypothesis. The results are of interest because, on the one hand, they appear to refute the hypothesis proposed by Hrushesky et al. (4) 13 years ago. According to Love et al. (12), in premenopausal patients treated with mastectomy or lumpectomy, the timing of surgery in relation to the phases of the menstrual cycle had no effect on outcome. On the other hand, Love et al. (12) report a secondary, unexpected result of their analysis: that the timing of ovarian ablation and initiation of tamoxifen therapy in relation to the phase of the menstrual cycle appeared to have a substantial effect on outcome. Premenopausal patients who had their breast surgery and ovarian ablation during the luteal phase