Contemporary breast cancer treatment research has focused on systemic postoperative adjuvant treatment and the elimination of established micrometastases. An alternative approach addresses the potential for seeding at the time of primary surgery. Several retrospective reports have suggested that the hormonal milieu during lumpectomy or mastectomy impacts on the likelihood of tumor cell shedding and implantation at distant sites.
Senie and Tenser comprehensively review the literature on the menstrual timing of breast cancer surgery and have, I believe, accurately summarized the state of the art with their call for “collaborative multidisciplinary studies” to help bring order to a confusing area. As they point out, the clinical applicability of published studies of menstrual timing remains limited by the inherent faults of retrospective analysis, conflicting results, the lack of uniformity in divisions of the menstrual cycle, and the variability over which surgical procedure was considered definitive for the purposes of the study.
Source of the Controversy
Hrushesky et al initiated the controversy in 1989 when they reported a fourfold increase in the risk of recurrence and death from breast cancer in premenopausal women who underwent resection during the perimenstrual period (days 0-6 and 21-36 of the menstrual cycle), compared to those who had surgery during the periovulatory period (days 7-20). These findings were based on a retrospective review of 41 cases. Although this division could not be confirmed by others, several retrospective reviews have suggested an adverse outcome when surgery is performed during periods of unopposed estrogen stimulation (days 3-12 in some series, 0-14 in others). The bulk of the disadvantage was seen in node-positive patients.
Several other studies failed to confirm this finding or have found opposite results. Most recently, the largest study to date involved 1,870 patients with small (0.3 to 3.5 cm) breast cancers; in 1,279 of these women, the beginning of the last menstrual period could be ascertained. A statistically significant advantage in disease-free survival was noted for the group undergoing surgery during the luteal phase (last menstrual period 15 to 36 days before surgery) compared with those operated on during the follicular phase (last menstrual period 0 to 14 days before surgery), with the advantage seemingly confined to node-positive patients. No survival data were included in the report, which served mainly to emphasize the need for prospective studies that provide definitive guidance for patients and surgeons.
Biological Plausibility of the Timing Hypothesis
A major contribution of this review is to focus on the biological plausibility of the timing hypothesis. The authors note that the mitotic activity of breast tissue peaks during the luteal phase, which might suggest a disadvantage for performing surgery during this period. They speculate, however, that the heightened proliferation is more than offset by a higher rate of programmed cell death (apoptosis), which may, in turn, inhibit metastasis. The authors suggest the possibility that natural killer cell activity might be suppressed during the follicular phase, although if that were true, why would we not see a disadvantage to follicular phase surgery for other malignant tumors, such as colon cancer? Finally, they imply that unopposed estrogen during the follicular phase might decrease cell-to-cell adhesion and thereby promote tumor cell dissemination at the time of surgery.
Other plausible mechanisms include the possibility that follicle-stimulating hormone (FSH) and estradiol, the levels of which peak just before ovulation and which promote the synthesis within ovarian follicles of insulin-like growth factors known as breast cancer mitogens, might induce the synthesis of these mitogens within the breast cancer itself and thereby promote metastasis. In addition, cycle dependency of the production of such substances as basic fibroblast growth factor, a promoter of neovascularization, might encourage metastasis. Perhaps, even hormonal surges promote stromal invasion. Ovulation is aided by the action of FSH, luteinizing hormone, and progesterone, which lead to generation of collagenase. Increased concentrations of collagenase within tumors might engender adhesive interactions with extracellular matrix proteins that allow for invasion.
Prospective Trials Planned
Two large-scale prospective trials now planned, one in Europe, one in the United States, may allow us to ground such speculation in reliable data. As the authors point out, given the variability in cycle length both for any individual and between individuals, it is probably best to define menstrual cycle phase through some agreed upon level of serum progesterone. These measurements, in turn, raise the hope that an optimal hormonal environment for breast cancer surgery might be created pharmacologically, rather than having to deal with the logistical difficulties of trying to plan surgery to coincide with a favorable point in a woman’s cycle.
1. Hrushensky WJM, Bluming AZ, Gruber SA, et al: Menstrual influence on surgical cure of breast cancer. Lancet 2:52, 1989.
2. Veronesi U, Luini A, Mariano L, et al: Effect of menstrual phase on surgical treatment of breast cancer. Lancet 343:1415-1457, 1994.
3. Randal J: Does the timing of breast cancer surgery affect survival? J Natl Cancer Inst 89(7):473-477, 1997.