Timing of breast cancer surgery during the menstrual cycle‑is there an optimal time of the month? (Review)

Abstract

An intriguing relationship between menstrual cycle phase at the time of breast cancer surgery and clinical outcomes was first proposed in the late 1980s. Despite a number of clinical studies conducted to address this, as well as meta-analyses and systematic reviews, there remains significant controversy surrounding the effect of menstrual cycle phase at time of surgery on the prognosis of premenopausal breast cancer. While some studies have suggested that surgery performed during the luteal phase results in the most favourable outcome, other studies report the follicular phase is more favourable, and others show no association. Given the conflicting results, there remains insufficient evidence to determine whether there is an optimal time of the month to perform surgery. This issue has dogged breast cancer surgery for decades; knowledge of an optimal time of the month to conduct surgery would be a simple approach to improving patient outcomes. This review explores the potential biological mechanisms through which the hormonal milieu might contribute to differences in prognosis, and why clinical findings are so variable. It is concluded that a significant problem with current clinical research is the lack of insight from mechanistic studies. While there are a number of plausible biological mechanisms that could lead to altered survival, supporting evidence is limited. There are also variable approaches to defining the menstrual cycle phase and hormone receptor status of the tumour and few studies controlled for prognostic factors such as tumour size and stage, or addressed the impact of adjuvant treatments. Elucidation of the specific confounding factors, as well as biological mechanistic pathways that could explain the potential relationship between timing of surgery and survival, will greatly assist in designing robust well-controlled prospective clinical studies to evaluate this paradigm.

A common allele increases endometrial Wnt4 expression, with antagonistic implications for pregnancy, reproductive cancers, and endometriosis

“…These effects have been suggested to be due to cycle-phase-dependent fluctuation in angiogenic factors (e.g. VEGF) and factors promoting epithelial-to-mesenchymal transition, downstream of estrogen 63 . The results of the present study suggest that vulnerability to this effect may be genetically enhanced by the alternate allele at the locus rs3820282.…”

Oncotype DX Recurrence Score in premenopausal women

“…Some have hypothesized that the tumor microenvironment may be significantly influenced by menstrual cycling, such that tumors may have less metastatic potential when removed at certain points of the menstrual cycle. 44 This has been the focus of a number of clinical studies since the 1980s, though multiple systematic reviews have determined that there is insufficient evidence to recommend surgery during one phase of the menstrual cycle over another. 45 – 47 These inconclusive findings may be in part due to inherent challenges in studying the menstrual cycle, which include disagreement in the establishment of menstrual cycle windows, variability in hormone profiles between women, and the paucity of prospective randomized controlled trials.…”

“… 45 – 47 These inconclusive findings may be in part due to inherent challenges in studying the menstrual cycle, which include disagreement in the establishment of menstrual cycle windows, variability in hormone profiles between women, and the paucity of prospective randomized controlled trials. 44 …”

“…[45][46][47] These inconclusive findings may be in part due to inherent challenges in studying the menstrual cycle, which include disagreement in the establishment of menstrual cycle windows, variability in hormone profiles between women, and the paucity of prospective randomized controlled trials. 44 There are also data demonstrating that prognostic biomarkers may be influenced by the menstrual cycle. Horimoto et al published an observational study of premenopausal patients with breast cancer showing that expression of Ki67, a marker of proliferation, fluctuates during different phases of the menstrual cycle, with higher mean expression seen in the luteal phase.…”

A SNP affects Wnt4 expression in endometrial stroma, with antagonistic implications for pregnancy, endometriosis and reproductive cancers

“…Such menstrual phasedependent cancer invasibility has previously been suggested with respect to the propensity towards post-resection metastasis in breast cancer 79 . These effects have been suggested to be due to cycle-phase-dependent fluctuation in angiogenic factors (e.g., VEGF) and factors promoting epithelial-to-mesenchymal transition, downstream of estrogen 80 . The results of the present study suggest that vulnerability to this effect may be genetically enhanced by the alternate allele at the locus rs3820282.…”