The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).
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Bornes, L. et al. Nature. 637: 195–204. (2025).
doi: 10.1038/s41586-024-08276-1.
Summary of the findings
Summary of the findingsAlthough female physiology changes significantly during the menstrual cycle, these fluctuations are rarely considered in cancer treatment strategies. This study demonstrates that hormonal cycling can influence the sensitivity of breast cancer to neoadjuvant chemotherapy.
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In three breast cancer mouse models, reduced responses to chemotherapy were observed when treatment was initiated during the progesterone-high dioestrus phase, compared to the progesterone-low oestrus phase. This difference in sensitivity is linked to several systemic and localized changes associated with the oestrous cycle, including alterations in tumour cell proliferation, an increased presence of epithelial-to-mesenchymal transition (a known chemoresistance mechanism), and a reduced tumour vessel diameter, suggesting impaired drug delivery. In addition, fluctuations in macrophage abundance were observed, with elevated levels during the dioestrus phase. Notably, these different macrophage levels persisted even after disruption of the oestrous cycle due to the chemotherapy treatment, leading to lasting differences in the tumour microenvironments and sustained variation in treatment sensitivity across subsequent rounds of chemotherapy. Importantly, macrophage depletion during the dioestrus phase restored chemosensitivity to levels comparable to those during the oestrus phase.
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Overall, the findings identify the oestrous cycle as a critical infradian rhythm influencing tumour chemosensitivity, highlighting treatment timing as a potential factor to optimize therapeutic outcomes.
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Future impact
Retrospective analyses in two small cohorts of premenopausal patients with ER+ and triple-negative breast cancer suggest that these findings may translate to the human setting. Prospective clinical trials are needed to confirm this relationship and draw clinical conclusions. If validated, timing neoadjuvant chemotherapy to specific phases of the menstrual cycle could offer a low-cost strategy to enhance treatment efficacy. Beyond breast cancer, the results underscore the importance of accounting for cyclical physiological changes in the female body when designing and administering treatments, potentially improving therapeutic responses across a range of diseases and interventions.
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