Phase-primed chemotherapy to improve chemotherapy efficacy in metastatic breast cancer patients

Systemic chemotherapy is often the treatment of choice for breast cancer (BC). However, the response to chemotherapy is highly heterogeneous and difficult to predict, even for tumors of the same molecular and pathological subtype. We identified menstrual cycle stage as a determinant of chemotherapy efficacy in primary BC. The clinical implications of this finding are very concrete: by simply timing the first chemotherapy treatment to the follicular phase, a better response rate can be achieved. If this simple intervention could also improve chemotherapy response in the metastatic setting, this would provide a much larger group of pre-menopausal women with metastatic BC, with very limited treatment options, a way of improving the chemotherapy response. The aim of this proposal is to explore whether the menstrual cycle stage impacts on chemotherapy response in metastatic BC. Obtaining preliminary data in the metastatic setting will open up many new opportunities to explore phase-priming of chemotherapy, not only in metastatic BC, but also for other (metastatic) cancers in females. With these data, we can speed up clinical validation of our findings and initiate prospective trials in a much larger group of pre-menopausal BC patients with a pressing need for improved and effective therapies.

Approximately 35% of breast cancer cases are detected in premenopausal women, and the majority of these patients are treated with systemic chemotherapy. The response to chemotherapy is difficult to predict and often highly heterogeneous between patients. We discovered that one of the factors influencing chemotherapy response is the stage of the menstrual cycle. In a retrospective patient cohort, we identified that chemotherapy administered in the phase directly after menstruation (the follicular phase) led to an overall better response compared to patients treated after ovulation, during the luteal phase.

Using our preclinical mouse models of breast cancer, we found that this superior response to chemotherapy also resulted in extended survival of the mice. With the support of the Beug Foundation, we extended our study to include models of metastatic breast cancer. In these experiments, we found that the metastatic load in the lungs was significantly reduced in mice that began chemotherapy during the estrus stage (the equivalent of the follicular phase in humans), compared to those that started treatment during the diestrus stage. Furthermore, at the mechanistic level, we found that several systemic and local factors influenced by the menstrual cycle stage contributed to this effect. These included differences in vascularization, macrophage influx, and the number of cancer cells in a mesenchymal state. 

Thanks to the Beug Foundation award, we now have sufficient preliminary data to initiate several prospective clinical studies, where we aim to validate our findings in a larger patient cohort, including different breast cancer subtypes. Ultimately, we hope that our findings will lead to improved treatment outcomes for all young women with breast cancer.

colinda.scheele@kuleuven.be

www.scheelelab.sites.vib.be