Syncing Cancer Therapy with the Menstrual Cycle May Boost Outcomes

In 2016, Colinda Scheele, a cancer biologist at Catholic University Leuven, was studying how chemotherapy affects breast cancer cells in mice. However, she observed an inconsistency: Some cell subtypes did not always respond to the drugs.

“We were thinking what could cause all this heterogeneity [where] one time we see a response, another time we don't,” recalled Scheele. That is when her team, which was predominantly female, had an epiphany. “We thought, could it be that the menstrual cycle, [what] we call estrous cycle in mice, is maybe causing all these inconclusive results?”

Now, research by Scheele and her collaborators at the Netherlands Cancer Institute and Leiden University Medical Center reveals that the reproductive cycle in mice influences their sensitivity to chemotherapy.¹ The team observed similar findings when analyzing patient data. Their findings, published in Nature, suggest that accounting for hormonal variation may be crucial in optimizing cancer treatment outcomes.

“I was very impressed by the paper and very excited about the findings,” said Wendy Ingman, a breast and women’s health researcher at the University of Adelaide who was not involved in the study. “It really opens up a whole new avenue of research which could lead to changes in how we treat breast cancer.”

While humans experience about a month-long menstrual cycle, female mice undergo a four to five day estrous cycle, driven by hormonal variations that regulate fertile and non-fertile phases.² These hormonal fluctuations cause tissue remodeling in the uterus and breasts. In the mammary glands, cells proliferate during the low-progesterone estrus stage in preparation for pregnancy and die during the high-progesterone diestrus stage in the absence of pregnancy.

Scheele and her team explored whether the estrous cycle influenced breast tumor cell behavior, potentially explaining the inconsistent results they had observed. By tracking fluorescently-labeled tumor cells in a mouse model of breast cancer, they found that tumor cell populations expanded during the estrus stage and regressed during the diestrus stage.

A yin-yang concept to show how ovarian hormone levels fluctuate during the reproductive cycle and affect breast cancer and its response to treatment. — Ying and Yang: The menstrual cycle influences breast cancer and its response to treatment.
Laura Bornes, Netherlands Cancer Institute

The researchers hypothesized that this cyclic growth pattern could influence sensitivity to chemotherapeutics, as these drugs are designed to target rapidly proliferating cells.³ Consistent with this idea, tumors treated during the highly proliferative estrus stage exhibited more cell death than those treated in the diestrus stage.

To test the effect of successive treatments, the researchers administered repeated doses of chemotherapy to mice. Although the cancer treatment disrupted most of the mice’s estrous cycles, their responses to the drugs varied depending on where they were in their cycle when they received their first dose. Mice treated during the estrus stage showed greater tumor cell death, fewer lung metastases, and higher survival rates compared to those treated during the diestrus stage.

These findings are novel, said Ingman, who added, “We do multiple doses of chemotherapy and if you’re trying to time a treatment to the menstrual cycle, you’re only going to be able to do it for the first one,” noting that many women stop cycling when they're undergoing treatment.

Next, the researchers investigated the basis of this cycle-dependent drug response. Factors influencing chemosensitivity include the tumor’s immune landscape and the transition of epithelial cells into more invasive mesenchymal cells.^4,5 The team observed that during the diestrus stage, tumors contained more mesenchymal cells and macrophages, both of which are associated with drug resistance. Depleting macrophages resulted in enhanced tumor shrinkage, even when treatment was initiated during the diestrus stage.

To assess the clinical relevance of their findings, the researchers analyzed historical data collected from patients treated for breast cancer. They determined the menstrual cycle stage at the start of chemotherapy by measuring progesterone levels in stored serum samples from patients’ first treatment visits. They found that individuals who received their first dose of chemotherapy during a low-progesterone stage had a better response compared to those treated during a high-progesterone stage.

Scheele said that it was not unexpected that the reproductive cycle influences chemotherapy response but added “It was very surprising to us when we discovered that this is really overlooked and not even thought of. I hope that the findings will open the eyes of other researchers.”

“[The] menstrual cycle has really been very neglected [in research],” agreed Ingman. “But this study really demonstrates why we need to study it and why we need a better understanding [of it].” However, she cautioned that more work is needed to establish the relevance of the findings in a clinical setting.

Given that they tested the connection retrospectively in existing data from a small number of people, Scheele cautioned, “We want to be a bit careful there with the translation or the possible impact that it may have in the clinic.” The team is now designing a prospective study to investigate how timing therapy to the menstrual cycle may influence treatment outcomes, she added. “If [the results] indeed hold true in our prospective study, I really hope that the cycle will be taken into account.”

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