Research led by Oncode Investigator Jacco van Rheenen (Netherlands Cancer Institute) demonstrates that the menstrual cycle phase affects has impact on the effectiveness of chemotherapy by mice. This insight might pave the way for more personalized treatments, particularly for triple-negative breast cancer, improving outcomes for many women.

For decades, medical research has largely overlooked the role of female physiology, particularly the menstrual cycle, in disease treatment. Historically, researchers viewed the menstrual cycle as a confounding variable in drug trials. Along with concerns about the potential impact of drugs on reproduction, this led to the inclusion of fewer women in clinical studies.

Understanding the impact of the menstrual cycle

That approach has left a gap in our understanding of how women respond to treatments like chemotherapy, says Sabine Linn, internist-oncologist at the Netherlands Cancer Institute (NKI). “Women have historically been underrepresented in drug research, except when it comes to gender-specific diseases like breast cancer.” However, recent findings suggest that these hormonal fluctuations could be the key to more effective treatments.

Jacco van Rheenen recalls how this gap in understanding became apparent during his research. “We were studying how chemotherapy can make cancer cells more resistant and noticed that some mice responded differently. Two of my colleagues suggested that the estrous cycle — the mouse equivalent of the menstrual cycle — might play a role. Initially, I didn’t pay much attention to it, but after discussing the idea at home, my wife said, ‘Of course, the cycle could affect it!’ That was the lightbulb moment. Thanks to Oncode Institute’s base funding, we were able to instantly continue and investigate this new perspective.”

Chemotherapy sensitivity

The team’s earlier studies on mice revealed a remarkable fact: the menstrual cycle phase appears to influence the effect of chemotherapy targeting cancer cells. “We saw a phase of the cycle where chemotherapy killed more cancer cells,” says Van Rheenen. Even after chemotherapy had disrupted the cycle, the initial phase during which patients received treatment continued to influence the effectiveness of the therapy.

This observation is critical because it implies that timing the first dose of chemotherapy to a specific phase of the menstrual cycle could enhance its effectiveness. The menstrual cycle affects several physiological factors that could explain this sensitivity, says Van Rheenen. “The permeability of blood vessels is crucial for chemotherapy to reach the tumor and varies throughout the cycle.” Additionally, hormonal changes influence the immune system.

Nationwide study

This finding sparked the team’s interest in examining whether they could replicate these effects in human patients. To test this, the researchers turned to retrospective data from 55 women who had previously undergone chemotherapy. Preliminary analyses suggested that women who began chemotherapy during the first half of the cycle had better outcomes than those who started in the phase occurring after ovulation. But while these results were promising, they were not conclusive, says Van Rheenen. “The sample size was too small, and we didn’t design the study to answer this question.”

With support from Oncode Institute through its dedicated Clinical Proof of Concept (CPoC) program, the team is now launching a nationwide clinical study. This new CPoC study will specifically focus on women with triple-negative breast cancer (TNBC), a subtype of breast cancer that tends to be more aggressive and challenging to treat. For TNBC, chemotherapy is the primary treatment. The team aims to confirm that timing chemotherapy with the menstrual cycle can improve outcomes.

Implications

The study aims to enroll 100 women under 50 who have not yet started chemotherapy. Before administering treatment, the researchers will collect blood samples to determine each patient’s menstrual cycle phase. They will then monitor the effectiveness of the chemotherapy and analyze whether those who start treatment in the follicular phase experience better outcomes. “There won’t be any changes in the treatment itself,” adds Linn.

If this study confirms the hypothesis, the implications could be profound – the possibility of improving chemotherapy outcomes by simply adjusting the timing of the treatment. The approach wouldn’t require new drugs or complex interventions but only a better understanding of the timing of the therapy. But while the potential is exciting, Van Rheenen and Linn carefully manage expectations. “We need to see the study results before we can make any definitive claims,” says Linn. “But if the data supports what we’ve seen so far, this could be a relatively simple way to make chemotherapy more effective for many women.”

Oncode base research funding and cooperation

Van Rheenen notes that at the root of their finding, the layout of Oncode Institute played a key role. “The base funding allows us to pursue fundamental questions that pop up, without first having to write a separate grant proposal. That also goes toward funding the cPOC (Clinical Proof of Concept) study, financed by ZonMw and KWF. Thanks to their support, We can continue working on tangible results without any notable delays.”

The fact that Van Rheenen is part of Oncode Institute also secures a solid team, he says. “Our research is a team effort. We’re surrounded by experts, and we’re actively participating in Oncode’s Patient Engagement program, which allows us to highlight the subject from different perspectives. As a team, we’re able to study all relevant aspects – from microscopy to therapy – at the same time.” Cooperation is the magic word, adds Linn. “We’re also part of BOOG, the Dutch study center for clinical breast cancer research, in which all Dutch hospitals have a seat at the table. Also, their patient advocates safeguard the feasibility of the study design.”

Moving forward

Meanwhile, Van Rheenen and Linn’s research is not just about improving outcomes for breast cancer patients. It is also part of a broader movement toward more inclusive and gender-specific medical research. The fact that hormonal variability caused many studies to focus on men, ignoring these differences may be costing women the best possible care. “I hope this study will draw attention to the importance of including women in medical research, not just for breast cancer but across the board,” says Linn. “For a long time, we’ve known that hormones can influence the body’s response to treatment. It’s time for us to start taking that seriously.”

Van Rheenen echoes that sentiment. “There’s a lot we still don’t know about how the female body responds to drugs,” he says. “By taking these factors into account, we could potentially improve outcomes. Not just for breast cancer patients but for women with a wide range of conditions.”