Breakthroughs in breast cancer don’t always mean the development of new drugs – they’re also made by optimizing currently available treatments. Researchers are re-examining some breast cancer treatments through dose optimization.
Maximum tolerated dose (MTD) has been the status quo in breast cancer treatment. Clinical trials determine the MTD by finding the highest drug or treatment amount (dose) with acceptable or tolerable side effects for participants. However, some individuals receiving treatments at MTD still experience significant side effects that may impact their quality of life, treatment adherence and outcomes.
The goal of dose optimization is to maximize treatment efficacy (treatment response) while minimizing treatment side effects. Evidence-based decision-making through clinical trials is needed to determine if we can lower the dose of some drugs, thereby minimizing side effects, without compromising the effectiveness of the drug.
In this episode of Breast Cancer Breakthroughs, we speak with Komen Scholar Alumni and Chief Medical Officer of the American Society of Clinical Oncology (ASCO), Julie Gralow, M.D., and Director of Breast Cancer Clinical Research at Dana-Farber Cancer Institute and Associate Professor of Medicine at Harvard Medical School, Erica Mayer, M.D., M.P.H., as they discuss clinical trials that are right-sizing breast cancer treatment by testing how different dosing may impact treatment adherence, quality of life and outcomes.
The TRADE Clinical Trial
One trial aimed at optimizing a dosing strategy is the TRADE trial, which was designed as a follow-up to a different trial called monarchE. Both trials involve abemaciclib, a CDK4/6 inhibitor. CDK4/6 inhibitors, such as abemaciclib, block the growth of cancer cells. Individuals taking these drugs may experience side effects, such as diarrhea, nausea and fatigue.
Results from the monarchE clinical trial showed that the addition of abemaciclib to hormone therapy, for patients with early-stage hormone receptor-positive/HER2-negative (HR-positive/HER2-negative) breast cancer, reduced the risk of recurrence for some patients at a high risk of breast cancer recurrence. In fact, abemaciclib is the first and only CDK4/6 inhibitor to demonstrate a survival benefit in high-risk early-stage breast cancer, based on recently reported data from monarchE. Results presented at the 2025 European Society for Medical Oncology (ESMO) meeting showed overall survival improvement of 15.8% for those receiving abemaciclib. It also continued to reduce the risk of recurrence at seven years.
Despite these favorable results, 18.5% of participants in the monarchE study discontinued abemaciclib early due to side effects, with the highest rate of discontinuation happening within the first month of treatment. This led to the TRADE clinical trial.
Mayer, said, “When we designed the [TRADE] study, what we were looking at was to see if this gradual introduction of the medication would improve a composite endpoint, which was looking at how many patients could reach the target dose, could maintain the target dose, and importantly, could stay on abemaciclib without discontinuation.”
Recently published results show that use of this dose escalation strategy resulted in more patients (93.9%) remaining on the therapy at 12 weeks.
“We hope that strategies like what we studied in TRADE, using these gradual introductions of medications, could also be extended to other oral therapies, some of our other novel cancer therapies that are in development that do have risks of side effects, so we can try to improve tolerability across the board,” said Mayer. Long-term follow-up data in the TRADE study is still needed to capture the full picture of how dose escalation impacts outcomes.
Dose Optimization from a Patient’s Perspective
Jamie Houghton was one of the participants in the monarchE trial that experienced side effects from abemaciclib, but she chose to stay on the trial. She shared, “I didn’t want to be removed from the study for not being able to tolerate the drug. [And] I was afraid the drug wasn’t going to be as effective if the dose was lowered.”
Jamie was fully vested in the clinical trial and wanted the best possible outcomes, so she delayed reporting the side effects to her doctor, fearing she might not get the same benefit. However, she eventually reported her side effects and was able to stay on the monarchE trial at a lower, more tolerable dose because there was sufficient evidence to show that a lower dose did not appear to compromise treatment effectiveness. “At that point, my doctor reassured me that there would be no change in my outcome by lowering the dose. I was so relieved,” said Jamie.
Jamie’s experience is just one that underscores the need for trials to optimize treatment dosing strategies. Helping patients stay on their medication by lowering the dose without impacting drug efficacy is essential, as it gives them the best chance to experience the full benefits of treatment. “We want treatments that work, and when doses need to be adjusted because of side effects, we need to be confident that even with a lower dose or a change in dose, the treatment is still going to be very effective [and] it’s going to have the same outcomes,” Jamie said.
Improving breast cancer care, providing better outcomes and offering optimized treatment can only happen with research and clinical trials. “These trials and research are about improving survival rates [and] improving how you feel throughout active treatment,” Jamie shared. “Each discovery gives us a longer life and tangible futures. We want more time with our families. And this is what the hope of every clinical trial is about — improving outcomes for patients.”
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