Key Takeaways:
- A panel led by Sara Tolaney, MD, MPH, of Dana-Farber recommends modifying the clinical trial endpoints used to evaluate adjuvant therapy for early breast cancer.
- The proposal is aimed at improving a trial’s ability to detect a clinically meaningful effect of a drug designed to reduce cancer recurrences.
The majority of women diagnosed with breast cancer have early-stage disease that is confined to the breast or nearby lymph nodes and is effectively treated by lumpectomy or mastectomy. Nevertheless, small clusters of cancer cells remaining after surgery — called micrometastases — have the potential to spread at some point and cause a cancer recurrence, although the risk is generally low.
For this reason, many women treated for early breast cancer undergo post-operative or “adjuvant” therapy to reduce the risk of distant metastases and improve survival. Adjuvant treatment includes chemotherapy, radiation, or hormone-blocking drugs aimed at eradicating or blocking the growth of micrometastases. Over the past several decades, adjuvant therapy has helped lower the mortality rate for breast cancer, and many clinical trials are underway seeking to improve outcomes further and individualize therapy so that women at low risk of recurrence can be spared overtreatment.
Recently, a panel of experts co-led led by Dana-Farber’s Sara Tolaney, MD, MPH, and the American Society of Clinical Oncology’s director of biostatistics, Elizabeth Garrett-Mayer, PhD, recommended changes in the current benchmarks used in clinical trials to evaluate the effectiveness of adjuvant therapy. The choice of a primary endpoint is critical for detecting a treatment effect – that is, whether one drug reduces cancer recurrences more effectively than another drug. The endpoints currently in use were set in 2007 by a previous expert panel: the criteria are known as STEEP (Standardized Definitions for Efficacy Endpoints).
In a recommendation published in the Journal of Clinical Oncology, Tolaney, who is associate director of the Susan F. Smith Center for Women’s Cancers at Dana-Farber, and other members of the new expert panel suggest an additional end point, termed invasive breast cancer-free survival, as a better measure of a clinical trial therapy’s effectiveness when compared to current endpoints. Eric P. Winer, MD, chief of the division of Breast Oncology in the Susan F. Smith Center, is also a panel member.
Their recommendation, which they are calling STEEP 2.0, is based on a review of adjuvant therapy trials that revealed several of them deviated from the STEEP criteria. The researchers also carried out simulations showing that when a clinical trial looking at cancer recurrences included cancers that weren’t related to breast cancer, it could “increase the probability of incorrect inferences, can decrease power to detect clinically relevant efficacy effects, and may mask difference in recurrence rates, especially when recurrence rates are low.”
The challenge, Tolaney explains, is that “when you evaluate a new therapy in a trial where you don’t expect a lot of recurrences on that therapy, you need to be careful because counting another cancer or dying from something not related to the cancer makes it hard to interpret the data.”
“If I compared two drugs and in one of the groups people died from other causes, not related to their breast cancer, that will make it look like a drug isn’t working,” says Tolaney. “So, you couldn’t compare drug effectiveness across studies.”
The new adjuvant clinical trial endpoint — invasive breast cancer-free survival — proposed by Tolaney’s panel, excludes second non-breast primary cancers. In other words, if a patient develops an unrelated cancer, like a melanoma, it would not count as an event on the study.
“This endpoint should be considered for trials in which the toxicities of agents are well-known and where the risk of second primary cancer is small,” say the authors.
The expert group also provided endpoint recommendations for local therapy trials, low-risk populations, noninferiority trials, and trials incorporating patient-reported outcomes.