The current standard of care recommends two or three years of an adjuvant CDK4/6 inhibitor in combination with endocrine therapy for patients with intermediate-risk, hormone receptor (HR) positive, HER2 negative, early stage breast cancer. This is despite the fact that only ~3% of eligible patients derive benefit, over 60% of patients experience serious adverse events,1-2 and the U.S. retail costs can be over $400,000 for a full course of treatment. Meanwhile, data presented at SABCS 2025 from the PALLAS trial show that HR+ breast cancer patients who tested MRD-negative with Signatera had excellent long-term outcomes, with >95% distant recurrence-free interval at 5 years. This suggests that MRD-negative patients can safely defer CDK4/6 inhibition with no impact to clinical outcomes, with the provision that it be added if and when MRD is detected on serial testing using a TOMR (Treatment on MRD) approach.

SIGNAL-ER 101 plans to enroll approximately 725 patients across 50 sites in the United States. Patients who test MRD-positive will receive endocrine therapy plus CDK4/6 inhibitors, while those who test MRD-negative (the vast majority of patients) will receive endocrine therapy alone with quarterly Signatera monitoring. Patients who become MRD-positive during surveillance will be eligible to initiate CDK4/6 inhibition at that time, consistent with the TOMR approach.

"Many women with this type and stage of breast cancer are overtreated, which can have a profound impact on their quality of life," said Minetta Liu, M.D., chief medical officer, oncology and early cancer detection at Natera. "SIGNAL-ER 101 is a key part of our evidence generation roadmap, to support Signatera-guided treatment optimization without compromising the survival benefit from CDK4/6 inhibitors. This approach also allows patients to get the most effective treatment when Signatera shows it is necessary."

SIGNAL-ER 101 is the first in a series of innovative Natera-sponsored SIGNAL trials across multiple cancer types, designed to demonstrate that MRD-negative patients may be able to delay or defer treatment. There are many instances of overtreatment in cancer. This concept has already been studied in the IMvigor011 trial where MRD-negative patients with muscle-invasive bladder cancer achieved 97% overall survival at 2 years without any adjuvant therapy, and in the GALAXY and CALGB/SWOG 80702 trials, where MRD-negative patients with colorectal cancer saw no clinical benefit from adjuvant chemotherapy and celecoxib, respectively.