SIGNAL-ER-101: Signatera-guided CDK4/6 inhibitor therapy in breast cancer.

TPS648 Background: The monarchE and NATALEE trials showed that the addition of a CDK4/6 inhibitor (CDK4/6i; abemaciclib or ribociclib) to adjuvant endocrine therapy (ET) improves invasive disease-free survival (iDFS) in patients with ER+/HER2- high-risk and high-intermediate risk early breast cancer (eBC), including those with node-positive disease and select high-risk node negative tumors. However, the absolute benefit was modest (monarchE: 6.4% at 4 years; NATALEE: 3.3% at 3 years) suggesting that while a subset of patients derive benefit, many high-risk patients will not recur following ET alone. Improved strategies are needed to more precisely identify patients most likely to benefit from adjuvant CDK4/6i. Circulating tumor DNA (ctDNA) is an established biomarker of molecular residual disease (MRD) in eBC; its detection is associated with a significant risk of recurrence, and lack of detection with highly sensitive assays is associated with excellent prognosis. The SIGNAL-ER-101 trial evaluates whether tumor informed ctDNA detection during post-surgical adjuvant therapy can identify ER+/HER2- patients at highest risk of recurrence who are most likely to benefit from the addition of a CDK4/6i to standard-of-care (SOC) adjuvant ET and avoid overtreatment in patients who are likely to benefit with ET alone. Methods: SIGNAL-ER-101 is a Natera-sponsored prospective, open-label, single-arm, multicenter phase II treat-on-MRD study that aims to enroll 725 patients with intermediate-risk, stage II ER+/HER2- eBC who have undergone surgical resection and have no prior exposure to a CDK4/6i. Patients will be enrolled before receipt of any planned chemotherapy and/or radiation and within 6 months of initiating ET. Personalized, tumor-informed ctDNA testing will be performed using the Signatera Genome assay (Natera, Inc.), developed from archived tumor tissue and matched normal DNA to detect tumor-specific variants in plasma. Patients who are ctDNA-positive at baseline will be initiated on adjuvant CDK4/6i (ribociclib or abemaciclib) plus ET for a minimum of two years. Patients who are ctDNA-negative will receive ET alone and undergo MRD surveillance with ctDNA testing every three months. Upon detection of ctDNA during surveillance, patients will undergo staging scans to exclude distant metastatic disease prior to the addition of CDK4/6i therapy to ET. Selection of the specific CDK4/6i and ET will be at the discretion of the treating physician based on available SOC adjuvant therapy options. Patients will be followed for up to nine years to assess outcomes, including the study primary endpoint (iDFS) and key secondary endpoints (e.g., overall survival). The primary endpoint will be met if 4-year IDFS is non-inferior to that from NATALEE (3% non-inferiority margin: 93.9% vs 90.9%), aiming to evaluate whether ctDNA-guided treatment preserves efficacy while reducing over-treatment. Recruitment is expected to begin in March 2026. Clinical trial information: NCT07214532 .