AUSTIN, Texas — May 27, 2026
Natera, Inc. announced the enrollment of the first patients in the SIGNAL-ER 101 study, a prospective interventional clinical trial evaluating the use of Signatera™ molecular residual disease (MRD) testing to guide treatment decisions in patients with early-stage HR-positive/HER2-negative breast cancer. The study is designed to determine whether MRD-negative patients can safely delay or avoid treatment with adjuvant CDK4/6 inhibitors, potentially reducing overtreatment, toxicity, and healthcare costs while preserving long-term outcomes.
SIGNAL-ER 101 Evaluates MRD-Guided Treatment Strategy
The SIGNAL-ER 101 trial is a prospective, single-arm, multi-center study expected to enroll approximately 725 patients across 50 clinical sites in the United States. The trial focuses on patients with intermediate-risk HR+/HER2- early breast cancer, where the current standard of care often recommends two to three years of adjuvant CDK4/6 inhibitor therapy combined with endocrine treatment.
According to Natera, only a small proportion of patients derive meaningful benefit from prolonged CDK4/6 inhibitor treatment, while a majority experience substantial side effects and treatment burden. The company highlighted that adverse events occur in more than 60% of patients receiving these therapies, while the total retail cost of treatment may exceed $400,000 per patient.
Under the study design, patients testing MRD-positive using Signatera will receive endocrine therapy combined with CDK4/6 inhibitors. Patients testing MRD-negative, representing the majority of participants, will receive endocrine therapy alone alongside quarterly Signatera surveillance monitoring. If MRD becomes detectable during follow-up, patients may then initiate CDK4/6 inhibitor therapy using a Treatment on MRD (TOMR) approach.
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Signatera Data Supports De-Escalation Strategy
The clinical strategy behind SIGNAL-ER 101 is supported by previously presented data from the PALLAS trial, shared at SABCS 2025, showing that MRD-negative HR+ breast cancer patients monitored with Signatera achieved greater than 95% distant recurrence-free interval at five years. These findings suggest many patients may safely avoid immediate escalation to intensive adjuvant therapy without compromising outcomes.
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Natera stated that the SIGNAL program is intended to establish broader clinical utility for MRD-guided treatment de-escalation across multiple cancer types. Similar MRD-based treatment optimization strategies have already shown encouraging results in other malignancies, including bladder cancer and colorectal cancer studies such as IMvigor011, GALAXY, and CALGB/SWOG 80702.
Dr. Minetta Liu, Chief Medical Officer for Oncology and Early Cancer Detection at Natera, said many breast cancer patients currently receive more treatment than necessary, negatively affecting quality of life. She noted that the trial aims to support personalized treatment decisions by using MRD testing to determine when escalation therapy is truly needed.
Natera Expands Precision Oncology Strategy
The launch of SIGNAL-ER 101 strengthens Natera’s position in the rapidly growing field of precision oncology and liquid biopsy diagnostics. Signatera is one of the company’s flagship personalized circulating tumor DNA (ctDNA) platforms designed to detect molecular residual disease and cancer recurrence at extremely low levels.
Natera has increasingly focused on integrating MRD testing into routine oncology decision-making, particularly in settings where treatment intensity remains controversial. By using real-time molecular monitoring to guide therapy escalation or de-escalation, the company aims to improve patient outcomes while reducing unnecessary toxicity and healthcare spending.
The broader SIGNAL clinical program reflects growing industry interest in MRD-directed oncology strategies, especially as precision diagnostics become increasingly integrated into standard cancer care pathways. If successful, the trial could help reshape treatment approaches for early-stage breast cancer by supporting a more individualized approach to adjuvant therapy selection.
Source: Natera press release
