The central question of the trial reflects a growing tension in modern oncology. CDK4/6 inhibitors, when combined with endocrine therapy, have demonstrated meaningful reductions in recurrence risk for patients with higher-risk hormone receptor-positive disease. Yet these agents also bring side effects, frequent monitoring, and a substantial treatment burden. Not every patient faces the same risk of recurrence, but adjuvant treatment decisions today are still largely based on clinical and pathological features measured at the time of diagnosis, such as tumor size, nodal status, and grade. AFT-70 NAVIGATE proposes a fundamentally different approach: using dynamic, biology-driven information from circulating tumor DNA to calibrate treatment intensity for each individual patient over time.

The design of the study pairs two recent technological and therapeutic advances. The first is giredestrant, an investigational next-generation oral selective estrogen receptor degrader (SERD) developed by Genentech. Giredestrant was selected as the endocrine therapy backbone for the investigational arm based on results from the phase III lidERA trial, which showed that the drug achieved a statistically significant and clinically meaningful improvement in invasive disease-free survival compared with standard endocrine monotherapy in patients with ER-positive/HER2-negative early breast cancer. Those findings support the potential for giredestrant to serve as a foundation on which an MRD-guided treatment strategy can be built, providing potent estrogen receptor blockade while remaining an oral, outpatient therapy.

The second advance is Signatera, Natera’s ultrasensitive MRD test, which will be deployed in its newest form, Signatera Genome with phased and structural variants. This technology reports analytical sensitivity below one part per million, a level of detection that allows researchers to identify vanishingly small quantities of circulating tumor DNA in a patient’s bloodstream. Signatera was chosen for the trial based on its extensive clinical evidence in HR-positive/HER2-negative early breast cancer, including its use in the AFT-05 PALLAS and MonarchE trials. In those settings, the presence or absence of molecular residual disease after standard treatment proved to be a powerful indicator of recurrence risk, often outperforming traditional pathological measures.

AFT expects to enroll more than 2,000 patients with stage II-III ER-positive/HER2-negative breast cancer who are eligible for endocrine therapy. Recruitment will take place at approximately 200 sites across the United States and internationally, underscoring the scale of the logistical and scientific undertaking. Patients will first complete standard-of-care treatment, including surgery, radiotherapy, and chemotherapy when indicated. Those with no detectable MRD by Signatera after completing this treatment will then be randomly assigned to one of two approaches, creating a head-to-head comparison between current practice and the MRD-guided strategy.

In the control arm, patients will receive standard-of-care endocrine therapy plus upfront CDK4/6 inhibition, reflecting the current movement toward intensifying adjuvant treatment for higher-risk disease. In the investigational arm, patients will receive giredestrant monotherapy, with a CDK4/6 inhibitor added only if Signatera testing subsequently becomes positive. The primary endpoint is non-inferiority in four-year distant recurrence-free survival, a measure that directly captures whether deferring intensification compromises long-term control of metastatic disease. If the investigational strategy proves non-inferior, it would suggest that many patients can avoid unnecessary CDK4/6 inhibitor exposure without sacrificing outcomes.

Leadership of the trial emphasizes that the study addresses a question patients and clinicians confront daily. Evanthia Galanis, MD, DSc, president of Alliance Foundation Trials, LLC, noted that the collaboration brings together leading expertise in breast cancer research, clinical care, and molecular testing to address how treatment can be made more precise while avoiding unnecessary toxicity. She stated that by using MRD technology to guide treatment decisions, the trial has the potential to transform care for eligible breast cancer patients and individualize treatment intensity. Her comments frame the study not merely as a test of a drug or a diagnostic, but as a test of an entirely new treatment paradigm.

Komal Jhaveri, MD, FACP, FASCO, the study chair, a breast medical oncologist, and an early drug development specialist at Memorial Sloan Kettering Cancer Center, highlighted the mismatch between current risk assessment and actual tumor biology. She observed that patients with ER-positive, HER2-negative breast cancer do not all face the same risk of recurrence, yet adjuvant decisions remain anchored to features measured at diagnosis. According to Jhaveri, the trial combines two important advances: an endocrine backbone with giredestrant and longitudinal MRD testing with Signatera that can provide a dynamic measure of recurrence risk. She described the study as an important step forward in using biology, rather than just baseline risk, to guide adjuvant therapy, and said it will determine whether MRD-guided monitoring can distinguish patients most likely to benefit from adding a CDK4/6 inhibitor from those in whom it can be safely omitted.

Gaorav Gupta, MD, PhD, study co-chair, a breast radiation oncologist, and co-leader of the Breast Cancer Research Program at UNC Lineberger Comprehensive Cancer Center, offered a succinct summary of the trial’s philosophy: more treatment is not always better treatment. He acknowledged that CDK4/6 inhibitors can be an important part of care for some patients but noted that they can also add side effects, monitoring, and treatment burden. If highly sensitive blood-based MRD testing can identify patients who can safely defer additional therapy, he explained, clinicians may be able to spare many patients from the burdens of more treatment while maintaining excellent cancer control. That, he said, is the promise the study hopes to explore.

The collaboration also reflects a deepening partnership between academic cooperative groups and precision medicine companies. Minetta Liu, MD, chief medical officer of oncology and early cancer detection at Natera, pointed to the longstanding relationship between Natera and AFT and their shared commitment to cutting-edge trials across many cancer types, describing AFT-70 NAVIGATE as creating enormous potential to enhance treatment options for patients with intermediate and high-risk, hormone receptor-positive breast cancer. If the trial succeeds, the implications could extend well beyond breast cancer, offering a template for using serial liquid biopsy monitoring to individualize adjuvant therapy across tumor types. For the thousands of patients diagnosed each year with ER-positive/HER2-negative disease, the study represents a bid to replace one-size-fits-all intensification with a strategy that escalates treatment only when molecular evidence says it is needed, potentially sparing many women years of additional therapy and its accompanying toxicities while preserving the excellent outcomes that modern adjuvant care has achieved.

Subject of Research: MRD-guided adjuvant therapy with giredestrant and CDK4/6 inhibitors in ER-positive/HER2-negative early breast cancer

Article Title: Alliance Foundation Trials and Natera announce AFT-70 Navigate: a Global, Randomized, Phase III Trial Evaluating Genentech’s Oral Selective Estrogen Receptor Degrader (SERD) with SignateraTM MRD-Guided CDK4/6 Inhibitor Therapy in ER+/HER2− Breast Canc

Article References: Alliance Foundation Trials and Natera announce AFT-70 Navigate: a Global, Randomized, Phase III Trial Evaluating Genentech’s Oral Selective Estrogen Receptor Degrader (SERD) with SignateraTM MRD-Guided CDK4/6 Inhibitor Therapy in ER+/HER2− Breast Canc. (n.d.). Original publication

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DOI: Not provided

Keywords: AFT-70 NAVIGATE, breast cancer, molecular residual disease, Signatera, giredestrant, SERD, CDK4/6 inhibitors, liquid biopsy, clinical trial, endocrine therapy, ER-positive HER2-negative, precision oncology