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Phase 2 Trial to Study Palbociclib in Early Stage Breast Cancer Based on ctDNA Monitoring


Natera’s Signatera ctDNA test will determine study eligibility and treatment effectiveness in HR-positive, HER2-negative breast cancer patients.

Natera’s molecular residual disease (MRD) test, Signatera, will be used in an upcoming phase 2 trial of palbociclib (Ibrance), a CDK4/6 inhibitor developed by Pfizer, in combination with fulvestrant for the treatment of early stage HR-positive, HER2-negative breast cancer.1

The prospective DARE trial, which will be run by Criterium, Inc. known as the Academic Breast Cancer Consortium (ABRCC) network, will include about 100 stage II-III, HR-positive, HER2-negative breast cancer patients currently undergoing adjuvant endocrine therapy. MRD-positive patients identified with Signatera test results will be randomized to either continue with their current endocrine therapy or begin a regimen of palbociclib in combination with an aromatase inhibitor or fulvestrant for 2 years.

Palbociclib was the first CDK4/6 inhibitor approved by the FDA for use in conjunction with endocrine therapy in advanced HR-positive, HER2-negative advanced breast cancer, but research has yet to determine its efficacy in early-stage disease. Throughout the trial, continued molecular monitoring with Signatera ctDNA testing will be used to track treatment effectiveness.

“These are women who have molecular recurrence, but not clinical radiological recurrence,” Natera senior medical director Alexey Aleshin, MD, MBA, told The American Journal of Managed Care® (AJMC®) in an interview. “Can we actually treat these women with the now preferred frontline metastatic regimen, which is palbociclib, to see if some of these women can have their outcomes improved with this early intervention strategy compared to the standard of care, which, unfortunately, is actually just continuing the endocrine therapy that these women are on?”

Improving relapse-free survival is the primary end point in the DARE trial, with secondary outcomes including survival and ctDNA clearance. Enrollment is scheduled to begin in December.

Signatera is tumor-informed, sequencing the mutations in a patient’s initial tumor and using that data to personalize testing to each patient. This leads to earlier and more accurate results that have been validated across cancer types. Signatera was recently approved for Medicare coverage in stage II-III colorectal cancer,2 and a proposed expansion would cover its use for immuno-oncology monitoring in other solid tumors.3

“Actually testing serially in patients who are, for example, breast cancer survivors, can identify early signals that their cancer is coming back molecularly months to sometimes years before the cancer comes back clinically,” Aleshin said. “That provides this window of opportunity where certain interventions can be started to hopefully modify that course for these patients.”

The most significant findings for Signatera’s clinical validity in detecting ctDNA ahead of clinical or radiologic relapse in breast cancer patients came in a 2019 study published in Clinical Cancer Research, Aleshin notes. The research showed that patient-specific ctDNA analysis resulted in earlier detection of up to 2 years and is a sensitive and specific method of monitoring patients with breast cancer.4 Early detection and detailed monitoring are both pillars in the DARE trial. Aleshin also hopes to see evidence that early MRD detection with Signatera can significantly improve patient outcomes.

“If we can show in the study that by treating women earlier using knowledge that they have molecular recurrence, not only can we delay recurrence in some of these women, but possibly cure some of them and actually prevent somebody from developing metastatic disease that invariably is lethal in many of these women, that'll be a huge advancement for the field and clearly demonstrate why doing a test like Signatera is beneficial in the setting,” Aleshin said.


1. Natera Announces Prospective Randomized Clinical Trial to Evaluate Palbociclib in Early Stage Breast Cancer Patients Who Test Positive with Signatera. News Release. Natera. October 2, 2020. Accessed October 9, 2020. https://www.natera.com/press-releases/natera-announces-prospective-randomized-clinical-trial-evaluate-palbociclib-early

2.FUTURE Local Coverage Article:Billing and Coding: MolDX: Minimal Residual Disease Testing for Colorectal Cancer (A58283). CMS.gov. Accessed October 9, 2020. https://www.cms.gov/medicare-coverage-database/details/article-details.aspx?articleId=58283&ver=4&LCDId=38290&ContrId=391&ContrVer=1&DraftContr=All&bc=AAAAAIAAIAAA&

3. Proposed Local Coverage Determination (LCD):MOLDX: Minimal Residual Disease Testing for Cancer (DL38779). CMS.gov. Accessed October 9, 2020. https://www.cms.gov/medicare-coverage-database/details/lcd-details.aspx?LCDId=38778&ver=7&SearchType=Advanced&CoverageSelection=Local&PolicyType=Both&AdvSearchName=2&KeyWord=MolDX&KeyWordLookUp=Title&KeyWordSearchType=Exact&kq=true&bc=IAAAAAgAAAAA&

4. Coombes RC, Page K, Salari R. Personalized Detection of Circulating Tumor DNA Antedates Breast Cancer Metastatic Recurrence. Clin Cancer Res. Published Online April 16, 2019; doi:10.1158/1078-0432.CCR-18-3663

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