Signatera-Guided CDK4/6 Inhibitor Therapy in Breast Cancer
SIGNAL-ER 101
SIgnatera-Guided Initiation of Adjuvant CDK4/6 Inhibitor in Intermediate Risk HR+ HER2- Breast Cancer
1 other identifier
interventional
725
1 country
39
Brief Summary
The purpose of this study is to evaluate the efficacy and safety of ctDNA-guided initiation of CDK4/6 inhibitor therapy using the Signatera™ Designed on Genome test (referred to as "Signatera Genome") in participants with intermediate-risk HR+/HER2- early-stage breast cancer. Based on ctDNA test results, participants will either start CDK4/6 inhibitor therapy in addition to hormone therapy or continue hormone therapy with ongoing ctDNA surveillance. This study will compare outcomes to historical controls from the NataLEE trial to determine whether ctDNA-guided timing maintains efficacy while reducing unnecessary treatment. Participants will be followed for up to 9 years with regular blood draws, hormone therapy, imaging as needed, and quality-of-life assessments.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for not_applicable
Started Mar 2026
Longer than P75 for not_applicable
39 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
September 24, 2025
CompletedFirst Posted
Study publicly available on registry
October 9, 2025
CompletedStudy Start
First participant enrolled
March 24, 2026
CompletedPrimary Completion
Last participant's last visit for primary outcome
November 15, 2037
ExpectedStudy Completion
Last participant's last visit for all outcomes
December 30, 2037
April 8, 2026
April 1, 2026
11.7 years
September 24, 2025
April 2, 2026
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
Invasive Disease-Free Survival
The primary objective of this study is to to evaluate disease free survival (iDFS) in patients with intermediate risk breast cancer receiving standard endocrine therapy with the addition of CDK4/6 inhibitor therapy upon positive ctDNA test results as compared to historical data of treated patients (NataLEE).
From the date of surgery up to 9 years
Study Arms (1)
ctDNA-Guided Therapy
EXPERIMENTALAll participants receive circulating tumor DNA (ctDNA) testing using Signatera Genome every 3 months to guide treatment decisions. Participants with positive ctDNA results initiate CDK4/6 inhibitor therapy (ribociclib or abemaciclib) in addition to standard endocrine therapy. Participants with negative ctDNA results continue endocrine therapy alone with ongoing ctDNA surveillance. All participants continue their assigned treatment pathway until disease progression, unacceptable toxicity, or study completion.
Interventions
Circulating tumor DNA testing using Signatera Genome assay is performed every 3 months for up to 4 years to guide timing of CDK4/6 inhibitor initiation. Participants with positive ctDNA results initiate CDK4/6 inhibitor therapy (ribociclib or abemaciclib) plus standard endocrine therapy for a minimum of 2 years. Participants with negative ctDNA results continue endocrine therapy alone with ongoing surveillance. CDK4/6 inhibitor selection and endocrine therapy regimen per the physician's choice following standard-of-care guidelines.
Eligibility Criteria
You may qualify if:
- Signed and dated Informed Consent Form (ICF) obtained prior to any trial-specific screening procedure.
- Patient is ≥ 18 years-old at the time of ICF signature.
- Patient is female with known menopausal status at the time of initiation of adjuvant endocrine therapy (ET), or male.
- Patient with histologically confirmed unilateral and unifocal primary invasive adenocarcinoma of the breast prior to initiating adjuvant chemotherapy, if indicated, or within 6 months of initiating adjuvant endocrine therapy if chemotherapy is not indicated. Patients who receive neoadjuvant endocrine therapy or chemotherapy are allowed to enroll.
- Patient has breast cancer that is positive for ER and/or PR according to the local laboratory as determined on the most recently analyzed tissue sample.
- Patient has HER2-negative breast cancer defined as a negative in situ hybridization test (FISH, CISH, or SISH) or an immunohistochemistry (IHC) status of 0 or 1+. If IHC is 2+, a negative in situ hybridization (ISH) test is required to confirm the HER2-negative status.
- Patient has available archival tumor tissue from the diagnostic biopsy or surgical specimen, for submission to a central laboratory for Signatera testing (unless Signatera Genome clinical testing has already been performed).
- Patient after surgical resection where tumor was removed completely (i.e., negative microscopic margins on final pathology) and have Anatomic Stage II that is either:
- N1 or,
- If N0, T2 or T3 with G2-3 and/or Ki67≥20% (testing for Ki67 not mandatory), excluding G1.
- Notes:
- Patients who received neoadjuvant treatment must meet the criteria for stage, grade, Ki67 in any presurgical staging/sample and/or in the surgical specimen.
- Categorization into the AJCC 8th edition Anatomic Stage Groups requires determination of the T, N and M categories. ALND can be omitted.
- Patient has no contraindication to adjuvant ET and is planned to be treated with ET for 5 years (since enrollment date) or more.
- Provider and patient must be agreeable to initiate CDK4/6 inhibitors only upon ctDNA detection.
- +6 more criteria
You may not qualify if:
- Patient has had prior exposure to a CDK4/6 inhibitor.
- Patient is concurrently using hormone replacement therapy.
- Patient with a known contraindication or hypersensitivity to ribociclib or abemaciclib as per the FDA indication label.
- Patients with a multicentric and/or multifocal and synchronous contralateral breast cancer are ineligible.
- Patient with distant metastases of breast cancer beyond regional lymph nodes (stage IV according to AJCC 8th edition) and/or evidence of recurrence after curative surgery.
- Patient has a concurrent invasive malignancy or a prior invasive malignancy whose treatment was completed within 5 years before ICF signature. Note: Patients with prior or concurrent in situ malignancies are eligible provided that adequate curative treatment is completed prior to enrollment.
- Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the Investigator's judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical trial or compromise compliance with the protocol (e.g. chronic pancreatitis, chronic active hepatitis, liver cirrhosis or any other significant liver disease, active untreated or uncontrolled fungal, bacterial or viral infections, active infection requiring systemic antibacterial therapy, etc.) or limit life expectancy to ≤5 years.
- Patient participated in another interventional study and received treatment with an investigational product (or used an investigational device) within 30 days prior to enrollment or within 5 half-lives of the investigational product, whichever is longer.
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- Natera, Inc.lead
Study Sites (39)
University of Alabama at Birmingham
Birmingham, Alabama, 35294, United States
Mayo Clinic Arizona
Phoenix, Arizona, 85054, United States
Honor Health Research Institute
Scottsdale, Arizona, 85258, United States
University of Arizona Cancer Center
Tucson, Arizona, 85719, United States
Adventist Health/AIS Cancer Center
Bakersfield, California, 93301, United States
Marin Cancer Care
Greenbrae, California, 94904, United States
Loma Linda University
Loma Linda, California, 92354, United States
UCLA David Geffen School of Medicine
Santa Monica, California, 90404, United States
Stockton Hematology Oncology Medical Group
Stockton, California, 95204, United States
Kaiser Permanente NorCal
Vallejo, California, 94589, United States
Hartford Healthcare Institute
Hartford, Connecticut, 06102, United States
Yale Cancer Center
New Haven, Connecticut, 06520, United States
Baptist MD Anderson
Jacksonville, Florida, 32207, United States
Mayo Clinic Florida
Jacksonville, Florida, 32224, United States
Jupiter Medical Cancer
Jupiter, Florida, 33458, United States
Miami Cancer Institute
Miami, Florida, 33176, United States
Ocala Oncology
Ocala, Florida, 34474, United States
Northwestern University
Chicago, Illinois, 60611, United States
Northwest Cancer Center
Dyer, Indiana, 46311, United States
New England Cancer Specialists
Westbrook, Maine, 04092, United States
Karmanos Cancer Center - Wayne State University
Detroit, Michigan, 48201, United States
Cancer & Hematology Centers
Grand Rapids, Michigan, 49504, United States
Munson Medical Center Cowell Family Cancer Center
Traverse City, Michigan, 49684, United States
Mayo Clinic
Rochester, Minnesota, 55905, United States
Mercy Health - Sindelar Cancer Center
St Louis, Missouri, 63128, United States
Mercy Health - Pratt Cancer Center
St Louis, Missouri, 63141, United States
Cooper Health
Camden, New Jersey, 08103, United States
Rutgers
New Brunswick, New Jersey, 08901, United States
New York Cancer and Blood Specialists
Babylon, New York, 11702, United States
Atrium Levine Cancer Institute
Charlotte, North Carolina, 28204, United States
Allegheny (AHN)
Pittsburgh, Pennsylvania, 15212, United States
Sanford Health
Sioux Falls, South Dakota, 57104, United States
West Cancer Center
Germantown, Tennessee, 38138, United States
Vanderbilt
Nashville, Tennessee, 37232, United States
Houston Methodist Hospital
Houston, Texas, 77030, United States
Northwest Medical Specialties, PLLC
Puyallup, Washington, 98373, United States
Fred Hutch Cancer Center
Seattle, Washington, 98109, United States
MultiCare Cancer Institute
Tacoma, Washington, 98405, United States
West Virginia University
Morgantown, West Virginia, 26506, United States
Related Publications (10)
Cohen SA, Liu MC, Aleshin A. Practical recommendations for using ctDNA in clinical decision making. Nature. 2023 Jul;619(7969):259-268. doi: 10.1038/s41586-023-06225-y. Epub 2023 Jul 12.
PMID: 37438589BACKGROUNDKanjanapan Y, Anderson W, Smith M, Green J, Chalker E, Craft P. Real-World Analysis of Breast Cancer Patients Qualifying for Adjuvant CDK4/6 Inhibitors. Clin Breast Cancer. 2025 Feb;25(2):e159-e169.e2. doi: 10.1016/j.clbc.2024.08.022. Epub 2024 Aug 29.
PMID: 39294027BACKGROUNDMagbanua MJM, Brown Swigart L, Ahmed Z, Sayaman RW, Renner D, Kalashnikova E, Hirst GL, Yau C, Wolf DM, Li W, Delson AL, Asare S, Liu MC, Albain K, Chien AJ, Forero-Torres A, Isaacs C, Nanda R, Tripathy D, Rodriguez A, Sethi H, Aleshin A, Rabinowitz M, Perlmutter J, Symmans WF, Yee D, Hylton NM, Esserman LJ, DeMichele AM, Rugo HS, van 't Veer LJ. Clinical significance and biology of circulating tumor DNA in high-risk early-stage HER2-negative breast cancer receiving neoadjuvant chemotherapy. Cancer Cell. 2023 Jun 12;41(6):1091-1102.e4. doi: 10.1016/j.ccell.2023.04.008. Epub 2023 May 4.
PMID: 37146605BACKGROUNDCutts R, Ulrich L, Beaney M, Robert M, Coakley M, Bunce C, Crestani GW, Hrebien S, Kalashnikova E, Wu HT, Dashner S, Sethi H, Aleshin A, Liu M, Ring A, Okines A, Smith IE, Barry P, Turner NC, Garcia-Murillas I. Association of post-operative ctDNA detection with outcomes of patients with early breast cancers. ESMO Open. 2024 Sep;9(9):103687. doi: 10.1016/j.esmoop.2024.103687. Epub 2024 Aug 30.
PMID: 39216186BACKGROUNDNatarajan A, Tolaney SM. Is adjuvant ribociclib ready for prime time? Ann Oncol. 2024 Dec;35(12):1200-1201. doi: 10.1016/j.annonc.2024.08.2341. Epub 2024 Sep 4. No abstract available.
PMID: 39241962BACKGROUNDJohnston SRD, Harbeck N, Toi M, Martin M, O'Shaughnessy J, Rastogi P. Reply to K. Hashimoto and A. Shimomura. J Clin Oncol. 2021 May 1;39(13):1507-1508. doi: 10.1200/JCO.20.03477. Epub 2021 Feb 25. No abstract available.
PMID: 33630658BACKGROUNDKay C, Martinez-Perez C, Dixon JM, Turnbull AK. The Role of Nodes and Nodal Assessment in Diagnosis, Treatment and Prediction in ER+, Node-Positive Breast Cancer. J Pers Med. 2023 Oct 8;13(10):1476. doi: 10.3390/jpm13101476.
PMID: 37888087BACKGROUNDNelson DR, Brown J, Morikawa A, Method M. Breast cancer-specific mortality in early breast cancer as defined by high-risk clinical and pathologic characteristics. PLoS One. 2022 Feb 25;17(2):e0264637. doi: 10.1371/journal.pone.0264637. eCollection 2022.
PMID: 35213669BACKGROUNDSmolarz B, Nowak AZ, Romanowicz H. Breast Cancer-Epidemiology, Classification, Pathogenesis and Treatment (Review of Literature). Cancers (Basel). 2022 May 23;14(10):2569. doi: 10.3390/cancers14102569.
PMID: 35626173BACKGROUNDSiegel RL, Kratzer TB, Giaquinto AN, Sung H, Jemal A. Cancer statistics, 2025. CA Cancer J Clin. 2025 Jan-Feb;75(1):10-45. doi: 10.3322/caac.21871. Epub 2025 Jan 16.
PMID: 39817679BACKGROUND
Related Links
MeSH Terms
Conditions
Condition Hierarchy (Ancestors)
Study Officials
- STUDY DIRECTOR
Angel Rodriguez, MD
Natera, Inc.
Central Study Contacts
Study Design
- Study Type
- interventional
- Phase
- not applicable
- Allocation
- NA
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- SINGLE GROUP
- Sponsor Type
- INDUSTRY
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
September 24, 2025
First Posted
October 9, 2025
Study Start
March 24, 2026
Primary Completion (Estimated)
November 15, 2037
Study Completion (Estimated)
December 30, 2037
Last Updated
April 8, 2026
Record last verified: 2026-04
Data Sharing
- IPD Sharing
- Will not share