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Signatera‑guided timing of CDK4/6 inhibitor (ribociclib) with hormone therapy for intermediate‑risk HR+/HER2‑ breast cancer

SIgnatera-Guided Initiation of Adjuvant CDK4/6 Inhibitor in Intermediate Risk HR+ HER2- Breast Cancer

Not applicable Interventional Natera, Inc. · NCT07214532

This trial will test whether using Signatera ctDNA testing to time when to start a CDK4/6 inhibitor alongside hormone therapy can help adults with intermediate‑risk HR+/HER2‑ early breast cancer avoid unnecessary treatment while keeping cancer control.

Quick facts

PhaseNot applicable
Study typeInterventional
Enrollment725 (estimated)
Ages18 Years and up
SexAll
SponsorNatera, Inc. Industry-sponsored
Drugs / interventionschemotherapy
Locations39 sites (Birmingham, Alabama and 38 other locations)
Trial IDNCT07214532 on ClinicalTrials.gov

What this trial studies

This is a prospective, single‑arm, multicenter phase II study using the personalized Signatera Genome ctDNA assay to guide initiation of CDK4/6 inhibitor therapy in intermediate‑risk HR+/HER2‑ early breast cancer. Participants who are ctDNA‑positive at baseline start ribociclib plus endocrine therapy, while ctDNA‑negative participants continue endocrine therapy with ctDNA monitoring every three months and begin ribociclib only if ctDNA becomes positive after staging excludes distant disease. Four‑year outcomes will be compared with historical controls from the NataLEE trial, and all participants will be followed for up to nine years with serial blood draws, imaging as needed, and quality‑of‑life assessments. The primary goal is to determine whether ctDNA‑guided timing maintains cancer control while reducing exposure to CDK4/6 inhibition.

Who should consider this trial

Good fit: Adults with intermediate‑risk, early‑stage ER+/PR+ and HER2‑ breast cancer who have available archived tumor tissue and are within the allowed window after surgery or initiation of endocrine therapy are ideal candidates.

Not a fit: Patients with HER2‑positive or non‑hormone receptor‑positive disease, known distant metastatic disease, or those unable or unwilling to provide tumor tissue or attend serial blood draws and clinic visits are unlikely to benefit from this ctDNA‑guided approach.

Why it matters

Potential benefit: If successful, this approach could spare ctDNA‑negative patients months to years of CDK4/6 inhibitor exposure and its side effects while preserving cancer outcomes.

How similar studies have performed: ctDNA assays have shown strong prognostic value for minimal residual disease and have been used to guide adjuvant therapy in other cancers (for example DYNAMIC in colon cancer), and adjuvant ribociclib showed benefit in large trials like NATALEE, but ctDNA‑guided timing in HR+/HER2‑ breast cancer is still relatively novel.

Eligibility criteria

Show full inclusion / exclusion criteria 
Inclusion Criteria:

1. Signed and dated Informed Consent Form (ICF) obtained prior to any trial-specific screening procedure.
2. Patient is ≥ 18 years-old at the time of ICF signature.
3. Patient is female with known menopausal status at the time of initiation of adjuvant endocrine therapy (ET), or male.
4. 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.
5. 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.
6. 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.
7. 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).
8. 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:
   1. Patients who received neoadjuvant treatment must meet the criteria for stage, grade, Ki67 in any presurgical staging/sample and/or in the surgical specimen.
   2. Categorization into the AJCC 8th edition Anatomic Stage Groups requires determination of the T, N and M categories. ALND can be omitted.
9. Patient has no contraindication to adjuvant ET and is planned to be treated with ET for 5 years (since enrollment date) or more.
10. Provider and patient must be agreeable to initiate CDK4/6 inhibitors only upon ctDNA detection.
11. Patient may have received up to 6 months of standard adjuvant ET at the time of enrollment and any amount of neoadjuvant endocrine therapy.
12. Patient has an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
13. Patient must not have a clinical contraindication to ribociclib or abemaciclib.
14. Patient must be willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other trial procedures.
15. Women of childbearing potential (CBP) must have a confirmed negative serum pregnancy test within 14 days prior to enrollment.
16. Women of reproductive potential should be advised of the potential risk of CDK4/6 inhibitors to a fetus, and use effective contraception during CDK 4/6 inhibitor therapy.

Exclusion Criteria:

1. Patient has had prior exposure to a CDK4/6 inhibitor.
2. Patient is concurrently using hormone replacement therapy.
3. Patient with a known contraindication or hypersensitivity to ribociclib or abemaciclib as per the FDA indication label.
4. Patients with a multicentric and/or multifocal and synchronous contralateral breast cancer are ineligible.
5. 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.
6. 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.
7. 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.
8. 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.

Where this trial is running

Birmingham, Alabama and 38 other locations

Study contacts

How to participate

  1. Review the eligibility criteria above with your treating physician.
  2. Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
  3. Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.
View on ClinicalTrials.gov → Find more trials like this →
Conditions Breast NeoplasmsCarcinoma, Ductal, BreastReceptors, EstrogenctDNACirculating tumor DNASignateraCDK4/6 inhibitorRibociclib
Last reviewed 2026-06-10 by the Find a Trial editorial team. Information on this page is for educational purposes and is not medical advice. Always consult qualified healthcare professionals about clinical trial participation.