Personalized pre-surgery treatment for ER-positive, HER2-negative breast cancer using blood tumor DNA and early hormone-response

ABCSG 61 / TEODOR (Neoadjuvant TrEatment Optimization Driven by ctDNA and endOcrine Responsiveness): A Prospective, Randomized, Controlled, Openlabel Multicenter Phase II Study Investigating Neoadjuvant Endocrine Therapy Versus Chemotherapy in HR-positive, HER2negative, ctDNA-negative and Endocrine Responsive Early and Locally Advanced Breast Cancer

This trial tests whether people with ER+/HER2− early or locally advanced breast cancer who have no detectable tumor DNA in the blood and show an early hormone response can be treated with pre-surgery hormone therapy instead of chemotherapy and have similar outcomes with better quality of life.

Quick facts

• Phase: Not applicable
• Study type: Interventional
• Enrollment: 350 (estimated)
• Ages: 18 Years to 100 Years
• Sex: All
• Sponsor: Austrian Breast & Colorectal Cancer Study Group (Research network)
• Drugs / interventions: chemotherapy
• Locations: 14 sites (Vienna, Austria and 13 other locations)
• Trial ID: NCT07084558 on ClinicalTrials.gov

What this trial studies

Participants with newly diagnosed ER+/HER2− early or locally advanced breast cancer first have a Signatera blood test and start a 3-week aromatase inhibitor run-in (or tamoxifen if AI is not tolerated). If ctDNA is undetectable and the tumor Ki-67 falls to ≤10% after 3 weeks, participants are randomized 2:1 to continue neoadjuvant endocrine therapy or receive neoadjuvant chemotherapy, while those with detectable ctDNA or Ki-67 >10% receive chemotherapy. Treatments follow standard-of-care regimens for approximately 6–8 months after the run-in, and the primary outcome is the modified PEPI score measured after surgery with five years of follow-up. The design tests a biomarker-guided approach to safely reduce chemotherapy exposure where appropriate.

Who should consider this trial

Good fit: Adults (≥18) with newly diagnosed, unilateral ER-positive, HER2-negative stage IIA–III breast cancer who have not received prior treatment, are ctDNA-negative by Signatera, and show endocrine responsiveness (Ki-67 ≤10% after a 3-week aromatase inhibitor run-in) are ideal candidates.

Not a fit: Patients with detectable ctDNA, a Ki-67 value >10% after the run-in, HER2-positive or metastatic disease, prior breast cancer treatment, or inability to provide required tissue/blood samples or undergo biopsies are unlikely to benefit from the endocrine-deescalation approach.

Why it matters

Potential benefit: If successful, this approach could allow some patients to avoid chemotherapy and its side effects while maintaining similar cancer control and improving quality of life.

How similar studies have performed: Earlier trials have shown early Ki-67 changes predict endocrine response and ctDNA can track residual disease, but combining ctDNA and early Ki-67 to guide neoadjuvant de-escalation is relatively novel and not yet widely validated.

Eligibility criteria

Inclusion Criteria:

1. Signed informed consent obtained prior to any study specific assessments and procedures
2. Women and men of age ≥18 years
3. Patients must have histologically confirmed invasive, unilateral and locally advanced breast cancer with the following characteristics:

   * Stage IIA-III per AJCC (American Joint Committee on Cancer) Breast Cancer Staging version 8
   * Histologically confirmed hormone receptor positive and HER2 negative tumor(s); HER2 measurement to be assessed locally according to the ASCO/CAP guidelines. In case the tumor is multicentric and/or multifocal, all histopathologically examined tumors must meet the pathologic criteria for hormone receptor positive and HER2 negative
   * ER positive tumors, i.e. \>20% positive stained tumor cells
   * PR positive or negative tumors
4. Systemic chemotherapy indicated by multidisciplinary tumor board
5. Absence of prior breast cancer specific treatment for the current malignancy when entering screening
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
7. Adequate bone marrow and organ function as defined by the following local laboratory values within 8 weeks before study treatment start:

   1. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L
   2. Platelets ≥ 100 × 109/L
   3. Hemoglobin ≥ 10.0 g/dL
   4. Serum creatinine within normal institutional limits or creatinine clearance ≥ 60 mL/min/1.73 m² for patients with serum creatinine levels above institutional ULN.
   5. Alanine amino transferase (ALT or SGPT) ≤ 1.5 × Upper Limit Normal (ULN); Aspartate amino transferase (AST or SGOT) ≤ 1.5 × ULN f. Total serum bilirubin ≤ ULN; or total bilirubin ≤ 3.0 × ULN with direct bilirubin within normal range in patients with well documented Gilbert's Syndrome
8. Patients must be able and willing to swallow and retain oral medication without a condition that would interfere with enteric absorption.
9. Patient must be willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
10. In women of childbearing potential, urine or serum pregnancy test must be negative within 28 days prior to registration. In postmenopausal women or hysterectomized patients, pregnancy tests do not need to be performed

Exclusion Criteria:

1. Ineligible for appropriate locoregional treatment (breast surgery and or radiotherapy when indicated)
2. Bilateral invasive breast cancer or synchronous DCIS in contralateral breast
3. Patients receiving concurrent systemic exogenous sexual hormone therapy during the study (hormone replacement therapy, oral or any other hormonal contraceptives such as hormonal contraceptive coil, etc.) are not eligible but topical vaginal estrogen therapy is allowable.
4. Any chronic medication contraindicated for antineoplastic treatment
5. Participation in a prior or concurrent interventional study and receiving study treatment (concurrent or within 30 days prior to treatment start) 6) Patients receiving any prior systemic cancer therapy for invasive breast cancer

7\) Patients with a history of any malignancy are ineligible except for the following circumstances:

* Patients with a malignancy history other than adequately treated invasive breast cancer are eligible if they have been disease-free for at least 2 years and are deemed by the investigator to be at very low risk for recurrence of that malignancy (e.g. stage I gastric cancer or skin cancer)
* Patients with the following cancers are eligible, even if diagnosed and adequately treated within the past 2 years: ductal carcinoma in situ of the breast, cervical cancer in situ, and non-metastatic nonmelanomatous skin cancers 8) Patient has medical or psychiatric disorders that would, in the investigator's judgement, interfere with the patient's safety or informed consent (e.g. known uncontrolled HIV infection, chronic/active viral or other known hepatitis and/or chronic liver disease, cirrhosis etc.).

  9\) Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, diabetes, or psychiatric illness/social situations that would limit compliance with study requirements. Ability to comply with study requirements is to be assessed by each investigator at the time of screening for study participation 10) Patient has current impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the oral study treatments (e.g., uncontrolled ulcerative diseases, uncontrolled nausea, vomiting or diarrhea, malabsorption syndrome, or small bowel resection) 11) 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 study or compromise compliance with the protocol or limit life expectancy to ≤5 years 12) Pregnant or breast-feeding (lactating) women or women who plan to become pregnant or breast-feed during study treatment and 6 months thereafter

Where this trial is running

Vienna, Austria and 13 other locations

• Allg. Gynäkologie u. gyn. Onkologie/Senologie — Vienna, Austria, Austria (Recruiting)
• Landesklinikum Baden BGZ; Abt. f. Allgemein- u. Viszeralchirurgie — Baden, Austria (Active_not_recruiting)
• Dornbirn BGZ; Frauenheilkunde u. Geburtshilfe — Dornbirn, Austria (Active_not_recruiting)
• Landeskrankenhaus Feldkirch Interne E — Feldkirch, Austria (Active_not_recruiting)
• MUG - LKH Graz Klin. Abt. f. Onkologie — Graz, Austria (Active_not_recruiting)
• MUG - Univ. Frauenklinik Graz, Gyn. Abteilung — Graz, Austria (Active_not_recruiting)
• MUI - Univ. Klinik f. Frauenheilkunde Innsbruck Klin. Abteilung f. Gynäkologie u. Geburtshilfe — Innsbruck, Austria (Recruiting)
• TumorZentrum Kepler Universitätsklinikum Linz — Linz, Austria (Active_not_recruiting)
• LKH Salzburg - PMU, Univ.Klinik f. Innere Medizin III / SCRI CCCIT — Salzburg, Austria (Not_yet_recruiting)
• Universitätsklinikum St. Pölten, Klin. Abteilung f. Innere Medizin 1 — Sankt Pölten, Austria (Active_not_recruiting)
• KH BHB St. Veit/Glan Brustzentrum Kärnten — Sankt Veit an der Glan, Austria (Active_not_recruiting)
• Hanusch Krankenhaus, 3. Medizinische Abteilung — Vienna, Austria (Active_not_recruiting)
• Klinik Hietzing, Gyn. Abteilung; Karl Landsteiner Institut f. gyn. Onkologie u. Senologie — Vienna, Austria (Active_not_recruiting)
• Universitätsklinikum Wiener Neustadt, Abteilung für Innere Medizin, Hämatologie und int. Onkologie — Wiener Neustadt, Austria (Not_yet_recruiting)

Study contacts

• Study coordinator: Katharina Jarolim, PhD

Conditions Early and Locally Advanced Breast Cancer; early breast cancer; locally advanced breast cancer; neoadjuvant endocrine therapy; chemotherapy; HR-positive; HER2-negative; ABCSG 61