neoAGORA: Exploring Clinical Utility of Serial Liquid Biopsy (ctDNA) in Patients With Early-Stage Breast Cancer (neoAGORA)

neoAGORA: A Prospective Observational Study to Explore the Clinical Utility of Serial Liquid Biopsy in Patients With Early-stage Breast Cancer Receiving Neoadjuvant Therapy.

The goal of this observational study is to explore the utility of analytical techniques that enable the study of small amounts of tumor-derived material circulating in the blood, such as fragments of circulating tumor DNA (also known as ctDNA), cells, or other particles. This type of sample is generally referred to as a liquid biopsy, and its analysis is a minimally invasive test, as it only requires the collection of blood samples. The study includes women and men with early-stage breast cancer (EBC) who are about to start neoadjuvant treatment (treatment given before surgery). The main questions it aims to answer are:

• Can liquid biopsy analyses (ctDNA) provide additional information about the type of tumor before treatment starts?
• Can these analyses help to detect early whether the tumor is responding to treatment?
• Can these tests identify if any cancer remains after neoadjuvant treatment or after surgery?
• Is this information related to the risk of the cancer coming back?
• Can these analyses, when performed during follow-up, help detect cancer recurrence earlier?

Participants will:

• Continue receiving standard medical care for their breast cancer, including neoadjuvant therapy and surgery.
• Provide blood samples at different time points during treatment and follow-up.
• Provide residual tumor samples from the routine clinical care.

Study Overview

• Status: Not yet recruiting
• Conditions: Early Breast Cancer (EBC)
• Intervention / Treatment: Other: biological samples, images, and clinical data

Detailed Description

Study Rationale:

Neoadjuvant therapy (NAT) is a standard treatment approach for patients with early-stage breast cancer (EBC), its benefits extend beyond enabling breast conserving surgery: it provides an early dynamic assessment of treatment sensitivity and creates an in vivo framework to interrogate tumor biology under therapeutic pressure. Pathological complete response (pCR) is an established surrogate marker of prognosis, particularly in triple negative (TN) and Human Epidermal Growth Factor Receptor 2(HER2)-positive breast cancer; however, the ability to predict response early during treatment and to identify patients at risk of residual disease or relapse remains limited.

Circulating tumor DNA (ctDNA) has emerged as a promising minimally invasive biomarker for monitoring tumor burden and treatment response in real time. Previous studies have shown that baseline ctDNA levels, early ctDNA clearance during NAT, and postoperative ctDNA detection are associated with treatment response, minimal residual disease (MRD), and relapse risk. Nevertheless, the clinical utility of ctDNA across breast cancer subtypes and its integration into routine clinical decision-making remain incompletely defined.

The neoAGORA study aims to evaluate subtype-specific ctDNA dynamics during standard NAT and to investigate their relationship with clinical outcomes, pathological response, advanced imaging findings, and digital pathology assessments. By integrating these complementary sources of information, the study seeks to improve response assessment and support the development of personalized management strategies for patients with EBC.

Study design:

The neoAGORA study is a multicenter observational study designed to investigate the value of liquid biopsy technologies in patients with EBC receiving standard neoadjuvant therapy. The study will include patients with luminal, HER2-positive, and TN tumors treated according to routine clinical practice.

The neoAGORA prospective cohort will systematically collect clinical data, biological samples, and imaging information throughout treatment and follow-up. Serial blood samples will be collected at predefined time points before, during, and after neoadjuvant therapy, as well as tumor samples obtained at diagnosis, during treatment when available, at surgery, and at disease relapse. In addition, detailed clinical data will be collected, including demographic and clinical characteristics, treatments administered, radiological response, pathological response, and recurrence and survival outcomes.

The study will incorporate a centralized biorepository and a common infrastructure for standardized collection of data and biological samples, enabling the evaluation of liquid biopsy-derived biomarkers, digital pathology, and advanced imaging in a real-world clinical setting.

At least 300 patients (approximately 100 per breast cancer subtype) are expected to be enrolled. The platform is designed to allow future cohort expansions and to facilitate collaborative research aimed at evaluating the clinical utility of novel biomarkers and personalized medicine strategies in EBC.

Study population and length of study:

The neoAGORA study is a continuous recruitment study that will remain open indefinitely. The first cohort will include at least 300 patients, distributed evenly across the main breast cancer tumor subtypes. Recruitment of this cohort is expected to be completed in approximately 18 months.

All participants will be followed for a minimum of 5 years after surgery. The study completion date for this cohort will be defined as the last visit of the last patient enrolled, resulting in an estimated total study duration of approximately 7 years from the inclusion of the first patient.

• Study Type: Observational
• Enrollment (Estimated): 300

Contacts and Locations

• Study Contact: Name: Study Project Manager; Phone Number: +34916592870; Email: inicio_ensayos@geicam.org
• Study Contact Backup: Name: Start-Up Unit Manager; Phone Number: +34916592870; Email: inicio_ensayos@geicam.org

Study Locations

• Spain
  • Barcelona
    • Barcelona, Barcelona, Spain, 08003
      • Hospital del Mar
      • Contact: Principal Investigator
  • Guipúzcoa
    • San Sebastián, Guipúzcoa, Spain, 20014
      • Hospital Universitario Donostia
      • Contact: CHIEF INVESTIGATOR
  • Madrid
    • Madrid, Madrid, Spain, 28040
      • Hospital Clínico Universitario San Carlos
      • Contact: CHIEF INVESTIGATOR
    • Madrid, Madrid, Spain, 28009
      • Hospital General Universitario Gregorio Marañon
      • Contact: CHIEF INVESTIGATOR
  • Málaga
    • Málaga, Málaga, Spain, 29010
      • Hospital Clínico Universitario Virgen De la Victoria
      • Contact: CHIEF INVESTIGATOR
  • Sevilla
    • Seville, Sevilla, Spain, 41013
      • Hospital Universitario Virgen del Rocío
      • Contact: Principal Investigator
    • Seville, Sevilla, Spain, 41009
      • Hospital Universitario Virgen Macarena
      • Contact: Principal Investigator
  • Toledo
    • Toledo, Toledo, Spain, 45007
      • Hospital Universitario de Toledo
      • Contact: Principal Investigator
  • Valencia
    • Valencia, Valencia, Spain, 46010
      • Hospital Clínico Universitario de Valencia
      • Contact: Principal Investigator
    • Valencia, Valencia, Spain, 46009
      • Instituto Valenciano de Oncología
      • Contact: CHIEF INVESTIGATOR

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

The target population for inclusion in this study is BC patients scheduled to receive neoadjuvant treatment.

Description

Inclusion Criteria:

1. Written informed consent prior to any specific study procedure.
2. Patients with willingness and ability to comply with study procedures.
3. Patients (women and men) ≥18 years of age.

4. Patients with a first diagnosis of the UICC (Union for International Cancer Control) stage I-III primary invasive BC whose tumors are of any of the following subtypes:

   • Luminal: Hormonal Receptor(HR)-positive and HER2-negative.
   • HER2-positive: HER2-positive regardless of the HR status.
   • Triple negative: Hormonal Receptor(HR)-negative and HER2-negative. HR and HER2 status should be based on local laboratory determination following the criteria of the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) international guidelines in effect at the time of testing.
5. Patients that are scheduled to receive NAT as determined by the treating physician according to standard clinical practice.
6. Archival Formalin-Fixed, Paraffin-Embedded (FFPE) sample of the primary tumor must be available to analyze tumor-informed ctDNA assays.

Exclusion Criteria:

1. Patients with stage IV BC.
2. Patients with previous anti-cancer treatment for the current BC.
3. Patients with diagnosis of any other invasive malignancy in the 5 prior years, unless the malignancy has been treated with curative intent and is considered at low risk of recurrence, with no evidence of active disease at study entry.
4. Patients with a diagnosis of bilateral or multifocal breast tumors with different HR or HER2 status.
5. Patients with any severe acute or chronic medical or psychiatric condition or laboratory abnormality that may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
6. Patients who are concurrently enrolled in clinical trials.
7. Females who are pregnant or breastfeeding.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Patients diagnosed with EBC with luminal, HER2-positive and TN tumors scheduled to receive NAT.; The neoAGORA prospective cohort will include patients diagnosed with Early-stage Breast Cancer with luminal, HER2-positive and Triple Negative tumors scheduled to receive Neoadjuvant Therapy. Patients will be treated according to standard clinical practice.

Other: biological samples, images, and clinical data; This is an observational study in which clinical decisions concerning the optimum therapy for a particular patient are taken independently of, and prior to, offering the patient to participate in the study. The treating physician will make all treatment decisions according to his/her regular clinical practice independent of this study. The study will systematically collect and integrate biological samples, images, and clinical data in the neoadjuvant and follow-up period. Serial blood samples are collected for neoAGORA study align with blood extractions performed as part of the patient's standard clinical care and tumor samples are residual samples from clinical practice.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prognostic and Predictive Value of ctDNA in Patients Receiving NAT	To evaluate the association between ctDNA detection, molecular profiling, and longitudinal ctDNA dynamics (at baseline, during NAT and pre-surgery) and efficacy outcomes. The ctDNA metrics and patterns assessed before surgery will be: ctDNA status/levels and molecular profiling at baseline, during NAT and post-NAT (pre-surgery),; early ctDNA dynamics during NAT (e.g. clearance vs. persistence),; ctDNA dynamics patterns post-NAT (pre-surgery) (e.g. clearance, persistence, rebound). Specific objectives: To evaluate the association between the ctDNA metrics and patterns detailed in the protocol.; To derive candidate early ctDNA change thresholds during NAT and estimate their predictive and prognostic value.	From Study Start Date to Primary Completion Date (25 months).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prognostic and predictive value of molecular residual disease (MRD) assessed by ctDNA	To evaluate the association between post-surgery Molecular Residual Disease (MRD) and pre-surgery ctDNA status, and the correlation of post-surgery MRD with pathological residual disease at surgery, radiological response, and time-to-event efficacy outcomes.	From Study Start Date to Study Completion Date (84 months).
Characterization of tumor evolution	To characterize tumor molecular evolution using longitudinal liquid biopsies (ctDNA, ctRNA, etc) collected at baseline, throughout NAT, and during follow-up.	From Study Start Date to Study Completion Date (84 months).
Biomarker discovery	To identify candidate molecular biomarkers and profiles from liquid biopsies and tumor tissue that predict efficacy outcomes in early-stage disease (hypothesis-generating).	From Study Start Date to Study Completion Date (84 months).
Reduction in the need for invasive procedures	To assess ctDNA as a minimal or non-invasive complement to tissue biopsies for tumor characterization and treatment monitoring across the early-stage disease.	From Study Start Date to Study Completion Date (84months).
Imaging predictions of tumor response and disease relapse	To explore the ability of advanced imaging modalities and quantitative analysis (including AI-enabled tools) to accurately predict pathological response and efficacy outcomes.	From Study Start Date to Study Completion Date (84 months). This will only be conducted if funding is obtained.
Multimodal integration: ctDNA, imaging, and digital pathology readouts	To evaluate the incremental prognostic and predictive value of ctDNA-derived metrics within an integrated multimodal framework, incorporating imaging and pathology readouts, including AI-enabled approaches.	From Study Start Date to Study Completion Date (84 months).
Effectiveness in routine clinical practice	To explore effectiveness outcomes in specific populations often underrepresented in clinical studies (such as elderly patients, those with organ dysfunction, or those requiring dose adjustments) while also describing effectiveness outcomes across different NAT regimens within routine clinical practice that encompasses a broader and more heterogeneous population than the one typically represented in drug-register oriented clinical studies.	From Study Start Date to Study Completion Date (84 months).
Pharmacoeconomics	To evaluate the economic impact and social value generated by incorporating ctDNA-based liquid biopsy and MRD status analysis into the care pathway of patients with EBC treated with NAT in real-world clinical practice, through the characterization of observed care trajectories, the estimation of associated costs and clinical outcomes, and the multidimensional quantification of the value generated for the patient, the healthcare system, and society as a whole.	From Study Start Date to Study Completion Date (84 months). This will only be conducted if funding is obtained.

Collaborators and Investigators

• Sponsor: Spanish Breast Cancer Research Group
• Investigators: Study Director: Study Director, Instituto Valenciano de Oncología; Study Director: Study Director, Hospital Clínico Universitario Virgen De la Victoria; Study Director: Study Director, Hospital General Universitario Gregorio Marañon; Study Director: Study Director, Hospital Donostia; Study Director: Study Director, Hospital Clínico Universitario San Carlos

Publications and helpful links

Helpful Links

• GEICAM is a Spanish Breast Cancer Research Group

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2026
• Primary Completion (Estimated): September 1, 2028
• Study Completion (Estimated): August 1, 2033

Study Registration Dates

• First Submitted: July 3, 2026
• First Submitted That Met QC Criteria: July 17, 2026
• First Posted (Actual): July 22, 2026

Study Record Updates

• Last Update Posted (Actual): July 22, 2026
• Last Update Submitted That Met QC Criteria: July 17, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: ctDNA; liquid biopsy; digital pathology; early-stage breast cancer; neoadjuvant therapy (NAT)
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Skin and Connective Tissue Diseases; Breast Neoplasms
• Other Study ID Numbers: GEICAM/2023-14

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No