Standard Surveillance vs. Intensive Surveillance in Early Breast Cancer

NCT05658172 | Recruiting DMC

• 3 other identifiers: SURVIVE01KD2202DRKS00030745
• Study Type: interventional
• Target: 3,500
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this clinical study is to evaluate the potential benefits of intensified surveillance versus standard surveillance in medium-risk and high-risk early breast cancer patients. The main questions it aims to answer are:

• Comparison of the 5-year ob´verall survival rates between patients in the Standard Surveillance arm versus patients in the liquid-biopsy guided Intensive Surveillance arm
• Determination of the Overall Lead Time Effect generated due to tumor marker/CTC/ctDNA guided Intensive Surveillance compared to Standard Surveillance after primary therapy in early breast cancer patients. Participants will recieve regular blood drawals. Solely the blood samples of the intensive surveillance arm will be analysed for prospective tumor markers/CTCs/ctDNAs. Abnormal findings of either marker will trigger diagnostic imaging to search for possible metastases. The blood samples of the standard surveillance arm will solely be biobanked for future research purposes.

Conditions

Breast Cancer

Keywords

medium risk; high risk

Outcome Measures

Primary Outcomes (2)

• Overall Survival (OS)

  OS is defined as time from randomization until the death of the patient independent of cause of death. If a patient is not known to have died, OS is censored at the date of last contact.

  10 years

• Overall Lead Time Effect

  This endpoint is a composite measure, defined as the median time from molecular to via Imaging verified Recurrence Lead Time (calculated only for patients in the liquid-biopsy guided Intensive Surveillance arm) + Difference in time to distant recurrence between the two arms (i.e., difference between median time from randomization to distant recurrence for all patients with distant recurrence in the Standard Surveillance arm and median time from randomization to distant recurrence for all patients with distant recurrence in the liquid-biopsy guided Intensive Surveillance arm). The Overall Lead Time Effect will be assessed for all markers in combination.

  5 years

Secondary Outcomes (14)

• Invasive disease-free survival (IDFS)

  10 years

• Distant disease-free survival (DDFS)

  10 years

• Distant recurrence-free survival (DRFS)

  10 years

• Breast cancer specific survival (BCSS)

  10 years

• Invasive breast cancer free survival (IBCFS)

  10 years

Other Outcomes (1)

• Establishment of a Biobank for Translational Research Endpoint

  5 years

Study Arms (2)

Intensive Surveillance arm

ACTIVE COMPARATOR

Intensified surveillance. Prospective tumor marker (CA27.29, CA125, CEA), CTC and ctDNA testing of the blood samples. Abnormal findings of either marker (CA27.29 and/or CA125 and/or CEA and/or CTC and/or ctDNA) will be regarded as molecular relapse and trigger diagnostic imaging.

Diagnostic Test: Determination of tumormarkers (CA27.29, CEA, CA125); Diagnostic Test: Determination of CTC levels; Diagnostic Test: Determination of ctDNA levels

Standard Surveillance arm

PLACEBO COMPARATOR

Surveillance according to national guidelines. Blood samples will not be analyzed immediately and will therefore not trigger imaging. A biobank will be established for retrospective and translational studies. This procedure is necessary to ensure the partially double-blinded study design.

Other: Biobanking of blood samples

Interventions

Determination of tumormarkers (CA27.29, CEA, CA125) DIAGNOSTIC_TEST

CA27.29, CEA and CA125 will be measured with the AIA®-CL1200 by TOSOH BIOSCIENCE (TOSOH CORPORATION, Tokyo, Japan). The CL AIA-PACK assays are two-step chemiluminescence enzyme immunoassay kits. CA27.29/CEA/CA125 present in a test sample is bound to the anti- CA27.29/CEA/CA125 mouse monoclonal antibody immobilized on the magnetic microparticles in one cell (Cell-I). After first incubation, the magnetic microparticles are washed and the enzyme-labeled anti- CA27.29/CEA/CA125 mouse monoclonal antibody that has been reconstituted in another cell (Cell-II) is dispensed into Cell-I. After second incubation, the magnetic microparticles are washed again and are incubated with a chemiluminescent substrate, DIFURAT®. The amount of enzyme-labeled antibodies that bind to the magnetic microparticles is directly proportional to the CA27.29/CEA/CA125 concentration in the test sample. A standard curve is constructed, unknown sample concentrations are calculated by using this curve.

Also known as: Chemiluminescence enzyme immunoassay

Intensive Surveillance arm

Determination of CTC levels DIAGNOSTIC_TEST

CTCs will be analyzed using the CellSearch® System (Menarini Silicon Biosystems). The CellSearch® system is designed to enumerate CTCs of epithelial origin (CD45-, EpCAM+, cytokeratin 8+ / 18+ and/or 19+). The basic principle is linking a magnetic ferrofluid reagent that contains i. a. antibodies targeting the EpCAM antigen to CTCs. After steps of immunomagnetic capture and enrichment as well as addition of fluorescent reagents (that contain anti-CK-PE, DAPI and anti-CD45-APC), the automatic dispersion to a magnetic cartridge holder takes place. Via strong magnetic field, the magnetically labeled epithelial cells are attracted to the surface of the cartridge where they can be scanned automatically. Images of events where CK-PE and DAPI fluorescence are co-located are presented to the user for final classification. An event is classified as a tumor cell when its morphological features are consistent with that of a tumor cell and it exhibits the phenotype EpCAM+, CK+, DAPI+ and CD45-.

Also known as: CellSearch® System

Intensive Surveillance arm

Determination of ctDNA levels DIAGNOSTIC_TEST

Presence of ctDNA will be analyzed centrally at Inivata Inc. using the RaDaRTM assay. Therefore, primary tumor tissue and peripheral blood specimens will be shipped for centralized analysis to Inivata Inc. RaDaRTM is a tumor-informed approach, beginning with whole exome sequencing of a tumor specimen from a patient's biopsy or surgical resection. SNVs and indels identified from the exome sequencing are prioritized to build a patient specific primer panel of up to 48 tumor-specific somatic variants. Patient specific primers are combined with common SNP primers for NGS for quality control purposes. To detect patient specific ctDNA, NGS testing is performed with the RaDaRTM assay using a multiplex PCR based on the InVision® platform.

Also known as: RaDaRTM assay

Intensive Surveillance arm

Biobanking of blood samples OTHER

To ensure the possibility of retrospective studies during and after the ongoing study, a biobank will be implemented.

Also known as: Translational research

Standard Surveillance arm

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent for all study procedures according to local regulatory requirements prior to beginning specific protocol procedures.
• Unilateral or bilateral primary invasive carcinoma of the breast, confirmed histologically.
• Patients with intermediate- to high-risk early breast cancer defined as either
• an indication for (neo-)adjuvant chemotherapy (regardless whether performed or not), and/or
• Large tumor (\> 50 mm), and/or
• Positive lymph nodes, and/or
• High grade (\>= G3). Indication to (neo-)adjuvant chemotherapy is seen as stated in the German S3 guideline for breast cancer as well as stated in the guidelines from the AGO.
• A complete resection of the primary tumor, with resection margins free of invasive carcinoma.
• Completion of primary anti-tumor therapy (adjuvant chemotherapy, surgery or radiotherapy, whichever occurs last) at least 4 weeks but no more than 24 months previously. Enrollment of patients during any kind of adjuvant therapy except chemotherapy (e.g., but not limited to endocrine therapy, antibody therapy, CDK4/6-inhibitors, PARP inhibitors, PI3K inhibitors, antibody-drug conjugates and other novel agents) is allowed.
• Availability of primary tumor tissue from core biopsy or surgical removed tissue (FFPE Slide (≥ 6 mm³, min. 10 slides, thickness: 5 µm-10 µm, area \>150 mm² and 1 H\&E stained slide, minimum 20% tumor content) or FFPE Block (≥ 6 mm³ thickness: 100 µm, area: \>150 mm² and 1 H\&E stained slide, minimum 20% tumor content) or Genomic DNA extracted from FFPE slides or block (≥ 600 ng, Minimum volume: 25 µL, concentration: 20 ng/µL, buffer: 10 mM Tris pH 8, 1 mM EDTA)) at timepoint of enrollment.
• Patients with primary systemic therapy: tissue from core biopsy
• Patients receiving surgery as primary therapy: surgically removed cancer tissue.
• No current clinical evidence for distant metastases.
• Females or males ≥ 18 years and ≤ 75 years of age.
• Performance status ≤ 1, Eastern Cooperative Oncology Group (ECOG) scale.

You may not qualify if:

• Patients with a history of any secondary primary malignancy are ineligible with the following exceptions:
• in situ carcinoma of the cervix or
• adequately treated basal cell carcinoma of the skin or
• ipsi- or contralateral non-invasive carcinoma of the breast (DCIS).
• History of significant neurological or psychiatric disorders including psychotic disorders, dementia or seizures that would prohibit the understanding and giving of informed consent.
• Renal insufficiency with GFR \< 30 mL/min.
• Previous or concomitant cytotoxic or other systemic antineoplastic treatment that is not used for treating the primary breast cancer.

Sponsors & Collaborators

• Prof. Wolfgang Janni: lead
• German Federal Ministry of Education and Research: collaborator

Study Sites (1)

University Hospital Ulm Gynecology/Obstetrics

Ulm, 89075, Germany

RECRUITING

Related Links

• Related Info

MeSH Terms

Conditions

Breast Neoplasms

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• Sophia Huesmann, Dr.

  Universitätsklinikum Ulm

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Sophia Huesmann, Dr.

CONTACT

+4973150058577; sophia.huesmann@uniklinik-ulm.de

Forca Mehmeti, M.Sc.

CONTACT

+4973150058536; forca.mehmeti@uniklinik-ulm.de

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: This study will be performed as partially double-blinded. This means, all patients and doctors are blinded initially as blood sampling is done in all patients, irrespective of randomization to the Standard Surveillance arm or the Intensive Surveillance arm. If one of the biomarkers (CA27.29, CEA, CA125, CTC, ctDNA) is abnormal and requires a confirmatory blood sampling or triggers imaging, unblinding is the consequence as these patients will be asked to undergo further assessments and the responsible doctor will arrange these. Unblinding in this case is the ethical consequence of not letting all patients undergo a confirmatory blood sampling or even undergo additional imaging without elevated biomarkers. If no confirmatory blood sampling or imaging is necessary, patients in the Intensive Surveillance arm will not be unblinded as there is no purpose to serve. Patients in the Standard Surveillance arm will not be unblinded altogether.
• Purpose: DIAGNOSTIC
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Director of the clinic for gynecology and obstetrics

Model Details: This is a partially double-blinded, multi-center, randomized, controlled superiority study.

Study Record Dates

• First Submitted: November 23, 2022
• First Posted: December 20, 2022
• Study Start: December 7, 2022
• Primary Completion (Estimated): December 1, 2035
• Study Completion (Estimated): December 1, 2035
• Last Updated: May 2, 2025

Record last verified: 2025-04

Locations

DE (1)