Standard Surveillance vs. Intensive Surveillance in Early Breast Cancer

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

NA

Total Enrollment

3500 participants

Study Classification

INTERVENTIONAL

Study Start Date

2022-12-07

Study Completion Date

2035-12-31

Brief Summary

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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.

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RECRUITING

Detailed Description

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This is a partially double-blinded, multi-center, randomized, controlled superiority study to evaluate the potential benefits of intensified surveillance versus standard surveillance in medium-risk and high-risk early breast cancer patients.

3500 patients will be enrolled after completion of primary anti-tumor therapy (adjuvant chemotherapy, surgery or radiotherapy, whichever occurs last) and randomized in a 1:1 ratio to receive:

* Standard Surveillance according to national guidelines or
* Intensive Surveillance with additional testing of blood samples for prospective tumor markers (CA27.29, CA125, CEA), CTC and ctDNA

In both study arms patients will receive standard surveillance according to national guidelines, including clinical follow-up visits every 3 months for the first 3 years and every 6 months for the following 2 years. Additionally, blood samples will be drawn and Quality of Life (QoL) will be analyzed at these clinical follow-up visits in both arms.

In the Standard Surveillance arm blood samples will be stored in a biobank. In the Intensive Surveillance arm blood samples will be tested for prospective tumor markers (CA27.29, CA125, CEA), CTCs and ctDNA. Abnormal findings of either marker (CA27.29 or CA125 or CEA or CTC or ctDNA) will trigger diagnostic imaging. Additionally, blood samples will be stored in a biobank for retrospective analysis.

In both study arms detection of distant recurrence will terminate the surveillance protocol and treatment will be initiated according to national guidelines.

Planned enrollment period is approximately 24 months, total study duration is approximately 144 months (2-year recruitment period, 5-year interventional period, 5-year follow up period). In terms of long-term follow-up after end of study, patients have the possibility to participate in the patient self-reporting registry (Patientenselbstauskunft).

Conditions

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Breast Cancer

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

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

Primary Study Purpose

DIAGNOSTIC

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

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.

Study Groups

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Intensive Surveillance arm

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.

Group Type ACTIVE_COMPARATOR

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

Intervention Type 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.

Determination of CTC levels

Intervention Type 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-.

Determination of ctDNA levels

Intervention Type 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.

Standard Surveillance arm

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.

Group Type PLACEBO_COMPARATOR

Biobanking of blood samples

Intervention Type OTHER

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

Interventions

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

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.

Intervention Type DIAGNOSTIC_TEST

Determination of CTC levels

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-.

Intervention Type DIAGNOSTIC_TEST

Determination of ctDNA levels

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.

Intervention Type DIAGNOSTIC_TEST

Biobanking of blood samples

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

Intervention Type OTHER

Other Intervention Names

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Chemiluminescence enzyme immunoassay CellSearch® System RaDaRTM assay Translational research

Eligibility Criteria

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Inclusion Criteria

1. Written informed consent for all study procedures according to local regulatory requirements prior to beginning specific protocol procedures.
2. Unilateral or bilateral primary invasive carcinoma of the breast, confirmed histologically.
3. 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.
4. A complete resection of the primary tumor, with resection margins free of invasive carcinoma.
5. 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.
6. 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.
7. No current clinical evidence for distant metastases.
8. Females or males ≥ 18 years and ≤ 75 years of age.
9. Performance status ≤ 1, Eastern Cooperative Oncology Group (ECOG) scale.
10. Patient must be willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.

Exclusion Criteria

1. 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).
2. Patients in pregnancy or breastfeeding. If a patient gets pregnant during the participation in the interventional phase of the study (Year 1-5), an end of intervention visit will be scheduled and the patient will enter the follow-up phase of the study. Pregnancy during the follow-up phase of the study is to be reported but does not lead to an exclusion of the study.
3. History of significant neurological or psychiatric disorders including psychotic disorders, dementia or seizures that would prohibit the understanding and giving of informed consent.
4. Renal insufficiency with GFR \< 30 mL/min.
5. Previous or concomitant cytotoxic or other systemic antineoplastic treatment that is not used for treating the primary breast cancer.

Minimum Eligible Age

18 Years

Maximum Eligible Age

75 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No