Monitoring Plasma Tumor DNA in Early-Stage Breast Cancer

Plasma Tumor DNA and Pathologic Complete Response in Early-Stage, High-Risk Breast Cancer

This study is being done to see if it is possible to use blood samples to predict response to treatment in breast cancer patients receiving preoperative (or neoadjuvant) therapy. Research has shown that most breast cancers release tumor-specific DNA into the blood (that is, DNA that is specific to the tumor cells or cancer). This DNA can be detected in blood testing known as plasma tumor-DNA or "ptDNA." This DNA is separate from that found in the blood and tissue samples which serve as the "instruction book" or "genetic code" for the cells that make-up the human body. The changes in ptDNA before and after treatment, as well as after surgery, may also help investigators to understand more about a patient's risk of cancer returning and long-term outcomes.

Study Overview

• Status: Active, not recruiting
• Conditions: Breast Cancer
• Intervention / Treatment: Other: ptDNA; Other: Tissue sample

Detailed Description

This is a prospectively designed study. Up to 229 newly diagnosed invasive HER2-positive or triple-negative breast cancer patients planning neoadjuvant therapy (NAT) will be enrolled. Blood samples will be collected pre-operatively at the time of diagnosis/prior to NAT, post-cycle 1/pre-cycle 2 of NAT, after all NAT/immediately before surgery, and post-operatively at 6, 12, 24, and 36 months, and annually thereafter if funding allows. Researchers will also collect representative tissue samples from the diagnostic biopsy (in all participants) and definitive surgery (if available). Additionally, to look at feasibility of tumor DNA analyses in urine samples, urine samples will be collected along with blood samples (urine tumor DNA or utDNA).

Next generation sequencing will be performed on core biopsies of all enrolled patients for tumor-specific mutations (TSM) discovery. Based on those findings, droplet digital PCR (ddPCR) on plasma DNA samples will also be performed to confirm the presence of the TSM in the plasma on diagnosis, and one TSM will be chosen to track as the plasma tumor DNA (ptDNA) mutation of interest. Investigators will perform ddPCR on pre-operative plasma DNA samples and will assess for the presence of ptDNA. Pathologists will assess surgical specimens for pathologic response (such as complete response/pCR and residual cancer burden/RCB). As primary endpoint, investigators will assess the number of patients with and without preoperative ptDNA who have pCR versus residual disease. As exploratory endpoints, the following will also be performed: (a) quantitative multiplex methylation-specific PCR (QM-MSP) in diagnostic biopsy and definitive residual surgery specimen; and, (b) the circulating methylated tumor DNA (cMethDNA) assay in plasma specimens (baseline and after NAT), and evaluate associations with pathologic response.

Additional endpoints include the association between plasma and tissue markers at baseline, after NAT, and (if available) during surveillance with long-term prognosis (invasive disease-free survival/IDFS and distant disease-free survival/DDFS).

• Study Type: Observational
• Enrollment (Actual): 229

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Newly diagnosed invasive HER2-positive or triple-negative breast cancer patients planning neoadjuvant therapy (NAT)

Description

Inclusion Criteria:

• Newly diagnosed, histologically confirmed invasive breast cancer that is triple negative (estrogen receptor [ER], progesterone receptor [PR], and HER2-neu negative) or HER2-positive (any ER/PR status)
• Unresected, untreated breast cancer that is T2, T3, or T4a-c; any N (nodal status); and M0 (not metastatic)
• ECOG Performance Status of 0 or 1
• Planning to receive a neoadjuvant chemotherapy regimen containing a taxane ± an anthracycline for at least 4 cycles. Patients with HER2-positive disease must also be planning to receive HER2-targeted therapy.
• Diagnostic tumor material must be available for correlative analyses
• Patients must have the ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• No prior treatment for the current breast cancer, though prior use of selective estrogen receptor modulators (SERMs) or aromatase inhibitors (AIs) for the prevention of breast cancer is acceptable.
• Women who are pregnant or nursing are excluded.
• No history of another primary malignancy in the last 5 years prior to registration. Patients with prior history of in situ cancer or basal or localized squamous cell skin cancer are eligible.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Stage II-III breast cancer; Up to 229 newly diagnosed stage II-III invasive HER2-positive or triple-negative breast cancer patients planning neoadjuvant therapy (NAT) will be enrolled. ptDNA blood samples as well as a representative tumor tissue sample from both the diagnostic and surgical procedure (if available) will be collected.

Other: ptDNA; Pre-operative blood samples for ptDNA will be collected at the time of diagnosis/prior to NAT, post-cycle 1/pre-cycle 2 of NAT, after all NAT/immediately before surgery, and post-operatively at 6, 12, 24, and 36 months, and annually thereafter if funding allows.; Other Names: Blood sample; Other: Tissue sample; Representative tissue sample will be collected from the diagnostic biopsy (in all participants) and definitive surgery (if available)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation of absence of plasma tumor DNA (ptDNA) with pathologic complete response (pCR)	To estimate the negative predictive value (NPV) of the absence of plasma tumor DNA (ptDNA) Tumor Specific Mutations (TSMs) after neoadjuvant therapy (NAT) for the absence of residual disease as defined by pathologic complete response (pCR) in stage II-III HER2-positive or triple negative breast cancer (TNBC) NPV = True Negative/True Negative + False Negative (probability that the disease is not present when the test is negative)	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prognostic value of ptDNA for invasive disease-free survival and distant disease-free survival	To estimate the prognostic value of ptDNA for 5-year invasive disease-free survival (IDFS) and distant disease-free survival (DDFS) in TNBC patients following completion of loco-regional and systemic therapy	5 years
Correlation of absence of ptDNA with residual cancer burden (RCB)	To estimate the NPV of the absence of ptDNA TSMs after NAT for the absence of residual disease as defined by residual cancer burden (RCB) 0 or 1	6 months

Collaborators and Investigators

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborators: Translational Breast Cancer Research Consortium
• Investigators: Study Chair: Antonio C Wolff, M.D., Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Study record dates

Study Major Dates

• Study Start: July 1, 2016
• Primary Completion (Actual): February 1, 2019
• Study Completion (Estimated): July 1, 2026

Study Registration Dates

• First Submitted: April 15, 2016
• First Submitted That Met QC Criteria: April 15, 2016
• First Posted (Estimated): April 19, 2016

Study Record Updates

• Last Update Posted (Actual): July 17, 2025
• Last Update Submitted That Met QC Criteria: July 14, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: neoadjuvant; preoperative; plasma tumor DNA; ptDNA
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Breast Neoplasms
• Other Study ID Numbers: TBCRC040; TBCRC 040 (Other Identifier: Translational Breast Cancer Research Consortium (TBCRC)); IRB00093688 (Other Identifier: JHMIRB)

Plan for Individual participant data (IPD)

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