EXActDNA-003: Breast Cancer Clinical Validation Study to Predict Recurrence of High-Risk Early Breast Cancer Treated with Neoadjuvant Therapy Using a Bespoke Circulating Tumor DNA Assay to Detect Molecular Residual Disease (NSABP B-64)
Objective
Primary Objective: Analyses will be done across the 3 subtypes in Part 1 and per breast cancer subtype in tissue-evaluable participants in Part 2. For the purposes of this study, subtypes will be defined as follows: Triple Negative Breast Cancer (TNBC), Hormone Receptor-Positive (HR+)/Human Epidermal Growth Factor Receptor 2 Negative (HER2-), or HER2+ (inclusive of HR- and HR+), with hormone receptor status and HER2 status defined by current ASCO/CAP guidelines.
Part 1: To establish the rate of evaluable tissue submissions, defined as the proportion of participants for whom available material from their FFPE diagnostic breast biopsy is sufficient for creation of a participant-specific bespoke ctDNA assay. Feasibility for completing Part 2 will be defined by receipt of evaluable FFPE tissue from diagnostic biopsies in > 60% of participants.
Part 2: The Primary Objectives for Part 2 will be performed sequentially as listed below: To validate the association of serially measured ctDNA status, starting at the first blood draw following completion of cytotoxic adjuvant therapy for those receiving adjuvant cytotoxic therapy, and at the post-surgery blood draw for those not receiving cytotoxic adjuvant therapy, with distant recurrence-free interval (dRFI). To validate the association of ctDNA positivity detected at the first blood draw following completion of cytotoxic adjuvant therapy for those receiving adjuvant cytotoxic therapy, and at the post-surgery blood draw for those not receiving adjuvant cytotoxic therapy, with dRFI.
Secondary Objectives: All secondary analyses will be done among tissue evaluable participants across the 3 subtypes in the cohort in Part 1 and per breast cancer subtype in Part 2 (TNBC, HR+/HER2-, or HER2+).
Part 1: To assess the association of ctDNA status collected at various timepoints during neoadjuvant therapy (pretreatment baseline, early-neoadjuvant therapy, post-neoadjuvant therapy/pre-surgery) with pathologic complete response (pCR) status. To assess the prevalence of tumor mutations and germline variants of interest.
Part 2: To assess the association of ctDNA status at baseline, early-neoadjuvant therapy, post-neoadjuvant therapy/pre-surgery, post-surgery/pre-cytotoxic adjuvant therapy (if administered), and post-cytotoxic adjuvant therapy (if administered) time points with dRFI, with and without adjustment for clinicopathologic and genomic risk factors. To assess the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of post-neoadjuvant therapy/pre-surgery ctDNA status for pCR status. To assess the sensitivity and specificity of post-surgery/post-cytotoxic adjuvant therapy (if administered) ctDNA status measured serially and at the post-surgery/post-cytotoxic adjuvant therapy (if administered) time point for subsequent distant recurrence. To assess time from first post-treatment positive ctDNA to clinically detected distant recurrence in participants who had a positive ctDNA result at or following the post-surgery/post-cytotoxic adjuvant therapy (if administered) completion time point. To assess the association of ctDNA clearance, defined as change from positive baseline ctDNA result to negative ctDNA result prior to surgery and post-surgery/pre-cytotoxic adjuvant therapy (if administered), with pCR and dRFI. To assess the association of ctDNA, both serially and at the post-surgery/post-cytotoxic adjuvant therapy (if administered) completion time point with the endpoints of recurrence-free interval (RFI), invasive breast cancer-free survival (IBCFS), event-free survival (EFS), and overall survival (OS).
