Evaluation of whole-exome and whole-genome sequencing tumor-informed circulating tumor DNA MRD assays in patients with early triple-negative breast cancer (TNBC) receiving neoadjuvant chemotherapy (NAC) with or without olaparib: A prospective sub-study of the PARTNER trial.

Abstract

570 Background: Detection of molecular residual disease (MRD), using circulating tumor DNA (ctDNA), following treatment for early-stage TNBC is associated with a high risk of recurrence. ctDNA clearance in response to NAC has shown potential for predicting pathologic compete response (pCR) and improving the prognostic ability of pCR status. PARTNER is a prospective, phase II-III, randomized controlled clinical trial, which recruited early-stage basal TNBC BRCA1/2 wild-type patients (Nature April 2024). Control regimen was neoadjuvant carboplatin–paclitaxel followed by anthracycline-based NAC. Experimental arms added olaparib to the platinum-taxane backbone. A sub-study of serial blood samples for ctDNA analysis during NAC and post-op were analyzed with 2 tumor informed MRD assays using primary tumor and germline sequencing: 1) whole-exome sequencing (WES) to select ≤200 variants and 2) whole-genome sequencing (WGS) to select 400-5000 variants for the two bespoke MRD assays, respectively. Both assays were independently used to assess available plasma samples collected for the presence or absence of ctDNA. Methods: This prospective sub study included TNBC patients enrolled within PARTNER with serial blood collections at baseline (prior to NAC), mid-NAC, post-NAC, 2-4 weeks post-op, 3 months post-op and 12 months post-op. Germline and somatic DNA were provided via the Personalised Breast Cancer Program. The primary objective was to determine the association of ctDNA positivity post-op with distant recurrence-free interval (DRFI). The distribution of DRFI by ctDNA status was compared using the log-rank test. The Cox proportional hazards regression model was used to estimate the strength of the relationship between ctDNA positivity and DRFI. Results: Median WES MRD assay panel size was 159 variants (range 47 – 200). At baseline ctDNA was detected in 50 of 55 patients (91%). After NAC, 4 of 63 patients had detectable ctDNA. 24 of 28 non-pCR patients were ctDNA negative and 0 of 35 pCR patients were ctDNA positive. Of 61 post-op patients available to assess DRFI distant recurrences developed in 8 patients (13.1%) within a median follow up of 5 years. Post-op 5 patients were ctDNA positive and 3 developed distant recurrences (log-rank p < 0.0001, HR = 20.2, 95% CI = 4.3, 95.1). In addition, 56 were ctDNA negative and 51 (91%) were distant recurrence free. Median WGS MRD assay panel size was 2962 variants (range 552 - 5000). At baseline ctDNA was detected in 46 of 47 patients (98%). Additional WGS MRD results are being generated and will be presented at the meeting. Conclusions: Post-op detection of ctDNA using a WES MRD assay was highly prognostic for distant recurrence in TNBC patients following NAC. WGS MRD improved baseline detection.