Abstract 1209: Tumor informed circulating tumor DNA monitoring for early treatment response and survival outcomes on trastuzumab + pertuzumab
Authors: Kurzrock Razelle , Childress Merrida , Li Wenshu , Muse Anna , Malato Julia , Wang Yong , Liu Minetta , Aleshin Alexey , Wang Richard S. , Thierauf Julia , Sweeney Christopher J. , Hainsworth John , Szado Tania , Young Amanda , Schulze Katja , Spigel David , Meric-Bernstam Funda , Swanton Charles , Burris Howard A. 
Published: March 2024

Abstract
Background: Advances in cancer treatment have led to the rise of targeted therapies as practice-changing modalities, demonstrating significant efficacy in molecularly selected patients. However, depth of response and survival benefit is variable. Limitations in radiographic imaging create challenges in determining a clinical response. Circulating tumor DNA (ctDNA) is a promising minimally-invasive, predictive biomarker. Here we explore the utility of tumor-informed, on-treatment ctDNA dynamics for early response monitoring and prognostication in patients with HER2-positive tumors of various histologies receiving trastuzumab + pertuzumab on the phase II basket trial, MyPathway (NCT02091141).
Methods: In this retrospective study, 58 patients were included based on availability of tissue comprehensive genomic profiling (CGP) results and baseline/on-treatment plasma. FoundationOne® Tracker was utilized to detect and quantify ctDNA, selecting 2-16 tumor-derived variants from tissue CGP and monitoring the corresponding patient’s plasma with multiplex PCR. ctDNA was assessed at baseline and Cycle 3 Day 1 (C3D1) of therapy. Correlations between ctDNA changes and objective response, progression-free survival (PFS) and overall survival (OS) were made using Kaplan Meier analyses and landmarked at C3D1. Patients ctDNA- at baseline and C3D1 were excluded.
Results: Of the 58 patients, personalized ctDNA assays were successfully designed for 52 (89.7%) representing 14 unique tumor histologies. Of 52, 48 (92.3%) had ctDNA results available for baseline analysis with a median of 100.7 mean tumor molecules per mL (MTM/mL); 89.6% were ctDNA+ with a median of 119.5 MTM/mL. A total of 39 patients had both baseline and C3D1 results for ctDNA response analyses. On-treatment ctDNA decline &gt;90% (N=10) was associated with longer survival compared to &lt;90% decline (N=16) or any increase (N=13) in ctDNA (OS: NR, 9.4 months (mo); P= 0.007). CtDNA dynamics remained predictive in a disease specific analysis of colorectal cancer (N=18; OS: NR, 10.2 mo; P= 0.04). Similar results were seen when stratifying patients by baseline ctDNA level (above/below median MTM/mL) or HER2 (ERBB2) mutation vs amplification. ctDNA increase at C3D1 preceded radiographic progression by a median of 1.3 mo. In patients with stable disease, &gt;90% decline in ctDNA was associated with longer OS compared to &lt;90% decline or any increase (NR, 9.4 mo; P= 0.01).
Conclusion: Tumor-informed ctDNA monitoring provides insight into early treatment response and survival outcomes in patients with diverse HER2 amplified or mutated tumors receiving HER2 targeted therapy. On-treatment ctDNA dynamics refine and can potentially detect response/progression ahead of standard of care response assessments, suggesting early ctDNA monitoring as a valuable complementary tool for real-time treatment response monitoring.
Citation Format: Razelle Kurzrock, Merrida Childress, Wenshu Li, Anna Muse, Julia Malato, Yong Wang, Minetta Liu, Alexey Aleshin, Richard S. Wang, Julia Thierauf, Christopher J. Sweeney, John Hainsworth, Tania Szado, Amanda Young, Katja Schulze, David Spigel, Funda Meric-Bernstam, Charles Swanton, Howard A. Burris. Tumor informed circulating tumor DNA monitoring for early treatment response and survival outcomes on trastuzumab + pertuzumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1209.