Early Detection of Treatment Futility in Patients with Metastatic Colorectal Cancer

Overview

Journal Oncotarget

Specialty Oncology

Date 2022 Jan 14

PMID 35028011

Authors

Jodi I Rattner

Karen A Kopciuk

Hans J Vogel

Patricia A Tang

Jeremy D Shapiro

Dongsheng Tu

Derek J Jonker

Lillian L Siu

Chris J OCallaghan

Oliver F Bathe

Affiliations

Soon will be listed here.

Abstract

Purpose: Chemotherapy options for treating CRC have rapidly expanded in recent years, and few have predictive biomarkers. Oncologists are challenged with evidence-based selection of treatments, and response is evaluated retrospectively based on serial imaging beginning after 2-3 months. As a result, cumulative toxicities may appear in patients who will not benefit. Early recognition of non-benefit would reduce cumulative toxicities. Our objective was to determine treatment-related changes in the circulating metabolome corresponding to treatment futility.

Methods: Metabolomic studies were performed on serial plasma samples from patients with CRC in a randomized controlled trial of cetuximab vs. cetuximab + brivanib ( = 188). GC-MS quantified named 94 metabolites and concentrations were evaluated at baseline, Weeks 1, 4 and 12 after treatment initiation. In a discovery cohort ( = 68), a model distinguishing changes in metabolites associated with radiographic disease progression and response was generated using OPLS-DA. A cohort of 120 patients was used for validation of the model.

Results: By one week after treatment, a stable model of 21 metabolites could distinguish between progression and partial response (R2Y = 0.859; Q2Y = 0.605; = 5e-4). In the validation cohort, patients with the biomarker had a significantly shorter OS ( < 0.0001). In a separate cohort of patients with HCC on axitinib, appearance of the biomarker also signified a shorter PFS (1.7 months vs. 9.2 months, = 0.001).

Conclusion: We have identified changes in the metabolome that appear within 1 week of starting treatment associated with treatment futility. The novel approach described is applicable to future efforts in developing a biomarker for early assessment of treatment efficacy.

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