Clinical validation of liquid biopsy-RECIST (LB-RECIST) in metastatic colorectal cancer (mCRC) patients: findings from the PLATFORM-B study

Abstract

Liquid biopsy; Metastatic colorectal cancer; Response assessment

Biòpsia líquida; Càncer colorectal metastàtic; Avaluació de la resposta

Biopsia líquida; Cáncer colorrectal metastásico; Evaluación de la respuesta

Background Circulating tumor DNA (ctDNA) variations predict tumor response to systemic treatment (so-called molecular response) earlier than radiological assessment. However, a standardized categorization of molecular response is an unmet clinical need. Liquid biopsy-RECIST (LB-RECIST), based on aggregate variant allele frequency (aggVAF; sum of all detected variant allele frequencies in a sample) variations, has been proposed to stratify molecular response. Metastatic colorectal cancer (mCRC) may be an attractive clinical scenario for LB-RECIST clinical implementation; however, specific data on clinical validity is still lacking. Patients and methods The prospective PLATFORM-B study enrolled 130 mCRC patients who received standard frontline treatment and underwent serial ctDNA analysis at baseline and week 8 of treatment. ctDNA was analyzed by next-generation sequencing (Oncomine Colon cfDNA Assay; Ion Torrent S5). LB-RECIST, both qualitative (changes in ctDNA detection) and quantitative (percentage variations of aggVAF), were used to categorize molecular response, and were correlated with clinical outcomes, including progression-free survival (PFS) and overall survival (OS). Results ctDNA results were available for 106 patients at baseline and 90 patients at week 8 of treatment. Single timepoint aggVAFWEEK8 >0% showed significantly worse survival outcomes compared to aggVAFWEEK8 = 0% (PFS P < 0.0001; OS P = 0.0069). Complete clearance of ctDNA at week 8 (ctDNA complete response, CCR) demonstrated the best prognostic and predictive values [median (m) OS 41.8 months; mPFS not reached (NR)], similar to persistent undetectable ctDNA (ctDNA non-measurable disease, CND; mOS 41.1 months; mPFS NR). Conversely, patients with ctDNA partial response (CPR) and ctDNA progressive disease (CPD) had the worst clinical outcomes (mOS 16.4 and 25.5 months, and mPFS 12.7 and 11.9 months, respectively). Conclusions LB-RECIST is prognostic and predictive of clinical outcomes in frontline mCRC. The clinical utility of LB-RECIST to guide early treatment decisions is warranted through interventional trials.

This work was supported by Instituto de Salud Carlos III FEDER [grant number PI21/00045] and Fundacion CRIS Excellence [grant number 19-30] (to CM).