Ruolo della biopsia liquida nella malattia colorettale metastatica trattata con chemioterapia di I linea in associazione ad anti-EGFR: analisi dello studio PLATFORM-B

Abstract

Background: Nel trattamento del carcinoma del colon-retto metastatico (mCRC), è cruciale identificare biomarcatori predittivi per terapie specifiche, come l'instabilità dei microsatelliti per l'immunoterapia, le mutazioni RAS/RAF per inibitori dell'EGFR (cetuximab) e la mutazione BRAFV600E per encorafenib e cetuximab. La biopsia liquida è un'alternativa quando la biopsia tissutale è invasiva o ritardata. Purpose: Questa seconda analisi dello studio PLATFORM-B esamina le mutazioni troncali e le mutazioni secondarie nel ctDNA al momento della progressione della malattia per comprendere le dinamiche di resistenza alle terapie anti-EGFR e la progressione del mCRC. Experimental design: Il ctDNA al baseline e alla progressione è stato analizzato tramite next-generation sequencing (NGS). Le mutazioni troncali sono state considerate come biomarcatori del carico tumorale totale, mentre le mutazioni RAS/BRAF/MEK/EGFR-ECD come mutazioni di resistenza. I risultati del ctDNA sono stati correlati agli outcome clinici. Results: Al momento della stesura, le analisi dei campioni di plasma sono completate, ma le analisi statistiche sono ancora in corso. Pertanto, vengono riportati risultati parziali e preliminari. Conclusions: Questo studio potrà fornire nuove intuizioni sui meccanismi di resistenza alle terapie di prima linea con anti-EGFR nel mCRC.

Background: The treatment of metastatic colorectal cancer (mCRC) requires testing three prognostic and predictive biomarkers on tumor tissue samples: microsatellite instability status and mutations in the RAS and BRAF genes. Patients with RAS/BRAF wild-type (wt) tumors benefit from adding to chemotherapy monoclonal antibodies (mAbs) that inhibit the activation of the epidermal growth factor receptor (EGFR) -cetuximab and panitumumab. Circulating tumor DNA (ctDNA) analysis through liquid biopsy is a valuable alternative for genotyping tumor biomarkers, since it is less “invasive” than tissue biopsy and its reporting times are relatively short. PLATFORM-B was the first study to demonstrate the role of ctDNA in predicting the response to first-line chemotherapy plus Cetuximab in mCRC patients with RAS wt tumors.

Purpose: This second analysis of the PLATFORM-B study evaluates changes over time in trunk mutations and secondary mutations found in liquid biopsies at disease progression. The aim is to better understand the dynamics of resistance to anti-EGFR therapies and the mechanisms behind the progression of mCRC tumors.

Experimental design: ctDNA at baseline and progression was analyzed using next-generation sequencing (NGS). Trunk mutations were considered as surrogate biomarkers for the total tumor burden, while RAS/BRAF/MEK/EGFR-ECD mutations were considered resistance mutations. The ctDNA results were subsequently correlated with clinical outcomes.

Results: As of the writing of this work, plasma sample analyses have been completed, but statistical analyses are still in progress. Therefore, the text reports partial and preliminary results.

Conclusions: ctDNA analysis will make patient selection more accurate, minimizing the risk of unnecessary toxicity from ineffective treatments, thanks to a better understanding of tumor dynamics and the mechanisms of resistance to anti-EGFR.