Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, with metastatic disease posing significant therapeutic challenges. While anti-EGFR therapy has improved outcomes for patients with RAS and BRAF wild-type tumors, resistance remains a major hurdle, limiting treatment efficacy. The concept of negative hyperselection has emerged as a refinement of molecular profiling, identifying additional genomic alterations—such as HER2 and MET amplificationsand MAP2K1 mutations—that predict resistance to anti-EGFR agents. Studies incorporating these expanded assessments have demonstrated that nearly half of patients with RAS/BRAF wild-type tumors harbor alternative resistance biomarkers, underscoring the need for expanded selection criteria. Liquid biopsies, particularly circulating tumor DNA (ctDNA) analysis, have revolutionized precision oncology by providing a minimally invasive, real-time assessment of tumor dynamics. ctDNA-based hyperselection enables the detection of resistance-associated alterations, guiding treatment decisions with greater accuracy than conventional tissue biopsies. Recent trials support the predictive value of ctDNA-defined negative hyperselection, revealing superior outcomes for patients stratified through liquid biopsy. This narrative review explores the evolving role of molecular hyperselection in first-line anti-EGFR therapy, emphasizing the integration of ctDNA to refine patient selection, enhance therapeutic efficacy, and pave the way for personalized treatment strategies in metastatic CRC.
Negative Hyperselection in Metastatic Colorectal Cancer for First-Line Anti-EGFR Therapy: A Narrative Review
Ciappina G.;Toscano E.;Consolo P.;Maiorana E.;Carroccio P.;Franchina T.;Ieni A.;Berretta M.
2025-01-01
Abstract
Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, with metastatic disease posing significant therapeutic challenges. While anti-EGFR therapy has improved outcomes for patients with RAS and BRAF wild-type tumors, resistance remains a major hurdle, limiting treatment efficacy. The concept of negative hyperselection has emerged as a refinement of molecular profiling, identifying additional genomic alterations—such as HER2 and MET amplificationsand MAP2K1 mutations—that predict resistance to anti-EGFR agents. Studies incorporating these expanded assessments have demonstrated that nearly half of patients with RAS/BRAF wild-type tumors harbor alternative resistance biomarkers, underscoring the need for expanded selection criteria. Liquid biopsies, particularly circulating tumor DNA (ctDNA) analysis, have revolutionized precision oncology by providing a minimally invasive, real-time assessment of tumor dynamics. ctDNA-based hyperselection enables the detection of resistance-associated alterations, guiding treatment decisions with greater accuracy than conventional tissue biopsies. Recent trials support the predictive value of ctDNA-defined negative hyperselection, revealing superior outcomes for patients stratified through liquid biopsy. This narrative review explores the evolving role of molecular hyperselection in first-line anti-EGFR therapy, emphasizing the integration of ctDNA to refine patient selection, enhance therapeutic efficacy, and pave the way for personalized treatment strategies in metastatic CRC.Pubblicazioni consigliate
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
