AUTHOR=Germani Marco Maria , Vetere Guglielmo , Giordano Mirella , Ciracì Paolo , Capone Iolanda , Tamborini Elena , Conca Elena , Busico Adele , Pietrantonio Filippo , Piva Vittoria Matilde , Boccaccino Alessandra , Simionato Francesca , Bortolot Martina , Manca Paolo , Lonardi Sara , Conca Veronica , Borelli Beatrice , Carullo Martina , Del Re Marzia , Fontanini Gabriella , Rossini Daniele , Cremolini Chiara 

TITLE=Molecular screening with liquid biopsy for anti-EGFR retreatment in metastatic colorectal cancer: preliminary data from the randomized phase 2 PARERE trial

JOURNAL=Frontiers in Oncology

VOLUME=13

YEAR=2024

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2023.1307545

DOI=10.3389/fonc.2023.1307545

ISSN=2234-943X

ABSTRACT=<sec><title>Background</title><p>Retreatment with anti-EGFR monoclonal antibodies is a promising strategy in patients with <italic>RAS/BRAF</italic> wild-type (wt) metastatic colorectal cancer (mCRC) who achieved benefit from previous anti-EGFR exposure upon exclusion of mutations in <italic>RAS/BRAF</italic> genes according to circulating tumor DNA (ctDNA) analysis by means of liquid biopsy (LB). This treatment approach is now being investigated in the randomized phase II trial PARERE (NCT04787341). We here present preliminary findings of molecular screening.</p></sec><sec><title>Methods</title><p>Patients with <italic>RAS/BRAF</italic>V600E wt mCRC according to tissue genotyping who benefited from previous anti-EGFR-based treatment (fluoropyrimidines, oxaliplatin, irinotecan, and antiangiogenics) and then experienced disease progression to EGFR targeting were eligible for screening in the PARERE trial. The next-generation sequencing (NGS) panel Oncomine™ was employed for ctDNA testing.</p></sec><sec><title>Results</title><p>A total of 218 patients underwent LB, and ctDNA sequencing was successful in 201 of them (92%). <italic>RAS/BRAF</italic>V600E mutations were found in 68 (34%) patients and were mainly subclonal (median variant allele fraction [VAF] for <italic>KRAS</italic>, <italic>NRAS</italic>, and <italic>BRAF</italic> mutant clones: 0.52%, 0.62%, and 0.12%, respectively; <italic>p</italic> = 0.01), with <italic>KRAS</italic>Q61H being the most frequently detected (31%). Anti-EGFR-free intervals did not predict ctDNA molecular status (<italic>p</italic> = 0.12). Among the 133 patients with <italic>RAS/BRAF</italic>V600E wt tumors according to LB, 40 (30%) harbored a mutation in at least another gene potentially implied in anti-EGFR resistance, mainly with subclonal expression (median VAF, 0.56%). In detail, alterations in <italic>PIK3CA</italic>, <italic>FBXW7</italic>, <italic>GNAS</italic>, <italic>MAP2K</italic>, <italic>ERBB2</italic>, <italic>BRAF</italic> (class I and II non-BRAFV600E), <italic>SMAD</italic>, <italic>EGFR</italic>, <italic>AKT1</italic>, and <italic>CTNNB1</italic> occurred in 13%, 8%, 7%, 3%, 2%, 2%, 1%, 1%, 1%, and 1% cases, respectively. Co-mutations were detected in 13 (33%) out of 40 patients.</p></sec><sec><title>Conclusions</title><p>This is the largest prospective cohort of mCRC patients screened with LB for anti-EGFR retreatment in a randomized study. ctDNA genotyping reveals that at least one out of three patients candidate for retreatment should be excluded from this therapy, and other potential drivers of anti-EGFR resistance are found in approximately one out of three patients with <italic>RAS/BRAF</italic>V600E wt ctDNA.</p></sec>