Molecular screening with liquid biopsy for anti-EGFR retreatment in metastatic colorectal cancer: preliminary data from the randomized phase 2 PARERE trial.
Marco Maria Germani, Guglielmo Vetere, Mirella Giordano, Paolo Ciracì, Iolanda Capone, Elena Tamborini, Elena Conca, Adele Busico, Filippo Pietrantonio, Vittoria Matilde Piva, Alessandra Boccaccino, Francesca Simionato, Martina Bortolot, Paolo Manca, Sara Lonardi, Veronica Conca, Beatrice Borelli, Martina Carullo, Marzia Del Re, Gabriella Fontanini, Daniele Rossini, Chiara Cremolini
Author Information
Marco Maria Germani: Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy.
Guglielmo Vetere: Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy.
Mirella Giordano: Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy.
Paolo Ciracì: Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy.
Iolanda Capone: Molecular Pathology Laboratory, Department of Pathology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale Dei Tumori, Milan, Italy.
Elena Tamborini: Molecular Pathology Laboratory, Department of Pathology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale Dei Tumori, Milan, Italy.
Elena Conca: Molecular Pathology Laboratory, Department of Pathology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale Dei Tumori, Milan, Italy.
Adele Busico: Molecular Pathology Laboratory, Department of Pathology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale Dei Tumori, Milan, Italy.
Filippo Pietrantonio: Department of Medical Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori, Milan, Italy.
Vittoria Matilde Piva: Oncology Unit 1, Veneto Institute of Oncology - Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padua, Italy.
Alessandra Boccaccino: Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy.
Francesca Simionato: Department of Oncology, San Bortolo General Hospital, Vicenza, Italy.
Martina Bortolot: Department of Medicine (DAME), University of Udine, Udine, Italy.
Paolo Manca: Department of Medical Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori, Milan, Italy.
Sara Lonardi: Oncology Unit 3, Veneto Institute of Oncology - Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padua, Italy.
Veronica Conca: Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy.
Beatrice Borelli: Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy.
Martina Carullo: Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy.
Marzia Del Re: Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
Gabriella Fontanini: Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy.
Daniele Rossini: Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
Chiara Cremolini: Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy.
Background: Retreatment with anti-EGFR monoclonal antibodies is a promising strategy in patients with wild-type (wt) metastatic colorectal cancer (mCRC) who achieved benefit from previous anti-EGFR exposure upon exclusion of mutations in 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. Methods: Patients with 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. Results: A total of 218 patients underwent LB, and ctDNA sequencing was successful in 201 of them (92%). V600E mutations were found in 68 (34%) patients and were mainly subclonal (median variant allele fraction [VAF] for , , and mutant clones: 0.52%, 0.62%, and 0.12%, respectively; = 0.01), with Q61H being the most frequently detected (31%). Anti-EGFR-free intervals did not predict ctDNA molecular status ( = 0.12). Among the 133 patients with 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 , , , , , (class I and II non-BRAFV600E), , , , and 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. Conclusions: 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 V600E wt ctDNA.
