Radiologic and Genomic Evolution of Individual Metastases during HER2 Blockade in Colorectal Cancer
Giulia Siravegna, Luca Lazzari, Giovanni Crisafulli, Andrea Sartore-Bianchi, Benedetta Mussolin, Andrea Cassingena, Cosimo Martino, Richard B Lanman, Rebecca J Nagy, Stephen Fairclough, Giuseppe Rospo, Giorgio Corti, Alice Bartolini, Pamela Arcella, Monica Montone, Francesca Lodi, Annalisa Lorenzato, Alice Vanzati, Emanuele Valtorta, Giovanni Cappello, Andrea Bertotti, Sara Lonardi, Vittorina Zagonel, Francesco Leone, Mariangela Russo, Antonella Balsamo, Mauro Truini, Federica Di Nicolantonio, Alessio Amatu, Erica Bonazzina, Silvia Ghezzi, Daniele Regge, Angelo Vanzulli, Livio Trusolino, Salvatore Siena, Silvia Marsoni, Alberto Bardelli, Giulia Siravegna, Luca Lazzari, Giovanni Crisafulli, Andrea Sartore-Bianchi, Benedetta Mussolin, Andrea Cassingena, Cosimo Martino, Richard B Lanman, Rebecca J Nagy, Stephen Fairclough, Giuseppe Rospo, Giorgio Corti, Alice Bartolini, Pamela Arcella, Monica Montone, Francesca Lodi, Annalisa Lorenzato, Alice Vanzati, Emanuele Valtorta, Giovanni Cappello, Andrea Bertotti, Sara Lonardi, Vittorina Zagonel, Francesco Leone, Mariangela Russo, Antonella Balsamo, Mauro Truini, Federica Di Nicolantonio, Alessio Amatu, Erica Bonazzina, Silvia Ghezzi, Daniele Regge, Angelo Vanzulli, Livio Trusolino, Salvatore Siena, Silvia Marsoni, Alberto Bardelli
Abstract
Targeting HER2 is effective in 24% of ERBB2 amplified metastatic colorectal cancer; however, secondary resistance occurs in most of the cases. We studied the evolution of individual metastases during treatment to discover spatially resolved determinants of resistance. Circulating tumor DNA (ctDNA) analysis identified alterations associated with resistance in the majority of refractory patients. ctDNA profiles and lesion-specific radiographic reports revealed organ- or metastasis-private evolutionary patterns. When radiologic assessments documented progressive disease in target lesions, response to HER2 blockade was retained in other metastases. Genomic and functional analyses on samples and cell models from eight metastases of a patient co-recruited to a postmortem study unveiled lesion-specific evolutionary trees and pharmacologic vulnerabilities. Lesion size and contribution of distinct metastases to plasma ctDNA were correlated.
Keywords: HER2 amplification; clonal evolution; colorectal cancer; ctDNA; lapatinib; liquid biopsy; rapid autopsy; resistance; targeted therapy; trastuzumab.
Copyright © 2018 Elsevier Inc. All rights reserved.
Source: PubMed