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. Im Brief: Siravegna et al. identify genetic events associated with ERBB2 amplified metastatic colorectal cancers resistant to trastuzumab plus lapatinib treatment and reveal lesion-private evolutionary patterns. Analyses of metastases from a patient unveil metastasis-specific evolution and pharmacologic vulnerabilities.
Radiologic and Genomic Evolution of Individual Metastases during HER2 Blockade in Colorectal Cancer / G. Siravegna, L. Lazzari, G. Crisafulli, A. Sartore-Bianchi, B. Mussolin, A. Cassingena, C. Martino, R.B. Lanman, R.J. Nagy, S. Fairclough, G. Rospo, G. Corti, A. Bartolini, P. Arcella, M. Montone, F. Lodi, A. Lorenzato, A. Vanzati, E. Valtorta, G. Cappello, A. Bertotti, S. Lonardi, V. Zagonel, F. Leone, M. Russo, A. Balsamo, M. Truini, F. Di Nicolantonio, A. Amatu, E. Bonazzina, S. Ghezzi, D. Regge, A. Vanzulli, L. Trusolino, S. Siena, S. Marsoni, A. Bardelli. - In: CANCER CELL. - ISSN 1535-6108. - 34:1(2018 Jul 01), pp. 148-162.e7.
|Titolo:||Radiologic and Genomic Evolution of Individual Metastases during HER2 Blockade in Colorectal Cancer|
|Parole Chiave:||clonal evolution; colorectal cancer; ctDNA; HER2 amplification; lapatinib; liquid biopsy; rapid autopsy; resistance; targeted therapy; trastuzumab; Oncology; Cell Biology; Cancer Research|
|Settore Scientifico Disciplinare:||Settore MED/06 - Oncologia Medica|
|Data di pubblicazione:||1-lug-2018|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.ccell.2018.06.004|
|Appare nelle tipologie:||01 - Articolo su periodico|