Abstract
Only a fraction of patients with metastatic colorectal cancer receive clinical benefit from therapy with anti-epidermal growth factor receptor (EGFR) antibodies, which calls for the identification of novel biomarkers for better personalized medicine. We produced large xenograft cohorts from 85 patient-derived, genetically characterized metastatic colorectal cancer samples ("xenopatients") to discover novel determinants of therapeutic response and new oncoprotein targets. Serially passaged tumors retained the morphologic and genomic features of their original counterparts. A validation trial confirmed the robustness of this approach: xenopatients responded to the anti-EGFR antibody cetuximab with rates and extents analogous to those observed in the clinic and could be prospectively stratified as responders or nonresponders on the basis of several predictive biomarkers. Genotype-response correlations indicated HER2 amplification specifically in a subset of cetuximab-resistant, KRAS/NRAS/BRAF/PIK3CA wild-type cases. Importantly, HER2 amplification was also enriched in clinically nonresponsive KRAS wild-type patients. A proof-of-concept, multiarm study in HER2-amplified xenopatients revealed that the combined inhibition of HER2 and EGFR induced overt, long-lasting tumor regression. Our results suggest promising therapeutic opportunities in cetuximab-resistant patients with metastatic colorectal cancer, whose medical treatment in the chemorefractory setting remains an unmet clinical need. Direct transfer xenografts of tumor surgical specimens conserve the interindividual diversity and the genetic heterogeneity typical of the tumors of origin, combining the flexibility of preclinical analysis with the informative value of population-based studies. Our suite of patient-derived xenografts from metastatic colorectal carcinomas reliably mimicked disease response in humans, prospectively recapitulated biomarker-based case stratification, and identified HER2 as a predictor of resistance to anti-epidermal growth factor receptor antibodies and of response to combination therapies against HER2 and epidermal growth factor receptor in this tumor setting.
Highlights
With a global incidence of more than one million cases and a disease-specific mortality of approximately 33% in the developed world, colorectal cancer is a major health burden ( 1 )
One prototypical example is provided by the anti-epidermal growth factor receptor (EGFR) monoclonal antibodies cetuximab and panitumumab, which are approved for the treatment of metastatic colorectal cancer
By performing a meta-analysis of the available data on the activity of anti-epidermal growth factor receptor (EGFR) monotherapy in both heavily pretreated and chemo-naïve subjects, regardless of KRAS status, we found that average objective response was 10% and stable disease occurred in 30% of cases [4, 5, 25,26,27,28,29]
Summary
With a global incidence of more than one million cases and a disease-specific mortality of approximately 33% in the developed world, colorectal cancer is a major health burden ( 1 ). As for other types of malignancy, colorectal cancer is not a homogeneous disease but comprises multiple entities that vary in natural history and molecular pathogenesis. This heterogeneity explains why molecular cancer therapeutics against individual disease driver targets have proven to be effective in only a fraction of cases. The authors of both retrospective and prospective trials have convincingly demonstrated the inefficacy of EGFR-neutralizing antibodies in metastatic colorectal cancer patients with common (codons 12 and 13) KRAS mutations ( 7–12 ). When considering the cumulative incidence of NOVEMBER 2011 CANCER DISCOVERY | 509
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