It is increasingly apparent that cancer is a heterogeneous disease with a spectrum of mutations present in individual minor clones that aren't represented in the bulk of the tumor cells. The overall hypothesis is that tumor heterogeneity has important clinical implications for treatment sensitivity and acquired resistance to targeted therapies, using EGFR inhibitors in colorectal cancer as a model system. The introduction of more sophisticated techniques for gene sequencing has made possible the identification of low frequency mutations that were missed with standard sequencing techniques. As KRAS mutations represent a well-recognized and clinically utilized predictive biomarker, it represents an opportunity to explore the implications of KRAS heterogeneity in the setting of EGFR monoclonal antibody (mAb) therapy. Recently, we and others have shown that the presence of low frequency KRAS mutations has been detected in tissue from approximately 15% of metastatic colorectal cancer (mCRC) patients when high-sensitivity sequencing is utilized. These rare KRAS mutant cells are present in what are usually identified as KRAS wild type tumor by less sensitive standard-of-care testing methodologies currently used in the clinic, thereby leading to the hypothesis that these clones are rapidly selected under treatment pressure, resulting in clinical progression to treatment. Retrospective, nonrandomized datasets support this hypothesis; these low-frequency KRAS mutations have been correlated with resistance to anti-EGFR treatment. Specifically, further selection of patients eligible for EGFR mAb therapy would reduce the cost of such therapies to the health care system (with modeled savings of $200 million per year given the prospective identification of 25% of non-responding patients). In this proposal we hypothesize that treatment-induced clonal changes are a dynamic balance in a heterogeneous tumor population. We propose to evaluate tumor genetic changes by studying samples from large randomized trials, including the primary tumor and circulating free tumor DNA (cfDNA) obtained from patient plasma samples. To capture longer-term dynamics, we will apply these monitoring techniques to a longitudinal cohort with an embedded prospective clinical trial of anti-EGFR retreatment. Patient-derived murine xenograft models will be utilized to more precisely quantify tumor dynamics. Understand the mechanisms of resistance of CRC will require a more detailed understanding of the heterogeneity and temporal dynamics of genomic changes, thereby leading to improved biomarkers for benefit and novel strategies to re-challenge tumors with previously effective therapy.
Tumor heterogeneity has important clinical implications for treatment sensitivity and acquired resistance to targeted therapies, using EGFR inhibitors in colorectal cancer as a model system. High-sensitivity sequencing technology and non-invasive blood-based assays will improve outcomes of patients by improved selection of patients for EGFR inhibitor therapy.
|Dasari, Arvind; Grothey, Axel; Kopetz, Scott (2018) Circulating Tumor DNA-Defined Minimal Residual Disease in Solid Tumors: Opportunities to Accelerate the Development of Adjuvant Therapies. J Clin Oncol :JCO2018789032|
|Kanikarla-Marie, Preeti; Kopetz, Scott; Hawk, Ernest T et al. (2018) Bioactive lipid metabolism in platelet ""first responder"" and cancer biology. Cancer Metastasis Rev 37:439-454|
|Strickler, John H; Loree, Jonathan M; Ahronian, Leanne G et al. (2018) Genomic Landscape of Cell-Free DNA in Patients with Colorectal Cancer. Cancer Discov 8:164-173|
|Menter, David G; Kopetz, Scott; Hawk, Ernest et al. (2017) Platelet ""first responders"" in wound response, cancer, and metastasis. Cancer Metastasis Rev 36:199-213|
|Leung, Marco L; Davis, Alexander; Gao, Ruli et al. (2017) Single-cell DNA sequencing reveals a late-dissemination model in metastatic colorectal cancer. Genome Res 27:1287-1299|
|Mehrvarz Sarshekeh, Amir; Advani, Shailesh; Overman, Michael J et al. (2017) Association of SMAD4 mutation with patient demographics, tumor characteristics, and clinical outcomes in colorectal cancer. PLoS One 12:e0173345|
|Lee, Michael S; Menter, David G; Kopetz, Scott (2017) Right Versus Left Colon Cancer Biology: Integrating the Consensus Molecular Subtypes. J Natl Compr Canc Netw 15:411-419|
|Katsiampoura, Anastasia; Raghav, Kanwal; Jiang, Zhi-Qin et al. (2017) Modeling of Patient-Derived Xenografts in Colorectal Cancer. Mol Cancer Ther 16:1435-1442|
|Thierry, Alain R; Pastor, Brice; Jiang, Zhi-Qin et al. (2017) Circulating DNA Demonstrates Convergent Evolution and Common Resistance Mechanisms during Treatment of Colorectal Cancer. Clin Cancer Res 23:4578-4591|
|Parseghian, Christine M; Parikh, Nila U; Wu, Ji Yuan et al. (2017) Dual Inhibition of EGFR and c-Src by Cetuximab and Dasatinib Combined with FOLFOX Chemotherapy in Patients with Metastatic Colorectal Cancer. Clin Cancer Res 23:4146-4154|
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