Snehal B Patel1,2, Robert Bookstein1, Navid Farahani1, Myriam Chevarie-Davis1, Andy Pao1, Angela Aguiluz1, Christian Riley1, Jennelle C Hodge1, Serhan Alkan1, Zhenqui Liu3, Nan Deng3, Jean R Lopategui4. 1. Cedars-Sinai Medical Center, Division of Molecular Pathology and Cytogenetics, Department of Pathology and Laboratory Medicine, 8700 Beverly Blvd., SSB #362, Los Angeles, CA, 90048, USA. 2. HeloGenika LLC, Dexter, MI, 48130, USA. 3. Cedars-Sinai Medical Center, Biostatistics and Bioinformatics Research Center, Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA. 4. Cedars-Sinai Medical Center, Division of Molecular Pathology and Cytogenetics, Department of Pathology and Laboratory Medicine, 8700 Beverly Blvd., SSB #362, Los Angeles, CA, 90048, USA. Jean.Lopategui@cshs.org.
Abstract
INTRODUCTION: Next-generation sequencing has emerged as a clinical tool for the identification of actionable mutations to triage advanced colorectal cancer patients for targeted therapies. The literature is conflicted as to whether primaries or their metastases should be selected for sequencing. Some authors suggest that either site may be sequenced, whereas others recommend sequencing the primary, the metastasis, or even both tumors. Here, we address this issue head on with a meta-analysis and provide for the first time a set of sensible recommendations to make this determination. METHODS: From our own series, we include 43 tumors from 13 patients including 14 primaries, 10 regional lymph node metastases, 17 distant metastases, and two anastomotic recurrences sequenced using the 50 gene Ion AmpliSeq cancer NGS panel v2. RESULTS: Based on our new cohort and a meta-analysis, we found that ~ 77% of patient-matched primary-metastatic pairs have identical alterations in these 50 cancer-associated genes. CONCLUSIONS: Low tumor cellularity, tumor heterogeneity, clonal evolution, treatment status, sample quality, and/or size of the sequencing panel accounted for a proportion of the differential detection of mutations at primary and metastatic sites. The therapeutic implications of the most frequently discordant alterations (TP53, APC, PIK3CA, and SMAD4) are discussed. Our meta-analysis indicates that a subset of patients who fail initial therapy may benefit from sequencing of additional sites to identify new actionable genomic abnormalities not present in the initial analysis. Evidence-based recommendations are proposed.
INTRODUCTION: Next-generation sequencing has emerged as a clinical tool for the identification of actionable mutations to triage advanced colorectal cancerpatients for targeted therapies. The literature is conflicted as to whether primaries or their metastases should be selected for sequencing. Some authors suggest that either site may be sequenced, whereas others recommend sequencing the primary, the metastasis, or even both tumors. Here, we address this issue head on with a meta-analysis and provide for the first time a set of sensible recommendations to make this determination. METHODS: From our own series, we include 43 tumors from 13 patients including 14 primaries, 10 regional lymph node metastases, 17 distant metastases, and two anastomotic recurrences sequenced using the 50 gene Ion AmpliSeq cancer NGS panel v2. RESULTS: Based on our new cohort and a meta-analysis, we found that ~ 77% of patient-matched primary-metastatic pairs have identical alterations in these 50 cancer-associated genes. CONCLUSIONS:Low tumor cellularity, tumor heterogeneity, clonal evolution, treatment status, sample quality, and/or size of the sequencing panel accounted for a proportion of the differential detection of mutations at primary and metastatic sites. The therapeutic implications of the most frequently discordant alterations (TP53, APC, PIK3CA, and SMAD4) are discussed. Our meta-analysis indicates that a subset of patients who fail initial therapy may benefit from sequencing of additional sites to identify new actionable genomic abnormalities not present in the initial analysis. Evidence-based recommendations are proposed.
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