The responses and benefit from targeted therapies in gastric cancer (GC) remain limited and improved biologic understanding is needed. Both inter-tumoral and intra-tumoral heterogeneity for HER2 and EGFR has been observed in small datasets and may limit efficacy of targeted therapies. Broader heterogeneity assessment has not been studied. We sought to explore intra-tumoral heterogeneity in GC by multi-region sampling of primary gastric tumors with subsequent interrogation of mutational differences via next generation sequencing (NGS) and cell-free DNA (cfDNA) analyses.
Patients with newly diagnosed advanced GC underwent endoscopic mapping and pre-determined 8-region biopsy of the primary with concurrent plasma cfDNA sampling. Biopsy samples were subjected to NGS using a 32-gene custom panel and plasma cfDNA analyzed via 28-gene cfDNA assay. Clinicopathologic features and genomic alterations (GA) were abstracted and descriptive statistics were used to compare samples.
All six initial patients underwent multi-region biopsy and NGS. Within a given patient the average number of GA observed in all biopsies (shared GA) was 3.3 with an average of 12.8 non-shared alterations (p = < 0.05). There was no significant difference in the average mutant allele frequency (MAF) or MAF variability between shared and non-shared GA in the primary tumor (p = > 0.05). Cell free DNA analyses identified GA not found in each respective case’s multi-region primary tumor analysis, likely reflective of GA derived from metastatic sites. An updated cohort will be presented.
Endoscopic multi-region biopsy of GC is feasible and significant genomic heterogeneity existed within the primary in all patients. Paired cfDNA analyses should also be included to complement studies of intra-tumoral heterogeneity. Standardized methods to determine intra and inter-tumoral heterogeneity are needed and stratification by heterogeneity score in prospective trials may inform optimal patient selection, particularly in targeted therapies.
Clinical trial identification
Legal entity responsible for the study
Samsung Medical Center.
Samsung Medical Center.
S.J. Klempner: Consulting, Advisory: Lilly Oncology, Boston Biomedical, Astellas, Merck. J. Chao: Consulting, Advisory: Boston Biomedical, Merck, Five Prime Therapeutics. All other authors have declared no conflicts of interest.