Abstract
Intertumoral heterogeneity among actionable biomarkers including ERBB2, FGFR2 and EGFR has been observed to occur under therapeutic pressure in advanced gastric cancer. However, baseline intratumoral heterogeneity at diagnosis is understudied and may impact clinical outcomes. We sought to explore intratumoral heterogeneity in primary advanced gastric cancers via DNA sequencing from multi-region endoscopic sampling at diagnosis. Patients with newly diagnosed advanced gastric adenocarcinoma underwent endoscopic mapping and pre-determined 8-sector biopsy of the primary tumor with concurrent plasma cfDNA sampling. Biopsy samples were subjected to targeted next generation sequencing and plasma cfDNA was analyzed via a 28-gene cfDNA assay. Expectedly, we observed that the majority of genetic alterations were shared among multi-sector biopsies within the same gastric primary tumor. However, all samples contained private subclonal alterations between biopsy sectors, including actionable alterations in GNAS and STK11. Cell free DNA analyses also exhibited both shared and non-shared alterations between mutations detected in cfDNA and tumor tissue biopsies confirming baseline intertumoral heterogeneity. This is the first dataset to confirm baseline intratumoral heterogeneity and confirms that multi-sector endoscopic biopsy is feasible and capable of capturing intratumoral heterogeneity among relevant genomic alterations in gastric cancer. Both multi-sector endoscopic biopsies and cfDNA analyses are complementary in capturing the diverse mutational landscape at disease presentation.
Highlights
Treatment options for gastric and gastroesophageal junction (GEJ) cancers have continually evolved with improved understanding of the diverse molecular landscape stemming from large scale generation sequencing efforts [1, 2]
Case III is a young woman with diffuse type signet ring cell gastric cancer, a subset enriched for the The Cancer Genome Atlas (TCGA) genomically stable subtype which may explain lower tumoral cellularity and DNA content [1]
The variation of genetic alterations in differing regions of a primary gastric cancer adds to the literature of caution needed in informing clinical treatment decisions from single gene or next generation sequencing (NGS) analyses of small biopsy samples in which a biomarker may be absent from a biopsy region [29]
Summary
Treatment options for gastric and gastroesophageal junction (GEJ) cancers have continually evolved with improved understanding of the diverse molecular landscape stemming from large scale generation sequencing efforts [1, 2]. Reliable determination of tumor biomarker status is hindered by the recognition that gastric cancer intratumoral heterogeneity exists, consistent with the theory that cancers should be viewed as macro-evolutionary clonal populations [3]. Further hindrance to the study of intratumoral heterogeneity for gastroesophageal cancer is standard endoscopic biopsies typically have limited sampling of the primary tumor. Advent of generation sequencing (NGS) has enabled detailed genomic study of clonal evolution events and development of intratumoral heterogeneity across multiple malignancies [13,14,15]. We conducted an initial study implementing systematic multi-spatial endoscopic sampling of gastroesophageal tumors paired with downstream NGS in attempts to characterize intratumoral heterogeneity of oncogenic alterations beyond HER2
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