Circulating Tumor DNA Sequencing Analysis of Gastroesophageal Adenocarcinoma

Abstract

Purpose: Gastroesophageal adenocarcinoma (GEA) has a poor prognosis and few therapeutic options. Utilizing a 73gene plasma-based next-generation sequencing (NGS) cellfree circulating tumor DNA (ctDNA-NGS) test, we sought to evaluate the role of ctDNA-NGS in guiding clinical decisionmaking in GEA. Experimental Design: We evaluated a large cohort (n ¼ 2,140 tests; 1,630 patients) of ctDNA-NGS results (including 369 clinically annotated patients). Patients were assessed for genomic alteration (GA) distribution and correlation with clinicopathologic characteristics and outcomes. Results: Treatment history, tumor site, and disease burden dictated tumor-DNA shedding and consequent ctDNA-NGS maximum somatic variant allele frequency. Patients with locally advanced disease having detectable ctDNA postoperatively experienced inferior median disease-free survival (P ¼ 0.03). The genomic landscape was similar but not identical to tissue-NGS, reflecting temporospatial molecular heterogeneity, with some targetable GAs identified at higher frequency via ctDNA-NGS compared with previous primary tumor-NGS cohorts. Patients with known microsatellite instabilityhigh (MSI-High) tumors were robustly detected with ctDNA-NGS. Predictive biomarker assessment was optimized by incorporating tissue-NGS and ctDNA-NGS assessment in a complementary manner. HER2 inhibition demonstrated a profound survival benefit in HER2-amplified patients by ctDNA-NGS and/or tissue-NGS (median overall survival, 26.3 vs. 7.4 months; P ¼ 0.002), as did EGFR inhibition in EGFR-amplified patients (median overall survival, 21.1 vs. 14.4 months; P ¼ 0.01). Conclusions: ctDNA-NGS characterized GEA molecular heterogeneity and rendered important prognostic and predictive information, complementary to tissue-NGS. See related commentary by Frankell and Smyth, p. 6893

Allelic Imbalance Analysis in Liquid Biopsy to Monitor Locally Advanced Esophageal Cancer Patients During Treatment

“…The limitations of this study are its retrospective nature and the relatively low number of patients enrolled, which renders it an exploratory and hypothesis-driven study that needs further prospective confirmatory trials. Nevertheless, our work is in line with previous studies that, using next-generation sequencing technology (NGS), highlighted the relevance of cfDNA analysis to follow EC patient behavior ( 30 – 32 ). The Kato et al ( 30 ) and Maron et al ( 32 ) studies have cohorts that include mainly gastric and junction adenocarcinomas.…”

“…Nevertheless, our work is in line with previous studies that, using next-generation sequencing technology (NGS), highlighted the relevance of cfDNA analysis to follow EC patient behavior ( 30 – 32 ). The Kato et al ( 30 ) and Maron et al ( 32 ) studies have cohorts that include mainly gastric and junction adenocarcinomas. More similar to our study is the paper of Azad et al ( 31 ), which includes a cohort of 45 EADC and ESCC patients.…”

Biomarkers for Precision Treatment in Gastric Cancer

“…In particular, ctDNA allows a non-invasive method to define the tumor's molecular profile, monitor the tumor response to treatment, or monitor relapse following surgery and to consider the impact of tumor heterogeneity [48][49][50][51]. For example, when a liquid biopsy was used to detect HER2 overexpression in metastatic GC patients, concordance with HER2 tissue results was demonstrated in only 28% of cases [52]. Therefore, although detection of a molecular alteration in ctDNA can provide useful information, it should be used in a complementary manner to tissue biopsy rather than to replace it.…”

Circulating Tumour DNA to Guide Treatment of Gastrointestinal Malignancies

“…The utility of ctDNA in upper gastrointestinal (UGI) cancers as a prognostic biomarker post-surgery has been explored. Maron et al [42] measured the variant allele fraction (VAF) of somatic alterations in plasma from 1,630 patients diagnosed with oesophageal, gastroesophageal junction (GOJ), or gastric adenocarcinoma. Patients with positive post-surgery ctDNA, using a VAF detection cut-off of 0.25%, had worse DFS than those with negative ctDNA (median 2.5 months vs. unreached, p = 0.03).…”