Changes in plasma genomic abnormalities at chromosome 8 and 20 predict treatment response and monitor disease progression in advanced gastric cancer

Gastric cancer (GC) is the fifth most common cancer diagnosis with roughly 60% of patients with metastatic disease. Tumor heterogeneity represents a major challenge to personalized cancer therapy. Intratumor heterogeneity can result in missing critical DNA genomic alterations using conventional tumor biopsies. Circulating cell-free DNA (cfDNA) in the peripheral blood has the potential to capture DNA alterations in a more dynamic manner in particular types of advanced tumors where feasibility of repeat tissue biopsies is limited. Using low-pass whole-genome sequencing (LP-WGS) data from 329 blood plasma samples collected from 63 1L metastatic (mGC) patients enrolled in phase II trial NCT01590719, receiving either onartuzumab or placebo in combination with mFOLFOX6, we evaluated the global percent genome change (%GC) and copy number (CN) gain at baseline and throughout the course of treatment. cfDNA samples were isolated with the automated QIAsymphony system and analyzed on the Illumina NextSeq 500 system with a novel LP-WGS protocol at 0.5x coverage. Seven chromosomes (chr1, 7, 8, 14, 15, 20, and 21) showed the most frequent CN gains of evaluated patients (≥15%). Of these seven chromosomes, chr8 and 20 featured the largest number of genes at baseline with CN gains with 30.2% (19/63) at chr8 and 25.4% (16/63) at chr20. 81% of patients (13/16) with chr20 CN gain also showed an increase in CN at chr8. Patients with gains at chr8 and/or 20 have higher %GC compared to patients with normal copy status. Recurrent CN gains at chr8 and 20 in tumor tissues were previously reported in GC patients and correlated with tumor progression. Copy number gains at chr8 and 20 in cfDNA from mGC patients, reported here for the first time, suggests a potential utility for early detection of disease progression. Moreover, patients with CN gains at chr8 and/or 20 had higher circulating tumor cells detected at baseline (p=0.003) and also showed the most decrease in %GC post-treatment. 75% (9/12) of the patients with CN gains at chr8 and/or 20 were responders and showed a mean 3-fold decrease (range of 1.6-4.7 fold change) in tumor size post-treatment. This suggests CN gain at chr8 or 20 in cfDNA could be used as a noninvasive measure to identify a novel subset of mGC patients sensitive to chemo-based treatment. When comparing %GC pre- and post-treatment, the %GC decreased significantly at C2D1 (p=0.006). This decrease in %GC correlates with a decrease in tumor burden in patients with response, while %GC and tumor burden remain unchanged or increased in nonresponders. Monitoring %GC pre- and post-treatment demonstrates the ability to assess the depth of the treatment and early detection of disease progression. Findings from this study suggest that plasma genomic abnormality monitoring may be used for treatment decision-making in mGC and should be evaluated further in clinical trials. Citation Format: An D. Do, Charles D. Baudo, Samir Seshadri, Xiaoji Chen, Rebecca Suttmann, David S. Shames, Mark R. Lackner, Shih-Min A. Huang, Teiko Sumiyoshi. Changes in plasma genomic abnormalities at chromosome 8 and 20 predict treatment response and monitor disease progression in advanced gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5571.