The Mutational Landscape of Gastrointestinal Malignancies as Reflected by Circulating Tumor DNA

Abstract

We aimed to assess the utility of a novel, noninvasive method of detecting genomic alterations in patients with gastrointestinal malignancies, i.e., the use of liquid biopsies to obtain blood-derived circulating tumor DNA (ctDNA) through an analysis of the genomic landscape of ctDNA (68 genes) from 213 patients with advanced gastrointestinal cancers. The most common cancer types were colorectal adenocarcinoma (N = 55; 26%), appendiceal adenocarcinoma (N = 46; 22%), hepatocellular carcinoma (N = 31; 15%), and pancreatic ductal adenocarcinoma (N = 25; 12%). The majority of patients (58%) had ≥1 characterized alteration (excluded variants of unknown significance). The median number of characterized alterations was 1 (range, 0-13). The number of detected alterations per patient varied between different cancer types: in hepatocellular carcinoma, 74% of patients (23/31) had ≥1 characterized alteration(s) versus 24% of appendiceal adenocarcinoma patients (11/46). The median percent ctDNA among characterized alterations was 2.50% (interquartile range, 0.76%-8.96%). Overall, 95% of patients (117/123) had distinct molecular portfolios with 143 unique characterized alterations within 56 genes. Overall, concordance rates of 96%, 94%, 95%, and 91%, respectively, were found between ctDNA and tissue biopsy (N = 105 patients) in the four most common alterations (KRAS amplification, MYC amplification, KRAS G12V, and EGFR amplification). Of 123 patients with characterized alterations, >99% (122/123; 57% of entire population tested; 122/213) had one or more alterations potentially actionable by experimental or approved drugs. These observations suggest that many patients with gastrointestinal tumors, including difficult-to-biopsy malignancies like hepatocellular cancers, frequently have discernible and theoretically pharmacologically tractable ctDNA alterations that merit further studies in prospective trials. Mol Cancer Ther; 17(1); 297-305. ©2017 AACR.

Figure 1. Most frequently altered genes and percent ctDNA by gene

Abbreviations: VUS = variant of unknown significance A: Bar plot representing the number of patients with an alteration(s) in a given gene, and the number of unique alterations in each gene. Unique alterations are defined as the number of specific alterations (point mutation, amplification, etc.) occurring in a given gene across the population. This plot only includes genes for which there were >5 patients with an alteration in the given gene; for others, refer to Figure S1. B: Bar plot representing median percent ctDNA (see Methods for definition) and 1^st and 3^rd quartiles. Only patients who had a characterized alteration in the specified gene were included in the calculation. Variants of unknown significance were excluded. In patients who had multiple tests that detected the same alteration, only the greatest value was included.

Figure 2. Number of patients with a given number of alterations and percent breakdown by cancer type (excludes VUS)

A: Histogram representing the number of patients with each given number of detected alterations. There were 123 patients with characterized alteration(s) (excluding VUSs), and 149 patients with detected alteration(s) (including VUSs). B: Percentage of patients with given number(s) of characterized alterations, separated by most common cancers in data set. All 213 patients were included. Patients for whom all detected alterations were VUS, as well as patients with no alterations were counted as having zero characterized alterations. In some cancers such as hepatocellular carcinoma, the majority of patients (74%) harbor one or more characterized alterations; in contrast, the vast majority (76%) of the patients with appendiceal adenocarcinoma patients had no characterized alterations (either no detected alterations, or all detected were VUS).

Figure 3. Overall potential actionability of characterized alterations based on available agents

Almost all patients (122/123) with characterized alterations(s) had one or more targeted therapy(ies) available, either through an on-label drug, an off-label drug, or a clinical trial. For patients who had multiple therapies available, FDA approved agents were prioritized over experimental drugs. Amongst FDA approved agents, on-label drugs were prioritized over off-label drugs.

Figure 4. Theoretical treatment options for characterized alterations across diverse gastrointestinal cancers

Abbreviations: FDA = Food and Drug Administration; pts = patients Excluding variants of unknown significance, the percent breakdown of available treatment options for patients with the most common cancer-types in the cohort. FDA approved agents were prioritized over experimental drugs. Amongst FDA approved agents, on-label drugs were prioritized over off-label drugs. In our population, all of the patients who were candidates for an experimental agent also had targeted FDA-approved drugs available, either on or off-label (see Figure 3).