Comprehensive Genetic Profiling and Clinical Outcomes in Gastrointestinal Cancers Treated with Radiotherapy

Abstract

The clinical significance of many genetic mutations in gastrointestinal cancers is not well characterized. As next-generation sequencing (NGS) has become more commercially available, there is opportunity to better establish the role of mutations in DNA damage and repair (DDR), tumor suppressor (TS), cell cycle (CC) and immune checkpoint (IC) genes. This information may be used to better predict local control (LC), distant metastasis (DM) or overall survival (OS). Commercially available DNA sequencing was conducted on patients with gastrointestinal (GI) cancers to identify significant genetic mutations. A total of 86 solid tumor biopsy specimens from GI cancers were submitted for molecular profiling with NGS. Clinical outcomes were measured from time of radiotherapy (RT) to time of progression or last follow-up and included RT to primary lesions and distant metastases. DDR genes included MGMT, MSH 2/6, and ERCC1. CC genes included cMET, EGFR, ERBB2 and KRAS. TS genes included APC, PTEN, and TP53. IC genes included PD-1 and PDL-1. Patients with locally controlled versus progressive disease were compared with regards to prevalence of genetic mutations in order to identify predictors of LC and OS. Patients were treated locally or distantly for colorectal (CRC, n = 36), gastroesophageal (GE, n = 5), liver and bile duct (LBD, n = 14), pancreatic (PC, n = 26) and other (OC, n = 5) GI cancers. Overall, patients had at least one mutation in DDR (46.3%), CC (55.2%), TS (65.5%), or IC (25.3%). DDR and CC mutations were most common in PC (57.7% and 69.2%, respectively), TS mutations were most common in CRC (80.6%), and IC was most common in CE (80.0%). Patients with at least one mutation in DDR, CC, or IC did not have any difference in LC following RT compared to patients without mutations. Mutations in TS genes were associated with improved local control following RT versus those without mutations in TS genes (p = 0.035). Mutations in TS, DDR, CC, and IC were not significantly associated with overall survival. Genetic mutations may be used to predict better response to local radiotherapy in patients with gastrointestinal cancer. In our analysis, patients with mutations in tumor suppressor genes including APC, PTEN, and TP53 had better local control following radiotherapy than patients without mutations in tumor suppressor genes. This information may be useful in future studies to identify patients at increased risk of local failure.