216P - PTCH1 mutation as a potential predictor of immune checkpoint inhibitors in gastrointestinal cancer

Background

The association between genetic alterations and benefit of immunotherapy is well documented, but evidence for gastrointestinal cancer (GC) remains limited. Patched1 (PTCH1) mutation, a frequently altered gene in GC, lead to dysregulation of Hedgehog signaling. However, the efficacy of PTCH1 mutations in immunotherapy in patients with GC remains unclear. Herein, we aimed to analyze the association between PTCH1 mutations and immune checkpoint inhibitors (ICIs) efficacy in patients with GC.

Methods

We screened the following 3 cohorts: (1) MSKCC cohort (N=236) of GC (including esophageal, gastric and colorectal cancers) who received ICIs. (2) Peking University Cancer Hospital (PUCH) GC cohort (N=92) who received ICIs. (3) the TCGA cohort (N=914) of GC. The patients were divided into PTCH1 mutant type (PTCH1-MT) group and PTCH1 wild type (PTCH1-WT) group. We analyzed the differences in overall survival (OS) and TMB between the two groups. Tumor immune microenvironment (TIME) was evaluated by calculating the cell infiltration score as the arithmetic mean analysis of the constituent genes.

Results

In MSKCC cohort, PTCH1-MT group (9.3%) had significantly better OS (p=0.017, median OS, 34m vs. 13m) and higher TMB (p<0.01). The results of the multivariate analysis showed that PTCH1 had a significant effect on OS, with the PTCH1-MT group had better OS (p=0.035; HR=0.37; 95%CI: 0.15-0.93). Furthermore, we consistently observed in the PUCH cohort that the PTCH1-MT group (7.6%) significantly prolonged OS (p=0.036). Additionally, in the TCGA cohort, we similarly observed a trend towards longer OS (p=0.63, mOS, 70.2m vs. 61.8m) and higher TMB (p<0.01) in PTCH1-MT group (5.8%). It shows that PTCH1 is a predictor, but not a prognostic factor. Subsequently, we assessed the abundance of 22 predefined immune cells. The score of CD4 T cells, CD8 T cells, NK cells, mast cells, and M1 cells were all significantly higher in the PTCH1-MT group (p<0.05). It shows that the PTCH1-MT group has a higher activation TIME.

Conclusions

Our study demonstrated that PTCH1 mutation could act as a potential predictor for ICIs therapy in GC. In the future, relevant prospective clinical trials need to be designed to verify this conclusion.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.