Clinical responses to PD-1 inhibition and their molecular characterization in six patients with mismatch repair-deficient metastatic cancer of the digestive system

Abstract

Purpose Immune checkpoint inhibitors have shown efficacy in patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) gastrointestinal (GI) cancers. However, depth and duration of clinical response is not uniform. We assessed tumor mutation burden (TMB) as a response marker in patients with GI cancers treated with immune checkpoint inhibitors. Methods Detailed clinical and response data were collected from six patients with metastatic MSI-H/dMMR GI cancers treated with immune checkpoint inhibitors. Efficacy was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Tumors and matched normal tissue were profiled by targeted next generation sequencing (127 gene panel, size 0.8 Mb). Impact of included mutation types, germline filtering methodology and different variant allele frequency thresholds on TMB estimation was assessed. Results Objective radiographic responses were observed in all six patients, and complete response was achieved in two of the six patients. Responses were durable (minimum 25 months). TMB estimates were clearly above the two recently reported cut-offs for metastatic colorectal cancer of 12 or 37 mutations per megabase for five of six patients, respectively, while one patient had borderline TMB elevation. TMB did not show an association with extent and duration of response but was influenced by included mutation types, germline filtering method and variant allele frequency threshold. Conclusion Our case series confirms the clinical benefit of immune checkpoint blockade in patients with metastatic MSI-H/dMMR GI cancers and illustrates the vulnerability of TMB as predictive marker in a subset of patients. Electronic supplementary material The online version of this article (10.1007/s00432-020-03335-2) contains supplementary material, which is available to authorized users.

Perspectives on Immunotherapy of Metastatic Colorectal Cancer

“…MSI-H tumors tend to have high tumor mutational burden (TMB), and studies have demonstrated that TMB is commonly increased in MSI-H mCRC, but still unclear (54). In mCRC patients treated with durvalumab and tremelimumab, OS is the greatest in MSS Patients with more plasma TMB of 28 variants per megabase or more (HR, 0.34; 90% CI, 0.18-0.63; P = .004) ( 37 (57). By comparing the expression of 44 selected immune-related genes in the primary colon tumor between responders (n = 13) and nonresponders (n = 6) after anti-PD-1 therapy, Llosa et al concluded that preexisting antitumor immune response has little predictive value for immunoreactive pMMR CRC (58).…”

“…However, based on the clinical response data collected from six patients with metastatic MSIH/DMMR GI cancers treated by ICIS, Hirsch et al. found that TMB wasn’t associated with extent and duration of response ( 57 ). By comparing the expression of 44 selected immune-related genes in the primary colon tumor between responders (n = 13) and nonresponders (n = 6) after anti-PD-1 therapy, Llosa et al.…”

Bottleneck Feature-Based U-Net for Automated Detection and Segmentation of Gastrointestinal Tract Tumors from CT Scans

“…Various diagnostic methods including endoscopic ultrasound (EUS), magnetic resonance imaging (MRI), computed tomography (CT), ultrasound (US), and positron emission computed tomography (PET) are routinely used to identify malignancies [3][4][5]. These imaging techniques assist doctors in evaluating and examining the digestive system, thereby pinpointing the precise location and segmented sections of the cancer.…”

Predicting Mismatch-Repair Status in Rectal Cancer Using Multiparametric MRI-Based Radiomics Models: A Preliminary Study

“…To date, immune checkpoint inhibitors (ICIs) have become a crucial therapeutic option for improving prognosis in several solid tumors [4,5]. Previous clinical trials have shown that microsatellite instability (MSI) and/or mismatch-repair deficiency (dMMR) constitute significant tissue-agnostic molecular markers for the prediction of ICIs' efficacy [6][7][8][9]. Because genetic and immunohistochemical (IHC) tests for MMR deficiency are available, pem-brolizumab and nivolumab as monotherapies or combined with ipilimumab have had approval from the US Food and Drug Administration (FDA) for treating chemoresistant MSI/dMMR mCRC cases [10].…”