Resistance to immune checkpoint inhibitors in colorectal cancer with deficient mismatch repair/microsatellite instability: misdiagnosis, pseudoprogression and/or tumor heterogeneity?

Author:

Normanno Nicola1ORCID,Caridi Vincenza2,Fassan Matteo3ORCID,Avallone Antonio4ORCID,Ciardiello Fortunato5ORCID,Pinto Carmine6ORCID

Affiliation:

1. IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy

2. Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Naples, Italy

3. Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, 35100 Padua, Italy; Veneto Institute of Oncology, IOV-IRCCS, 35100 Padua, Italy

4. Medical Oncology, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Naples, Italy

5. Department of Precision Medicine, The University of Campania Luigi Vanvitelli, 80138 Naples, Italy

6. Medical Oncology, Comprehensive Cancer Centre IRCCS-AUSL Reggio Emilia, 42121 Reggio Emilia, Italy

Abstract

Colorectal carcinoma (CRC) with deficiency of the deficient mismatch repair (dMMR) pathway/ microsatellite instability (MSI) is characterized by a high mutation load and infiltration of immune cells in the tumor microenvironment. In agreement with these findings, clinical trials have demonstrated a significant activity of immune checkpoint inhibitors (ICIs) in dMMR/MSI metastatic CRC (mCRC) patients and, more recently, in CRC patients with early disease undergoing neoadjuvant therapy. However, despite high response rates and durable clinical benefits, a fraction of mCRC patients, up to 30%, showed progressive disease when treated with single agent anti-programmed cell death 1 (PD-1) antibody. This article discusses the three main causes that have been associated with early progression of dMMR/MSI mCRC patients while on treatment with ICIs, i.e., misdiagnosis, pseudoprogression and tumor heterogeneity. While pseudoprogression probably does not play a relevant role, data from clinical studies demonstrate that some dMMR/MSI CRC cases with rapid progression on ICIs may be misdiagnosed, underlining the importance of correct diagnostics. More importantly, evidence suggests that dMMR/MSI mCRC is a heterogeneous group of tumors with different sensitivity to ICIs. Therefore, we propose novel diagnostic and therapeutic strategies to improve the outcome of dMMR/MSI CRC patients.

Publisher

Open Exploration Publishing

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