Dados do Resumo

Título

Molecular Evaluation of Colorectal and Gastric Carcinomas with Heterogeneous Expression of Mismatch Repair Proteins

Introdução

Microsatellite instability (MSI) is a molecular category of colorectal and gastric carcinomas, caused by deficiency in the DNA mismatch repair system (d-MMR). Guidelines recommend assessing MMR status in these tumors using immunohistochemistry (IHC). Tumors with heterogeneous MMR protein expression (h-MMR) may need additional tests. MSI/d-MMR tumors benefit from treatment with immune checkpoint inhibitors (ICIs). Accurate molecular evaluation is crucial for tailoring personalized treatment.

Objetivo

The aim of this study is to assess the molecular profiles of colorectal and gastric carcinomas with heterogeneous protein expression of the MMR genes and to identify which patient profiles may benefit from ICI as an alternative treatment.

Métodos

Consecutive cases of colorectal and gastric carcinomas with MMR evaluation by IHC from 2014 to 2022 will be reviewed. Formalin-fixed paraffin-embedded blocks from cases with h-MMR will be retrieved from the archives of the Department of Pathology at A. C. Camargo Cancer Center. Tumoral areas with retained and lost protein expression will be macrodissected for molecular testing. Molecular features of each area will be assessed separately using Idylla or next-generation sequencing to determine MSI status, MLH1 methylation status, and genomic profile. After molecular analysis, clinical, epidemiological, and pathological data will be correlated to characterize the study population at a molecular level. Clinical data on survival rates and treatment response will be collected for cases with MMR deficiency, using progression-free survival, overall survival, overall response rate, and Response Evaluation Criteria in Solid Tumors (RECIST).

Resultados

A systematic search of consecutive cases with evaluation of MMR status by IHC was performed using the Pathox system. After extracting pathology data, 3,948 gastrointestinal tumor cases were selected for pathological review. The distribution of cases by year is as follows: 68 in 2014, 368 in 2015, 395 in 2016, 525 in 2017, 538 in 2018, 562 in 2019, 571 in 2020, 559 in 2021, and 362 in 2022. Immunohistochemical analysis revealed that 285 cases (7.2%) showed loss of expression in at least one of the four evaluated MMR proteins: MLH1, MSH2, MSH6, and PMS2. Immunohistochemical slides were retrieved from the Pathology Department archives for digitization. A digital pathology review will be conducted to identify cases with heterogeneous protein expression, which may indicate subclonal loss.

Conclusões

The data suggest that MMR status is a promising predictive biomarker for ICI response, applicable not just in adjuvant therapy for metastatic tumors but also in non-metastatic neoadjuvant settings. Reflex testing of IHC studies for molecular classification of these tumors is recommended. Accurate molecular evaluation in colorectal and gastric tumors with heterogeneous expression of MMR should be prioritized to enable access to novel alternative therapies.

Palavras Chave

Mismatch Repair Genes; Molecular Pathology; Precision Oncology