Association Between Tumor Mutation Profile and Clinical Outcomes Among Hispanic-Latino Patients With Metastatic Colorectal Cancer.

Alexander Philipovskiy,Nawar Hakim,Reshad Ghafouri,Richard Mccallum,Felipe Maegawa,Scott Shurmur,Ioannis T Konstantinidis,Luis Alvarado,Sanjay Awasthi,Javier Corral,Sumit Gaur,Alok Kumar Dwivedi

doi:10.3389/fonc.2021.772225

Abstract

In the United States, CRC is the third most common type of cancer and the second leading cause of cancer-related death. Although the incidence of CRC among the Hispanic population has been declining, recently, a dramatic increase in CRC incidents among HL younger than 50 years of age has been reported. The incidence of early-onset CRC is more significant in HL population (45%) than in non-Hispanic Whites (27%) and African-Americans (15%). The reason for these racial disparities and the biology of CRC in the HL are not well understood. We performed this study to understand the biology of the disease in HL patients. We analyzed formalin-fixed paraffin-embedded tumor tissue samples from 52 HL patients with mCRC. We compared the results with individual patient clinical histories and outcomes. We identified commonly altered genes in HL patients (APC, TP53, KRAS, GNAS, and NOTCH). Importantly, mutation frequencies in the APC gene were significantly higher among HL patients. The combination of mutations in the APC, NOTCH, and KRAS genes in the same tumors was associated with a higher risk of progression after first-line of chemotherapy and overall survival. Our data support the notion that the molecular drivers of CRC might be different in HL patients.

Highlights

According to the World Health Organization GLOBOCAN database, in 2019, approximately 1.8 million new colorectal cancer cases were diagnosed, and almost 861,000 deaths were reported
Mutation frequencies in the APC gene were significantly higher among HL patients with mCRC
We found that in patients whose tumors had a combination of mutations in APC, NOTCH, and KRAS genes, the overall survival was much shorter (HR 4.39, 95%CI 1.0917.74) and the risk of progression after first-line chemotherapy with mFOLFOX6 was increased (Table 4)

Summary

Introduction

According to the World Health Organization GLOBOCAN database, in 2019, approximately 1.8 million new colorectal cancer cases were diagnosed, and almost 861,000 deaths were reported. According to the American Cancer Society, in 2021, approximately 147,950 individuals in the United States will be diagnosed with CRC and 53,500 will die from the disease. Approximately 17,930 new cases of colorectal cancer (CRC) and 3640 deaths will occur in 2021 in individuals aged younger than 50 years [1]. Approximately 40% of all patients with CRC have metastatic disease at initial presentation [2]. Combined chemotherapy with 5-fluorouracil (5-FU) and oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) continues to be the best available frontline treatment for metastatic CRC, with an objective response rate of approximately 50% [4, 5]. We have learned that specific genes related to the DNA damage repair system, such as TGF-b1, thymidylate synthase, and kallikrein-related peptidase, are related to resistance to 5-FU and oxaliplatin, and that mutations in RAS family genes are responsible for resistance to anti-EGFR therapy, the general nature of resistance to chemotherapy is unknown

Objectives

Methods

Results

Discussion

Conclusion