Navigating Beyond the Surface -Prognostic Significance of KRAS, NRAS, BRAF, PIK3CA, and TP53 Mutations Examined by Exons

Vlad Adrian Afrăsânie^1,2Mihai Vasile Marinca^1,2*Bogdan Gafton^1,2Alexandra Rusu²Eliza Maria Froicu^2,3Daniel Sur^4,5Cristian Lungulescu⁶Raluca Cezara Popa³Irina Afrăsânie⁷Anca Viorica Ivanov⁸Georgiana Gîlcă-Blanariu⁹Lucian Miron^1,2Cristina Rusu¹⁰Teodora Alexa-Stratulat^1,2

• ¹Department of Medical Oncology-Radiation therapy, Grigore T. Popa University of Medicine and Pharmacy, Iași, Romania
• ²Regional Institute of Oncology (IRO), Iasi, Iasi, Romania
• ³Grigore T. Popa University of Medicine and Pharmacy, Iași, Romania
• ⁴Department of Oncology, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj Napoca, Cluj, Romania
• ⁵Department of Oncology, Oncology Institute Prof. Dr. Ion Chiricuta, Cluj-Napoca, Romania
• ⁶Department of Oncology, University of Medicine and Pharmacy of Craiova, Craiova, Dolj, Romania
• ⁷Department of Internal Medicine, Grigore T. Popa University of Medicine and Pharmacy, Iași, Iasi, Romania
• ⁸Department of Pediatrics, Grigore T. Popa University of Medicine and Pharmacy, Iași, Romania
• ⁹Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, Iași, Romania
• ¹⁰Department of Genetics, Grigore T. Popa University of Medicine and Pharmacy, Iași, Romania

Metastatic colorectal cancer (mCRC) is a disease with various molecular profiles that exhibit different evolution patterns. Although most mCRC patients receive the same chemotherapy drugs in the first-line setting, treatment response is heterogeneous suggesting some tumors are inherently resistant to oxaliplatin/fluoropyrimidine regimen. Genomic-based markers may help identify these patients and guide treatment decisions due to potential prognostic and predictive value. We performed a retrospective analysis on 77 patients diagnosed with mCRC treated with an oxaliplatin/fluoropyrimidine regimen in the Regional Institute of Oncology Iași between April 2017 and December 2019. We studied the impact of KRAS, NRAS, BRAF, PIK3CA and TP53 genes and their mutations in a treatment-naive population. The median progression free survival (PFS) was 11 Formatted: Tab stops: 3.39", Centered months (95% CI, 10.2-11.7 months) and the median overall survival (OS) was 23.6 months (16.3-30.8 months). Multivariate analysis of factors affecting PFS revealed that KRAS exon 4 3 mutation is associated with quicker progression while on oxaliplatin-based chemotherapy (p=0.02, HR=7.06, 95% CI 1. 28-38.85). A similar analysis indicated that the KRAS exon 4 3 mutation is also associated with decreased OS (p=0.03, HR=4.37, 95% CI 1.14-16.75). Additional factors associated with poor survival in multivariate analysis included the presence of KRAS exon 3 mutation (p=0.03, HR=3.03, 95% CI 1. 05-8.72). The presence of the TP53 in exon 8 was associated with an increased OS (p=0.0014, HR=0.4, 95% CI 0.22-0.74).). The present analysis offers insights into the prognostic implications of genes and exon-distributed mutations within RAS, BRAF, PIK3CA, and TP53 in mCRC. Subsequent prospective investigations with a more extensive patient cohort are needed to clarify the influence of exon-distributed mutations on therapeutic decision-making and prognostic outcomes.