Frequency of KRAS, NRAS, and BRAF mutations in colorectal cancer in an Argentinian population.
Authors: Barbier Agustín , Mendez Guillermo , Garino Natalia , Dibarbora Delfina , Salanova Ruben , Mendoza Bertelli Andrea , Ruiz Alan , Romero Agustin , Cantarella Florencia , Colombero Cecilia 
Published: June 2023

e15604

Background: Colorectal cancer (CRC) is one of the major causes of morbidity and mortality worldwide. At diagnosis, about 25% of patients are metastatic (mCRC); also 50% patients will develop metastases during the disease First line treatment (1L) for mCRC is guided by clinical and molecular features and includes the use of chemotherapy combined with monoclonal antibodies, like anti-epidermal growth factor receptor, such as cetuximab and panitumumab, or anti-vascular endothelial growth factor, such as bevacizumab. Treatment guidelines advise assessing the mutational status of some oncogenes (KRAS, NRAS and BRAF) prior to the choice of 1L The aim of this study is to analyze the population characteristics of patients with CRC in Argentina and to determine the incidence of mutations in KRAS, NRAS and BRAF in this population. Methods: Tissue (TB) or liquid biopsies (LB) were collected and analyzed from March 2018 to November 2022 from an adult patient population with CRC in Argentina. Mutations in KRAS, NRAS and BRAF were determined using real time PCR (cut-off values TB: KRAS/NRAS 1-5%; BRAF 5%; LB: KRAS 25-75 copies/mL in 64000 copies of normal DNA; RAS/BRAF 100-200 copies/mL in 160000 copies of normal DNA). Also population characteristics (age, sex, and geographic location) were considered for analysis. Only patients having results for the three genes were included. Results: A total of 9150 samples were analyzed, 91% (N = 8326) for TB and 9% (N = 824) for LB; from these, 56.6% came from male (N = 5181) and 43.4% female (N = 3969) patients. The median age was 64 years (range 22-89) Patients tested by TB mainly had stage IV 68.6% (N = 6129), 1.7% (N = 149) stage II and 5.9% (N = 523) stage III disease. For LB patients, also stage IV 79.7% (N = 610) disease was the most common followed by stage III 4.4% (N = 34), and stage II 0.7% (N = 5) For stage IV patients with TB, 81.6% (N = 5060) were tested prior 1L therapy, 10.9% (N = 674) before second line (2L) and 0.6% (N = 34) before third line (3L). For LB patients, 1L was the most common 48.5% (N = 361), followed by 2L 5.0% (N = 37), and 3L 19.1% (N = 142) In stage IV patients tested before 1L by TB, the frequency of mutations in the RAS family genes was 47% (N = 2257), KRAS mutations were found in 91.4% of cases (N = 2084) and 8.7% in NRAS (N = 173). RAS wt patients were 52.9% (N = 2537). Mutations in BRAF were found in 12.1% of cases For those patients tested using LB, mutations in RAS were found in 38.3% (N = 121) of cases, KRAS in 92.6% (N = 112) and NRAS in 7.4% (N = 9). RAS wt patients were 61.7% (N = 195) while BRAF mutated patients were 13.3%. Conclusions: This analysis is the largest cohort showing the molecular profile in CRC patients from Argentinean population. Mutations in RAS genes arose in 38-47% of mCRC patients before 1L. BRAF mutations were found in 12.1-13.3% slightly higher than in other series. Testing rates for RAS and BRAF before starting treatment was high, this reinforces the need of mutational screening before deciding any therapy in mCRC.