Retrospective evaluation of the relationship between clinical pathological features,survival times,and treatment responses of kras wild type metastatic colorectal cancer patients and pi3kca mutation

Colorectal cancer is a significant cause of morbidity and mortality worldwide. It ranks third in terms of cancer morbidity and mortality globally. Despite many advancements in recent years, traditional treatment strategies are unable to effectively target all cancer cells due to the rapid development of drug resistance and cancer recurrence. Tumor heterogeneity, particularly due to genetic and epigenetic mechanisms, is one of the key mechanisms of drug resistance in colorectal cancer. Therefore, understanding the molecular biology of colorectal cancer is crucial for the development of alternative therapeutic approaches.In our study, patients diagnosed with colorectal cancer between April 1, 2017, and August 31, 2023, at the Trakya University Medical Faculty Hospital's Medical Oncology outpatient clinic, or diagnosed at an external center and followed up at Trakya University Medical Faculty Hospital, were included. These patients were identified as KRAS wild type using Next-Generation Sequencing (NGS) and clinically assessed as Stage 4. Medical records of 261 patients were retrospectively examined. A total of 146 patients were excluded from the study due to having an active second malignancy, receiving fewer than 6 cycles of systemic chemotherapy, not having response evaluation through radiological imaging, experiencing 98death unrelated to malignancy, or having incomplete clinical and/or laboratory data during screening. Demographic characteristics, presenting symptoms, tumor location, tumor grade and stage, histopathological features, tumor markers, treatment methods applied, clinical response evaluations, and survival durations were retrospectively analyzed and recorded.A statistically significant difference was found between the two groups in terms of ECOG score among the patients with PI3KCA wild-type and PI3KCA mutant-type included in the study. No statistically significant difference was observed between PI3KCA wild-type and mutant-type patients in terms of overall survival and progression-free survival. PI3KCA wildtype patients with bone metastasis at the time of diagnosis were found to have a longer overall survival compared to the group without metastasis. Similarly, PI3KCA wild-type patients with lung metastasis at the time of diagnosis had a longer overall survival compared to the group without metastasis. In the PI3KCA wild-type group, patients with classical adenocarcinoma had statistically significantly better progression-free survival compared to those with mucinous adenocarcinoma. No statistically significant difference in progression-free survival was found between the MSI-stable and MSI-unstable groups among the PI3KCA wild-type patients. Multivariate Cox analysis of factors affecting overall survival identified lymphovascular invasion and lung metastasis at the time of diagnosis as risk factors for overall survival. Multivariate Cox analysis of factors affecting progression-free survival identified lymphovascular invasion, liver metastasis at the time of diagnosis, and lung metastasis at the time of diagnosis as risk factors for progression-free survival.In conclusion, due to the retrospective design of our study and the relatively low number of patients, larger randomized studies involving larger patient groups are needed to draw definitive results that could influence current clinical practices.Keywords: Colorectal cancer, NGS, KRAS, BRAF, PIK3CA