Prognostic Impact of Ras Mutation on Surgical Strategy in Rectal Cancer Patients Undergoing Neoadjuvant Treatment

Abstract

Background/aim: Complete clinical response in rectal cancer after neoadjuvant chemo-radiotherapy is challenging. Indeed, indication to surgery vs. "watch and wait" is a debate due the poor predictive value of restaging exams in order to identify a pathological complete response (pCR). Improving the knowledge on mutational pathways such as MAPK/ERK could be helpful in assessing the real impact of disease on prognosis and in choosing the best therapeutic target. This study aimed to evaluate the significance of biomolecular parameters as prognostic factors in patients undergoing radical surgery after chemo-radiotherapy.

Patients and methods: A retrospective analysis was performed including 39 patients who had undergone radical surgery after neoadjuvant chemo-radiotherapy for rectal adenocarcinoma stage II-III through additional evaluation of the following biomolecular markers on surgical specimens: exons 2, 3 and 4 of the KRAS and NRAS genes and exon 15 of BRAF by pyrosequencing. Kaplan-Meier survival curves were plotted to evaluate the association of pathologic response and RAS status with progression-free survival (PFS) and overall survival (OS). The log-rank test was used to assess statistical differences among the survival curves.

Results: Data analysis showed RAS mutation in 15 patients (38.46%). pCR was achieved in seven patients (18%), including only two RAS mutation cases. The distribution of evaluated variables was homogeneous in the two groups based on pathological response. The Kaplan-Meier curve showed poor outcomes in OS and PFS in patients with RAS mutation (p=0.0022 and p=0.000392, respectively), but no significant differences based on pathological response for both OS and PFS.

Conclusion: RAS mutation seems to be related to poor prognosis and increased risk of recurrence in rectal cancer patients undergoing radical surgery after chemo-radiotherapy.

Keywords: Neoadjuvant therapy; Ras genes; antineoplastic protocols; rectal neoplasms; watchful waiting.