Predictive and Prognostic Value of Oncogene Mutations and Microsatellite Instability in Locally-Advanced Rectal Cancer Treated with Neoadjuvant Radiation-Based Therapy: A Systematic Review and Meta-Analysis

SIMPLE SUMMARY: Identification of novel molecular markers of pathological complete response (pCR) to preoperative radiation-based therapy in locally advanced rectal cancer (LARC) is strongly needed. Given the established predictive and/or prognostic role of somatic mutations in key oncogenes (RAS, TP53, BRAF, PIK3CA, SMAD4) and microsatellite instability (MSI) status in colorectal cancer, we aimed to investigate the clinical value of the same markers in LARC patients by systematically reviewing the published literature and performing a quantitative analysis of the data. We found that KRAS mutations were significantly associated with the risk of not achieving pCR after preoperative treatment. This association was even more significant in patients who did not receive cetuximab than in patients who did. No other markers were associated with pCR. Based on our results, the implementation of KRAS mutation testing into clinical practice could improve the management of LARC patients. ABSTRACT: Markers of pathological complete response (pCR) to preoperative radiation-based therapy in locally advanced rectal cancer (LARC) are strongly needed. This meta-analysis aimed at elucidating the predictive/prognostic role of tumor markers in LARC. We systematically reviewed the impact of RAS, TP53, BRAF, PIK3CA, and SMAD4 mutations and MSI status on response (pCR, downstaging) and prognosis (risk of recurrence, survival) in LARC according to PRISMA guidelines and the PICO model. PubMed, Cochrane Library, and Web of Science Core Collection were systematically searched to identify relevant studies published before October 2022. KRAS mutations were significantly associated with the risk of not achieving pCR after preoperative treatment (summary OR = 1.80, 95% CI: 1.23–2.64). This association was even more significant in patients not receiving cetuximab (summary OR = 2.17, 95% CI: 1.41–3.33) than in patients receiving cetuximab (summary OR = 0.89, 95% CI: 0.39–20.05). MSI status was not associated with pCR (summary OR = 0.80, 95% CI: 0.41–1.57). No effect of KRAS mutation or MSI status on downstaging was detected. Meta-analysis of survival outcomes was not possible due to the large heterogeneity among studies in endpoint assessment. The minimum number of eligible studies to assess the predictive/prognostic role of TP53, BRAF, PIK3CA, and SMAD4 mutations was not reached. KRAS mutation, but not MSI status, proved to be a detrimental marker for response to preoperative radiation-based therapy in LARC. Translating this finding into the clinic could improve the management of LARC patients. More data are needed to clarify the clinical impact of TP53, BRAF, PIK3CA, and SMAD4 mutations.