The evolving impact of genomic biomarker landscape in stage II colorectal cancer (CRC).

Background The absolute benefit of 5-fluorouracil-based adjuvant chemotherapy in stage II CRC is only 3-4%. The identification of biomarkers through deep molecular profiling could provide information about diagnosis, prognosis, but especially to identify those patients who will benefit more from adjuvant chemotherapy. Methods This is a single-institution retrospective analysis that has examined formalin-fixed paraffin-embedded (FFPE) tissue blocks retrieved from surgical resection, from patients affected by refractory stage II CRC, who underwent surgery from 2009 to 2015 and whose comprehensive genomic profiling of tumors was conducted through next-generation sequencing (NGS) via Roche-FoundationOne©. Results A total of 174 patients with stage II CRC were screened, and 17 patients with a relapse of disease were included in our study (median age 71 years old; 82% male; 71% right-side CRC, 82% pT3, 65% G3). Mutations were found frequently in APC (76.5%), TP53 (58.8%) and KRAS (52.9%). FBXW7 were found only in KRAS wild-type samples. APC frameshit mutations and MLH1 splice variant were conversely significant correlated (7% v 93%, P=0.014). The median number of gene mutations reported was 6 (range 2-14). TP53 mutation was associated with disease recurrence more frequently in the lung than the liver or other metastatic site (55 % v 27 v 18, P=0.07) and with high tumor budding (88% v 12%, P=0.03). Despite no statistical significance, high stage risk, lung recurrence, pT4 tumor, LVI/Pni, MSI, FBXW7 mutant carriers and more than 6 genetic mutations were correlated to worse DFS; while age>70, right colon cancer, lung recurrence, LVI/Pni, grade G3, MSI, carriers of PIK3CA, FBW7 or MLH1 mutations, and more than 6 genetic mutations showed the worse OS. Patients carried co-mutations of TP53-FBW7 reported the worse DFS (4 v 14 months) and OS (4 v 65 months) compared to the other patients studied. Conclusions A deep molecular characterization of tumors is a key element for optimal patient management: uniform guidelines to detect and classify variants, to interpret results should be recommended and adopted. Thanks to our analysis, the setting of relapsed and refractory CRC emerges as one of the fields of greatest utility for NGS in future looking at personalized cancer care.