Subgroups and prognostication in stage III colon cancer: future perspectives for adjuvant therapy

Abstract

Since the MOSAIC study, oxaliplatin-based adjuvant chemotherapy has been the standard treatment of stage III colon cancer. Combination therapy with fluoropyrimidines and oxaliplatin has improved overall survival (OS) and reduced the risk of recurrence in patients with resected stage III colon cancer. However, only 20% of patients really benefit from adjuvant chemotherapy, exposing 80% of patients to unnecessary toxicity. Recent analyses of large multicenter adjuvant studies have focused on the prognostication of OS and disease-free survival in stage III colon cancer in order to reduce over-treatment and to find more accurate prognostic tools than those used for adjuvant treatment decision-making in stage II disease. Indeed, clinical and pathological prognostic factors, although important, are not sufficient to decide which stage III patients will benefit from adjuvant therapy, and biomarkers will help select patient that need adjuvant treatment. Molecular markers such as microsatellite status and BRAF and KRAS mutations have recently been explored, and molecular signatures have been identified as promising prognostic factor for OS. Furthermore, recent studies have highlighted the prognostic value of immune infiltration. This review focuses on pathologic, immunologic and molecular prognostic markers for stage III colon cancer that could help clinicians tailor adjuvant treatment in a comprehensive transversal approach.

RNA sequencing reveals PNN and KCNQ1OT1 as predictive biomarkers of clinical outcome in stage III colorectal cancer patients treated with adjuvant chemotherapy

“…a fluoropyrimidine alone—5‐FU or capecitabine—or a fluoropyrimidine plus oxaliplatin) and the comprehension of the reason for which some patients develop an early relapse and others do not, remains an unmet goal. Several attempts through genomic, transcriptomic approaches have been performed in order to identify prognostic signatures and only to a lesser degree predictive signatures in CRC . However, none of these signatures is currently in routine clinical use in CRC.…”

“…However, it is well known that only 20% of stage III patients are cured by the addition of adjuvant chemotherapy to surgery while 50% are cured by surgery alone, and 30% experience recurrence. Recurrence of disease is generally fatal within 2–3 years . This occurrence is mainly due to the high biological heterogeneity of CRC that confers considerable stage‐independent variability in CRC prognosis.…”

Noninferiority of three months versus six months of oxaliplatin‐based adjuvant chemotherapy for resected colon cancer. How should IDEA findings affect clinical practice?

“…BRAF mutations, and in particular the commonest V600E transversion, is found in about 10% of Stage II–III colon cancer . Its adverse prognostic impact in localized colon cancer is not as clear as in the metastatic setting.…”

RAS genes in colorectal carcinoma: pathogenesis, testing guidelines and treatment implications

“…Patients with mutations involving codons 12 and 61 usually fare worse than those with other mutations,31–37 while mutations in codon 146 are associated with a better outcome 31. While the adverse prognostic effects of mutations involving exon 2 are supported by multiple studies, conflicting results regarding the differences in outcome between the common exon 2 mutated codons, 12 and 13, are seen in the literature 38. Unlike in pancreatic adenocarcinoma, in colorectal cancers, studies failed to show a significant outcome difference between G12D and G12V mutations affecting codon 2 31…”