Tejpar, Bertagnolli, Bosman et al. 393 Table 2. Summary of studies investigating candidate genes and phenotypes as independent prognostic and predictive biomarkers in adjuvantly treated colon cancer patients Prognostic utilitya Predictive utilityb Candidate biomarker Tumor MSI-H phenotype (or dMMR) Tumor 18q AI Tumor p53 expression/ mutation Tumor KRAS mutation Tumor TYMS expression TYMS genotypes In favor MSI-H is associated with longer survival [32–34, 36, 40, 42, 107] 18q AI is associated with shorter survival [45–48, 50, 51, 154] p53 mutation/overexpression is associated with poor patient prognosis—lower DFS [62], RFS [66], and OS [67] rates KRAS mutation is associated with shorter survival [69, 74, 75] High TYMS expression is associated with shorter survival (mainly in patients receiving 5-FU–based adjuvant therapy) [65, 66, 101–104] High TYMS expression is associated with longer survival in patients receiving adjuvant therapy [101, 102, 106] Low TYMS expression is associated with shorter survival in patients receiving surgery alone [105] High TYMS expression genotypes and haplotypes have been associated with tumor recurrence in patients with stage II and stage III colon cancer [113] High TYMS expression genotypes have been associated with longer DFS and OS in patients receiving adjuvant therapy [115] Against No evidence that MSI-H is associated with longer survival [152, 153] No evidence that 18q AI is associated with shorter survival [34, 49] No evidence that p53 status provides prognostic value [63, 68] No evidence that KRAS mutation has prognostic value [62, 77, 78, 80–84] In favor MSI-H is associated with longer survival in patients receiving adjuvant 5-FU–based therapy than those receiving surgery alone [38, 61] MSI-H is predictive of response to irinotecan plus 5-FU and LV in stage III colon cancer patients [41] NR p53 mutation and overexpression is associated with shorter survival in patients receiving 5-FU–based adjuvant therapy [61, 67, 69] Wild-type KRAS patients benefit from adjuvant therapy [69] Against No evidence that MSI-H is associated with longer survival in patients receiving adjuvant therapy [33, 36, 39, 40, 42, 152] NR No evidence that p53 status is predictive in treated or untreated patients [66, 70] CALGB 89803 study suggests that KRAS gene mutations are not predictive of outcome for patients receiving adjuvant irinotecan plus 5-FU and LV. No evidence that TYMS expression has prognostic value [68, 107, 108] High TYMS expression is associated with longer survival in patients receiving 5-FU–based adjuvant therapy [101, 102] No evidence that High TYMS expression is predictive of response to adjuvant therapy [66, 108] NR Low TYMS expression genotypes in patients treated with 5-FU–based adjuvant therapy have been associated with longer survival [114] NR General comments MSI-H phenotype is largely associated with good prognosis There is a call for patients with stage II colon cancers with MSI-H tumors to not receive adjuvant chemotherapy [39, 43] The predicative value of the MSI-H phenotype is being tested in the ongoing E5202 adjuvant colon cancer trial The prognostic and predictive value of 18q AI is being examined in the ongoing E5202 adjuvant colon cancer trial Different methodologies have been used to assess p53 status, making comparison between studies difficult Tumor KRAS mutation status is not a prognostic factor in large adjuvant trials and in mCRC patients receiving BSC [79] KRAS mutation status is predictive of outcome with EGFR-targeted agents in mCRC patients Adjuvant trials (PETACC- 8) are under way to investigate tumor KRAS status in patient response to EGFR-targeted agents TYMS expression has been determined by a number of different technologies— RT-PCR, IHC (different scoring systems used)—the clinical value of TYMS expression remains to be determined The relationship between germline variation and TYMS gene function remains to be elucidated and the clinical value needs to be further determined Only studies from published (peer-reviewed) reports in which 100 patients were studied and in which biomarkers were shown to be independently associated with clinical outcome are shown. aPrognostic utility was assessed in relation to reported data from meta-analyses or analyses (retrospective and prospective) of patient clinical samples from single-arm studies, large population- based studies, or large collaborative group studies. bPredictive utility was assessed in relation to reported data from studies in which patients receiving adjuvant 5-FU– based chemotherapy and nontreated patients were described and compared including: single randomized trials, large intergroup studies, and meta-analyses. Abbreviations: 5-FU, 5-fluorouracil; AI, allelic imbalance; BSC, best supportive care; DFS, disease-free survival; dMMR, deficient mismatch repair; EGFR, epidermal growth factor receptor; IHC, immunohistochemistry; LV, leucovorin; mCRC, metastatic colorectal cancer; MSI-H, microsatellite instability high; NR, no published reports; OS, overall survival; PETACC, Pan European Trials in Adjuvant Colon Cancer; RFS, relapse-free survival; RT-PCR, reverse transcription-polymerase chain reaction. www.TheOncologist.com