Ras is a membrane-bound protein that regulates multiple downstream pathways, including the Raf/MAPK and the PI3K/Akt signaling pathways.1 When bound to guanosine triphosphate (GTP), it remains in an active state but is inactivated by intrinsic GTPase activity that hydrolyzes GTP to guanosine diphosphate (GDP). Ras is activated by upstream receptor tyrosine kinases, including epidermal growth factor receptor (EGFR), that recruit guanine nucleotide exchange factors (GEFs) to the cell membrane to open up the GTP binding site of Ras. Ras-GTPase then deactivates Ras with the assistance of GTPase activating proteins (GAPs). This intricate balance between activation and deactivation of Ras efficiently regulates the communication of signals arising from receptor tyrosine kinases on the cell membrane to effector molecules in the cytoplasm and nucleus. Mutations in the KRAS gene disrupt this fine balance.Acquired mutations in KRAS are an early step in carcinogenesis, identified in approximately 40 % of colorectal cancers. The most common mutations occur at codons 12 and 13 of exon 2 of the KRAS gene, which encode glycine. These mutations in the phosphate-binding loop of Ras deactivate its intrinsic GTPase activity and render it resistant to GAP-mediated GTP hydrolysis, thereby locking Ras into the activated state. Constitutively active Ras is no longer dependent on upstream activation of receptor tyrosine kinases and as a corollary, insensitive to anti-EGFR chemotherapy. An abundance of literature confirming that the presence of KRAS mutation predicts lack of response of colon cancers to anti-EGFR therapy has resulted in the increasing use of KRAS mutation analysis in clinical practice. However, its role as a prognostic marker of overall survival independent of anti-EGFR therapy remains less clear.2 This is especially true for rectal cancer where studies have shown conflicting results on the predictive value of KRAS mutation status on response to neoadjuvant chemoradiation therapy. This was corroborated by a meta-analysis showing no difference in pathologic complete response rates, tumor downstaging, or cancer-specific survival between KRAS wild-type and KRAS mutant rectal cancer patients treated with chemoradiation irrespective of the use of anti-EGFR therapy.3 The authors of the accompanying manuscript have previously reported on the associations between KRAS mutations and pathologic complete response following neoadjuvant chemoradiation therapy for rectal cancer among patients treated on a parent study examining the effect of time interval to surgery following neoadjuvant chemoradiation therapy. 4 In the present study, the authors explore this issue further by asking (1) whether the type of KRAS mutation has an impact on predicting treatment outcomes and (2) whether there are any notable associations between KRAS and TP53 mutations that might explain the heterogeneity of treatment responses observed. 5 We consider these two questions separately below.Not all KRAS mutations are created equal. As noted by the authors in ...