Sclafani F, et al. - In order to assess the clinical significance of cancer-related genes such as KRAS, NRAS, BRAF, PIK3CA and TP53 in nonmetastatic rectal cancer, researchers examined a large prospective series of locally advanced rectal cancer (LARC) patients who were recruited into two phase II trials for mutations of these genes. They assessed 210 of 269 (78%) patients and identified mutations of KRAS, NRAS, BRAF, PIK3CA and TP53 in 43%, 9%, 4%, 9% and 60% of patients, respectively. Biopsy and resection specimens displayed concordance of 82% for KRAS, 95% for NRAS, 99% for BRAF, 96% for PIK3CA and 63% for TP53. They noted correlation of TP53 mutations with extramural venous invasion on baseline MRI (78% vs 65%), poor pathological tumor regression (23% vs 36%) and a trend toward a worse 5-year progression-free survival (PFS; 60% vs 74%). A worse 5-year PFS was evident for patients with tumors harboring mutation of TP53 and either KRAS or NRAS (32%) vs those with TP53/KRAS/NRAS wild-type tumors (54% vs 72%). In univariate analysis, patients treated without cetuximab had poor 5-year overall survival in correlation to BRAF mutation (20% vs 73%). This study is one of the largest biomarker studies in a prospective, largely homogeneous, LARC population phase and provide hypothesis-generating findings.