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RAS family proteins (including KRAS and NRAS) play important roles in the epidermal growth factor receptor (EGFR) signaling pathway. Mutations in RAS genes (occurring at loci in exons 2, 3, and 4) often result in constitutive activation of RAS proteins and persistent downstream signaling. Mutations in KRAS exon 2 (codon 12/13) are an established predictor of lack of response to the anti-EGFR monoclonal antibodies cetuximab and panitumumab in patients with metastatic colorectal cancer (mCRC), and have been used routinely in clinical practice to identify patients unlikely to derive benefit from these therapies. However, a meaningful proportion of patients with mCRC have tumors bearing other mutations in RAS genes. Recent studies have demonstrated that evaluation of an extended panel of RAS mutations—including mutations in KRAS exon 2, 3, and 4 and NRAS exons 2, 3, and 4—can better define the patient population that is unlikely to benefit from anti-EGFR therapy, with concomitant improvements in outcomes in the more highly selected RAS wild-type group. This discovery has changed the practice of oncology and has the potential to spare patients from exposure to ineffective therapy. In the near future, it is important for the oncology community to validate extended RAS analysis assays and make certain that patients who are candidates for anti-EGFR therapy undergo appropriate testing and treatment.

Summary Background Bevacizumab improves the efficacy of oxaliplatin-based chemotherapy in metastatic colorectal cancer. Our aim was to assess the use of bevacizumab in combination with oxaliplatin-based chemotherapy in the adjuvant treatment of patients with resected stage III or high-risk stage II colon carcinoma. Methods Patients from 330 centres in 34 countries were enrolled into this phase 3, open-label randomised trial. Patients with curatively resected stage III or high-risk stage II colon carcinoma were randomly assigned (1:1:1) to receive FOLFOX4 (oxaliplatin 85 mg/m 2 , leucovorin 200 mg/m 2 , and fluorouracil 400 mg/m 2 bolus plus 600 mg/m 2 22-h continuous infusion on day 1; leucovorin 200 mg/m 2 plus fluorouracil 400 mg/m 2 bolus plus 600 mg/m 2 22-h continuous infusion on day 2) every 2 weeks for 12 cycles; bevacizumab 5 mg/kg plus FOLFOX4 (every 2 weeks for 12 cycles) followed by bevacizumab monotherapy 7·5 mg/kg every 3 weeks (eight cycles over 24 weeks); or bevacizumab 7·5 mg/kg plus XELOX (oxaliplatin 130 mg/m 2 on day 1 every 2 weeks plus oral capecitabine 1000 mg/m 2 twice daily on days 1–15) every 3 weeks for eight cycles followed by bevacizumab monotherapy 7·5 mg/kg every 3 weeks (eight cycles over 24 weeks). Block randomisation was done with a central interactive computerised system, stratified by geographic region and disease stage. Surgery with curative intent occurred 4–8 weeks before randomisation. The primary endpoint was disease-free survival, analysed for all randomised patients with stage III disease. This study is registered with ClinicalTrials.gov, number NCT00112918. Findings Of the total intention-to-treat population (n=3451), 2867 patients had stage III disease, of whom 955 were randomly assigned to receive FOLFOX4, 960 to receive bevacizumab–FOLFOX4, and 952 to receive bevacizumab–XELOX. After a median follow-up of 48 months (range 0–66 months), 237 patients (25%) in the FOLFOX4 group, 280 (29%) in the bevacizumab–FOLFOX4 group, and 253 (27%) in the bevacizumab–XELOX group had relapsed, developed a new colon cancer, or died. The disease-free survival hazard ratio for bevacizumab–FOLFOX4 versus FOLFOX4 was 1·17 (95% CI 0·98–1·39; p=0·07), and for bevacizumab–XELOX versus FOLFOX4 was 1·07 (0·90–1·28; p=0·44). After a minimum follow-up of 60 months, the overall survival hazard ratio for bevacizumab–FOLFOX4 versus FOLFOX4 was 1·27 (1·03–1·57; p=0·02), and for bevacizumab–XELOX versus FOLFOX4 was 1·15 (0·93–1·42; p=0·21). The 573 patients with high-risk stage II cancer were included in the safety analysis. The most common grade 3–5 adverse events were neutropenia (FOLFOX4: 477 [42%] of 1126 patients, bevacizumab-FOLFOX4: 416 [36%] of 1145 patients, and bevacizumab–XELOX: 74 [7%] of 1135 patients), diarrhoea (110 [10%], 135 [12%], and 181 [16%], respectively), and hypertension (12 [1%], 122 [11%], and 116 [10%], respectively). Serious adverse events were more common in the bevacizumab groups (bevacizumab–FOLFOX4: 297 [26%]; bevacizumab–XELOX: 284 [25%]) than in the FOLFOX4 group (226 [20%]). Treatment-related deaths were reported in one patient receiving FOLFOX4, two receiving bevacizumab–FOLFOX4, and five receiving bevacizumab–XELOX. Interpretation Bevacizumab does not prolong disease-free survival when added to adjuvant chemotherapy in resected stage III colon cancer. Overall survival data suggest a potential detrimental effect with bevacizumab plus oxaliplatin-based adjuvant therapy in these patients. On the basis of these and other data, we do not recommend the use of bevacizumab in the adjuvant treatment of patients with curatively resected stage III colon cancer. Funding Genentech, Roche, and Chugai.

Background Identifying predictive biomarkers is important to optimally treat patients. This analysis evaluated the association of K- ras , BRAF , and PIK3CA gene mutations with tumor resistance to panitumumab alone. Patients and Methods From 3 phase II panitumumab metastatic colorectal cancer (mCRC) studies, 62 of 533 patient samples were available. Mutations were identified from genomic DNA by sequencing. Results Of the 62 samples, 24 (38.7%) harbored a K- ras mutation, and 38 (61.3%) were wild type. In the wild-type K- ras group, 11% of patients had a partial response (PR), 53% had stable disease (SD), and 37% had progressive disease (PD). In the mutant K- ras group, 21% of patients had SD, and 79% of patients had PD; there were no responses. The absence of a K- ras mutation was associated with response to panitumumab (PR vs. SD vs. PD; P = .0028). The hazard ratio for wild-type versus mutant K- ras was 0.4 (95% CI, 0.2-0.7) for progression-free survival and 0.5 (95% CI, 0.3-0.9) for overall survival. Four patients had a V600E BRAF mutation, and 2 patients had a PIK3CA mutation. Conclusion These data suggest that patients with mCRC with activating K- ras mutations are less likely to respond to panitumumab alone. The small sample size limits us from defining a predictive role of PIK3CA and BRAF mutations for panitumumab treatment.

The pathobiology of precursor lesions leading to invasive pancreatic adenocarcinoma remains a controversial area, but knowledge of the mechanisms of tumorigenesis may lead to possibly earlier detection, prevention, and treatment in the future. We hypothesize that ductal hyperplasia and dysplasia of the pancreas represent precursor lesions and are part of a continuous developmental spectrum evolving into ductal adenocarcinoma of the pancreas. To further define this sequence, we studied the immunohistochemical markers HER-2/neu, K-ras, and p53 in 15 adenocarcinomas and 15 nonmalignant specimens of the pancreas. The 15 nonmalignant specimens of the pancreas included both normal pancreas and chronic pancreatitis. Overall, HER-2/neu was positive in normal ducts, ductal hyperplasia, dysplasia, and carcinoma cells in 0 of 30, 11 of 20 (55%), 10 of 15 (67%), and 12 of 15 (80%), respectively, with progressive increase in the intensity of staining; p53 was positive in 1 of 30 (3%), 0 of 20, 3 of 15 (20%), and 13 of 15 (80%), respectively, and K-ras was positive in 1 of 30 (3%), 6 of 20 (30%), 11 of 15 (73%), and 8 of 15% (53%), respectively. These data support the hypothesis that ductal hyperplasia and dysplasia of the pancreas represent precursor lesions, and, in a fashion similar to that in colorectal tumorigenesis, pancreatic cancer seems to accumulate progressive genetic alterations.

A Novel Gene Transfer Therapy Against Pancreatic Cancer (TNFerade) Delivered by Endoscopic Ultrasound (EUS) and Percutaneous Guided Fine Needle Injection (FNI) Kenneth J. Chang, Neil Senzer, Theodore Chung, J. Randolph Hecht, Stephen Vogel, Alexander Rosemurgy, John Nemunaitis, John Gibbs, Milind Javle, Tony Reid, Jennifer Macko, Paul Kessler, Mitchell C. Posner, James Farrell, L. Shane Grundy, Roy Soetikno, Irving Waxman, Nader Hanna We published two trials utilizing EUS-guided FNI for the delivery of immune therapy (Cancer 2000) and oncolytic viral therapy (Clin Cancer Res 2003) against pancreatic cancer. We now present a novel gene transfer therapy, TNFerade, delivered by EUS and percutaneous approaches (PTA) guided by ultrasound or computerized tomography (CT), in the treatment of unresectable, locally advanced adenocarcinoma of the pancreas (LAPC). TNFerade is a replicationdeficient adenovector containing human TNFa gene, regulated by a radiationinducible promoter Egr-1. Purpose: 1) Assess safety and efficacy of TNFerade plus chemoradiation in pts with LAPC. 2) Compare EUS and PTA as delivery modalities. Methods: Dose-escalating run-in design. Five-week treatment of weekly intratumoral injections of TNFerade (43 10 particle units (pu) in 2mL) via EUS or PTA (each institution allowed one preferred technique), continuous iv 5-FU (200 mg/m/d 3 5 days/wk) and radiation (50.4 Gy). TNFerade was delivered with a single needle pass at a single site in the tumor for PTA, while up to 4 injections were given by EUS. Endpoints: Safety and tumor response on spiral CT (core lab). Results: Of 37 pts, 17 had EUS and 20 had PTA (similar TNFerade doses). EUS vs PTA: T4 staging = 88% vs. 75%; N1 staging = 29% vs. 40%, mean tumor area (cm)= 18 vs.19; mean CA19-9= 4,396 vs. 1,707, meanKPS= 88 vs. 90. (p=NS for all). 1 dose limiting toxicity (gr 3 hypotension) in a PTApt; all other adverse events (AEs) potentially related to TNFerade were grade 1-2. Procedure related AEs were all grade 1-2 and were similar, except for injection site pain: 35% PTA vs 0% EUS (p = .01). Tumor responses and disease control were similar (Table 1). 4 patients underwent resection; one, an EUS patient, had a complete pathologic response. Conclusions: 1) TNFerade plus chemoradiation was well tolerated with maximum tolerated dose not reached; 2) indications of clinical activity were demonstrated by local tumor control and progression-free survival at up to 3 months; 3) EUS and PTA appear to be similarly safe and effective for delivery of TNFerade.

Much of the morbidity of pancreatic carcinoma is due to the local effects of the primary tumors, which respond poorly to standard treatment. EUS has been shown to be useful for staging and biopsy of gastrointestinal malignancies and permits real-time injection of tumors. There have been no studies addressing the practicality and tolerability of repeated fine-needle injection into pancreatic neoplasms. ONYX-015 is a modified adenovirus which preferentially replicates in tumor cells.We report a phase I/II study of direct injection of ONYX-015 into pancreatic carcinomas in combination with intravenous gemcitabine. Methods: Pts underwent 8 sessions of virus injection over 8 weeks and received concomitant gemcitabine on the day of the last four treatments. Three pts received 109 and 15 pts 1010 pfu per session. The virus was diluted in 20% of the tumor volume and injected in 1-2 ml aliquots into the tumor in a fan-like fashion using a Pentax FG36 echoendoscopic ultrasound scope and Wilson-Cook Echotip needles. Results: Over 100 sessions of virus injection have been performed. Three pts have had minor responses with up to 47% tumor regression. Five pts had stable disease and 5 had progressive disease. With an additional 2-3 months of gemcitabine, 2 pts eventually achieved partial responses with 57 and 75% reduction of tumor size. Two pts were unevaluable and 3 are still on study. Toxicity: Two pts had sepsis, one with a possible abscess. No further infections were seen after oral antibiotic prophylaxis was begun. One pt had an asymptomatic cystic fluid collection. Several elevations of amylase and lipase were observed, but no episodes of clinical pancreatitis. Two patients had duodenal perforations from the rigid endoscope tip. Injections then were restricted to a transgastric approach. Summary: Direct injection of ONYX-015 under EUS guidance is a new and potentially valuable approach to the treatment of pancreatic tumors.