Claire Greene

Importance: Combining biologic monoclonal antibodies with chemotherapeutic cytotoxic drugs provides clinical benefit to patients with advanced or metastatic colorectal cancer, but the optimal choice of the initial biologic therapy in previously untreated patients is unknown. Objective: To determine if the addition of cetuximab vs bevacizumab to the combination of leucovorin, fluorouracil, and oxaliplatin (mFOLFOX6) regimen or the combination of leucovorin, fluorouracil, and irinotecan (FOLFIRI) regimen is superior as first-line therapy in advanced or metastatic KRAS wild-type (wt) colorectal cancer. Design, Setting, and Participants: Patients (≥18 years) enrolled at community and academic centers throughout the National Clinical Trials Network in the United States and Canada (November 2005-March 2012) with previously untreated advanced or metastatic colorectal cancer whose tumors were KRAS wt chose to take either the mFOLFOX6 regimen or the FOLFIRI regimen as chemotherapy and were randomized to receive either cetuximab (n = 578) or bevacizumab (n = 559). The last date of follow-up was December 15, 2015. Interventions: Cetuximab vs bevacizumab combined with either mFOLFOX6 or FOLFIRI chemotherapy regimen chosen by the treating physician and patient. Main Outcomes and Measures: The primary end point was overall survival. Secondary objectives included progression-free survival and overall response rate, site-reported confirmed or unconfirmed complete or partial response. Results: Among 1137 patients (median age, 59 years; 440 [39%] women), 1074 (94%) of patients met eligibility criteria. As of December 15, 2015, median follow-up for 263 surviving patients was 47.4 months (range, 0-110.7 months), and 82% of patients (938 of 1137) experienced disease progression. The median overall survival was 30.0 months in the cetuximab-chemotherapy group and 29.0 months in the bevacizumab-chemotherapy group with a stratified hazard ratio (HR) of 0.88 (95% CI, 0.77-1.01; P = .08). The median progression-free survival was 10.5 months in the cetuximab-chemotherapy group and 10.6 months in the bevacizumab-chemotherapy group with a stratified HR of 0.95 (95% CI, 0.84-1.08; P = .45). Response rates were not significantly different, 59.6% vs 55.2% for cetuximab and bevacizumab, respectively (difference, 4.4%, 95% CI, 1.0%-9.0%, P = .13). Conclusions and Relevance: Among patients with KRAS wt untreated advanced or metastatic colorectal cancer, there was no significant difference in overall survival between the addition of cetuximab vs bevacizumab to chemotherapy as initial biologic treatment. Trial Registration: clinicaltrials.gov identifier: NCT00265850.

3504 Background: 80405 found no OS or PFS difference when Bevacizumab (BV) or Cetuximab (Cet) was added to 1st-line FOLFOX or FOLFIRI in mCRC pts. As location of the 1° may affect mCRC outcome, we assessed the impact of 1° side (R v L) on OS and PFS in 80405 pts. Methods: 1° location was determined by chart review: 1137 pts w/KRAS wt (codons 12 and 13) in main cohort; 252 pts w/ KRAS mut tumors treated w/ BV or Cet pre-amendment. R-sided = cecum to hepatic flexure; L-sided = splenic flexure to rectum. Transverse (T) = hepatic to splenic flexure. PFS per investigator. Kaplan Meier and Cox regression methods used. Results: KRAS wt pts: Median age = 59; synchronous = 78%. 1° site: R – 280 (25%); L – 689 (61%); T- 62 (5%); unsure – 106 (9%). OS & PFS (Table) difference by side statistically significant if adjusted for age, gender, BV / Cet, chemotherapy, prior therapy. There was a significant 1° side by biologic interaction (P int = 0.003, PFS and OS) but not by chemo, gender or RAS. OS, L-sided: Cet v BV, superiority (Log rank p = 0.04); R-sided: BV v Cet, superiority (p = 0.03). Results similar for PFS and if T colon allocated to R side. KRAS mut pts: 1°s: R - 35%; L- 50%. No statistically significant difference in any subset although OS favors L > R (only OS data shown). Conclusions: mCRC arising in the R v L colon are clinically different. In KRAS wt mCRC, pts w/ L-sided 1° tumor have superior OS and PFS v pts w/ R-sided 1°. Though not pre-planned analyses, OS and PFS were prolonged w/ Cet in L and w/BV in R but were poorer w/ Cet in R. Forthcoming molecular analysis of 1°s - e.g. BRAF, MSI, methylation - may provide a biological explanation. For now, stratification in mCRC studies by R v L 1° sidedness is indicated. These data support BV in 1st line treatment for mCRC pts w/R-sided 1° tumor regardless of KRAS status. Support: U10CA180821, U10CA180882. Clinical trial information: NCT00265850. Right 1° Left 1° Hazard Ratio, 95% Confidence Interval (R v L, adjusted) Log Rank p-value (adjusted) OS (mos) All KRAS wt 19.4 34.2 1.56 (1.32, 1.84) < 0.0001 Cet 16.4 37.5 1.97 (1.56, 2.48) BV 24.5 32.1 1.26 (1.00, 1.58) All KRAS mut 23.1 30.3 1.28 (0.95, 1.73) PFS (mos) All KRAS wt 8.9 11.5 1.25 (1.08, 1.46) .002 Cet 7.7 12.0 1.54 (1.25, 1.91) BV 9.5 11.1 1.03 (0.83, 1.28)

UNLABELLED: Patients with pancreatic and biliary carcinomas lack personalized treatment options, in part because biopsies are often inadequate for molecular characterization. Cell-free DNA (cfDNA) sequencing may enable a precision oncology approach in this setting. We attempted to prospectively analyze 54 genes in tumor and cfDNA for 26 patients. Tumor sequencing failed in 9 patients (35%). In the remaining 17, 90.3% (95% confidence interval, 73.1%-97.5%) of mutations detected in tumor biopsies were also detected in cfDNA. The diagnostic accuracy of cfDNA sequencing was 97.7%, with 92.3% average sensitivity and 100% specificity across five informative genes. Changes in cfDNA correlated well with tumor marker dynamics in serial sampling (r = 0.93). We demonstrate that cfDNA sequencing is feasible, accurate, and sensitive in identifying tumor-derived mutations without prior knowledge of tumor genotype or the abundance of circulating tumor DNA. cfDNA sequencing should be considered in pancreatobiliary cancer trials where tissue sampling is unsafe, infeasible, or otherwise unsuccessful. SIGNIFICANCE: Precision medicine efforts in biliary and pancreatic cancers have been frustrated by difficulties in obtaining adequate tumor tissue for next-generation sequencing. cfDNA sequencing reliably and accurately detects tumor-derived mutations, paving the way for precision oncology approaches in these deadly diseases.

Objective: Irritable bowel syndrome (IBS) is a common gastrointestinal disorder that is difficult to diagnose and treat due to its inherent heterogeneity and unclear aetiology. Although there is evidence suggesting the importance of the microbiome in IBS, this association remains poorly defined. In the current study, we aimed to characterise a large cross-sectional cohort of patients with self-reported IBS in terms of microbiome composition, demographics, and risk factors. Design: Individuals who had previously submitted a stool sample for 16S microbiome sequencing were sent a comprehensive survey regarding IBS diagnosis, demographics, health history, comorbidities, family history, and symptoms. Log ratio-transformed abundances of microbial taxa were compared between individuals reporting a diagnosis of IBS without any comorbidities and individuals reporting no health conditions. Univariable testing was followed by a multivariable logistic regression model controlling for relevant confounders. Results: Out of 6386 respondents, 1692 reported a diagnosis of IBS without comorbidities and 1124 reported no health conditions. We identified 3 phyla, 15 genera, and 19 species as significantly associated with IBS after adjustment for confounding factors. Demographic risk factors include a family history of gut disorders and reported use of antibiotics in the last year. Conclusion: The results of this study confirm important IBS risk factors in a large cohort and support a connection for microbiome compositional changes in IBS pathogenesis. The results also suggest clinical relevance in monitoring and investigating the microbiome in patients with IBS. Further, the exploratory models described here provide a foundation for future studies.