Niedzwiecki, Donna

Abstract Background: Hyperinsulinemia is considered to be important in the development of colon cancer, but few studies have investigated the associations of hyperinsulinemia with colon cancer survival via dietary scores. Methods: Empirical dietary index for hyperinsulinemia (EDIH) was derived to assess the insulinemic potential of daily diets reflecting the long-term insulin exposure, with higher (more positive) scores indicating higher insulinemic diets. We prospectively estimated the HRs and 95% confidence intervals (CI) to investigate the association of EDIH with disease-free, recurrence-free, and overall survival among patients with stage III colon cancer (1999–2009) enrolled in a randomized adjuvant chemotherapy trial (CALGB 89803). Results: Of 1,024 patients (median follow-up: 7.3 years), 311 died, 350 had recurrences, and 394 had events for disease-free survival. Compared with patients in the lowest quintile of EDIH, the corresponding HRs of patients in the highest quintile for disease-free survival events, cancer recurrence, and overall mortality were 0.80 (95% CI, 0.56–1.15), 0.76 (95% CI, 0.51–1.11), and 0.77 (95% CI, 0.52–1.14). Conclusions: Higher EDIH was not associated with the risk of colon cancer recurrence or mortality in this population of patients with stage III colon cancer. Impact: EDIH, as a measure of dietary insulinemic potential, may be associated with colon cancer risk but not survival in patients with late-stage colon cancer.

Abstract Background Diabetes is a prognostic factor for some malignancies, but its association with outcome in patients with advanced or metastatic colorectal cancer (CRC) is less clear. Methods This cohort study was nested within a randomized trial of first-line chemotherapy and bevacizumab and/or cetuximab for advanced or metastatic CRC. Patients were enrolled at 508 community and academic centers throughout the National Clinical Trials Network. The primary exposure was physician-documented diabetes at the time of enrollment. The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS) and adverse events. Tests of statistical significance were two-sided. Results Among 2326 patients, 378 (16.3%) had diabetes. The median follow-up time was 6.0 years. We observed 1973 OS events and 2173 PFS events. The median time to an OS event was 22.7 months among those with diabetes and 27.1 months among those without diabetes (HR = 1.27, 95% CI = 1.13 to 1.44; P < .001). The median time to a PFS event was 9.7 months among those with diabetes and 10.8 months among those without diabetes (HR = 1.16, 95% CI = 1.03 to 1.30; P = .02). Patients with diabetes were more likely to experience no less than grade 3 hypertension (8.1% vs 4.4%; P = .054) but were not more likely to experience other adverse events, including neuropathy. Conclusions Diabetes is associated with an increased risk of mortality and tumor progression in patients with advanced or metastatic CRC. Patients with diabetes tolerate first-line treatment with chemotherapy and monoclonal antibodies similarly to patients without diabetes.

Abstract Purpose: Previous studies have suggested that higher circulating 25-hydroxyvitamin D [25(OH)D] levels are associated with decreased colorectal cancer risk and improved survival. However, the influence of vitamin D status on disease progression and patient survival remains largely unknown for patients with advanced or metastatic colorectal cancer. Experimental Design: We prospectively collected blood samples in 1,041 patients with previously untreated advanced or metastatic colorectal cancer participating in a randomized phase III clinical trial of first-line chemotherapy plus biologic therapy. We examined the association of baseline plasma 25(OH)D levels with overall survival (OS) and progression-free survival (PFS). Cox proportional hazards models were used to calculate hazard ratios (HRs) and confidence intervals (CIs), adjusted for prognostic factors and confounders. Results: At study entry, 63% of patients were vitamin D deficient (<20 ng/mL) and 31% were vitamin D insufficient (20–<30 ng/mL). Higher 25(OH)D levels were associated with an improvement in OS and PFS (Ptrend = 0.0009 and 0.03, respectively). Compared with patients in the bottom quintile of 25(OH)D (≤10.8 ng/mL), those in the top quintile (≥24.1 ng/mL) had a multivariable-adjusted HR of 0.66 (95% CI, 0.53–0.83) for OS and 0.81 (95% CI, 0.66–1.00) for PFS. The improved survival associated with higher 25(OH)D levels was consistent across patient subgroups of prognostic patient and tumor characteristics. Conclusions: In this large cohort of patients with advanced or metastatic colorectal cancer, higher plasma 25(OH)D levels were associated with improved OS and PFS. Clinical trials assessing the benefit of vitamin D supplementation in patients with colorectal cancer are warranted.

PURPOSERegular physical activity is associated with reduced risk of recurrence and mortality in patients with nonmetastatic colorectal cancer. Its influence on patients with advanced/metastatic colorectal cancer (mCRC) has been largely unexplored.PATIENTS AND METHODSWe conducted a prospective cohort study nested in Cancer and Leukemia Group B (Alliance)/SWOG 80405 (ClinicalTrials.gov identifier: NCT00265850 ), a National Cancer Institute–sponsored phase III trial of systemic therapy for mCRC. Within 1 month after therapy initiation, patients were invited to complete a validated questionnaire that reported average physical activity over the previous 2 months. On the basis of responses, we calculated metabolic equivalent task (MET) hours per week to quantify physical activity. The primary end point of the clinical trial and this companion study was overall survival (OS). Secondary end points included progression-free survival (PFS) and first grade 3 or greater treatment-related adverse events. To minimize confounding by poor and declining health, we excluded patients who experienced progression or died within 60 days of activity assessment and used Cox proportional hazards regression analysis to adjust for known prognostic factors, comorbidities, and weight loss.RESULTSThe final cohort included 1,218 patients. Compared with patients engaged in less than 3 MET hours per week of physical activity, patients engaged in 18 or more MET hours per week experienced an adjusted hazard ratio for OS of 0.85 (95% CI, 0.71 to 1.02; PTrend= .06) and for PFS of 0.83 (95% CI, 0.70 to 0.99; PTrend= .01). Compared with patients engaging in less than 9 MET hours per week, patients engaging in 9 or more MET hours per week experienced an adjusted hazard ratio for grade 3 or greater treatment-related adverse events of 0.73 (95% CI, 0.62 to 0.86; PTrend< .001).CONCLUSIONAmong patients with mCRC in Cancer and Leukemia Group B (Alliance)/SWOG 80405, association of physical activity with OS was not statistically significant. Greater physical activity was associated with longer PFS and lower adjusted risk for first grade 3 or greater treatment-related adverse events.

4005 Background: Patients (pts) with progressive advanced well-differentiated neuroendocrine tumors arising outside of the pancreas have limited systemic treatment options. Pazopanib (PZ) is an oral multi-kinase inhibitor with activity against VEGFR-2,-3, PDGFR-α, and β, and c-KIT, with initial data suggesting efficacy in CARC. Methods: This was a multicenter, randomized, double-blind, phase II study of PZ (800 mg/day) versus placebo (PL) in progressive CARC. Key eligibility: low-intermediate grade CARC, radiologic progressive disease (PD) < 12 months (mo), and adequate end-organ function. Prior somatostatin analog (SSA) mandated for midgut tumors. Concurrent SSA allowed if previous PD on SSA documented. Primary endpoint was progression-free survival (PFS), defined as time from randomization to PD by central review or death. Secondary endpoints included overall survival (OS), objective response rate (ORR) and safety. The trial had 85% power to detect a difference in median PFS of 14 v 9 mo (hazard ratio [HR] 0.64) at one-sided alpha = 0.1. A stratified log-rank test based on the intend-to-treat (ITT) principle was used. Unblinding and crossover were allowed if PD confirmed by central review. Results: 171 (97 PZ, 74 PL) pts were randomized between 6/2013-10/2015: median age 63; 56% female; 66% small bowel primary; 87% concurrent SSA. Median follow-up of 31 mo; 112 (56 PZ, 56 PL) PFS events observed. 6 pts (4 PZ, 2 PL) remain on initial treatment. Median PFS was 11.6 and 8.5 mo in PZ and PL, respectively (HR = 0.53, 1-sided 90% upper confidence limit [UCL] 0.69, p = 0.0005) which crossed the pre-specified protocol efficacy boundary. 49 PL pts received PZ after PD. Median OS was 41 and 42 mo in PZ and PL, respectively (HR = 1.13, 1-sided 90% UCL 1.51, p = 0.70). RR data will be presented. Notable grade 3+ adverse events were (PZ v. PL %) hypertension (35 v. 8), fatigue (11 v. 4), ALT (10 v. 0), AST (10 v. 0), and diarrhea (7 v. 4). Conclusions: PZ compared to PL was associated with significant improvement in PFS in patients with progressive CARC. The results confirm that VEGF signaling pathway is a valid target for therapy in CARC. Support: U10CA180821, U10CA180882 https://acknowledgments.alliancefound.org . Clinical trial information: NCT01841736.

3035 Background: Energy balance-associated biomarkers such as insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) have been associated with risk and prognosis of various malignancies. Their relationship to disease progression and mortality in metastatic colorectal cancer (mCRC) requires further study. Methods: In a prospective cohort study, baseline plasma IGFBP-3, IGFBP-7, C-peptide, IGF-I, and adiponectin were measured at trial registration among 1,086 patients participating in a National Cancer Institute-sponsored clinical trial of first-line therapy for mCRC. We used Cox proportional hazards regression to adjust for confounders and examine associations of biomarkers with overall (OS) and progression-free survival (PFS). Results: Higher plasma IGFBP-3 was associated with longer OS (adjusted Ptrend < .001) and PFS (adjusted Ptrend = .003). Compared to patients in the lowest IGFBP-3 quintile, patients in the highest quintile experienced an adjusted HR for all-cause mortality of 0.58 (95% CI 0.42 to 0.78) and for disease progression or mortality of 0.60 (95% CI 0.45 to 0.82). Higher plasma IGFBP-7 was associated with shorter OS (adjusted Ptrend < .001) and PFS (adjusted Ptrend = .02). Compared to patients in the lowest IGFBP-7 quintile, patients in the highest quintile experienced an adjusted HR for all-cause mortality of 1.52 (95% CI 1.24 to 1.88) and for disease progression or mortality of 1.28 (95% CI 1.05 to 1.57). C-peptide and IGF-I were not significantly associated with patient outcomes (adjusted Ptrend = .73 and .30 for OS). Adiponectin was not associated with OS; there was a U shaped association between adiponectin and PFS, wherein low and high values were associated with shorter PFS ( Pnon-linear trend = .03). Conclusions: In patients with mCRC, high plasma IGFBP-3 and low IGFBP-7 were associated with reduced risk of disease progression and mortality. These data suggest that energy-balance associated biomarkers may offer prognostic and biologic insights into mCRC. Support: U10CA180821, U10CA180882, BMS, Genentech, Pfizer, Sanofi; https://acknowledgments.alliancefound.org .

PURPOSETo determine the predictive and prognostic value of the consensus molecular subtypes (CMSs) of colorectal cancer (CRC) that represent a merging of gene expression–based features largely in primary tumors from six independent classification systems and provide a framework for capturing the intrinsic heterogeneity of CRC in patients enrolled in CALGB/SWOG 80405.PATIENTS AND METHODSCALGB/SWOG 80405 is a phase III trial that compared the addition of bevacizumab or cetuximab to infusional fluorouracil, leucovorin, and oxaliplatin or fluorouracil, leucovorin, and irinotecan as first-line treatment of advanced CRC. We characterized the CMS classification using a novel NanoString gene expression panel on primary CRCs from 581 patients enrolled in this study to assess the prognostic and predictive value of CMSs in these patients.RESULTSThe CMSs are highly prognostic for overall survival (OS; P < .001) and progression-free survival (PFS; P < .001). Furthermore, CMSs were predictive for both OS ( P for interaction < .001) and PFS ( P for interaction = .0032). In the CMS1 cohort, patients treated with bevacizumab had a significantly longer OS than those treated with cetuximab ( P < .001). In the CMS2 cohort, patients treated with cetuximab had a significantly longer OS than patients treated with bevacizumab ( P = .0046).CONCLUSIONThese findings highlight the possible clinical utility of CMSs and suggests that refinement of the CMS classification may provide a path toward identifying patients with metastatic CRC who are most likely to benefit from specific targeted therapy as part of the initial treatment.

PURPOSE CALGB/SWOG 80405 was a randomized phase III trial that found no statistically significant difference in overall survival (OS) in patients with first-line metastatic colorectal cancer treated with chemotherapy plus either bevacizumab or cetuximab. Primary tumor DNA from 843 patients has been used to discover genetic markers of OS. PATIENTS AND METHODS Gene mutations were determined by polymerase chain reaction. Microsatellite status was determined by genotyping of microsatellites. Tumor mutational burden (TMB) was determined by next-generation sequencing. Cox proportional hazard models were used, with adjusting factors. Interaction of molecular alterations with either the bevacizumab or the cetuximab arms was tested. RESULTS Patients with high TMB in their tumors had longer OS than did patients with low TMB (hazard ratio [HR], 0.73 [95% CI, 0.57 to 0.95]; P = .02). In patients with microsatellite instability–high (MSI-H) tumors, longer OS was observed in the bevacizumab arm than in the cetuximab arm (HR, 0.13 [95% CI, 0.06 to 0.30]; interaction P < .001 for interaction between microsatellite status and the two arms). Patients with BRAF mutant tumors had shorter OS than did patients with wild-type (WT) tumors (HR, 2.01 [95% CI, 1.49 to 2.71]; P < .001). Patients with extended RAS mutant tumors had shorter OS than did patients with WT tumors (HR, 1.52 [95% CI, 1.26 to 1.84]; P < .001). Patients with triple-negative tumors (WT for NRAS/ KRAS/ BRAF) had a median OS of 35.9 months (95% CI, 33.0 to 38.8 months) versus 22.2 months (95% CI, 19.6 to 24.4 months ) in patients with at least one mutated gene in their tumors ( P < .001). CONCLUSION In patients with metastatic colorectal cancer treated in first line, low TMB, and BRAF and RAS mutations are negative prognostic factors. Patients with MSI-H tumors benefited more from bevacizumab than from cetuximab, and studies to confirm this effect of MSI-H are warranted.