O’Neil, Bert H.

AbstractBackgroundEnergy balance-related biomarkers are associated with risk and prognosis of various malignancies. Their relationship to survival in metastatic colorectal cancer (mCRC) requires further study.MethodsBaseline plasma insulin-like growth factor (IGF)-1, IGF-binding protein (IGFBP)-3, IGFBP-7, C-peptide, and adiponectin were measured at time of trial registration in a prospective cohort of patients with mCRC participating in a National Cancer Institute–sponsored trial of first-line systemic therapy. We used Cox proportional hazards regression to adjust for confounders and examine associations of each biomarker with overall survival (OS) and progression-free survival (PFS). P values are 2-sided.ResultsMedian follow-up for 1086 patients was 6.2 years. Compared with patients in the lowest IGFBP-3 quintile, patients in the highest IGFBP-3 quintile experienced an adjusted hazard ratio (HR) for OS of 0.57 (95% confidence interval [CI] = 0.42 to 0.78; Pnonlinearity < .001) and for PFS of 0.61 (95% CI = 0.45 to 0.82; Ptrend = .003). Compared with patients in the lowest IGFBP-7 quintile, patients in the highest IGFBP-7 quintile experienced an adjusted hazard ratio for OS of 1.60 (95% CI = 1.30 to 1.97; Ptrend < .001) and for PFS of 1.38 (95% CI = 1.13 to 1.69; Ptrend < .001). Plasma C-peptide and IGF-1 were not associated with patient outcomes. Adiponectin was not associated with OS; there was a nonlinear U-shaped association between adiponectin and PFS (Pnonlinearity = .03).ConclusionsAmong patients with mCRC, high plasma IGFBP-3 and low IGFBP-7 were associated with longer OS and PFS. Extreme levels of adiponectin were associated with shorter PFS. These findings suggest potential avenues for prognostic and therapeutic innovation.

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.

Abstract Background: In non-metastatic colorectal cancer, a body mass index (BMI) paradox is observed where overweight and early obese patients experience improved outcomes compared to patients with normal, low, or morbidly obese BMI. The influence of obesity on patients with advanced or metastatic colorectal cancer (mCRC) is relatively unexplored. Methods: We conducted a prospective BMI companion study in CALGB (now Alliance for Clinical Trials in Oncology)/SWOG 80405, a phase III mCRC treatment trial. BMI was measured at trial registration. Primary and secondary endpoints were overall and progression-free survival, respectively. To minimize confounding by poor and rapidly declining health, we used Cox proportional hazards regression to adjust for known prognostic factors, comorbidities, physical activity, and weight loss, and excluded individuals with low BMI &lt;21 from statistical tests for trend. We also examined self-reported weight loss over the six months prior to trial enrollment as an independent predictor of patient outcome. Results: In this sub-study of a phase III mCRC trial, BMI was recorded for all 2,323 patients enrolled. Following adjustment for confounders, there were no significant associations between BMI and overall or progression-free survival (excluding BMI &lt;21, Ptrend with increasing BMI = 0.12 and 0.42, respectively). Conversely, weight loss prior to treatment was associated with shorter overall and progression-free survival; compared to individuals with weight change &lt;5%, individuals with weight loss &gt;20% experienced an adjusted hazard ratio of 1.46 for all-cause mortality (95% confidence interval 1.15 to 1.85, Ptrend &lt;.0001) and of 1.27 for disease progression or death (95% confidence interval 1.04 to 1.56, Ptrend = .009). Conclusion: In this prospective study of patients with mCRC, BMI at time of first-line chemotherapy initiation was not associated with patient outcome. Weight loss prior to study entry was associated with increased risk of patient mortality and disease progression. Citation Format: Brendan Guercio, Sui Zhang, Alan P. Venook, Fang-Shu Ou, Donna Niedzwiecki, Heinz-Josef Lenz, Federico Innocenti, Hanna Sanoff, Michelle R. Mahoney, Bert H. O'Neil, James E. Shaw, Blase N. Polite, Howard S. Hochster, James N. Atkins, Richard M. Goldberg, Robert J. Mayer, Charles D. Blanke, Charles S. Fuchs, Jeffrey A. Meyerhardt. Body mass index, weight loss, and progression and mortality in metastatic colorectal cancer: Results from CALGB/SWOG 80405 (Alliance) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3285.

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 .