Elizabeth M. Cespedes Feliciano

Explaining the Obesity Paradox: The Association between Body Composition and Colorectal Cancer Survival (C-SCANS Study)

Background: Body composition may partially explain the U-shaped association between body mass index (BMI) and colorectal cancer survival. Methods: Muscle and adiposity at colorectal cancer diagnosis and survival were examined in a retrospective cohort using Kaplan–Meier curves, multivariable Cox regression, and restricted cubic splines in 3,262 early-stage (I–III) male (50%) and female (50%) patients. Sarcopenia was defined using optimal stratification and sex- and BMI-specific cut points. High adiposity was defined as the highest tertile of sex-specific total adipose tissue (TAT). Primary outcomes were overall mortality and colorectal cancer–specific mortality (CRCsM). Results: Slightly over 42% patients were sarcopenic. During 5.8 years of follow-up, 788 deaths occurred, including 433 from colorectal cancer. Sarcopenic patients had a 27% [HR, 1.27; 95% confidence interval (CI), 1.09–1.48] higher risk of overall mortality than those who were not sarcopenic. Females with both low muscle and high adiposity had a 64% higher risk of overall mortality (HR, 1.64; 95% CI, 1.05–2.57) than females with adequate muscle and lower adiposity. The lowest risk of overall mortality was seen in patients with a BMI between 25 and <30 kg/m2, a range associated with the greatest number of patients (58.6%) who were not at increased risk of overall mortality due to either low muscle or high adiposity. Conclusions: Sarcopenia is prevalent among patients with non-metastatic colorectal cancer, and should, along with adiposity be a standard oncological marker. Impact: Our findings suggest a biologic explanation for the obesity paradox in colorectal cancer and refute the notion that the association between overweight and lower mortality is due solely to methodologic biases. Cancer Epidemiol Biomarkers Prev; 26(7); 1008–15. ©2017 AACR.

Association of Weight Change after Colorectal Cancer Diagnosis and Outcomes in the Kaiser Permanente Northern California Population

Background: Higher body mass index (BMI) is associated with incident colorectal cancer but not consistently with colorectal cancer survival. Whether weight gain or loss is associated with colorectal cancer survival is largely unknown. Methods: We identified 2,781 patients from Kaiser Permanente Northern California diagnosed with stages I–III colorectal cancer between 2006 and 2011 with weight and height measurements within 3 months of diagnosis and approximately 18 months after diagnosis. We evaluated associations between weight change and colorectal cancer–specific and overall mortality, adjusted for sociodemographics, disease severity, and treatment. Results: After completion of treatment and recovery from stage I–III colorectal cancer, loss of at least 10% of baseline weight was associated with significantly worse colorectal cancer–specific mortality (HR 3.20; 95% confidence interval [CI], 2.33–4.39; Ptrend < 0.0001) and overall mortality (HR 3.27; 95% CI, 2.56–4.18; Ptrend < 0.0001). For every 5% loss of baseline weight, there was a 41% increased risk of colorectal cancer–specific mortality (95% CI, 29%–56%). Weight gain was not significantly associated with colorectal cancer–specific mortality (Ptrend = 0.54) or overall mortality (Ptrend = 0.27). The associations were largely unchanged after restricting analyses to exclude patients who died within 6 months and 12 months of the second weight measurement. No significant interactions were demonstrated for weight loss or gain by gender, stage, primary tumor location, or baseline BMI. Conclusions: Weight loss after diagnosis was associated with worse colorectal cancer–specific mortality and overall mortality. Reverse causation does not appear to explain our findings. Impact: Understanding mechanistic underpinnings for the association of weight to worse mortality is important to improving patient outcomes. Cancer Epidemiol Biomarkers Prev; 26(1); 30–37. ©2016 AACR. See all the articles in this CEBP Focus section, “The Obesity Paradox in Cancer: Evidence and New Directions.”

Association of Systemic Inflammation and Sarcopenia With Survival in Nonmetastatic Colorectal Cancer: Results From the C SCANS Study

Importance Systemic inflammation and sarcopenia are easily evaluated, predict mortality in many cancers, and are potentially modifiable. The combination of inflammation and sarcopenia may be able to identify patients with early-stage colorectal cancer (CRC) with poor prognosis. Objective To examine associations of prediagnostic systemic inflammation with at-diagnosis sarcopenia, and determine whether these factors interact to predict CRC survival, adjusting for age, ethnicity, sex, body mass index, stage, and cancer site. Design, Setting, and Participants A prospective cohort of 2470 Kaiser Permanente patients with stage I to III CRC diagnosed from 2006 through 2011. Exposures Our primary measure of inflammation was the neutrophil to lymphocyte ratio (NLR). We averaged NLR in the 24 months before diagnosis (mean count = 3 measures; mean time before diagnosis = 7 mo). The reference group was NLR of less than 3, indicating low or no inflammation. Main Outcomes and Measures Using computed tomography scans, we calculated skeletal muscle index (muscle area at the third lumbar vertebra divided by squared height). Sarcopenia was defined as less than 52 cm2/m2 and less than 38 cm2/m2 for normal or overweight men and women, respectively, and less than 54 cm2/m2 and less than 47 cm2/m2 for obese men and women, respectively. The main outcome was death (overall or CRC related). Results Among 2470 patients, 1219 (49%) were female; mean (SD) age was 63 (12) years. An NLR of 3 or greater and sarcopenia were common (1133 [46%] and 1078 [44%], respectively). Over a median of 6 years of follow-up, we observed 656 deaths, 357 from CRC. Increasing NLR was associated with sarcopenia in a dose-response manner (compared with NLR < 3, odds ratio, 1.35; 95% CI, 1.10-1.67 for NLR 3 to <5; 1.47; 95% CI, 1.16-1.85 for NLR ≥ 5; P for trend < .001). An NLR of 3 or greater and sarcopenia independently predicted overall (hazard ratio [HR], 1.64; 95% CI, 1.40-1.91 and HR, 1.28; 95% CI, 1.10-1.53, respectively) and CRC-related death (HR, 1.71; 95% CI, 1.39-2.12 and HR, 1.42; 95% CI, 1.13-1.78, respectively). Patients with both sarcopenia and NLR of 3 or greater (vs neither) had double the risk of death, overall (HR, 2.12; 95% CI, 1.70-2.65) and CRC related (HR, 2.43; 95% CI, 1.79-3.29). Conclusions and Relevance Prediagnosis inflammation was associated with at-diagnosis sarcopenia. Sarcopenia combined with inflammation nearly doubled risk of death, suggesting that these commonly collected biomarkers could enhance prognostication. A better understanding of how the host inflammatory/immune response influences changes in skeletal muscle may open new therapeutic avenues to improve cancer outcomes.

Metabolic Dysfunction, Obesity, and Survival Among Patients With Early-Stage Colorectal Cancer.

PURPOSE The effects of obesity and metabolic dysregulation on cancer survival are inconsistent. To identify high-risk subgroups of obese patients and to examine the joint association of metabolic syndrome (MetSyn) in combination with obesity, we categorized patients with early-stage (I to III) colorectal cancer (CRC) into four metabolic categories defined by the presence of MetSyn and/or obesity and examined associations with survival. METHODS We studied 2,446 patients diagnosed from 2006 to 2011 at Kaiser Permanente. We assumed MetSyn if patients had three or more of five components present at diagnosis: fasting glucose > 100 mg/dL or diabetes; elevated blood pressure (systolic ≥ 130 mm Hg, diastolic ≥ 85 mm Hg, or antihypertensives); HDL cholesterol < 40 mg/dL (men) or < 50 mg/dL (women); triglycerides ≥ 150 mg/dL or antilipids; and/or highest sex-specific quartile of visceral fat by computed tomography scan (in lieu of waist circumference). We then classified participants according to the presence (or absence) of MetSyn and obesity (BMI < 30 or ≥ 30 kg/m2) and assessed associations with overall and CRC-related survival using Cox proportional hazards models adjusted for demographic, tumor, and treatment factors and muscle mass at diagnosis. RESULTS Over a median follow-up of 6 years, 601 patients died, 325 as a result of CRC. Mean (SD) age was 64 (11) years. Compared with the reference of nonobese patients without MetSyn (n = 1,225), for overall survival the hazard ratios (HR) and 95% CIs were 1.45 (1.12 to 1.82) for obese patients with MetSyn (n = 480); 1.09 (0.83 to 1.44) for the nonobese with MetSyn (n = 417), and 1.00 (0.80 to 1.26) for obese patients without MetSyn (n = 324). Obesity with MetSyn also predicted CRC-related survival: 1.49 (1.09 to 2.02). The hazard of death increased with the number of MetSyn components present, independent of obesity. CONCLUSION Patients with early-stage CRC with obesity and MetSyn have worse survival, overall and CRC related.

Association of Muscle and Adiposity Measured by Computed Tomography With Survival in Patients With Nonmetastatic Breast Cancer

Importance Sarcopenia (low muscle mass), poor muscle quality (low muscle radiodensity), and excess adiposity derived from computed tomography (CT) has been related to higher mortality in patients with metastatic breast cancer, but the association with prognosis in patients with nonmetastatic breast cancer is unknown. Objective To evaluate associations of all 3 body composition measures, derived from clinically acquired CT at diagnosis, with overall mortality in nonmetastatic breast cancer. Design, Setting, and Participants This observational study included 3241 women from Kaiser Permanente of Northern California and Dana Farber Cancer Institute diagnosed from January 2000 to December 2013 with stages II or III breast cancer. We calculated hazard ratios (HRs) to evaluate the associations of all-cause mortality with sarcopenia, low muscle radiodensity, and total adipose tissue (TAT). Models were adjusted for sociodemographics, tumor characteristics, treatment, body mass index (BMI; calculated as weight in kilograms divided by height in meters squared), and other body composition measures. We also evaluated the cross-classification of categories of sarcopenia (yes/no) and tertiles of TAT, with outcomes. Main Outcomes and Measures Overall survival time and all-cause mortality. Results Median (range) age of 3241 women included in this study was 54 (18-80) years, and median follow-up was 6.0 years; 1086 patients (34%) presented with sarcopenia, and 1199 patients (37%) had low muscle radiodensity. Among patients with nonmetastatic breast cancer, those with sarcopenia showed higher overall mortality (HR, 1.41; 95% CI, 1.18-1.69) compared with those without sarcopenia. Patients in the highest tertile of TAT also showed higher overall mortality (HR, 1.35; 95% CI, 1.08-1.69) compared with those in the lowest tertile. Low radiodensity was not associated with survival. In analyses of sarcopenia and TAT, highest mortality was seen in patients with sarcopenia and high TAT (HR, 1.89; 95% CI, 1.30-2.73); BMI alone was not significantly related to overall mortality and did not appropriately identify patients at risk of death owing to their body composition. Conclusions and Relevance Sarcopenia is underrecognized in nonmetastatic breast cancer and occurs in over one-third of newly diagnosed patients. Measures of both sarcopenia and adiposity from clinically acquired CT scans in nonmetastatic patients provide significant prognostic information that outperform BMI and will help to guide interventions to optimize survival outcomes.

Body mass index, PAM50 subtype, recurrence and survival among patients with nonmetastatic breast cancer

Studies of obesity and survival among patients with breast cancer produce conflicting results, possibly because of heterogeneity by molecular subtype.

Change in Dietary Patterns and Change in Waist Circumference and DXA Trunk Fat Among Postmenopausal Women

To examine whether changes in diet quality predict changes in central adiposity among postmenopausal women.

Associations of pre-existing co-morbidities with skeletal muscle mass and radiodensity in patients with non-metastatic colorectal cancer: Co-morbidities and Muscle Abnormalities in Colorectal Cancer

Co‐morbidities and computerized tomography‐measured muscle abnormalities are both common in cancer patients and independently adversely influence clinical outcomes. Muscle abnormalities are also evident in other diseases, such as diabetes and obesity. This study examined for the first time the association between co‐morbidities and muscle abnormalities in patients diagnosed with colorectal cancer (CRC).

Muscle radiodensity and mortality in patients with colorectal cancer: Muscle Radiodensity and Prognosis in CRC

Low skeletal muscle radiodensity (SMD) is related to higher mortality in several cancers, but the association with colorectal cancer (CRC) prognosis is unclear.

Variation in actigraphy-estimated rest-activity patterns by demographic factors

ABSTRACT Rest-activity patterns provide an indication of circadian rhythmicity in the free-living setting. We aimed to describe the distributions of rest-activity patterns in a sample of adults and children across demographic variables. A sample of adults (N = 590) and children (N = 58) wore an actigraph on their nondominant wrist for 7 days and nights. We generated rest-activity patterns from cosinor analysis (MESOR, acrophase and magnitude) and nonparametric circadian rhythm analysis (IS: interdaily stability; IV: intradaily variability; L5: least active 5-hour period; M10: most active 10-hour period; and RA: relative amplitude). Demographic variables included age, sex, race, education, marital status, and income. Linear mixed-effects models were used to test for demographic differences in rest-activity patterns. Adolescents, compared to younger children, had (1) later M10 midpoints (β = 1.12 hours [95% CI: 0.43, 1.18] and lower M10 activity levels; (2) later L5 midpoints (β = 1.6 hours [95% CI: 0.9, 2.3]) and lower L5 activity levels; (3) less regular rest-activity patterns (lower IS and higher IV); and 4) lower magnitudes (β = −0.95 [95% CI: −1.28, −0.63]) and relative amplitudes (β = −0.1 [95% CI: −0.14, −0.06]). Mid-to-older adults, compared to younger adults (aged 18–29 years), had (1) earlier M10 midpoints (β = −1.0 hours [95% CI: −1.6, −0.4]; (2) earlier L5 midpoints (β = −0.7 hours [95% CI: −1.2, −0.2]); and (3) more regular rest-activity patterns (higher IS and lower IV). The magnitudes and relative amplitudes were similar across the adult age categories. Sex, race and education level rest-activity differences were also observed. Rest-activity patterns vary across the lifespan, and differ by race, sex and education. Understanding population variation in these patterns provides a foundation for further elucidating the health implications of rest-activity patterns across the lifespan.