The Impact of Obesity on Cancer Survivorship Leslie Bernstein, Ph.D. Professor and Director, Division of Cancer Etiology Department of Population Sciences Beckman Research Institute City of Hope
Measuring obesity in studies Body mass index (kg per m 2 ) WHO cut points <18.5 underweight 30-39.9 obese 25-29.9 overweight 40+ morbidly obese Weight loss Central obesity (waist, hip) Lean vs. fat mass or visceral vs. subcutaneous fat (direct measures) When is body size measured? (before, during, or after diagnosis; after treatment)
Study Designs Observational Cancer patients from cohort studies follow-up starts at diagnosis Cases from case-control studies or cohorts of patients identified after diagnosis: follow-up starts after during treatment or after treatment completed Some restrict to patients seen at a single or selected health facilities Participants in randomized controlled phase III clinical trials
Potential biases vary by study type Observational Inability to control for treatment Cannot guarantee obese patients received sufficient doses of chemotherapy, immunotherapy or hormonal therapy Most often, self-reported body size measures Randomized controlled clinical trials Greater control over dosing received Lack some important covariate information (e.g., smoking, physical activity) Selection bias who participates in clinical trials?
Addition issue affecting all studies Cancers where screening employed E.g., breast cancer, colon cancer, prostate cancer Would obese individuals be as likely to have been screened?
Gaps In Knowledge Overall Would weight loss result in lower improved prognosis after cancer diagnosis? And if so, can loss be maintained? What is the effect on prognosis of weight cycling? Is the important factor weight maintenance? Does the impact of obesity differ by subtype of cancer?
Gaps in Knowledge Overall What factors contribute to obesity before diagnosis? After diagnosis? Genetics, nutrition, physical inactivity, treatment Sarcopenic obesity (loss of lean mass, increase in fat mass) What mechanisms account for the impact of obesity on cancer prognosis?
Objectives A brief overview of information on Fatal cancers and obesity A brief review of some cancers A focus on breast cancer Do we have sufficient information to make a recommendation regarding approaches to reduce obesity and improve prognosis
Obesity and Cancer Mortality Men TYPE OF CANCER All cancers Esophageal cancer Stomach cancer Colorectal cancer Liver cancer Gallbladder cancer Pancreatic cancer Lung cancer Melanoma Prostate cancer Bladder cancer Kidney cancer Brain cancer Non-Hodgkin s lymphoma Multiple myeloma Leukemia All other cancers 14% of cancer deaths in men Calle et al NEJM 2003; 348: 1625-38
Body Mass index and Cancer Mortality Women TYPE OF CANCER All cancers Esophageal cancer Stomach cancer Colorectal cancer Liver cancer Gallbladder cancer Pancreatic cancer Lung cancer Melanoma Breast cancer 20% of cancer deaths in women Endometrial cancer Cervical cancer Ovarian cancer Bladder cancer Kidney cancer Brain cancer Non-Hodgkin s lymphoma Multiple myeloma Leukemia All other cancers Calle et al NEJM 2003; 348: 1625-38
Move from cancer mortality in healthy cohort to studies of cancer patients
Cancers where obesity influences risk and may impact prognosis Pancreas cancer small studies (e.g., A) Balentine et al, J Gastrointest Surgery, 2010; B) Olson et al, Int J Cancer 2010) Greater intrabdominal fat poorer prognosis pattern of risk is non-linear (Study A) Greater BMI no impact (Studies A, B) Esophageal cancer (e.g., Madani et al, Int J Cardiothorac Surg 2010; Grotenhuis et al, World J Surg 2010) No impact of BMI Endometrial cancer a few studies suggest obesity impacts prognosis
Cancers where obesity influences risk and may impact prognosis Prostate cancer Higher risk of death from prostate cancer associated with higher BMI But results not all consistent Depending on study design different issues arise in interpretation of findings eg, androgen deprivation therapy may increase BMI
Cancers where obesity influences risk and may impact prognosis Ovarian cancer 40.2% of 336 patients who underwent cytoreductive surgery at one institution were overweight/obese Obesity unrelated to tumor stage, histology, differentiation, tumor marker levels or survival (Fotopoulou, Ann Surg Oncol 2011;18:2629) One study suggests no survival differences between obese and non-obese if optimal tumor debulking statuses are the same (Matthews, Gyn Oncol, 2009)..
Cancers where obesity influences risk and may impact prognosis Lung Cancer: 76,086 lung cancer patients with 8.7 month median follow-up (Yang et al, J Surg Res 2011; 170) Relative to weight stability/normal weight at diagnosis Weight loss at diagnosis associated with poorer survival Obesity at diagnosis associated with better survival Hong Kong study of lung cancer patients > 65 yrs at diagnosis, shows independent of smoking status (Leung et al, Int J Epidemiol 2011;40:174) Few studies of renal cell carcinoma (high BMI better prognosis), lymphoma and childhood ALL (high BMI poorer prognosis), etc.
Obesity and Colon Cancer Prognosis Review of 8 studies (Parekh et al, Ann Rev Nutr 2012, epub) 3 used pre-diagnosis measures 15% to 2-fold increased risk for colon but not rectal cancer mortality among obese persons. 5 used post-diagnosis measures: results are mixed 3 show statistically significantly increased risk among obese (includes one study also looking at pre-diagnosis BMI) 3 show increased risk but not statistically significant elevation in risk among obese Sex Difference: Intergroup 0089 trial: poorer survival among obese women but not among obese men (Meyerhardt et al., Cancer 2003)
Colon Cancer treatment difference Two large phase III clinical trials CAIRO 796 advanced colorectal cancer patients treated with chemotherapy CAIRO2 730 advanced colorectal cancer patients treated with chemo+targeted therapy CAIRO: High BMI associated with longer median overall survival CAIRO2: No association between BMI and overall survival Simkens et al, Eur J Cancer 2011;47:2560.
Obesity and Prognosis after Breast Cancer BMI considered an established negative prognostic factor for breast cancer in premenopausal and postmenopausal women although not all studies agree Does not matter when BMI assessed (before, at or after diagnosis) Similar results for weight gain Limited data on weight loss (few studies of intentional weight loss) Few studies consider other lifestyle factors
Obesity and Prognosis after Breast Cancer Few studies consider other lifestyle factors Studies conducting follow-up of women in clinical trials show more modest effects Most observational studies cannot assess recurrence (disease free survival) Most studies are of white women
Change in Body Mass Index Pre-dx to Post-dx: Relative risk of breast cancer death: 5,204 women with breast cancer from the Nurses Health Study Among Never Smokers Number of women with breast cancer Number of breast cancer deaths Relative risk (95% CI) Loss Maintain Gain Category of BMI Change 0.5 <2.0 kg/m 2 514 677 712 272 38 48 77 46 1.01 (0.65,1.58) 1.00 1.35 (0.93,1.95) Gain p 2.0 kg/m 2 1.64 (1.07,2.51) 0.03 Kroenke et al, JCO 2005
Obesity, Hormone Therapy Use and Prognosis after Breast Cancer in Swedish population Obesity at diagnosis was associated with tumors of larger size, lymph node positivity, positive progesterone receptor status and poorer prognosis. Patients followed from 1993-1995 through 2003 Body mass index (kg/m 2 ) and number of patients All Women Relative risk (95% CI) < 25 (n=1267) 1.0 25-30 (n=997) 0.9 (0.7-1.2) >30 (n=376) 1.2 (0.9-1.6) Adjusted for age at diagnosis, alcohol intake, tumor size and lymph node positivity Rosenberg et al, Br J Cancer 2009;100:1486
Obesity, Hormone Therapy Use and Prognosis after Breast Cancer in Swedish population In etiologic studies hormone therapy interacts or competes with obesity: hormone therapy increases risk of breast cancer among normal weight and thin women Body mass index (kg/m 2 ) and number of patients No hormone therapy Relative risk (95% CI) Estrogen+ progestin therapy Relative risk (95% CI) < 25 (n=1267) 1.0 1.0 25-30 (n=997) 0.8 (0.6-1.1) 1.0 (0.5-2.1) >30 (n=376) 0.9 (0.6-1.3) 2.3 (1.1-5.2) Adjusted for age at diagnosis, alcohol intake, tumor size and lymph node positivity Rosenberg et al, Br J Cancer 2009;100:1486
Does greater obesity among Black women explain mortality disparity in breast cancer? Women s Contraceptive and Reproductive Experiences (CARE) Study Population-based case-control study 1622 black and 2953 white women with invasive breast cancer Ages 35-64 years Women diagnosed between 1994 and 1998 Lu et al., J Clinical Oncol, 2011
Participants Los Angeles Atlanta Detroit Seattle Philadelphia 1604 black, 2934 white women Median yrs of follow-up: 8.6 yrs (25th-75th percentiles: 7.1-10.1 yrs) Deaths: 519 black, 534 white In-person interviews Height Weight 5 yrs before diagnosis Demographic factors Tumor characteristics breast cancer deaths 412 black, 416 white Lu et al., J Clinical Oncol, 2011
Results: BMI at 5 years before diagnosis and mortality Relative risk (95% CI) of mortality 1.6 1.4 1.2 1 0.8 0.6 0.4 0.2 0 0.89 1 0.99 1.23 0.86 1 0.99 1.20 <20 kg/m2 20-24.9 kg/m2 25-29.9 kg/m2 30 kg/m2 All cause mortality Breast cancer mortality P-trend<0.01 P-trend=0.03 Lu et al., J Clinical Oncol, 2011
Body Size Before Diagnosis and Mortality: Women with Invasive Breast Cancer in the Women s CARE Study (1604 Black women; 2934 white women) Cox proportional hazards models use age (days) as the time metric, are stratified by age at diagnosis in years, and include race, education, study site, tumor stage, estrogen receptor status and number of comorbidities Hazard Ratio 2 1.5 1 0.5 Whites Blacks Hazard Ratio 2 1.5 1 0.5 Whites Blacks 0 Overall Mortality <20 20-24.9 25-29.9 30+ BMI 5 yrs pre-dx (kg/m 2 ) 0 Breast Cancer Mortality <20 20-24.9 25-29.9 30+ BMI 5 yrs pre-dx (kg/m 2 ) Lu et al., J Clinical Oncol, 2011
Breast cancer-specific survival of Black and White women diagnosed with invasive breast cancer stratified by obesity status five years before breast cancer diagnosis 100% 95% 90% Estimated Probability of Survival 85% 80% 75% 70% 65% 60% 55% Non-obese white women Obese white women Non-obese black women Obese black women 50% 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Lu et al, J Clin Oncol, 2011 Follow-up years Cohort size: 1604 Black women; 2934 white women CARE=Contraceptive and Reproductive Experiences
Weight Loss and Breast Cancer Prognosis: A caveat for post-menopausal women Presume that hormones created by conversion of adrenal androgen to estrogen in body fat is a major part of the problem If on aromatase inhibitors (AIs), this conversion does not happen. HENCE, no known immediate benefit of weight loss for breast cancer if on these drugs although definitely other health benefits But woman will not be on AIs forever.
Do we have sufficient information to make a recommendation regarding approaches to reduce obesity and improve prognosis?
Thank you Would weight loss result in lower risk of cancer? And if so, can loss be maintained? What is the effect on risk of weight cycling? Is the important factor weight maintenance? What factors contribute to obesity: Genetics, nutrition, physical inactivity, choice