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Shalini Dalal, M.D. Associate Professor Department of Palliative Care and Rehab Medicine

Visceral adiposity and clinical outcomes in postmenopausal women with operable breast cancer. Does body shape matter?. Shalini Dalal, M.D. Associate Professor Department of Palliative Care and Rehab Medicine U.T. MD Anderson Cancer Center, Houston TX 10 th October 2014. Overview.

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Shalini Dalal, M.D. Associate Professor Department of Palliative Care and Rehab Medicine

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  1. Visceral adiposity and clinical outcomes in postmenopausal women withoperable breast cancer. Does body shape matter? Shalini Dalal, M.D. Associate Professor Department of Palliative Care and Rehab Medicine U.T. MD Anderson Cancer Center, Houston TX 10th October 2014

  2. Overview • Obesity definitions • National obesity trends • General vs Abdominal obesity • Obesity and cancer • Breast cancer retrospective study

  3. Obesity • Definition • an abnormal or excessive fat accumulation in adipose tissue, to the extent that health is impaired • Body mass index (BMI): kg/m2 • For adults aged 20 years or older, • Overweight : BMI 25.0to 29.9 • Obesity : BMI ≥30.0 • Obesity may be divided into • grade 1: BMI, 30 to <35 • grade 2: BMI, 35 to <40) • grade 3 BMI ≥40 • BMI does not discriminate between fat and lean mass, nor does it address body fat distribution • Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults: executive summary: Expert Panel on the Identification, Evaluation, and Treatment of Overweight in Adults. Am J ClinNutr. 1998 • WHO Expert Committee on Physical Status. Physical Status: The Use and Interpretation of Anthropometry. Geneva, Switzerland: World Health Organization; 1995

  4. Obesity prevalence in the US • NHANES (National Health and Nutrition Examination Survey): program of NCHS, CDC & Prevention • tracks trends in the prevalence of obesity by collecting data on height and weight measurements. • Cross-sectional survey of nationally representative sample of the US population. Initially started in 1960 • Since 1999 data released in 2-year cycles: • 2011-2012* • Overweight/obese (BMI≥25) • Overall 69%; males 71.6%, females 66.5% • Obese (BMI≥30) • Overall 34.9%; Males 33.7%, females 36.5 % • *Ogden et al. Prevalence of Childhood and Adult Obesity in the United States, 2011-2012. JAMA. 2014

  5. Trends in the prevalence of obesity among adults aged 20 years and over, by sex: United States 1960-2012 Percentage • No significant change from 2003-2004 to 2011-2012, • Except women ≥ 60 years • Obesity increased from 31.5% to more than 38%. Years

  6. General and Abdominal obesity • Fat is principally deposited in two compartments; subcutaneously and viscerally • Dr Jean Vague in 1947, first to draw attention to different patterns of fat distribution: • Android obesity: upper-body, male-type fat (visceral) • Gynoid obesity: lower-body, female-type fat (subcutaneous) .

  7. Body shape and obesity • Where the weight is deposited might be as important a consideration as overall weight gain. • Visceral fat more metabolically active and has multiple endocrine, metabolic and immunological functions • Shown to be central to the pathogenesis of the MetSyn, a pro-inflammatory, pro-coagulant state associated with insulin resistance • MetSyn: include abdominal obesity, dyslipidemia, elevated fasting plasma glucose and hypertension • ↑ Visceral fat accumulation associated Type 2 diabetes mellitus Hypertension Dyslipidemia CAD Cancer • The importance of fat location in terms of dysmetabolism risk is evident as an ↑ ratio of visceral fat area to subcutaneous fat area has been shown to be strongly related to disorders of glucose and lipid metabolism in obese subjects more strongly associated than BMI alone GalicS,. Adipose tissue as an endocrine organ. Mol Cell Endocrinol2010 Alberti KG. Metabolicsyndrome – A Consensus Statement from the International Diabetes Federation. DiabetMed 2006 Fujioka S Contributionofintra-abdominal fat accumulation to the impairment of glucose and lipid metabolism in human obesity. Metabolism 1987

  8. Waist circumference (WC) & waist-to-hip ratio (WHR) • Simple anthropometric measure of abdominal obesity, fat distribution • WC: visceral fat; WHR: visceral to subcutaneous fat distribution • Both WC and WHR are independent predictors of mortality. • may be more precise than BMI in assessing obesity-related health burden, including mortality, risk of type 2 diabetes and cardiovascular disease. • NHLB Institute clinical guidelines recommend that clinicians assess WC • Yusuf et al.. Obesity and the risk of myocardial infarction in 27,000 participants from 52countries: a case-control study. Lancet 2005 • Folsom et al. Associations of general and abdominal obesity with multiple health outcomes in older women:theIowa Women ’s Health Study. Arch Intern Med 2000 • Ashwell et al. Six reasons why the waist-to-height ratio is a rapid and effective global indicator for health risks of obesity and how its use could simplify the international public health message on obesity. Int J Food SciNutr 2005; • Pischonet al. General and abdominal adiposity and risk of death in Europe. N Engl J Med 2008;

  9. National prevalence of abdominal obesity

  10. RESEARCH LETTER JAMA September 2014Trends in Mean Waist Circumference and AbdominalObesity Among US Adults, 1999-2012 • Methods: Data from seven 2-year cycles of the NHANES starting with 1999-2000 and concluding with 2011-2012. • Response rates 69.5% to 79.6%. • Waist circumference measured just above the iliac crest • Abdominal obesity defined as a WC > 102 cm in men and > 88 cm in women. Ford ES, Maynard LM, Li C. Trends in Mean Waist Circumference and Abdominal Obesity Among US Adults, 1999-2012. JAMA. 2014

  11. Results • N=32 816 men and \women >/=20 yrs. • mean waist circumference • ↑ progressively and significantly to 98.5 cm in 2011-2012 from 95.5 cm in 1999-2000 • Significant increases occurred in men, women,non-Hispanic whites, non-Hispanic blacks, and Mexican Americans. • Particularly large increases between the first and last surveys were observed • non-Hispanic white women aged 40 to 49 years (6.6 cm) • non-Hispanic black men aged 30 to 39 years (8.1 cm) • Mexican American men aged 20 to 29 years (8.7 cm), • Mexican American women aged 70 years or older (11.2 cm), • non-Hispanic black women aged 30 to 39 years (11.6 cm).

  12. Trends in the prevalence of Abdominal obesity among adults: United States 1999-2012 Percentage • from 2003 to 2012, significant increases in mean WC • among all adults (P = .02 for linear trend), • women (P ≤ .01 for linear trend), • non-Hispanic blacks (P = .02 for linear trend), • Mexican Americans (P = .01 for linear trend). Years

  13. Conclusion • The prevalence of obesity as measured by BMI remains high, but has plateaued since 2003-2004 • In contrast prevalence of abdominal obesity as measured by WC is still increasing.

  14. Robust link between obesity and cancer • ↑ Cancer risk: • esophagus, pancreas, colorectal, breast (postmenopausal), endometrium, kidney • relative risk estimates of 1.1–1.66 per 5 kg/m2 incremental increase in BMI • ↑ Cancer-related mortality • 14% of all deaths from cancer in men and 20% in women. • Animal models energy restriction decreases spontaneous tumor occurrence • Wtloss following bariatric surgery associated with reduction in cancer incidence • Renéhan, et al. Body-mass index and incidence of cancer: A systematic review and meta-analysis of prospective observational studies. Lancet 2008 • Calle, EE et al. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. Adults. NEJM 2003; • Dirx et al. Energy restriction and the risk of spontaneous mammary tumors in mice: A meta-analysis. Int J Cancer 2003 • Mai et al.. Calorie restriction and diet composition modulate spontaneous intestinal tumorigenesis in Apc(Min) mice through different mechanisms. Cancer Res 2003 • Sjostrom et al. Effects of bariatric surgery on cancer incidence in obese patients in Sweden (Swedish obese subjects study): A prospective, controlled intervention trial. Lancet Oncol2009

  15. Mechanisms underlying obesity and tumorigenesis Doyle et al. Obesity-related cancers; Visceral obesity, metabolic syndrome, insulin resistance and cancer. Proceedings of the Nutrition Society (2012),

  16. Obesity and breast cancer • Epidemiological data links obesity (BMI) to higher risk for the development of post-menopausal breast cancer • Following diagnosis, higher BMI is also associated with higher risks of recurrence and death. • Litton et al JCO 2008 • high BMI associated with a decreased pCR to NC, which in part may explain the poorer outcomes observed in obese breast cancer patients. • Petrelliet al. Body mass index, height, and postmenopausal breast cancer mortality in a prospective cohort of US women. Cancer causes & control : CCC. 2002. • Morimoto et al. Obesity, body size, and risk of postmenopausal breast cancer: the Women's Health Initiative (United States). Cancer causes & control : CCC. Oct 2002; • Whiteman et al. Body mass and mortality after breast cancer diagnosis. Cancer Epidemiol Biomarkers Prev. Aug 2005;. • Majed et al.. Is obesity an independent prognosis factor in woman breast cancer? Breast Cancer Res Treat. Sep 2008; • Hahn et al. Factors associated with advanced disease stage at diagnosis in a population-based study of patients with newly diagnosed breast cancer. Am J Epidemiol. 2007; • Berclaz et al. Body mass index as a prognostic feature in operable breast cancer: the International Breast Cancer Study Group experience. Ann Oncol. Jun 2004 • Tao et al. . Association of overweight with breast cancer survival. Am J Epidemiol. 2006; • Loi et al. Obesity and outcomes in premenopausal and postmenopausal breast cancer. Cancer Epidemiol Biomarkers Prev. Jul 2005 • Litton et al. Relationship between obesity and pathologic response to neoadjuvant chemotherapy among women with operable breast cancer. J ClinOncol. 2008

  17. Studies of central obesity and breast cancer • Confined to epidemiological studies to define breast cancer risk. • In majority of these studies, WC and/or WHR, were positively associated with increased breast cancer risk • Connolly BS, Barnett C, Vogt KN, Li T, Stone J, Boyd NF. A meta-analysis of published literature on waist-to-hip ratio and risk of breast cancer. Nutrition and cancer. 2002 • HarvieM, Hooper L, Howell AH. Central obesity and breast cancer risk: a systematic review. Obesity reviews : an official journal of the International Association for the Study of Obesity. Aug 2003 • Stoll BA. Upper abdominal obesity, insulin resistance and breast cancer risk. Int J ObesRelatMetabDisord. Jun 2002

  18. Gold standard techniques to quantify body fat compartments • CT or MRI • Several studies using above suggest higher Visceral fat to be associated with immune and metabolic dysfunction and promotes tumorigenesis. • Fujioka S, Contribution of intra-abdominal fat accumulation to the impairment of glucose and lipid metabolism in human obesity. Metabolism. Jan 1987; • Pou et al. Visceral and subcutaneous adipose tissue volumes are cross-sectionally related to markers of inflammation and oxidative stress: the Framingham Heart Study. Circulation. 2007; • Pouliot et al. Visceral obesity in men. Associations with glucose tolerance, plasma insulin, and lipoprotein levels. Diabetes. 1992; • Ohki et al. Visceral fat accumulation is an independent risk factor for hepatocellular carcinoma recurrence after curative treatment in patients with suspected NASH. Gut. 2009 • Takahashi, et al. Association of visceral fat accumulation and plasma adiponectin with rectal dysplastic aberrant crypt foci in a clinical population. Cancer science. 2009 • Akiyama T, Yoneda M, Inamori M, et al. Visceral obesity and the risk of Barrett's esophagus in Japanese patients with non- • Allott, et al. MMP9 expression in oesophageal adenocarcinoma is upregulated with visceral obesity and is associated with poor tumour differentiation. Molecular carcinogenesis. 2013

  19. Association between visceral adiposity, BMI and Clinical Outcomes in Postmenopausal Women with Operable Breast Cancer 2014 ASCO Annual Meeting

  20. The Collaborative Team • ShaliniDalal1, David Hui1, Sai-chingJ2. Yeung, Gary B. Chisholm3, Ijeoma Stephanie Ihenacho1, Richard Ogunti4, Maxine De la Cruz1, MariebertaVidal1, Deepak Bedi4, RonyDev1, Eduardo Bruera1, and Jennifer Litton5 1 Palliative Care and Rehab Medicine 2 Emergency Medicine 3 Biostatistics 4 Diagnostic Imaging 5 Breast Medical Oncology

  21. Study hypothesis and objectives • High BMI shown to negatively impact breast cancer outcomes in some but not all studies. • Visceral fat is considered more pathogenic than subcutaneous fat, and systemic inflammation and dysmetabolism associated with may contribute to the negative impact of obesity on breast cancer outcomes. • To our knowledge no study to date have examined the relationship between CT determined adiposity parameters and clinical outcomes in postmenopausal women with breast cancer • Objective: • To examine the association between visceral adiposity as measured by gold standard technique on clinical outcomes • pCR • recurrence-free interval (RFI) • overall survival (OS)

  22. Methods • Retrospective study approved by the IRB • Consecutive female patients with invasive breast cancer diagnosed between years 2001-2012 • Inclusion criteria • Postmenopausal status • primary invasive ductal or lobular non-inflammatory breast cancer • Clinical Stage I-III • received neo-adjuvant chemotherapy (NC) followed by definitive surgery within 1 year of NC initiation • had abdominal CT images within 8 weeks of NC initiation

  23. Data collected Baseline factors • Demographics: age & race • Tumor related factors: • ER, PR, & HER-2 neu status, Clinical stage, nuclear grade, presence of lymphovascular invasion • Type of NC treatment • anthracycline, taxol or both based regimen • BMI : • Normal category (BMI 18.5 to <25 kg/m2), overweight (BMI 25 to 29.9 kg/m2), obese class (BMI 30 to 34.9 kg/m2), and severely obese (BMI ≥ 35 kg/m2), • Visceral adiposity assessment:. Clinical outcomes: • Lymph node (LN) status at surgery: • number of LNs positive: negative, 1-3 LNs, 4-9 LNs, ≥ 10 LNs • Pathologic complete response [pCR] • from surgical biopsy; defined as no residual invasive carcinoma in breast or axillary lymph nodes. Residual DCIS not included in the pCR group • Survival times: from date of NC initiation • Relapse-free [RFS]: date of recurrence (local/distant) or last followup • Overall survival [OS]: date of death or last followup • Disease-specific [DSS]: if death occurred in setting of distant recurrence

  24. CT Adiposity measurements • CT scans obtained within 8 weeks of NC initiation • L3 chosen as landmark. • The average of 2 consecutive crossectional images used to obtain visceral and subcutaneous fat areas (VFA and SFA, respectively)in cm2. • The VFA:SFA ratio (VSR) was used as a metric of regional fat distribution • Median cut-off values used

  25. Validated software: NIH Image J version 1.47 http://imagej.nih.gov/ij

  26. Statistical analysis: • Univariate and multivariate logistic regression models to predict pCR were run to compute odds ratio and corresponding 95% confidence intervals (CI). • Cox proportional hazards regression methods used to model RFS, DSS and OS outcomes as function of adiposity measures and other relevant clinical factors. • adiposity parameters (VFA, SFA, VSR, BMI) • and key outcomes (pCR, RFS, DSS & OS), All reported p values are two-sided, and p< 0.05 was considered statistically significant

  27. Results: Baseline characteristics • N= 1227 postmenopausal women with breast cancer • Median age 58 years (range 29 to 82 years) • 63% White, 17% Black, 15% Hispanic, 5% Other • BMI category: • normal BMI=24% (n=293) • includes 11 pts who were underweight (BMI range 16 to 18). • Overweight= 32% (n=386) • Obese = 24% (n=286) • Severely obese= 20% (n=252) • Median CT- Adiposity values: • VFA=109 cm2 • SFA=240 cm2 • VSR=0.41

  28. Results: Baseline tumor characteristics, N=1227

  29. Scatter plot matrix: Correlation between BMI and adiposity measures. r=0.70 r=0.20 r=0.84

  30. CT-Adiposity measures and pCRto NC • Median time from chemotherapy to surgery • = 182 days (range 39 to 334 days). • pCR achieved • ~20% (n=249) pts • In univariatemodeling • significant associations between achievement of pCRand VFA and VS ratio (for both categoric and continuous), but not with SFA or BMI. • also significantly associated with age, race, baseline clinical stage, nuclear grade, lymphovascular status, hormone receptor status, and the type of NC treatment.

  31. Odds of pCR:AdjustedLogistic Regression Model

  32. Survival outcomes. • Median survival times for RFS, DSS, and OS was not attained in the follow-up of this study. • Recurrent disease: 209 (17%) pts; • majority (n=195) had distant recurrences. • Deceased: 187 (15%) deaths. • Deaths were classified as caused by breast cancer if the death occurred after distant recurrence (n=140).

  33. Recurrence free survival:AdjustedCox Regression Model

  34. Overall survival: Adjusted Cox Regression Model

  35. Disease specific survival: Adjusted Cox Regression Model

  36. Adjusted Kaplan–Meier Estimates of Survival According to the Visceral to Subcutaneous ratio

  37. CONCLUSION • This retrospective study of postmenopausal women with operable stage breast cancer suggests fat-depot specific dfferencesin clinical outcomes. • Higher visceral fat and lower subcutaneous fat were independently associated with lower likelihood of pCR. • Higher visceral to subcutaneous fat ratio predicted worse RFS, DSS and OS. • The predisposition to accumulate fat viscerally versus subcutaneously may be a novel prognostic factor independent of BMI, absolute fat stores and tumor characteristics.

  38. Thank You!

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