visceral adiposity and clinical outcomes in postmenopausal women with operable breast cancer. does...

Visceral adiposity and clinical outcomes in postmenopausal women with operable breast cancer.

Does body shape matter?

Shalini Dalal, M.D.Associate ProfessorDepartment of Palliative Care and Rehab MedicineU.T. MD Anderson Cancer Center, Houston TX

10th October 2014

OverviewObesity definitionsNational obesity trendsGeneral vs Abdominal obesityObesity and cancerBreast cancer retrospective

study

ObesityDefinition

◦ 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 Clin Nutr. 1998

WHO Expert Committee on Physical Status. Physical Status: The Use and Interpretation of Anthropometry. Geneva, Switzerland: World Health Organization; 1995

Obesity prevalence in the USNHANES (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

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0

5

10

15

20

25

30

35

40

13.414.5 15

23.2

30.9 31.332.9

35.1 34.335.7 35.1

20.2

27.5 27.8

31.133.3

32.2

35.533.7

25.4

33.4 33.3 33.235.3 35.5 35.8 36.5

All Men Women

Trends in the prevalence of obesity among adults aged 20 years and over, by sex: United

States 1960-2012

Perc

en

tage

Years

• No significant change from 2003-2004 to 2011-2012,

• Except women ≥ 60 years• Obesity increased from 31.5%

to more than 38%.

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)

.

http://www.discount-supplements.co.uk/blog/apple-pear-body-shape-real-dangers-fat-distribution/apple-and-pear-body-shape/

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 CADCancer

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

Galic S,. Adipose tissue as an endocrine organ. Mol Cell Endocrinol 2010Alberti KG. Metabolic syndrome – A Consensus Statement from the International Diabetes

Federation. Diabet Med 2006Fujioka S Contributionof intra-abdominal fat accumulation to the impairment of glucose and lipid

metabolism in humanobesity. Metabolism 1987

more strongly associated than BMI alone

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:the Iowa 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 Sci Nutr 2005;

• Pischon et al. General and abdominal adiposity and risk of death in Europe. N Engl J Med 2008;

National prevalence of abdominal obesity

RESEARCH LETTER JAMA September 2014Trends in Mean Waist Circumference and Abdominal Obesity 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

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).

Perc

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tage

Years

1999-2000

2001-2002

2003-2004

2005-2006

2007-2008

2009-2010

2011-2012

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20

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70

46.4 48.452.1 51.6 52.7 52.8 54.2

37.1 39.142.5

44.8 43.4 43 43.5

55.4 57.161.3

58.261.6 62.3

64.7

Overall men women

Trends in the prevalence of Abdominal obesity among adults: United States 1999-2012

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).

ConclusionThe 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.

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

Wt loss 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 Oncol 2009

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),

Obesity and breast cancerEpidemiological 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. • Petrelli et 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 Clin Oncol. 2008

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

• Harvie M, 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 Obes Relat Metab Disord. Jun 2002

Gold standard techniques to quantify body fat compartmentsCT 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

http://2.bp.blogspot.com/_EhPVuiZadcA/SwN--MBoZDI/AAAAAAAAAOo/d9k8unCLzfE/s1600/VAT.jpg

Association between visceral adiposity, BMI and Clinical Outcomes in Postmenopausal Women with Operable Breast Cancer

2014 ASCO Annual Meeting

http://meetinglibrary.asco.org/subcategories/2014%20ASCO%20Annual%20Meeting

The Collaborative TeamShalini Dalal1, David Hui1, Sai-ching J2. Yeung,

Gary B. Chisholm3, Ijeoma Stephanie Ihenacho1, Richard Ogunti4, Maxine De la Cruz1, Marieberta Vidal1, Deepak Bedi4, Rony Dev1, Eduardo Bruera1, and Jennifer Litton5

1 Palliative Care and Rehab Medicine 2 Emergency Medicine3 Biostatistics4 Diagnostic Imaging5 Breast Medical Oncology

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)

MethodsRetrospective study approved by the IRBConsecutive female patients with invasive breast

cancer diagnosed between years 2001-2012Inclusion 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

Data collectedBaseline 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

CT Adiposity measurementsCT 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

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

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

Results: Baseline characteristicsN= 1227 postmenopausal women with breast cancerMedian 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

Results: Baseline tumor characteristics, N=1227

Characteristics N %

Baseline TNM Stage I 32 3II 736 60III 459 37

Nuclear Grade 1 52 42 382 313 786 64

Lymphovascular invasion Positive 272 22Negative 951 78

ER Status Positive 753 61Negative 474 39

PR Status Positive 526 43Negative 694 57

HER-2 Neu Status Positive 329 27Negative 898 73

NC Regimen included Anthracycline & Taxol 1073 87Taxol based 73 6Anthracycline based 81 7

Correlation between BMI and adiposity measures.

Scatter plot matrix:

r=0.70

r=0.84

r=0.20

CT-Adiposity measures and pCR to NCMedian time from chemotherapy to

surgery◦ = 182 days (range 39 to 334 days).

pCR achieved ◦ ~20% (n=249) pts

In univariate modeling◦ significant associations between achievement

of pCR and 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.

Odds of pCR:Adjusted Logistic Regression Model

Variable Comparison Odds Ratio 95% C.I. PAge 0.99 0.25 to 1.01 0.25

Race

Black vs. White 0.79 0.51 to 1.23 0.30Hispanic vs. White 1.64 1.06 to 2.51 0.03

Other vs. White 0.81 0.10 to 4.65 0.58

TNM Stage Stage III vs. I & II 0.67 0.47 to 0.95 0.02

Nuclear Grade 3 vs. 1 & 2 2.34 1.52 to 3.61 < 0.0001LV invasion Positive vs. Negative 0.36 0.21 to 0.58 < 0.0001

ER Status Positive vs. Negative 0.47 0.32 to 0.69 < 0.0001

PR Status Positive vs. Negative 0.50 0.32 to 0.77 0.002

HER-2 Neu Status Positive vs. Negative 2.76 1.98 to 3.83 < 0.0001

NC RegimenTaxane vs. Both 0.46 0.21 to 0.99 0.049Anthracycline vs. Both 0.52 0.22 to 1.21 0.128

SFA >median vs. ≤ median 1.69 1.18 to 2.42 0.004

VFA >median vs. ≤ median 0.51 0.36 to 0.73 < 0.0001

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).

Recurrence free survival:Adjusted Cox Regression ModelVariable Comparison OR 95% C.I. PAge 0.99 0.98 to 1.01 0.48Race

Black vs. White 1.59 1.12 to 2.27 0.01Hispanic vs. White .61 0.36 to 1.04 0.07Other vs. White 1.16 0.59 to 2.31 0.67

TNM Stage Stage III vs. I & II 1.56 1.15 to 2.12 0.004Nuclear Grade 3 vs. 1 & 2 1.41 1.00 to 1.99 0.05LV invasion Positive vs. Negative 1.46 1.07 to 2.00 0.02ER Status Positive vs. Negative 0.55 0.38 to 0.80 0.002PR Status Positive vs. Negative 0.74 .52 to 1.05 0.09HER-2 Neu Status Positive vs. Negative 0.74 0.51 to 1.06 0.10

NC Regimen Taxane vs. Both 1.05 0.58 to 1.87 0.88Anthracycline vs. Both 0.48 0.25 to 0.92 0.03

pCR achieved Positive vs. Negative 0.33 0.16 to 0.65 0.002

Number of Lymph nodes (LN) positive

1-3 LN Positive vs. Negative 1.82 1.18 to 2.79 0.0074-9 LN Positive vs. Negative 3.32 2.15 to 5.11 < 0.0001≥ 10 LN Positive vs. Negative 6.00 3.67 to 9.80 < 0.0001

BMI category

Overweight vs. Normal 0.80 0.56 to 1.18 0.25Obese vs. Normal 0.72 0.47 to 1.11 0.14Severely obese vs. Normal 1.03 0.69 to 1.56 0.88

Visceral to Subcut fat Ratio >median vs. ≤ median 1.45 1.08 to 1.96 0.02

Overall survival: Adjusted Cox Regression Model Variable Comparison OR 95% C.I. PAge 1.00 0.98 to 1.02 0.87Race

Black vs. White 1.20 0.80 to 1.80 0.39Hispanic vs. White 0.67 0.39 to 1.14 0.14Other vs. White 0.59 0.24 to 1.46 0.25

TNM Stage Stage III vs. I & II 1.74 1.26 to 2.40 0.001Nuclear Grade 3 vs. 1 & 2 1.27 0.88 to 1.82 0.20LV invasion Positive vs. Negative 1.28 0.92 to 1.79 0.15ER Status Positive vs. Negative 0.49 0.33 to 0.72 < 0.0001PR Status Positive vs. Negative 0.73 0.50 to 1.06 0.10HER-2 Neu Status Positive vs. Negative 0.72 0.49 to 1.05 0.09

NC Regimen included Taxane vs. Both 1.02 0.54 to 1.92 0.95Anthracycline vs. Both 0.82 0.47 to 1.44 0.48




BMI category


Visceral to Subcut fat Ratio >median vs. ≤ median 1.80 1.31 to 2.48 < 0.0001

Disease specific survival: Adjusted Cox Regression ModelVariable Comparison OR 95% C.I. PAge 0.99 0.97 to 1.01 0.32Race

Black vs. White 1.40 0.90 to 2.18 0.13Hispanic vs. White 0.56 0.29 to 1.09 0.09Other vs. White 0.78 0.31 to 1.95 0.59

TNM Stage Stage III vs. I & II 1.76 1.21 to 2.56 0.003Nuclear Grade 3 vs. 1 & 2 1.67 1.08 to 2.58 0.02LV invasion Positive vs. Negative 1.43 0.98 to 2.09 0.06ER Status Positive vs. Negative 0.50 0.32 to 0.77 0.002PR Status Positive vs. Negative 0.62 0.40 to 0.97 0.03HER-2 Neu Status Positive vs. Negative 0.62 0.40 to 0.97 0.04

NC Regimen included Taxane vs. Both 1.08 0.53 to 2.19 0.84Anthracycline vs. Both 0.42 0.18 to 0.97 0.04




BMI category


Visceral to Subcut fat Ratio >median vs. ≤ median 1.76 1.22 to 2.55 0.002

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

Relapse free survival

Overall survival

Disease specific survival

CONCLUSION

This retrospective study of postmenopausal women with operable stage breast cancer suggests fat-depot specific dfferences in 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.

THANK YOU!

visceral adiposity and clinical outcomes in postmenopausal women with operable breast cancer. does...

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