Obesity & Breast Cancer Outcome

P. Neven GYN ONCOL UZ Leuven

BMS - Brussels - 2013

Adiposity is a potential new target

Increased risk of developing cancers

Postmenopaual breast, Endometrium, Kidney,

Colon, Esophagus, Pancreas

Increased risk of dying of cancer

Breast, Colon

“OBESITY & CANCER”

“Obesity & (BREAST) Cancer Outcome”

…not a simple relationship…

BMI ~ Mortality

BMI ~ Breast Cancer Characteristics

Obesity ~ Mortality

Mortality in EPIC ~ BMI / WC

BMI-adjusted RR of Death by Waist Circumference

RR of Death by BMI

359387 participants

9 European Countries

-Educational Level, Smoking,

Alcohol, Physical Activity

-9.7 yrs of FU

Women: 24.3 kg/m²

↓ Women: Q5 RR = 1.78

J-shape

Linear General Obesity

Abdominal Obestiy

Waist Circumference > BMI

BMI: Works best in non-smokers

Death driven reasons

High BMI: CV & Cancer

Low BMI: Respiratory

Obesity & Breast Cancer Mortality

Presentation outline:

• Obesity: Risk factor for BC and outcome • Pre- (outcome)

• Postmenopausal (risk& outcome)

• Tumor Characteristics

• Implications for therapy?

• Implications for prevention?

• Breast cancer

• Relapse after breast cancer

Anovulatory cycle and less progestins: Controversial data

but once in the menopause: BMI ~BC risk

BC-risk ~ BMI (~HRT)

HRT increases BC-risk but ~ ER-pos &BMI

Pathways that directly link obesity with breast cancer.

Sinicrope F A , and Dannenberg A J JCO 2011;29:4-7

©2011 by American Society of Clinical Oncology

N = 1669 BMI ≤25

(n=817/48.9%)

BMI >25 and ≤30

(n=555/33.3%)

BMI >30

(n=297/17.8%)

>pT1 370 (45%) 294 (53%) 169 (57%)

Grade 3 204 (25%) 135 (24%) 91 (31%)

PR

positive 704 (86%) 502 (90%) 270 (91%)

>pN0 321 (39%) 194 (35%) 130 (44%)

Consecutive ER-Pos HER-2 neg breast cancer patients

Proportion >pT1, gr 3, PR-pos, LN-pos~ BMI at diagnosis

If ER-positive Less HER-2 pos

BC-specific survival obese vs non-obese ~ menopausal status

Meta-analysis

Niraula S. & Goodwin P. 2012 BCRT

BC-specific survival obese vs non-obese ~ ER status

Niraula S. & Goodwin P. 2012 BCRT

Meta-analysis

Obesity & Breast Cancer Specific Outcome

Presentation outline:

• Obesity: Risk factor for BC and outcome

• Pre- (outcome)

• Postmenopausal (risk& outcome)

• Tumor Characteristics

• Implications for therapy?

• E-downregulation by BMI

• Chemotherapy

• Trastuzumab

• Implications for prevention?

• Breast cancer

• Relapse after breast cancer

How does BMI affect response to endocrine therapy?

Aromatase & Inhibitors

better than TAMOXIFEN

E

A Reduce Estrogen • Aromatase Inhibitors

ER

Block ER • SERMs (Tamoxifen)

Anastrozole

Letrozole

Aromasin

MENOPAUZE

Target = Total Body Aromatisation

ATAC: Tam versus AI by baseline BMI 100 months of FU

J Clin Oncol 2010; 28: 3411-5.

Target = Total Body Aromatisation ~ BMI

ATAC: Tam versus AI by baseline BMI 100 months of FU

J Clin Oncol 2010; 28: 3411-5.

Target = Total Body Aromatisation ~ BMI

High BMI: AI + Fulvestrant > AI?

How does BMI affect response to chemotherapy?

High BMI and outcome to neoadjuvant chemotherapy by breast cancer

phenotype: own data and external validation on German Breast Group (GBG) patients.

%pCR1 %pCR2

BMI 1 17,0% (23/135) 25,2% (34/135)

BMI 2 16,6% (14/84) 27,4% (23/84)

BMI 3 16,6% (8/48) 16,6% (8/48)

M. Vanoppen et al. SABCS 2013

%pCR2 Luminal A/B

n=111 Luminal HER2

n=40 HER2 like

n=39 TNBC n=75

Total n=267

BMI 1 6,6% (4/61) 35,0% (7/20) 63,2% (12/19) 31,4% (11/35) 25,2%

(34/135)

BMI 2 3,1% (1/32) 50,0% (7/14) 56,3% (9/16) 27,3% (6/22) 27,3% (23/84)

BMI 3 0% (0/18) 33,3% (2/6) 50,0% (2/4) 15,8% (3/19) 16,6% (8/48)

Neo-Adjuvant CT: pCR by subtype & BMI

M Vanoppen et al. SABCS 2013

Neo-Adjuvant CT: pCR by subtype & BMI

C. Fontanella et al. SABCS 2013

Mechanisms that interfere with

chemotherapy response in high BMI

Dose capping*

Metabolism

Glucose (insuline, IGF)

More inflammatory status associated with high BMI

Cytokine signaling

Tumor Infiltrating Lymfocytes

Hormone receptor status?

More PR-pos and lower pCR

*We used dose capping indeed for BSA 2.0 and higher from 2000 till 2012,

and only dropped this capping last year (might also influence pCR in pts with BSA <2.0)

Higher BMI More grade 3

Higher BMI More PR-pos

Grade 3 is more likely PR-pos if high BMI

No Trastuzumab +Trastuzumab

Obesity & Breast Cancer Specific Outcome

Presentation outline:

• Obesity: Risk factor for BC and outcome

• Pre- (outcome)

• Postmenopausal (risk& outcome)

• Tumor Characteristics

• Implications for therapy?

• Implications for prevention?

• Breast cancer

• Relapse after breast cancer

Losing > 10% of body weight

-lowers estradiol, leptin, and insulin

-increases SHBG and adiponectin

- reduces pro-inflammatory cytokines

Changes in diet and increased physical activityhealthier body weight

-cancer-prevention strategy

-improve prognosis of BC-patients (other cancers)

Metformin has been evaluated in non-diabetic early stage breast cancer patients

-reduces insulin and body weight at 6 months

-prevention of breast cancer?

-adjuvant study is underway (IBIS-3)

Obesity is a target (agents that lower IGF-1 and adiponectin receptors).

More usefull in obese women (AI for prevention)?

*WHI-DM trial: 48.835 women (+)

*WINS trial: 2437 BC-patients (+)

WHEL trial: 3080 BC-patients (-)

Reducing dietary fat intake

*Lower BW was achieved

8-10yrs FU

BMJ 330:1304-1305, 2005

Metformin and reduced risk of cancer in diabetic patients.

Galega officinalis has been known since the

Middle Ages for relieving the symptoms of diabetes

Metformine

Pathologic Complete Response Between Study Groups (Metformin, No Metformin, Non-Diabetic)

Jiralersprong S et al. J Clin Oncol 2009; 20:3297-3302

NCIC CTG MA.32 Multicentre Phase III Randomized Double-Blind Placebo

Controlled Trial in Early Stage Breast Cancer

Metformin

850 mg po bid X 5 years

()

Identical Placebo

One caplet po bid X 5 years

R

A

N

D

O

M

I

Z

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FUNDED BY: NCI (US), CCS, BCRF, Apotex Canada

IBIS- 3

In summary Outcome Operable Breast Cancer ~BMI

In Conclusion

1. Obesity is complex physiologic state, many aspects of which may impact BC

2. Obesity is an independent adverse prognostic factor in BC

3. Not predicitve of AI vs Tam benefit after menopause

4. More research needed in many trials

5. Define targets (inflammatory targets, leptin, macrophages)

6. Prevention issues to be followed (Metformin, IGFR-blockers, Weight loss)

If the Body Mass Index (BMI) of all Belgian inhibitants with obesitas

with 1 kg/m² lowers, we will economize 4 billion euro over 20 years

(professor dr Lieven Annemans, health economics, Universiteit van Gent