obesity & breast cancer outcome - menopause...
TRANSCRIPT
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Obesity & Breast Cancer Outcome
P. Neven GYN ONCOL UZ Leuven
BMS - Brussels - 2013
Adiposity is a potential new target
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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
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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
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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
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Anovulatory cycle and less progestins: Controversial data
but once in the menopause: BMI ~BC risk
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BC-risk ~ BMI (~HRT)
HRT increases BC-risk but ~ ER-pos &BMI
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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
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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
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If ER-positive Less HER-2 pos
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BC-specific survival obese vs non-obese ~ menopausal status
Meta-analysis
Niraula S. & Goodwin P. 2012 BCRT
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BC-specific survival obese vs non-obese ~ ER status
Niraula S. & Goodwin P. 2012 BCRT
Meta-analysis
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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
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How does BMI affect response to endocrine therapy?
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Aromatase & Inhibitors
better than TAMOXIFEN
E
A Reduce Estrogen • Aromatase Inhibitors
ER
Block ER • SERMs (Tamoxifen)
Anastrozole
Letrozole
Aromasin
MENOPAUZE
Target = Total Body Aromatisation
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ATAC: Tam versus AI by baseline BMI 100 months of FU
J Clin Oncol 2010; 28: 3411-5.
Target = Total Body Aromatisation ~ BMI
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ATAC: Tam versus AI by baseline BMI 100 months of FU
J Clin Oncol 2010; 28: 3411-5.
Target = Total Body Aromatisation ~ BMI
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High BMI: AI + Fulvestrant > AI?
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How does BMI affect response to chemotherapy?
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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
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%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
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Neo-Adjuvant CT: pCR by subtype & BMI
C. Fontanella et al. SABCS 2013
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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
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No Trastuzumab +Trastuzumab
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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
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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
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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
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Pathologic Complete Response Between Study Groups (Metformin, No Metformin, Non-Diabetic)
Jiralersprong S et al. J Clin Oncol 2009; 20:3297-3302
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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
E
FUNDED BY: NCI (US), CCS, BCRF, Apotex Canada
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IBIS- 3
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In summary Outcome Operable Breast Cancer ~BMI
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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)
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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