Histologic Types of Endometrial Cancer: Have They Different Risk - - PowerPoint PPT Presentation

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Histologic Types of Endometrial Cancer: Have They Different Risk Factors? Have They Different Risk Factors? Advances in Endometrial Cancer Epidemiology and Biology Boston MA Boston, MA March 17-18, 2014 V. Wendy Setiawan, Ph.D. Department of

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Histologic Types of Endometrial Cancer: Have They Different Risk Factors? Have They Different Risk Factors?

Advances in Endometrial Cancer Epidemiology and Biology Boston MA Boston, MA March 17-18, 2014

  • V. Wendy Setiawan, Ph.D.

Department of Preventive Medicine Keck School of Medicine, University of Southern California

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Endometrial Cancer Subtypes yp

  • Type I

– 80% of EC – Endometrioid adenocarcinoma – PTEN mutation & microsatellite instability – Endometrial hyperplasia – Estrogen dependent tumors

  • Type II

– Mainly serous tumors (high-grade endometrioid, squamous and clear cell) – p53 mutations and HER-2/neu overexpression – Atrophic endometrium in older women Atrophic endometrium in older women – More common in Blacks – High grade, poor prognosis (~40% of EC deaths) – Non-estrogen dependent tumors g p

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Previous Studies Previous Studies

  • Most epidemiologic studies lacked sufficient cases to

p g study type II/non-endometrioid tumors

  • A case-control study with 26 serous and 328

endometrioid cases (Sherman et al 1997) endometrioid cases (Sherman et al., 1997)

  • BMI, ET use, age at menarche and parity were significantly

associated with endometrioid tumors but not with serous tumors

  • OC use and smoking were associated with reduced risk of both

tumor types

  • Age- and BMI-adjusted serum levels of endogenous estrogen

and SHBG were different between patients with endometrioid tumors and patients with serous tumors

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Previous Studies Previous Studies

  • Few epi studies have been reported since the

Few epi studies have been reported since the initial study

– Divided into type I and type II tumors – Divided into type I and type II tumors – Focused on BMI (McCullough et al 2008, Bjorge et al 2007) al 2007) – Limited in the number of type II cases (McCullough et al 2008, Felix et al 2010) (McCullough et al 2008, Felix et al 2010) – Lacked of confounder adjustment (Bjorge et al 2007)

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J Clin Oncol. 2013 Jul 10;31(20):2607-18

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The goal of this analysis is to examine whether known endometrial cancer risk factors endometrial cancer risk factors associated with the risk of type / d d II/non-endometrioid tumors

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Epidemiology of Endometrial Cancer Consortium (E2C2) Consortium (E2C2)

  • NCI sponsored
  • >30 studies from US Canada Europe China
  • >30 studies from US, Canada, Europe, China,

and Australia

  • To combine resources to study genetic and
  • To combine resources to study genetic and

environment risk factors that are difficult to study in individual studies study in individual studies

– Rare exposures – Rare subtypes yp – Modest effects (SNP association)

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Participating Studies

(10 cohorts 14 case control st dies) (10 cohorts; 14 case-control studies)

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Study Design Study Design

  • Cohort studies were analyzed as nested case-control studies
  • Risk factor ascertainment

– From interview or questionnaire – Individual level data were harmonized across 24 studies

  • Histology data source

i h l / di l h lid i – Registry, pathology report/medical chart, slide review

  • Pooled analysis

S ifi d b d d – Stratified by study, age and race – Adjusted for potential confounders – Specific histology and major subtype (type I/II)

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Tumor subtypes and number of cases

Histology ICD-O-3 Major Subtype

  • No. Cases (%)

Endometrioid Endometrioid adenocarcinoma 8380, 8381, 8382, 8383 Type I 7,246 (52%) Adenocarcinoma NOS 8140 Type I 4,830 (34%) Adenocarcinoma with squamous differentiation 8560, 8570 Type I 777 (6%) Serous/papillary serous 8441, 8460, 8461 Type II 508 (4%) Mixed cell 8323 Type II 346 (2%) adenocarcinoma 8323 Type II 346 (2%) Clear cell 8310 196 (1%) Mucinous adenocarcinoma 8480, 8481, 8482 166 (1%)

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Characteristics of women by case-control status

Cases N=14,069 Controls N=35,312 A ( ) 62 9 64 3 Age (years), mean 62.9 64.3 Race White Black 83% 2% 87% 4% Black Asian Other 11% 4% 6% 3% Postmenopausal 83% 84% Postmenopausal 83% 84% BMI (kg/m2), mean 28.3 25.7 Parous 81% 87% Smokers 37% 46% HRT use 36% 42%

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Characteristics of cases by histology y gy

Endometrioid Adenoca NOS Adenoca w/ squamous Serous Mixed Clear cell Mucinous Mean Age 61.9 64.1 61.8 66.5 62.4 65.6 64.6 Mean BMI 28.9 28.1 29.0 27.6 28.5 27.7 28.1 Race White Black Asian 78% 2% 16% 90% 2% 5% 90% 2% 4% 82% 9% 5% 90% 3% 3% 83% 5% 6% 90% 3% 5% Other 4% 3% 4% 5% 4% 7% 1% Postmenopausal 80% 88% 83% 93% 90% 85% 81%

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Association of BMI with specific histologic types Association of BMI with specific histologic types

9 6 7 8 endometrioid

P’s trend <0.0001

dds Ratio

4 5 6 adenoca NOS adenoca squamous serous

Od

2 3 mixed cell clear cell mucinous 1 <25 25-<30 30-<35 35-<40 40+

BMI (kg/m2)

Referent

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Association of BMI (per 2 kg/m2 increase) with specific tumor histology with specific tumor histology

Endometrioid Adenoca NOS Adenoca w/ squamous Serous Mixed Clear cell Mucinous OR (95% CI) 1.21 (1.20, 1.22) 1.20 (1.18, 1.21) 1.20 (1.17, 1.23) 1.10* (1.07, 1.14) 1.13* (1.09, 1.18) 1.14** (1.08, 1.20) 1.16* (1.10, 1.22)

*Compared to endometrioid, P het ≤0.0001 **P het=0.008

T I T II P h t Type I Type II P het

  • No. Cases

12,853 854 OR* (95% CI) 1.20 (1.19, 1.21) 1.12 (1.09, 1.14) <0.0001

*stratified by age, study and race and adjusted for age at menarche, parity, OC use, menopausal hormone use, menopausal status, and smoking.

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Association of BMI by tumor grade Association of BMI by tumor grade

9 7 8

ds Ratio

4 5 6 endometrioid & adenoca NOS grade 1,2 endometrioid & adenoca d

P <0.0001

Od

2 3 4 NOS grade 3+ type II

P=0.02

1 <25 25 <30 30 <35 35 <40 40+

P <0.0001 BMI (kg/m2)

(Referent)

<25 25-<30 30-<35 35-<40 40+

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Association of number of children with specific hi l i histologic types

1.2 0 8 1 endometrioid

dds Ratio

0.6 0.8 adenoca NOS adenoca squamous serous

Od

0 2 0.4 mixed cell clear cell mucinous 0.2 1 2 3 4+ P’s trend <0.0002 except for clear cell (P trend=0.19)

  • No. of children

Referent

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Association of number of children i h I & II T with type I & type II Tumors

1.1 0.9 1 0 6 0.7 0.8 ds Ratio 0.4 0.5 0.6 Odd

type II

P=0.31 P’ t d 0 0001

0.2 0.3 0.4

type I

P’s trend <0.0001

1 2 3 4+

Referent

  • No. of Children
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Association of age at menarche with specific hi l i histologic types

1.2 0 8 1 endometrioid

dds Ratio

0.6 0.8 adenoca NOS adenoca squamous serous

Od

0 2 0.4 mixed cell clear cell mucinous 0.2 <11 11-12 13-14 15+ P’s trend <0.05 except for clear cell (P trend=0.81)

Age at menarche

(Referent)

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Association of age at menarche i h I & II T with type I & type II Tumors

1.1 0 9 1 ds Ratio 0 7 0.8 0.9 Odd 0.6 0.7

T II Type I

P=0.11

0.4 0.5 <11 11 12 13 14 15+

Type II

P’s trend ≤0.0002

(Referent)

Age at menarche (years)

<11 11-12 13-14 15+

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Association of age at last birth i h I & II ( 17 di ) with type I & type II tumors (n=17 studies)

1.3 1.1 1.2

P trend type II =0 01

ds Ratio 0 8 0.9 1

P trend type II =0.01

Odd 0.6 0.7 0.8

P t d t I 0 0001

P h t 0 38 0.4 0.5 <25 25 <30 30 <35 35 <40 40+

P trend type I <0.0001

P het=0.38 <25 25-<30 30-<35 35-<40 40+

(Referent)

Age at last birth (years)

(Setiawan et al., AJE 2012)

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Association of oral contraceptive use (never/ever) with ifi t hi t l specific tumor histology

Endometrio id Adenoca NOS Adenoca w/ squamous Serous Mixed Clear cell Mucinous OR* 0.78 0.67 0.64 0.87 0.54 0.66 0.65 (95% CI) (0.73, 0.84) (0.62, 0.73) (0.53, 0.78) (0.70, 1.07) (0.40, 0.72) (0.46, 0.94) (0.44, 0.95)

Type I Type II P het OR* (95% CI) 0.73 (0.69, 0.77) 0.74 (0.62, 0.89) 0.17

* ifi d b d d d dj d f h i *stratified by age, study and race and adjusted for age at menarche, parity, BMI, menopausal status, menopausal hormone use, and smoking.

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Association of smoking with specific tumor histology (OR & 95% CI)

Endometrioid Adenoca NOS Adenoca w/ squamous Never Past 1.00 0.83 (0.78, 0.89) 1.00 0.91 (0.84, 0.98) 1.00 0.83 (0.69, 0.99) Current ( , ) 0.61 (0.55, 0.68) ( , ) 0.64 (0.57, 0.71) ( , ) 0.88 (0.70, 1.10) Serous Mixed cell Clear cell Mucinous Never Past Current 1.00 0.76 (0.61, 0.94) 0.66 (0.48, 0.91) 1.00 0.62 (0.47, 0.81) 0.53 (0.36, 0.78) 1.00 0.78 (0.54, 1.11) 1.13 (0.73, 1.73) 1.00 1.14 (0.80, 1.62) 0.41 (0.19, 0.85)

Type I Type II P het

( , ) ( , ) ( , ) ( , )

Type I Type II P het Never Past C t 1.00 0.87 (0.82, 0.91) 0 64 (0 60 0 70) 1.00 0.70 (0.59, 0.83) 0 60 (0 46 0 77) 0.11 0 79 Current 0.64 (0.60, 0.70) 0.60 (0.46, 0.77) 0.79

*OR stratified by age, study and race and adjusted for age at menarche, parity, BMI, OC use, menopausal status, and menopausal hormone use.

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Association of pack-years of smoking with specific hi l i histologic types

1.2 0 8 1 endometrioid

dds Ratio

0.6 0.8 adenoca NOS adenoca squamous serous

Od

0 2 0.4 mixed cell clear cell mucinous 0.2 Never <20 20+

Pack-years of smoking

(Referent)

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Association of pack-years of smoking i h T I & T II T with Type I & Type II Tumors

1.1 1 ds Ratio 0.8 0.9

P trend type I <0.0001

Odd 0.7

P trend type II=0.0006

P het=0.44

0.5 0.6 Non smokers <20 20+ Non smokers <20 20+

Pack-years of smoking

(Referent)

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Association of diabetes with specific tumor histology p gy

Endometrioid Adenoca Adenoca w/ Serous Mixed Clear cell Mucinous NOS squamous OR* (95% CI) 1.28 (1.16, 1.42) 1.25 (1.10, 1.43) 1.04 (0.76, 1.41) 1.33 (0.98, 1.81) 1.93 (1.30, 2.85) 1.23 (0.73, 2.09) 1.37 (0.73, 2.55)

Type I Type II P het OR* (95% CI) 1.27 (1.17, 1.38) 1.53 (1.19, 1.95) 0.14

* ifi d b d d d dj d f h i OC *stratified by age, study and race and adjusted for age at menarche, parity, BMI, OC use, menopausal status, menopausal hormone use, and smoking.

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Strengths and Limitations Strengths and Limitations

  • Large sample size

Large sample size

  • Minimal publication bias

di id l l l d d d di d d

  • Individual level data and standardized data

for exposures and confounders

  • No central pathologic review

p g

  • Detailed HRT data were unavailable
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Summary of Results

  • Classical endometrial cancer risk factors influence the risk of type II

tumors (serous and mixed cell)

– The BMI association is weaker in serous and mixed cell than in endometrioid tumors

  • BMI-associated estrogen driven proliferation is also important for serous and mixed

cell, but maybe to a lesser extent

  • Additional mechanisms behind BMI other than estrogens

– Chronic inflammation H i li i – Hyperinsulinemia

  • Serous and mixed cell tumors may not be completely estrogen

independent

  • Risk factor pattern of high-grade endometrioid tumor s and type II

tumors are similar

  • Clear cell tumors seem to have a different risk factor profile from other

histologic types

– Should not be lumped in type I/II category

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SLIDE 28

Conclusion Conclusion

  • This pooled analysis provides epidemiologic

This pooled analysis provides epidemiologic evidence that in a number of respects the risk factor profiles for Type II and I tumors are quite similar

  • We should move away from the oversimplified

Type I vs. Type II distinction and start looking at specific histology and finer tumor classification

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Acknowledgments

Investigators: Hannah P. Yang, Malcolm C. Pike, Susan McCann, Herbert Yu, Yong-Bing Xiang, Alicja Wolk, Nicolas Wentzensen, Noel S. Weiss, Penelope M. Webb, Piet A. van den Brandt, Koen van de Vijver, Pamela J Thompson Brian L Strom Amanda B Spurdle Xiao-ou Shu Catherine Schairer Carlotta Pamela J. Thompson, Brian L. Strom, Amanda B. Spurdle, Xiao-ou Shu, Catherine Schairer, Carlotta Sacerdote, Thomas E. Rohan, Kim Robien, Harvey Risch, Fulvio Ricceri, Timothy R. Rebbeck, Radhai Rastogi, Jennifer Prescott, Silvia Polidoro, Yikyung Park, Sara H. Olson, Kirsten B. Moysich, Anthony

  • B. Miller, Marjorie L. McCullough, Rayna K. Matsuno, Anthony M. Magliocco, Galina Lurie, Lingeng

Lu Jolanta Lissowska Xiaolin Liang James V Lacey Jr Laurence N Kolonel Brian E Henderson Lu, Jolanta Lissowska, Xiaolin Liang, James V. Lacey Jr., Laurence N. Kolonel, Brian E. Henderson, Susan E. Hankinson, Niclas Håkansson, Marc T. Goodman, Mia M. Gaudet, Montserrat Garcia- Closas, Christine Friedenreich, Jo L. Freudenheim, Jennifer Doherty, Immaculata De Vivo, Kerry S. Courneya, Linda S. Cook, Chu Chen, James R. Cerhan , Hui Cai, Louise A. Brinton, Leslie Bernstein, Kristin E Anderson Hoda Anton-Culver Leo J Schouten Pamela L Horn-Ross Kristin E. Anderson, Hoda Anton Culver, Leo J. Schouten, Pamela L. Horn Ross Special thanks to: Rob Soslow and Robert Kurman Support/Fundings: Leah Mechanic NCI grant # CA135632, CA116543