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

Advances in Endometrial Cancer Epidemiology and BiologyBoston MABoston, MA

March 17-18, 2014

V. Wendy Setiawan, Ph.D.Department of Preventive Medicine

Keck School of Medicine, University of Southern California

Endometrial Cancer Subtypesyp• 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 womenAtrophic endometrium in older women– More common in Blacks– High grade, poor prognosis (~40% of EC deaths)– Non-estrogen dependent tumorsg p

Previous StudiesPrevious 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 ttumors

• 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 endometrioidtumors and patients with serous tumors

Previous StudiesPrevious Studies

• Few epi studies have been reported since theFew 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))

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

The goal of this analysis is to examine whether known

endometrial cancer risk factorsendometrial cancer risk factors associated with the risk of type

/ d dII/non-endometrioid tumors

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 studiesstudy in individual studies– Rare exposures– Rare subtypes yp– Modest effects (SNP association)

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

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

• Pooled analysisS ifi d b d d– Stratified by study, age and race

– Adjusted for potential confounders– Specific histology and major subtype (type I/II)

Tumor subtypes and number of casesHistology ICD-O-3 Major

SubtypeNo. Cases (%)

EndometrioidEndometrioidadenocarcinoma 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%)

Characteristics of women by case-control statusCases

N=14,069Controls

N=35,312

A ( ) 62 9 64 3Age (years), mean 62.9 64.3

RaceWhiteBlack

83%2%

87%4%Black

AsianOther

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%

Characteristics of cases by histologyy gyEndometrioid Adenoca

NOSAdenoca 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

RaceWhiteBlackAsian

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%

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

9

6

7

8

endometrioidP’s trend <0.0001

dds R

atio

4

5

6 adenoca NOSadenoca squamousserous

Od

2

3 mixed cellclear cell mucinous

0

1

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

BMI (kg/m2)Referent

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

Endometrioid AdenocaNOS

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 tType 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.

Association of BMI by tumor gradeAssociation of BMI by tumor grade

9

7

8

ds R

atio

4

5

6 endometrioid & adenoca NOS grade 1,2endometrioid & adenoca

d

P <0.0001

Od

2

3

4 NOS grade 3+type IIP=0.02

0

1

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

P <0.0001

BMI (kg/m2)(Referent)<25 25-<30 30-<35 35-<40 40+

Association of number of children with specific hi l ihistologic types

1.2

0 8

1

endometrioid

dds R

atio

0.6

0.8 adenoca NOSadenoca squamousserous

Od

0 2

0.4 mixed cellclear cell mucinous

0

0.2

0 1 2 3 4+

P’s trend <0.0002 except for clear cell (P trend=0.19)

No. of childrenReferent

Association of number of children i h I & II Twith type I & type II Tumors

1.1

0.9

1

0 6

0.7

0.8

ds R

atio

0.4

0.5

0.6

Odd

type IIP=0.31

P’ t d 0 0001

0.2

0.3

0.4type IP’s trend <0.0001

0 1 2 3 4+Referent No. of Children

Association of age at menarche with specific hi l ihistologic types

1.2

0 8

1

endometrioid

dds R

atio

0.6

0.8 adenoca NOSadenoca squamousserous

Od

0 2

0.4 mixed cellclear cell mucinous

0

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)

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

1.1

0 9

1

ds R

atio

0 7

0.8

0.9

Odd

0.6

0.7

T II

Type IP=0.11

0.4

0.5

<11 11 12 13 14 15+

Type IIP’s trend ≤0.0002

(Referent)Age at menarche (years)

<11 11-12 13-14 15+

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 R

atio

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)

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

Endometrioid

AdenocaNOS

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.

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

Endometrioid Adenoca NOS Adenoca w/ squamous

NeverPast

1.000.83 (0.78, 0.89)

1.000.91 (0.84, 0.98)

1.000.83 (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

NeverPast Current

1.000.76 (0.61, 0.94)0.66 (0.48, 0.91)

1.000.62 (0.47, 0.81)0.53 (0.36, 0.78)

1.000.78 (0.54, 1.11)1.13 (0.73, 1.73)

1.001.14 (0.80, 1.62)0.41 (0.19, 0.85)

Type I Type II P het

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

Type I Type II P het

NeverPastC t

1.000.87 (0.82, 0.91)0 64 (0 60 0 70)

1.000.70 (0.59, 0.83)0 60 (0 46 0 77)

0.110 79Current 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.

Association of pack-years of smoking with specific hi l ihistologic types

1.2

0 8

1

endometrioid

dds R

atio

0.6

0.8 adenoca NOSadenoca squamousserous

Od

0 2

0.4 mixed cellclear cell mucinous

0

0.2

Never <20 20+

Pack-years of smoking(Referent)

Association of pack-years of smokingi h T I & T II Twith Type I & Type II Tumors

1.1

1

ds R

atio

0.8

0.9P trend type I <0.0001

Odd

0.7P 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)

Association of diabetes with specific tumor histologyp gy

Endometrioid Adenoca Adenoca w/ Serous Mixed Clear cell MucinousNOS 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.

Strengths and LimitationsStrengths and Limitations

• Large sample sizeLarge 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 reviewp g• Detailed HRT data were unavailable

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

ConclusionConclusion

• This pooled analysis provides epidemiologicThis 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

AcknowledgmentsInvestigators: 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 CarlottaPamela 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, RadhaiRastogi, 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, LingengLu Jolanta Lissowska Xiaolin Liang James V Lacey Jr Laurence N Kolonel Brian E HendersonLu, 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-RossKristin 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