Etiologic Heterogeneity Etiologic Heterogeneity In Endometrial Cancer Advances in Endometrial Cancer E id Epidemiology and Biology i l d Bi l March 17-18, 2014 Louise A. Brinton, Ph.D. Division of Cancer Epidemiology and Genetics Di i i f C E id i l d G ti National Cancer Institute Bethesda, MD h d
Background Bokhman in 1983 proposed two endometrial • cancer groups based on endocrine/metabolic cancer groups based on endocrine/metabolic functioning and risk factor differences Type I cancers correspond pathologically to Type I cancers correspond pathologically to • endometrioid adenocarcinomas, whereas Type II cancers encompass most non- Type II cancers encompass most non endometrioid types (serous as prototype) Epidemiologic studies suggest Type II cancers Epidemiologic studies suggest Type II cancers • less strongly linked to classic risk factors, albeit based on small numbers, incomplete , p risk factors, non-standardized pathology
Endometrial Cancer Progression Model g PTEN mutations PTEN mutations MMR defects Endometrioid Hyperplasia Atypical cancer (EC) ( ) without atypia ith t t i hyperplasia (EH) h l i (EH) (>90%) 5% risk of invasion 28% risk of invasion over 14 years over 12 years Obesity Normal Normal endometrium Hormone exposure Endometrial Serous cancer intraepithelial p Atrophy Atrophy (5 10%) (5-10%) carcinoma (EIC) TP53 mutations Sherman 2000 Mod Pathol; Lacey 2011 JCO
Etiologic Heterogeneity of Endometrial Cancer within the d i l i hi h NIH-AARP Diet & Health Study • Cohort was established in 1995-1996 in 6 Cohort was established in 1995 1996 in 6 states and 2 metropolitan areas, by inviting 3.5 million AARP members aged 50-71 years 3.5 million AARP members aged 50 7 years to complete a questionnaire • Follow-up of 114 409 members through 2006 • Follow-up of 114,409 members through 2006 1,491 incident endometrial cancers 1,312 Type I and 138 Type II cancers
Definition of Type I and II Tumors • Type I Endometrioid, mucinous, tubular, Endometrioid, mucinous, tubular, adenocarcinoma with squamous differentiation, and adenocarcinoma NOS • Type II Serous, clear cell, mixed cell, small cell, Serous, clear cell, mixed cell, small cell, squamous cell
Significant Risk Factor Relationships for Type I and II Endometrial Cancers: NIH-AARP Study d II E d i l C NIH AARP S d Risk Type I (N=1,312) yp ( , ) Type II (N=138) yp ( ) P-het factor N RR 95% CI N RR 95% CI Race Race White 1,228 1.00 referent 115 1.00 referent Black 47 0.66 0.49-0.88 14 2.18 1.24-3.84 Other Oth 37 37 0.57 0 57 0 41 0 79 0.41-0.79 9 9 1 35 1.35 0 68 2 67 0.68-2.67 0 0004 0.0004 BMI <30 708 1.00 referent 86 1.00 referent >30 570 2.93 2.62-3.2 47 1.83 1.27-2.63 0.001 MHT use N Never 787 787 1.00 1 00 referent f 93 93 1 00 1.00 referent f Ever 525 1.18 1.05-1.32 45 0.84 0.57-1.22 0.01
Study Population: GOG-210 • Endometrial cancer patients, recruited at 53 sites between 2003-2007 into a i b 2003 2007 i molecular/surgico-pathological staging trial • Questionnaires obtained from 91% of trial participants, enabling risk factor evaluation for disease subtypes among 3,434 patients • Specialized review conducted for select p histologies (grade 3 endometrioid, serous, carcinosarcomas, mucinous, clear cell , , tumors, mixed epithelial)
Statistical Analyses • Logistic regression used to estimate ORs and 95% CIs with referent group and 95% CIs, with referent group comprised of patients with grades 1-2 endometriod (EM) tumors endometriod (EM) tumors • ORs >1.0 indicated more common risk factors among patients with either Type f t ti t ith ith T II or grade 3 EM • Linear hypothesis testing compared equality of ORs across specific tumor subgroups (e.g., Type II vs. grades 1-2 EM; Type II vs. grade 3 EM )
Patient Characteristics • 56% of patients were >60 years of age and 11% were non-white d 11% hi • Tumor classification 75% Type I (2,244 grades 1-2 EM, 354 grade 3 EM 17% Type II (321 serous, 141 carcinosarcomas, 77 clear cell, 42 mixed with serous or clear cell components) i h l ll ) • Type II patients older, more often non- whites as compared with grades 1-2 EM
ORs for Type II and Grade 3 EM (vs. Grades 1-2 EM) for BMI 2 ) BMI (kg/m OR (95% CI) OR (95% CI) % % n n p het *<0.001 Type II, n=581 p het **=0.57 Normal 119 20.5 Reference 0.88 (0.66, 1.18) 149 25.6 Overweight Obese 244 42.0 0.58 (0.45, 0.76) Grade 3 Endometrioid, n=354 Normal 76 21.5 Reference Overweight 25.4 0.91 (0.65, 1.28) 90 Obese 160 45.2 0.62 (0.46, 0.84) 0.1 1.0 10.0 Comparison Group: Grade 1-2 Endometrioid Cancers, n=2,244 Normal: 16.6% Overweight: 19.7% Obese: 51.8%
ORs for Type II and Grade 3 EM (vs. Grades 1-2 EM) for Number of Livebirths Total number of live births OR OR (95% CI) (95% CI) n n % % p het *<0.001 Type II, n=581 p het **=0.92 12.7 Reference 0 74 1 52 9.0 0.91 (0.61, 1.35) ( , ) 150 25.8 2 1.19 (0.86, 1.63) 3 115 19.8 1.26 (0.90, 1.77) > 4 1.83 (1.31, 2.55) 171 29.4 Grade 3 Endometrioid, n=354 0 54 Reference 15.3 1 11.0 39 1.04 (0.67, 1.62) 101 28.5 1.26 (0.88, 1.80) 2 21.2 3 75 1.40 (0.96, 2.06) 21.2 > 4 75 1.65 (1.11, 2.46) 0.1 1.0 10.0 Comparison Group: Grade 1-2 Endometrioid Cancers, n=2,244 Nulliparous: 21.4% 1: 13.8% 2: 29.3% 3: 18.4% >4: 13.6%
ORs for Type II and Grade 3 EM (vs. Grades 1-2 EM) for Smoking Status Smoking status OR OR (95% CI) (95% CI) n % p het *=0.02 Type II, n=581 p het **=0.40 Non-smoker 363 62.5 Reference Current smoker 41 7.1 1.80 (1.22, 2.67) Former smoker 156 26.9 1.09 (0.87, 1.36) Grade 3 Endometrioid, n=354 220 62.1 Non-smoker Reference 31 8.8 Current smoker 1.80 (1.18, 2.75) Former smoker 27.7 98 1.06 (0.82, 1.38) 0.1 1.0 10.0 Comparison Group: Grade 1-2 Endometrioid Cancers, n=2,244 Non-smoker: 64.9% Current smoker: 6.0% Former smoker: 26.8%
ORs for Type II and Grade 3 EM (vs. Grades 1-2 EM) for Breast Cancer & Tamoxifen use EM) f B C & T if Breast cancer and tamoxifen use (Br/tam) OR (95% CI) ( ) % n p het *<0.001 Type II, n=581 p het **=0.004 Br-/tam- 466 80.2 Reference Br+/tam Br+/tam- 3.3 3 3 19 19 1.29 (0.74, 2.27) Br-/tam+ 2 0.3 1.04 (0.16, 6.55) 7.9 Br+/tam+ 46 3.02 (1.95, 4.67) Grade 3 Endometrioid, n=354 Br-/tam- 310 87.6 Reference 19 5.4 2.25 (1.30, 3.92) Br+/tam- Br-/tam+ 1 0.3 1.08 (0.12, 9.55) 9 Br+/tam+ 2.5 0.98 (0.48, 2.02) 0.1 1.0 10.0 Comparison Group: Grade 1-2 Endometrioid Cancers, n=2,244 Br-/tam- : 89.4% Br+/tam- : 2.1% Br-/tam+ : 0.2% Br+/tam+ 2.4%
Summary of Findings: Type II vs. Grades 1-2 EM Type II vs Grades 1 2 EM • Obesity less frequent – Provides support for a less hormonally- dependent etiology of Type II cancers, although we cannot rule out some effect of obesity t l t ff t f b it • Multiparity and current smoking more frequent – Less protective effect – Hormonal factors likely driving smoking association, but mechanism for parity less clear • More frequent treatment with Tamoxifen for breast cancer
Summary of Findings: y g Grades 3 vs. 1-2 EM • Risk factors for grade 3 EM and Type II cancers were generally similar • Patients with grade 3 EM tumors had more non-Tamoxifen treated breast cancer. Possible explanations include: – Similar risk profiles as for breast cancer p – Radiation treatment of proximate organs – Rare inherited cancer syndromes y – Mutations in cancer predisposing genes
Classification of Type I and II Cancers • Type I • 2,244 grades 1-2 EM • 354 grade 3 EM • Type II • 321 serous • 141 carcinosarcomas • 77 clear cell 77 l ll • 42 mixed with serous or clear cell components) components)
Type II Histologies vs Grade 1 2 EM Type II Histologies vs. Grade 1-2 EM • Multiparity and current smoking were M lti it d t ki more common among women with carcinosarcomas and clear cell cancers i d l ll – Implies less protective effects for these tumors • Obesity was less common among those with serous or clear cell cancers – Less of a risk factor for these cancers
ORs for Type II Histologic Subgroups (vs. Grades 1 2 EM) f 1-2 EM) for Breast Cancer/Tamoxifen B t C /T if Breast cancer and tamoxifen use (Br/tam) OR (95% CI) n % p het <0.001 Serous, n=321 Br-/tam- 252 78.5 Reference Br+/tam- 12 3.7 1.53 (0.78, 3.01) Br-/tam+ 2 0.6 1.52 (0.21, 10.86) Br+/tam+ 7.8 25 3.24 (1.92, 5.46) Carcinosarcoma, n=141 Br-/tam- 108 76.6 Reference 3.5 Br+/tam- 5 1.48 (0.56, 3.94) Br-/tam+ not estimable 0 0.0 Br+/tam+ 11.3 5.37 (2.88, 10.03) 16 Clear cell, n=77 Reference Br-/tam- 69 89.6 1.3 Br+/tam- 1 0.44 (0.06, 3.30) Br-/tam+ 0 0.0 not estimable Br+/tam+ 3 3.9 1.40 (0.42, 4.66) 0.1 1.0 10.0 Comparison Group: Grade 1-2 Endometrioid Cancers, n=2,244 Br-/tam- : 89.4% Br+/tam- : 2.1% Br-/tam+ : 0.2% Br+/tam+ : 2.4%
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