Tumor Characteristics in Blacks and Whites with Endometrial Cancerwith Endometrial Cancer

Larry Maxwell, M.D.Chairman, Dept of OB-GYN at Inova Fairfax Hospital

Co-Director, GYN Cancer Center of ExcellenceProfessor, Virginia Commonwealth University

17 March 2014

Mortality Associated with Endometrial CancerMortality Associated with Endometrial Cancer

• According to SEER, the mortality associated with yuterine cancer has almost doubled over the past 20 years and has been associated withand has been associated with a steady increase in the incidence of disease

Racial Disparity in Cancer MortalityRacial Disparity in Cancer Mortality

8

African American Caucasian

4

6

0

2

0

Relation Between Ethnicity and Racey

Race Hispanic or Latino % of U.S. Non H/L % of U.S.Any Races 35,305,818 12.5 246,116,088 87.5 White 16,907,852 6.0 194,552,774 69.1Black/AA 710,353 0.3 33,947,837 12.1Asian 119,829 <0.1 10,123,169 3.6Hawaiian/PI 45,326 <0.1 353,509 0.1

**2000 C f P l ti P bli L 94 171

Amer Indian/Alaska 407,073 0.1 2,068,883 0.7

**2000 Census of Population, Public Law 94-171

DiversityDiversity

R Hi i L ti % f U S N H/L % f U SRace Hispanic or Latino % of U.S. Non H/L % of U.S.One race 33,081,736 11.8 241,513,942 85.82+ races 2,224,082 0.8 2,602,146 1.6

Access to Care and Equivalency of Treatmentq y

• Conflicting reports regarding inequalities in frequency of hysterectomy• No apparent racial disparities in referral to gynecologic oncologist for

management • Adjuvant radiation and chemotherapy found to be similar in population

studies

Liu et al: Obstet Gynecol 1995;86:486-90Sherman et al: Cancer 2003;98:176-86Trimble et al: Gynecol Oncol 2004;93:125-30Randall et al: J Clin Oncol 2003;21:4200-6Hicks et al: Cancer 1998;83:2629-37Madison et al: Am J Public Health 2004;94:2104-11

Endometrial Cancer Outcome According to Raceg

Prevalence Mortality

Blacks (denoted by red line) with endometrial cancer have a lowerBlacks (denoted by red line) with endometrial cancer have a lower incidence but higher mortality compared to other racial groups

Long et al: Gynecol Oncol 2013;130:562-659

Racial Disparities in T S d Hi lTumor Stage and Histology

• Blacks are less likely to present with endometrioid histology and more likely• Blacks are less likely to present with endometrioid histology and more likely to present with less favorable histologic subtypes (i.e. serous, clear cell, etc)

• Blacks present more often with regional or systemic metastasis than Whites U diff ti t d hi t l ft f d i Bl k d t Whit• Undifferentiated histology more often found in Blacks compared to Whites

Setiwan et al: Am J Epidemiol 2007;165:262-70Wright et al: Cancer 2009;115:1276-85Jemal et al: Cancer 2008;58:71-96

Overall Survival in African Americans and Caucasians with Advanced/Recurrent Endometrial Carcinomawith Advanced/Recurrent Endometrial Carcinoma

1.0 LogLog--rank test: p=0.005rank test: p=0.005

0 70.80.9

ving

ving

gg pp

0 40.50.60.7

on su

rviv

on su

rviv

WhiteWhite

0.20.30.4

Prop

ortio

Prop

ortio

BlackBlack

0.00.1

0 12 24 36 48 60

PP

Months on StudyMonths on StudyMaxwell et al: Cancer 2006;107:2197-205

Tumor Response to Treatment by Race

White BlackProtocol Patients (No.) Response (%) Protocol (No.) Response (%)GOG 107

A 127 35 17 11.8P 110 42.7 17 41.2

GOG 139GOG 139A+P 271 47.6 53 43.4

GOG 163A+P 128 40 6 21 28 6A+P 128 40.6 21 28.6A+T 130 43.9 24 33.3

GOG 177A+P 111 37 8 12 8 3A+P 111 37.8 12 8.3A/P/T 105 59.1 25 48.0

Total 982 43.2 169 34.9

Maxwell et al: Cancer 2006;107:2197-205

Treatment Related Adverse Events by Race in Advanced Stage Endometrial CancerAdvanced Stage Endometrial Cancer

White BlackpAdverse Effect (n=982) (n=169) p-

value% %

Selected Grade 3 or 4 LeukopeniaThrombocytopeniaNeutropenia

61.610.367.9

55.69.563.9

0.140.750.30p

AnemiaGastrointestinalGenitourinary

14.216.71 4

20.110.14 7

0.050.030 009Genitourinary

NeurologicCardiovascular

A G d 3 4

1.43.05.382 1

4.73.64.182 3

0.0090.680.530 96Any Grade 3 or 4 82.1 82.3 0.96

Farley et al: Cancer 2010;116:355-61

Recurrence Free Survival in African A i ith St I E d t i l CAmericans with Stage I Endometrial Cancer

Estrogen Replacement Therapy Placebo

Log-rank test: p=0.00020.7

0.8

0.9

1.0

Log-rank test: p=0.2470.7

0.8

0.9

1.0

RFS

0.2

0.3

0.4

0.5

0.6

RFS

0.2

0.3

0.4

0.5

0.6

0.0

0.1

Time from Entry onto Study (Months)0 12 24 36 48 60

WhiteBlack 0.0

0.1

Time from Entry onto Study (Months)0 12 24 36 48 60

WhiteBlack

Maxwell et al: Cancer 2008;113:1431-7

Obesity in Minorities

• 77% of Black women are overweight• 77% of Black women are overweight• 50% are obese

Molecular Features of Endometrial CancerTYPE I TYPE II

Ploidy diploid aneuploidK-ras yes yesHER-2/neu no yesp53 no yesp53 no yesMSI yes noPTEN yes noCTNNB1 yes no

Mean Racial Genetic Admixture ScoresS lf i d Af i A iSelf-Designated African American

Admixture Mean Min Max

African 65% 4% 86%

Amerindian 15% 4% 50%

European 20% 5% 83%

Rocconi et al: SGO book of abstracts, 2013

Analysis of PFS by Quintile of R i l G i Ad iRacial Genetic Admixture

African Admixture (%) N HR (95% CI) †

0 – 2% 49 Reference Category

3 – 5% 44 1.18 (0.42, 3.31)

6 – 10% 37 3.01 (0.95, 9.55)

11 – 71% 45 2.95 (0.81, 10.80)

72 – 86% 42 7.75 (3.22, 18.65)

The risk of “genetic definition of race” exists irrespective of self-designated raceg

Rocconi et al: SGO book of abstracts, 2013

Racial Disparity in Gene Mutations Among African American Patients with Advanced Endometrial CancerAmerican Patients with Advanced Endometrial Cancer

PTEN Mutation P53 Mutation

50

6025

30

40

50

10

15

20

%% %%

0

10

20

0

5

African-AmericanCaucasian

Kohler et al: Am J Obstet Gynecol. 1996;175:1246-52Clin Cancer Res. 2000;6:2999-3005

aGCH Analysis of Endometrioid Cancer and Comparison of Blacks vs WhitesComparison of Blacks vs Whites

• aCGH performed on 80 d t i id d t i lendometrioid endometrial cancers

from GOG-210 (40 Blacks and 40 Whites matched from stage, histology and grade

• A 1.6-Mbp region of gain at 1q23 was identified by aCGH in all Black patients and high grade Whit ti t b t t Whit lWhite patients, but not White low grade patients.

• The number of Blacks in the validation set was too small tovalidation set was too small to confirm the CGH association with racial disparity

Morrison et al: Genes, Chromosomes and Cancer 2010;49:791-802

Her-2 Neu Expression in Blacks and Whites with Endometrial Cancer

Race HER-2 Positive IHC HER-2Positive FISHNo. % No. % No. %

White: 446 (91) 58 (13) 26 (6)Black: 33 (8) 11 (33) 6 (18)

p=0 004 p=0 017p=0.004 p=0.017

Santin et al: 2005;192:813-8Morrison et al: JCO 2006;24:2376-85

Phosphoserine Phosphatase Like (PSPHL)

• PSPH identified on Affy could not be internally validatedbe internally validated

• We acknowledged that PSPHL shares homology with PSPH and is the differentially expressed transcript by race

• PSPHL increased in ovarian cancer from Blacks compared to WhitesWhites

• PSPHL increased in normal endometrium and normal ovary from Blacks compared to Whitesfrom Blacks compared to Whites

Ferguson et al: Gynecol Oncol 2006;101:209-13Risinger et al: Front Oncol 2012;2:1-15

Global Transcript Expression in Endometrial Cancers: Preliminary Analysis of RaceCancers: Preliminary Analysis of Race

• Transcript expression compared between 18 Blacks All Cases

and 27 Whites with endometrial cancers• Differences noted in early stage cancers but not

advanced stage cancers with internal validation and consistency with published dataconsistency with published data

• Concerns over imbalanced groups and lack of external validation prompted further investigation

Early Stage CasesEarly Stage Cases

African AmericanCaucasian

Global Transcript Expression in Endometrial Cancers: A i ti ith St Hi t l d R

Stage I/IIStage III/IV-0.20 2 0

Associations with Stage Histology and Race

• 25 Black and 25 White women withStage III/IV0.2-0.1

Y

Z

0

0

0.05

-0.1525 Black and 25 White women with endometrial cancers matched by stage, grade and histology

• Global differences in gene expression noted in early versus advanced stage as well as

d t i id d t i id0.15

X

endometrioid vs non-endometrioidcomparisons

• No racial differences in tumor transcript expression observed

0.1

Z 0.05-0.15

BlackWhite

EndometrioidSerous

0.1

Z 0.05-0.15

-0.1

Y

0

0 2-0.1

Y

0

0

-0.2 0.2X0-0.2 0.2

X0

Maxwell et al: Gynecol Oncol 2013;130:169-73

Global Transcript Expression in Endometrial Cancers: A i ti ith R d T h i P ti

LCM prepared, BlackLCM d Whi

Associations with Race and Technique or Preparation

LCM prepared, WhiteWhole tumor, BlackWhole tumor, White

0.150

0.1

-0.1

-150 150150

4%)

0

-0.15

PC

#2

(14

0

Multidimensional Scaling Principal Component Analysis

-150

PC #1 (23%)PC #3 (6%)

Multidimensional Scaling Principal Component Analysis

Maxwell et al: Gynecol Oncol 2013;130:169-73

Global miRNA Expression i E d t i l C i Bl k d Whit

Bl k Whit

in Endometrial Cancers in Blacks and Whites

Black WhiteZ

BlackWhite

Y

X

<1/4 >41

X

<1/4 >41Ratio

miR-337 Expression in Endometrial Cancers from Blacks and Whites

0.06

0.07l R

atio

BlackWhiteBlackWhiteR

atio

0.01

ol R

atio

Rat

io

AveragesTaqMan q-RT PCR

0 01

0.02

0.03

0.04

0.05

R-3

37-3

p / C

ontro

WhiteWhite

R-3

37-3

p / R

NU

48

-337

-3p/

Con

troR

-337

-3p

/ RN

U48

0

0.01

2010

022

2010

061

2010

108

2010

140

2010

141

7010

034

2004

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820

05-0

7-G

656

2005

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G68

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05-1

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929

2006

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020

07-0

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634

M62

18M

6222

M70

89M

7099

M71

39M

7299

M80

24M

8164

M81

78M

8186

M82

06M

8211

2010

038

2010

040

2010

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2010

065

2010

079

2010

158

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120

05-0

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2005

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G69

420

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M61

71M

6204

M70

19M

7119

M71

59M

7179

M72

14M

7229

M80

81M

8218

M81

38

Black White

miR

Black White

miR

0.001AA C

miR

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hsa-miR-337-3p

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orm

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214

299

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225

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195

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279

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710

609

125

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356

673

612

966

726

895

993

589

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640

188

855

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log2

(Exp

ress

ion)

(-C

miR

-337

-3p

/ Con

t

M82

M72

M82

M82

M90

M81

M82

M81

M61

M81

M72

M70

M81

M81

M70

M70

M81

M81

M81

M70

M62

M60

M81

M72

M81

M70

M72

M70

M82

M82

M82

M62

M70

M81

M81

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M81

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M62

M70

M81

M61

M82

M81

M70

M81

M81

M81

M81

M81

M81

M81

2001

-06-

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2000

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G4

2004

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G6

2000

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2002

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2005

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2000

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TP07

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06-7

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06-7

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AA IB --> AA IC C IA --> C IB --> C IC --> N AA--> N C -->Log2

( m

AA CCancer Normal

AA CBlack White

Black WhiteW IB W IC W IAB IB B IC

Intergromic Analysis

Proteomic Analysis of Blacks (red) and Whites (blue)with endometrial cancerwith endometrial cancer

• RNA-seq analysis of the matched pairs isRNA seq analysis of the matched pairs is underway

• Exomic sequencing being assessed using TCGA samplesp

• Analysis across the three datasets is planned

Tumor Characteristics in Blacks and Whites with Endometrial Cancerwith Endometrial Cancer

Larry Maxwell, M.D.Chairman, Dept of OB-GYN at Inova Fairfax Hospital

Co-Director, GYN Cancer Center of ExcellenceProfessor, Virginia Commonwealth University

17 March 2014