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
-09-
G51
820
05-0
7-G
656
2005
-09-
G68
520
05-1
2-G
929
2006
-04-
G97
020
07-0
3-G
634
M62
18M
6222
M70
89M
7099
M71
39M
7299
M80
24M
8164
M81
78M
8186
M82
06M
8211
2010
038
2010
040
2010
052
2010
065
2010
079
2010
158
2004
-07-
G51
120
05-0
1-G
644
2005
-07-
G69
420
05-1
0-G
648
2006
-01-
G62
820
06-0
5-G
742
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
-m
iR
Black White
hsa-miR-337-3p
-15
-13
-11
Ct n
orm
aliz
ed)
rol R
atio
)
Black WhiteBlack White
-25
-23
-21
-19
-17
214
299
211
225
064
174
206
195
199
141
279
084
159
132
034
039
198
162
168
024
204
000
136
259
185
029
249
054
213
204
222
213
049
165
117
138
157
000
220
079
192
192
201
197
059
194
135
147
150
129
156
180
206
425
668
029
026
710
609
125
913
356
673
612
966
726
895
993
589
407
004
640
188
855
998
152
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
M81
M81
M90
M62
M70
M81
M61
M82
M81
M70
M81
M81
M81
M81
M81
M81
M81
2001
-06-
G2
2000
-02-
G4
2004
-03-
G6
2000
-10-
G0
2002
-01-
G0
2005
-04-
G7
2000
-08-
G6
TP07
-11
TP07
-9TP
06-3
TP06
-6TP
06-6
TP07
-9TP
06-7
TP07
-8TP
06-7
27_9
TP06
-5TP
02-4
TP06
-10
TP06
-6TP
02-1
TP06
-8TP
06-9
TP07
-1
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