Tumor Characteristics in Blacks and Whites with Endometrial Cancer - - PowerPoint PPT Presentation

Tumor Characteristics in Blacks and Whites with Endometrial Cancer with Endometrial Cancer

Larry Maxwell, M.D. Chairman, Dept of OB-GYN at Inova Fairfax Hospital Co-Director, GYN Cancer Center of Excellence Professor, Virginia Commonwealth University 17 March 2014

Mortality Associated with Endometrial Cancer Mortality Associated with Endometrial Cancer

• According to SEER, the

mortality associated with y uterine cancer has almost doubled over the past 20 years and has been associated with and has been associated with a steady increase in the incidence of disease

Racial Disparity in Cancer Mortality Racial Disparity in Cancer Mortality

8 African American Caucasian 4 6 2

Relation Between Ethnicity and Race y

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 69.1 Black/AA 710,353 0.3 33,947,837 12.1 Asian 119,829 <0.1 10,123,169 3.6 Hawaiian/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

Diversity Diversity

R Hi i L ti % f U S N H/L % f U S Race Hispanic or Latino % of U.S. Non H/L % of U.S. One race 33,081,736 11.8 241,513,942 85.8 2+ races 2,224,082 0.8 2,602,146 1.6

Access to Care and Equivalency of Treatment q 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;86:486-90 Sherman et al: Cancer 2003;98:176-86 Trimble et al: Gynecol Oncol 2004;93:125-30 Randall et al: J Clin Oncol 2003;21:4200-6 Hicks et al: Cancer 1998;83:2629-37 Madison et al: Am J Public Health 2004;94:2104-11

Endometrial Cancer Outcome According to Race g

Prevalence Mortality Blacks (denoted by red line) with endometrial cancer have a lower Blacks (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 l Tumor 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;165:262-70 Wright et al: Cancer 2009;115:1276-85 Jemal et al: Cancer 2008;58:71-96

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

1.0

Log Log-rank test: p=0.005 rank test: p=0.005

0 7 0.8 0.9

ving ving

g p

0 4 0.5 0.6 0.7

• n surviv
• n surviv

White White

0.2 0.3 0.4

Proportio Proportio Black Black

0.0 0.1 12 24 36 48 60

P Months on Study Months on Study

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

Tumor Response to Treatment by Race

White Black Protocol Patients (No.) Response (%) Protocol (No.) Response (%) GOG 107 A 127 35 17 11.8 P 110 42.7 17 41.2 GOG 139 GOG 139 A+P 271 47.6 53 43.4 GOG 163 A+P 128 40 6 21 28 6 A+P 128 40.6 21 28.6 A+T 130 43.9 24 33.3 GOG 177 A+P 111 37 8 12 8 3 A+P 111 37.8 12 8.3 A/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 Cancer Advanced Stage Endometrial Cancer

White Black p Adverse Effect (n=982) (n=169) p- value % % Selected Grade 3 or 4 Leukopenia Thrombocytopenia Neutropenia 61.6 10.3 67.9 55.6 9.5 63.9 0.14 0.75 0.30 p Anemia Gastrointestinal Genitourinary 14.2 16.7 1 4 20.1 10.1 4 7 0.05 0.03 0 009 Genitourinary Neurologic Cardiovascular A G d 3 4 1.4 3.0 5.3 82 1 4.7 3.6 4.1 82 3 0.009 0.68 0.53 0 96 Any 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 C Americans with Stage I Endometrial Cancer

Estrogen Replacement Therapy Placebo

Log-rank test: p=0.0002

0.7 0.8 0.9 1.0

Log-rank test: p=0.247

0.7 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) 12 24 36 48 60

White Black

0.0 0.1 Time from Entry onto Study (Months) 12 24 36 48 60

White Black

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 Cancer

TYPE I TYPE II

Ploidy diploid aneuploid K-ras yes yes HER-2/neu no yes p53 no yes p53 no yes MSI yes no PTEN yes no CTNNB1 yes no

Mean Racial Genetic Admixture Scores

S lf i d Af i A i Self-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 i Racial 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

• f self-designated race

g

Rocconi et al: SGO book of abstracts, 2013

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

PTEN Mutation P53 Mutation

50 60 25 30 40 50 10 15 20

% % %

10 20 5

African-American Caucasian

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

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

• aCGH performed on 80

d t i id d t i l endometrioid 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 l White patients, but not White low grade patients.

• The number of Blacks in the

validation set was too small to validation 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 FISH

• No. %
• No. %
• No. %

White: 446 (91) 58 (13) 26 (6) Black: 33 (8) 11 (33) 6 (18) p=0 004 p=0 017 p=0.004 p=0.017 Santin et al: 2005;192:813-8 Morrison et al: JCO 2006;24:2376-85

Phosphoserine Phosphatase Like (PSPHL)

• PSPH identified on Affy could not

be internally validated be 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 Whites Whites

• PSPHL increased in normal

endometrium and normal ovary from Blacks compared to Whites from Blacks compared to Whites Ferguson et al: Gynecol Oncol 2006;101:209-13 Risinger et al: Front Oncol 2012;2:1-15

Global Transcript Expression in Endometrial Cancers: Preliminary Analysis of Race Cancers: 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 data consistency with published data

• Concerns over imbalanced groups and lack of

external validation prompted further investigation

Early Stage Cases Early Stage Cases African American Caucasian

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

Stage I/II Stage III/IV

• 0.2

0 2

Associations with Stage Histology and Race

• 25 Black and 25 White women with

Stage III/IV

0.2

• 0.1

Y Z 0.05

• 0.15

25 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 id

0.15 X

endometrioid vs non-endometrioid comparisons

• No racial differences in tumor transcript

expression observed

0.1 Z 0.05

• 0.15

Black White Endometrioid Serous

0.1 Z 0.05

• 0.15
• 0.1

Y 0 2

• 0.1

Y

• 0.2

0.2 X

• 0.2

0.2 X

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, Black LCM d Whi

Associations with Race and Technique or Preparation

LCM prepared, White Whole tumor, Black Whole tumor, White

0.15 0.1

• 0.1
• 150

150 150 4%)

• 0.15

PC #2 (14 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 White

Z

Black White

Y X

<1/4 >4 1

X

<1/4 >4 1 Ratio

miR-337 Expression in Endometrial Cancers from Blacks and Whites

0.06 0.07 l Ratio Black White

Black White

Ratio

0.01

• l Ratio

Ratio

Averages TaqMan q-RT PCR

0 01 0.02 0.03 0.04 0.05 R-337-3p / Contro White

White

R-337-3p / RNU48

• 337-3p/Contro

R-337-3p / RNU48 0.01

2010022 2010061 2010108 2010140 2010141 7010034 2004-09-G518 2005-07-G656 2005-09-G685 2005-12-G929 2006-04-G970 2007-03-G634 M6218 M6222 M7089 M7099 M7139 M7299 M8024 M8164 M8178 M8186 M8206 M8211 2010038 2010040 2010052 2010065 2010079 2010158 2004-07-G511 2005-01-G644 2005-07-G694 2005-10-G648 2006-01-G628 2006-05-G742 M6171 M6204 M7019 M7119 M7159 M7179 M7214 M7229 M8081 M8218 M8138 Black White

miR

Black White

miR

0.001 AA C

miR-

miR

Black White

hsa-miR-337-3p

• 15
• 13
• 11

Ct normalized)

rol Ratio)

Black White

Black 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(Expression) (-C

miR-337-3p / Cont

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 TP07-9 TP06-3 TP06-6 TP06-6 TP07-9 TP06-7 TP07-8 TP06-727_9 TP06-5 TP02-4 TP06-10 TP06-6 TP02-1 TP06-8 TP06-9 TP07-1 AA IB --> AA IC C IA --> C IB --> C IC --> N AA--> N C -->

Log2( m

AA C Cancer Normal AA C

Black White Black White

W IB  W IC 

W IA B IB  B IC

Intergromic Analysis

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

• RNA-seq analysis of the matched pairs is

RNA seq analysis of the matched pairs is underway

• Exomic sequencing being assessed using

TCGA samples p

• Analysis across the three datasets is planned

Tumor Characteristics in Blacks and Whites with Endometrial Cancer with Endometrial Cancer

Larry Maxwell, M.D. Chairman, Dept of OB-GYN at Inova Fairfax Hospital Co-Director, GYN Cancer Center of Excellence Professor, Virginia Commonwealth University 17 March 2014