Tumor Characteristics in Blacks and Whites

Tumor Characteristics in Blacks and Whites 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 According to SEER, the mortality associated with uterine cancer has almost doubled over the past 20 years and has been associated with a steady increase in the incidence of disease

Racial Disparity in Cancer Mortality African American Caucasian 8 6 4 2 0

Relation Between Ethnicity and Race 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 Amer Indian/Alaska 407,073 0.1 2,068,883 0.7 **2000 Census of Population, Public Law 94-171

Diversity Race Hispanic i 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 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 Prevalence Mortality 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 Tumor Stage and Histology 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 Undifferentiated t dhistology more often found din Blacks compared dto 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 Proportio on surviv ving 1.0 Log 0.9 0.8 07 0.7 0.6 0.5 04 0.4 0.3 0.2 0.1 Black White Log-rank test: p=0.005 0.0 0 12 24 36 48 60 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 A+P 271 47.6 53 43.4 GOG 163 A+P 128 40.6 21 28.6 A+T 130 43.9 24 33.3 GOG 177 A+P 111 37.8 12 83 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 Adverse Effect White Black p- (n=982) (n=169) 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 Anemia Gastrointestinal Genitourinary 14.2 16.7 14 1.4 20.1 10.1 47 4.7 0.05 0.03 0.009009 Neurologic Cardiovascular Any Grade 3 or 4 3.0 5.3 82.1 3.6 4.1 82.3 0.68 0.53 096 0.96 Farley et al: Cancer 2010;116:355-61

Recurrence Free Survival in African Americans with Stage I Endometrial Cancer Estrogen Replacement Therapy Placebo RFS 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 White Black Log-rank test: p=0.0002 0 12 24 36 48 60 Time from Entry onto Study (Months) RFS 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 White Black Log-rank test: p=0.247 0 12 24 36 48 60 Time from Entry onto Study (Months) 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 MSI yes no PTEN yes no CTNNB1 yes no

Mean Racial Genetic Admixture Scores Slf Self-Designated dafrican 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 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 of self-designated race Rocconi et al: SGO book of abstracts, 2013

Racial Disparity in Gene Mutations Among African American Patients with Advanced Endometrial Cancer PTEN Mutation P53 Mutation 25 20 % 15 % 10 5 0 60 50 40 30 20 10 0 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 acgh performed on 80 endometrioid id 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 White patients, t but not White low grade patients. The number of Blacks in the 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=0.004004 p=0.017017 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 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 PSPHL increased in normal endometrium and normal ovary 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 All Cases Early Stage Cases Transcript expression compared between 18 Blacks 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 Concerns over imbalanced groups and lack of external validation prompted further investigation African American Caucasian

Global Transcript Expression in Endometrial Cancers: Associations with Stage Histology and Race Y -0.1 0 0.15 02 0.2 0 X -0.2 Stage I/II Stage III/IV -0.15 Z 0.05 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 endometrioid idvs non-endometrioid id comparisons No racial differences in tumor transcript expression observed Z 0.05-0.15 Endometrioid Serous Z 0.05-0.15 Black White 0.1 0.1 Y 0 Y 0-0.1-0.2 02 0 0.2 X -0.1-0.2 0 X 0.2 Maxwell et al: Gynecol Oncol 2013;130:169-73

Global Transcript Expression in Endometrial Cancers: Associations with Race and Technique or Preparation 0.15-0.15 0 LCM prepared, Black LCM prepared, White Whole tumor, Black Whole tumor, White -0.1 0.1 PC #2 (14 4%) -150 0 150 150 0-150 Multidimensional Scaling PC #3 (6%) PC #1 (23%) Principal Component Analysis Maxwell et al: Gynecol Oncol 2013;130:169-73

Global mirna Expression in Endometrial lcancers in Blacks and dwhites Z Black White Black White Y X <1/4 1 >4 Ratio

mir-337 Expression in Endometrial Cancers from Blacks and Whites 0.07 0.06 TaqMan q-rt PCR Black White 0.01 Averages l Ratio mir- R-337-3p -337-3p/Contro / RNU48 ol Ratio 0.05 0.04 0.03 0.02 001 0.01 0 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 mir R-337-3p / RNU48 Contro Black White 0.001 Black AA White C hsa-mir-337-3p -11-13 -15-17 -19-21 -23 rol Ratio) -25 Log2( mir-337-3p / Cont M8214 M7299 M8211 M8225 M9064 M8174 M8206 M8195 M6199 M8141 M7279 M7084 M8159 M8132 M7034 M7039 M8198 M8162 M8168 M7024 M6204 M6000 M8136 M7259 M8185 M7029 M7249 M7054 M8213 M8204 M8222 M6213 M7049 M8165 M8117 M8138 M8157 M9000 M6220 M7079 M8192 M6192 M8201 M8197 M7059 M8194 M8135 M8147 M8150 M8129 M8156 M8180 2001-06-G206 2000-02-G425 2004-03-G668 2000-10-G029 2002-01-G026 2005-04-G710 2000-08-G609 TP07-1125 TP07-913 TP06-356 TP06-673 TP06-612 TP07-966 TP06-726 TP07-895 TP06-727_993 TP06-589 TP02-407 TP06-1004 TP06-640 TP02-188 TP06-855 TP06-998 TP07-152 log2(expression) (-Ct normalized) W IA W IB W IC Black AA White C AA Black White C Cancer Normal B IB B IC AA IB --> AA IC C IA --> C IB --> C IC --> N AA--> N C -->

Intergromic Analysis Proteomic Analysis of Blacks (red) and Whites (blue) with endometrial cancer RNA-seq analysis of the matched pairs is underway Exomic sequencing being assessed using TCGA samples Analysis across the three datasets is planned

Tumor Characteristics in Blacks and Whites 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