. 2024 Apr:183:103-114.

doi: 10.1016/j.ygyno.2024.03.026. Epub 2024 Apr 8.

Disease progression, survival, and molecular disparities in Black and White patients with endometrioid endometrial carcinoma in real-world registries and GOG/NRG oncology randomized phase III clinical trials

Zachary A Kopelman¹, Chunqiao Tian², Jordyn Tumas¹, Neil T Phippen¹, Christopher M Tarney¹, Erica R Hope³, Stuart S Winkler³, Suzanne Jokajtys¹, Calen W Kucera¹, John K Chan⁴, Michael T Richardson⁵, Daniel S Kapp⁶, Chad A Hamilton⁷, Charles A Leath 3rd⁸, Nathaniel L Jones⁹, Rodney P Rocconi¹⁰, John H Farley¹¹, Angeles Alvarez Secord¹², Casey M Cosgrove¹³, Matthew A Powell¹⁴, Ann Klopp¹⁵, Joan L Walker¹⁶, Gini F Fleming¹⁷, Nicholas W Bateman¹⁸, Thomas P Conrads¹⁹, G Larry Maxwell²⁰, Kathleen M Darcy²¹

Affiliations

¹ Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD, USA; Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD, USA.
² Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD, USA; Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD, USA; The Henry M Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA.
³ Division of Gynecologic Oncology, Department of Gynecologic Surgery and Obstetrics, Brooke Army Medical Center, San Antonio, TX, USA.
⁴ Palo Alto Medical Foundation, California Pacific Medical Center, Sutter Health, San Francisco, CA, USA.
⁵ Department of Obstetrics and Gynecology, University of California, Los Angeles School of Medicine, Los Angeles, CA, USA.
⁶ Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA.
⁷ Gynecologic Oncology Section, Women's Services and The Ochsner Cancer Institute, Ochsner Health, New Orleans, LA, USA.
⁸ Division of Gynecologic Oncology, University of Alabama at Birmingham, O'Neal Comprehensive Cancer Center, Birmingham, AL, USA.
⁹ Division of Gynecologic Oncology, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA.
¹⁰ Division of Gynecologic Oncology, Cancer Center & Research Institute, the University of Mississippi Medical Center, Jackson, MS, USA.
¹¹ Division of Gynecologic Oncology, Center for Women's Health, Cancer Institute, Dignity Health St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA.
¹² Division of Gynecologic Oncology, Duke University Medical Center, Durham, NC, USA.
¹³ Division of Gynecologic Oncology, The Ohio State University, Columbus, OH, USA.
¹⁴ Division of Gynecologic Oncology, Siteman Cancer Center, Washington University, St Louis, MO, USA.
¹⁵ Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁶ Gynecologic Oncology Division, Stephenson Cancer Center, Oklahoma University Health Sciences Center, Oklahoma City, OK, USA.
¹⁷ Department of Medicine, University of Chicago, Chicago, IL, USA.
¹⁸ Division of Gynecologic Oncology, Center for Women's Health, Cancer Institute, Dignity Health St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA; The Henry M Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA.
¹⁹ Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD, USA; The Henry M Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA; Women's Health Integrated Research Center, Inova Women's Service Line, Inova Health System, Falls Church, VA, USA.
²⁰ Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD, USA; The Henry M Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA; Women's Health Integrated Research Center, Inova Women's Service Line, Inova Health System, Falls Church, VA, USA. Electronic address: George.Maxwell@inova.org.
²¹ Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD, USA; Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD, USA; The Henry M Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA. Electronic address: darcyk@whirc.org.

PMID: 38593674
PMCID: PMC11894812
DOI: 10.1016/j.ygyno.2024.03.026

Disease progression, survival, and molecular disparities in Black and White patients with endometrioid endometrial carcinoma in real-world registries and GOG/NRG oncology randomized phase III clinical trials

Zachary A Kopelman et al. Gynecol Oncol. 2024 Apr.

. 2024 Apr:183:103-114.

doi: 10.1016/j.ygyno.2024.03.026. Epub 2024 Apr 8.

Authors

Affiliations

¹ Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD, USA; Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD, USA.
² Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD, USA; Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD, USA; The Henry M Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA.
³ Division of Gynecologic Oncology, Department of Gynecologic Surgery and Obstetrics, Brooke Army Medical Center, San Antonio, TX, USA.
⁴ Palo Alto Medical Foundation, California Pacific Medical Center, Sutter Health, San Francisco, CA, USA.
⁵ Department of Obstetrics and Gynecology, University of California, Los Angeles School of Medicine, Los Angeles, CA, USA.
⁶ Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA.
⁷ Gynecologic Oncology Section, Women's Services and The Ochsner Cancer Institute, Ochsner Health, New Orleans, LA, USA.
⁸ Division of Gynecologic Oncology, University of Alabama at Birmingham, O'Neal Comprehensive Cancer Center, Birmingham, AL, USA.
⁹ Division of Gynecologic Oncology, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA.
¹⁰ Division of Gynecologic Oncology, Cancer Center & Research Institute, the University of Mississippi Medical Center, Jackson, MS, USA.
¹¹ Division of Gynecologic Oncology, Center for Women's Health, Cancer Institute, Dignity Health St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA.
¹² Division of Gynecologic Oncology, Duke University Medical Center, Durham, NC, USA.
¹³ Division of Gynecologic Oncology, The Ohio State University, Columbus, OH, USA.
¹⁴ Division of Gynecologic Oncology, Siteman Cancer Center, Washington University, St Louis, MO, USA.
¹⁵ Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁶ Gynecologic Oncology Division, Stephenson Cancer Center, Oklahoma University Health Sciences Center, Oklahoma City, OK, USA.
¹⁷ Department of Medicine, University of Chicago, Chicago, IL, USA.
¹⁸ Division of Gynecologic Oncology, Center for Women's Health, Cancer Institute, Dignity Health St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA; The Henry M Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA.
¹⁹ Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD, USA; The Henry M Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA; Women's Health Integrated Research Center, Inova Women's Service Line, Inova Health System, Falls Church, VA, USA.
²⁰ Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD, USA; The Henry M Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA; Women's Health Integrated Research Center, Inova Women's Service Line, Inova Health System, Falls Church, VA, USA. Electronic address: George.Maxwell@inova.org.
²¹ Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD, USA; Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD, USA; The Henry M Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA. Electronic address: darcyk@whirc.org.

PMID: 38593674
PMCID: PMC11894812
DOI: 10.1016/j.ygyno.2024.03.026

Abstract

Objective: Investigate racial disparities in outcomes and molecular features in Black and White patients with endometrioid endometrial carcinoma (EEC).

Methods: Black and White patients diagnosed with EEC who underwent hysterectomy ± adjuvant treatment in SEER, National Cancer Database (NCDB), the Genomics Evidence Neoplasia Information Exchange (GENIE) project (v.13.0), and eight NCI-sponsored randomized phase III clinical trials (RCTs) were studied. Hazard ratio (HR) and 95% confidence interval (CI) were estimated for cancer-related death (CRD), non-cancer death (NCD), and all-cause death.

Results: Black (n = 4397) vs. White (n = 47,959) patients in SEER had a HR (95% CI) of 2.04 (1.87-2.23) for CRD and 1.22 (1.09-1.36) for NCD. In NCDB, the HR (95% CI) for death in Black (n = 13,468) vs. White (n = 155,706) patients was 1.52 (1.46-1.58) dropping to 1.29 (1.23-1.36) after propensity-score matching for age, comorbidity, income, insurance, grade, stage, LVSI, and treatment. In GENIE, Black (n = 109) vs. White (n = 1780) patients had fewer PTEN, PIK3R1, FBXW7, NF1, mTOR, CCND1, and PI3K-pathway-related gene mutations. In contrast, TP53 and DNA-repair-related gene mutation frequency as well as tumor mutational burden-high status were similar in Black and White patients. In RCTs, Black (n = 187) vs. White (n = 2877) patients were more likely to have advanced or recurrent disease, higher grade, worse performance status and progressive disease. Risk of death in Black vs. White patients in RCTs was 2.19 (1.77-2.71) persisting to 1.32 (1.09-1.61) after matching for grade, stage, and treatment arm while balancing age and performance status.

Conclusions: Differences exist in clinical presentation, outcomes, and molecular features in Black vs. White patients with EEC in real-world registries and RCTs. Targeted-drug development, strategies to modify social determinants, and diverse inclusion in RCTs are approaches to reduce disparities.

Keywords: AACR GENIE; Endometrioid endometrial cancer; NCDB; Racial disparities; Randomized phase III clinical trial; SEER.

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Conflict of interest statement

Declaration of interests Zachary A. Kopelman, Chunqiao Tian, Jordyn Tumas, Neil T. Phippen, Christopher M. Tarney, Erica R. Hope, Stuart S. Winkler, Suzanne Jokajtys, Calen W. Kucera, Michael T. Richardson, Daniel S. Kapp, Nathaniel L. Jones, Rodney P. Rocconi, John H. Farley, Angeles Alvarez Secord, Casey M. Cosgrove, Matthew A. Powell, Ann Klopp, Joan L Walker, Gini F. Fleming, Nicholas W. Bateman, G. Larry Maxwell, and Kathleen M. Darcy do not have any conflicts to report. John K. Chan reported personal fees from Agenus, AstraZeneca, Eisai, Genmab, GlaxoSmithKline, Immunogen, Mersana, Molecular Targeting Technologies, Myriad, Roche, and Seagen outside the submitted work. Chad A. Hamilton reported personal fees from GlaxoSmithKline outside the submitted work. Charles A. Leath, III received funding from the NIH UG1 CA23330 and P50 CA098252, contracted research with GSK and Merck, and served on a scientific advisory board for GSK and Merck, all outside of the submitted work. Thomas P. Conrads is a ThermoFisher Scientific, Inc. SAB member and receives research funding from AbbVie outside the submitted work.

Figures

**Figure 1.**
Surgically managed Black and White patients diagnosed between 2004 and 2016 with stage I-IV low-grade (grade 1–2 tumor) or high-grade (grade 3 tumor) endometrioid endometrial cancer from the National Cancer Institute’s SEER-18 registries. Bar graphs showing the distribution of Black vs. White patients by age at diagnosis (A) or stage of disease (B). Probability of cancer-related and non-cancer death in White (C) or Black patients (D). Racial disparities in cumulative incidence of cancer-related deaths (E) or non-cancer deaths (F) for Black vs. White patients. Table displaying the number of patients and deaths, 5-year cancer-related death (CRD) or non-cancer death (NCD) rates and hazard ratio (HR) and 95% confidence interval (CI) for CRD or NCD in White vs. Black patients (G).

**Figure 2.**
Overall survival (OS) in Black vs. White patients diagnosed between 2004–2017 with stage I-IV low grade (grade 1–2) and high grade (grade 3) endometrioid endometrial cancer in the original cohort (A) and propensity-score matched cohort (B) in the National Cancer Database. Propensity score matching analysis adjusted for patient age, comorbidity score, neighborhood income, insurance status, year of diagnosis, tumor grade, stage, LVSI, lymphadenectomy and adjuvant treatment. Hazard ratio (HR) or adjusted HR (aHR) and 95% confidence interval (CI) for risk of death were estimated from Cox modeling. Bar graph (C) displays the mutation frequency in selected genes and pathways for Black vs. White patients with endometrioid endometrial cancer in GENIE v13.0. Difference by race were evaluated by Fisher’s exact test for somatic mutations or by t-test for tumor mutational burden (TMB) with significant differences (p <0.05) highlighted with an Asterix. TMB indicating total number of mutations per Mb, with TMB-high defined as 10 or more mutations per Mb.

**Figure 3.**
A pooled analysis in eight NCI-sponsored randomized phase III clinical trials (RCTs) in patients with stage I-IV or recurrent endometrioid endometrial cancer. Highlights of these RCTs are summarized in Table 2 and eTable 1. Progression-free survival (PFS, A, C) and overall survival (OS, B, D) in Black vs. White patients in the original cohort (A, B) or the matched cohort (C, D) after exactly matching for tumor grade, stage and treatment arm and balancing for age and performance based on propensity scores. Hazard ratio (HR) or adjusted HR (aHR) and 95% confidence interval (CI) for risk of disease progression or death were estimated from Cox modeling.

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References

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Disease progression, survival, and molecular disparities in Black and White patients with endometrioid endometrial carcinoma in real-world registries and GOG/NRG oncology randomized phase III clinical trials

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Disease progression, survival, and molecular disparities in Black and White patients with endometrioid endometrial carcinoma in real-world registries and GOG/NRG oncology randomized phase III clinical trials

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