Molecular characterization of endometrial carcinomas in Black and White patients reveals disparate drivers with therapeutic implications

Authors

Weigelt B

Marra A

Selenica P

Rios-Doria E

Momeni-Boroujeni A

Berger MF

Arora K

Nemirovsky D

Iasonos A

Chakravarty D

Abu-Rustum NR

Da Cruz Paula A

Dessources K

Ellenson LH

Liu YL

Aghajanian C

Brown CL

Doi

10.1158/2159-8290.CD-23-0546

PMID: 37651310 · DOI: 10.1158/2159-8290.CD-23-0546 · Journal: Cancer Discovery (2023)

TL;DR

Weigelt, Marra et al. analyzed 1,882 prospectively sequenced endometrial carcinomas (ECs) from self-identified Black (n=259) and White (n=1,623) patients using MSK-IMPACT at Memorial Sloan Kettering. Black patients had a significantly higher prevalence of aggressive histologic subtypes (serous, carcinosarcoma) and the CN-H/TP53abn molecular subtype (69% vs 35%), with higher rates of CCNE1 amplification and ERBB2 amplification. Conversely, clinically actionable features such as high TMB (>=10 Mut/Mb) and MSI-H – which confer benefit from immune checkpoint inhibitors – were significantly less frequent in ECs from Black patients (15% vs 33% TMB-H; 14% vs 25% MSI-H), revealing molecular underpinnings of therapeutic disparities.

Cohort & data

  • 1,882 endometrial carcinoma patients: 259 self-identified Black, 1,623 self-identified White, from MSK (1/2014–12/2021) (PMID:37651310).
  • Cancer types: endometrial carcinoma (UCEC), including serous (USC), carcinosarcoma (UCS), endometrioid, clear cell, and mixed/high-grade NOS subtypes.
  • Sequenced with MSK-IMPACT (341–505 gene panel), tumor-normal, FDA-authorized.
  • Dataset: ucec_ancestry_cds_msk_2023.
  • Molecular subtyping: POLE, MSI-H, CN-H/TP53abn, CN-L/NSMP using integrated sequencing and immunohistochemistry.
  • Genetic ancestry inferred from MSK-IMPACT data; 70% of Black patients had African ancestry, 30% Admixed.
  • Copy number analysis performed with FACETS.

Key findings

  • Histologic distribution differs by race: Black patients had significantly more high-risk histologies – serous (29% vs 13%), carcinosarcoma (20% vs 11%), and less low-grade endometrioid (21% vs 47%; p<0.01) (PMID:37651310).
  • Molecular subtype enrichment: 69% of ECs in Black patients were CN-H/TP53abn vs 35% in White patients (p<0.001). POLE subtype was rare in Black patients (1.2% vs 5.8%) (PMID:37651310).
  • Lower TMB in Black patients: Median TMB 4 vs 7 Mut/Mb (p<0.001). Only 15% of Black vs 33% of White patients had TMB >=10 Mut/Mb (p<0.001) (PMID:37651310).
  • Higher chromosomal instability: FGA median 30% vs 10% (p<0.001); WGD 32% vs 18% (p<0.001) in Black vs White patients (PMID:37651310).
  • TP53 mutations enriched: 72% vs 42% (q<0.001) in Black vs White patients (PMID:37651310).
  • CCNE1 amplification more common in Black patients: 15% vs 4% overall (q<0.001); 21% vs 11% in CN-H/TP53abn ECs (q<0.1); 29% vs 10% in carcinosarcomas (q<0.1) (PMID:37651310).
  • ERBB2 amplification enriched in Black patients: 12% vs 3% (q<0.001), driven by gene amplification rather than point mutations (PMID:37651310).
  • PI3K pathway alterations less common in Black patients: PTEN 26% vs 55% (q<0.001), PIK3R1 13% vs 28% (q<0.001), KRAS 12% vs 21% (q=0.01) (PMID:37651310).
  • PIK3CA alteration mechanism differs: Similar overall frequency (38% vs 46%, q>0.1), but PIK3CA amplification accounted for 12% of alterations in Black vs 4% in White patients (p=0.002) (PMID:37651310).
  • PPP2R1A and PTEN mutually exclusive (p<0.01): Both less frequent in CN-H/TP53abn ECs from Black patients (PMID:37651310).
  • Clinically actionable alterations (OncoKB Level 1/2/3A) less frequent in Black patients: 22.4% vs 39.7% (p<0.001) (PMID:37651310).
  • Within carcinosarcomas: KMT2B mutations (31% vs 10%, q<0.1) and NF1 mutations (12% vs 1%, q<0.1) more frequent in Black patients (PMID:37651310).
  • Genetic ancestry concordance: No significant differences in histologic or molecular subtype distribution between Black patients of African vs Admixed ancestry, validated in TCGA (PMID:37651310).

Genes & alterations

  • TP53 – Somatic mutations enriched in Black patients (72% vs 42%), consistent with CN-H/TP53abn subtype enrichment (PMID:37651310).
  • CCNE1 – Amplification more prevalent in Black patients overall (15% vs 4%) and specifically in carcinosarcomas (29% vs 10%); associated with replication stress and chromosomal instability (PMID:37651310).
  • ERBB2 – Amplification enriched in Black patients (12% vs 3%); therapeutic target for trastuzumab and trastuzumab deruxtecan (PMID:37651310).
  • PTEN – Mutations less frequent in Black patients (26% vs 55%); associated with endometrioid histology and PI3K pathway activation (PMID:37651310).
  • PIK3CA – Similar mutation frequency but distinct alteration mechanism (more amplification in Black patients) (PMID:37651310).
  • PIK3R1 – Mutations less common in Black patients (13% vs 28%) (PMID:37651310).
  • KRAS – Oncogenic alterations less frequent in Black patients (12% vs 21%) (PMID:37651310).
  • ARID1A – Mutations less frequent in Black patients (19% vs 47%), consistent with fewer endometrioid ECs (PMID:37651310).
  • CTNNB1 – Less common in Black patients (9% vs 17%) (PMID:37651310).
  • PPP2R1A – Mutations less frequent in CN-H/TP53abn ECs from Black patients (15% vs 28%); negative PI3K regulator (PMID:37651310).
  • AKT2 – Amplification more common in Black patients (9% vs 3%, q<0.01) (PMID:37651310).
  • POLE – Exonuclease domain hotspot mutations rare in Black patients (1.2% vs 5.8%); favorable prognosis subtype (PMID:37651310).
  • KMT2B – Mutations enriched in CN-H/TP53abn ECs (16% vs 8%) and carcinosarcomas (31% vs 10%) from Black patients (PMID:37651310).
  • NF1 – Mutations more frequent in carcinosarcomas from Black patients (12% vs 1%) (PMID:37651310).
  • BRCA1 – Somatic mutations more frequent in CN-H/TP53abn ECs from Black patients (3% vs 0.3%) (PMID:37651310).
  • MED12 – Hotspot mutations (p.G44A/D/S/R/V) more prevalent in serous ECs from Black patients (11% vs 0%) (PMID:37651310).
  • FBXW7 – Co-occurs with TP53 mutations in serous/carcinosarcoma ECs (PMID:37651310).

Clinical implications

  • Black EC patients are significantly less likely to harbor MSI-H or TMB-H tumors, reducing eligibility for immune checkpoint inhibitors (pembrolizumab, dostarlimab) that have demonstrated practice-changing benefit in dMMR/MSI-H ECs (PMID:37651310).
  • ERBB2 amplification is more prevalent in Black patients, representing a therapeutic opportunity with anti-HER2 agents including trastuzumab and trastuzumab deruxtecan, the latter showing clinical activity even in low-HER2-expressing carcinosarcomas (PMID:37651310).
  • CCNE1 amplification, enriched in Black patients, is a potential target for WEE1 inhibitors, ATR inhibitor combinations, and PKMYT1 kinase inhibitors under clinical investigation (PMID:37651310).
  • Lower frequency of PI3K pathway alterations (PTEN, PIK3R1, KRAS) in Black patients suggests fewer may benefit from hormonal therapies or PI3K/AKT/mTOR pathway-targeted trials (PMID:37651310).
  • The disparity in clinically actionable alterations (22.4% vs 39.7%, OncoKB Level 1/2/3A) underscores the need for greater diversity in clinical trial design and enrollment (PMID:37651310).

Limitations & open questions

  • Self-reported race/ethnicity is a socio-political construct and may not fully capture biological heterogeneity; genetic ancestry analysis was exploratory and limited by sample size (PMID:37651310).
  • MSK-IMPACT gene panel was designed based on studies predominantly of European ancestry populations, potentially missing population-specific cancer-associated genes relevant to African populations (PMID:37651310).
  • Black patient cohort (n=259), while the largest with comprehensive clinical multigene panel sequencing, remains limited in size; validation in larger, more diverse cohorts is needed (PMID:37651310).
  • The mechanistic basis for the low occurrence of favorable-outcome POLE ECs in Black patients remains unknown (PMID:37651310).
  • Single-institution study at a referral cancer center may not fully represent community-level EC populations (PMID:37651310).
  • The mutual exclusivity of PTEN and PPP2R1A mutations in CN-H/TP53abn ECs, potentially reflecting synthetic lethality, warrants functional validation (PMID:37651310).

Citations from this paper used in the wiki

  • “Although the incidence of endometrial carcinoma (EC) is similar in Black and White women, racial disparities are stark with the highest mortality rates observed among Black patients.” (PMID:37651310)
  • “Clinically actionable alterations, including high tumor mutational burden/microsatellite-instability, which confer benefit from immunotherapy, were less frequent in ECs from Black than from White patients.” (PMID:37651310)
  • “CCNE1 gene amplification, which is associated with aggressive clinical behavior, was more prevalent in carcinosarcomas occurring in Black than in White patients.” (PMID:37651310)
  • “the frequency of a clinically actionable alteration making an EC patient eligible for treatment with an FDA-approved drug (level 1 or 2, including TMB >= 10 Mut/Mb and MSI-H) or enrollment into a clinical trial (level 3A) was significantly less in Black than in White EC patients (22.4% vs 39.7%, p<0.001)” (PMID:37651310)
  • “69% of ECs in Black patients were of CN-H/TP53abn molecular subtype” (PMID:37651310)

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