Highlights
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Report highlighting comprehensive TCGA molecular sequencing and HER2 expression in G3 EEC with 18% POLEmut expression.
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There was no difference in HER2 or Molecular subtype in G3 EEC between Black and White patients.
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HER2 2 + expression at 2 + level was common in G3 EEC, with 41 % expression noted, serving as a possible therapeutic target.
Keywords: Grade 3 endometrioid endometrial cancer, Molecular subtype, Race, HER2
Abstract
Objectives
To characterize stage I-III Grade 3 endometroid endometrial cancer (Gr3 EEC) by molecular subtype and human epithelial growth factor receptor 2 (HER2) status and explore differences in characteristics by race.
Methods
We identified patients with a diagnosis of stage I-III Gr3 EEC from a single-institution health system cancer registry and pathologically confirmed the diagnosis. Review of the electronic health record was performed as needed to confirm patient characteristics. Next-generation sequencing (NGS) and immunohistochemical staining (IHC) for HER2 was performed on all primary tumors.
Results
Thirty-four primary cases remained classified as stage I-III Gr3 EEC after pathologic review and exclusion of cases lacking in-house primary tumor for re-review. Fifteen were categorized as microsatellite unstable (MSI; 44 %), 10 as copy number high (CNH; 29 %), six as polymerase E mutant (POLEmut; 17.6 %) and three as copy number low (CNL; 8.8 %). Thirteen patients were Black, 18 were White, and 3 had a race of “other and/or unknown”. HER2 status by IHC in the primary tumor was 0 (n = 7; 20.5 %), 1+ (n = 11; 32 %), 2+ (n = 14; 41 %), 3+ (n = 1; 3 %). There was no difference in the distribution of TCGA subtype or HER2 status by race.
Conclusion
In stage I-III stage Gr3 EEC HER2 positivity (3 + ) was uncommon, but expression at the 2 + level was frequent, and did not differ by race. In this limited sample, there were no differences in distribution of TCGA subtype amongst patients with grade 3 EEC. Other causes should be explored to explain reported differences in outcomes in EEC by race.
1. Introduction
In 2012 Voss et al published their findings on the prognosis of women with grade 3 endometrioid endometrial cancer (Gr3 EEC), concluding that Gr3 EEC and Uterine Serous Cancer (USC) shared similar poor survival. They opined that Gr3 EEC is better characterized as type 2 cancer and should be treated with similar adjuvant therapy to USC. (Voss, 2012) Since then, it has been recognized that Gr3 EEC comprises a mixture of biologic subtypes, with copy number high (CNH) Gr3 EEC conferring a worse prognosis and POLE mutated Gr3 EEC conferring a better prognosis. (Bosse, 2018).
While a substantial contribution to the stark racial disparities in outcomes of endometrial cancer may be related to different rates of uterine serous carcinoma (USC) and carcinosarcoma between Black and White women, Black women with EEC have been reported to have worse outcomes and a higher percentage of grade 3 tumors than white women with EEC. (Kopelman, 2024, Weigelt, 2023) Kopelman et al reported that the disparity in outcomes between Black and White women with EEC decreased, but did not disappear, after propensity-score matching for age, comorbidity, income, insurance, stage, LVSI, treatment, and grade. (Kopelman, 2024) We hypothesized that Black women with Gr3 EEC would have a different distribution of TCGA molecular subtypes than white women with Gr3 EEC. Specifically, we hypothesized that there might be a higher percentage of CNH-high tumors in Black women compared to White women, and this might account for some of the reported difference in outcomes between these groups. It has also been reported that amongst women with USC, those whose tumors have HER2 overexpression have a worse prognosis, and that Black women with USC are more likely to have high levels of HER2 expression than white women. (Santin, 2005, Slomovitz, 2004) We therefore also evaluated HER2 status by immunohistochemistry (IHC) in Gr3 EEC to explore this secondary end point. We chose to limit our analyses to women with stage I-III disease, as we wished to focus on the subset of women with potentially curable disease.
2. Methods
We identified cases of stage I-III Gr3 EEC with from the institutional cancer registry at our urban, academic health system from 2006 to 2022. Cases with no primary tumor sample available in-house were excluded from analysis. One of us (J.A.B; gynecologic pathologist) reviewed the H&E of all cases and determined whether they would currently qualify as Gr3 EEC based on the WHO 2020 Classification of Female Genital Tumors. We did not include carcinosarcomas, undifferentiated, or de-differentiated carcinomas. Cases that were both originally classified as Gr3 EEC and retained this diagnosis on re-review were included along with cases in Black women that had an original classification other than Gr3 EEC but were reclassified as Gr3 EEC during a pathologic review of endometrial cancers in Black women (Fig. 1). Clinical data were obtained through the cancer registry and supplemented through review of the electronic health record. The study was approved as a minimal-risk study by the University of Chicago Institutional Review Board.
Fig. 1.
Consort diagram.
2.1. HER2 immunohistochemistry
HER2 immunohistochemistry (clone c-erbB-2, dilution 1:320, Agilent, Santa Clara, CA) was performed by the core facility on a representative slide of all tumors and scored from 0 to 3 + according to the endometrial carcinoma-specific HER2 testing algorithm. (Buza, N., HER2 Testing and Reporting in Endometrial Serous Carcinoma: Practical Recommendations for HER2 Immunohistochemistry and Fluorescent In Situ Hybridization: Proceedings of the ISGyP Companion Society Session at the, 2020).
2.2. Next-generation sequencing
Genomic DNA was isolated from formalin-fixed paraffin-embedded (FFPE) sections on 31 tumors. NGS was performed using the University of Chicago Medicine OncoPlus (UCM-OncoPlus) panel, a hybrid-capture panel targeting 1005–1213 cancer-associated genes with 154–168 clinically reported genes, as previously described. (Kadri, 2017) Somatic mutation calling was performed across all genes using a custom in-house bioinformatics pipeline as previously described. (Kadri, 2017) Variant review was performed by one of the authors (J.A.B.) and included filters based on population variant frequencies (The 1000 GenomesProject, https://www.internationalgenome.org/), variant frequencies in cancer databases (COSMIC: Catalogue of Somatic Mutations in Cancer, https://cancer.sanger.ac.uk/cosmic and cBioPortal, https://www.cbioportal.org/ ), and coding effects. Somatic variant calls were inspected using Integrated Genomics Viewer (IGV; Broad Institute, MIT Harvard, Cambridge, MA). Copy number results were calculated using a combination of CNVkit (Talevich, 2016) software and additional in-house intrarun normalization to eliminate run-specific artifacts by comparison with a pooled cohort of clinical controls. (Parilla, 2019) Gene-level changes were called using the UCM-OncoPlus clinical interpretation criteria as previously described. (Kadri, 2017) As part of the OncoPlus panel, a microsatellite instability detection module using data from 336 incidentally captured homopolymers across the 1005 captured genes was utilized as previously described. (Chapel, 2019) Tumors with ≥ 20 % unstable loci (≥15 or ≥ 18.5 for earlier versions) were classified as microsatellite-unstable (MSI) and the remainder as microsatellite-stable (MSS).
2.3. Statistics
Non-parametric descriptive statistics were performed to summarize the characteristics of the population. Kaplan-Meier method was used to estimate progression-free survival (PFS) and overall survival (OS). The log-rank test was applied to compare survival distributions across groups. All analysis was performed using R software (version 4.2.1).
3. Results
Cases initially classified as Gr3 EEC made up 16 % of cases recorded as stage I-III EEC in our cancer registry from 1992 to 2022. There were a total of thirty-four cases of Stage I – III Gr3 EEC in our study. Thirty-one cases both had a tissue block from the primary tumor available for review and were still identified as stage I-III Gr3 EEC after pathologic review (Fig. 1). Three additional cases that had been reclassified as Gr3 EEC during a pathologic review of endometrial cancers in Black women and had tissue available were also included. In the review of pathology cases in Black women, 180 cases were reviewed and the three cases that that were reclassified as G3 endometrioid adenocarcinoma were originally diagnosed as: carcinosarcoma, dedifferentiated carcinoma, and poorly differentiated adenocarcinoma. The total cohort of G3 cases included 13 patients who were Black, 18 White, and 3 other/unknown.
Of the 34 tumors included, 21 were stage I, 2 stage II and 11 stage III using the 2009 FIGO staging system (Abu-Rustum, 2011) (Table 1; Fig. 2); using the 2023 FIGO staging system (Berek, 2023) 6 were stage I, 16 were stage II and 11 were stage III (Table 1). There was no difference in stage at diagnosis by race (Table 1).
Table 1.
Cohort demographic and clinical characteristics.
| Allb N = 34 |
Black N = 13 |
White N = 18 |
Black vs White p-value |
|
|---|---|---|---|---|
| Age (years; median, IQRa) | 65 (57.2–70.5) | 69 (61–71) | 61.5 (54–66) | 0.12 |
| Never smoker [n (%)] | 27 (79.4 %) | 10 (76.9 %) | 15 (83.3 %) | 0.19 |
| BMI (kg/m2; median, IQR) | 32.0 (29.0–36.0) | 35.6 (29.6–41.2) | 31.8 (28.6–35.7) | 0.16 |
| Charlson Co-Morbidity Score(median(IQR) ) |
7.0 (4.0–9.8) |
8.0 (6.0–9.0) |
7.0 (3.2–10.0) |
0.64 |
| FIGO 2023 staging I II III |
6 (17.6 %)17 (50.0 %)11 (32.4 %) |
2 (15.4 %)7 (53.8 %)4 (30.8 %) |
3 (16.7 %)8 (44.4 %)7 (38.9 %) |
0.87 |
| FIGO 2009 staging I II III |
21 (61.8 %)2 (5.9 %)11 (32.4 %) |
9 (69.2 %)0 (0.0 %)4 (30.8 %) |
9 (50 %)2 (11.1 %)7 (38.9 %) |
0.36 |
| Surgical Staging Approach Open approach Minimally invasive approach |
9 (26.5 %)25 (73.5 %) |
5 (38.5 %)8 (61.5 %) |
3 (16.7 15 |
0.73 |
| Lymphadenectomy procedure Sentinel lymph node dissection Pelvic lymphadenecomy alone Pelvic and para-aoritic LND No lymph node dissection |
11 (32.4 %)2 (5.9 %)18 (52.9 %)3 (8.8 %) |
4 (30.8 %)1 (7.7 %)7 (53.8 %)1 (7.7 %) |
7 (38.9 %)1 (5.6 %)9 (50.0 %)1 (5.6 %) |
0.64 |
| TCGA Molecular Group POLE MSI CNL CNH |
6 (17.6 %)15 (44.1 %)3 (8.8 %)10 (29.4 %) |
2 (15.4 %)5 (38.5 %)2 (15.4 %)4 (30.8 %) |
3 (16.7 %)9 (50.0 %)1 (5.6 %)5 (27.8 %) |
0.80 |
| Year of diagnosis 2006–2012 2012–2018 2018–2022 |
7 (20.6 %)15 (44.1 %)12 (35.3 %) |
5 (38.5 %)4 (30.8 %)4 (30.8 %) |
1 (5.6 %)9 (50 %)8 (44.4 %) |
0.07 |
| Treatment received − primary Radiation therapy receipt Brachytherapy External Beam Radiation Chemotherapy receipt |
26 (76.5 %)21 (61.8 %)11 (32.4 %)15 (44.1 %) |
10 (76.9 %)9 (69.2 %)2 (15.4 %)5 (38.5 %) |
14 (77.8 %)10 (55.6 %)8 (44.4 %)10 (55.6 %) |
1.0 − − 0.57 |
| Recurrence Site of first recurrence Local/adjacent Distant |
8 (23.5 %) 4 (12.9 %)4 (12.9 %) |
4 (22.2 %) 2 (15.4 %)2 (15.4 %) |
4 (31.8 %) 2 (11 %)2 (11 %) |
0.87 |
IQR = interquartile range.
3 patients had race of “other” or “unknown” and are included in the ALL column.
Fig. 2.
Progression-free (2a, 2c) and overall survival (2b, 2d) for patients by FIGO 2009 stage (2a,2b) and TCGA molecular group (2c, 2d).
Black patients did not have an increased proportion of CNH tumors; there was no difference in the distribution of TCGA subtype by race. Neither did we see any difference in the level of HER2 expression by race (Table 2), although the only patient with a tumor expressing HER2 at the 3 + level (MSI and ERBB2 amplified on NGS) was Black.Table 3..
Table 2.
HER2 staining by Race and Molecular group.
| HER2 staining | 0 N = 6 |
1+ N = 11 |
2+ N = 13 |
3+ N = 1 |
||||
|---|---|---|---|---|---|---|---|---|
| Black N = 4 |
White N = 2 |
Black N = 5 |
White N = 6 | Black N = 3 |
White N = 10 |
Black N = 1 |
White N = 0 |
|
| Molecular Group | ||||||||
| POLE | 0 | 1 | 2 | 2 | 0 | 0 | 0 | 0 |
| MSI | 1 | 1 | 1 | 1 | 2 | 7 | 1 | 0 |
| CNH | 2 | 0 | 1 | 3 | 1 | 2 | 0 | 0 |
| CNL | 1 | 0 | 1 | 0 | 0 | 1 | 0 | 0 |
| Mismatch Repair Immunohistochemistry | ||||||||
| MMRd | 1 | 1 | 1 | 0 | 2 | 7 | 0 | 0 |
| MMRp | 0 | 0 | 2 | 4 | 1 | 1 | 0 | 0 |
| Unknown** | 3 | 1 | 2 | 2 | 0 | 2 | 1 | 0 |
*Of the 3 tumors from patients with race of other/unknown, one stained 0 (CNH/IHC MMRp), one stained 1+ (POLE/IHC not available) and one stained 2+ (MSI/IHC MMRd).
** Unknown = cases prior to *** did not have MMR immunohistochemistry (IHC) performed.
MMR = mismatch repair (MMR) proficient (p) or deficient (d).
Table 3.
Series of molecular classification in Gr3 EEC.
|
Series |
Year |
n |
Black n |
Stages (FIGO 2019) |
POLEm |
MMRd (or MSI) |
P53abn (or CNH) |
NSMP (or CNL) |
|---|---|---|---|---|---|---|---|---|
| Bosse (Bosse, 2018) | 2018 | 381 | n/a | all | 13 % | 36 % | 21 % | 30 % |
| Joehlin-Price (Consortium and R.r., 2022) | 2021 | 95 | n/a | all | 11 % | 37 % | 19 % | 27 % |
| Zammarelli (Horeweg, 2023) | 2022 | 75 | 11 | Ia/b | 32 % | 35 % | 20 % | 13 % |
| Cun (Casanova, 2024) | 2024 | 46 | 0 | Ib | 22 % | 39 % | 13 % | 26 % |
| Current | 34 | 13 | I-III | 17.6 % | 44 % | 29 % | 8.8 % |
In five cases, tumor from a recurrence was available for IHC. In three cases (two 2+, one 1 + ) staining of the recurrence was identical to staining of the primary tumor. The MSI tumor that initially stained 3 + in the hysterectomy showed no staining (0) in the recurrence; one CNH tumor that was initially 1 + had three successive recurrence samples that were 2+, 1+, and 0, respectively.
On NGS, there was no difference in the frequency by race of the most common potentially targetable tumor genomic mutations (PTEN, PIK3CA, ARID1A; Fig. 3). Five patients were noted to have a tumor BRCA2 mutation, of which 4 were Black and 1 was White. (Fig. 3) Complete data on mutations is given in supplementary Table 1.We saw no difference in rate of recurrence between Black and White patients.
Fig. 3.
Most common mutations by molecular subtype (Oncoprint).
4. Discussion
There were no differences in TCGA subtype, stage at presentation, or HER2 status by race in women with Stage I-III Gr3 EEC. Based on our limited data, differences in outcomes between Black and White women with EEC seem unlikely to be related to molecular differences by race in Gr3 EEC.
There have been several other small series examining NGS in Gr3 EEC. (Bosse, 2018, Cun, 2024, Zammarrelli, 2022, Joehlin-Price, 2021) Reports with mostly stage I disease noted 22–32 % of POLEmut tumors, consistent with our results. Most publications had very few Black patients, or none at all. The one other study that has reported on TCGA subtypes in Black patients separately (17 Black patients with Gr3 EEC) showed the results graphically without giving exact numbers but suggested a smaller percentage of CNL tumors amongst Black than White patients with Gr3 EEC. (Weigelt, 2023) Our series was remarkable for the low number of CNL tumors overall, which may be chance or a drift in pathologic assessment of grade 3 disease.
Our data support the broader use of NGS, particularly POLE testing, in early-stage Gr3 EEC. We found that 17.6 % of cases (and 28.6 % FIGO 2019 stage I cases) had POLE exonuclease domain mutations. As expected, patients whose tumors had POLE mutations had the best outcomes, with no recurrences [five were treated with radiation therapy, none with chemotherapy (Fig. 1)]. One of these also had a TP53 mutation (c916C > T). If TP53 status alone were to be used to select more aggressive treatment for Gr3 EEC, this is likely to result in overtreatment for those whose tumors have both POLE and TP53 mutations, who are expected to have a good prognosis. (Casanova, 2024) Moreover, while results of the RAINBO POLEmut-BLUE trial, which assigns women with stage I node negative POLEmut disease to no adjuvant therapy, are not yet available, it may be that even radiation represents overtreatment for women with POLE mutated stage I Gr3 EEC. (Horeweg, 2023, Consortium and R.r., 2022).
Only one tumor in our series exhibited 3 + HER2 expression. We had previously reported on a trial including women with metastatic endometrial cancer and found that 21 % of Gr3 EEC had HER2 amplification (Grushko, 2008, Santin, 2005) compared to only 3 % of Gr1 EEC and 2 % of Gr2 EEC. This discrepancy may be due to a propensity of HER2 3 + Gr3 EEC tumors to recur (hence enriching the levels of HER2 amplified tumor in series of metastatic disease). Krakstad et al recently reported on HER2 by IHC in a series of endometrial cancer patients from Norway (including stage IV disease and recurrences); amongst those with Gr 3 EEC overall, 33 % were 2 + and 23 % were 3 + . (Krakstad, 2024) It has been published that HER2 amplification is largely limited to p53-aberrant endometrial cancer, (Ross, 2022) but a recent study limited to p53 abnormal mismatch-repair proficient Gr3 EEC found only 4/59 cases (6.7 %) to be 3 + by IHC. (Santin, 2005) The one tumor that expressed HER2 at the 3 + level in our series was MSI, not CNH. HER2 expression at the 2 + level was common, seen in 14/34 (41 %) of tumors in our series. This is important as endometrial cancers with HER2 2 + expression may respond to some anti-HER2 antibody drug conjugates, (Meric-Bernstam, 2024) and a clinical trial testing trastuzumab deruxtecan in the adjuvant setting is awaited. The rate of 2 + staining was highest in MSI tumors (9/15); optimal adjuvant therapy for a group of tumors that could be targeted by both anti-HER2 therapy and immune checkpoint inhibitors remains to be determined. A limitation of our HER2 analysis was that we did not test for FISH amplification but instead used NGS, which can come from a heterologous sample, and which did not demonstrate ERBB2 expression in any of the HER2 2 + samples.
In breast cancer low levels of HER2 expression are known to be dynamic, with discordance in primary versus metastatic disease and in subsequent biopsies. (Anderson, 2023) We found no consistent change in the level of HER2 positivity on rebiopsy of metastatic lesions, although our sample size was small.
In our five BRCA2 mutations, three of them were in POLEmut tumors and one in a MSI tumor where they might be passenger mutations of limited importance, but one was in a CNL tumor, where such a finding might lead to use of targeted therapies. These findings are in line with those of Kopelman et al, who reported that BRCA2 mutations were found in 10 % of EEC in white patients and in 8.5 % of Black patients (all grades and stages combined). (Kopelman, 2024) Germline testing in the setting of such a finding could be considered, but the mutations are likely somatic, as BRCA2 germline mutations are not frequently associated with endometrial cancer. Gordhandas et al recently reported that only 11 of 1625 patients with endometrial cancer carried a germline BRCA2 mutation. (Gordhandas, 2023).
In conclusion, based on our results, any Black/White differences in cancer-specific outcomes in women with Gr3 EEC seem unlikely to be related to differences in frequency of TCGA subtype by race, at least amongst patients who present with stage I-III disease. Gr3 EEC is a very heterogeneous disease, and we believe our results support broader genomic testing in early stage Gr3 EEC as use of chemotherapy, radiotherapy and targeted agents will increasingly be depending on results of such testing.
CRediT authorship contribution statement
Sarah A. Ackroyd: Writing – original draft, Validation, Supervision, Project administration, Methodology, Investigation, Formal analysis, Data curation. Gabrielle Sudilovsky: Writing – review & editing, Methodology, Investigation, Data curation. Yan Che: Writing – review & editing, Validation, Software, Methodology, Data curation. Jennifer A. Bennett: Writing – review & editing, Methodology, Formal analysis, Data curation. S Diane Yamada: Writing – review & editing. Gini F Fleming: Writing – review & editing, Writing – original draft, Validation, Supervision, Project administration, Methodology, Investigation, Formal analysis, Conceptualization.
Acknowledgments
We gratefully acknowledge funding support from Judith L Sensibar.
We acknowledge support from core resources utilized at The University of Chicago which are supported by The University of Chicago Comprehensive Cancer Center Support Grant (P30CA014599), and The University of Chicago Human Tissue Resource Center (HTRC) for assistance with biospecimen banking, histology and immunohistochemistry study (RRID:SCR_019199); the Molecular & genomic Diagnostic Laboratory for assistance with next generation sequencing; and the biostatics core.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.gore.2025.101936.
Appendix A. Supplementary data
The following are the Supplementary data to this article:
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