
==== Front
Discov Oncol
Discov Oncol
Discover Oncology
2730-6011
Springer US New York

39294393
1344
10.1007/s12672-024-01344-y
Research
Clinical characteristics and genomic profiling of outpatients with endometrial cancer at a Chinese tertiary cancer center
Feng Zheng 12
Wen Hao 12
Chen Yaqiong 23
Chen Xiaojun 12
Bi Rui 24
Wu Xiaohua wu.xh@fudan.edu.cn

12
Li Jin phenomena126@126.com

12
Ju Xingzhu xingzi_ju@163.com

12
1 https://ror.org/00my25942 grid.452404.3 0000 0004 1808 0942 Department of Gynecological Oncology, Fudan University Shanghai Cancer Center, 270 Dong-an Road, Shanghai, 200032 China
2 grid.11841.3d 0000 0004 0619 8943 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032 China
3 https://ror.org/00my25942 grid.452404.3 0000 0004 1808 0942 Department of Nursing, Fudan University Shanghai Cancer Center, Shanghai, 200032 China
4 https://ror.org/00my25942 grid.452404.3 0000 0004 1808 0942 Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032 China
18 9 2024
18 9 2024
12 2024
15 46117 6 2024
12 9 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Objective

Endometrial cancer is stepping into the era of precision therapy. Genomic test is recommended for newly diagnostic patients. However, outpatients displayed more complex characteristics. Here, we elucidated the clinical characteristics and genomic profiling of outpatients with endometrial cancer at our institution.

Methods

Between 2018 and 2023, 68 endometrial cancer received genomic tests at outpatient department of Fudan University Shanghai Cancer Center. Data, including age, pathological histology, FIGO stage and treatment strategy were collected. Germline mutations, molecular subtypes and other somatic mutations were also summarized.

Results

Overall, 72.1% (49/68) of patients receive genomic tests at primary diagnosis, while 27.9% (19/68) of patients received tests at recurrence. Nine patients had deleterious germline mutations, including BRCA1(2), MLH1(1), MSH2(2, including one with co-mutation of RAD50), MSH6(2), FANCA(1), MUTYH(1). Molecular subtypes were recognized among 62 patients, as POLE super-mutation(4, 6.5%), MSI-H(7, 11.3%), CN-Low(36, 58.1%) and CN-High(15, 24.2%). Ten patients received anti-PD1 monotherapy or in combination with chemotherapy or anti-angiogenic therapy, with the duration of disease control of 1 to 35 months. The ORR rate was 30%, and six patients had stable disease. The median (range) follow-up time was 18(2–160) months. 23(33.8%) relapses were recorded, and CN-High subtype displayed worst PFS compared with other subtypes (P < 0.01). 6 deaths were reported including 2(5.6%) of CN-Low and 4(26.7%) of CN-High.

Conclusion

Outpatients department gathered a considerable proportion of recurrent patients with complex genomic features. Patients with worse prognosis could be well studied, and anti-PD1 therapy was a promising salvage therapy in the real world.

Keywords

Endometrial cancer
Molecular subtype
Germline mutation
Anti-PD1 therapy
issue-copyright-statement© Springer Science+Business Media, LLC 2024
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pmcIntroduction

Endometrial cancer (EC) is one of the most common gynecological cancers around the world, and the incidence rates is increasing in China [1, 2]. Previously, the risk stratification of patients with EC was mainly based upon tumor stage/grade, and histological type. In 2013, the Cancer Genome Atlas (TCGA) has classified endometrial cancer into four molecular subgroups, including POLE super-mutation, microsatellite unstable (MSI-H), copy-number low (CN-Low) and copy-number high (CN-High), for the first time [3]. Patients with different molecular subtypes display distinct clinical features and outcomes. Thus, the risk stratification and corresponding adjuvant therapy has been adjusted based on both clinical characteristics and molecular classifications [4]. Besides, treatment of endometrial cancer is stepping into the era of precision therapy, especially for the development of immunotherapy [5–9].

Genomic profiling is encouraged at the initial evaluation of endometrial cancer patients [10]. Several studies focused on individualized treatment strategy for the newly diagnosed patients in the era of molecular classification [11–13]. Genomic profiling and clinical characteristics of consecutive EC patients has been reported among different ethnics [14–16]. For treatment naïve patients, systemic therapy including surgery, radiotherapy, chemotherapy or targeted therapy is always scheduled according to the clinical characteristics and molecular classification [17, 18]. However, outpatients displayed more complex characteristics, gathering more recurrent patients with complex treatments.

Here, we enrolled EC outpatients for genomic tests at our institution in the recent five years. The main aim of our study was to elucidate the clinical characteristics and genomic profiling of outpatients. While the study also presented treatment strategies and response of anti-PD1 therapy in the real world.

Methods

Patients and data collection

The data are anonymous, and the requirement for informed consent was therefore waived (Committee at Fudan University Shanghai Cancer Center, IRB number: 050432–4-1212B).

Between June 2018 and March 2023, 68 endometrial cancer patients who received genomic tests at outpatient department were enrolled. The pathological diagnoses were reviewed according to the WHO criteria by two experienced gynecological pathologists. Data, including age, pathological histology, FIGO stage and treatment strategy were collected. Progression-free survival (PFS) was defined as the time interval from the date of diagnosis to the date of disease progression or recurrence, or the date of last follow-up with no relapsed disease. Overall survival (OS) referred to the time interval from the date of primary diagnosis to the date of death or the last follow-up (May, 2023).

NGS analysis

DNA was extracted from FFPE and peripheral blood mononuclear cells (PBMCs) using the FFPE DNA Automated Extraction Kit (Accbio, Jaxing, China) and TIANamp Blood DNA kit (DP348, TIANGEN BITOCH CO.,LTD, Beijing, China), respectively. The purified DNA was then quantified using the StepOnePlus System and Qubit 3.0 Fluorometer (Life Technologies, Inc.). At least 50 ng of DNA extracted from matched PBMCs and tumor samples was sheared with the Covaris E210 system (Covaris, Inc.) to obtain an average of 200 bp fragments. We prepared NGS libraries of tumor gDNA and matched germline gDNA using the Accel-NGS 2S DNA Library Kit (Swift Biosciences, Inc.) and xGen Lockdown Probes kit (IDT, Inc.). The median coverage rate of the tumor DNA was 1800 × . Genome Analysis Toolkit (GATK) and ANNOVAR software tools were utilized to identify single nucleotide variation (SNV)/insertion and deletion (inDel) and annotate variants, respectively. Copy number variations were analyzed using CNVkit [19].

Germline variant interpretation

Variants identified in germline DNA from PBMCs with allele fraction (AF) beyond 25% were determined as germline variants. Variants with frequency ≥ 1% in ExAC, 1000 Genomes or ESP6500 databases were removed. The interpretation of germline alterations followed the standards and guidelines of American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) by two genetic counsellors independently [20].

Somatic genomic alterations (GAs) interpretation

Variants identified in the tumor samples with AF beyond 1% and were not identified as germline variants were identified as tumor somatic GAs. The functional classification of each somatic GAs was followed the interpretation and reporting standards and guidelines recommended by the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists (ASCO/CAP) [21]. Furthermore, the biological function and therapeutic implications of each GA was annotated using OncoKB database (http:// oncokb.org) which was granted recognition by the US Food and Drug Administration [22].

Analysis of the microsatellite instability (MSI)

MSI analysis was performed by mSINGS using 24 informative microsatellite regions integrated in the same targeted panel. We analyzed the concordance in MSI results of 87 samples between this method and MSI Analysis System (Promega) with the widely acknowledged mononucleotide repeat markers (BAT-25, BAT-26, NR-21, NR-24, and MONO-27). The accuracy of the panel-based MSI evaluation was 0.97.

TCGA molecular classification

Patients were categorized into four groups according to the TCGA classification system [3]. The presence of POLE gene hotspot mutations (P286R, V411L, S297F, S497F, and A456P) was classified as POLE super-mutation. For POLE wild-type samples, MSI-H has its priority in the subclassifications. For the rest samples, the presence of TP53 gene mutation was regarded as CN-High, while the absence of TP53 gene mutation was regarded as CN-Low.

Statistical analysis

We used SPSS software (version 21.0) and GraphPad Prism (version 9.0) for the statistical analyses. Demographic data were described as the medians with ranges or the frequencies with percentages. The PFS and OS were illustrated with the Kaplan–Meier curves. P < 0.05 was considered statistically significant, and all reported P values were 2-sided.

Results

Patient characteristics were shown in Table 1. The median (range) onset age of patients was 54 (33–77) years old. The majority of patients were stage I (43/68, 63.2%), while the proportion of FIGO stage II-IV was 33.8%. Endometroid carcinoma was the most common histology, including 23 with grade I, 22 with grade II and 9 with grade III. Serous carcinoma (7), clear cell carcinoma (2), carcinosarcoma (1) and undifferentiated carcinoma (4) were among the rest histologies. Table 1 Patient characteristics (N = 68)

Age at diagnosis	Median (range)	54 (33–77)	
FIGO stage	IA	37	54.4%	
IB	6	8.8%	
II	4	5.9%	
IIIA	4	5.9%	
IIIB	1	1.5%	
IIIC1	6	8.8%	
IIIC2	4	5.9%	
IV	4	5.9%	
Unknown	2	2.9%	
Histology	EC I	23	33.8%	
EC II	22	32.4%	
EC III	9	13.2%	
CCC	2	2.9%	
UCS	1	1.5%	
UPSC	7	10.3%	
Undifferentiated	4	5.9%	
Molecular subtype	POLE	4	5.9%	
MSI-H	7	10.3%	
CNL	36	52.9%	
CNH	15	22.1%	
Unknown	6	8.8%	
Time for genomic tests	Primary surgery	49	72.1%	
Recurrence	19	27.9%	
Adjuvant therapy	N	32	47.1%	
RT	3	4.4%	
RT + CT	7	10.3%	
CT	23	33.8%	
CT + Immunotherapy	1	1.5%	
Unknown	2	3.0%	
EC, endometroid carcinoma; CCC, clear cell carcinoma; UCS uterine carcinosarcoma; UPSC, uterine papillary serous carcinoma; CNL, copy number low; CNH, copy number high; RT, radiotherapy; CT, chemotherapy

Among the 68 patients, 6 patients had only germline genetic tests, while somatic tests were done in 62 patients (Fig. 1A). Nine patients had deleterious germline mutations, including BRCA1(2), MLH1(1), MSH2(2, including one with co-mutation of RAD50), MSH6(2), FANCA(1), MUTYH(1). Details for patients with deleterious germline mutations were shown in Table 2. The majority of these patients had family histories. Two patients with homologous repair recombination gene defects (BRCA1and FANCA) were subscribed to the CN-High group. Three patients diagnosed with Lynch syndrome were classified to the CN-Low group, considering MSS or MSI-Low status for the NGS tests. Another patient with MUTYH mutation were diagnosed with stage IA grade II endometroid carcinoma. However, her molecular subtype was CN-High, and she suffered relapse within 17 months and died within 48 months after multi-line therapies.Fig. 1 Flow diagram of patients and distribution of molecular subtypes

Table 2 List of patients with deleterious germline mutations

Gene	Age	Family history	Pathology	Molecular subtype	FIGO stage	Recurrence	PFS	Status	OS	
BRCA1	48	N	UPSC	CNH	IV	N	2	Alive	2	
BRCA1	50	Colon cancer	EC III	NA	IB	N	103	Alive	103	
MLH1	47	Colon cancer	EC I	NA	IA	N	58	Alive	58	
MSH2	54	Cancer of unknown origin	EC I	CNL	IA	N	9	Alive	9	
MSH2/RAD50	43	Colon cancer, ovarian cancer, lung cancer	Undifferentiated	MSI-H	IIIC1	N	43	Alive	43	
MSH6	48	N	EC I	CNL	IIIA	N	5	Alive	5	
MSH6	53	N	EC III	CNL	IA	N	15	Alive	15	
FANCA	59	Colon cancer	UCS	CNH	IA	N	10	Alive	10	
MUTYH	66	Stomach cancer, renal cancer	EC II	CNH	IA	Y	17	Dead	48	
CNL, copy number low; CNH, copy number high

Molecular subtypes in company with clinical characteristics were shown in Fig. 1B. Subgroup distributions were as follows: POLE super-mutation(4, 6.5%), MSI-H(7, 11.3%), CN-Low(36, 58.1%) and CN-High(15, 24.2%). The majority of patients in the POLE super-mutation and MSI-H groups were endometroid carcinoma with early stage. CN-High subgroup composed of patients with high-grade histologic types and advanced stage. The component of CN-Low was diverse. A large amount of patients were grade I or II endometroid carcinoma with early stage. While the rest of patients were high grade histologic types with early stage or low grade histology types with advanced stage.

More and more patients received genomic tests in the recent five years, and the proportion of tests at initial diagnosis is also increasing (Fig. 2A). Overall, 72.1% (49/68) of patients receive genomic tests at primary diagnosis, while 27.9% (19/68) of patients received tests at recurrence. At our last follow-up, 26 (38.2%) patients suffered from disease recurrence. The most common relapsed pattern was local recurrence (10/68, 14.7%), while lymph node metastasis (6/68, 8.8%) and hematological metastasis (4/68, 5.9%) ranked second and third, respectively (Fig. 2B).Fig. 2 Trends of genetic tests and patterns of recurrence

Ten patients received anti-PD1 monotherapy or in combination with chemotherapy or anti-angiogenic therapy, with the duration of disease control of 1 to 35 months (Table 3). The ORR rate was 30%, and 6 patients had stable disease. The median (range) follow-up time was 18 (2–160) months. 23(33.8%) recurrent events were recorded, and CN-High subtype displayed worst PFS compared with other subtypes (P < 0.01, Fig. 3). 6 deaths were reported including 2(5.6%) of CN-Low and 4(26.7%) of CN-High. Table 3 Characteristics and treatment outcomes of patients with anti-PD1 therapy

Patient	Age	FIGO stage	Histology	Molecular subtype	Treatment pattern	DDC (month)	Response	PFS	OS	
1	58	IA	EC I	MSI-H	PD1 + BEV	11	SD	20	56	
2	59	IA	EC II	CNH	PD1 + TKI	17	SD	60	108	
3	44	IA	EC I	CNL	PD1 + CT	1	PD	80	88	
4	61	IB	EC II	CNL	PD1 + TKI	4	SD	17	33	
5	66	IA	EC II	CNH	PD1	7	SD	17	48	
6	35	IV	EC I	CNL	PD1 + TKI	 > 35	CR	44	44	
7	61	IA	EC III	CNL	PD1 + CT	11	CR	21	61	
8	49	IA	EC I	CNL	PD1 + TKI	6	SD	28	50	
9	66	IA	CCC	CNL	PD1 + CT	 > 5	SD	5	13	
10	70	Unknown	Undifferentiated	CNH	PD1 + CT	 > 4	PR	12	16	
CNL, copy number low; CNH, copy number high; CT, chemotherapy; DDC, duration of disease control

Patient 6, 9, 10 continued anti-PD1 therapy at last follow-up

Fig. 3 Kaplan–Meier curves of PFS and OS stratified by molecular subgroups

Discussion

Endometrial cancer is stepping into the era of individualized treatment, and molecular classification is widely used in recent years. However, the management is quite complex in clinical application, especially at outpatient department. Here, we summarized the clinical characteristics and genomic profiling of outpatients with endometrial cancer.

Several patients required genetic counseling regarding the inherited genes. Lynch syndrome associated genes were the most frequent, with around 3% rates in literature [23]. The rate in our cohort was much higher, up to 7.4%. This may be due to the requirement of family histories. Homologous repair recombination gene defects were also important, and might indicate potential targeted therapies such as PARP inhibitors [24]. MUTYH gene mutation was also reported in our cohort. Although it is not well recognized, previous study reported life-time incidence risk of 3% for endometrial cancer [25].

Besides, outpatient department gathered patients with comprehensive situations, and the majority of patients seek for treatment strategies. Genetic tests were more acceptable for recurrent patients or patients with poor prognosis. Thus, our cohort consisted of a considerable proportion of advanced stage patients compared with other cohorts [16, 26]. In addition, more relapses were observed in our cohort. Salvage therapy and deaths were also recorded. Hence, the correlation of treatment response and molecular subtypes in the real world could be well illustrated.

Consistent with previous reports, around half of patients were in the CN-Low subgroup [11, 26]. However, the rate of MSI-H group was quite lower in our group, only 10% compared with 30% as reported. Although the prognosis in the CN-Low group is similar with that in the MSH-H group [3]. In our cohort, there were no significant differences between two groups regarding PFS, while the overall survival rate in the CN-Low group is lower than that in the MSI-H group. Patients with worse prognosis in the CN-Low group preferred genetic tests at follow-up, and this would lead to selection bias.

Immunotherapy is developing rapidly nowadays, and anti-PD1 therapy was recommended as first-line therapy for recurrent diseases [10]. In our cohort, patients always received anti-PD1 therapy as salvage therapy, and the ORR rate was 30%. This is consistent with previous reports, with ORR rates around 30% as monotherapy or in combination with other therapy [27–29]. Thus, anti-PD1 therapy was very promising in the real world.

Another issue should be mentioned was the correlation of MSI and deficiency of mismatch repair deficiency (dMMR). Previous studies reported the concordance rate over 98% [30, 31]. In our cohort, 1 patient with MSH2 mutation and 1 patient with MSH6 mutation were regarded as MSS via NGS analyses. While 1 patient with MSH6 mutation was regarded as MSI-Low. Heterogeneity of tumor or functional compensation by other molecular might be the underlying mechanism. Whether this discordance would influence response to immunotherapy was still unclear.

The limitation of our study was the small sample size with unreached statistical differences. Despite the limitation, our study illustrated the clinical pathological features of outpatients with endometrial cancer for the first time. Potential targeted genes and efficacy of anti-PD1 therapies were also analyzed.

In conclusion, our study gathered a considerable proportion of recurrent patients with complex genomic features. Patients with worse prognosis could be well studied, and anti-PD1 therapy was a promising salvage therapy in the real world.

Abbreviations

MSI-H Microsatellite unstable

CN-Low Copy-number low

CN-High Copy-number high

PFS Progression-free survival

OS Overall survival

Acknowledgements

We would like to thank all doctors, nurses, patients, and their family members for their kindness in supporting our study.

Author contributions

ZF, HW and YQC participated in the study design, collected and analyzed the data, and drafted the manuscript. RB participated in the pathological review of all slides. XJC collected the data and reviewed and edited the manuscript. XHW, JL and XZJ conceived the study and participated in its design and coordination. All authors read and approved the final manuscript.

Funding

None.

Data availability 

The institutional database contains sensitive patient information, which is available upon request. Anyone who is interested in this information should contact the corresponding authors at xingzi_ju@163.com.

Declarations

Ethics approval and consent to participate

This study was approved by the Committee at Fudan University Shanghai Cancer Center (IRB number: 050432–4-1212B) and conducted in accordance with the 1964 Helsinki Declaration and its amendments or comparable ethical standards. The data are anonymous, and the requirement for informed consent was therefore waived.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Zheng Feng, Hao Wen and Yaqiong Chen contributed equally to this work.
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