Cancer Research and Treatment

Original Articles

Gynecologic cancer

Frequency of Mismatch Repair Deficiency/High Microsatellite Instability and Its Role as a Predictive Biomarker of Response to Immune Checkpoint Inhibitors in Gynecologic Cancers: Joseph J. Noh, Min Kyu Kim, Min Chul Choi, Jeong-Won Lee, Hyun Park, Sang Geun Jung, Won Duk Joo, Seung Hun Song, Chan Lee; Cancer Res Treat. 2022;54(4):1200-1208. Published online December 13, 2021; DOI: https://doi.org/10.4143/crt.2021.828

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Purpose
This study was to investigate the frequency of mismatch repair deficiency/high microsatellite instability (MMRd/MSI-H) in gynecologic malignancies and the efficacy of immune checkpoint inhibitors (ICIs) in patients with recurrent gynecologic cancers according to MMR/MSI status.
Materials and Methods
We conducted a multi-center retrospective review on the patients who were diagnosed with gynecologic cancers between 2015 and 2020. Their clinicopathologic information, results of immunohistochemistry staining for MLH1/MSH2/MSH6/PMS2 and MSI analysis, tumor response to treatment with ICIs were investigated.
Results
Among 1,093 patients included in the analysis, MMRd/MSI-H was most frequent in endometrial/uterine cancers (34.8%, 164/471), followed by ovarian, tubal, and peritoneal cancers (12.8%, 54/422) and cervical cancer (11.3%, 21/186). When assessed by histology without regard for cancer types, the frequency of MMRd/MSI-H was 11.0% (38/345) in high-grade serous adenocarcinoma, 38.6% (117/303) in endometrioid adenocarcinoma, and 30.2% (16/53) in carcinosarcoma. A total of 114 patients were treated with ICIs at least once. The objective response rate (ORR) was 21.6% (8/37) in cervical cancer, 4.7% (2/43) in ovarian cancer, and 25.8% (8/31) in endometrial/uterine cancers. Univariate regression analysis identified MMRd/MSI-H as the only significant factor associated with the ORR (28.9% [11/38] vs. 11.8% [9/76]; odds ratio, 3.033; 95% confidence interval, 1.129–8.144; p=0.028).
Conclusion
The frequency of MMRd/MSI-H is moderate to high in gynecologic cancers in the Korean population. MMRd/MSI-H could be effective predictive biomarkers in gynecologic cancers of any type.

Citations

Citations to this article as recorded by

Immunotherapy plus chemotherapy in patients with advanced endometrial cancer: a cost-effectiveness analysis
Youwen Zhu, Kun Liu, Hong Zhu
Journal of Gynecologic Oncology.2025;[Epub] CrossRef
Cervical lymphoepithelioma-like carcinoma with deficient mismatch repair and loss of SMARCA4/BRG1: a case report and five related cases
Yu Miyama, Tomomi Kato, Masayasu Sato, Akira Yabuno, Kosei Hasegawa, Masanori Yasuda
Diagnostic Pathology.2024;[Epub] CrossRef
Prognostic factors of 87 ovarian yolk sac tumor (OYST) patients and molecular characteristics of persistent and recurrent OYST
Shanhui Liang, Huijuan Ge, Shuling Zhou, Jie Tang, Yanzi Gu, Xiaohua Wu, Jin Li
Gynecologic Oncology.2024; 187: 64. CrossRef
Immunotherapy in MMR-d/MSI-H recurrent/metastatic endometrial cancer
Renata Pacholczak-Madej, Michele Bartoletti, Lucia Musacchio, Mirosława Püsküllüoglu, Paweł Blecharz, Domenica Lorusso
Expert Review of Anticancer Therapy.2024; 24(8): 717. CrossRef
Expression patterns of mismatch repair proteins in cervical cancer uncover independent prognostic value of MSH-2
Madeleine Charlotte van den Berg, Hege F Berg, Tomasz Stokowy, Erling A Hoivik, Kathrine Woie, Hilde Engerud, Akinyemi I Ojesina, Ingfrid Salvesen Haldorsen, Jone Trovik, Bjørn I Bertelsen, Camilla Krakstad, Mari Kyllesø Halle, Janie Foote
International Journal of Gynecological Cancer.2024; 34(7): 993. CrossRef
Cervical cancer: a new era
Giuseppe Caruso, Matthew K Wagar, Heng-Cheng Hsu, Jorge Hoegl, Guido Martin Rey Valzacchi, Andreina Fernandes, Giuseppe Cucinella, Seda Sahin Aker, Aarthi S Jayraj, Jessica Mauro, Rene Pareja, Pedro T Ramirez
International Journal of Gynecological Cancer.2024; 34(12): 1946. CrossRef
Unraveling the Heterogeneity of Deficiency of Mismatch Repair Proteins in Endometrial Cancer: Predictive Biomarkers and Assessment Challenges
Filomena M. Carvalho, Jesus P. Carvalho
Cancers.2024; 16(20): 3452. CrossRef
Long-term benefit of immunotherapy in a patient with squamous lung cancer exhibiting mismatch repair deficient/high microsatellite instability/high tumor mutational burden: A case report and literature review
Na Li, Zixuan Wan, Dongyan Lu, Ruilian Chen, Xiaowei Ye
Frontiers in Immunology.2023;[Epub] CrossRef
Immune escape and resistance to immunotherapy in mismatch repair deficient tumors
Guillaume Mestrallet, Matthew Brown, Cansu Cimen Bozkus, Nina Bhardwaj
Frontiers in Immunology.2023;[Epub] CrossRef
Heterogeneous expression of mismatch repair proteins and interpretation of immunohistochemical results in colorectal cancer and endometrial cancer
Xiangzhao Li, Shifen Zhang, Jiamin Zeng, Sha-sha Song, Xiaoqing Liu, Wei Kang, Minyi Liang, Rui Yang, Hong Li, Li Liang
Pathology - Research and Practice.2023; 248: 154647. CrossRef
Rechallenge with Anti-PD-1 Inhibitors in Patients with Recurrent Gynecologic Malignancies
Migang Kim, Chi-Son Chang, Min Chul Choi, Jeong-Won Lee, Hyun Park, Won Duk Joo
Yonsei Medical Journal.2023; 64(10): 587. CrossRef
Successful neoadjuvant chemotherapy plus sintilimab for locally advanced cervical cancer: case series and review of the literature
Linlin Liu, Xianbo Deng, Shuang Guo, Shouhua Yang
Diagnostic Pathology.2023;[Epub] CrossRef
Adverse Effect of the Duration of Antibiotic Use Prior to Immune Checkpoint Inhibitors on the Overall Survival of Patients with Recurrent Gynecologic Malignancies
Hye-Ji Jung, Jong-Ho Park, Jina Oh, Sae-Mi Lee, Il-Yeo Jang, Jung-Yong Hong, Yoo-Young Lee, Hyun Jin Choi
Cancers.2023; 15(24): 5745. CrossRef
Uterine carcinosarcoma with microsatellite instability - does immunotherapy modify the therapeutic scenario? A case report and literature review
Diocesio Alves Pinto Andrade, Eduardo Paulino, Isabela Panzeri Carlotti Buzatto, Danilo Tadao Wada, Warne Pedro Andrade, Andreia Cristina Melo, Angelica Nogueira-Rodrigues
Brazilian Journal of Oncology.2023;[Epub] CrossRef
Immune checkpoint inhibitors in cervical cancer: Current status and research progress
Yunkai Xie, Weimin Kong, Xiaoling Zhao, He Zhang, Dan Luo, Shuning Chen
Frontiers in Oncology.2022;[Epub] CrossRef

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Clinical Impact of Somatic Variants in Homologous Recombination Repair-Related Genes in Ovarian High-Grade Serous Carcinoma: Min Chul Choi, Sohyun Hwang, Sewha Kim, Sang Geun Jung, Hyun Park, Won Duk Joo, Seung Hun Song, Chan Lee, Tae-Heon Kim, Haeyoun Kang, Hee Jung An; Cancer Res Treat. 2020;52(2):634-644. Published online January 6, 2020; DOI: https://doi.org/10.4143/crt.2019.207

Abstract PDF Supplementary Material PubReader ePub

Purpose
In this study, we investigated the frequencies of mutations in DNA damage repair genes including BRCA1, BRCA2, homologous recombination genes and TP53 gene in ovarian high-grade serous carcinoma, alongside those of germline and somatic BRCA mutations, with the aim of improving the identification of patients suitable for treatment with poly(ADP-ribose) polymerase inhibitors.
Materials and Methods
Tissue samples from 77 Korean patients with ovarian high-grade serous carcinoma were subjected to next-generation sequencing. Pathogenic alterations of 38 DNA damage repair genes and TP53 gene and their relationships with patient survival were examined. Additionally, we analyzed BRCA germline variants in blood samples from 47 of the patients for comparison.
Results
BRCA1, BRCA2, and TP53 mutations were detected in 28.6%, 5.2%, and 80.5% of the 77 patients, respectively. Alterations in RAD50, ATR, MSH6, MSH2, and FANCA were also identified. At least one mutation in a DNA damage repair gene was detected in 40.3% of patients (31/77). Germline and somatic BRCA mutations were found in 20 of 47 patients (42.6%), and four patients had only somatic mutations without germline mutations (8.5%, 4/47). Patients with DNA damage repair gene alterations with or without TP53mutation, exhibited better disease-free survival than those with TP53 mutation alone.
Conclusion
DNA damage repair genes were mutated in 40.3% of patients with high-grade serous carcinoma, with somatic BRCA mutations in the absence of germline mutation in 8.5%. Somatic variant examination, along with germline testing of DNA damage repair genes, has potential to detect additional candidates for PARP inhibitor treatment.

Citations

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Genomic instability in ovarian cancer: Through the lens of single nucleotide polymorphisms
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Clinica Chimica Acta.2025; 565: 119992. CrossRef
BRCA1, BRCA2, and TP53 germline and somatic variants and clinicopathological characteristics of Brazilian patients with epithelial ovarian cancer
Caroline Stahnke Richau, Nicole de Miranda Scherer, Bruna Palma Matta, Elvismary Molina de Armas, Fábio Carvalho de Barros Moreira, Anke Bergmann, Claudia Bessa Pereira Chaves, Mariana Boroni, Anna Claudia Evangelista dos Santos, Miguel Angelo Martins Mor
Cancer Medicine.2024;[Epub] CrossRef
Proteomic landscape of epithelial ovarian cancer
Liujia Qian, Jianqing Zhu, Zhangzhi Xue, Yan Zhou, Nan Xiang, Hong Xu, Rui Sun, Wangang Gong, Xue Cai, Lu Sun, Weigang Ge, Yufeng Liu, Ying Su, Wangmin Lin, Yuecheng Zhan, Junjian Wang, Shuang Song, Xiao Yi, Maowei Ni, Yi Zhu, Yuejin Hua, Zhiguo Zheng, Ti
Nature Communications.2024;[Epub] CrossRef
T-Cell Receptor Repertoire Characteristics Associated with Prognostic Significance in High-Grade Serous Ovarian Carcinoma
Ju-Won Kim, Sewha Kim, So-Yun Yang, Je-Gun Joung, Sohyun Hwang
Genes.2023; 14(4): 785. CrossRef
Potential prognostic role of somatic mutations in a set of cancer susceptibility genes in ovarian carcinoma: A follow-up multicentric study from Pakistan
Atika Masood, Rahat Sarfaraz, Saima Zaki, Amira Shami, Saba Khaliq, Nadia Naseem
Cancer Biomarkers.2023; 36(3): 207. CrossRef
Deleterious and ethnic-related BRCA1/2 mutations in tissue and blood of Egyptian colorectal cancer patients and its correlation with human papillomavirus
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Molecular Oncology.2022; 16(4): 860. CrossRef
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International Journal of Cancer.2022; 151(7): 1086. CrossRef
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Alexandre André Balieiro Anastácio da Costa, Glauco Baiocchi
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The Prognostic and Predictive Role of Somatic BRCA Mutations in Ovarian Cancer: Results from a Multicenter Cohort Study
Angela Toss, Claudia Piombino, Elena Tenedini, Alessandra Bologna, Elisa Gasparini, Vittoria Tarantino, Maria Elisabetta Filieri, Luca Cottafavi, Filippo Giovanardi, Stefano Madrigali, Monica Civallero, Luigi Marcheselli, Isabella Marchi, Federica Domati,
Diagnostics.2021; 11(3): 565. CrossRef
USP19 and RPL23 as Candidate Prognostic Markers for Advanced-Stage High-Grade Serous Ovarian Carcinoma
Haeyoun Kang, Min Chul Choi, Sewha Kim, Ju-Yeon Jeong, Ah-Young Kwon, Tae-Hoen Kim, Gwangil Kim, Won Duk Joo, Hyun Park, Chan Lee, Seung Hun Song, Sang Geun Jung, Sohyun Hwang, Hee Jung An
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Malwina Suszynska, Piotr Kozlowski
Genes.2020; 11(7): 798. CrossRef
Prevalence of pathogenic variants in actionable genes in advanced ovarian cancer: a next-generation sequencing analysis of a nationwide registry study
Sokbom Kang, Ye L. Yu, Soo Y. Cho, Seog-Yun Park
European Journal of Cancer.2020; 141: 185. CrossRef
PARP Inhibition Increases the Reliance on ATR/CHK1 Checkpoint Signaling Leading to Synthetic Lethality—An Alternative Treatment Strategy for Epithelial Ovarian Cancer Cells Independent from HR Effectiveness
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International Journal of Molecular Sciences.2020; 21(24): 9715. CrossRef

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Expression and Significance of c-erbB-2 in Radically Resected Colorectal Cancer: Hyun Cheol Chung, Sun Young Rha, Joon Oh Park, Seung Hun Song, Jae Yong Cho, Jung Bae Aha, Hye Ran Lee, Chong In Lee, Nae Choon Yoo, Joo Hang Kim, Jae Kyung Roh, Jin Sil Seong, Gwi Eon Kim, Jin Sik M; J Korean Cancer Assoc. 1995;27(3):389-403.

Abstract PDF: Overexpression of c-erbB-2 oncoprotein has been shown to correlate with poor prognosis and drug-resistance to the conventional chemotherapy with 5-fluorouracil in breast and gastric cancers. To evaluate the clinical significance of c-erbB-2 overexpreseion in colorectal cancer, immunohistochemical staining was performed with the paraffin-embedded tiasues of 141 colorectal cancer patients with curative surgery. The follow-up duration ranged from 7 to 61 months(median 30 months). Two-year disease- free and overall survival rate of the total patients were 77%, 91%, respectively. The c-erbB-2 positive rate was 24.8%, Even if patients with c-erbB-2 overexpression showed a tendency of poor prognosis than c-erbB-2 negative patients, T-factor and the TNM stage were independent prognostic factors in multivariate analysis. In subset analysis with c-erbB-2 negative patienta, there were no differences in recurrence rate and 2-year disease-free survival rate between pa- tients with chemotherapy and without chemotherapy(20.0% versus 26.1%)(80.0% versus 82.0%). However, in c-erbB-2 positive patients, those subgroup with chemotherapy showed tendencies toward advantages in relapse rate and 2-year disease-free survival rate than those of subgroup without chemotherapy(21.0% versus 50.0%; p=0.09)(76.0% versus 50.0%: p=0.06). Also, there was a tendency of increased time to relapse in patients with chemotherapy comparing to that of the patients without chemotherapy(7.5 months versus l7.0 months; p = 0.09). In stage III, patients with c-erbB-2 overexpression showed increased 2-year disease-free survival rate with chemotherapy as comparing to that of patients without chemotherapy(81.0% versus 29.0%; p= 0.003). Again, this survival benefit was not found in c-erbB-2 negative stage III patients regard- less of chemotherapy. In conclusion, c-erbB-2 overexyression might be a marker of relative drug resistance to 5-FU which will be converted with the high dose treatment of modulation with leucovorin. A prospective randomized trial is warrented to confirm this suggestion and for the clinical applica- tion of c-erbB-2 overexpression.

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