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Original Articles
Target-Enhanced Whole-Genome Sequencing Shows Clinical Validity Equivalent to Commercially Available Targeted Oncology Panel
Sangmoon Lee, Jin Roh, Jun Sung Park, Islam Oguz Tuncay, Wonchul Lee, Jung-Ah Kim, Brian Baek-Lok Oh, Jong-Yeon Shin, Jeong Seok Lee, Young Seok Ju, Ryul Kim, Seongyeol Park, Jaemo Koo, Hansol Park, Joonoh Lim, Erin Connolly-Strong, Tae-Hwan Kim, Yong Won Choi, Mi Sun Ahn, Hyun Woo Lee, Seokhwi Kim, Jang-Hee Kim, Minsuk Kwon
Received February 3, 2024  Accepted September 12, 2024  Published online September 19, 2024  
DOI: https://doi.org/10.4143/crt.2024.114    [Epub ahead of print]
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Cancer poses a significant global health challenge, demanding precise genomic testing for individualized treatment strategies. Targeted-panel sequencing (TPS) has improved personalized oncology but often lacks comprehensive coverage of crucial cancer alterations. Whole-genome sequencing (WGS) addresses this gap, offering extensive genomic testing. This study demonstrates the medical potential of WGS.
Materials and Methods
This study evaluates target-enhanced WGS (TE-WGS), a clinical-grade WGS method sequencing both cancer and matched normal tissues. Forty-nine patients with various solid cancer types underwent both TE-WGS and TruSight Oncology 500 (TSO500), one of the mainstream TPS approaches.
Results
TE-WGS detected all variants reported by TSO500 (100%, 498/498). A high correlation in variant allele fractions was observed between TE-WGS and TSO500 (r=0.978). Notably, 223 variants (44.8%) within the common set were discerned exclusively by TE-WGS in peripheral blood, suggesting their germline origin. Conversely, the remaining subset of 275 variants (55.2%) were not detected in peripheral blood using the TE-WGS, signifying them as bona fide somatic variants. Further, TE-WGS provided accurate copy number profiles, fusion genes, microsatellite instability, and homologous recombination deficiency scores, which were essential for clinical decision-making.
Conclusion
TE-WGS is a comprehensive approach in personalized oncology, matching TSO500’s key biomarker detection capabilities. It uniquely identifies germline variants and genomic instability markers, offering additional clinical actions. Its adaptability and cost-effectiveness underscore its clinical utility, making TE-WGS a valuable tool in personalized cancer treatment.
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Harnessing Institutionally Developed Clinical Targeted Sequencing to Improve Patient Survival in Breast Cancer: A Seven-Year Experience
Jiwon Koh, Jinyong Kim, Go-Un Woo, Hanbaek Yi, So Yean Kwon, Jeongmin Seo, Jeong Mo Bae, Jung Ho Kim, Jae Kyung Won, Han Suk Ryu, Yoon Kyung Jeon, Dae-Won Lee, Miso Kim, Tae-Yong Kim, Kyung-Hun Lee, Tae-You Kim, Jee-Soo Lee, Moon-Woo Seong, Sheehyun Kim, Sungyoung Lee, Hongseok Yun, Myung Geun Song, Jaeyong Choi, Jong-Il Kim, Seock-Ah Im
Received March 23, 2024  Accepted August 18, 2024  Published online August 21, 2024  
DOI: https://doi.org/10.4143/crt.2024.296    [Epub ahead of print]
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Considering the high disease burden and unique features of Asian patients with breast cancer (BC), it is essential to have a comprehensive view of genetic characteristics in this population. An institutional targeted sequencing platform was developed through the Korea Research-Driven Hospitals project and was incorporated into clinical practice. This study explores the use of targeted next-generation sequencing (NGS) and its outcomes in patients with advanced/metastatic BC in the real world.
Materials and Methods
We reviewed the results of NGS tests administered to BC patients using a customized sequencing platform—FiRST Cancer Panel (FCP)—over 7 years. We systematically described clinical translation of FCP for precise diagnostics, personalized therapeutic strategies, and unraveling disease pathogenesis.
Results
NGS tests were conducted on 548 samples from 522 patients with BC. Ninety-seven point six percentage of tested samples harbored at least one pathogenic alteration. The common alterations included mutations in TP53 (56.2%), PIK3CA (31.2%), GATA3 (13.8%), BRCA2 (10.2%), and amplifications of CCND1 (10.8%), FGF19 (10.0%), and ERBB2 (9.5%). NGS analysis of ERBB2 amplification correlated well with human epidermal growth factor receptor 2 immunohistochemistry and in situ hybridization. RNA panel analyses found potentially actionable and prognostic fusion genes. FCP effectively screened for potentially germline pathogenic/likely pathogenic mutation. Ten point three percent of BC patients received matched therapy guided by NGS, resulting in a significant overall survival advantage (p=0.022), especially for metastatic BCs.
Conclusion
Clinical NGS provided multifaceted benefits, deepening our understanding of the disease, improving diagnostic precision, and paving the way for targeted therapies. The concrete advantages of FCP highlight the importance of multi-gene testing for BC, especially for metastatic conditions.
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Lung and Thoracic cancer
Association of TP53 Mutation Status and Sex with Clinical Outcome in Non–Small Cell Lung Cancer Treated with Immune Checkpoint Inhibitors: A Retrospective Cohort Study
Songji Choi, Se Hyun Kim, Sejoon Lee, Jeongmin Seo, Minsu Kang, Eun Hee Jung, Sang-A Kim, Koung Jin Suh, Ji Yun Lee, Ji-Won Kim, Jin Won Kim, Jeong-Ok Lee, Yu Jung Kim, Keun-Wook Lee, Jee Hyun Kim, Soo-Mee Bang, Jong Seok Lee
Cancer Res Treat. 2025;57(1):70-82.   Published online August 7, 2024
DOI: https://doi.org/10.4143/crt.2024.046
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Some studies suggest that TP53 mutations are associated with the response to immune checkpoint inhibitors (ICI) in patients with non–small cell lung cancer (NSCLC) and also contribute to sex disparities in several cancers. Thus, we hypothesized that TP53 mutations might serve as sex-dependent genomic biomarkers of ICI treatment response in patients with NSCLC.
Materials and Methods
Clinical data of 100 patients with metastatic NSCLC treated with ICI monotherapy at Seoul National University Bundang Hospital (SNUBH) were retrospectively reviewed. Genomic and clinical datasets of The Cancer Genome Atlas and an ICI-treated lung cancer cohort (cBioPortal) were also analyzed.
Results
In SNUBH cohort, no statistically significant difference was observed in the median progression-free survival (PFS) according to TP53 mutation status (p=0.930); however, female patients with TP53 mutations (MT) had a significantly prolonged median PFS compared to wild-type (WT) (6.1 months in TP53 MT vs. 2.6 months in TP53 WT; p=0.021). Programmed death-ligand 1 (PD-L1) high (≥ 50%) expression was significantly enriched in female patients with TP53 MT (p=0.005). The analysis from publicly available dataset also revealed that females with NSCLC with TP53 MT showed significantly longer PFS than those with TP53 WT (p < 0.001). In The Cancer Genome Atlas analysis, expression of immune-related genes, and tumor mutation burden score in TP53 MT females were higher than in males without TP53 MT.
Conclusion
Female patients with NSCLC with TP53 mutations had high PD-L1 expression and showed favorable clinical outcomes following ICI therapy, suggesting a need for further research to explore the role of TP53 mutations for sex disparities in response to ICI therapy.
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Review Article
Recent Advances in Genomic Approaches for the Detection of Homologous Recombination Deficiency
Yoo-Na Kim, Doga C. Gulhan, Hu Jin, Dominik Glodzik, Peter J. Park
Cancer Res Treat. 2024;56(4):975-990.   Published online July 17, 2024
DOI: https://doi.org/10.4143/crt.2024.154
AbstractAbstract PDFPubReaderePub
Accurate detection of homologous recombination deficiency (HRD) in cancer patients is paramount in clinical applications, as HRD confers sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. With the advances in genome sequencing technology, mutational profiling on a genome-wide scale has become readily accessible, and our knowledge of the genomic consequences of HRD has been greatly expanded and refined. Here, we review the recent advances in HRD detection methods. We examine the copy number and structural alterations that often accompany the genome instability that results from HRD, describe the advantages of mutational signature-based methods that do not rely on specific gene mutations, and review some of the existing algorithms used for HRD detection. We also discuss the choice of sequencing platforms (panel, exome, or whole-genome) and catalog the HRD detection assays used in key PARP inhibitor trials.
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Original Articles
Gastrointestinal cancer
Identification of New Pathogenic Variants of Hereditary Diffuse Gastric Cancer
Seung-Young Oh, Giyong Jang, Jaeryuk Kim, Kyoung-Yun Jeong, Hyun Myong Kim, Yoon Jin Kwak, Seong-Ho Kong, Do Joong Park, Hyuk-Joon Lee, Sung-Yup Cho, Jong-Il Kim, Han-Kwang Yang
Cancer Res Treat. 2024;56(4):1126-1135.   Published online April 11, 2024
DOI: https://doi.org/10.4143/crt.2024.328
AbstractAbstract PDFPubReaderePub
Purpose
Hereditary diffuse gastric cancer (HDGC) presents a significant genetic predisposition, notably linked to mutations in the CDH1 and CTNNA1. However, the genetic basis for over half of HDGC cases remains unidentified. The aim of this study is to identify novel pathogenic variants in HDGC and evaluate their protein expression.
Materials and Methods
Among 20 qualifying families, two were selected based on available pedigree and DNA. Whole genome sequencing (WGS) on DNA extracted from blood and whole exome sequencing on DNA from formalin-fixed paraffin-embedded tissues were performed to find potential pathogenic variants in HDGC. After selection of a candidate variant, functional validation, and enrichment analysis were performed.
Results
As a result of WGS, three candidate germline mutations (EPHA5, MCOA2, and RHOA) were identified in one family. After literature review and in-silico analyses, the RHOA mutation (R129W) was selected as a candidate. This mutation was found in two gastric cancer patients within the family. In functional validation, it showed RhoA overexpression and a higher GTP-bound state in the RhoaR129W mutant. Decreased phosphorylation at Ser127/397 suggested altered YAP1 regulation in the Rho-ROCK pathway. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses linked RhoaR129W overexpression to changed migration/adhesion in MKN1 cell line. However, this RHOA mutation (R129W) was not found in index patients in other families.
Conclusion
The RHOA mutation (R129W) emerges as a potential causative gene for HDGC, but only in one family, indicating a need for further studies to understand its role in HDGC pathogenesis fully.

Citations

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  • Current advances and challenges in Managing Hereditary Diffuse Gastric Cancer (HDGC): a narrative review
    L. van der Sluis, J.M. van Dieren, R.S. van der Post, T.M. Bisseling
    Hereditary Cancer in Clinical Practice.2024;[Epub]     CrossRef
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Hematologic malignancy
Feasibility of Circulating Tumor DNA Analysis in Patients with Follicular Lymphoma
Sang Eun Yoon, Seung-Ho Shin, Dae Keun Nam, Junhun Cho, Won Seog Kim, Seok Jin Kim
Cancer Res Treat. 2024;56(3):920-935.   Published online January 16, 2024
DOI: https://doi.org/10.4143/crt.2023.869
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
The feasibility of sequencing circulating tumor DNA (ctDNA) in plasma as a biomarker to predict early relapse or poor prognosis in patients with follicular lymphoma (FL) receiving systemic immunochemotherapy is not clear.
Materials and Methods
We sequenced DNA from cell-free plasma that was serially obtained from newly diagnosed FL patients undergoing systemic immunochemotherapy. The mutation profiles of ctDNA at the time of diagnosis and at response evaluation and relapse and/or progression were compared with clinical course and treatment outcomes.
Results
Forty samples from patients receiving rituximab-containing immunochemotherapy were analyzed. Baseline sequencing detected mutations in all cases, with the major detected mutations being KMT2C (50%), CREBBP (45%), and KMT2D (45%). The concentration of ctDNA and tumor mutation burden showed a significant association with survival outcome. In particular, the presence of mutations in CREBBP and TP53 showed poor prognosis compared with patients without them. Longitudinal analysis of ctDNA using serially collected plasma samples showed an association between persistence or reappearance of ctDNA mutations and disease relapse or progression.
Conclusion
Analysis of ctDNA mutations in plasma at diagnosis might help predict outcome of disease, while analysis during follow-up may help to monitor disease status of patients with advanced FL. However, the feasibility of ctDNA measurement must be improved in order for it to become an appropriate and clinically relevant test in FL patients.

Citations

Citations to this article as recorded by  
  • Feasibility of Circulating Tumor DNA Detection in the Cerebrospinal Fluid of Patients With Central Nervous System Involvement in Large B-Cell Lymphoma
    Seok Jin Kim, Jin Ju Kim, Mi Ri Park, Bon Park, Kyung Ju Ryu, Sang Eun Yoon, Won Seog Kim, Saeam Shin, Seung-Tae Lee
    Annals of Laboratory Medicine.2025; 45(1): 90.     CrossRef
  • Clinical applications of circulating tumor DNA in hematological malignancies: From past to the future
    Jun-Ying Li, Li-Ping Zuo, Jian Xu, Chun-Yan Sun
    Blood Reviews.2024; 68: 101237.     CrossRef
  • Molecular Biomarkers in Prediction of High-Grade Transformation and Outcome in Patients with Follicular Lymphoma: A Comprehensive Systemic Review
    Marie Hairing Enemark, Jonas Klejs Hemmingsen, Maja Lund Jensen, Robert Kridel, Maja Ludvigsen
    International Journal of Molecular Sciences.2024; 25(20): 11179.     CrossRef
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Lung and Thoracic cancer
Analytical and Clinical Validation of a Highly Sensitive NGS-Based ctDNA Assay with Real-World Concordance in Non–Small Cell Lung Cancer
Hanbaek Yi, Jeonghwan Youk, Yoojoo Lim, Hanseong Roh, Dongsoo Kyung, Hwang-Phill Kim, Duhee Bang, Bhumsuk Keam, Tae-Min Kim, Miso Kim, Dong-Wan Kim, Tae-You Kim
Cancer Res Treat. 2024;56(3):765-773.   Published online January 8, 2024
DOI: https://doi.org/10.4143/crt.2023.1294
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
There have been needs to improve the sensitivity of liquid biopsy. This report aims to report the analytical and clinical validation of a next-generation sequencing (NGS)–based circulating tumor DNA (ctDNA) assay.
Materials and Methods
Analytical validation was conducted in vitro by evaluating the limit of detection (LOD), precision, and specificity for various genomic aberrations. The real-world performance in non–small cell lung cancer (NSCLC) was assessed by comparing the results of AlphaLiquid100 to the tissue-based results.
Results
The LODs with 30 ng input DNA were 0.11%, 0.11%, 0.06%, 0.21%, and 2.13 copies for detecting single nucleotide variants, insertions, deletions, fusions, and copy number alterations (CNA), respectively. Quantitatively, single nucleotide variants/insertions and deletions, fusions, and CNAs showed a good correlation (R2=0.91, 0.40, and 0.65; y=0.95, 1.06, and 1.19) to the manufacturer’s values, and per-base specificities for all types of variants were near 100%. In real-world NSCLC (n=122), key actionable mutations in NSCLC were detected in 60.7% (74/122) with the ctDNA assay. Comparative analysis against the NGS-based tissue results for all key mutations showed positive percent agreement (PPA) of 85.3%. For individual genes, the PPA was as high as 95.7% for epidermal growth factor receptor (EGFR) mutations and 83.3% for ALK translocations. AlphaLiquid100 detected drug-sensitive EGFR mutation at a variant allele frequency as low as 0.02% and also identified an EGFR mutation in a case where tissue sample missed. Blood samples collected post-targeted therapies revealed additional acquired mutations.
Conclusion
The AlphaLiquid100 ctDNA assay demonstrates robust analytical validity, offering clinically important information for NSCLC patients.

Citations

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  • Next-generation sequencing impact on cancer care: applications, challenges, and future directions
    Mariano Zalis, Gilson Gabriel Viana Veloso, Pedro Nazareth Aguiar Jr., Nathalia Gimenes, Marina Xavier Reis, Silvio Matsas, Carlos Gil Ferreira
    Frontiers in Genetics.2024;[Epub]     CrossRef
  • Profiling Cell-Free DNA from Malignant Pleural Effusion for Oncogenic Driver Mutations in Patients with Treatment-Naive Stage IV Adenocarcinoma: A Multicenter Prospective Study
    Shih-Chieh Chang, Yu-Feng Wei, Chung-Yu Chen, Yi-Chun Lai, Po-Wei Hu, Jui-Chi Hung, Cheng-Yu Chang
    Molecular Diagnosis & Therapy.2024; 28(6): 803.     CrossRef
  • Concordance of ctDNA and tissue genomic profiling in advanced biliary tract cancer
    Sohyun Hwang, Seonjeong Woo, Beodeul Kang, Haeyoun Kang, Jung Sun Kim, Sung Hwan Lee, Chang Il Kwon, Dong Soo Kyung, Hwang-Phill Kim, Gwangil Kim, Chan Kim, Hong Jae Chon
    Journal of Hepatology.2024;[Epub]     CrossRef
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Tissue and Plasma-Based Highly Sensitive Blocker Displacement Amplicon Nanopore Sequencing for EGFR Mutations in Lung Cancer
Patinya Akkhasutthikun, Pornchai Kaewsapsak, Pattaraporn Nimsamer, Pavit Klomkliew, Suthida Visedthorn, Pragwalai Chanchaem, Chinachote Teerapakpinyo, Sunchai Payungporn, Sutima Luangdilok
Cancer Res Treat. 2024;56(2):455-463.   Published online November 20, 2023
DOI: https://doi.org/10.4143/crt.2023.1108
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
The epidermal growth factor receptor (EGFR) mutation is a widely prevalent oncogene driver in non–small cell lung cancer (NSCLC) in East Asia. The detection of EGFR mutations is a standard biomarker test performed routinely in patients with NSCLC for the selection of targeted therapy. Here, our objective was to develop a portable new technique for detecting EGFR (19Del, T790M, and L858R) mutations based on Nanopore sequencing.
Materials and Methods
The assay employed a blocker displacement amplification (BDA)–based polymerase chain reaction (PCR) technique combined with Nanopore sequencing to detect EGFR mutations. Mutant and wild-type EGFR clones were generated from DNA from H1650 (19Del heterozygous) and H1975 (T790M and L858R heterozygous) lung cancer cell lines. Then, they were mixed to assess the performance of this technique for detecting low variant allele frequencies (VAFs). Subsequently, formalin-fixed, paraffin-embedded (FFPE) tissue and cell-free DNA (cfDNA) from patients with NSCLC were used for clinical validation.
Results
The assay can detect low VAF at 0.5% mutant mixed in wild-type EGFR. Using FFPE DNA, the concordance rates of EGFR 19Del, T790M, and L858R mutations between our method and Cobas real-time PCR were 98.46%, 100%, and 100%, respectively. For cfDNA, the concordance rates of EGFR 19Del, T790M, and L858R mutations between our method and droplet digital PCR were 94.74%, 100%, and 100%, respectively.
Conclusion
The BDA amplicon Nanopore sequencing is a highly accurate and sensitive method for the detection of EGFR mutations in clinical specimens.

Citations

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  • Cancer liquid biopsies by Oxford Nanopore Technologies sequencing of cell-free DNA: from basic research to clinical applications
    Hua-Qi Si, Peng Wang, Fei Long, Wei Zhong, Yuan-Dong Meng, Yuan Rong, Xiang-Yu Meng, Fu-Bing Wang
    Molecular Cancer.2024;[Epub]     CrossRef
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Breast cancer
Short-term Impact of Hormone Replacement Therapy on Risk of Breast Cancer in BRCA Mutation Carriers: A Nationwide Study in South Korea
Hye Yeon Kim, Jisoo Park, Seok Joo Moon, Sohyeon Jeong, Jin Hwa Hong, Jae Kwan Lee, Geum Joon Cho, Hyun-Woong Cho
Cancer Res Treat. 2024;56(1):143-148.   Published online August 16, 2023
DOI: https://doi.org/10.4143/crt.2023.653
AbstractAbstract PDFPubReaderePub
Purpose
BRCA1/2 mutations are well-known risk factors for breast and ovarian cancers in women. Risk-reducing salpingo-oophorectomy (RRSO) is the standard treatment for preventing ovarian cancer with BRCA mutations. Postmenopausal syndrome (symptoms after RRSO can be alleviated by hormone replacement therapy (HRT); however, the use of HRT in carriers of BRCA mutations has been controversial because of the concern that HRT increases the risk of breast cancer. This study aimed to evaluate the effects of HRT in BRCA mutation carriers who underwent RRSO.
Materials and Methods
A total of 151 carriers, who underwent RRSO between 2013 and 2020 after the diagnosis of BRCA1 or BRCA2 mutations were selected and followed up for a median of 3.03 years. Patients were divided into two groups: those who received HRT after RRSO (n=33) and those who did not (n=118). We compared the incidence of breast cancer over time between these two groups.
Results
There was no significant difference in the incidence of breast cancer between women who received HRT and those who did not (p=0.229). Multivariate logistic regression analysis, adjusted for age and parity revealed no significant difference in the risk of breast cancer between these two groups (hazard ratio, 0.312; 95% confidence interval, 0.039 to 2.480; p=0.278).
Conclusion
In this study, we found no relationship between post-RRSO HRT and breast cancer in the population with BRCA mutations. Therefore, healthcare providers may consider the alleviation of symptoms of postmenopausal syndrome through HRT in patients who underwent RRSO.

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  • A contemporary review of breast cancer risk factors and the role of artificial intelligence
    Orietta Nicolis, Denisse De Los Angeles, Carla Taramasco
    Frontiers in Oncology.2024;[Epub]     CrossRef
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Rare cancer
Clinical Features of Li-Fraumeni Syndrome in Korea
Ran Song, Sun-Young Kong, Wonyoung Choi, Eun-Gyeong Lee, Jaeyeon Woo, Jai Hong Han, Seeyoun Lee, Han-Sung Kang, So-Youn Jung
Cancer Res Treat. 2024;56(1):334-341.   Published online August 9, 2023
DOI: https://doi.org/10.4143/crt.2023.794
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Li-Fraumeni syndrome (LFS) is a hereditary disorder caused by germline mutation in TP53. Owing to the rarity of LFS, data on its clinical features are limited. This study aimed to evaluate the clinical characteristics and prognosis of Korean patients with LFS.
Materials and Methods
Patients who underwent genetic counseling and confirmed with germline TP53 mutation in the National Cancer Center in Korea between 2011 and 2022 were retrospectively reviewed. Data on family history with pedigree, types of mutation, clinical features, and prognosis were collected.
Results
Fourteen patients with LFS were included in this study. The median age at diagnosis of the first tumor was 32 years. Missense and nonsense mutations were observed in 13 and one patients, respectively. The repeated mutations were p.Arg273His, p.Ala138Val, and pPro190Leu. The sister with breast cancer harbored the same mutation of p.Ala138Val. Seven patients had multiple primary cancers. Breast cancer was most frequently observed, and other types of tumor included sarcoma, thyroid cancer, pancreatic cancer, brain tumor, adrenocortical carcinoma, ovarian cancer, endometrial cancer, colon cancer, vaginal cancer, skin cancer, and leukemia. The median follow-up period was 51.5 months. Two and four patients showed local recurrence and distant metastasis, respectively. Two patients died of leukemia and pancreatic cancer 3 and 23 months after diagnosis, respectively.
Conclusion
This study provides information on different characteristics of patients with LFS, including types of mutation, types of cancer, and prognostic outcomes. For more appropriate management of these patients, proper genetic screening and multidisciplinary discussion are required.

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  • Consensus Statement: Recommendations on Actionable Biomarker Testing for Thyroid Cancer Management
    Ozgur Mete, Andrée Boucher, Kasmintan A. Schrader, Omar Abdel-Rahman, Houda Bahig, Cheryl Ho, Olfat Kamel Hasan, Bernard Lemieux, Eric Winquist, Ralph Wong, Jonn Wu, Nicole Chau, Shereen Ezzat
    Endocrine Pathology.2024; 35(4): 293.     CrossRef
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Lung and Thoracic cancer
Clinical Impact of Genomic and Pathway Alterations in Stage I EGFR-Mutant Lung Adenocarcinoma
Jae Seok Lee, Eun Kyung Kim, Kyung A Kim, Hyo Sup Shim
Cancer Res Treat. 2024;56(1):104-114.   Published online July 24, 2023
DOI: https://doi.org/10.4143/crt.2023.728
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
We investigated the clinical impact of genomic and pathway alterations in stage I epidermal growth factor receptor (EGFR)–mutant lung adenocarcinomas, which have a high recurrence rate despite complete surgical resection.
Materials and Methods
Out of the initial cohort of 257 patients with completely resected stage I EGFR-mutant lung adenocarcinoma, tumor samples from 105 patients were subjected to analysis using large-panel next-generation sequencing. We analyzed 11 canonical oncogenic pathways and determined the number of pathway alterations (NPA). Survival analyses were performed based on co-occurring alterations and NPA in three patient groups: all patients, patients with International Association for the Study of Lung Cancer (IASLC) pathology grade 2, and patients with recurrent tumors treated with EGFR–tyrosine kinase inhibitor (TKI).
Results
In the univariate analysis, pathological stage, IASLC grade, TP53 mutation, NPA, phosphoinositide 3-kinase pathway, p53 pathway, and cell cycle pathway exhibited significant associations with worse recurrence-free survival (RFS). Moreover, RPS6KB1 or EGFR amplifications were linked to a poorer RFS. Multivariate analysis revealed that pathologic stage, IASLC grade, and cell cycle pathway alteration were independent poor prognostic factors for RFS (p=0.002, p < 0.001, and p=0.006, respectively). In the grade 2 subgroup, higher NPA was independently associated with worse RFS (p=0.003). Additionally, in patients with recurrence treated with EGFR-TKIs, co-occurring TP53 mutations were linked to shorter progression-free survival (p=0.025).
Conclusion
Genomic and pathway alterations, particularly cell cycle alterations, high NPA, and TP53 mutations, were associated with worse clinical outcomes in stage I EGFR-mutant lung adenocarcinoma. These findings may have implications for risk stratification and the development of new therapeutic strategies in early-stage EGFR-mutant lung cancer patients.

Citations

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  • Stage-specific efficacy of osimertinib in treatment-naïve EGFR-mutant non-small cell lung cancer according to baseline genetic alterations in circulating tumor DNA
    Yoshihiko Taniguchi, Akihiro Tamiya, Mitsuo Osuga, Shun-ichi Isa, Keiichi Nakamura, Yasuyuki Mizumori, Tsutomu Shinohara, Hidetoshi Yanai, Katsumi Nakatomi, Masahide Oki, Masahide Mori, Tomohito Kuwako, Koji Yamazaki, Masahiro Shimada, Masahiko Ando, Yasu
    Investigational New Drugs.2025;[Epub]     CrossRef
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Lazertinib versus Gefitinib as First-Line Treatment for EGFR-mutated Locally Advanced or Metastatic NSCLC: LASER301 Korean Subset
Ki Hyeong Lee, Byoung Chul Cho, Myung-Ju Ahn, Yun-Gyoo Lee, Youngjoo Lee, Jong-Seok Lee, Joo-Hang Kim, Young Joo Min, Gyeong-Won Lee, Sung Sook Lee, Kyung-Hee Lee, Yoon Ho Ko, Byoung Yong Shim, Sang-We Kim, Sang Won Shin, Jin-Hyuk Choi, Dong-Wan Kim, Eun Kyung Cho, Keon Uk Park, Jin-Soo Kim, Sang Hoon Chun, Jangyoung Wang, SeokYoung Choi, Jin Hyoung Kang
Cancer Res Treat. 2024;56(1):48-60.   Published online June 27, 2023
DOI: https://doi.org/10.4143/crt.2023.453
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
This subgroup analysis of the Korean subset of patients in the phase 3 LASER301 trial evaluated the efficacy and safety of lazertinib versus gefitinib as first-line therapy for epidermal growth factor receptor mutated (EGFRm) non–small cell lung cancer (NSCLC).
Materials and Methods
Patients with locally advanced or metastatic EGFRm NSCLC were randomized 1:1 to lazertinib (240 mg/day) or gefitinib (250 mg/day). The primary endpoint was investigator-assessed progression-free survival (PFS).
Results
In total, 172 Korean patients were enrolled (lazertinib, n=87; gefitinib, n=85). Baseline characteristics were balanced between the treatment groups. One-third of patients had brain metastases (BM) at baseline. Median PFS was 20.8 months (95% confidence interval [CI], 16.7 to 26.1) for lazertinib and 9.6 months (95% CI, 8.2 to 12.3) for gefitinib (hazard ratio [HR], 0.41; 95% CI, 0.28 to 0.60). This was supported by PFS analysis based on blinded independent central review. Significant PFS benefit with lazertinib was consistently observed across predefined subgroups, including patients with BM (HR, 0.28; 95% CI, 0.15 to 0.53) and those with L858R mutations (HR, 0.36; 95% CI, 0.20 to 0.63). Lazertinib safety data were consistent with its previously reported safety profile. Common adverse events (AEs) in both groups included rash, pruritus, and diarrhoea. Numerically fewer severe AEs and severe treatment–related AEs occurred with lazertinib than gefitinib.
Conclusion
Consistent with results for the overall LASER301 population, this analysis showed significant PFS benefit with lazertinib versus gefitinib with comparable safety in Korean patients with untreated EGFRm NSCLC, supporting lazertinib as a new potential treatment option for this patient population.

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  • First-line treatment of EGFR-mutated non-small cell lung cancer with brain metastases: a systematic review and meta-analysis
    Jietao Ma, Xiaoxue Pang, Shuling Zhang, Letian Huang, Li Sun, Chengbo Han
    Scientific Reports.2024;[Epub]     CrossRef
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Clinical Validation of the Unparalleled Sensitivity of the Novel Allele-Discriminating Priming System Technology–Based EGFR Mutation Assay in Patients with Operable Non–Small Cell Lung Cancer
Il-Hyun Park, Dae-Soon Son, Yoon-La Choi, Ji-Hyeon Choi, Ji-Eun Park, Yeong Jeong Jeon, Minseob Cho, Hong Kwan Kim, Yong Soo Choi, Young Mog Shim, Jung Hee Kang, Suzy Park, Jinseon Lee, Sung-Hyun Kim, Byung-Chul Lee, Jhingook Kim
Cancer Res Treat. 2024;56(1):81-91.   Published online June 20, 2023
DOI: https://doi.org/10.4143/crt.2023.408
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Recently, we developed allele-discriminating priming system (ADPS) technology. This method increases the sensitivity of conventional quantitative polymerase chain reaction up to 100 folds, with limit of detection, 0.01%, with reinforced specificity. This prospective study aimed to develop and validate the accuracy of ADPS epidermal growth factor receptor (EGFR) Mutation Test Kit using clinical specimens.
Materials and Methods
In total 189 formalin-fixed paraffin-embedded tumor tissues resected from patients with non–small cell lung cancer were used to perform a comparative evaluation of the ADPS EGFR Mutation Test Kit versus the cobas EGFR Mutation Test v2, which is the current gold standard. When the two methods had inconsistent results, next-generation sequencing–based CancerSCAN was utilized as a referee.
Results
The overall agreement of the two methods was 97.4% (93.9%-99.1%); the positive percent agreement, 95.0% (88.7%-98.4%); and the negative percent agreement, 100.0% (95.9%-100.0%). EGFR mutations were detected at a frequency of 50.3% using the ADPS EGFR Mutation Test Kit and 52.9% using the cobas EGFR Mutation Test v2. There were 10 discrepant mutation calls between the two methods. CancerSCAN reproduced eight ADPS results. In two cases, mutant allele fraction was ultra-low at 0.02% and 0.06%, which are significantly below the limit of detection of the cobas assay and CancerSCAN. Based on the EGFR genotyping by ADPS, the treatment options could be switched in five patients.
Conclusion
The highly sensitive and specific ADPS EGFR Mutation Test Kit would be useful in detecting the patients who have lung cancer with EGFR mutation, and can benefit from the EGFR targeted therapy.

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  • Highly Sensitive 3D‐Nanoplasmonic‐Based Epidermal Growth Factor Receptor Mutation Multiplex Assay Chip for Liquid Biopsy
    Ji Young Lee, Byeong‐Ho Jeong, Ho Sang Jung, Taejoon Kang, Yeonkyung Park, Jin Kyung Rho, Sung‐Gyu Park, Min‐Young Lee
    Small Science.2024;[Epub]     CrossRef
  • The Advantage of Targeted Next-Generation Sequencing over qPCR in Testing for Druggable EGFR Variants in Non-Small-Cell Lung Cancer
    Adam Szpechcinski, Joanna Moes-Sosnowska, Paulina Skronska, Urszula Lechowicz, Magdalena Pelc, Malgorzata Szolkowska, Piotr Rudzinski, Emil Wojda, Krystyna Maszkowska-Kopij, Renata Langfort, Tadeusz Orlowski, Pawel Sliwinski, Mateusz Polaczek, Joanna Chor
    International Journal of Molecular Sciences.2024; 25(14): 7908.     CrossRef
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Gastrointestinal cancer
Specific Mutations in APC, with Prognostic Implications in Metastatic Colorectal Cancer
Huan Peng, Jun Ying, Jia Zang, Hao Lu, Xiaokai Zhao, Pengmin Yang, Xintao Wang, Jieyi Li, Ziying Gong, Daoyun Zhang, Zhiguo Wang
Cancer Res Treat. 2023;55(4):1270-1280.   Published online April 24, 2023
DOI: https://doi.org/10.4143/crt.2023.415
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Loss-of-function mutations in the adenomatous polyposis coli (APC) gene are common in metastatic colorectal cancer (mCRC). However, the characteristic of APC specific mutations in mCRC is poorly understood. Here, we explored the clinical and molecular characteristics of N-terminal and C-terminal side APC mutations in Chinese patients with mCRC.
Materials and Methods
Hybrid capture-based next-generation sequencing was performed on tumor tissues from 275 mCRC pati-ents to detect mutations in 639 tumor-associated genes. The prognostic value and gene-pathway difference between APC specific mutations in mCRC patients were analyzed.
Results
APC mutations were highly clustered, accounting for 73% of all mCRC patients, and most of them were truncating mutations. The tumor mutation burden of the N-terminal side APC mutations group (n=76) was significantly lower than that of the C-terminal side group (n=123) (p < 0.001), further confirmed by the public database. Survival analysis showed that mCRC patients with N-terminus side APC mutations had longer overall survival than C-terminus side. Tumor gene pathway analysis showed that gene mutations in the RTK/RAS, Wnt and transforming growth factor β signaling pathways of the C-terminal group were significantly higher than those of the N-terminal group (p < 0.05). Additionally, KRAS, AMER1, TGFBR2, and ARID1A driver mutations were more common in patients with C-terminal side APC mutations.
Conclusion
APC specific mutations have potential function as mCRC prognostic biomarkers. There are obvious differences in the gene mutation patterns between the C-terminus and N-terminus APC mutations group, which may have certain guiding significance for the subsequent precise treatment of mCRC.

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  • Advances in Precision Medicine Approaches for Colorectal Cancer: From Molecular Profiling to Targeted Therapies
    Neelakanta Sarvashiva Kiran, Chandrashekar Yashaswini, Rahul Maheshwari, Sankha Bhattacharya, Bhupendra G. Prajapati
    ACS Pharmacology & Translational Science.2024; 7(4): 967.     CrossRef
  • Clinical implications of PD-L1 expression and pathway-related molecular subtypes in advanced Asian colorectal cancer patients
    Qingqing Qiu
    American Journal of Cancer Research.2024; 14(2): 796.     CrossRef
  • Mechanism of APC truncation involved in colorectal cancer tumorigenesis (Review)
    Tuya Wang, Jing Fu, Ye Huang, Chun Fu
    Oncology Letters.2024;[Epub]     CrossRef
  • 4,770 View
  • 231 Download
  • 3 Web of Science
  • 3 Crossref
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Lung and Thoracic cancer
Should We Perform Repeated Re-biopsy for the Detection of T790M Mutation?
Saerom Kim, Soo Han Kim, Jinmi Kim, Mi-Hyun Kim, Min Ki Lee, Jung Seop Eom
Cancer Res Treat. 2023;55(4):1190-1197.   Published online April 17, 2023
DOI: https://doi.org/10.4143/crt.2023.320
AbstractAbstract PDFPubReaderePub
Purpose
Epidermal growth factor receptor (EGFR) T790M mutations have been detected in the second or third rebiopsy, even if the T790M mutation was not identified in the first rebiopsy. This meta-analysis investigated the EGFR T790M mutation detection rates and its additional advantages with repeated rebiopsies.
Materials and Methods
We searched through the PubMed and EMBASE databases up to June 2022. Studies reporting rebiopsy to identify the EGFR T790M mutation in case of disease progression among patients with advanced non-small cell lung cancer and multiple rebiopsies were included. The quality of the included studies was checked using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool.
Results
Eight studies meeting the eligibility criteria, reporting 1,031 EGFR mutation–positive patients were selected. The pooled EGFR T790M mutation detection rate of the first and repeated rebiopsies were 0.442 (95% confidence interval [CI], 0.411 to 0.473; I2=84%; p < 0.01) and 0.465 (95% CI, 0.400 to 0.530; I2=69%; p < 0.01), respectively. Overall, the pooled detection rate of EGFR T790M mutation was 0.545 (95% CI, 0.513 to 0.576), which increased by 10.3% with repeated rebiopsies.
Conclusion
This meta-analysis identified that repeated rebiopsy increases the detection rate of EGFR T790M mutation by 10.3%, even if EGFR T790M mutation is not detected in the first rebiopsy. Our results indicate that the spatiotemporal T790M heterogeneity can be overcome with repeated rebiopsy.

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  • Clinical utility of repeated rebiopsy for EGFR T790M mutation detection in non-small cell lung cancer
    Eun Hye Lee, Se Hyun Kwak, Kyeong Yeon Kim, Chi Young Kim, Sang Hoon Lee, Seok-Jae Heo, Yoon Soo Chang, Eun Young Kim
    Frontiers in Oncology.2024;[Epub]     CrossRef
  • Repeated rebiopsy for detection of EGFR T790M mutation in patients with advanced-stage lung adenocarcinoma: Associated factors and treatment outcomes of Osimertinib
    Taeyun Kim, Junsu Choe, Sun Hye Shin, Byeong-Ho Jeong, Kyungjong Lee, Hojoong Kim, Se-Hoon Lee, Sang-Won Um, Hamidreza Montazeri Aliabadi
    PLOS ONE.2024; 19(9): e0310079.     CrossRef
  • Rebiopsie tumorale : quand ? pour qui ? pourquoi ? comment ?
    V. Fallet
    Revue des Maladies Respiratoires Actualités.2023; 15(2): 2S121.     CrossRef
  • 2,808 View
  • 203 Download
  • 2 Web of Science
  • 3 Crossref
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Genomic Characteristics and the Potential Clinical Implications in Oligometastatic Non–Small Cell Lung Cancer
Rongxin Liao, Kehong Chen, Jinjin Li, Hengqiu He, Guangming Yi, Mingfeng Huang, Rongrong Chen, Lu Shen, Xiaoyue Zhang, Zaicheng Xu, Zhenzhou Yang, Yuan Peng
Cancer Res Treat. 2023;55(3):814-831.   Published online January 12, 2023
DOI: https://doi.org/10.4143/crt.2022.1315
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Oligometastatic non–small cell lung cancer (NSCLC) patients have been increasingly regarded as a distinct group that could benefit from local treatment to achieve a better clinical outcome. However, current definitions of oligometastasis are solely numerical, which are imprecise because of ignoring the biological heterogeneity caused by genomic characteristics. Our study aimed to profile the molecular alterations of oligometastatic NSCLC and elucidate its potential difference from polymetastasis.
Materials and Methods
We performed next-generation sequencing to analyze tumors and paired peripheral blood from 77 oligometastatic and 21 polymetastatic NSCLC patients to reveal their genomic characteristics and assess the genetic heterogeneity.
Results
We found ERBB2, ALK, MLL4, PIK3CB, and TOP2A were mutated at a significantly lower frequency in oligometastasis compared with polymetastasis. EGFR and KEAP1 alterations were mutually exclusive in oligometastatic group. More importantly, oligometastasis has a unique significant enrichment of apoptosis signaling pathway. In contrast to polymetastasis, a highly enriched COSMIC signature 4 and a special mutational process, COSMIC signature 14, were observed in the oligometastatic cohort. According to OncoKB database, 74.03% of oligometastatic NSCLC patients harbored at least one actionable alteration. The median tumor mutation burden of oligometastasis was 5.00 mutations/Mb, which was significantly associated with smoking, DNA damage repair genes, TP53 mutation, SMARCA4 mutation, LRP1B mutation, ABL1 mutation.
Conclusion
Our results shall help redefine oligometastasis beyond simple lesion enumeration that will ultimately improve the selection of patients with real oligometastatic state and optimize personalized cancer therapy for oligometastatic NSCLC.

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  • Prognostic and Predictive Biomarkers of Oligometastatic NSCLC: New Insights and Clinical Applications
    Mandy Jongbloed, Martina Bortolot, Leonard Wee, Jarno W.J. Huijs, Murillo Bellezo, Rianne D.W. Vaes, Frank Aboubakar Nana, Koen J. Hartemink, Dirk K.M. De Ruysscher, Lizza E.L. Hendriks
    JTO Clinical and Research Reports.2024; 5(12): 100740.     CrossRef
  • Genomic characteristics of PD-L1-Induced resistance to EGFR-TKIs in lung adenocarcinoma
    Guangming Yi, Fanghao Cai, Liangzhong Liu, Rongxin Liao, Xuan Jiang, Zhenzhou Yang, Xiaoyue Zhang
    Future Oncology.2024; 20(40): 3477.     CrossRef
  • 4,442 View
  • 197 Download
  • 3 Web of Science
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General
Validation and Clinical Application of ONCOaccuPanel for Targeted Next-Generation Sequencing of Solid Tumors
Moonsik Kim, Changseon Lee, Juyeon Hong, Juhee Kim, Ji Yun Jeong, Nora Jee-Young Park, Ji-Eun Kim, Ji Young Park
Cancer Res Treat. 2023;55(2):429-441.   Published online November 25, 2022
DOI: https://doi.org/10.4143/crt.2022.891
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Targeted next-generation sequencing (NGS) is widely used for simultaneously detecting clinically informative genetic alterations in a single assay. Its application in clinical settings requires the validation of NGS gene panels. In this study, we aimed to validate a targeted hybridization capture-based DNA panel (ONCOaccuPanel) using the Illumina MiSeq sequencing platform. The panel allows the simultaneous detection of single-nucleotide variants (SNVs), insertions, deletions, and copy number changes of 323 genes and fusions of 17 genes in solid tumors.
Materials and Methods
We used 16 formalin-fixed paraffin-embedded (FFPE) tumor samples with previously known genetic mutations and one reference material (HD827) for validation. Moreover, we sequenced an additional 117 FFPE tumor samples to demonstrate the clinical utility of this panel.
Results
Validation revealed a 100% positive percentage agreement and positive predictive value for the detection of SNVs, insertions, deletions, copy number changes, fusion genes, and microsatellite instability–high types. We observed high levels of reproducibility and repeatability (R2 correlation coefficients=0.96-0.98). In the limit of detection assessment, we identified all clinically relevant genes with allele frequencies > 3%. Furthermore, the clinical application of ONCOaccuPanel using 117 FFPE samples demonstrated robust detection of oncogenic alterations. Oncogenic alterations and targetable genetic alterations were detected in 98.2% and 27.4% cases, respectively.
Conclusion
ONCOaccuPanel demonstrated high analytical sensitivity, reproducibility, and repeatability and is feasible for the detection of clinically relevant mutations in clinical settings.

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  • Primary Solid Pseudopapillary Tumor of the Ovary: A Case Report and Review of the Literature
    Juhun Lee, Seung Ho Song, In Hee Lee, Dong Ja Kim, Hyun Jung Lee
    Journal of Clinical Medicine.2024; 13(10): 2791.     CrossRef
  • Genome-scale mutational signature analysis in archived fixed tissues
    Bérénice Chavanel, François Virard, Vincent Cahais, Claire Renard, Cécilia Sirand, Kim M. Smits, Leo J. Schouten, Béatrice Fervers, Barbara Charbotel, Behnoush Abedi-Ardekani, Michael Korenjak, Jiri Zavadil
    Mutation Research - Reviews in Mutation Research.2024; 794: 108512.     CrossRef
  • Artificial intelligence algorithm for neoplastic cell percentage estimation and its application to copy number variation in urinary tract cancer
    Jinahn Jeong, Deokhoon Kim, Yeon-Mi Ryu, Ja-Min Park, Sun Young Yoon, Bokyung Ahn, Gi Hwan Kim, Se Un Jeong, Hyun-Jung Sung, Yong Il Lee, Sang-Yeob Kim, Yong Mee Cho
    Journal of Pathology and Translational Medicine.2024; 58(5): 229.     CrossRef
  • CDKN2A Homozygous Deletion Is a Stronger Predictor of Outcome than IDH1/2-Mutation in CNS WHO Grade 4 Gliomas
    Sang Hyuk Lee, Tae Gyu Kim, Kyeong Hwa Ryu, Seok Hyun Kim, Young Zoon Kim
    Biomedicines.2024; 12(10): 2256.     CrossRef
  • Risk prediction criteria for the primary hepatic perivascular epithelioid cell tumour family, including angiomyolipoma: analysis of 132 cases with a literature review
    Youngeun Yoo, Jihun Kim, In Hye Song
    Histopathology.2024;[Epub]     CrossRef
  • Comparison of immunohistochemistry and next-generation sequencing results in oncogenic PTEN missense mutations
    Moonsik Kim, Jinhee Kim, An Na Seo, Ji Yun Jeong, Nora Jee-Young Park, Gun Oh Chong, Dae Gy Hong, Ji Young Park
    Pathology - Research and Practice.2023; 251: 154879.     CrossRef
  • BRCA-mutated gastric adenocarcinomas are associated with chromosomal instability and responsiveness to platinum-based chemotherapy
    Ji Hyun Oh, Chang Ohk Sung, Hyung-Don Kim, Sung-Min Chun, Jihun Kim
    Journal of Pathology and Translational Medicine.2023; 57(6): 323.     CrossRef
  • Clinical Application of the Association between Genetic Alteration and Intraoperative Fluorescence Activity of 5-Aminolevulinic Acid during the Resection of Brain Metastasis of Lung Adenocarcinoma
    Hyeon Yeong Jeong, Won Jun Suh, Seung Hwan Kim, Taek Min Nam, Ji Hwan Jang, Kyu Hong Kim, Seok Hyun Kim, Young Zoon Kim
    Cancers.2023; 16(1): 88.     CrossRef
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Lung and Thoracic cancer
Real World Characteristics and Clinical Outcomes of HER2-Mutant Non–Small Cell Lung Cancer Patients Detected by Next-Generation Sequencing
Beung-Chul Ahn, Ye-Jeong Han, Hye Ryun Kim, Min Hee Hong, Byoung Chul Cho, Sun Min Lim
Cancer Res Treat. 2023;55(2):488-497.   Published online November 9, 2022
DOI: https://doi.org/10.4143/crt.2022.359
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
This study was conducted to investigate the clinical characteristics of patients with advanced non–small cell lung cancer (NSCLC) harboring human epidermal growth factor receptor 2 (HER2) mutations and to evaluate response to standard treatment and HER2-targeted agents.
Materials and Methods
Using tissue and/or blood next-generation sequencing, we identified 44 patients with NSCLC harboring HER2 mutations who were treated at Severance Hospital between December 2016 and February 2021. Clinical data, including patient characteristics, mutation status, incidence of metastasis for distant lesions, and response to chemotherapy, were retrospectively analyzed.
Results
The median age was 58 years, and 61% of the patients were female. Most patients (64%) were never-smokers. Adenocarcinoma was the most predominant subtype (98%). A total of 66% of the patients had extrathoracic metastatic lesions, and 32% had intracranial lesions at initial presentation. The median time to the development of brain metastasis was 15.6 months (range, 2.4 to 43.7). The most common type of HER2 mutation was 12 base pair in-frame insertion in exon 20, A775_G776insYVMA. Of the 44 patients, two had concomitant driver mutations, one with epidermal growth factor receptor (EGFR) mutation (V769M), and one with BRAF mutation (V600E). Patients treated with pemetrexed-based chemotherapy (75%) had an overall response rate (ORR) and progression-free survival (PFS) of 30% and 8.3 months (95% confidence interval [CI], 3.9 to 12.7), respectively. The ORR and PFS of HER2-targeted agent treated patients (14%) were 0.0% and 1.9 months (95% CI, 0.1 to 2.8), respectively.
Conclusion
Given its distinct characteristics and treatment responses, novel treatment strategies for HER2-mutant NSCLC should be developed promptly to improve survival outcomes of patients.

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  • Targeted therapy for older patients with an oncogene driven non-small cell lung cancer: Recommendations from a SIOG expert group
    L. Decoster, D.R. Camidge, J.A. Fletcher, A. Addeo, A. Greystoke, K. Kantilal, L.Bigay Game, R. Kanesvaran, F. Gomes
    Lung Cancer.2025; 200: 108087.     CrossRef
  • Prognostic factors in non-metastatic HER2 ‘low’ and HER2 ‘negative’ breast cancer: single institute experience
    Alper Türkel, Mutlu Doğan, Elif Sertesen, Cengiz Karaçin, Sultan Çiğdem Irkkan, Öztürk Ateş
    Wiener klinische Wochenschrift.2024; 136(11-12): 340.     CrossRef
  • Clinicopathologic and Molecular Characteristics of HER2 (ERBB2)-Altered Non–Small Cell Lung Cancer: Implications for Precision Medicine
    Yurimi Lee, Boram Lee, Yoon-La Choi, Dong-Wook Kang, Joungho Han
    Modern Pathology.2024; 37(6): 100490.     CrossRef
  • Current status and breakthroughs in treating advanced non-small cell lung cancer with EGFR exon 20 insertion mutations
    Meng Hu, Congying Zhong, Jiabing Wang, JinQin Chen, Tao Zhou
    Frontiers in Immunology.2024;[Epub]     CrossRef
  • Efficacy of chemotherapy plus immune checkpoint inhibitors in patients with non-small cell lung cancer who have rare oncogenic driver mutations: a retrospective analysis
    Teppei Yamaguchi, Junichi Shimizu, Reiko Matsuzawa, Naohiro Watanabe, Yoshitsugu Horio, Yutaka Fujiwara
    BMC Cancer.2024;[Epub]     CrossRef
  • Antibody–Drug Conjugates for the Treatment of Non-Small Cell Lung Cancer with Central Nervous System Metastases
    David J. H. Bian, Sara F. Cohen, Anna-Maria Lazaratos, Nathaniel Bouganim, Matthew Dankner
    Current Oncology.2024; 31(10): 6314.     CrossRef
  • Real-World Clinical Outcomes for Patients with EGFR and HER2 Exon 20 Insertion-Mutated Non-Small-Cell Lung Cancer
    Kelly Li, Ian Bosdet, Stephen Yip, Cheryl Ho, Janessa Laskin, Barbara Melosky, Ying Wang, Sophie Sun
    Current Oncology.2023; 30(8): 7099.     CrossRef
  • 5,980 View
  • 285 Download
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EGFR Mutation–Positive Unresectable Stage III Non-Squamous Lung Cancer Is Associated with a High Incidence of Brain Metastasis
Hongsik Kim, Sehhoon Park, Hyun Ae Jung, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Myung-Ju Ahn
Cancer Res Treat. 2023;55(2):498-505.   Published online October 4, 2022
DOI: https://doi.org/10.4143/crt.2022.388
AbstractAbstract PDFPubReaderePub
Purpose
The impact of epidermal growth factor receptor (EGFR) mutation in locally advanced non–small cell lung cancer (NSCLC) remains controversial. This study was conducted to investigate the clinical outcomes and recurrence patterns after definitive chemoradiotherapy (CRT) in patients with unresectable stage III non-squamous-cell lung cancer according to EGFR mutation status.
Materials and Methods
We retrospectively reviewed 604 patients with pathologically confirmed stage III NSCLC who were treated with definitive CRT and were examined for EGFR mutation at Samsung Medical Center, Korea, from January 2013 to December 2018. Among them, we identified 236 patients with stage III non-squamous-cell lung cancer who were treated with definitive CRT and were examined for EGFR mutation status. We analyzed the frequency of EGFR mutation, progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and recurrence pattern.
Results
Among 236 patients, EGFR mutation was detected in 71 patients (30.1%) and the median follow-up duration was 41.7 months. There were no significant differences in PFS (9.9 vs. 10.9 months, p=0.236), and ORR to CRT (93.0% vs. 90.3%, p=0.623) according to EGFR mutation status. However, the EGFR mutant group showed significantly higher recurrence (88.7% vs. 75.2%, p=0.022), distant metastasis (76.1% vs. 61.2%, p=0.036) rates, especially brain (38.0% vs. 12.7%, p < 0.001), and better median OS (59.2 vs. 41.3 months, p=0.037) compared with patients without EGFR mutation.
Conclusion
Patients with EGFR mutation–positive unresectable stage III non-squamous lung cancer exhibited higher recurrence and distant metastasis rates, especially brain metastasis.

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  • Prognostic Factors in Postoperative Brain Metastases Derive From Non-small Cell Lung Cancer: A Retrospective Analysis
    Haibin Chen, Liang Sun, Zhi Yang, Yuanyuan Qu, Nanyang Tong, Caixing Sun, Liang Xia
    Clinical Medicine Insights: Oncology.2024;[Epub]     CrossRef
  • Brain metastasis screening in the molecular age
    Joanna K Tabor, Amanda Onoichenco, Vinayak Narayan, A Gabriella Wernicke, Randy S D’Amico, Morana Vojnic
    Neuro-Oncology Advances.2023;[Epub]     CrossRef
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Breast cancer
Genomic Signatures from Clinical Tumor Sequencing in Patients with Breast Cancer Having Germline BRCA1/2 Mutation
Ju Won Kim, Hyo Eun Kang, Jimi Choi, Seung Gyu Yun, Seung Pil Jung, Soo Yeon Bae, Ji Young You, Yoon-Ji Choi, Yeul Hong Kim, Kyong Hwa Park
Cancer Res Treat. 2023;55(1):155-166.   Published online June 8, 2022
DOI: https://doi.org/10.4143/crt.2021.1567
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
BRCA1 and BRCA2 are among the most important genes involved in DNA repair via homologous recombination (HR). Germline BRCA1/2 (gBRCA1/2)-related cancers have specific characteristics and treatment options but conducting gBRCA1/2 testing and interpreting the genetic imprint are sometimes complicated. Here, we describe the concordance of gBRCA1/2 derived from a panel of clinical tumor tissues using next-generation sequencing (NGS) and genetic aspects of tumors harboring gBRCA1/2 pathogenic variants.
Materials and Methods
Targeted sequencing was performed using available tumor tissue from patients who underwent gBRCA1/2 testing. Comparative genomic analysis was performed according to gBRCA1/2 pathogenicity.
Results
A total of 321 patients who underwent gBRCA1/2 testing were screened, and 26 patients with gBRCA1/2 pathogenic (gBRCA1/2p) variants, eight patients with gBRCA1/2 variants of uncertain significance (VUS; gBRCA1/2v), and 43 patients with gBRCA1/2 wild-type (gBRCA1/2w) were included in analysis. Mutations in TP53 (49.4%) and PIK3CA (23.4%) were frequently detected in all samples. The number of single-nucleotide variants (SNVs) per tumor tissue was higher in the gBRCA1/2w group than that in the gBRCA1/2p group (14.81 vs. 18.86, p=0.278). Tumor mutation burden (TMB) was significantly higher in the gBRCA1/2w group than in the gBRCA1/2p group (10.21 vs. 13.47, p=0.017). Except for BRCA1/2, other HR-related genes were frequently mutated in patients with gBRCA1/2w.
Conclusion
We demonstrated high sensitivity of gBRCA1/2 in tumors analyzed by NGS using a panel of tumor tissues. TMB value and aberration of non-BRCA1/2 HR-related genes differed significantly according to gBRCA1/2 pathogenicity in patients with breast cancer.

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  • Clinico-Pathological Factors Determining Recurrence of Phyllodes Tumors of the Breast: The 25-Year Experience at a Tertiary Cancer Centre
    Baijaeek Sain, Arnab Gupta, Aruni Ghose, Sudip Halder, Vishal Mukherjee, Samir Bhattacharya, Radha Raman Mondal, Aditya Narayan Sen, Bijan Saha, Shravasti Roy, Stergios Boussios
    Journal of Personalized Medicine.2023; 13(5): 866.     CrossRef
  • 6,336 View
  • 206 Download
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Lung and Thoracic cancer
The Feasibility of Using Biomarkers Derived from Circulating Tumor DNA Sequencing as Predictive Classifiers in Patients with Small-Cell Lung Cancer
Yu Feng, Yutao Liu, Mingming Yuan, Guilan Dong, Hongxia Zhang, Tongmei Zhang, Lianpeng Chang, Xuefeng Xia, Lifeng Li, Haohua Zhu, Puyuan Xing, Hongyu Wang, Yuankai Shi, Zhijie Wang, Xingsheng Hu
Cancer Res Treat. 2022;54(3):753-766.   Published online October 5, 2021
DOI: https://doi.org/10.4143/crt.2021.905
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
To investigate the feasibility of biomarkers based on dynamic circulating tumor DNA (ctDNA) to classify small cell lung cancer (SCLC) into different subtypes.
Materials and Methods
Tumor and longitudinal plasma ctDNA samples were analyzed by next-generation sequencing of 1,021 genes. PyClone was used to infer the molecular tumor burden index (mTBI). Pre-treatment tumor tissues [T1] and serial plasma samples were collected (pre-treatment [B1], after two [B2], six [B3] cycles of chemotherapy and at progression [B4]).
Results
Overall concordance between T1 and B1 sequencing (n=30) was 66.5%, and 89.5% in the gene of RB1. A classification method was designed according to the changes of RB1 mutation, named as subtype Ⅰ (both positive at B1 and B2), subtype Ⅱ (positive at B1 but negative at B2), and subtype Ⅲ (both negative at B1 and B2). The median progressive-free survival for subtype Ⅰ patients (4.5 months [95%CI: 2.6-5.8]) was inferior to subtype Ⅱ (not reached, p<0.0001) and subtype Ⅲ (10.8 months [95%CI: 6.0-14.4], p=0.002). The median overall survival for subtype Ⅰ patients (16.3 months [95%CI: 5.3-22.9]) was inferior to subtype Ⅱ (not reached, p=0.01) and subtype Ⅲ (not reached, p=0.02). Patients with a mTBI dropped to zero at B2 had longer median overall survival (not reached vs. 19.5 months, p=0.01). The changes of mTBI from B4 to B1 were sensitive to predict new metastases, with a sensitivity of 100% and a specificity of 85.7%.
Conclusion
Monitoring ctDNA based RB1 mutation and mTBI provided a feasible tool to predict the prognosis of SCLC.

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  • Cell-free and extrachromosomal DNA profiling of small cell lung cancer
    Roya Behrouzi, Alexandra Clipson, Kathryn L. Simpson, Fiona Blackhall, Dominic G. Rothwell, Caroline Dive, Florent Mouliere
    Trends in Molecular Medicine.2025; 31(1): 64.     CrossRef
  • Circulating tumor DNA as liquid biopsy in lung cancer: Biological characteristics and clinical integration
    Changshu Li, Jun Shao, Peiyi Li, Jiaming Feng, Jingwei Li, Chengdi Wang
    Cancer Letters.2023; 577: 216365.     CrossRef
  • Prognostic and predictive impact of molecular tumor burden index in non‐small cell lung cancer patients
    Fan Yang, Min Tang, Liang Cui, Jing Bai, Jiangyong Yu, Jiayi Gao, Xin Nie, Xu Li, Xuefeng Xia, Xin Yi, Ping Zhang, Lin Li
    Thoracic Cancer.2023; 14(31): 3097.     CrossRef
  • Genomic and Gene Expression Studies Helped to Define the Heterogeneity of Small-Cell Lung Cancer and Other Lung Neuroendocrine Tumors and to Identify New Therapeutic Targets
    Ugo Testa, Elvira Pelosi, Germana Castelli
    Onco.2022; 2(3): 186.     CrossRef
  • 6,772 View
  • 199 Download
  • 4 Web of Science
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Close layer
Integrin αvβ3 Induces HSP90 Inhibitor Resistance via FAK Activation in KRAS-Mutant Non-Small Cell Lung Cancer
Shinkyo Yoon, Hannah Yang, Hyun-Min Ryu, Eunjin Lee, Yujin Jo, Seyoung Seo, Deokhoon Kim, Chang Hoon Lee, Wanlim Kim, Kyung Hae Jung, Sook Ryun Park, Eun Kyung Choi, Sang-We Kim, Kang-Seo Park, Dae Ho Lee
Cancer Res Treat. 2022;54(3):767-781.   Published online September 30, 2021
DOI: https://doi.org/10.4143/crt.2021.651
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Heat shock protein-90 (HSP90) remains an important cancer target because of its involvement in multiple oncogenic protein pathways and biologic processes. Although many HSP90 inhibitors have been tested in the treatment of KRAS-mutant non–small cell lung cancer (NSCLC), most, including AUY922, have failed due to toxic effects and resistance generation, even though a modest efficacy has been observed for these drugs in clinical trials. In our present study, we investigated the novel mechanism of resistance to AUY922 to explore possible avenues of overcoming and want to provide some insights that may assist with the future development of successful next-generation HSP90 inhibitors.
Materials and Methods
We established two AUY922-resistant KRAS-mutated NSCLC cells and conducted RNA sequencing to identify novel resistance biomarker.
Results
We identified novel two resistance biomarkers. We observed that both integrin Av (ITGAv) and β3 (ITGB3) induce AUY922-resistance via focal adhesion kinase (FAK) activation, as well as an epithelial-mesenchymal transition, in both in vitro and in vivo xenograft model. mRNAs of both ITGAv and ITGB3 were also found to be elevated in a patient who had shown acquired resistance in a clinical trial of AUY922. ITGAv was induced by miR-142 downregulation, and ITGB3 was increased by miR-150 downregulation during the development of AUY922-resistance. Therefore, miR-150 and miR-142 overexpression effectively inhibited ITGAvB3-dependent FAK activation, restoring sensitivity to AUY922.
Conclusion
The synergistic co-targeting of FAK and HSP90 attenuated the growth of ITGAvB3-induced AUY922-resistant KRAS-mutated NSCLC cells in vitro and in vivo, suggesting that this combination may overcome acquired AUY922-resistance in KRAS-mutant NSCLC.

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  • Integrin αV Inhibition by GMI, a Ganoderma Microsporum Immunomodulatory Protein, Abolish Stemness and Migration in EGFR‐Mutated Lung Cancer Cells Resistant to Osimertinib
    Yu‐Ting Kang, Hui‐Yi Chang, Ya‐Chu Hsieh, Chia‐Hsuan Chou, I‐Lun Hsin, Jiunn‐Liang Ko
    Environmental Toxicology.2024; 39(12): 5238.     CrossRef
  • Junctional adhesion molecular 3 (JAM3) is a novel tumor suppressor and improves the prognosis in breast cancer brain metastases via the TGF-β/Smad signal pathway
    Kaitao Zhu, Shiwei Li, Hongru Yao, Jilong Hei, WenGuo Jiang, Tracey Martin, Shanyi Zhang
    Journal of Neuro-Oncology.2024; 170(2): 331.     CrossRef
  • Autophagy, molecular chaperones, and unfolded protein response as promoters of tumor recurrence
    Bashar Alhasan, Marina Mikeladze, Irina Guzhova, Boris Margulis
    Cancer and Metastasis Reviews.2023; 42(1): 217.     CrossRef
  • 8,901 View
  • 275 Download
  • 2 Web of Science
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General
Attitudes toward Risk-Reducing Mastectomy and Risk-Reducing Salpingo-oophorectomy among Young, Unmarried, Healthy Women in Korea
Boyoung Park, Dongwon Kim, Jiyoung Kim, Bom Yi Lee, Junghyun Yoon, Sung-Won Kim
Cancer Res Treat. 2022;54(2):375-382.   Published online August 9, 2021
DOI: https://doi.org/10.4143/crt.2021.449
AbstractAbstract PDFPubReaderePub
Purpose
This study investigated the attitudes toward risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO) as cancer prevention options for BRCA1/2 carriers in healthy, young, unmarried Korean women.
Materials and Methods
A nationally representative sample of 600 women, aged 20-39 years, completed a questionnaire on sociodemographic variables, preference for genetic testing, and intention to undergo risk-reducing surgeries after receiving information on the cancer risk of BRCA1/2 mutations and benefits of risk-reducing surgeries.
Results
A total of 54.7% and 57.7% had the intention to undergo RRM and RRSO, respectively, on the assumption that they were BRCA1/2 carriers. Older age and no intention to undergo genetic testing were associated with a reduced likelihood of undergoing RRM (odds ratio [OR], 0.30; 95% confidence interval [CI], 0.14 to 0.61 for age 35-39 years and OR, 0.35; 95% CI, 0.20 to 0.62 for no intention for genetic testing) and RRSO (OR, 0.39; 95% CI, 0.19 to 0.79 for age 35-39 years and OR, 0.30; 95% CI, 0.17 to 0.53 for no intention for genetic testing). Women who chose to be single were likely to undergo risk-reducing surgeries (OR, 1.67; 95% CI, 1.07 to 2.60 for RRM and OR, 1.56; 95% CI, 1.00 to 2.44 for RRSO).
Conclusion
More than 50% of healthy, unmarried, young Korean women were inclined to undergo prophylactic surgeries if they were BRCA1/2 mutation carriers. Further studies on decision-making process for cancer prevention in individuals at high risk for cancer need to be conducted.

Citations

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  • A Scoping Review of Primary Breast Cancer Risk Reduction Strategies in East and Southeast Asia
    Filipa Alpeza, Christine Kim Yan Loo, Qingyuan Zhuang, Mikael Hartman, Serene Si Ning Goh, Jingmei Li
    Cancers.2025; 17(2): 168.     CrossRef
  • Impact of graphical display on the intention to undergo risk-reducing salpingo-oophorectomy and mastectomy in individuals positive for BRCA pathogenic variant
    Yoon-Jung Choi, Younju Park, Boyoung Park, Heejung Chae, So-Youn Jung, Kum Hei Ryu, Myong Cheol Lim, Soo Jin Park, Yoon Jung Chang, Sun-Young Kong
    Scientific Reports.2024;[Epub]     CrossRef
  • 5,680 View
  • 166 Download
  • 2 Web of Science
  • 2 Crossref
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Lung and Thoracic cancer
Comparison of the Predictive Power of a Combination versus Individual Biomarker Testing in Non–Small Cell Lung Cancer Patients Treated with Immune Checkpoint Inhibitors
Hyojin Kim, Hyun Jung Kwon, Eun Sun Kim, Soohyeon Kwon, Kyoung Jin Suh, Se Hyun Kim, Yu Jung Kim, Jong Seok Lee, Jin-Haeng Chung
Cancer Res Treat. 2022;54(2):424-433.   Published online July 7, 2021
DOI: https://doi.org/10.4143/crt.2021.583
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Since tumor mutational burden (TMB) and gene expression profiling (GEP) have complementary effects, they may have improved predictive power when used in combination. Here, we investigated the ability of TMB and GEP to predict the immunotherapy response in patients with non–small cell lung cancer (NSCLC) and assessed if this combination can improve predictive power compared to that when used individually.
Materials and Methods
This retrospective cohort study included 30 patients with NSCLC who received immune checkpoint inhibitors (ICI) therapy at the Seoul National University Bundang Hospital. programmed cell death-ligand-1 (PD-L1) protein expression was assessed using immunohistochemistry, and TMB was measured by targeted deep sequencing. Gene expression was determined using NanoString nCounter analysis for the PanCancer IO360 panel, and enrichment analysis were performed.
Results
Eleven patients (36.7%) showed a durable clinical benefit (DCB), whereas 19 (63.3%) showed no durable benefit (NDB). TMB and enrichment scores (ES) showed significant differences between the DCB and NDB groups (p=0.044 and p=0.017, respectively); however, no significant correlations were observed among TMB, ES, and PD-L1. ES was the best single biomarker for predicting DCB (area under the curve [AUC], 0.794), followed by TMB (AUC, 0.679) and PD-L1 (AUC, 0.622). TMB and ES showed the highest AUC (0.837) among other combinations (AUC [TMB and PD-L1], 0.777; AUC [PD-L1 and ES], 0.763) and was similar to that of all biomarkers used together (0.832).
Conclusion
The combination of TMB and ES may be an effective predictive tool to identify patients with NSCLC patients who would possibly benefit from ICI therapies.

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  • Microdroplet-enhanced chip platform for high-throughput immunotherapy marker screening from extracellular vesicle RNAs and membrane proteins
    Chuanhao Tang, Zaizai Dong, Shi Yan, Bing Liu, Zhiying Wang, Long Cheng, Feng Liu, Hong Sun, Yimeng Du, Lu Pan, Yuhao Zhou, Zhiyuan Jin, Libo Zhao, Nan Wu, Lingqian Chang, Xiaojie Xu
    Biosensors and Bioelectronics.2025; 267: 116748.     CrossRef
  • Exploring the ferroptosis-related gene lipocalin 2 as a potential biomarker for sepsis-induced acute respiratory distress syndrome based on machine learning
    Jiayi Zhan, Junming Chen, Liyan Deng, Yining Lu, Lianxiang Luo
    Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease.2024; 1870(4): 167101.     CrossRef
  • Evaluation of Blood Tumor Mutation Burden for the Efficacy of Second-Line Atezolizumab Treatment in Non-Small Cell Lung Cancer: BUDDY Trial
    Cheol-Kyu Park, Ha Ra Jun, Hyung-Joo Oh, Ji-Young Lee, Hyun-Ju Cho, Young-Chul Kim, Jeong Eun Lee, Seong Hoon Yoon, Chang Min Choi, Jae Cheol Lee, Sung Yong Lee, Shin Yup Lee, Sung-Min Chun, In-Jae Oh
    Cells.2023; 12(9): 1246.     CrossRef
  • Unveiling the role of regulatory T cells in the tumor microenvironment of pancreatic cancer through single-cell transcriptomics and in vitro experiments
    Wei Xu, Wenjia Zhang, Dongxu Zhao, Qi Wang, Man Zhang, Qiang Li, Wenxin Zhu, Chunfang Xu
    Frontiers in Immunology.2023;[Epub]     CrossRef
  • Facilitating “Omics” for Phenotype Classification Using a User-Friendly AI-Driven Platform: Application in Cancer Prognostics
    Uraquitan Lima Filho, Tiago Alexandre Pais, Ricardo Jorge Pais
    BioMedInformatics.2023; 3(4): 1071.     CrossRef
  • Current state and challenges of emerging biomarkers for immunotherapy in hepatocellular carcinoma (Review)
    Mo Cheng, Xiufeng Zheng, Jing Wei, Ming Liu
    Experimental and Therapeutic Medicine.2023;[Epub]     CrossRef
  • 7,984 View
  • 221 Download
  • 12 Web of Science
  • 6 Crossref
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Acquired Resistance Mechanism of EGFR Kinase Domain Duplication to EGFR TKIs in Non–Small Cell Lung Cancer
Chaelin Lee, Miso Kim, Dong-Wan Kim, Tae Min Kim, Soyeon Kim, Sun-Wha Im, Yoon Kyung Jeon, Bhumsuk Keam, Ja-Lok Ku, Dae Seog Heo
Cancer Res Treat. 2022;54(1):140-149.   Published online May 3, 2021
DOI: https://doi.org/10.4143/crt.2021.385
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Epidermal growth factor receptor kinase domain duplication (EGFR-KDD) is a rare and poorly understood oncogenic mutation in non–small cell lung cancer (NSCLC). We aimed to investigate the acquired resistance mechanism of EGFR-KDD against EGFR-TKIs.
Materials and Methods
We identified EGFR-KDD in tumor tissue obtained from a patient with stage IV lung adenocarcinoma and established the patient-derived cell line SNU-4784. We also established several EGFR-KDD Ba/F3 cell lines: EGFR-KDD wild type (EGFR-KDDWT), EGFR-KDD domain 1 T790M (EGFR-KDDD1T), EGFR-KDD domain 2 T790M (EGFR-KDDD2T), and EGFR-KDD both domain T790M (EGFR-KDDBDT). We treated the cells with EGFR tyrosine kinase inhibitors (TKIs) and performed cell viability assays, immunoblot assays, and ENU (N-ethyl-N-nitrosourea) mutagenesis screening.
Results
In cell viability assays, SNU-4784 cells and EGFR-KDDWT Ba/F3 cells were sensitive to 2nd generation and 3rd generation EGFR TKIs. In contrast, the T790M-positive EGFR-KDD Ba/F3 cell lines (EGFR-KDDT790M) were only sensitive to 3rd generation EGFR TKIs. In ENU mutagenesis screening, we identified the C797S mutation in kinase domain 2 of EGFR-KDDBDT Ba/F3 cells. Based on this finding, we established an EGFR-KDD domain 1 T790M/domain 2 cis-T790M+C797S (EGFR-KDDT/T+C) Ba/F3 model, which was resistant to EGFR TKIs and anti-EGFR monoclonal antibody combined with EGFR TKIs.
Conclusion
Our study reveals that the T790M mutation in EGFR-KDD confers resistance to 1st and 2nd generation EGFR TKIs, but is sensitive to 3rd generation EGFR TKIs. In addition, we identified that the C797S mutation in kinase domain 2 of EGFR-KDDT790M mediates a resistance mechanism against 3rd generation EGFR TKIs.

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  • A Constitutive EGFR Kinase Dimer to Study Inhibitor Pharmacology
    Justin J. Kim, Ilse K. Schaeffner, David E. Heppner, Ciric To, Pasi A. Jänne, Tyler S. Beyett, Michael J. Eck
    Molecular Pharmacology.2024; 105(2): 97.     CrossRef
  • Tumor-associated Macrophages Mediate Gefitinib Resistance in Lung Cancer through HGF/c-met Signaling Pathway
    Xiali Tang, Yu Chen, Demin Jiao, Xiang Liu, Jun Chen, Yongyang Liu, Chunyan Jiang, Qingyong Chen
    Anti-Cancer Agents in Medicinal Chemistry.2024; 24(1): 30.     CrossRef
  • Colorectal cancer harboring EGFR kinase domain duplication response to EGFR tyrosine kinase inhibitors
    Tomohiro Kondo, Osamu Kikuchi, Yoshihiro Yamamoto, Tomohiko Sunami, Yafeng Wang, Keita Fukuyama, Tomoki Saito, Hideto Nakahara, Sachiko Minamiguchi, Masashi Kanai, Atsushi Sueyoshi, Manabu Muto
    The Oncologist.2024;[Epub]     CrossRef
  • Research progress on the role of bypass activation mechanisms in resistance to tyrosine kinase inhibitors in non-small cell lung cancer
    Ziyang Jiang, Zhihan Gu, Xiaomin Yu, Tao Cheng, Bofu Liu
    Frontiers in Oncology.2024;[Epub]     CrossRef
  • Molecular Targets and Mechanisms of Casein-Derived Tripeptides Ile-Pro-Pro and Val-Pro-Pro on Hepatic Glucose Metabolism
    Chenyang Wang, Lin Zheng, Mouming Zhao
    Journal of Agricultural and Food Chemistry.2023; 71(48): 18802.     CrossRef
  • Erlotinib

    Reactions Weekly.2022; 1907(1): 208.     CrossRef
  • 9,071 View
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Breast Cancer
Talazoparib Versus Chemotherapy in Patients with HER2-negative Advanced Breast Cancer and a Germline BRCA1/2 Mutation Enrolled in Asian Countries: Exploratory Subgroup Analysis of the Phase III EMBRACA Trial
Kyung-Hun Lee, Joohyuk Sohn, Annabel Goodwin, Tiziana Usari, Silvana Lanzalone, Seock-Ah Im, Sung-Bae Kim
Cancer Res Treat. 2021;53(4):1084-1095.   Published online March 24, 2021
DOI: https://doi.org/10.4143/crt.2020.1381
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
We evaluated study outcomes in patients enrolled in Asian regions in the phase III EMBRACA trial of talazoparib vs. chemotherapy.
Materials and Methods
Patients with human epidermal growth factor receptor 2–negative germline BRCA1/2-mutated advanced breast cancer who received prior chemotherapy were randomized 2:1 to talazoparib 1 mg/day or chemotherapy (physician’s choice). Primary endpoint was progression-free survival (PFS) per independent central review in the intent-to-treat (ITT) population. This post-hoc analysis evaluated efficacy/safety endpoints in the ITT population of patients enrolled in Asian regions.
Results
Thirty-three patients were enrolled at Asian sites (talazoparib, n=23; chemotherapy, n=10). Baseline characteristics were generally comparable with the overall EMBRACA population. In Asian patients, median PFS was 9.0 months (95% confidence interval [CI] 3.0, 15.2) for talazoparib and 7.1 months (95% CI, 1.2, not reached) for chemotherapy (hazard ratio [HR] 0.74 [95% CI, 0.22, 2.44]). Objective response rate was numerically higher for talazoparib vs. chemotherapy (62.5% [95% CI, 35.4, 84.8] vs. 25.0% [95% CI, 3.2, 65.1]). Median overall survival was 20.7 months (95% CI, 9.4, 40.1) versus 21.2 months (95% CI, 2.7, 35.0) months (HR, 1.41 [95% CI, 0.49, 4.05]). In Asian patients, fewer grade 3/4 adverse events (AEs), serious AEs (SAEs), grade 3/4 SAEs, and AEs resulting in dose reduction/discontinuation occurred with talazoparib than chemotherapy; for talazoparib, the frequency of these events was lower in Asian patients versus overall EMBRACA population.
Conclusion
In this subgroup analysis, talazoparib numerically improved efficacy versus chemotherapy and was generally well tolerated in Asian patients, with fewer grade 3/4 TEAEs, SAEs, and TEAEs leading to dose modification vs. the overall EMBRACA population.

Citations

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  • HR-positive/HER2-negative breast cancer arising in patients with or without BRCA2 mutation: different biological phenotype and similar prognosis
    Pu-Chun Li, Yi-Fan Zhu, Jia-Ni Pan, Qiao-Yan Zhu, Yu-Yang Liao, Xiao-Wen Ding, Lin-Feng Zheng, Wen-Ming Cao
    Therapeutic Advances in Medical Oncology.2024;[Epub]     CrossRef
  • Detection and analysis of the safety profile of talazoparib based on FAERS database
    Mufei Tang, Peiyan Liu, Linzhe Du, Yuanyuan Li, Jinjin Chen, Yang Li
    Expert Opinion on Drug Safety.2024; : 1.     CrossRef
  • Facing inevitable PARPis resistance: Mechanisms and therapeutic strategies for breast cancer treatment
    Haixia Liu, Xiaohui Chen, Yimin Jia, Hengyi Chen, Xiaohui Wang, Guoxiang Liu, Yang Luo
    Interdisciplinary Medicine.2023;[Epub]     CrossRef
  • Sustained delivery of PARP inhibitor Talazoparib for the treatment of BRCA-deficient ovarian cancer
    Shicheng Yang, Allen Green, Needa Brown, Alexis Robinson, Merline Senat, Bryanna Testino, Daniela M. Dinulescu, Srinivas Sridhar
    Frontiers in Oncology.2023;[Epub]     CrossRef
  • Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, staging and treatment of patients with metastatic breast cancer
    S.-A. Im, A. Gennari, Y.H. Park, J.H. Kim, Z.-F. Jiang, S. Gupta, T.H. Fadjari, K. Tamura, M.Y. Mastura, M.L.T. Abesamis-Tiambeng, E.H. Lim, C.-H. Lin, A. Sookprasert, N. Parinyanitikul, L.-M. Tseng, S.-C. Lee, P. Caguioa, M. Singh, Y. Naito, R.A. Hukom,
    ESMO Open.2023; 8(3): 101541.     CrossRef
  • Molecular Biology Mechanisms and Emerging Therapeutics of Triple-Negative Breast Cancer
    Zhiying Zhang, Rui Zhang, Donghai Li
    Biologics: Targets and Therapy.2023; Volume 17: 113.     CrossRef
  • Development of the PARP inhibitor talazoparib for the treatment of advanced BRCA1 and BRCA2 mutated breast cancer
    Evthokia A. Hobbs, Jennifer K. Litton, Timothy A. Yap
    Expert Opinion on Pharmacotherapy.2021; : 1.     CrossRef
  • 8,420 View
  • 270 Download
  • 6 Web of Science
  • 7 Crossref
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General
Pan-cancer Analysis of Tumor Mutational Burden and Homologous Recombination DNA Damage Repair Using Targeted Next-Generation Sequencing
Hai-Yun Wang, Ling Deng, Ying-Qing Li, Xiao Zhang, Ya-Kang Long, Xu Zhang, Yan-Fen Feng, Yuan He, Tao Tang, Xin-Hua Yang, Fang Wang
Cancer Res Treat. 2021;53(4):973-982.   Published online February 18, 2021
DOI: https://doi.org/10.4143/crt.2020.798
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Current variability in methods for tumor mutational burden (TMB) estimation and reporting demonstrates the urgent need for a homogeneous TMB assessment approach. Here, we compared TMB distributions in different cancer types using two customized targeted panels commonly used in clinical practice.
Materials and Methods
TMB spectra of 295- and 1021-gene panels in multiple cancer types were compared using targeted next-generation sequencing (NGS). The TMB distributions across a diverse cohort of 2,332 cancer cases were then investigated for their associations with clinical features. Treatment response data were collected for 222 patients who received immune-checkpoint inhibitors (ICIs) and their homologous recombination DNA damage repair (HR-DDR) and programmed death-ligand 1 (PD-L1) expression were additionally assessed and compared with the TMB and response rate.
Results
The median TMB between gene panels was similar despite a wide range in TMB values. The highest TMB was 8 and 10 in patients with squamous cell carcinoma and esophageal carcinoma according to the classification of histopathology and cancer types, respectively. Twenty-three out of 103 patients (22.3%) were HR-DDR‒positive and could benefit from ICI therapy; out of those 23 patients, seven patients had high TMB (p=0.004). Additionally, PD-L1 expression was not associated with TMB or treatment response among patients receiving ICIs.
Conclusion
Targeted NGS assays demonstrated the ability to evaluate TMB in pan-cancer samples as a tool to predict response to ICIs. In addition, TMB integrated with HR-DDR‒positive status could be a significant biomarker for predicting ICI response in patients.

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  • Comprehensive molecular findings in primary malignant melanoma of the esophagus: A multicenter study
    Ling Deng, Hai‐Yun Wang, Chun‐Fang Hu, Xiao‐Yun Liu, Kuntai Jiang, Juan‐Juan Yong, Xiao‐Yan Wu, Kai‐Hua Guo, Fang Wang
    Pigment Cell & Melanoma Research.2024; 37(3): 363.     CrossRef
  • Genomic Features of Homologous Recombination Deficiency in Breast Cancer: Impact on Testing and Immunotherapy
    Umer Ali, Sunitha Vungarala, Venkataswarup Tiriveedhi
    Genes.2024; 15(2): 162.     CrossRef
  • Biomarkers to predict efficacy of immune checkpoint inhibitors in colorectal cancer patients: a systematic review and meta-analysis
    Hang Yu, Qingquan Liu, Keting Wu, Shuang Tang
    Clinical and Experimental Medicine.2024;[Epub]     CrossRef
  • Clinical significance of genetic profiling based on different anatomic sites in patients with mucosal melanoma who received or did not receive immune checkpoint inhibitors
    Hai-Yun Wang, Ye Liu, Ling Deng, Kuntai Jiang, Xin-Hua Yang, Xiao-Yan Wu, Kai-Hua Guo, Fang Wang
    Cancer Cell International.2023;[Epub]     CrossRef
  • Homologous recombination repair gene mutations as a predictive biomarker for immunotherapy in patients with advanced melanoma
    Zhixuan You, Meng Lv, Xuanyu He, Yingqin Pan, Junfeng Ge, Xue Hu, Yating Zheng, Mengli Huang, Chengzhi Zhou, Changxuan You
    Frontiers in Immunology.2022;[Epub]     CrossRef
  • The role of DNA damage repair (DDR) system in response to immune checkpoint inhibitor (ICI) therapy
    Congqi Shi, Kaiyu Qin, Anqi Lin, Aimin Jiang, Quan Cheng, Zaoqu Liu, Jian Zhang, Peng Luo
    Journal of Experimental & Clinical Cancer Research.2022;[Epub]     CrossRef
  • Maximizing Small Biopsy Patient Samples: Unified RNA-Seq Platform Assessment of over 120,000 Patient Biopsies
    P. Sean Walsh, Yangyang Hao, Jie Ding, Jianghan Qu, Jonathan Wilde, Ruochen Jiang, Richard T. Kloos, Jing Huang, Giulia C. Kennedy
    Journal of Personalized Medicine.2022; 13(1): 24.     CrossRef
  • 7,700 View
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  • 7 Web of Science
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Lung cancer
A Phase II Trial of Osimertinib as the First-Line Treatment of Non–Small Cell Lung Cancer Harboring Activating EGFR Mutations in Circulating Tumor DNA: LiquidLung-O-Cohort 1
Cheol-Kyu Park, Hyun-Ju Cho, Yoo-Duk Choi, In-Jae Oh, Young-Chul Kim
Cancer Res Treat. 2021;53(1):93-103.   Published online September 21, 2020
DOI: https://doi.org/10.4143/crt.2020.459
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Osimertinib is a potent, irreversible third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor for both EGFR-activating and T790M resistant mutation. The treatment efficacy of osimertinib was assessed in previously untreated patients with metastatic non–small cell lung carcinoma (NSCLC) harboring activating EGFR mutations in circulating tumor DNA (ctDNA) as well as tumor DNA.
Materials and Methods
Patients with activating EGFR mutations in their tumor DNA underwent screening with ctDNA analysis using Mutyper and Cobas v2 assays. Enrolled subjects received osimertinib 80 mg, once daily. Primary endpoint was objective response rate (ORR) and secondary endpoints were ctDNA test sensitivity, progression-free survival (PFS), duration of response (DoR), and safety.
Results
Among 39 screened patients, 29 were ctDNA positive for activating EGFR mutations and 19 were enrolled (ex19del, n=11; L858R/L861Q, n=7; G719A, n=1). Median age was 70 and most patients had brain metastases (15/19, 79%). ctDNA test sensitivity for activating EGFR mutations was 74% using both methods and 62% (Mutyper) or 64% (Cobas v2) for individual methods. ORR was 68% (13/19), median PFS was 11.1 months (95% confidence interval [CI], 0.0 to 26.7), and median DoR was 17.6 months (95% CI, 3.5 to 31.7). ORR and median PFS were significantly superior with ex19del (91%; 21.9 months; 95% CI, 5.5 to 38.3) than with L858R/L861Q (43%; 5.1 months; 95% CI, 2.3 to 7.9). One patient discontinued the drug because of drug-related interstitial pneumonitis.
Conclusion
Osimertinib had favorable efficacy in the first-line treatment of metastatic NSCLC harboring activating EGFR mutations in ctDNA as well as tumor DNA.

Citations

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  • Non-small cell lung cancer: an update on emerging EGFR-targeted therapies
    Valentina Favorito, Ilaria Ricciotti, Andrea De Giglio, Laura Fabbri, Renata Seminerio, Alessandro Di Federico, Eleonora Gariazzo, Silvia Costabile, Giulio Metro
    Expert Opinion on Emerging Drugs.2024; 29(2): 139.     CrossRef
  • Identification and Application of Emerging Biomarkers in Treatment of Non-Small-Cell Lung Cancer: Systematic Review
    Juan Carlos Restrepo, Darly Martínez Guevara, Andrés Pareja López, John Fernando Montenegro Palacios, Yamil Liscano
    Cancers.2024; 16(13): 2338.     CrossRef
  • ctDNA SNORD3F Hypermethylation is a Prognostic Indicator in EGFR-TKI-Treated Advanced Non-Small Cell Lung Cancer
    Bin Liu, Bingtian Zhao, Yan Yin, Yan Jiang, Xue Feng, Lei Wang, Liang Zhai, Guangxin Liu, Dongsheng Shi, Jianwen Qin
    Cancer Management and Research.2024; Volume 16: 1405.     CrossRef
  • Can Liquid Biopsy Based on ctDNA/cfDNA Replace Tissue Biopsy for the Precision Treatment of EGFR-Mutated NSCLC?
    Yi-Ze Li, Sheng-Nan Kong, Yun-Peng Liu, Yue Yang, Hong-Mei Zhang
    Journal of Clinical Medicine.2023; 12(4): 1438.     CrossRef
  • Effect of Osimertinib on CTCs and ctDNA in EGFR Mutant Non-Small Cell Lung Cancer Patients: The Prognostic Relevance of Liquid Biopsy
    Galatea Kallergi, Emmanouil Kontopodis, Aliki Ntzifa, Núria Jordana-Ariza, Niki Karachaliou, Evangelia Pantazaka, Haris A. Charalambous, Amanda Psyrri, Emily Tsaroucha, Ioannis Boukovinas, Anna Koumarianou, Dora Hatzidaki, Evi Lianidou, Vassilis Georgouli
    Cancers.2022; 14(6): 1574.     CrossRef
  • 8,328 View
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  • 5 Web of Science
  • 5 Crossref
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Gynecologic cancer
Uptake of Family-Specific Mutation Genetic Testing Among Relatives of Patients with Ovarian Cancer with BRCA1 or BRCA2 Mutation
Go Woon Jeong, Wonkyo Shin, Dong Ock Lee, Sang-Soo Seo, Sokbom Kang, Sang-Yoon Park, Myong Cheol Lim
Cancer Res Treat. 2021;53(1):207-211.   Published online August 11, 2020
DOI: https://doi.org/10.4143/crt.2020.364
AbstractAbstract PDFPubReaderePub
Purpose
The BRCA1 or BRCA2 gene is transmitted in an autosomal dominant fashion, and genetic testing of first-degree relatives of patients with family-specific mutation (FSM) is recommended. This study examined factors affecting the uptake of FSM testing among relatives of patients with peritoneal, ovarian, or fallopian tube (POFT) cancer with confirmed BRCA1 or BRCA2 germline mutation.
Materials and Methods
Data from medical charts of 392 eligible patients and their relatives who had undergone outpatient genetic counseling/testing were retrospectively reviewed. Clinical factors were compared between family members who had and had not undergone genetic counseling/testing.
Results
The uptake of FSM testing was 30.5% (129/423) among first-degree living relatives and 53.5% (69/129) within the overall family unit. The average time from genetic testing of the proband to the first FSM test within a family was 168 days (range, 23 to 681 days). Having a living father (33.8% vs. 13.3%, p=0.007) and daughter (79.4% vs. 60.3%, p=0.019) increased the uptake of FSM testing. FSM testing was more likely among female than among male relatives of cancer patients (40.9% vs. 17.6%, p < 0.001).
Conclusion
Approximately one-third of first-degree relatives of patients with a POFT cancer with BRCA1 or BRCA2 mutation underwent FSM testing. Having a living father or daughter was a factor affecting the uptake of FSM testing, which was higher among female than among male relatives of the proband. This discrepancy might be due to a misconception that the BRCA gene is associated with women rather than with men.

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Germline and Somatic BRCA1/2 Gene Mutational Status and Clinical Outcomes in Epithelial Peritoneal, Ovarian, and Fallopian Tube Cancer: Over a Decade of Experience in a Single Institution in Korea
Se Ik Kim, Maria Lee, Hee Seung Kim, Hyun Hoon Chung, Jae-Weon Kim, Noh Hyun Park, Yong-Sang Song
Cancer Res Treat. 2020;52(4):1229-1241.   Published online July 27, 2020
DOI: https://doi.org/10.4143/crt.2020.557
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
This study aimed to present a single institutional experience with BRCA1/2 gene tests and the effects of pathogenic mutations in epithelial peritoneal, ovarian, and fallopian tube cancer (POFTC) on survival outcomes.
Materials and Methods
We identified patients with epithelial POFTCs who underwent BRCA1/2 gene testing by either germline or somatic methods between March 2007 and March 2020. Based on the BRCA1/2 test results, patients were divided into BRCA mutation and wild-type groups, followed by comparisons of clinicopathologic characteristics and survival outcomes after primary treatment.
Results
The annual number of POFTC patients who received BRCA1/2 gene tests increased gradually. In total, 511 patients were included and BRCA1/2 mutations were observed in 143 (28.0%). Among 57 patients who received both germline and somatic tests, three (5.3%) showed discordant results from the two tests. Overall, no differences in progression-free survival (PFS; p=0.467) and overall survival (p=0.641) were observed between the BRCA mutation and wild-type groups; however, multivariate analyses identified BRCA1/2 mutation as an independent favorable prognostic factor for PFS (adjusted hazard ratio [aHR], 0.765; 95% confidence interval [CI], 0.593 to 0.987; p=0.040). In 389 patients with International Federation of Gynecology and Obstetrics stage III-IV, different results were shown depending on primary treatment strategy: while BRCA1/2 mutation significantly improved PFS in the subgroup of neoadjuvant chemotherapy (aHR, 0.619; 95% CI, 0.385 to 0.995; p=0.048), it did not affect patient PFS in the subgroup of primary debulking surgery (aHR, 0.759; 95% CI, 0.530 to 1.089; p=0.135).
Conclusion
BRCA1/2 mutations are frequently observed in patients with epithelial POFTCs, and such patients showed better PFS than did those harboring wild-type BRCA1/2.

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