Cancer Research and Treatment

Original Articles

Breast cancer

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; Cancer Res Treat. 2025;57(2):443-456. Published online August 21, 2024; DOI: https://doi.org/10.4143/crt.2024.296

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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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Comprehensive analysis of FGFR2b and its correlation with essential biomarkers, intratumoral heterogeneity, and survival in advanced gastric cancer
Yoonjin Kwak, Tae-Yong Kim, Hye Seung Lee, Soo Kyung Nam, Hyeon Jeong Oh, Do-Youn Oh, Seock-Ah Im
British Journal of Cancer.2026;[Epub] CrossRef
Genomic and transcriptomic analyses of residual invasive triple-negative breast cancer after neoadjuvant chemotherapy in the prospective MIRINAE trial (a randomized phase II trial of adjuvant atezolizumab plus capecitabine compared to capecitabine; KCSG-B
S.-A. Im, K. Park, J. Koh, C. Park, K.H. Jung, J. Lee, H.K. Ahn, A. Lee, S.H. Sim, M.H. Kim, J.H. Kim, J.H. Kim, K.E. Lee, K.H. Park, J. Bae, M.H. Lee, S. Lim, H.J. Kim, D.-W. Lee, J.H. Jeong, K.S. Lee, J. Sohn, K.J. Suh, J.-Y. Kim, Y.J. Cha, J. Moon, C.-
ESMO Open.2025; 10(10): 105804. CrossRef

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Gastrointestinal cancer

Longitudinal Comparative Analysis of Circulating Tumor DNA and Matched Tumor Tissue DNA in Patients with Metastatic Colorectal Cancer Receiving Palliative First-Line Systemic Anti-Cancer Therapy: Seung-been Lee, Ji-Won Kim, Hong-Geun Kim, Sung-Hyun Hwang, Kui-Jin Kim, Ju Hyun Lee, Jeongmin Seo, Minsu Kang, Eun Hee Jung, Koung Jin Suh, Se Hyun Kim, Jin Won Kim, Yu Jung Kim, Jee Hyun Kim, Nak-Jung Kwon, Keun-Wook Lee; Cancer Res Treat. 2024;56(4):1171-1182. Published online April 29, 2024; DOI: https://doi.org/10.4143/crt.2024.016

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Purpose
This study aimed to compare tumor tissue DNA (ttDNA) and circulating tumor DNA (ctDNA) to explore the clinical applicability of ctDNA and to better understand clonal evolution in patients with metastatic colorectal cancer undergoing palliative first-line systemic therapy.
Materials and Methods
We performed targeted sequencing analysis of 88 cancer-associated genes using germline DNA, ctDNA at baseline (baseline-ctDNA), and ctDNA at progressive disease (PD-ctDNA). The results were compared with ttDNA data.
Results
Among 208 consecutively enrolled patients, we selected 84 (41 males; median age, 59 years; range, 35 to 90 years) with all four sample types available. A total of 202 driver mutations were found in 34 genes. ttDNA exhibited the highest mutation frequency (n=232), followed by baseline-ctDNA (n=155) and PD-ctDNA (n=117). Sequencing ctDNA alongside ttDNA revealed additional mutations in 40 patients (47.6%). PD-ctDNA detected 13 novel mutations in 10 patients (11.9%) compared to ttDNA and baseline-ctDNA. Notably, seven mutations in five patients (6.0%) were missense or nonsense mutations in APC, TP53, SMAD4, and CDH1 genes. In baseline-ctDNA, higher maximal variant allele frequency (VAF) values (p=0.010) and higher VAF values of APC (p=0.012), TP53 (p=0.012), and KRAS (p=0.005) mutations were significantly associated with worse overall survival.
Conclusion
While ttDNA remains more sensitive than ctDNA, our ctDNA platform demonstrated validity and potential value when ttDNA was unavailable. Post-treatment analysis of PD-ctDNA unveiled new pathogenic mutations, signifying cancer’s clonal evolution. Additionally, baseline-ctDNA’s VAF values were prognostic after treatment.

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Liquid biopsy in precision oncology: Current insights and future perspectives
Rajalakshmi Geetha, Subramania Iyer
Indian Journal of Precision Medicine and Molecular Medicine.2026; 2(1): 22. CrossRef
Metastatic Odyssey: Decoding the Genomic Journey from Primary Colorectal Cancer to Disseminated Disease
Taxiarchis Konstantinos Nikolouzakis, John Souglakos, Epameinondas Evangelos Kantidakis, Katerina Achilleos, Troye van Staden, Emmanuel Chrysos
Cancers.2026; 18(7): 1062. CrossRef
Precision-Guided Durable Response From Venetoclax With Decitabine in a Patient With a Metastatic Refractory IDH2 -Mutant Cholangiocarcinoma
Eylül Özgü, Ünal Metin Tokat, Ashkan Adibi, Şevval Nur Bilgiç, Esranur Aydın, Onur Tutar, Mutlu Demiray
JCO Precision Oncology.2025;[Epub] CrossRef
Evolution of Neo-RAS-WT in Circulating Tumor DNA from First-Line to Subsequent Therapies in Metastatic Colorectal Cancer
Marco Siringo, Michela De Meo, Irene Bottillo, Paola Grammatico, Enrico Cortesi, Chiara Nicolazzo, Paola Gazzaniga
Cancers.2025; 17(7): 1070. CrossRef
Liquid biopsy in gastrointestinal oncology: clinical applications and translational integration of ctDNA, CTCs, and sEVs
Rita Palieri, Maria De Luca, Francesco Balestra, Giorgia Panzetta, Claudio Lotesoriere, Federica Rizzi, Angela Dalia Ricci, Rita Mastrogiacomo, Maria Lucia Curri, Luigi Andrea Laghi, Gianluigi Giannelli, Nicoletta Depalo, Maria Principia Scavo
Oncology Reviews.2025;[Epub] CrossRef
Circulating Tumor DNA as a Biomarker for Precision Medicine in Prostate Cancer: A Systematic Review
Nouhaila Chanhih, Abdelilah Laraqui, Salma Hassine, Ahmed Ameur, Larbi Hamedoun, Hicham El Annaz, Rachid Abi, Mohamed Rida Tagajdid, Idriss Lahlou Amine, Khalid Ennibi, Abdelaziz Benjouad, Lamiae Belayachi
International Journal of Molecular Sciences.2025; 26(22): 11049. CrossRef

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Breast cancer

Prognostic Value of the Evolution of HER2-Low Expression after Neoadjuvant Chemotherapy: Youzhao Ma, Mingda Zhu, Jingyang Zhang, Minhao Lv, Xiuchun Chen, Zhenzhen Liu; Cancer Res Treat. 2023;55(4):1210-1221. Published online April 4, 2023; DOI: https://doi.org/10.4143/crt.2022.1633

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Purpose
Patients with human epidermal growth factor receptor 2 (HER2)–low advanced breast cancer can benefit from trastuzumab deruxtecan. Given the unclear prognostic characteristics of HER2-low breast cancer, we investigated the prognostic characteristics of HER2-low expression from primary tumor to residual disease after neoadjuvant chemotherapy (NACT).
Materials and Methods
The data of HER2-negative patients receiving NACT at our center were collected. Pathological complete response (pCR) rate were compared between HER2-0 and HER2-low patients. The evolution of HER2 expression from primary tumor to residual disease and its impact on disease-free survival (DFS) were examined.
Results
Of the 690 patients, 494 patients had HER2-low status, of which 72.3% were hormone receptor (HR)–positive (p < 0.001). The pCR rates of HER2-low and HER2-0 patients (14.2% vs. 23.0%) showed no difference in multivariate analysis regardless of HR status. No association was observed between DFS and HER2 status. Of the 564 non-pCR patients, 57 (10.1%) changed to HER2-positive, and 64 of the 150 patients (42.7%) with HER2-0 tumors changed to HER2-low. HER2-low (p=0.004) and HR-positive (p=0.010) tumors before NACT were prone to HER2 gain. HER2 gain patients had a better DFS compared with HER2-negative maintained patients (87.9% vs. 79.5%, p=0.048), and the DFS of targeted therapy group was better than that of no targeted therapy group (92.4% vs. 66.7%, p=0.016).
Conclusion
Although HER2-low did not affect the pCR rate and DFS, significant evolution of HER2-low expression after NACT creates opportunities for targeted therapy including trastuzumab.

Citations

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HER2-low breast cancer: a new biological entity or a therapeutic defnition? A current view of the problem
S. V. Vtorushin, A. A. Chernyakov, L. A. Tashireva
Siberian journal of oncology.2026; 25(1): 135. CrossRef
Preoperative Differentiation of HER2‐Zero and HER2‐Low from HER2‐Positive Invasive Ductal Breast Cancers Using BI‐RADS MRI Features and Machine Learning Modeling
Jiejie Zhou, Yang Zhang, Haiwei Miao, Ga Young Yoon, Jinhao Wang, Yezhi Lin, Hailing Wang, Yan‐Lin Liu, Jeon‐Hor Chen, Zhifang Pan, Min‐Ying Su, Meihao Wang
Journal of Magnetic Resonance Imaging.2025; 61(2): 928. CrossRef
Combining ultrasound and immunohistochemistry to differentiate HER-2-low from HER-2-null breast cancer: A diagnostic value analysis
Lu Li, Meng Zhang, Chen Qian, Hao Wu, Kexin Zhang, Wenying Wu
Journal of Radiation Research and Applied Sciences.2025; 18(4): 101918. CrossRef
HER2-low status as a dynamic biomarker in breast cancer: molecular and clinical correlations
A. I. Stukan, S. V. Vtorushin, A. P. Bogdan, T. Yu. Semiglazova, V. V. Kudrina, V. N. Bodnya, V. A. Porkhanov, A. A. Dovlatbekyan, M. A. Chagiev, A. A. Naniz
Siberian journal of oncology.2025; 24(4): 29. CrossRef
Prognostic significance of HER2-low and HER2-zero status before and after neoadjuvant chemotherapy in patients with HER2-negative breast cancer
Youzhao Ma, Jingyang Zhang, Lina Wang, Dechuang Jiao, Xiuchun Chen, Zhenzhen Liu
Therapeutic Advances in Medical Oncology.2025;[Epub] CrossRef
The Modified Neo-Bioscore System for Staging Breast Cancer Treated with Neoadjuvant Therapy Based on Prognostic Significance of HER2-Low Expression
Yingying Zhao, Xinru Chen, Yaohui Wang, Xueqing Zhang, Jingsong Lu, Wenjin Yin
Journal of Clinical Medicine.2024; 13(7): 1850. CrossRef
Comparison of the Pathological Complete Response Rate and Survival Between HER2-Low and HER2-Zero Breast Cancer in Neoadjuvant Chemotherapy Setting: A Systematic Review and Meta-Analysis
Mei Liu, Qin Xiang, Fengsheng Dai, Yixiao Yuan, Zhongjun Wu, Tingxiu Xiang
Clinical Breast Cancer.2024; 24(7): 575. CrossRef
Neoadjuvant chemotherapy efficacy and prognosis in HER2-low and HER2-zero breast cancer patients by HR status: a retrospective study in China
Shaorong Zhao, Yuyun Wang, Angxiao Zhou, Xu Liu, Yi Zhang, Jin Zhang
PeerJ.2024; 12: e17492. CrossRef
Alteration of HER2 Status During Breast Cancer Progression: A Clinicopathological Analysis Focusing on HER2-Low Status
Kyungah Bai, Ji Won Woo, Hyun Jung Kwon, Yul Ri Chung, Koung Jin Suh, Se Hyun Kim, Jee Hyun Kim, So Yeon Park
Laboratory Investigation.2024; 104(8): 102092. CrossRef
HER2-Low Breast Cancer: Now and in the Future
Sora Kang, Sung-Bae Kim
Cancer Research and Treatment.2024; 56(3): 700. CrossRef
Stable or at least once HER2-low status during neoadjuvant chemotherapy confers survival benefit in patients with breast cancer
Yingying Zhao, Xinru Chen, Yaohui Wang, Xueqing Zhang, Yumei Ye, Shuguang Xu, Liheng Zhou, Yanping Lin, Jingsong Lu, Wenjin Yin
Annals of Medicine.2024;[Epub] CrossRef
The prognostic impact of Her2 status in early triple negative breast cancer: a Turkish Oncology Group (TOG) study
Neslihan Özyurt, Ali Alkan, Burcu Gülbağcı, Mustafa Seyyar, Esra Aşık, Mustafa Şahbazlar, Mehmet Türker, Oğuzcan Kınıkoğlu, Tahir Yerlikaya, Gülhan Dinç, Ali Aytaç, Ziya Kalkan, Senar Ebinç, İlkay Gültürk, Merve Keskinkılıç, Zehra Sucuoğlu İşleyen, Dilek
Scientific Reports.2024;[Epub] CrossRef
Prognostic implications of HER2 changes after neoadjuvant chemotherapy in patients with HER2-zero and HER2-low breast cancer
Sora Kang, So Heun Lee, Hee Jin Lee, Hyehyun Jeong, Jae Ho Jeong, Jeong Eun Kim, Jin-Hee Ahn, Kyung Hae Jung, Gyungyub Gong, Hak Hee Kim, Saebyeol Lee, Jongwon Lee, Sung-Bae Kim
European Journal of Cancer.2023; : 112956. CrossRef

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Lung cancer

Genetic Alterations in Preinvasive Lung Synchronous Lesions: Soyeon Ahn, Jisun Lim, Soo Young Park, Hyojin Kim, Hyun Jung Kwon, Yeon Bi Han, Choon-Taek Lee, Sukki Cho, Jin-Haeng Chung; Cancer Res Treat. 2020;52(4):1120-1134. Published online June 5, 2020; DOI: https://doi.org/10.4143/crt.2020.307

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Purpose
Despite advances in treatment, lung cancer remains the leading cause of cancer mortality. This study aimed to characterise genome-wide tumorigenesis events and to understand the hypothesis of the multistep carcinogenesis of lung adenocarcinoma (LUAD)
Materials and Methods
We conducted multiregion whole-exome sequencing of LUAD with synchronous atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ, or minimally invasive adenocarcinoma of 19 samples from three patients to characterize genome-wide tumorigenesis events and validate the hypothesis of the multistep carcinogenesis of LUAD. We identified potential pathogenic mutations preserved in preinvasive lesions and supplemented the finding by allelic variant level from RNA sequencing.
Results
Overall, independent mutational profiles were observed per patient and between patients. Some shared mutations including epidermal growth factor receptor (EGFR , p.L858R) were present across synchronous lesions.
Conclusion
Here, we show that there are driver gene mutations in AAH, and they may exacerbate as a sequence in a histological continuum, supporting the Darwinian evolution model of cancer genome. The intertumoral and intratumoral heterogeneity of synchronous LUAD implies that multi-biomarker strategies might be necessary for appropriate treatment.

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Gene Expression Profiles of Multiple Synchronous Lesions in Lung Adenocarcinoma
Jisun Lim, Yeon Bi Han, Soo Young Park, Soyeon Ahn, Hyojin Kim, Hyun Jung Kwon, Choon-Taek Lee, Sukki Cho, Jin-Haeng Chung
Cells.2021; 10(12): 3484. CrossRef

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Coexisting with Clonal Evolution and BCR-ABL Mutant in CML Patients Treated with Second-generation Tyrosine Kinase Inhibitors Predict the Discrepancy of in vitro Drug Sensitivity: Jae-Sook Ahn, Yeo-Kyeoung Kim, Se Ryeon Lee, Li Yu, Deok-Hwan Yang, Sang-Hee Cho, Hyun Jeong Shim, Woo Kyun Bae, Je-Jung Lee, Ik-Joo Chung, Myung Gun Shin, Hyeoung-Joon Kim; Cancer Res Treat. 2010;42(1):37-41. Published online March 31, 2010; DOI: https://doi.org/10.4143/crt.2010.42.1.37

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Purpose

Second-generation tyrosine kinase inhibitors (second TKIs) such as nilotinib and dasatinib control the activity of most ABL kinase domain mutations observed in patients with imatinib resistance. Although in vitro data show that both agents can inhibit all mutations except T315I, some discrepancies have been observed in a small subset of mutation clones. Cytogenetic clonal evolution is the important resistance mechanism of chronic myeloid leukemia (CML). Accordingly, we observed the clinical significance of coexisting with clonal evolution and BCR-ABL mutant in CML patients treated with second TKIs.

Materials and Methods

We monitored BCR-ABL transcript kinetics, interrelationship of clones expressing non-mutated and mutant transcripts and clonal aberrations within Philadelphia (Ph) positive and negative clones, respectively, in eight patients with CML receiving dasatinib or nilotinib for 3~41 months.

Results

Clinical responses were correlated with in vitro sensitivity of the BCR-ABL mutants to the second TKIs in four patients. Four patients showed resistance to the second TKIs as compared to in vitro observations; three of them developed chromosomal abnormalities in the Ph chromosome positive or negative metaphases. Another patient lost the original mutation but acquired a more resistant new mutation and became resistant to the second TKI.

Conclusion

Cytogenetic clonal evolution is an independent poor prognostic factor in CML, which could explain the onset of mechanisms for second TKIs resistance to ABL kinase domain mutations. The results indicate that an additional evaluation of chromosomal abnormalities is warranted when BCR-ABL mutants are more resistant than indicated by in vitro data.

Citations

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Concomitant T315I and E459K mutations in chronic myeloid leukemia: A case report
Xin Zhou, Shi-Ting Huang, Ning-Ning Shan
Oncology Letters.2025; 30(3): 1. CrossRef
T315I – a gatekeeper point mutation and its impact on the prognosis of chronic myeloid leukemia
Bushra Kaleem, Sadaf Shahab, Tahir Sultan Shamsi
Advances in Laboratory Medicine / Avances en Medicina de Laboratorio.2024; 5(4): 412. CrossRef
Impacto de la mutación T315I en el pronóstico de la leucemia mieloide crónica
Bushra Kaleem, Sadaf Shahab, Tahir Sultan Shamsi
Advances in Laboratory Medicine / Avances en Medicina de Laboratorio.2024; 5(4): 418. CrossRef
BCR-ABL1 mutation development during first-line treatment with dasatinib or imatinib for chronic myeloid leukemia in chronic phase
T P Hughes, G Saglio, A Quintás-Cardama, M J Mauro, D-W Kim, J H Lipton, M B Bradley-Garelik, J Ukropec, A Hochhaus
Leukemia.2015; 29(9): 1832. CrossRef

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