Cancer Research and Treatment

Original Articles

Spatial Interactions of CD103+ Tissue-Resident Memory T Cells in the Tumor Periphery Are Associated with Clinical Outcomes in Triple-Negative Breast Cancer Following Neoadjuvant Chemotherapy: Hyun Lee, Byung-Kwan Jeong, Gyungyub Gong, Miseon Lee, Hee Jin Lee; Received December 29, 2025 Accepted March 14, 2026 Published online March 18, 2026; DOI: https://doi.org/10.4143/crt.2025.1416 [Accepted]

Abstract PDF Supplementary Material: Purpose
Triple-negative breast cancer (TNBC) is an aggressive subtype with poor prognosis. CD103+ tissue-resident memory T (TRM) cells are crucial for anti-tumor immunity in TNBC. We investigated whether their spatial interactions with other T-cells influence clinical outcomes, particularly following neoadjuvant chemotherapy (NAC).
Materials and Methods
This retrospective study analyzed 182 TNBC patients (98 NAC-treated; 84 non-NAC). Using Opal™ multiplex immunohistochemistry data and the Spatial Image Analysis of Tissues (SPIAT) R package, we analysed spatial interactions between CD103+ cells and other T cell subsets (CD45RO, CD8, CD4, PD-1) in central/peripheral tumor regions. Normalized mixing score (NMS) quantified spatial interactions.
Results
NMS-based clustering revealed two distinct CD103+ cell interaction patterns—Cluster 1 (low NMS) characterized by weaker and Cluster 2 (high NMS) by stronger spatial interactions between CD103+ and other T cell subsets. In the NAC group, Cluster 2 in the tumor periphery was associated with lower pathologic stage (p=0.002), higher stromal tumor-infiltrating lymphocyte level (p=0.031), and significantly improved recurrence-free survival (p=0.028) and overall survival (p=0.018) compared to Cluster 1. Central tumor region clustering patterns had no association with prognosis. No significant survival-related differences were observed in the non-NAC group according to NMS-based clustering.
Conclusion
Spatial interaction patterns between CD103+ and other T cell subsets in the tumor periphery influence clinical outcomes in NAC-treated TNBC patients. Analysing such spatial relationships between T cells, rather than their presence alone, may provide additional prognostic information for patients undergoing NAC.

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Breast cancer

Keratin 6A Overexpression in the Lymphovascular Invasion–Associated Tumor Subgroup Promotes Progression of Triple-Negative Breast Cancer: Wei Luo, Yiping Zou, Yantao Jiang, Xi Ma, Shuyue Guo, Yao Wang, Yuxiao Liu, Linyue Hai, Wenbin Jia, Wenbo Liu, Ran Meng, Xuchen Cao, Xianhui Ruan, Yue Yu; Cancer Res Treat. 2026;58(3):790-814. Published online July 14, 2025; DOI: https://doi.org/10.4143/crt.2025.423

Abstract PDF Supplementary Material PubReader ePub

Purpose
Lymphovascular invasion (LVI) is a strong predictor of poor prognosis in triple-negative breast cancer (TNBC), yet its molecular basis remains unclear. This study investigates epithelial regulators associated with LVI and their functional roles in TNBC progression.
Materials and Methods
We utilized single-cell sequencing data to further characterize epithelial cell populations in TNBC, identifying dominant epithelial clusters in LVI-positive TNBC tissues. The prognostic significance of dominant epithelial marker genes was explored through transcriptomic analysis and immunohistochemical staining of patient samples from our center. Additionally, the effects of the marker gene on TNBC cell invasion and metastasis were validated in vitro and in vivo.
Results
Single-cell data analysis revealed nine distinct epithelial cell clusters within TNBC tissues. Among these, cluster 4 was identified as the dominant epithelial subpopulation in LVI-positive TNBC, marked by the prognostic gene KRT6A. Multiple datasets confirmed KRT6A as a crucial prognostic marker in TNBC. Functional assays, including Cell Counting Kit-8, wound healing, transwell assays, and animal experiments, demonstrated that KRT6A knockdown significantly impaired the proliferation, invasion, and metastatic potential of TNBC cells. Mechanistically, KRT6A promoted epithelial-mesenchymal transition (EMT) and activated Wnt/β-catenin signaling by stabilizing β-catenin through glycogen synthase kinase-3β phosphorylation.
Conclusion
KRT6A promotes EMT and metastasis in TNBC via Wnt/β-catenin signaling, contributing to LVI and chemoresistance. It may serve as a prognostic biomarker and therapeutic target in TNBC.

Citations

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Targeting keratin 6 A overcomes gemcitabine resistance by restoring equilibrative nucleoside transporter 1 and TAM-mediated metabolic compensation in pancreatic cancer
Junfeng Zhang, Xianxing Wang, Silue Zeng, Bo Tang, Xinyi Yang, Shaowen Xie, Haihan Sun, Ru Wang, Renpei Xia, Jinghe Li, Huaizhi Wang, Zhitian Shi, Jianyou Gu, Dong Wei
Drug Resistance Updates.2026; 87: 101404. CrossRef
Signaling Networks Regulating Metastatic Progression in Triple-Negative Breast Cancer
Zuzanna Senkowska, Katarzyna Owczarek, Karolina Niewinna, Urszula Lewandowska
Cells.2026; 15(9): 809. CrossRef
Inhibition of IGF1R in Early MMTV-Wnt1 Mammary Tumors: A Transcriptomic Analysis
Joseph J. Bulatowicz, Alexander Lemenze, Elvan Dogan, Christopher A. Galifi, Krystopher Maingrette, Quan Shang, Teresa L. Wood
Cancers.2026; 18(11): 1749. CrossRef

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Breast Conservation Therapy Versus Mastectomy in Patients with T1-2N1 Triple-Negative Breast Cancer: Pooled Analysis of KROG 14-18 and 14-23: Kyubo Kim, Hae Jin Park, Kyung Hwan Shin, Jin Ho Kim, Doo Ho Choi, Won Park, Seung Do Ahn, Su Ssan Kim, Dae Yong Kim, Tae Hyun Kim, Jin Hee Kim, Jiyoung Kim; Cancer Res Treat. 2018;50(4):1316-1323. Published online January 8, 2018; DOI: https://doi.org/10.4143/crt.2017.575

Abstract PDF PubReader ePub

Purpose
The aim of this study is to compare the treatment outcomes of breast conserving surgery (BCS) plus radiotherapy (RT) versus mastectomy for patients with pT1-2N1 triple-negative breast cancer (TNBC).
Materials and Methods
Using two multicenter retrospective studies on breast cancer, a pooled analysis was performed among 320 patients with pT1-2N1 TNBC. All patients who underwent BCS (n=212) receivedwhole breast RTwith orwithoutregional nodal RT,while nonewho underwent mastectomy (n=108)received it. All patients received taxane-based adjuvant chemotherapy. The median follow-up periods were 65 months in the BCS+RT group, and 74 months in the mastectomy group.
Results
The median age of all patients was 48 years (range, 24 to 70 years). Mastectomy group had more patients with multiple tumors (p < 0.001), no lymphovascular invasion (p=0.001), higher number of involved lymph node (p=0.028), and higher nodal ratio ≥ 0.2 (p=0.037). Other characteristics were not significantly different between the two groups. The 5-year locoregionalrecurrence-free, disease-free, and overall survivalrates of BCS+RT group versus mastectomy group were 94.6% versus 87.7%, 89.5% versus 80.4%, and 95.0% versus 87.8%, respectively, and the differences were statistically significant after adjusting for covariates (p=0.010, p=0.006, and p=0.005, respectively).
Conclusion
In pT1-2N1 TNBC, breast conservation therapy achieved better locoregional recurrencefree, disease-free, and overall survival rates compared with mastectomy.

Citations

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Breast conserving surgery combined with radiation therapy offers improved survival over mastectomy in early-stage breast cancer
Elizaveta Vasilyeva, Alan Nichol, Brendan Bakos, Anise Barton, Michelle Goecke, Elaine Lam, Erin Martin, Caroline Lohrisch, Elaine McKevitt
The American Journal of Surgery.2024; 231: 70. CrossRef
Oncoplastic Breast Conservation for Central Tumors: Definition, Classification, and the Analysis of Single Institution Experience
Andrii Zhygulin, Artem Fedosov
Plastic and Reconstructive Surgery - Global Open.2024; 12(5): e5789. CrossRef
Treatment Outcomes after Postoperative Radiotherapy in Triple-Negative Breast Cancer: Multi-Institutional Retrospective Study (KROG 17-05)
Jin Kim, Sang Byun, Myeongsoo Kim, Kyung Shin, Dong Kim, Han Lee, Tae Kim, Yeon Kim, Yong Kim, Jee Chang, Kyubo Kim, Sun Lee
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Recent Advances in Targeted Nanocarriers for the Management of Triple Negative Breast Cancer
Rajesh Pradhan, Anuradha Dey, Rajeev Taliyan, Anu Puri, Sanskruti Kharavtekar, Sunil Kumar Dubey
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Breast-Conserving Therapy is Associated with Improved Survival Without an Increased Risk of Locoregional Recurrence Compared with Mastectomy in Both Clinically Node-Positive and Node-Negative Breast Cancer Patients
Elizaveta Vasilyeva, Jeremy Hamm, Alan Nichol, Kathryn V. Isaac, Amy Bazzarelli, Carl Brown, Caroline Lohrisch, Elaine McKevitt
Annals of Surgical Oncology.2023; 30(11): 6413. CrossRef
Postmastectomy Radiation Therapy in Patients With Minimally Involved Lymph Nodes: A Review of the Current Data and Future Directions
Bum-Sup Jang, Kyung Hwan Shin
Journal of Breast Cancer.2022; 25(1): 1. CrossRef
A Review of Current treatment for Triple-Negative Breast Cancer (TNBC)
Wahyuni Wahyuni, Ajeng Diantini, Mohammad Ghozali, Sahidin I
Research Journal of Pharmacy and Technology.2022; : 409. CrossRef
Long non-coding RNA MRPS30 divergent transcript can be detected in the cytoplasm of triple-negative breast cancer cells and is targeted by microRNA-130b
Dongtao Wang, Qiang Song, Tianyong Zhao, Fang Wang, Yang Yu, Jing Qi, Pengfei Lyu, Xiangyang Duan
Bioengineered.2022; 13(3): 5954. CrossRef
Breast-conserving surgery versus mastectomy for older women with triple-negative breast cancer: population-based study
Waruiru Mburu, Shalini Kulasingam, James S Hodges, Beth A Virnig
Journal of Comparative Effectiveness Research.2022; 11(13): 953. CrossRef
Determining prognostic factors and optimal surgical intervention for early-onset triple-negative breast cancer
Yi-Zi Zheng, Yan Liu, Zhen-Han Deng, Guo-Wen Liu, Ni Xie
Frontiers in Oncology.2022;[Epub] CrossRef
Postoperative Radiotherapy Contributes to the Survival Benefit of Breast-Conserving Therapy over Mastectomy
Chu-Ying Chen, Si-Yue Zheng, Gang Cai, Cheng Xu, Rong Cai, Min Li, Kun-Wei Shen, Xiao-Song Chen, Dan Ou, Wei-Xiang Qi, Lu Cao, Jia-Yi Chen, Weiren Luo
Journal of Oncology.2022; 2022: 1. CrossRef
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M.V. Pavlushenko, R.V. Liubota, R.I. Vereshchako, O.S. Zotov, M.F. Anikusko, I.I. Liubota
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Breast conservation therapy confers survival and distant recurrence advantage over mastectomy for stage II Triple Negative Breast cancer
Rebekah Macfie, Cynthia Aks, Kathryn Panwala, Nathalie Johnson, Jennifer Garreau
The American Journal of Surgery.2021; 221(4): 809. CrossRef
Outcomes after breast-conserving surgery or mastectomy in patients with triple-negative breast cancer: meta-analysis
A Fancellu, N Houssami, V Sanna, A Porcu, C Ninniri, M L Marinovich
British Journal of Surgery.2021; 108(7): 760. CrossRef
Are the Outcomes of Breast Conservation Surgery Inferior to Those of Mastectomy in Patients with Stage II-IIIA Triple-Negative Breast Cancer?
Seungju Lee, Hyun Yul Kim, Youn Joo Jung, Hyun-June Paik, Dong-Il Kim, Chang Shin Jung, Seok-Kyung Kang, Jee Yeon Kim, Seokwon Lee, Youngtae Bae
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Antitumor Effect of KX-01 through Inhibiting Src Family Kinases and Mitosis: Seongyeong Kim, Ahrum Min, Kyung-Hun Lee, Yaewon Yang, Tae-Yong Kim, Jee Min Lim, So Jung Park, Hyun-Jin Nam, Jung Eun Kim, Sang-Hyun Song, Sae-Won Han, Do-Youn Oh, Jee Hyun Kim, Tae-You Kim, David Hangauer, Johnson Yiu-Nam Lau, Kyongok Im, Dong Soon Lee, Yung-Jue Bang, Seock-Ah Im; Cancer Res Treat. 2017;49(3):643-655. Published online October 6, 2016; DOI: https://doi.org/10.4143/crt.2016.168

Abstract PDF Supplementary Material PubReader ePub

Purpose
KX-01 is a novel dual inhibitor of Src and tubulin. Unlike previous Src inhibitors that failed to show clinical benefit during treatment of breast cancer, KX-01 can potentially overcome the therapeutic limitations of current Src inhibitors through inhibition of both Src and tubulin. The present study further evaluates the activity and mechanism of KX-01 in vitro and in vivo.
Materials and Methods
The antitumor effect of KX-01 in triple negative breast cancer (TNBC) cell lines was determined by MTT assay. Wound healing and immunofluorescence assays were performed to evaluate the action mechanisms of KX-01. Changes in the cell cycle and molecular changes induced by KX-01 were also evaluated. A MDA-MB-231 mouse xenograft model was used to demonstrate the in vivo effects.
Results
KX-01 effectively inhibited the growth of breast cancer cell lines. The expression of phospho- Src and proliferative-signaling molecules were down-regulated in KX-01–sensitive TNBC cell lines. In addition, migration inhibition was observed by wound healing assay. KX-01– induced G2/M cell cycle arrest and increased the aneuploid cell population in KX-01–sensitive cell lines. Multi-nucleated cells were significantly increased after KX-01 treatment. Furthermore, KX-01 effectively delayed tumor growth in a MDA-MB-231 mouse xenograft model.
Conclusion
KX-01 effectively inhibited cell growth and migration of TNBC cells. Moreover, this study demonstrated that KX-01 showed antitumor effects through the inhibition of Src signaling and the induction of mitotic catastrophe. The antitumor effects of KX-01 were also demonstrated in vivo using a mouse xenograft model.

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