Cancer Research and Treatment

Original Articles

Ten-Year Follow-Up Clinical Outcomes and the Role of Adjuvant Chemotherapy in HER2-Positive Patients with Microinvasive Breast Cancer: Yeokyeong Shin, Soo-Young Lee, Hyehyun Jeong, Jin-Hee Ahn, Kyung Hae Jung, Sung-Bae Kim, Hee Jeong Kim, Jong Won Lee, Byung Ho Son, BeomSeok Ko, Ji Sun Kim, Il Yong Chung, Hee Jin Lee, Gyungyub Gong, Sae Byul Lee, Jae Ho Jeong; Received November 22, 2024 Accepted March 3, 2025 Published online March 5, 2025; DOI: https://doi.org/10.4143/crt.2024.1120 [Accepted]

Abstract PDF: Purpose
Although HER2 positivity is prevalent in microinvasive breast cancer (MIBC), data focused on HER2-positive MIBC are limited. We investigated the clinical course and long-term outcomes of HER2-positive MIBC and evaluated the role of adjuvant chemotherapy.
Materials and Methods
The study included patients with curatively resected pT1mi pN0 HER2-positive breast cancer between January 2000 and January 2020. Treatments and survival outcomes, including invasive breast cancer-free survival (IBCFS), distant recurrence-free survival (DRFS), and overall survival (OS) were analyzed.
Results
The analysis included 799 female patients. The median age was 51 years (range, 23–79), and 51.6% (n=412) were premenopausal. Multifocality was confirmed in 17.3% (n=138), and estrogen receptor (ER) positivity in 29.8% (n = 238). Adjuvant chemotherapy was administered to 17.5% (n=140), with doxifluridine in 96.4% of cases. One patient (0.1%) received trastuzumab. With a median follow-up of 119.0 months (95% CI, 114.0–127.0), the 8-year IBCFS, DRFS, and OS were 91.2% (95% CI, 89.1–93.3), 97.5% (95% CI, 96.4–98.7), and 98.8% (95% CI, 98.0–99.6), respectively. No significant differences were observed between patients with and without adjuvant chemotherapy. The lack of differences in IBCFS by chemotherapy was consistent across subgroups, including pre-/postmenopausal patients, grade 1-2/3 tumors, and ER-negative disease.
Conclusion
A clinically meaningful proportion of HER2-positive MIBC patients experience IBCFS events with long-term follow-up. Adjuvant chemotherapy did not improve survival, potentially due to the use of an outdated, ineffective regimen. The role of modern adjuvant regimens, particularly those incorporating HER2-targeted therapy, warrants further exploration.

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Prognostic Performance of the Next-Generation Sequencing-Based Multigene Assay in Early Breast Cancer Patients Treated According to the 21-Gene Assay Results: Eunhye Kang, Jong-Ho Cheun, Jeeyeon Lee, Jiwon Koh, Hyunwoo Lee, Ji-Young Park, Hee Jin Lee, Byeongju Kang, Woong Ki Park, Jeongeun Son, Bumjoon Kim, Woosung Chung, Wonshik Han, Han-Byoel Lee, Sae Byul Lee, Jai Min Ryu; Received October 28, 2024 Accepted December 22, 2024 Published online December 23, 2024; DOI: https://doi.org/10.4143/crt.2024.1035 [Accepted]

Abstract PDF: Purpose
Multigene assays guide treatment decisions in early-stage hormone receptor-positive breast cancer. OncoFREE, a next-generation sequencing assay using 179 genes, was developed for this purpose. This study aimed to evaluate the concordance between the Oncotype DX (ODX) Recurrence Score (RS) and the OncoFREE Decision Index (DI) and to compare their performance.
Materials and Methods
We retrospectively collected tumor blocks from patients who underwent ODX and treatment between 2012 and 2022 at four tertiary hospitals and performed OncoFREE on these samples. Distant metastasis-free survival (DMFS) was compared using RS and DI, with score cut-offs of 25 and 20, respectively.
Results
Among 838 patients, a strong correlation was observed between RS and DI (Pearson correlation coefficient 0.83). At a median follow-up of 54 months, patients with high DI had significantly worse DMFS compared to those with low DI (log-rank p < 0.001, hazard ratio [HR] 5.73, 95% confidence interval [CI] 1.87–17.57; multivariable p=0.048, HR 3.45, 95% CI 1.01–11.76). In 513 patients aged ≤50 years, DMFS was significantly different as a function of DI (p=0.035, HR 3.98, 95% CI 1.00–15.89) but not RS (p=0.792). Among 376 patients aged ≤50 years who avoided chemotherapy based on low RS, 64 with high DI had worse DMFS (p=0.015, HR 5.91, 95% CI 1.17–29.78).
Conclusion
OncoFREE showed strong concordance with ODX and effectively identified high-risk patients, particularly in younger individuals. It could be an affordable alternative to ODX for guiding treatment in hormone receptor-positive early breast cancer.

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Breast cancer

A Nationwide Study on HER2-Low Breast Cancer in South Korea: Its Incidence of 2022 Real World Data and the Importance of Immunohistochemical Staining Protocols: Min Chong Kim, Eun Yoon Cho, So Yeon Park, Hee Jin Lee, Ji Shin Lee, Jee Yeon Kim, Ho-chang Lee, Jin Ye Yoo, Hee Sung Kim, Bomi Kim, Wan Seop Kim, Nari Shin, Young Hee Maeng, Hun Soo Kim, Sun Young Kwon, Chungyeul Kim, Sun-Young Jun, Gui Young Kwon, Hye Jeong Choi, So Mang Lee, Ji Eun Choi, Ae Ri An, Hyun Joo Choi, EunKyung Kim, Ahrong Kim, Ji-Young Kim, Jeong Yun Shim, Gyungyub Gong, Young Kyung Bae; Cancer Res Treat. 2024;56(4):1096-1104. Published online March 6, 2024; DOI: https://doi.org/10.4143/crt.2024.092

Abstract PDF Supplementary Material PubReader ePub

Purpose
Notable effectiveness of trastuzumab deruxtecan in patients with human epidermal growth factor receptor 2 (HER2)–low advanced breast cancer (BC) has focused pathologists’ attention. We studied the incidence and clinicopathologic characteristics of HER2-low BC, and the effects of immunohistochemistry (IHC) associated factors on HER2 IHC results.
Materials and Methods
The Breast Pathology Study Group of the Korean Society of Pathologists conducted a nationwide study using real-world data on HER2 status generated between January 2022 and December 2022. Information on HER2 IHC protocols at each participating institution was also collected.
Results
Total 11,416 patients from 25 institutions included in this study. Of these patients, 40.7% (range, 6.0% to 76.3%) were classified as HER2-zero, 41.7% (range, 10.5% to 69.1%) as HER2-low, and 17.5% (range, 6.7% to 34.0%) as HER2-positive. HER2-low tumors were associated with positive estrogen receptor and progesterone receptor statuses (p < 0.001 and p < 0.001, respectively). Antigen retrieval times (≥ 36 minutes vs. < 36 minutes) and antibody incubation times (≥ 12 minutes vs. < 12 minutes) affected on the frequency of HER2 IHC 1+ BC at institutions using the PATHWAY HER2 (4B5) IHC assay and BenchMark XT or Ultra staining instruments. Furthermore, discordant results between core needle biopsy and subsequent resection specimen HER2 statuses were observed in 24.1% (787/3,259) of the patients.
Conclusion
The overall incidence of HER2-low BC in South Korea concurs with those reported in previously published studies. Significant inter-institutional differences in HER2 IHC protocols were observed, and it may have impact on HER2-low status. Thus, we recommend standardizing HER2 IHC conditions to ensure precise patient selection for targeted therapy.

Citations

Citations to this article as recorded by

Impact of immunohistochemistry staining conditions on the incidence of human epidermal growth factor receptor 2 (HER2)-low breast cancer
Min Chong Kim, Sun Young Kwon, Hye Ra Jung, Young Kyung Bae
Virchows Archiv.2024; 485(6): 1117. CrossRef
Breast Cancer: Extracellular Matrix and Microbiome Interactions
Lourdes Herrera-Quintana, Héctor Vázquez-Lorente, Julio Plaza-Diaz
International Journal of Molecular Sciences.2024; 25(13): 7226. CrossRef

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Gastrointestinal cancer

Establishing Patient-Derived Cancer Cell Cultures and Xenografts in Biliary Tract Cancer: Jihoon Kang, Ji-Young Lee, Sunmin Lee, Danbee Kim, Jinyeong Lim, Ha Ra Jun, Seyeon Jeon, Young-Ae Kim, Hye Seon Park, Kyu-pyo Kim, Sung-Min Chun, Hee Jin Lee, Changhoon Yoo; Cancer Res Treat. 2023;55(1):219-230. Published online April 6, 2022; DOI: https://doi.org/10.4143/crt.2021.1166

Abstract PDF Supplementary Material PubReader ePub

Purpose
Biliary tract cancers (BTCs) are rare and show a dismal prognosis with limited treatment options. To improve our understanding of these heterogeneous tumors and develop effective therapeutic agents, suitable preclinical models reflecting diverse tumor characteristics are needed. We established and characterized new patient-derived cancer cell cultures and patient-derived xenograft (PDX) models using malignant ascites from five patients with BTC.
Materials and Methods
Five patient-derived cancer cell cultures and three PDX models derived from malignant ascites of five patients with BTC, AMCBTC-01, -02, -03, -04, and -05, were established. To characterize the models histogenetically and confirm whether characteristics of the primary tumor were maintained, targeted sequencing and histopathological comparison between primary tissue and xenograft tumors were performed.
Results
From malignant ascites of five BTC patients, five patient-derived cancer cell cultures (100% success rate), and three PDXs (60% success rate) were established. The morphological characteristics of three primary xenograft tumors were compared with those of matched primary tumors, and they displayed a similar morphology. The mutated genes in samples (models, primary tumor tissue, or both) from more than one patient were TP53 (n=2), KRAS (n=2), and STK11 (n=2). Overall, the pattern of commonly mutated genes in BTC cell cultures was different from that in commercially available BTC cell lines.
Conclusion
We successfully established the patient-derived cancer cell cultures and xenograft models derived from malignant ascites in BTC patients. These models accompanied by different genetic characteristics from commercially available models will help better understand BTC biology.

Citations

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Felix J. Krendl, Florian Primavesi, Rupert Oberhuber, Daniel Neureiter, Matthias Ocker, Dino Bekric, Tobias Kiesslich, Christian Mayr
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Ruri Nishie, Tomohito Tanaka, Kensuke Hirosuna, Shunsuke Miyamoto, Hikaru Murakami, Hiromitsu Tsuchihashi, Akihiko Toji, Shoko Ueda, Natsuko Morita, Sousuke Hashida, Atsushi Daimon, Shinichi Terada, Hiroshi Maruoka, Hiromi Konishi, Yuhei Kogata, Kohei Tan
Journal of Clinical Medicine.2024; 13(9): 2718. CrossRef

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Breast cancer

The Association of Estrogen Receptor Activity, Interferon Signaling, and MHC Class I Expression in Breast Cancer: In Hye Song, Young-Ae Kim, Sun-Hee Heo, Won Seon Bang, Hye Seon Park, Yeon ho Choi, Heejae Lee, Jeong-Han Seo, Youngjin Cho, Sung Wook Jung, Hee Jeong Kim, Sei Hyun Ahn, Hee Jin Lee, Gyungyub Gong; Cancer Res Treat. 2022;54(4):1111-1120. Published online December 21, 2021; DOI: https://doi.org/10.4143/crt.2021.1017

Abstract PDF Supplementary Material PubReader ePub

Purpose
The expression of major histocompatibility complex class I (MHC I) has previously been reported to be negatively associated with estrogen receptor (ER) expression. Furthermore, MHC I expression, level of tumor-infiltrating lymphocytes (TILs), and expression of interferon (IFN) mediator MxA are positively associated with one another in human breast cancers. This study aimed to investigate the mechanisms of association of MHC I with ER and IFN signaling.
Materials and Methods
The human leukocyte antigen (HLA)-ABC protein expression was analyzed in breast cancer cell lines. The expressions of HLA-A and MxA mRNAs were analyzed in MCF-7 cells in Gene Expression Omnibus (GEO) data. ER and HLA-ABC expressions, Ki-67 labeling index and TIL levels in tumor tissue were also analyzed in ER+/ human epidermal growth factor receptor 2 (HER2)- breast cancer patients who randomly received either neoadjuvant chemotherapy or estrogen modulator treatment followed by resection.
Results
HLA-ABC protein expression was decreased after β-estradiol treatment or hESR-GFP transfection and increased after fulvestrant or IFN-γ treatment in cell lines. In GEO data, HLA-A and MxA expression was increased after ESR1 shRNA transfection. In patients, ER Allred score was significantly lower and the HLA-ABC expression, TIL levels, and Ki-67 were significantly higher in the estrogen modulator treated group than the chemotherapy treated group.
Conclusion
MHC I expression and TIL levels might be affected by ER pathway modulation and IFN treatment. Further studies elucidating the mechanism of MHC I regulation could suggest a way to boost TIL influx in cancer in a clinical setting.

Citations

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Identifying Safeguards Disabled by Epstein-Barr Virus Infections in Genomes From Patients With Breast Cancer: Chromosomal Bioinformatics Analysis
Bernard Friedenson
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Julio C Tinoco, Harmony I Saunders, Lauryn Rose Werner, Xiaopeng Sun, Eilidh I Chowanec, Amanda Heard, Prabhakar Chalise, Jeffery M Vahrenkamp, Andrea E Wilson, Cong-Xiao Liu, Gangjun Lei, Junping Wei, Hugo Cros, Hisham Mohammed, Melissa Troester, Charles
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Estrogen receptor regulation of the immune microenvironment in breast cancer
Conor McGuinness, Kara L. Britt
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Bioinformatic-Experimental Screening Uncovers Multiple Targets for Increase of MHC-I Expression through Activating the Interferon Response in Breast Cancer
Xin Li, Zilun Ruan, Shuzhen Yang, Qing Yang, Jinpeng Li, Mingming Hu
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Alexandra Moisand, Mathilde Madéry, Thomas Boyer, Charlotte Domblides, Céline Blaye, Nicolas Larmonier
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6,885 View
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Expression of Immunoproteasome Subunit LMP7 in Breast Cancer and Its Association with Immune-Related Markers: Miseon Lee, In Hye Song, Sun-Hee Heo, Young-Ae Kim, In Ah Park, Won Seon Bang, Hye Seon Park, Gyungyub Gong, Hee Jin Lee; Cancer Res Treat. 2019;51(1):80-89. Published online February 26, 2018; DOI: https://doi.org/10.4143/crt.2017.500

Abstract PDF PubReader ePub

Purpose
In the presence of interferon, proteasome subunits are replaced by their inducible counterparts to form an immunoproteasome (IP) plays a key role in generation of antigenic peptides presented by MHC class I molecules, leading to elicitation of a T cell‒mediated immune response. Although the roles of IP in other cancers, and inflammatory diseases have been extensively studied, its significance in breast cancer is unclear.
Materials and Methods
We investigated the expression of LMP7, an IP subunit, and its relationship with immune system components in two breast cancer cohorts.
Results
In 668 consecutive breast cancer cohort, 40% of tumors showed high level of LMP7 expression, and tumors with high expression of LMP7 had more tumor-infiltrating lymphocytes (TILs) in each subtype of breast cancer. In another cohort of 681 triple-negative breast cancer patients cohort, the expression of LMP7 in tumor cells was significantly correlated with the amount of TILs and the expression of interferon-associated molecules (MxA [p < 0.001] and PKR [p < 0.001]), endoplasmic reticulum stress-associated molecules (PERK [p=0.012], p-eIF2a [p=0.001], and XBP1 [p < 0.001]), and damage-associated molecular patterns (HMGN1 [p < 0.001] and HMGB1 [p < 0.001]). Patients with higher LMP7 expression had better disease-free survival outcomes than those with no or low expression in the positive lymph node metastasis group (p=0.041).
Conclusion
Close association between the TIL levels and LMP7 expression in breast cancer indicates that better antigen presentation through greater LMP7 expression might be associated with more TILs.

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Predictive Value of Tertiary Lymphoid Structures Assessed by High Endothelial Venule Counts in the Neoadjuvant Setting of Triple-Negative Breast Cancer: In Hye Song, Sun-Hee Heo, Won Seon Bang, Hye Seon Park, In Ah Park, Young-Ae Kim, Suk Young Park, Jin Roh, Gyungyub Gong, Hee Jin Lee; Cancer Res Treat. 2017;49(2):399-407. Published online July 27, 2016; DOI: https://doi.org/10.4143/crt.2016.215

Abstract PDF Supplementary Material PubReader ePub

Purpose
The tertiary lymphoid structure (TLS) is an important source of tumor-infiltrating lymphocytes (TILs), which have a strong prognostic and predictive value in triple-negative breast cancer (TNBC). A previous study reported that the levels of CXCL13 mRNA expression were associated with TLSs, but measuring the gene expression is challenging in routine practice. Therefore, this study evaluated the MECA79-positive high endothelial venule (HEV) densities and their association with the histopathologically assessed TLSs in biopsy samples. In addition, the relationship of TLSs with the CXCL13 transcript levels and clinical outcomes were examined.
Materials and Methods
A total of 108 TNBC patients treated with neoadjuvant chemotherapy (NAC) were studied. The amounts of TILs and TLSs were measured histopathologically using hematoxylin and eosin–stained slides. The HEV densities and TIL subpopulations were measured by immunohistochemistry for MECA79, CD3, CD8, and CD20. CXCL13 mRNA expression levels using a NanoString assay (NanoString Technologies).
Results
The mean number of HEVs in pre-NAC biopsies was 12 (range, 0 to 72). The amounts of TILs and TLSs, HEV density, and CXCL13 expression showed robust correlations with each other. A lower pre-NAC clinical T stage, higher TIL and TLS levels, a higher HEV density, CD20-positive cell density, and CXCL13 expression were significant predictors of a pathologic complete response (pCR). Higher CD8-positive cell density and levels of CXCL13 expression were significantly associated with a better disease-free survival rate.
Conclusion
MECA79-positive HEV density in pre-NAC biopsies is an objective and quantitative surrogate marker of TLS and might be a valuable tool for predicting pCR of TNBC in routine pathology practice.

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Expression of Myxovirus Resistance A (MxA) Is Associated with Tumor-Infiltrating Lymphocytes in Human Epidermal Growth Factor Receptor 2 (HER2)–Positive Breast Cancers: So Jeong Lee, Cheong-Soo Hwang, Young-Keum Kim, Hyun Jung Lee, Sang-Jeong Ahn, Nari Shin, Jung Hee Lee, Dong Hoon Shin, Kyung Un Choi, Do Youn Park, Chang Hun Lee, Gi Young Huh, Mi Young Sol, Hee Jin Lee, Gyungyub Gong, Jee Yeon Kim, Ahrong Kim; Cancer Res Treat. 2017;49(2):313-321. Published online July 7, 2016; DOI: https://doi.org/10.4143/crt.2016.098

Abstract PDF PubReader ePub

Purpose
The prognostic significance of tumor-infiltrating lymphocytes (TILs) has been determined in breast cancers. Interferons can affect T-cell activity through direct and indirect mechanisms. Myxovirus resistance A (MxA) is an excellent marker of interferon activity. Here,we evaluated TILs and MxA expression in human epidermal growth factor receptor 2 (HER2)–positive breast cancers.
Materials and Methods
Ninety cases of hormone receptor (HR)+/HER2+ tumors and 78 cases of HR–/HER2+ tumors were included. The TILs level was assessed using hematoxylin and eosin–stained full face sections, and MxA expressionwas evaluated by immunohistochemistrywith a tissue microarray.
Results
MxA protein expression was significantly higher in tumors with high histologic grade (p=0.023) and high levels of TILs (p=0.002). High levels of TILs were correlated with high histological grade (p=0.001), negative lymphovascular invasion (p=0.007), negative lymph node metastasis (p=0.007), absence of HR expression (p < 0.001), abundant tertiary lymphoid structures (TLSs) around ductal carcinoma in situ (p=0.018), and abundant TLSs around the invasive component (p < 0.001). High levels of TILs were also associated with improved disease-free survival, particularly in HR–/HER2+ breast cancers. However, MxA was not a prognostic factor.
Conclusion
High expression of MxA in tumor cells was associated with high levels of TILs in HER2-positive breast cancers. Additionally, a high level of TILs was a prognostic factor for breast cancer, whereas the level of MxA expression had no prognostic value.

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