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1
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Bian Y, Song C, Nie Y, Shen X, Hui F, Yu G. Breast cancer metastasis to the nasopharynx: A case report. Oncol Lett 2025; 30:331. [PMID: 40376199 PMCID: PMC12080101 DOI: 10.3892/ol.2025.15077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Accepted: 03/27/2025] [Indexed: 05/18/2025] Open
Abstract
Breast cancer is a leading cause of cancer-related mortality in women, with metastasis posing a significant clinical challenge. However, spread to the nasopharynx and nasal cavity is exceptionally rare. The current study presents the case of a 53-year-old woman diagnosed with invasive ductal carcinoma of the right breast, which later metastasized to the nasopharynx. Despite undergoing modified radical mastectomy, chemotherapy and endocrine therapy, the patient developed symptoms indicative of distant metastasis. The present study reviews the diagnostic and therapeutic approaches for such rare occurrences, offering insights into effective management. The study analyzes this case alongside previously reported instances with the aim of enhancing awareness and facilitating early detection and intervention.
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Affiliation(s)
- Yandong Bian
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong 261000, P.R. China
| | - Chen Song
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong 261000, P.R. China
| | - Yuhui Nie
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong 261000, P.R. China
| | - Xin Shen
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong 261000, P.R. China
| | - Fu Hui
- Department of Oncology, Weifang People's Hospital, The First Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong 261000, P.R. China
| | - Guohua Yu
- Department of Oncology, Weifang People's Hospital, The First Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong 261000, P.R. China
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2
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Cheung AM, Wang D, Quintayo MA, Yerofeyeva Y, Spears M, Bartlett JMS, Stein L, Bayani J, Yaffe MJ. Intra-tumoral spatial heterogeneity in breast cancer quantified using high-dimensional protein multiplexing and single cell phenotyping. Breast Cancer Res 2025; 27:88. [PMID: 40399910 PMCID: PMC12096620 DOI: 10.1186/s13058-025-02038-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Accepted: 04/29/2025] [Indexed: 05/23/2025] Open
Abstract
BACKGROUND Breast cancer is a highly heterogeneous disease where variations of biomarker expression may exist between individual foci of a cancer (intra-tumoral heterogeneity). The extent of variation of biomarker expression in the cancer cells, distribution of cell types in the local tumor microenvironment and their spatial arrangement could impact on diagnosis, treatment planning and subsequent response to treatment. METHODS Using quantitative multiplex immunofluorescence (MxIF) imaging, we assessed the level of variations in biomarker expression levels among individual cells, density of cell cluster groups and spatial arrangement of immune subsets from regions sampled from 38 multi-focal breast cancers that were processed using whole-mount histopathology techniques. Molecular profiling was conducted to determine the intrinsic molecular subtype of each analysed region. RESULTS A subset of cancers (34.2%) showed intra-tumoral regions with more than one molecular subtype classification. High levels of intra-tumoral variations in biomarker expression levels were observed in the majority of cancers studied, particularly in Luminal A cancers. HER2 expression quantified with MxIF did not correlate well with HER2 gene expression, nor with clinical HER2 scores. Unsupervised clustering revealed the presence of various cell clusters with unique IHC4 protein co-expression patterns and the composition of these clusters were mostly similar among intra-tumoral regions. MxIF with immune markers and image patch analysis classified immune niche phenotypes and the prevalence of each phenotype in breast cancer subtypes was illustrated. CONCLUSIONS Our work illustrates the extent of spatial heterogeneity in biomarker expression and immune phenotypes, and highlights the importance of a comprehensive spatial assessment of the disease for prognosis and treatment planning.
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Affiliation(s)
- Alison M Cheung
- Biomarker Imaging Research Lab (BIRL), Sunnybrook Research Institute, Rm S658, 2075 Bayview Avenue, Toronto, ON, Canada
| | - Dan Wang
- Biomarker Imaging Research Lab (BIRL), Sunnybrook Research Institute, Rm S658, 2075 Bayview Avenue, Toronto, ON, Canada
| | - Mary Anne Quintayo
- Diagnostic Development, Ontario Institute for Cancer Research, Toronto, ON, Canada
| | - Yulia Yerofeyeva
- Biomarker Imaging Research Lab (BIRL), Sunnybrook Research Institute, Rm S658, 2075 Bayview Avenue, Toronto, ON, Canada
| | - Melanie Spears
- Diagnostic Development, Ontario Institute for Cancer Research, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - John M S Bartlett
- Diagnostic Development, Ontario Institute for Cancer Research, Toronto, ON, Canada
- University of Edinburgh, Edinburgh, UK
| | - Lincoln Stein
- Informatics and Bio-Computing, Ontario Institute for Cancer Research, Toronto, ON, Canada
| | - Jane Bayani
- Diagnostic Development, Ontario Institute for Cancer Research, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Martin J Yaffe
- Biomarker Imaging Research Lab (BIRL), Sunnybrook Research Institute, Rm S658, 2075 Bayview Avenue, Toronto, ON, Canada.
- Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
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3
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Chen P, Bordeau BM, Zhang W, Balthasar JP. Investigations of Influence of Antibody Binding Kinetics on Tumor Distribution and Anti-Tumor Efficacy. AAPS J 2025; 27:91. [PMID: 40341444 DOI: 10.1208/s12248-025-01076-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Accepted: 04/19/2025] [Indexed: 05/10/2025] Open
Abstract
The pharmacokinetics of antibodies with varied binding kinetics were simulated to assess the role of affinity and binding microconstants (kon, koff) on tumor exposure and intra-tumoral distribution. Anti-HER2 constructs (trastuzumab, pertuzumab, VK3VH6, and conjugates with DM1 and gelonin) were produced, purified, and tested for binding and cytotoxicity in vitro, and for intra-tumoral distribution and anti-tumor efficacy in mice. Simulations demonstrated that homogeneity in intra-tumoral distribution increases with increases in koff and with decreases in kon. Interestingly, simulations also predicted that homogeneity in tumor distribution may be improved by decreasing kon and koff in parallel (without changing affinity). Relative to trastuzumab, pertuzumab exhibits similar affinity but a ~ fivefold smaller kon and koff, while VK3VH6 exhibits a similar koff but a ~ 30-fold lower kon and affinity. Conjugate concentrations associated with 50% inhibition of cell proliferation (IC50s) were found to vary with affinity, where IC50 values were similar for pertuzumab and trastuzumab, and higher for VK3VH6. Consistent with model simulations, VK3VH6 and pertuzumab demonstrated more homogeneous tumor distribution than trastuzumab. Although treatment differences were not statistically significant, pertuzumab and VK3VH6 conjugates showed trends for increased survival time relative to mice treated with trastuzumab conjugates. Our simulation and experimental results demonstrate complex relationships between antibody-antigen binding kinetics, intratumoral distribution, and efficacy. The rate constant of association, kon, is an underappreciated determinant of intra-tumoral distribution; among high-affinity antibodies, those with lower values of kon may be expected to exhibit improved intra-tumoral distribution and, potentially, efficacy.
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MESH Headings
- Animals
- Receptor, ErbB-2/immunology
- Receptor, ErbB-2/antagonists & inhibitors
- Receptor, ErbB-2/metabolism
- Mice
- Humans
- Antibodies, Monoclonal, Humanized/pharmacokinetics
- Antibodies, Monoclonal, Humanized/pharmacology
- Antibodies, Monoclonal, Humanized/administration & dosage
- Trastuzumab/pharmacokinetics
- Cell Line, Tumor
- Kinetics
- Female
- Antineoplastic Agents, Immunological/pharmacokinetics
- Antineoplastic Agents, Immunological/pharmacology
- Xenograft Model Antitumor Assays
- Immunoconjugates/pharmacokinetics
- Immunoconjugates/pharmacology
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Affiliation(s)
- Ping Chen
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, 452 Pharmacy Building, Buffalo, New York, 14214, USA
| | - Brandon M Bordeau
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, 452 Pharmacy Building, Buffalo, New York, 14214, USA
| | - Wenqiu Zhang
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, 452 Pharmacy Building, Buffalo, New York, 14214, USA
| | - Joseph P Balthasar
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, 452 Pharmacy Building, Buffalo, New York, 14214, USA.
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4
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Dai W, Navolotskaia O, Fine JL, Harinath L, Motanagh SA, Villatoro TM, Bhargava R, Clark BZ, Yu J. Not All HER2-Positive Breast Cancers Are the Same: Intratumoral Heterogeneity, Low-Level HER2 Amplification, and Their Impact on Neoadjuvant Therapy Response. Mod Pathol 2025; 38:100785. [PMID: 40311762 DOI: 10.1016/j.modpat.2025.100785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2025] [Revised: 04/15/2025] [Accepted: 04/21/2025] [Indexed: 05/03/2025]
Abstract
Human epidermal growth factor receptor 2 (HER2)-positive breast cancers are frequently treated with neoadjuvant anti-HER2 and chemotherapy (NACT). However, treatment response varies, with a subset of tumors showing high residual cancer burden (RCB). This study investigates the relationship between HER2 immunohistochemical (IHC) intratumoral heterogeneity (ITH), low-level HER2 amplification, and tumor response to NACT. A total of 205 post-NACT HER2-positive breast carcinomas with available RCB results were classified into the following 5 HER2 groups: (1) IHC 3+ (HER2 IHC positive, no fluorescence in situ hybridization performed), (2) Group 1-High (fluorescence in situ hybridization HER2 copies > 8 or HER2/CEP17 ratio > 4), (3) Group 1-Intermediate (HER2 copies > 6-8 or HER2/CEP17 ratio > 3-4), (4) Group 1-Low (HER2 copies 4-6 and HER2/CEP17 ratio 2-3), and (5) Group 3 (HER2 copies ≥ 6 and HER2/CEP17 ratio < 2). Low-level HER2 amplification, collectively designated as HER2 copies 4 to 8 or HER2/CEP17 ratio < 4, was associated with reduced response to HER2-targeted therapy and higher RCB post-NACT. HER2 IHC ITH, defined as the presence of at least 3 distinct staining intensities, with at least 10% of tumor cells exhibiting weak or no staining, was significantly more prevalent in low-level HER2 amplification groups (Group 1-Intermediate: 93.3%, Group 1-Low: 87.5%, and Group 3: 80.0%) compared with high-level amplification groups (IHC 3+: 24.7% and Group 1-High: 28.6%) (P < .001). Both low-level HER2 amplification and HER2 IHC ITH, regardless of hormone receptor status, were independently associated with poor treatment response, and tumors demonstrating both features had the highest likelihood of low therapeutic efficiency. These findings suggest that both low-level HER2 amplification and HER2 IHC ITH contribute to poor NACT response and may warrant alternative therapeutic strategies. Further prospective studies are needed to refine the clinical significance of low-level HER2 amplification and IHC ITH, particularly in the context of novel HER2-targeted therapies such as antibody-drug conjugates.
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Affiliation(s)
- Wenli Dai
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Olga Navolotskaia
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Department of Pathology, University of Pittsburgh Medical Center Magee-Womens Hospital, Pittsburgh, Pennsylvania
| | - Jeffrey L Fine
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Department of Pathology, University of Pittsburgh Medical Center Magee-Womens Hospital, Pittsburgh, Pennsylvania
| | - Lakshmi Harinath
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Department of Pathology, University of Pittsburgh Medical Center Magee-Womens Hospital, Pittsburgh, Pennsylvania
| | - Samaneh A Motanagh
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Department of Pathology, University of Pittsburgh Medical Center Magee-Womens Hospital, Pittsburgh, Pennsylvania
| | - Tatiana M Villatoro
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Department of Pathology, University of Pittsburgh Medical Center Magee-Womens Hospital, Pittsburgh, Pennsylvania
| | - Rohit Bhargava
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Department of Pathology, University of Pittsburgh Medical Center Magee-Womens Hospital, Pittsburgh, Pennsylvania
| | - Beth Z Clark
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Department of Pathology, University of Pittsburgh Medical Center Magee-Womens Hospital, Pittsburgh, Pennsylvania.
| | - Jing Yu
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Department of Pathology, University of Pittsburgh Medical Center Magee-Womens Hospital, Pittsburgh, Pennsylvania.
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5
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Liao C, Engelberts P, van Dijk M, Timmermans A, Martens JWM, Neubert E, Danen EH. CD3xHER2 bsAb-Mediated Activation of Resting T-cells at HER2 Positive Tumor Clusters Is Sufficient to Trigger Bystander Eradication of Distant HER2 Negative Clusters Through IFNγ and TNFα. Eur J Immunol 2025; 55:e202451589. [PMID: 40178291 PMCID: PMC11967296 DOI: 10.1002/eji.202451589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 03/17/2025] [Accepted: 03/20/2025] [Indexed: 04/05/2025]
Abstract
Bispecific antibodies (bsAbs) bridging CD3 on T-cells to tumor-associated antigens (TAA) on tumor cells can direct T-cell immunity to solid tumors. "Bystander killing", where T-cell targeting of TAA-positive tumor cells also leads to the eradication of TAA-negative cells, may overcome TAA heterogeneity. While bystander activity of activated, engineered T-cells has been shown to be robust and wide-reaching, spatiotemporal aspects of bsAb-mediated bystander activity are unresolved. Here, we developed a model where breast cancer tumoroids varying in HER2 expression were printed in to extracellular matrix (ECM) scaffolds. We generated (1) mixed tumors containing different ratios of HER2+ and HER2- tumor cells, and (2) HER2+ and HER2- tumoroids spaced at different distances within the ECM scaffold. Subsequently, tumors were exposed to peripheral blood-derived T-cells in the presence of CD3xHER2 bsAbs. We find that CD3xHER2 bsAb-mediated interaction of resting, nonactivated T-cells with HER2+ tumor cells is sufficient (1) to eliminate 50% HER2- cells in mixed tumor areas, and (2) to eradicate distant HER2- tumor areas. Such bystander killing involves paracrine IFNγ and TNFα activity but does not require T-cell accumulation in HER2- areas. These findings indicate that bystander eradication of TAA-negative cells can significantly contribute to bsAb therapy for solid tumors.
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Affiliation(s)
- Chen‐Yi Liao
- Leiden Academic Centre for Drug ResearchLeiden UniversityLeidenthe Netherlands
| | | | - Michiel van Dijk
- Leiden Academic Centre for Drug ResearchLeiden UniversityLeidenthe Netherlands
| | - Annemieke Timmermans
- Department of Medical OncologyErasmus MC Cancer InstituteErasmus University Medical CenterRotterdamthe Netherlands
| | - John W. M. Martens
- Department of Medical OncologyErasmus MC Cancer InstituteErasmus University Medical CenterRotterdamthe Netherlands
| | - Elsa Neubert
- Leiden Academic Centre for Drug ResearchLeiden UniversityLeidenthe Netherlands
| | - Erik H.J. Danen
- Leiden Academic Centre for Drug ResearchLeiden UniversityLeidenthe Netherlands
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6
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Atallah N, Makhlouf S, Li X, Zhang Y, Mongan NP, Rakha E. Prediction of Response to Anti-HER2 Therapy Using A Multigene Assay. Mod Pathol 2025; 38:100713. [PMID: 39826800 DOI: 10.1016/j.modpat.2025.100713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 11/22/2024] [Accepted: 01/08/2025] [Indexed: 01/22/2025]
Abstract
HER2-positive breast cancer (BC), which constitutes 13% to 15% of cases, shows variable response to anti-HER2 therapies. HER2 positivity, defined as protein overexpression (immunohistochemistry [IHC] score 3+) or equivocal expression (IHC 2+) with evidence of HER2 gene amplification, determines the eligibility for anti-HER2 therapy. The MammaTyper assay (Cerca Biotech GmbH) is an RT-qPCR BC subtyping platform based on the micro RNA expression of ERBB2, ESR1, PGR, and MKI67. This study aimed to evaluate the accuracy of the MammaTyper assay in predicting the response of HER2-positive patients to therapy. A well-characterized HER2-positive BC cohort of 287 cases diagnosed at Nottingham University hospitals between 2006 and 2018 was included. The cohort was divided into 2 groups: a trastuzumab-treated group (n = 159) and a chemotherapy-only treated group (n = 128). Tumor clinicopathologic characteristics were matched between the 2 groups. Cases with discordant HER2 status were validated through staining of surgical excision specimens. ERBB2 micro RNA identified 251/287 (87.5%) cases as HER2-positive, 10.8% (31/287) as HER2 low and 1.7% (5/287) as HER2 negative. According to the MammaTyper assay, ERBB2-positive patients treated with anti-HER2 therapy had significantly prolonged 5-year disease-free survival and distant metastasis-free survival (hazard ratio = 0.56, P = .003 and hazard ratio = 0.62, P = .023, respectively). MammaTyper-defined HER2-enriched subtype showed a better response to anti-HER2 therapy compared with IHC-defined subtypes, with significant differences in both 5-year disease-free survival and BC-specific survival (P = .01 and < .001, respectively). Patients who were ERBB2 negative did not show a survival difference between the group of patients who were treated with trastuzumab and those who were treated with chemotherapy only (P > .05). Validation analysis revealed that 11/36 ERBB2-negative cases were IHC 2+/ISH positive with very low level of gene amplification and 25 cases were false classified as HER2-positive using current protocols. Combining the MammaTyper assay with IHC to assess HER2 status improves the identification of HER2-positive patients with BC who would benefit from anti-HER2 therapy.
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Affiliation(s)
- Nehal Atallah
- Translational Medical Science, School of Medicine, the University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom; Department of Pathology, Faculty of Medicine, Menoufia University, Egypt
| | - Shorouk Makhlouf
- Translational Medical Science, School of Medicine, the University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom; Department of Pathology, Faculty of Medicine, Assiut University, Egypt
| | | | | | - Nigel P Mongan
- Translational Medical Science, School of Medicine, the University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom; Translational Medical Science, School of Veterinary Medicine and Sciences, University of Nottingham, Sutton Bonington, United Kingdom; Department of Pharmacology, Weill Cornell Medicine, New York, New York
| | - Emad Rakha
- Translational Medical Science, School of Medicine, the University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom; Department of Pathology, Hamad Medical Corporation, Doha, Qatar.
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7
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Wilcock D, Sirohi D, Coleman JF, Adelhardt P, Kim JT, Albertson D, Affolter K, Beech C, Jedrzkiewicz J, Ruano AL, Cleary AS, Mahlow J, Balatico M, Gulbahce HE. HER2 fluorescence in situ hybridization groups 2-4 breast cancers classified as positive after targeted recounts following equivocal (2+) immunohistochemistry. Am J Clin Pathol 2025:aqaf006. [PMID: 39937121 DOI: 10.1093/ajcp/aqaf006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Accepted: 01/13/2025] [Indexed: 02/13/2025] Open
Abstract
OBJECTIVES To investigate the correlation between the extent of (percentage of tumor cells) immunohistochemistry (IHC) staining and final human epidermal growth factor receptor 2 (HER2)-positive result in fluorescence in situ hybridization (FISH) groups 2 to 4 with equivocal (2+) IHC requiring second, blinded FISH evaluation. METHODS Breast cancer cases submitted for HER2 FISH testing with group 2 to 4 results were included. RESULTS Of the 2548 cases with HER2 FISH groups 2 to 4 that had HER2 IHC performed, 1104 (43.3%) (76/182 [41.8%] of group 2, 94/161 [58.4%] of group 3, 934/2205 [42.4%] of group 4) had equivocal (2+) IHC. After second blinded, IHC-guided recounts, 217 of 1104 (19.7%) (17/76 [22.4%], 75/94 [79.8%], 125/934 [13.4%] of FISH groups 2, 3, 4 with IHC 2+, respectively) had final HER2-positive status. Only 13 of 217 (6%) of the cases with HER2-positive status had more than 50% circumferential staining of the tumor targeted for rescoring. CONCLUSIONS In over 90% of HER2 FISH group 2 to 4 breast cancers with equivocal (2+) IHC followed by targeted, blinded second FISH evaluation and final HER2-positive result, the amplified population of tumor cells was limited (<50%). Current guidelines recommend cancers having 10% to 50% of the subpopulation with amplified cells classified as having genetic heterogeneity (GH), which have a poor response to targeted therapies. Identifying these tumors as having GH and/or repeat testing may be recommended.
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Affiliation(s)
| | - Deepika Sirohi
- Department of Pathology, University of California-San Francisco, San Francisco, California, US
| | - Joshua F Coleman
- ARUP Laboratories, Salt Lake City, Utah, US
- Department of Pathology and Laboratory Medicine, Huntsman Cancer Institute, University of Utah Health, Salt Lake City, Utah, US
| | - Parisa Adelhardt
- ARUP Laboratories, Salt Lake City, Utah, US
- Department of Pathology and Laboratory Medicine, Huntsman Cancer Institute, University of Utah Health, Salt Lake City, Utah, US
| | - Jong Taek Kim
- ARUP Laboratories, Salt Lake City, Utah, US
- Department of Pathology and Laboratory Medicine, Huntsman Cancer Institute, University of Utah Health, Salt Lake City, Utah, US
| | - Daniel Albertson
- ARUP Laboratories, Salt Lake City, Utah, US
- Department of Pathology and Laboratory Medicine, Huntsman Cancer Institute, University of Utah Health, Salt Lake City, Utah, US
| | - Kajsa Affolter
- ARUP Laboratories, Salt Lake City, Utah, US
- Department of Pathology and Laboratory Medicine, Huntsman Cancer Institute, University of Utah Health, Salt Lake City, Utah, US
| | - Cameron Beech
- ARUP Laboratories, Salt Lake City, Utah, US
- Department of Pathology and Laboratory Medicine, Huntsman Cancer Institute, University of Utah Health, Salt Lake City, Utah, US
| | - Jolanta Jedrzkiewicz
- ARUP Laboratories, Salt Lake City, Utah, US
- Department of Pathology and Laboratory Medicine, Huntsman Cancer Institute, University of Utah Health, Salt Lake City, Utah, US
| | - Ana L Ruano
- ARUP Laboratories, Salt Lake City, Utah, US
- Department of Pathology and Laboratory Medicine, Huntsman Cancer Institute, University of Utah Health, Salt Lake City, Utah, US
| | - Allison S Cleary
- ARUP Laboratories, Salt Lake City, Utah, US
- Department of Pathology and Laboratory Medicine, Huntsman Cancer Institute, University of Utah Health, Salt Lake City, Utah, US
| | - Jonathan Mahlow
- ARUP Laboratories, Salt Lake City, Utah, US
- Department of Pathology and Laboratory Medicine, Huntsman Cancer Institute, University of Utah Health, Salt Lake City, Utah, US
| | - Michael Balatico
- ARUP Laboratories, Salt Lake City, Utah, US
- Department of Pathology and Laboratory Medicine, Huntsman Cancer Institute, University of Utah Health, Salt Lake City, Utah, US
| | - H Evin Gulbahce
- ARUP Laboratories, Salt Lake City, Utah, US
- Department of Pathology and Laboratory Medicine, Huntsman Cancer Institute, University of Utah Health, Salt Lake City, Utah, US
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8
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Gui X, Liang X, Guo X, Yang Z, Song G. Impact of HER2-targeted PET/CT imaging in patients with breast cancer and therapeutic response monitoring. Oncologist 2025; 30:oyae188. [PMID: 39083323 PMCID: PMC11783325 DOI: 10.1093/oncolo/oyae188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 05/14/2024] [Indexed: 02/01/2025] Open
Abstract
BACKGROUND Patients with breast cancer exhibit heterogeneity in the expression of the human epithelial growth factor receptor 2 (HER2). Clinically, re-biopsying recurrent or metastatic lesions presents substantial challenges. This study aimed to evaluate the efficacy of HER2-targeted PET/CT imaging in identifying HER2 expression in breast cancer lesions and monitoring therapeutic responses. PATIENTS AND METHODS This exploratory analysis used data from a prospective study that included adult patients with breast cancer who underwent both Al18F-NOTA-HER2-BCH and 18F-FDG PET/CT imaging at Beijing Cancer Hospital between June 2020 and July 2023 (NCT04547309). RESULTS Fifty-nine participants, with a median age of 55 years, were analyzed. Lesions imaged with HER2-targeted PET/CT before anti-HER2 therapy exhibited higher SUVmax values than after therapy in HER2 immunohistochemistry (IHC) 3 + lesions (19.9, 95% CI: 15.7-25.3 vs 9.8, 95% CI: 5.6-14.7; P = .006). A significant positive correlation was observed between SUVmax on HER2-targeted PET/CT and IHC before therapy (P = .034), with higher SUVmax values noted in lesions with positive HER2 pathology compared to those with negative HER2 status (17.9 ± 13.2 vs 1.1 ± 0.3; P = .007). HER2 expression heterogeneity was confirmed both between primary and metastatic lesions (22.9%) and among different metastatic sites (26.7%) as assessed by HER2-targeted PET/CT. A superior therapeutic response correlated with higher pretreatment SUVmax values. The HER2-targeted PET/CT procedure was well-tolerated by all patients. CONCLUSION HER2-targeted PET/CT imaging offers a practical, non-invasive, and quantitative approach for assessing HER2 status in breast cancer patients, facilitating the optimization and personalization of therapeutic strategies by oncologists.
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Affiliation(s)
- Xinyu Gui
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital and Institute, Beijing 100142, People’s Republic of China
| | - Xu Liang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital and Institute, Beijing 100142, People’s Republic of China
| | - Xiaoyi Guo
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing 100142, People’s Republic of China
| | - Zhi Yang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing 100142, People’s Republic of China
| | - Guohong Song
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital and Institute, Beijing 100142, People’s Republic of China
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9
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Suwanvecho S, Kiatikajornthada N, Phikulsod P, Suwanrusme H, Jirawatnotai S. Durable and Drastic Response to the Trastuzumab, Letrozole, Abemaciclib, and Goserelin Combination as First-Line Therapy in HER2-Positive and Hormone Receptor-Positive Metastatic Breast Cancer: A Case Report. Case Rep Oncol 2025; 18:130-136. [PMID: 39980517 PMCID: PMC11737885 DOI: 10.1159/000542926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Accepted: 11/26/2024] [Indexed: 02/22/2025] Open
Abstract
Introduction Chemotherapy combined with anti-human epidermal growth factor receptor 2 (HER2)-targeted therapy is currently a standard treatment for advanced HER2/HR-positive breast cancer (BC), although evidences showed that HR expression compromised effectiveness of the treatment. While cyclin-dependent kinase (CDK) 4/6 inhibitors combined with endocrine therapy is a key therapy for the BC with HR expression, data on the effectiveness and safety of CDK 4/6 inhibitors combined with trastuzumab and endocrine therapy as a first-line treatment for HER2-positive and HR-positive metastatic BC are limited. Case Presentation Here, we report a case of a 46-year-old premenopausal woman diagnosed with stage 4 HER2/HR-positive invasive ductal carcinoma from both right and left breast with hypermetabolic activities in multiple lymph nodes, adrenal, bone, and skin. Interventions Due to the patient's refusal to use chemotherapy, she was started on goserelin, abemaciclib, letrozole, and trastuzumab. Outcomes The patient's symptoms were relieved with near resolution of the primary breast mass and nearly all of the metastatic sites. Metabolic resolution was observed in bone lesions. The disease was under control for 57 weeks. During the treatment, neutropenia (grade 1-2) and anemia (grade 1) occurred, which spontaneously recovered. Additionally, diarrhea improved after symptomatic treatment. Conclusion We believe that the combination of trastuzumab, hormone suppression, and abemaciclib is a practicable and effective treatment for HER2-positive and HR-positive metastatic BC in premenopausal patients who cannot tolerate the first-line chemotherapy.
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Affiliation(s)
- Suthida Suwanvecho
- Horizon Cancer Center, Bumrungrad International Hospital, Bangkok, Thailand
| | | | - Ployploen Phikulsod
- Hematology Unit, Department of Internal Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Harit Suwanrusme
- Horizon Cancer Center, Bumrungrad International Hospital, Bangkok, Thailand
| | - Siwanon Jirawatnotai
- Department of Pharmacology, and Siriraj Center of Research Excellence for Precision Medicine and Systems Pharmacology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
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10
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Shi X, Sheng Y, Fei H, Wei B, Zhang Z, Xia X, Mao C, Si X. Combined transcriptome and proteome analysis reveals MSN and ARFIP2 as biomarkers for trastuzumab resistance of breast cancer. Breast Cancer Res Treat 2024; 207:187-201. [PMID: 38750271 DOI: 10.1007/s10549-024-07355-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 04/24/2024] [Indexed: 07/09/2024]
Abstract
PURPOSE HER2-positive breast cancer (BC) accounts for 20-30% of all BC subtypes and is linked to poor prognosis. Trastuzumab (Tz), a humanized anti-HER2 monoclonal antibody, is a first-line treatment for HER2-positive breast cancer which faces resistance challenges. This study aimed to identify the biomarkers driving trastuzumab resistance. METHODS Differential expression analysis of genes and proteins between trastuzumab-sensitive (TS) and trastuzumab-resistant (TR) cells was conducted using RNA-seq and iTRAQ. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) were used to study their functions. The prognostic significance and protein levels of ARFIP2 and MSN were evaluated using online tools and immunohistochemistry. Sensitivity of MSN and ARFIP2 to other therapies was assessed using public pharmacogenomics databases and the R language. RESULTS Five genes were up-regulated, and nine genes were down-regulated in TR cells at both transcriptional and protein levels. Low ARFIP2 and high MSN expression linked to poor BC prognosis. MSN increased and ARFIP2 decreased in TR patients, correlating with shorter OS. MSN negatively impacted fulvestrant and immunotherapy sensitivity, while ARFIP2 had a positive impact. CONCLUSION Our findings suggest that MSN and ARFIP2 could serve as promising biomarkers for predicting response to Tz, offering valuable insights for future research in the identification of diagnostic and therapeutic targets for BC patients with Tz resistance.
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Affiliation(s)
- Xiao Shi
- Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, Jiangsu Key Laboratory of Marine Biotechnology, Co-Innovation Center of Jiangsu Marine Bio-Industry Technology, School of Pharmacy, Jiangsu Ocean University, Lianyungang, 222005, China
| | - Yuan Sheng
- Department of Pharmacy, Sir Run Run Hospital, Nanjing Medical University, Nanjing, 211116, China
| | - Haoran Fei
- Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, Jiangsu Key Laboratory of Marine Biotechnology, Co-Innovation Center of Jiangsu Marine Bio-Industry Technology, School of Pharmacy, Jiangsu Ocean University, Lianyungang, 222005, China
| | - Bangbang Wei
- Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, Jiangsu Key Laboratory of Marine Biotechnology, Co-Innovation Center of Jiangsu Marine Bio-Industry Technology, School of Pharmacy, Jiangsu Ocean University, Lianyungang, 222005, China
| | - Zhenyu Zhang
- Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, Jiangsu Key Laboratory of Marine Biotechnology, Co-Innovation Center of Jiangsu Marine Bio-Industry Technology, School of Pharmacy, Jiangsu Ocean University, Lianyungang, 222005, China
| | - Xinyu Xia
- Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, Jiangsu Key Laboratory of Marine Biotechnology, Co-Innovation Center of Jiangsu Marine Bio-Industry Technology, School of Pharmacy, Jiangsu Ocean University, Lianyungang, 222005, China
| | - Changfei Mao
- Department of General Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210009, China.
| | - Xinxin Si
- Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, Jiangsu Key Laboratory of Marine Biotechnology, Co-Innovation Center of Jiangsu Marine Bio-Industry Technology, School of Pharmacy, Jiangsu Ocean University, Lianyungang, 222005, China.
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11
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Zhu S, Zhu W, Zhao K, Yu J, Lu W, Zhou R, Fan S, Kong W, Yang F, Shan P. Discovery of a novel hybrid coumarin-hydroxamate conjugate targeting the HDAC1-Sp1-FOSL2 signaling axis for breast cancer therapy. Cell Commun Signal 2024; 22:361. [PMID: 39010083 PMCID: PMC11247895 DOI: 10.1186/s12964-024-01733-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 07/02/2024] [Indexed: 07/17/2024] Open
Abstract
BACKGROUND Breast cancer is one of the most lethal cancers in women. Despite significant advances in the diagnosis and treatment of breast cancer, many patients still succumb to this disease, and thus, novel effective treatments are urgently needed. Natural product coumarin has been broadly investigated since it reveals various biological properties in the medicinal field. Accumulating evidence indicates that histone deacetylase inhibitors (HDACIs) are promising novel anti-breast cancer agents. However, most current HDACIs exhibit only moderate effects against solid tumors and are associated with severe side effects. Thus, to develop more effective HDACIs for breast cancer therapy, hydroxamate of HDACIs was linked to coumarin core, and coumarin-hydroxamate hybrids were designed and synthesized. METHODS A substituted coumarin moiety was incorporated into the classic hydroxamate HDACIs by the pharmacophore fusion strategy. ZN444B was identified by using the HDACI screening kit and cell viability assay. Molecular docking was performed to explore the binding mode of ZN444B with HDAC1. Western blot, immunofluorescent staining, cell viability, colony formation and cell migration and flow cytometry assays were used to analyze the anti-breast cancer effects of ZN444B in vitro. Orthotopic studies in mouse models were applied for preclinical evaluation of efficacy and toxicity in vivo. Proteomic analysis, dual-luciferase reporter assay, chromatin immunoprecipitation, co-immunoprecipitation, immunofluorescent staining assays along with immunohistochemical (IHC) analysis were used to elucidate the molecular basis of the actions of ZN444B. RESULTS We synthesized and identified a novel coumarin-hydroxamate conjugate, ZN444B which possesses promising anti-breast cancer activity both in vitro and in vivo. A molecular docking model showed that ZN444B binds to HDAC1 with high affinity. Further mechanistic studies revealed that ZN444B specifically decreases FOS-like antigen 2 (FOSL2) mRNA levels by inhibiting the deacetylase activity of HDAC1 on Sp1 at K703 and abrogates the binding ability of Sp1 to the FOSL2 promoter. Furthermore, FOSL2 expression positively correlates with breast cancer progression and metastasis. Silencing FOSL2 expression decreases the sensitivity of breast cancer cells to ZN444B treatment. In addition, ZN444B shows no systemic toxicity in mice. CONCLUSIONS Our findings highlight the potential of FOSL2 as a new biomarker and therapeutic target for breast cancer and that targeting the HDAC1-Sp1-FOSL2 signaling axis with ZN444B may be a promising therapeutic strategy for breast cancer.
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Affiliation(s)
- Sujie Zhu
- Institute of Translational Medicine, College of Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, 266021, China
| | - Wenjing Zhu
- Clinical Research Center, Qingdao Municipal Hospital, Qingdao, 266071, China
| | - Kaihua Zhao
- Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Hospital), Qingdao, 266042, China
| | - Jie Yu
- Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Hospital), Qingdao, 266042, China
| | - Wenxia Lu
- School of Biological Science and Technology, University of Jinan, Jinan, 250022, China
| | - Rui Zhou
- Department of Marine Bio-Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai, 201306, China
| | - Shule Fan
- School of Biological Science and Technology, University of Jinan, Jinan, 250022, China
| | - Weikaixin Kong
- Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, 100191, China.
- Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, 00250, Finland.
- Institute Sanqu Technology (Hangzhou) Co., Ltd., Hangzhou, China.
| | - Feifei Yang
- School of Biological Science and Technology, University of Jinan, Jinan, 250022, China.
| | - Peipei Shan
- Institute of Translational Medicine, College of Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, 266021, China.
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12
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Kwon LY, Cai Z, Al-Mahrouki A, Reilly RM. Bispecific radioimmunoconjugates exploit receptor heterogeneity for positron emission tomography of tumors expressing HER2 and/or EGFR. iScience 2024; 27:109750. [PMID: 38711454 PMCID: PMC11070661 DOI: 10.1016/j.isci.2024.109750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 02/15/2024] [Accepted: 04/11/2024] [Indexed: 05/08/2024] Open
Abstract
HER2 heterogeneity is a challenge for molecular imaging or treating HER2-positive breast cancer (BC). EGFR is coexpressed in some tumors exhibiting HER2 heterogeneity. Bispecific radioimmunoconjugates (bsRICs) that bind HER2 and EGFR were constructed by linking trastuzumab Fab through polyethyleneglycol (PEG24) to EGF. We established s.c. tumors in NOD-SCID mice that homogeneously or heterogeneously expressed HER2 and/or EGFR by the inoculation of HER2-positive/EGFR-negative SK-OV-3 cells, EGFR-positive/HER2-negative MDA-MB-468 cells or mixtures of these cells. [64Cu]Cu-NOTA-trastuzumab Fab-PEG24-EGF were compared to [64Cu]Cu-NOTA-trastuzumab Fab or [64Cu]Cu-NOTA-EGF for the PET imaging of HER2 and/or EGFR-positive tumors. [64Cu]Cu-NOTA-trastuzumab Fab-PEG24-EGF bsRICs imaged tumors expressing HER2 or EGFR or heterogeneously expressing these receptors, while monospecific agents only imaged HER2-or EGFR-positive tumors. Our results indicate that bsRICs labeled with 64Cu are able to exploit receptor heterogeneity for tumor imaging. PET may select patients for radioimmunotherapy with bsRICs complexed to the β-particle emitter, 177Lu or Auger electron-emitter, 111In in a theranostic approach.
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Affiliation(s)
- Luke Yongkyu Kwon
- Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON M5S 3M2, Canada
| | - Zhongli Cai
- Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON M5S 3M2, Canada
| | - Azza Al-Mahrouki
- Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON M5S 3M2, Canada
| | - Raymond M. Reilly
- Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON M5S 3M2, Canada
- Department of Medical Imaging, University of Toronto, Toronto, ON M5T 1W7, Canada
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada
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13
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Eissler N, Altena R, Alhuseinalkhudhur A, Bragina O, Feldwisch J, Wuerth G, Loftenius A, Brun N, Axelsson R, Tolmachev V, Sörensen J, Frejd FY. Affibody PET Imaging of HER2-Expressing Cancers as a Key to Guide HER2-Targeted Therapy. Biomedicines 2024; 12:1088. [PMID: 38791050 PMCID: PMC11118066 DOI: 10.3390/biomedicines12051088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 04/27/2024] [Accepted: 05/08/2024] [Indexed: 05/26/2024] Open
Abstract
Human epidermal growth factor receptor 2 (HER2) is a major prognostic and predictive marker overexpressed in 15-20% of breast cancers. The diagnostic reference standard for selecting patients for HER2-targeted therapy is based on the analysis of tumor biopsies. Previously patients were defined as HER2-positive or -negative; however, with the approval of novel treatment options, specifically the antibody-drug conjugate trastuzumab deruxtecan, many breast cancer patients with tumors expressing low levels of HER2 have become eligible for HER2-targeted therapy. Such patients will need to be reliably identified by suitable diagnostic methods. Biopsy-based diagnostics are invasive, and repeat biopsies are not always feasible. They cannot visualize the heterogeneity of HER2 expression, leading to a substantial number of misdiagnosed patients. An alternative and highly accurate diagnostic method is molecular imaging with radiotracers. In the case of HER2, various studies demonstrate the clinical utility and feasibility of such approaches. Radiotracers based on Affibody® molecules, small, engineered affinity proteins with a size of ~6.5 kDa, are clinically validated molecules with favorable characteristics for imaging. In this article, we summarize the HER2-targeted therapeutic landscape, describe our experience with imaging diagnostics for HER2, and review the currently available clinical data on HER2-Affibody-based molecular imaging as a novel diagnostic tool in breast cancer and beyond.
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Affiliation(s)
| | - Renske Altena
- Department of Oncology-Pathology, Karolinska Institutet, 17164 Solna, Sweden
- Medical Unit Breast, Endocrine Tumors and Sarcoma, Theme Cancer, Karolinska Comprehensive Cancer Center, Karolinska University Hospital, 17164 Solna, Sweden
- Medical Radiation Physics and Nuclear Medicine, Functional Unit of Nuclear Medicine, Karolinska University Hospital, 14157 Huddinge, Sweden
| | - Ali Alhuseinalkhudhur
- Nuclear Medicine and PET, Department of Surgical Sciences, Uppsala University, 75310 Uppsala, Sweden
- Department of Immunology, Genetics and Pathology, Uppsala University, 75310 Uppsala, Sweden
| | - Olga Bragina
- Department of Nuclear Therapy and Diagnostic, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634055 Tomsk, Russia
- Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, Russia
| | | | | | | | | | - Rimma Axelsson
- Medical Radiation Physics and Nuclear Medicine, Functional Unit of Nuclear Medicine, Karolinska University Hospital, 14157 Huddinge, Sweden
- Department of Molecular Medicine and Surgery, Karolinska Institutet, 14152 Stockholm, Sweden
| | - Vladimir Tolmachev
- Department of Immunology, Genetics and Pathology, Uppsala University, 75310 Uppsala, Sweden
| | - Jens Sörensen
- Nuclear Medicine and PET, Department of Surgical Sciences, Uppsala University, 75310 Uppsala, Sweden
| | - Fredrik Y. Frejd
- Affibody AB, 17165 Solna, Sweden
- Department of Immunology, Genetics and Pathology, Uppsala University, 75310 Uppsala, Sweden
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14
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Valenza C, Guidi L, Battaiotto E, Trapani D, Sartore Bianchi A, Siena S, Curigliano G. Targeting HER2 heterogeneity in breast and gastrointestinal cancers. Trends Cancer 2024; 10:113-123. [PMID: 38008666 DOI: 10.1016/j.trecan.2023.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 10/29/2023] [Accepted: 11/01/2023] [Indexed: 11/28/2023]
Abstract
About 20% of breast and gastric cancers and 3% of colorectal carcinomas overexpress the human epidermal growth factor receptor 2 (HER2) and are sensitive to HER2-directed agents. The expression of HER2 may differ within the same tumoral lesion (spatial intralesional heterogeneity), from different tumor locations (spatial interlesional heterogeneity), and throughout treatments (temporal heterogeneity). Spatial and temporal heterogeneity may impact on response and resistance to HER2-targeting agents and its prevalence and predictive role changes across HER2-overexpressing solid tumors. Therefore, the definition and the characterization of HER2 heterogeneity pose many challenges and its implementation as a reproducible predictive biomarker would help in guiding treatment modulation.
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Affiliation(s)
- Carmine Valenza
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Lorenzo Guidi
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Elena Battaiotto
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Dario Trapani
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Andrea Sartore Bianchi
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy; Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Salvatore Siena
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy; Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Giuseppe Curigliano
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
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15
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Tozbikian G, Krishnamurthy S, Bui MM, Feldman M, Hicks DG, Jaffer S, Khoury T, Wei S, Wen H, Pohlmann P. Emerging Landscape of Targeted Therapy of Breast Cancers With Low Human Epidermal Growth Factor Receptor 2 Protein Expression. Arch Pathol Lab Med 2024; 148:242-255. [PMID: 37014972 DOI: 10.5858/arpa.2022-0335-ra] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/19/2023] [Indexed: 04/06/2023]
Abstract
CONTEXT.— Human epidermal growth factor receptor 2 (HER2) status in breast cancer is currently classified as negative or positive for selecting patients for anti-HER2 targeted therapy. The evolution of the HER2 status has included a new HER2-low category defined as an HER2 immunohistochemistry score of 1+ or 2+ without gene amplification. This new category opens the door to a targetable HER2-low breast cancer population for which new treatments may be effective. OBJECTIVE.— To review the current literature on the emerging category of breast cancers with low HER2 protein expression, including the clinical, histopathologic, and molecular features, and outline the clinical trials and best practice recommendations for identifying HER2-low-expressing breast cancers by immunohistochemistry. DATA SOURCES.— We conducted a literature review based on peer-reviewed original articles, review articles, regulatory communications, ongoing and past clinical trials identified through ClinicalTrials.gov, and the authors' practice experience. CONCLUSIONS.— The availability of new targeted therapy potentially effective for patients with breast cancers with low HER2 protein expression requires multidisciplinary recognition. In particular, pathologists need to recognize and identify this category to allow the optimal selection of patients for targeted therapy.
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Affiliation(s)
- Gary Tozbikian
- From the Department of Pathology, The Ohio State University, Wexner Medical Center, Columbus (Tozbikian)
| | - Savitri Krishnamurthy
- the Department of Pathology (Krishnamurthy), The University of Texas MD Anderson Cancer Center, Houston
| | - Marilyn M Bui
- the Department of Pathology, Moffitt Cancer Center & Research Institute, Tampa, Florida (Bui)
| | - Michael Feldman
- the Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (Feldman)
| | - David G Hicks
- the Department of Pathology, University of Rochester Medical Center, Rochester, New York (Hicks)
| | - Shabnam Jaffer
- the Department of Pathology, Mount Sinai Medical Center, New York, New York (Jaffer)
| | - Thaer Khoury
- the Department of Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, New York (Khoury)
| | - Shi Wei
- the Department of Pathology, University of Kansas Medical Center; Kansas City (Wei)
| | - Hannah Wen
- the Department of Pathology, Memorial Sloan Kettering Cancer Center; New York, New York (Wen)
| | - Paula Pohlmann
- the Department of Breast Medical Oncology (Pohlmann), The University of Texas MD Anderson Cancer Center, Houston
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16
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Guerriero JL, Lin JR, Pastorello RG, Du Z, Chen YA, Townsend MG, Shimada K, Hughes ME, Ren S, Tayob N, Zheng K, Mei S, Patterson A, Taneja KL, Metzger O, Tolaney SM, Lin NU, Dillon DA, Schnitt SJ, Sorger PK, Mittendorf EA, Santagata S. Qualification of a multiplexed tissue imaging assay and detection of novel patterns of HER2 heterogeneity in breast cancer. NPJ Breast Cancer 2024; 10:2. [PMID: 38167908 PMCID: PMC10761880 DOI: 10.1038/s41523-023-00605-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Accepted: 12/02/2023] [Indexed: 01/05/2024] Open
Abstract
Emerging data suggests that HER2 intratumoral heterogeneity (ITH) is associated with therapy resistance, highlighting the need for new strategies to assess HER2 ITH. A promising approach is leveraging multiplexed tissue analysis techniques such as cyclic immunofluorescence (CyCIF), which enable visualization and quantification of 10-60 antigens at single-cell resolution from individual tissue sections. In this study, we qualified a breast cancer-specific antibody panel, including HER2, ER, and PR, for multiplexed tissue imaging. We then compared the performance of these antibodies against established clinical standards using pixel-, cell- and tissue-level analyses, utilizing 866 tissue cores (representing 294 patients). To ensure reliability, the CyCIF antibodies were qualified against HER2 immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) data from the same samples. Our findings demonstrate the successful qualification of a breast cancer antibody panel for CyCIF, showing high concordance with established clinical antibodies. Subsequently, we employed the qualified antibodies, along with antibodies for CD45, CD68, PD-L1, p53, Ki67, pRB, and AR, to characterize 567 HER2+ invasive breast cancer samples from 189 patients. Through single-cell analysis, we identified four distinct cell clusters within HER2+ breast cancer exhibiting heterogeneous HER2 expression. Furthermore, these clusters displayed variations in ER, PR, p53, AR, and PD-L1 expression. To quantify the extent of heterogeneity, we calculated heterogeneity scores based on the diversity among these clusters. Our analysis revealed expression patterns that are relevant to breast cancer biology, with correlations to HER2 ITH and potential relevance to clinical outcomes.
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Affiliation(s)
- Jennifer L Guerriero
- Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA, 02115, USA.
- Breast Tumor Immunology Laboratory, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
- Ludwig Center for Cancer Research at Harvard, Harvard Medical School, Boston, MA, 02215, USA.
- Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA, 02215, USA.
| | - Jia-Ren Lin
- Ludwig Center for Cancer Research at Harvard, Harvard Medical School, Boston, MA, 02215, USA
- Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA, 02215, USA
| | - Ricardo G Pastorello
- Breast Tumor Immunology Laboratory, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
- Department of Pathology, Hospital Sírio Libanês, São Paulo, SP, 01308-050, Brazil
| | - Ziming Du
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
- Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yu-An Chen
- Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA, 02215, USA
| | - Madeline G Townsend
- Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA, 02115, USA
- Breast Tumor Immunology Laboratory, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
| | - Kenichi Shimada
- Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA, 02115, USA
- Breast Tumor Immunology Laboratory, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
- Ludwig Center for Cancer Research at Harvard, Harvard Medical School, Boston, MA, 02215, USA
- Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA, 02215, USA
| | - Melissa E Hughes
- Breast Oncology Program, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, 02215, USA
| | - Siyang Ren
- Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
| | - Nabihah Tayob
- Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
| | - Kelly Zheng
- Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA, 02115, USA
| | - Shaolin Mei
- Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA, 02215, USA
| | - Alyssa Patterson
- Breast Oncology Program, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, 02215, USA
| | - Krishan L Taneja
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Otto Metzger
- Breast Oncology Program, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, 02215, USA
| | - Sara M Tolaney
- Breast Oncology Program, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, 02215, USA
| | - Nancy U Lin
- Breast Oncology Program, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, 02215, USA
| | - Deborah A Dillon
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Stuart J Schnitt
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Peter K Sorger
- Ludwig Center for Cancer Research at Harvard, Harvard Medical School, Boston, MA, 02215, USA
- Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA, 02215, USA
| | - Elizabeth A Mittendorf
- Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA, 02115, USA
- Breast Tumor Immunology Laboratory, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
- Ludwig Center for Cancer Research at Harvard, Harvard Medical School, Boston, MA, 02215, USA
- Breast Oncology Program, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, 02215, USA
| | - Sandro Santagata
- Ludwig Center for Cancer Research at Harvard, Harvard Medical School, Boston, MA, 02215, USA
- Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA, 02215, USA
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
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Shan P, Wang C, Chen H, Yu J, Zhang H. Inonotsutriol E from Inonotus obliquus exhibits promising anti breast cancer activity via regulating the JAK2/STAT3 signaling pathway. Bioorg Chem 2023; 139:106741. [PMID: 37480812 DOI: 10.1016/j.bioorg.2023.106741] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Revised: 07/06/2023] [Accepted: 07/16/2023] [Indexed: 07/24/2023]
Abstract
The aim of the present study was to investigate the small molecule anticancer agents in the medicinal fungus Inonotus obliquus and further characterize their possible molecular mechanisms. Chemical fractionation of the ethanol extract of this fungus yielded a panel of lanostane triterpenoids (1-13) and their structures were characterized on the basis of spectroscopic methods. Subsequent preliminary biological screening on these triterpenoids revealed significant cytotoxicity against various tumor cell lines, and inonotsutriol E (ITE, 1) showed the best activity. Of note, ITE displayed stronger inhibitory effect on breast cancer (BC) than other tumor cell lines. Functional assays revealed that ITE significantly inhibited the growth and migration of BC cells and exerted promising antitumor activity in patient-derived organoids (PDO). Further mechanistic study demonstrated that the anti-BC activity of ITE was achieved via inhibiting JAK2/STAT3 signal axis. Taken together, the current work has demonstrated the therapeutic material basis of I. obliquus and provided further evidence for the traditional application of this medicinal species in cancer prevention and treatment.
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Affiliation(s)
- Peipei Shan
- Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China.
| | - Chao Wang
- School of Biological Science and Technology, University of Jinan, Jinan 250022, China
| | - He Chen
- Department of Research and Education, Fuwai Hospital, Qingdao 266034, China
| | - Jie Yu
- Affiliated Qingdao Central Hospital of Qingdao University, Qingdao Cancer Hospital, Qingdao 266042, China
| | - Hua Zhang
- School of Biological Science and Technology, University of Jinan, Jinan 250022, China.
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18
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Hensing WL, Gerratana L, Clifton K, Medford AJ, Velimirovic M, Shah AN, D'Amico P, Reduzzi C, Zhang Q, Dai CS, Denault EN, Bagegni NA, Opyrchal M, Ademuyiwa FO, Bose R, Behdad A, Ma CX, Bardia A, Cristofanilli M, Davis AA. Genetic Alterations Detected by Circulating Tumor DNA in HER2-Low Metastatic Breast Cancer. Clin Cancer Res 2023; 29:3092-3100. [PMID: 37265453 DOI: 10.1158/1078-0432.ccr-22-3785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 02/10/2023] [Accepted: 05/30/2023] [Indexed: 06/03/2023]
Abstract
PURPOSE About 50% of breast cancers are defined as HER2-low and may benefit from HER2-directed antibody-drug conjugates. While tissue sequencing has evaluated potential differences in genomic profiles for patients with HER2-low breast cancer, genetic alterations in circulating tumor DNA (ctDNA) have not been well described. EXPERIMENTAL DESIGN We retrospectively analyzed 749 patients with metastatic breast cancer (MBC) and ctDNA evaluation by Guardant360 from three academic medical centers. Tumors were classified as HER2-low, HER2-0 (IHC 0) or HER2-positive. Single-nucleotide variants, copy-number variants, and oncogenic pathways were compared across the spectrum of HER2 expression. Overall survival (OS) was evaluated by HER2 status and according to oncogenic pathways. RESULTS Patients with HER2-low had higher rates of PIK3CA mutations [relative risk ratio (RRR), 1.57; P = 0.024] compared with HER2-0 MBC. There were no differences in ERBB2 alterations or oncogenic pathways between HER2-low and HER2-0 MBC. Patients with HER2-positive MBC had more ERBB2 alterations (RRR, 12.43; P = 0.002 for amplification; RRR, 3.22; P = 0.047 for mutations, in the hormone receptor-positive cohort), fewer ERS1 mutations (RRR, 0.458; P = 0.029), and fewer ER pathway alterations (RRR, 0.321; P < 0.001). There was no difference in OS for HER2-low and HER2-0 MBC [HR, 1.01; 95% confidence interval (CI), 0.79-1.29], while OS was improved in HER2-positive MBC (HR, 0.32; 95% CI, 0.21-0.49; P < 0.001). CONCLUSIONS We observed a higher rate of PIK3CA mutations, but no significant difference in ERBB2 alterations, oncogenic pathways, or prognosis, between patients with HER2-low and HER2-0 MBC. If validated, our findings support the conclusion that HER2-low MBC does not represent a unique biological subtype.
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Affiliation(s)
- Whitney L Hensing
- Saint Luke's Cancer Institute, University of Missouri-KC School of Medicine, Kansas City, Missouri
| | - Lorenzo Gerratana
- Department of Medical Oncology-CRO Aviano, National Cancer Institute, IRCCS, Aviano, Italy
| | - Katherine Clifton
- Department of Medicine, Division of Hematology and Oncology, Washington University in St. Louis, St. Louis, Missouri
| | | | | | - Ami N Shah
- Department of Medicine, Division of Hematology and Oncology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Paolo D'Amico
- Department of Medicine, Division of Hematology and Oncology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | | | - Qiang Zhang
- Department of Medicine, Division of Hematology and Oncology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Charles S Dai
- Massachusetts General Hospital, Boston, Massachusetts
| | | | - Nusayba A Bagegni
- Department of Medicine, Division of Hematology and Oncology, Washington University in St. Louis, St. Louis, Missouri
| | - Mateusz Opyrchal
- Department of Medicine, Division of Hematology and Oncology, Washington University in St. Louis, St. Louis, Missouri
| | - Foluso O Ademuyiwa
- Department of Medicine, Division of Hematology and Oncology, Washington University in St. Louis, St. Louis, Missouri
| | - Ron Bose
- Department of Medicine, Division of Hematology and Oncology, Washington University in St. Louis, St. Louis, Missouri
| | - Amir Behdad
- Department of Medicine, Division of Hematology and Oncology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Cynthia X Ma
- Department of Medicine, Division of Hematology and Oncology, Washington University in St. Louis, St. Louis, Missouri
| | - Aditya Bardia
- Massachusetts General Hospital, Boston, Massachusetts
| | | | - Andrew A Davis
- Department of Medicine, Division of Hematology and Oncology, Washington University in St. Louis, St. Louis, Missouri
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19
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Franchina M, Pizzimenti C, Fiorentino V, Martini M, Ricciardi GRR, Silvestris N, Ieni A, Tuccari G. Low and Ultra-Low HER2 in Human Breast Cancer: An Effort to Define New Neoplastic Subtypes. Int J Mol Sci 2023; 24:12795. [PMID: 37628975 PMCID: PMC10454084 DOI: 10.3390/ijms241612795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 08/09/2023] [Accepted: 08/13/2023] [Indexed: 08/27/2023] Open
Abstract
HER2-low and ultra-low breast cancer (BC) have been recently proposed as new subcategories of HER2 BC, supporting a re-consideration of immunohistochemical negative scores of 0, 1+ and the 2+/in situ hybridization (ISH) negative phenotype. In the present review, we outline the criteria needed to exactly distinguish HER2-low and ultra-low BC. Recent clinical trials have demonstrated significant clinical benefits of novel HER2 directing antibody-drug conjugates (ADCs) in treating these groups of tumors. In particular, trastuzumab-deruxtecan (T-Dxd), a HER2-directing ADC, has been recently approved by the US Food and Drug Administration as the first targeted therapy to treat HER2-low BC. Furthermore, ongoing trials, such as the DESTINY-Breast06 trial, are currently evaluating ADCs in patients with HER2-ultra low BC. Finally, we hope that new guidelines may help to codify HER2-low and ultra-low BC, increasing our knowledge of tumor biology and improving a targetable new therapeutical treatment.
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Affiliation(s)
- Mariausilia Franchina
- Department of Human Pathology in Adult and Developmental Age “Gaetano Barresi”, Section of Pathology, University of Messina, 98125 Messina, Italy; (M.F.); (V.F.); (M.M.); (N.S.); (A.I.)
| | - Cristina Pizzimenti
- Department of Biomedical, Dental, Morphological and Functional Imaging Sciences, University of Messina, 98125 Messina, Italy;
| | - Vincenzo Fiorentino
- Department of Human Pathology in Adult and Developmental Age “Gaetano Barresi”, Section of Pathology, University of Messina, 98125 Messina, Italy; (M.F.); (V.F.); (M.M.); (N.S.); (A.I.)
| | - Maurizio Martini
- Department of Human Pathology in Adult and Developmental Age “Gaetano Barresi”, Section of Pathology, University of Messina, 98125 Messina, Italy; (M.F.); (V.F.); (M.M.); (N.S.); (A.I.)
| | | | - Nicola Silvestris
- Department of Human Pathology in Adult and Developmental Age “Gaetano Barresi”, Section of Pathology, University of Messina, 98125 Messina, Italy; (M.F.); (V.F.); (M.M.); (N.S.); (A.I.)
| | - Antonio Ieni
- Department of Human Pathology in Adult and Developmental Age “Gaetano Barresi”, Section of Pathology, University of Messina, 98125 Messina, Italy; (M.F.); (V.F.); (M.M.); (N.S.); (A.I.)
| | - Giovanni Tuccari
- Department of Human Pathology in Adult and Developmental Age “Gaetano Barresi”, Section of Pathology, University of Messina, 98125 Messina, Italy; (M.F.); (V.F.); (M.M.); (N.S.); (A.I.)
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20
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Fan Y, Zou L, Zhong X, Wang Z, Wang Y, Luo C, Zheng H, Wang Y. Characteristics of DNA macro-alterations in breast cancer with liver metastasis before treatment. BMC Genomics 2023; 24:391. [PMID: 37434117 DOI: 10.1186/s12864-023-09497-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 06/30/2023] [Indexed: 07/13/2023] Open
Abstract
BACKGROUND Whole-genome doubling (WGD) has been observed in 30% of cancers, followed by a highly complex rearranged karyotype unfavourable to breast cancer's outcome. However, the macro-alterations that characterise liver metastasis in breast cancer(BC) are poorly understood. Here, we conducted a whole-genome sequencing analysis of liver metastases to explore the status and the time frame model of these macro-alterations in pre-treatment patients with metastatic breast cancer. RESULTS Whole-genome sequencing was conducted in 11 paired primary tumours, lymph node metastasis, and liver metastasis fresh samples from four patients with late-stage breast cancer. We also chose five postoperative frozen specimens from patients with early-stage breast cancer before any treatment as control. Surprisingly, all four liver metastasis samples were classified as WGD + . However, the previous study reported that WGD happened in 30% of cancers and 2/5 in our early-stage samples. WGD was not observed in the two separate primary tumours and one lymph node metastasis of one patient with metastatic BC, but her liver metastasis showed an early burst of bi-allelic copy number gain. The phylogenetic tree proves her 4 tumour samples were the polyclonal origin and only one WGD + clone metastasis to the liver. Another 3 metastatic BC patients' primary tumour and lymph node metastasis experienced WGD as well as liver metastasis, and they all showed similar molecular time-frame of copy number(CN) gain across locations within the same patient. These patients' tumours were of monoclonal origin, and WGD happened in a founding clone before metastasis, explaining that all samples share the CN-gain time frame. After WGD, the genomes usually face instability to evolve other macro-alterations. For example, a greater quantity and variety of complex structural variations (SVs) were detected in WGD + samples. The breakpoints were enriched in the chr17: 39 Mb-40 Mb tile, which contained the HER2 gene, resulting in the formation of tyfonas, breakage-fusion-bridge cycles, and double minutes. These complex SVs may be involved in the evolutionary mechanisms of the dramatic increase of HER2 copy number. CONCLUSION Our work revealed that the WGD + clone might be a critical evolution step for liver metastasis and favoured following complex SV of breast cancer.
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Affiliation(s)
- Yu Fan
- Breast Center and Multi-Omics Laboratory of Breast Diseases, West China Hospital, Sichuan University, 5 Gongxing Street, Wuhou District, Chengdu, 610041, China
| | - Linglin Zou
- Breast Center and Multi-Omics Laboratory of Breast Diseases, West China Hospital, Sichuan University, 5 Gongxing Street, Wuhou District, Chengdu, 610041, China
| | - Xiaorong Zhong
- Breast Center and Multi-Omics Laboratory of Breast Diseases, West China Hospital, Sichuan University, 5 Gongxing Street, Wuhou District, Chengdu, 610041, China
| | - Zhu Wang
- Breast Center and Multi-Omics Laboratory of Breast Diseases, West China Hospital, Sichuan University, 5 Gongxing Street, Wuhou District, Chengdu, 610041, China
| | - Yu Wang
- Breast Center and Multi-Omics Laboratory of Breast Diseases, West China Hospital, Sichuan University, 5 Gongxing Street, Wuhou District, Chengdu, 610041, China
| | - Chuanxu Luo
- Breast Center and Multi-Omics Laboratory of Breast Diseases, West China Hospital, Sichuan University, 5 Gongxing Street, Wuhou District, Chengdu, 610041, China
| | - Hong Zheng
- Breast Center and Multi-Omics Laboratory of Breast Diseases, West China Hospital, Sichuan University, 5 Gongxing Street, Wuhou District, Chengdu, 610041, China.
| | - Yanping Wang
- Breast Center and Multi-Omics Laboratory of Breast Diseases, West China Hospital, Sichuan University, 5 Gongxing Street, Wuhou District, Chengdu, 610041, China.
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21
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Hou Y, Nitta H, Li Z. HER2 Intratumoral Heterogeneity in Breast Cancer, an Evolving Concept. Cancers (Basel) 2023; 15:2664. [PMID: 37345001 DOI: 10.3390/cancers15102664] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 04/27/2023] [Accepted: 05/05/2023] [Indexed: 06/23/2023] Open
Abstract
Amplification and/or overexpression of human epidermal growth factor receptor 2 (HER2) in breast cancer is associated with an adverse prognosis. The introduction of anti-HER2 targeted therapy has dramatically improved the clinical outcomes of patients with HER2-positive breast cancer. Unfortunately, a significant number of patients eventually relapse and develop distant metastasis. HER2 intratumoral heterogeneity (ITH) has been reported to be associated with poor prognosis in patients with anti-HER2 targeted therapies and was proposed to be a potential mechanism for anti-HER2 resistance. In this review, we described the current definition, common types of HER2 ITH in breast cancer, the challenge in interpretation of HER2 status in cases showing ITH and the clinical applications of anti-HER2 agents in breast cancer showing heterogeneous HER2 expression. Digital image analysis has emerged as an objective and reproducible scoring method and its role in the assessment of HER2 status with ITH remains to be demonstrated.
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Affiliation(s)
- Yanjun Hou
- Department of Pathology and Laboratory Medicine, Atrium Health Wake Forest Baptist Medical Center, Winston-Salem, NC 28659, USA
| | | | - Zaibo Li
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
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22
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Zhang XN, Gao Y, Zhang XY, Guo NJ, Hou WQ, Wang SW, Zheng YC, Wang N, Liu HM, Wang B. Detailed curriculum vitae of HER2-targeted therapy. Pharmacol Ther 2023; 245:108417. [PMID: 37075933 DOI: 10.1016/j.pharmthera.2023.108417] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Revised: 04/10/2023] [Accepted: 04/13/2023] [Indexed: 04/21/2023]
Abstract
With the booming development of precision medicine, molecular targeted therapy has been widely used in clinical oncology treatment due to a smaller number of side effects and its superior accuracy compared to that of traditional strategies. Among them, human epidermal growth factor receptor 2 (HER2)-targeted therapy has attracted considerable attention and has been used in the clinical treatment of breast and gastric cancer. Despite excellent clinical effects, HER2-targeted therapy remains in its infancy due to its resulting inherent and acquired resistance. Here, a comprehensive overview of HER2 in numerous cancers is presented, including its biological role, involved signaling pathways, and the status of HER2-targeted therapy.
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Affiliation(s)
- Xiao-Nan Zhang
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, China
| | - Ya Gao
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, China
| | - Xi-Ya Zhang
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, China
| | - Ning-Jie Guo
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, China
| | - Wen-Qing Hou
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, China
| | - Shu-Wu Wang
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, China
| | - Yi-Chao Zheng
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, China
| | - Ning Wang
- The School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Hong-Min Liu
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, China.
| | - Bo Wang
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China; State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, China.
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23
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Unlocking the Resistance to Anti-HER2 Treatments in Breast Cancer: The Issue of HER2 Spatial Distribution. Cancers (Basel) 2023; 15:cancers15051385. [PMID: 36900178 PMCID: PMC10000152 DOI: 10.3390/cancers15051385] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 02/20/2023] [Accepted: 02/21/2023] [Indexed: 02/25/2023] Open
Abstract
Approximately 15% of breast cancers are classified as HER2-positive, with an amplification of the ERBB2 gene and/or an overexpression of the HER2 protein. Up to 30% of HER2-positive breast cancers shows heterogeneity in HER2 expression and different patterns of spatial distribution, i.e., the variability in the distribution and expression of the HER2 protein within a single tumour. Spatial heterogeneity may potentially affect treatment, response, assessment of HER2 status and consequently, may impact on the best treatment strategy. Understanding this feature can help clinicians to predict response to HER2-targeted therapies and patient outcomes, and to fine tune treatment decisions. This review summarizes the available evidence on HER2 heterogeneity and spatial distribution and how this may affect current available treatment choices, exploring possible opportunities for overcoming this issue, such as novel pharmacological agents, belonging to the group of antibody-drug conjugates.
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24
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Chen JW, Murugesan K, Newberg JY, Sokol ES, Savage HM, Stout TJ, Maund SL, Hutchinson KE. Comparison of PIK3CA Mutation Prevalence in Breast Cancer Across Predicted Ancestry Populations. JCO Precis Oncol 2022; 6:e2200341. [PMID: 36446041 PMCID: PMC9812634 DOI: 10.1200/po.22.00341] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 08/31/2022] [Accepted: 10/11/2022] [Indexed: 11/30/2022] Open
Abstract
PURPOSE Understanding the differences in biomarker prevalence that may exist among diverse populations is invaluable to accurately forecast biomarker-driven clinical trial enrollment metrics and to advance inclusive research and health equity. This study evaluated the frequency and types of PIK3CA mutations (PIK3CAmut) detected in predicted genetic ancestry subgroups across breast cancer (BC) subtypes. METHODS Analyses were conducted using real-world genomic data from adult patients with BC treated in an academic or community setting in the United States and whose tumor tissue was submitted for comprehensive genomic profiling. RESULTS Of 36,151 patients with BC (median age, 58 years; 99% female), the breakdown by predicted genetic ancestry was 75% European, 14% African, 6% Central/South American, 3% East Asian, and 1% South Asian. We demonstrated that patients of African ancestry are less likely to have tumors that harbor PIK3CAmut compared with patients of European ancestry with estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) BC (37% [949/2,593] v 44% [7,706/17,637]; q = 4.39E-11) and triple-negative breast cancer (8% [179/2,199] v 14% [991/7,072]; q = 6.07E-13). Moreover, we found that PIK3CAmut were predominantly composed of hotspot mutations, of which mutations at H1047 were the most prevalent across BC subtypes (35%-41% ER+/HER2- BC; 43%-61% HER2+ BC; 40%-59% triple-negative breast cancer). CONCLUSION This analysis established that tumor PIK3CAmut prevalence can differ among predicted genetic ancestries across BC subtypes on the basis of the largest comprehensive genomic profiling data set of patients with cancer treated in the United States. This study highlights the need for equitable representation in research studies, which is imperative to ensuring better health outcomes for all.
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Affiliation(s)
- Jessica W. Chen
- Oncology Biomarker Development, Genentech, Inc, South San Francisco, CA
| | | | | | - Ethan S. Sokol
- Cancer Genomics Research, Foundation Medicine, Inc, Cambridge, MA
| | - Heidi M. Savage
- Oncology Biomarker Development, Genentech, Inc, South San Francisco, CA
| | - Thomas J. Stout
- Product Development Oncology, Genentech, Inc, South San Francisco, CA
| | - Sophia L. Maund
- Oncology Biomarker Development, Genentech, Inc, South San Francisco, CA
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25
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Wang N, Cao Y, Si C, Shao P, Su G, Wang K, Bao J, Yang L. Emerging Role of ERBB2 in Targeted Therapy for Metastatic Colorectal Cancer: Signaling Pathways to Therapeutic Strategies. Cancers (Basel) 2022; 14:5160. [PMID: 36291943 PMCID: PMC9600272 DOI: 10.3390/cancers14205160] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 10/16/2022] [Accepted: 10/18/2022] [Indexed: 12/24/2022] Open
Abstract
Despite recent improvements in the comprehensive therapy of malignancy, metastatic colorectal cancer (mCRC) continues to have a poor prognosis. Notably, 5% of mCRC cases harbor Erb-B2 receptor tyrosine kinase 2 (ERBB2) alterations. ERBB2, commonly referred to as human epidermal growth factor receptor 2, is a member of the human epidermal growth factor receptor family of protein tyrosine kinases. In addition to being a recognized therapeutic target in the treatment of gastric and breast malignancies, it is considered crucial in the management of CRC. In this review, we describe the molecular biology of ERBB2 from the perspective of biomarkers for mCRC-targeted therapy, including receptor structures, signaling pathways, gene alterations, and their detection methods. We also discuss the relationship between ERBB2 aberrations and the underlying mechanisms of resistance to anti-EGFR therapy and immunotherapy tolerance in these patients with a focus on novel targeted therapeutics and ongoing clinical trials. This may aid the development of a new standard of care in patients with ERBB2-positive mCRC.
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Affiliation(s)
- Nannan Wang
- Department of Colorectal Surgery, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing 210009, China
| | - Yuepeng Cao
- Department of Colorectal Surgery, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing 210009, China
| | - Chengshuai Si
- Department of Colorectal Surgery, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing 210009, China
| | - Peng Shao
- Department of Colorectal Surgery, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing 210009, China
| | - Guoqing Su
- Department of Colorectal Surgery, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing 210009, China
| | - Ke Wang
- Department of Colorectal Surgery, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing 210009, China
| | - Jun Bao
- Department of Medical Oncology, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing 210009, China
| | - Liu Yang
- Department of Colorectal Surgery, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing 210009, China
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26
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Resistance to Trastuzumab. Cancers (Basel) 2022; 14:cancers14205115. [PMID: 36291900 PMCID: PMC9600208 DOI: 10.3390/cancers14205115] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Revised: 10/12/2022] [Accepted: 10/17/2022] [Indexed: 11/17/2022] Open
Abstract
Simple Summary Trastuzumab is a humanized antibody that has significantly improved the management and treatment outcomes of patients with cancers that overexpress HER2. Many research groups, both in academia and industry, have contributed towards understanding the various mechanisms engaged by trastuzumab to mediate its anti-tumor effects. Nevertheless, data from several clinical studies have indicated that a significant proportion of patients exhibit primary or acquired resistance to trastuzumab therapy. In this article, we discuss underlying mechanisms that contribute towards to resistance. Furthermore, we discuss the potential strategies to overcome some of the mechanisms of resistance to enhance the therapeutic efficacy of trastuzumab and other therapies based on it. Abstract One of the most impactful biologics for the treatment of breast cancer is the humanized monoclonal antibody, trastuzumab, which specifically recognizes the HER2/neu (HER2) protein encoded by the ERBB2 gene. Useful for both advanced and early breast cancers, trastuzumab has multiple mechanisms of action. Classical mechanisms attributed to trastuzumab action include cell cycle arrest, induction of apoptosis, and antibody-dependent cell-mediated cytotoxicity (ADCC). Recent studies have identified the role of the adaptive immune system in the clinical actions of trastuzumab. Despite the multiple mechanisms of action, many patients demonstrate resistance, primary or adaptive. Newly identified molecular and cellular mechanisms of trastuzumab resistance include induction of immune suppression, vascular mimicry, generation of breast cancer stem cells, deregulation of long non-coding RNAs, and metabolic escape. These newly identified mechanisms of resistance are discussed in detail in this review, particularly considering how they may lead to the development of well-rationalized, patient-tailored combinations that improve patient survival.
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27
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Jacobs AT, Martinez Castaneda-Cruz D, Rose MM, Connelly L. Targeted therapy for breast cancer: An overview of drug classes and outcomes. Biochem Pharmacol 2022; 204:115209. [PMID: 35973582 DOI: 10.1016/j.bcp.2022.115209] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 08/07/2022] [Accepted: 08/09/2022] [Indexed: 12/20/2022]
Abstract
The last 25 years have seen significant growth in new therapeutic options for breast cancer, termed targeted therapies based on their ability to block specific pathways known to drive breast tumor growth and survival. Introduction of these drugs has been made possible through advances in the understanding of breast cancer biology. While the promise of targeted therapy for breast cancer has been clear for some time, the experience of the clinical use of multiple drugs and drug classes allows us to now present a summary and perspective as to the success and impact of this endeavor. Here we will review breast cancer targeted therapeutics in clinical use. We will provide the rationale for their indications and summarize clinical data in patients with different breast cancer subtypes, their impact on breast cancer progression and survival and their major adverse effects. The focus of this review will be on the development that has occurred within classes of targeted therapies and subsequent impact on breast cancer patient outcomes. We will conclude with a perspective on the role of targeted therapy in breast cancer treatment and highlight future areas of development.
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Affiliation(s)
- Aaron T Jacobs
- California University of Science and Medicine, 1501 Violet Street, Colton, CA 92324, United States
| | | | - Mark M Rose
- California University of Science and Medicine, 1501 Violet Street, Colton, CA 92324, United States
| | - Linda Connelly
- California University of Science and Medicine, 1501 Violet Street, Colton, CA 92324, United States.
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Beyond Genetics: Metastasis as an Adaptive Response in Breast Cancer. Int J Mol Sci 2022; 23:ijms23116271. [PMID: 35682953 PMCID: PMC9181003 DOI: 10.3390/ijms23116271] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 05/26/2022] [Accepted: 06/01/2022] [Indexed: 01/27/2023] Open
Abstract
Metastatic disease represents the primary cause of breast cancer (BC) mortality, yet it is still one of the most enigmatic processes in the biology of this tumor. Metastatic progression includes distinct phases: invasion, intravasation, hematogenous dissemination, extravasation and seeding at distant sites, micro-metastasis formation and metastatic outgrowth. Whole-genome sequencing analyses of primary BC and metastases revealed that BC metastatization is a non-genetically selected trait, rather the result of transcriptional and metabolic adaptation to the unfavorable microenvironmental conditions which cancer cells are exposed to (e.g., hypoxia, low nutrients, endoplasmic reticulum stress and chemotherapy administration). In this regard, the latest multi-omics analyses unveiled intra-tumor phenotypic heterogeneity, which determines the polyclonal nature of breast tumors and constitutes a challenge for clinicians, correlating with patient poor prognosis. The present work reviews BC classification and epidemiology, focusing on the impact of metastatic disease on patient prognosis and survival, while describing general principles and current in vitro/in vivo models of the BC metastatic cascade. The authors address here both genetic and phenotypic intrinsic heterogeneity of breast tumors, reporting the latest studies that support the role of the latter in metastatic spreading. Finally, the review illustrates the mechanisms underlying adaptive stress responses during BC metastatic progression.
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29
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Digital Imaging Correlation of Immunohistochemistry and Fluorescence in Situ Hybridization in Breast Carcinoma Cases with HER2 Genetic Heterogeneity. Hum Pathol 2022; 126:129-135. [PMID: 35623464 DOI: 10.1016/j.humpath.2022.05.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 05/18/2022] [Indexed: 11/20/2022]
Abstract
Genetic Heterogeneity (GH) is a rare but important event in evaluation of HER2 amplification status. We investigated whether HER2 FISH Genetic Heterogeneity (GH) correlated with increased protein expression by immunohistochemistry (IHC) and/or morphologic features using image analyses. Retrospective search of HER2 FISH GH cases 2016-2020 was performed. Cases with both FISH and IHC slides available were considered eligible and were digitally imaged. Additional demographic, histological, and treatment information was compiled from pathology and medical records when available. Overall, 11/15 (73.3%) of the cases had HER2 FISH GH that matched to areas of HER2 over-expression or focally different morphology. Nine cases with areas of gene amplification overlapped with <10% of intense circumferential protein expression ("Mini 3+,"), and one case with focal micropapillary features. Clinical information was available on 6 (40%) patients, all were alive with no evidence of disease (mean follow up 30. 5 months; range 12-65 months). One patient with GH and a lymph node metastasis showed non-amplified population in the nodal tumor. GH when defined as discrete clusters of amplified cells following 2013 ASCO/CAP guidelines, -even when less than 10 % of the tumor cells-frequently has morphologic correlates such as focal intense protein overexpression or micropapillary morphology. Clinical significance of these focal gene amplification and protein over-expression needs to be further investigated.
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30
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Chen Y, Xu J, Pan W, Xu X, Ma X, Chu Y, Wang L, Pang S, Li Y, Zou B, Zhou G, Gu J. Galectin‐3 enhances trastuzumab resistance by regulating cancer malignancy and stemness in
HER2
‐positive breast cancer cells. Thorac Cancer 2022; 13:1961-1973. [PMID: 35599381 PMCID: PMC9250839 DOI: 10.1111/1759-7714.14474] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 04/29/2022] [Accepted: 05/02/2022] [Indexed: 11/30/2022] Open
Abstract
Purpose The aim of this study was to explore the role of galectin‐3 in human epidermal growth factor receptor 2 (HER2)‐positive breast cancer cells and the potential mechanism. Methods Kaplan–Meier (KM)‐plot and The Cancer Genome Atlas (TCGA) databases were used to study the role of galectin‐3 in the prognosis of HER2‐positive breast cancer. The effects of galectin‐3 on cell proliferation, migration, invasion, and colony formation ability in HER2‐positive breast cancer cells were examined. The relationship between galectin‐3 and important components in the HER2 pathways, including HER2, epidermal growth factor receptor (EGFR), protein kinase B (AKT), and phosphatase and tensin homolog (PTEN), was further studied. Lentivirus and CRISPR/Cas9 were used to construct stable cell lines. Cell counting kit‐8 (CCK‐8) and apoptosis assays were used to study the relationship between galectin‐3 and trastuzumab. The effect of galectin‐3 on cell stemness was studied by mammosphere formation assay. The effects of galectin‐3 on stemness biomarkers and the Notch1 pathway were examined. Tumorigenic models were used to evaluate the effects of galectin‐3 on tumorigenesis and the therapeutic effect of trastuzumab in vivo. Results HER2‐positive breast cancer patients with a high expression level of LGALS3 (the gene encoding galectin‐3) messenger RNA (mRNA) showed a poor prognosis. Galectin‐3 promoted cancer malignancy through phosphoinositide 3‐kinase (PI3K)/AKT signaling pathway activation and upregulated stemness by activating the Notch1 signaling pathway in HER2‐positive breast cancer cells. These two factors contributed to the enhancement of trastuzumab resistance in cells. Knockout of LGALS3 had a synergistic therapeutic effect with trastuzumab both in vitro and in vivo. Conclusions Galectin‐3 may represent a prognostic predictor and therapeutic target for HER2‐positive breast cancer.
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Affiliation(s)
- Yuqiu Chen
- Research Institute of General Surgery, Affiliated Jinling Hospital Medical School of Nanjing University Nanjing China
- Department of Clinical Pharmacy, Affiliated Jinling Hospital, State Key Laboratory of Analytical Chemistry for Life Science and Jiangsu Key Laboratory of Molecular Medicine Medical School of Nanjing University Nanjing China
| | - Jiawei Xu
- Research Institute of General Surgery, Affiliated Jinling Hospital Medical School of Nanjing University Nanjing China
| | - Wang Pan
- Department of Clinical Pharmacy, Affiliated Jinling Hospital, State Key Laboratory of Analytical Chemistry for Life Science and Jiangsu Key Laboratory of Molecular Medicine Medical School of Nanjing University Nanjing China
| | - Xiaofan Xu
- Research Institute of General Surgery, Affiliated Jinling Hospital Medical School of Nanjing University Nanjing China
| | - Xueping Ma
- Department of Clinical Pharmacy, Affiliated Jinling Hospital, State Key Laboratory of Analytical Chemistry for Life Science and Jiangsu Key Laboratory of Molecular Medicine Medical School of Nanjing University Nanjing China
| | - Ya'nan Chu
- Department of Clinical Pharmacy, Affiliated Jinling Hospital, State Key Laboratory of Analytical Chemistry for Life Science and Jiangsu Key Laboratory of Molecular Medicine Medical School of Nanjing University Nanjing China
| | - Lu Wang
- Research Institute of General Surgery, Affiliated Jinling Hospital Medical School of Nanjing University Nanjing China
| | - Shuyun Pang
- Department of Clinical Pharmacy, Affiliated Jinling Hospital, State Key Laboratory of Analytical Chemistry for Life Science and Jiangsu Key Laboratory of Molecular Medicine Medical School of Nanjing University Nanjing China
| | - Yujiao Li
- Department of Clinical Pharmacy, Affiliated Jinling Hospital, State Key Laboratory of Analytical Chemistry for Life Science and Jiangsu Key Laboratory of Molecular Medicine Medical School of Nanjing University Nanjing China
| | - Bingjie Zou
- Key Laboratory of Drug Quality Control and Pharmacovigilance of Ministry of Education, School of Pharmacy China Pharmaceutical University Nanjing China
| | - Guohua Zhou
- Department of Clinical Pharmacy, Affiliated Jinling Hospital, State Key Laboratory of Analytical Chemistry for Life Science and Jiangsu Key Laboratory of Molecular Medicine Medical School of Nanjing University Nanjing China
- Department of Clinical Pharmacy, Jinling Hospital, School of Pharmacy Southern Medical University Guangzhou China
| | - Jun Gu
- Research Institute of General Surgery, Affiliated Jinling Hospital Medical School of Nanjing University Nanjing China
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31
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Kazerouni AS, Hormuth DA, Davis T, Bloom MJ, Mounho S, Rahman G, Virostko J, Yankeelov TE, Sorace AG. Quantifying Tumor Heterogeneity via MRI Habitats to Characterize Microenvironmental Alterations in HER2+ Breast Cancer. Cancers (Basel) 2022; 14:1837. [PMID: 35406609 PMCID: PMC8997932 DOI: 10.3390/cancers14071837] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 04/02/2022] [Accepted: 04/02/2022] [Indexed: 01/27/2023] Open
Abstract
This study identifies physiological habitats using quantitative magnetic resonance imaging (MRI) to elucidate intertumoral differences and characterize microenvironmental response to targeted and cytotoxic therapy. BT-474 human epidermal growth factor receptor 2 (HER2+) breast tumors were imaged before and during treatment (trastuzumab, paclitaxel) with diffusion-weighted MRI and dynamic contrast-enhanced MRI to measure tumor cellularity and vascularity, respectively. Tumors were stained for anti-CD31, anti-ɑSMA, anti-CD45, anti-F4/80, anti-pimonidazole, and H&E. MRI data was clustered to identify and label each habitat in terms of vascularity and cellularity. Pre-treatment habitat composition was used stratify tumors into two "tumor imaging phenotypes" (Type 1, Type 2). Type 1 tumors showed significantly higher percent tumor volume of the high-vascularity high-cellularity (HV-HC) habitat compared to Type 2 tumors, and significantly lower volume of low-vascularity high-cellularity (LV-HC) and low-vascularity low-cellularity (LV-LC) habitats. Tumor phenotypes showed significant differences in treatment response, in both changes in tumor volume and physiological composition. Significant positive correlations were found between histological stains and tumor habitats. These findings suggest that the differential baseline imaging phenotypes can predict response to therapy. Specifically, the Type 1 phenotype indicates increased sensitivity to targeted or cytotoxic therapy compared to Type 2 tumors.
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Affiliation(s)
- Anum S. Kazerouni
- Department of Radiology, The University of Washington, Seattle, WA 98104, USA;
| | - David A. Hormuth
- Oden Institute for Computational Engineering and Sciences, The University of Texas at Austin, Austin, TX 78712, USA;
- Livestrong Cancer Institutes, The University of Texas at Austin, Austin, TX 78712, USA;
| | - Tessa Davis
- Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USA; (T.D.); (M.J.B.); (S.M.); (G.R.)
| | - Meghan J. Bloom
- Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USA; (T.D.); (M.J.B.); (S.M.); (G.R.)
| | - Sarah Mounho
- Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USA; (T.D.); (M.J.B.); (S.M.); (G.R.)
| | - Gibraan Rahman
- Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USA; (T.D.); (M.J.B.); (S.M.); (G.R.)
| | - John Virostko
- Livestrong Cancer Institutes, The University of Texas at Austin, Austin, TX 78712, USA;
- Department of Diagnostic Medicine, The University of Texas at Austin, Austin, TX 78712, USA
- Department of Oncology, The University of Texas at Austin, Austin, TX 78712, USA
| | - Thomas E. Yankeelov
- Oden Institute for Computational Engineering and Sciences, The University of Texas at Austin, Austin, TX 78712, USA;
- Livestrong Cancer Institutes, The University of Texas at Austin, Austin, TX 78712, USA;
- Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USA; (T.D.); (M.J.B.); (S.M.); (G.R.)
- Department of Diagnostic Medicine, The University of Texas at Austin, Austin, TX 78712, USA
- Department of Oncology, The University of Texas at Austin, Austin, TX 78712, USA
- Department of Imaging Physics, MD Anderson Cancer Center, The University of Texas, Houston, TX 77030, USA
| | - Anna G. Sorace
- Department of Biomedical Engineering, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Department of Radiology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
- O’Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
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32
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Shembrey C, Smith J, Grandin M, Williams N, Cho HJ, Mølck C, Behrenbruch C, Thomson BNJ, Heriot AG, Merino D, Hollande F. Longitudinal Monitoring of Intra-Tumoural Heterogeneity Using Optical Barcoding of Patient-Derived Colorectal Tumour Models. Cancers (Basel) 2022; 14:581. [PMID: 35158849 PMCID: PMC8833441 DOI: 10.3390/cancers14030581] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 01/16/2022] [Accepted: 01/19/2022] [Indexed: 02/01/2023] Open
Abstract
Geno- and phenotypic heterogeneity amongst cancer cell subpopulations are established drivers of treatment resistance and tumour recurrence. However, due to the technical difficulty associated with studying such intra-tumoural heterogeneity, this phenomenon is seldom interrogated in conventional cell culture models. Here, we employ a fluorescent lineage technique termed "optical barcoding" (OBC) to perform simultaneous longitudinal tracking of spatio-temporal fate in 64 patient-derived colorectal cancer subclones. To do so, patient-derived cancer cell lines and organoids were labelled with discrete combinations of reporter constructs, stably integrated into the genome and thus passed on from the founder cell to all its clonal descendants. This strategy enables the longitudinal monitoring of individual cell lineages based upon their unique optical barcodes. By designing a novel panel of six fluorescent proteins, the maximum theoretical subpopulation resolution of 64 discriminable subpopulations was achieved, greatly improving throughput compared with previous studies. We demonstrate that all subpopulations can be purified from complex clonal mixtures via flow cytometry, permitting the downstream isolation and analysis of any lineages of interest. Moreover, we outline an optimized imaging protocol that can be used to image optical barcodes in real-time, allowing for clonal dynamics to be resolved in live cells. In contrast with the limited intra-tumour heterogeneity observed in conventional 2D cell lines, the OBC technique was successfully used to quantify dynamic clonal expansions and contractions in 3D patient-derived organoids, which were previously demonstrated to better recapitulate the heterogeneity of their parental tumour material. In summary, we present OBC as a user-friendly, inexpensive, and high-throughput technique for monitoring intra-tumoural heterogeneity in in vitro cell culture models.
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Affiliation(s)
- Carolyn Shembrey
- Department of Clinical Pathology, University of Melbourne, Melbourne, VIC 3000, Australia; (C.S.); (J.S.); (M.G.); (N.W.); (C.M.); (C.B.)
- Victorian Comprehensive Cancer Centre, University of Melbourne Centre for Cancer Research, Melbourne, VIC 3000, Australia
| | - Jai Smith
- Department of Clinical Pathology, University of Melbourne, Melbourne, VIC 3000, Australia; (C.S.); (J.S.); (M.G.); (N.W.); (C.M.); (C.B.)
- Victorian Comprehensive Cancer Centre, University of Melbourne Centre for Cancer Research, Melbourne, VIC 3000, Australia
| | - Mélodie Grandin
- Department of Clinical Pathology, University of Melbourne, Melbourne, VIC 3000, Australia; (C.S.); (J.S.); (M.G.); (N.W.); (C.M.); (C.B.)
- Victorian Comprehensive Cancer Centre, University of Melbourne Centre for Cancer Research, Melbourne, VIC 3000, Australia
| | - Nathalia Williams
- Department of Clinical Pathology, University of Melbourne, Melbourne, VIC 3000, Australia; (C.S.); (J.S.); (M.G.); (N.W.); (C.M.); (C.B.)
- Victorian Comprehensive Cancer Centre, University of Melbourne Centre for Cancer Research, Melbourne, VIC 3000, Australia
| | - Hyun-Jung Cho
- Biological Optical Microscopy Platform, University of Melbourne, Melbourne, VIC 3010, Australia;
| | - Christina Mølck
- Department of Clinical Pathology, University of Melbourne, Melbourne, VIC 3000, Australia; (C.S.); (J.S.); (M.G.); (N.W.); (C.M.); (C.B.)
- Victorian Comprehensive Cancer Centre, University of Melbourne Centre for Cancer Research, Melbourne, VIC 3000, Australia
| | - Corina Behrenbruch
- Department of Clinical Pathology, University of Melbourne, Melbourne, VIC 3000, Australia; (C.S.); (J.S.); (M.G.); (N.W.); (C.M.); (C.B.)
- Victorian Comprehensive Cancer Centre, University of Melbourne Centre for Cancer Research, Melbourne, VIC 3000, Australia
- The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC 3010, Australia;
- Department of General Surgical Specialties, The Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC 3050, Australia;
| | - Benjamin NJ. Thomson
- Department of General Surgical Specialties, The Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC 3050, Australia;
- Department of Surgery, the Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC 3050, Australia
| | - Alexander G. Heriot
- The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC 3010, Australia;
- Department of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia
- Department of Surgery, St Vincent’s Hospital, Melbourne, VIC 3065, Australia
| | - Delphine Merino
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia;
- School of Cancer Medicine, La Trobe University, Melbourne, VIC 3086, Australia
- Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia
- Department of Medical Biology, The Faculty of Medicine, Dentistry and Health Science, University of Melbourne, Melbourne, VIC 3010, Australia
| | - Frédéric Hollande
- Department of Clinical Pathology, University of Melbourne, Melbourne, VIC 3000, Australia; (C.S.); (J.S.); (M.G.); (N.W.); (C.M.); (C.B.)
- Victorian Comprehensive Cancer Centre, University of Melbourne Centre for Cancer Research, Melbourne, VIC 3000, Australia
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Correia MP, Stojanovic A, Wels WS, Cerwenka A. Innate-like NKp30 +CD8 + T cells armed with TCR/CAR target tumor heterogeneity. Oncoimmunology 2022; 10:1973783. [PMID: 35036073 PMCID: PMC8758178 DOI: 10.1080/2162402x.2021.1973783] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
Abstract
Intratumoral heterogeneity is frequently associated with tumor immune escape, with MHC-class I and antigen expression loss rendering tumor cells invisible to T cell killing, representing a major challenge for the design of successful adoptive transfer protocols for cancer immunotherapy. While CD8+ T cell recognition of tumor cells is based on the detection of MHC-peptide complexes via specific T cell receptors (TCRs), Natural Killer (NK) cells detect tumor-associated NK ligands by an array of NK receptors. We have recently identified a population of innate-like CD8+ T cells marked by the expression of NKp30, a potent natural cytotoxicity activating NK receptor, whose tumor ligand, B7H6, is frequently upregulated on several cancer types. Here, we harnessed the dual-recognition potential of NKp30+CD8+ T cells, by arming these cells with TCRs or chimeric antigen receptors (CARs) targeting Epidermal Growth Factor Receptor 2 (ErbB2, or HER2), a tumor-associated target overexpressed in several malignancies. HER2-specific NKp30+CD8+ T cells killed not only HER2-expressing target cell lines, but also eliminated tumor cells in the absence of MHC-class I or antigen expression, making them especially effective in eliminating heterogeneous tumor cell populations. Our results show that NKp30+CD8+ T cells equipped with a specific TCR or CAR display a dual capacity to recognize and kill target cells, combining the anti-tumor activity of both CD8+ T and NK cells. This dual-recognition capacity allows these effector cells to target tumor heterogeneity, thus improving therapeutic strategies against tumor escape.
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Affiliation(s)
- Margareta P Correia
- Department of Immunobiochemistry, Mannheim Institute for Innate Immunosciences (MI3), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Cancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC), Porto, Portugal.,Department of Pathology and Molecular Immunology, School of Medicine & Biomedical Sciences, University of Porto (ICBAS-UP), Porto, Portugal
| | - Ana Stojanovic
- Department of Immunobiochemistry, Mannheim Institute for Innate Immunosciences (MI3), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Winfried S Wels
- Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt, Germany.,Frankfurt Cancer Institute, Goethe University, Frankfurt, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany.,German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Frankfurt, Germany
| | - Adelheid Cerwenka
- Department of Immunobiochemistry, Mannheim Institute for Innate Immunosciences (MI3), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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Liu X, Wang W, Liu X, Zhang Z, Yu L, Li R, Guo D, Cai W, Quan X, Wu H, Dai M, Liang Z. Multi-omics analysis of intra-tumoural and inter-tumoural heterogeneity in pancreatic ductal adenocarcinoma. Clin Transl Med 2022; 12:e670. [PMID: 35061935 PMCID: PMC8782496 DOI: 10.1002/ctm2.670] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 11/16/2021] [Accepted: 11/17/2021] [Indexed: 12/14/2022] Open
Abstract
The poor prognosis of pancreatic ductal adenocarcinoma (PDAC) is associated with the tumour heterogeneity. To explore intra- and inter-tumoural heterogeneity in PDAC, we analysed the multi-omics profiles of 61 PDAC lesion samples, along with the matched pancreatic normal tissue samples, from 19 PDAC patients. Haematoxylin and Eosin (H&E) staining revealed that diversely differentiated lesions coexisted both within and across individual tumours. Whole exome sequencing (WES) of samples from multi-region revealed diverse types of mutations in diverse genes between cancer cells within a tumour and between tumours from different individuals. The copy number variation (CNV) analysis also showed that PDAC exhibited intra- and inter-tumoural heterogeneity in CNV and that high average CNV burden was associated poor prognosis of the patients. Phylogenetic tree analysis and clonality/timing analysis of mutations displayed diverse evolutionary pathways and spatiotemporal characteristics of genomic alterations between different lesions from the same or different tumours. Hierarchical clustering analysis illustrated higher inter-tumoural heterogeneity than intra-tumoural heterogeneity of PDAC at the transcriptional levels as lesions from the same patients are grouped into a single cluster. Immune marker genes are differentially expressed in different regions and tumour samples as shown by tumour microenvironment (TME) analysis. TME appeared to be more heterogeneous than tumour cells in the same patient. Lesion-specific differentially methylated regions (DMRs) were identified by methylated DNA immunoprecipitation sequencing (MeDIP-seq). Furthermore, the integration analysis of multi-omics data showed that the mRNA levels of some genes, such as PLCB4, were significantly correlated with the gene copy numbers. The mRNA expressions of potential PDAC biomarkers ZNF521 and KDM6A were correlated with copy number alteration and methylation, respectively. Taken together, our results provide a comprehensive view of molecular heterogeneity and evolutionary trajectories of PDAC and may guide personalised treatment strategies in PDAC therapy.
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Affiliation(s)
- Xiaoqian Liu
- Department of PathologyState Key Laboratory of Complex Severe and Rare DiseasesMolecular Pathology Research CenterPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
- Department of PathologyQilu Hospital (Qingdao)Cheeloo College of MedicineShandong UniversityQingdaoShandongChina
| | - Wenqian Wang
- Department of General SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Xiaoding Liu
- Department of PathologyState Key Laboratory of Complex Severe and Rare DiseasesMolecular Pathology Research CenterPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Zhiwen Zhang
- Department of PathologyState Key Laboratory of Complex Severe and Rare DiseasesMolecular Pathology Research CenterPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Lianyuan Yu
- Department of PathologyState Key Laboratory of Complex Severe and Rare DiseasesMolecular Pathology Research CenterPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Ruiyu Li
- Department of PathologyState Key Laboratory of Complex Severe and Rare DiseasesMolecular Pathology Research CenterPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Dan Guo
- Clinical BiobankMedical Research CentrePeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Weijing Cai
- Shanghai Tongshu Biotechnology Co., LtdShanghaiChina
| | - Xueping Quan
- Shanghai Tongshu Biotechnology Co., LtdShanghaiChina
| | - Huanwen Wu
- Department of PathologyState Key Laboratory of Complex Severe and Rare DiseasesMolecular Pathology Research CenterPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Menghua Dai
- Department of General SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Zhiyong Liang
- Department of PathologyState Key Laboratory of Complex Severe and Rare DiseasesMolecular Pathology Research CenterPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
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35
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de Castria TB, Tang L, Queiroz MM, Awni BM, Paroder V, Shamseddine A, Bariani GM, Mukherji D, Matar CF, Fernandes GDS, El-Olayan A, Sabatin F, Elias R, Gupta R, Janjigian YY, Abou-Alfa GK. Hepatoid esophagogastric adenocarcinoma and tumoral heterogeneity: a case report. J Gastrointest Oncol 2021; 12:3123-3132. [PMID: 35070435 PMCID: PMC8748022 DOI: 10.21037/jgo-21-287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Accepted: 09/30/2021] [Indexed: 08/30/2023] Open
Abstract
Hepatoid adenocarcinoma of the stomach is an uncommon subtype of gastric cancer remarkably similar to hepatocellular carcinoma in histopathological analysis. It is also commonly associated with high serum alfa-fetoprotein and a poorer prognosis, despite the emergence of new therapeutic options. In recent years, next generation sequencing (NGS) technology has made it possible to identify and describe the genes and molecular alterations common to gastric cancer thereby contributing to the advancement of targeted therapies. A 62-year-old patient, with no prior risk factor for hepatocellular carcinoma (HCC), presented to the emergency room with dysphagia for solids, abdominal pain and weight loss of about 3 kilograms over 3 months. Histopathological analysis presented with disparities regarding HER2 and programmed death-ligand 1 (PD-L1) status in the primary and metastatic sites. We describe a case of a de novo metastatic, human epidermal growth factor receptor 2 (HER2) positive esophagogastric junction hepatoid adenocarcinoma. Although this is a rare subgroup of gastric cancer, treatment strategies were based in recent studies in immunotherapy and guided therapy, taking into consideration the molecular findings from the patient's tumor NGS analysis. Data about HER2 and PDL1 heterogeneity were also reviewed. Despite the aggressiveness and rarity of this histology, the patient had a good response to treatment.
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Affiliation(s)
- Tiago Biachi de Castria
- Centro de Oncologia, Hospital Sírio-Libanês, São Paulo, SP, Brasil
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Laura Tang
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Medical College at Cornell University, New York, NY, USA
| | | | | | - Viktoriya Paroder
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Medical College at Cornell University, New York, NY, USA
| | | | | | | | | | | | - Ashwaq El-Olayan
- National Guard Hospital, King Abdulaziz Medical City, Riyadh, Kingdom of Saudi Arabia
| | - Fouad Sabatin
- National Guard Hospital, King Abdulaziz Medical City, Riyadh, Kingdom of Saudi Arabia
| | | | | | - Yelena Y. Janjigian
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Medical College at Cornell University, New York, NY, USA
| | - Ghassan K. Abou-Alfa
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Medical College at Cornell University, New York, NY, USA
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36
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Hamilton E, Shastry M, Shiller SM, Ren R. Targeting HER2 heterogeneity in breast cancer. Cancer Treat Rev 2021; 100:102286. [PMID: 34534820 DOI: 10.1016/j.ctrv.2021.102286] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Accepted: 08/30/2021] [Indexed: 12/18/2022]
Abstract
The identification of Human epidermal growth factor receptor 2 (HER2) as a target in breast cancer and the subsequent development of HER2-targeted therapies has revolutionized the treatment of patients with HER2-positive breast cancer. However, there is an increasing awareness of how frequently tumors have low or heterogeneous expression of HER2. It is now recognized that this impacts the degree of benefit from HER2-targeted therapies. With the advent of novel and more potent antibody drug conjugates, targeting HER2 in traditional HER2-negative tumors with "HER2-low" expression is becoming possible. It is essential to refine the nomenclature around HER2 expression to enable clinicians to optimize treatment for patients across the HER2 expression spectrum in breast cancer. HER2 heterogeneity can be detected by conventional IHC, gene expression profiling or other methods and numerous studies have documented the correlation between the presence of HER2 heterogeneity and shorter disease-free survival (DFS) and overall survival (OS). Validation of techniques to identify HER2 heterogeneity in the clinic and concurrent development of agents to effectively treat tumors with non-uniform HER2 expression is needed.
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Affiliation(s)
- Erika Hamilton
- Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, United States.
| | - Mythili Shastry
- Sarah Cannon Research Institute, Nashville, TN, United States
| | - S Michelle Shiller
- Genomic and Molecular Pathology Services, Pathgroup, Nashville, TN, United States
| | - Rongqin Ren
- Genomic and Molecular Pathology Services, Pathgroup, Nashville, TN, United States
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37
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Breast Cancer Heterogeneity. Diagnostics (Basel) 2021; 11:diagnostics11091555. [PMID: 34573897 PMCID: PMC8468623 DOI: 10.3390/diagnostics11091555] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 08/22/2021] [Accepted: 08/26/2021] [Indexed: 01/22/2023] Open
Abstract
Breast tumor heterogeneity is a major challenge in the clinical management of breast cancer patients. Both inter-tumor and intra-tumor heterogeneity imply that each breast cancer (BC) could have different prognosis and would benefit from specific therapy. Breast cancer is a dynamic entity, changing during tumor progression and metastatization and this poses fundamental issues to the feasibility of a personalized medicine approach. The most effective therapeutic strategy for patients with recurrent disease should be assessed evaluating biopsies obtained from metastatic sites. Furthermore, the tumor progression and the treatment response should be strictly followed and radiogenomics and liquid biopsy might be valuable tools to assess BC heterogeneity in a non-invasive way.
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38
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Maruoka Y, Wakiyama H, Choyke PL, Kobayashi H. Near infrared photoimmunotherapy for cancers: A translational perspective. EBioMedicine 2021; 70:103501. [PMID: 34332294 PMCID: PMC8340111 DOI: 10.1016/j.ebiom.2021.103501] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 06/20/2021] [Accepted: 07/12/2021] [Indexed: 12/11/2022] Open
Abstract
Near-infrared photoimmunotherapy (NIR-PIT) is a newly-developed, highly-selective cancer treatment, which utilizes a monoclonal antibody conjugated to a photoabsorbing dye, IRDye700DX (IR700). The antibody conjugate is injected into the patient and accumulates in the tumour. Within 24 h of injection the tumour is exposed to NIR light which activates the conjugate and causes rapid, selective cancer cell death. A global phase III clinical trial of NIR-PIT in recurrent head and neck squamous cell cancer (HNSCC) patients is currently underway. Conditional clinical approval for NIR-PIT in recurrent HNSCC has been granted in Japan as of September 2020. Not only does NIR-PIT induce highly selective and immediate cancer cell killing, but it also stimulates highly active anti-tumour immunity. While monotherapy with NIR-PIT has proven effective it is likely that combinations with immune-checkpoint inhibitors or additional NIR-PIT targeting immune suppressive cells in the tumour microenvironment will further improve results. In this review, we discuss the translational aspects of NIR-PIT especially in HNSCC, and potential future applications.
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Affiliation(s)
- Yasuhiro Maruoka
- Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Departments of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Hiroaki Wakiyama
- Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Peter L Choyke
- Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Hisataka Kobayashi
- Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
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Drago JZ, Jhaveri K. Tailoring Therapy to Be Just Right in HER2-Positive Early-Stage Breast Cancer: The Goldilocks Problem. JCO Oncol Pract 2021; 17:334-335. [PMID: 34111379 DOI: 10.1200/op.21.00125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Affiliation(s)
- Joshua Z Drago
- Department of Medicine, Memorial Sloan Kettering Cancer Center, Evelyn H. Lauder Breast Center, 300 East 66th Street, New York, NY.,Department of Medicine, Weill Cornell Medical College, New York, NY
| | - Komal Jhaveri
- Department of Medicine, Memorial Sloan Kettering Cancer Center, Evelyn H. Lauder Breast Center, 300 East 66th Street, New York, NY.,Department of Medicine, Weill Cornell Medical College, New York, NY
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40
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Lower response to trastuzumab emtansine in metastatic breast cancer patients with human epidermal growth factor receptor 2 immunohistochemistry score of 2 and fluorescence in situ hybridization positive compared with immunohistochemistry score of 3: a retrospective study. Anticancer Drugs 2021; 31:973-978. [PMID: 32868644 DOI: 10.1097/cad.0000000000000939] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Tumor human epidermal growth factor receptor 2 (HER2) status is defined by either protein expression using immunohistochemistry (IHC) or gene amplification using fluorescence in situ hybridization (FISH). Approximately 20% of HER2-positive breast cancer is HER2 IHC 2+/FISH-positive. Unlike trastuzumab, it has not been studied whether the response to trastuzumab emtansine (T-DM1) differs according to HER2-positive status. We retrospectively identified and reviewed medical records of all patients with HER2-positive advanced breast cancer (ABC) who received T-DM1 in our hospital from October 2013 to December 2016. We compared the objective response rate (ORR) and progression-free survival (PFS) between patients in the HER2 IHC 3+ group and those in the HER2 IHC 2+/FISH-positive group. A total of 39 patients (IHC 3+: n = 32; IHC 2+/FISH-positive: n = 7) were analyzed. Nineteen (48.7%), 13 (33.3%), and 29 (74.4%) patients had received at least one prior chemotherapy, more than three lines of chemotherapy, and prior pertuzumab for ABC, respectively. ORR was significantly higher in the IHC 3+ group than in the IHC 2+/FISH-positive group (53.3% vs. 0%, P = 0.024). Median PFS was 7.9 months in the IHC 3+ group versus 3.9 months in the IHC 2+/FISH-positive group (hazard ratio 0.68; 95% confidence interval 0.28-1.69, P = 0.408). Among the HER2-positive ABC patients treated with T-DM1, ORR was significantly worse in HER2 IHC 2+/FISH-positive than in HER2 IHC 3+ patients. Median PFS tended to be shorter in patients with HER2 IHC 2+/FISH-positive.
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41
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Yamazaki CM, Yamaguchi A, Anami Y, Xiong W, Otani Y, Lee J, Ueno NT, Zhang N, An Z, Tsuchikama K. Antibody-drug conjugates with dual payloads for combating breast tumor heterogeneity and drug resistance. Nat Commun 2021; 12:3528. [PMID: 34112795 PMCID: PMC8192907 DOI: 10.1038/s41467-021-23793-7] [Citation(s) in RCA: 152] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 05/14/2021] [Indexed: 12/11/2022] Open
Abstract
Breast tumors generally consist of a diverse population of cells with varying gene expression profiles. Breast tumor heterogeneity is a major factor contributing to drug resistance, recurrence, and metastasis after chemotherapy. Antibody-drug conjugates (ADCs) are emerging chemotherapeutic agents with striking clinical success, including T-DM1 for HER2-positive breast cancer. However, these ADCs often suffer from issues associated with intratumor heterogeneity. Here, we show that homogeneous ADCs containing two distinct payloads are a promising drug class for addressing this clinical challenge. Our conjugates show HER2-specific cell killing potency, desirable pharmacokinetic profiles, minimal inflammatory response, and marginal toxicity at therapeutic doses. Notably, a dual-drug ADC exerts greater treatment effect and survival benefit than does co-administration of two single-drug variants in xenograft mouse models representing intratumor HER2 heterogeneity and elevated drug resistance. Our findings highlight the therapeutic potential of the dual-drug ADC format for treating refractory breast cancer and perhaps other cancers.
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Affiliation(s)
- Chisato M Yamazaki
- Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Aiko Yamaguchi
- Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Yasuaki Anami
- Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Wei Xiong
- Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Yoshihiro Otani
- Department of Neurosurgery, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Jangsoon Lee
- Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Naoto T Ueno
- Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ningyan Zhang
- Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Zhiqiang An
- Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Kyoji Tsuchikama
- Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA.
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Wang L, Asirvatham JR, Ma Y, Reisenbichler ES, Jorns JM. HER-2/neu-positive breast cancer neoadjuvant chemotherapy response after implementation of 2018 ASCO/CAP focused update. Breast J 2021; 27:631-637. [PMID: 34018281 DOI: 10.1111/tbj.14241] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 04/23/2021] [Accepted: 04/23/2021] [Indexed: 12/13/2022]
Abstract
Human Epidermal Growth Factor Receptor 2 (HER2), a routinely tested breast cancer marker, is associated with worse prognosis yet increased sensitivity to targeted neoadjuvant therapy (NAT) in breast cancer patients. The presence of HER2 in breast carcinoma can be detected with either immunohistochemistry (IHC) or in situ hybridization (ISH). In this study, we examine the relationship between clinicopathological features, HER2 detection method (IHC vs ISH), and prognostic outcomes in NAT-treated HER2-positive breast cancer patients. We included 99 HER2-positive patients from three academic institutions following 2018 HER2 testing updates and conducted a retrospective correlational study. Seventy-one (72%) were HER2-positive by IHC and 28 (28%) were positive following reflexive ISH. Multivariate analysis showed biomarker status to be significantly associated with pathologic complete response (pCR) (p = 0.003), Residual Cancer Burden (RCB) (p = 0.007), and tumor size downstaging (p = 0.002) and HER2 detection method of IHC to be significantly associated with pCR (p = 0.05), RCB (p = 0.004), and nodal downstaging (p= 0.03). In conclusion, HER2 detection method and biomarker subtype allow for further prognostic stratification of HER2-positive patients when 2018 American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guideline updates are applied.
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Affiliation(s)
- Lin Wang
- Medical College of Wisconsin, Milwaukee, WI, USA
| | | | - Yanlin Ma
- University of Virginia, Charlottesville, VA, USA
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43
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Wang C, Tsang JY, Poon IK, Shao Y, Li JJ, Shea KH, Hlaing T, Wong SI, Tse GM. An Evaluation of Clinicopathological Correlation and Outcome of Human Epidermal Growth Factor Receptor 2 Subgroups Reclassified According to the Latest ASCO/CAP Guideline. Clin Breast Cancer 2021; 22:e114-e122. [PMID: 34119429 DOI: 10.1016/j.clbc.2021.05.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 04/25/2021] [Accepted: 05/08/2021] [Indexed: 11/18/2022]
Abstract
BACKGROUND The latest American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guideline has updated the interpretation of uncommon human epidermal growth factor receptor 2 (HER2) in situ hybridization (ISH) patterns (groups 2-4) with concomitant HER2 immunohistochemistry, leading to changes in the diagnosis of these subgroups. We sought to assess the clinicopathological features and outcomes in these subgroups in detail with our local cohort. PATIENTS AND METHODS Clinicopathologic features of groups 2 to 4 were compared to the typical amplified group (group 1: HER2/CEP17 ≥ 2, HER2 ≥ 4) and non-amplified group (group 5: HER2/CEP17 < 2, HER2 < 4). RESULTS Group 2 (HER2/CEP17 ≥ 2, HER2 < 4) cases showed lower Ki67 expression and grade (P ≤ .002) than group 1 but no differences compared with group 5. Group 4 (HER2/CEP17 < 2, HER2 = 4-6) cases were associated with less necrosis, more estrogen receptor positivity, lower grade, more nodal metastases, and more special histotypes (P ≤ .037) than group 1, but higher grade and more nodal metastases (P ≤ .021) than group 5. Except for presenting as a larger tumor and of special histotypes, group 3 (HER2/CEP17 < 2, HER2 ≥ 6) cases showed no other significant differences from group 1, but were of higher grade and Ki67 level than groups 2, 4, and 5. Group 4, similar to group 5, showed worse survival than group 1 (disease-free survival: log-rank = 5.547, P = .019; overall survival: log-rank = 4.678, P = .031). The rate of relapse was similar in group 4 with and without anti-HER2 therapy, albeit with limited cases. CONCLUSION Our findings indicate more similarities among groups 2, 4, and 5 than between groups 1 and 3, supporting the HER2 categorization in the latest guideline. Additional studies may be warranted to assess the outcomes of these patients with different management approaches.
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Affiliation(s)
- Chao Wang
- Department of Pathology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Julia Y Tsang
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Ivan K Poon
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Yan Shao
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Joshua J Li
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Ka-Ho Shea
- Department of Pathology, Tuen Mun Hospital, Tuen Mun, Hong Kong
| | - Thazin Hlaing
- Department of Anatomic Pathology, Centro Hospitalar Conde de Sao Januario, Macau, People's Republic of China
| | - Sio-In Wong
- Department of Anatomic Pathology, Centro Hospitalar Conde de Sao Januario, Macau, People's Republic of China
| | - Gary M Tse
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong.
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Frankhauser DE, Jovanovic‐Talisman T, Lai L, Yee LD, Wang LV, Mahabal A, Geradts J, Rockne RC, Tomsic J, Jones V, Sistrunk C, Miranda‐Carboni G, Dietze EC, Erhunmwunsee L, Hyslop T, Seewaldt VL. Spatiotemporal strategies to identify aggressive biology in precancerous breast biopsies. WIREs Mech Dis 2021; 13:e1506. [PMID: 33001587 PMCID: PMC8544796 DOI: 10.1002/wsbm.1506] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Revised: 08/21/2020] [Accepted: 08/24/2020] [Indexed: 01/12/2023]
Abstract
Over 90% of breast cancer is cured; yet there remain highly aggressive breast cancers that develop rapidly and are extremely difficult to treat, much less prevent. Breast cancers that rapidly develop between breast image screening are called "interval cancers." The efforts of our team focus on identifying multiscale integrated strategies to identify biologically aggressive precancerous breast lesions. Our goal is to identify spatiotemporal changes that occur prior to development of interval breast cancers. To accomplish this requires integration of new technology. Our team has the ability to perform single cell in situ transcriptional profiling, noncontrast biological imaging, mathematical analysis, and nanoscale evaluation of receptor organization and signaling. These technological innovations allow us to start to identify multidimensional spatial and temporal relationships that drive the transition from biologically aggressive precancer to biologically aggressive interval breast cancer. This article is categorized under: Cancer > Computational Models Cancer > Molecular and Cellular Physiology Cancer > Genetics/Genomics/Epigenetics.
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Affiliation(s)
- David E. Frankhauser
- Department of Population SciencesCity of Hope Comprehensive Cancer CenterDuarteCaliforniaUSA
| | | | - Lily Lai
- Department of Population SciencesCity of Hope Comprehensive Cancer CenterDuarteCaliforniaUSA
| | - Lisa D. Yee
- Department of Population SciencesCity of Hope Comprehensive Cancer CenterDuarteCaliforniaUSA
| | - Lihong V. Wang
- Department of Medical EngineeringCalifornia Institute of TechnologyPasadena, CaliforniaUSA
| | - Ashish Mahabal
- Center for Data Driven DiscoveryCalifornia Institute of TechnologyPasadena, CaliforniaUSA
| | - Joseph Geradts
- Department of PathologyDuke UniversityDurhamNorth CarolinaUSA
| | - Russell C. Rockne
- Department of Population SciencesCity of Hope Comprehensive Cancer CenterDuarteCaliforniaUSA
| | - Jerneja Tomsic
- Department of Population SciencesCity of Hope Comprehensive Cancer CenterDuarteCaliforniaUSA
| | - Veronica Jones
- Department of Population SciencesCity of Hope Comprehensive Cancer CenterDuarteCaliforniaUSA
| | - Christopher Sistrunk
- Department of Population SciencesCity of Hope Comprehensive Cancer CenterDuarteCaliforniaUSA
| | | | - Eric C. Dietze
- Department of Population SciencesCity of Hope Comprehensive Cancer CenterDuarteCaliforniaUSA
| | - Loretta Erhunmwunsee
- Department of Population SciencesCity of Hope Comprehensive Cancer CenterDuarteCaliforniaUSA
| | - Terry Hyslop
- Department of BiostatisticsDuke UniversityDurhamNorth CarolinaUSA
| | - Victoria L. Seewaldt
- Department of Population SciencesCity of Hope Comprehensive Cancer CenterDuarteCaliforniaUSA
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Pally D, Pramanik D, Hussain S, Verma S, Srinivas A, Kumar RV, Everest-Dass A, Bhat R. Heterogeneity in 2,6-Linked Sialic Acids Potentiates Invasion of Breast Cancer Epithelia. ACS CENTRAL SCIENCE 2021; 7:110-125. [PMID: 33532574 PMCID: PMC7844859 DOI: 10.1021/acscentsci.0c00601] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Indexed: 05/22/2023]
Abstract
Heterogeneity in phenotypes of malignantly transformed cells and aberrant glycan expression on their surface are two prominent hallmarks of cancers that have hitherto not been linked to each other. In this paper, we identify differential levels of a specific glycan linkage: α2,6-linked sialic acids within breast cancer cells in vivo and in culture. Upon sorting out two populations with moderate, and relatively higher, cell surface α2,6-linked sialic acid levels from the triple-negative breast cancer cell line MDA-MB-231, both populations (denoted as medium and high 2,6-Sial cells, respectively) stably retained their levels in early passages. Upon continuous culturing, medium 2,6-Sial cells recapitulated the heterogeneity of the unsorted line whereas high 2,6-Sial cells showed no such tendency. Compared with high 2,6-Sial cells, the medium 2,6-Sial counterparts showed greater adhesion to reconstituted extracellular matrices (ECMs) and invaded faster as single cells. The level of α2,6-linked sialic acids in the two sublines was found to be consistent with the expression of a specific glycosyl transferase, ST6GAL1. Stably knocking down ST6GAL1 in the high 2,6-Sial cells enhanced their invasiveness. When cultured together, medium 2,6-Sial cells differentially migrated to the edge of growing tumoroid-like cocultures, whereas high 2,6-Sial cells formed the central bulk. Multiscale simulations in a Cellular Potts model-based computational environment calibrated to our experimental findings suggest that differential levels of cell-ECM adhesion, likely regulated by α2,6-linked sialic acids, facilitate niches of highly invasive cells to efficiently migrate centrifugally as the invasive front of a malignant breast tumor.
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Affiliation(s)
- Dharma Pally
- Department
of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore 560012, India
| | - Durjay Pramanik
- Department
of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore 560012, India
| | - Shahid Hussain
- Department
of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore 560012, India
| | - Shreya Verma
- Department
of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore 560012, India
| | - Anagha Srinivas
- Department
of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore 560012, India
| | - Rekha V. Kumar
- Department
of Pathology, Kidwai Memorial Institute
of Oncology, Bangalore 560029, India
| | - Arun Everest-Dass
- Institute
for Glycomics, Griffith University, Southport, Queensland 4215, Australia
| | - Ramray Bhat
- Department
of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore 560012, India
- E-mail: . Phone: 91-80-22932764
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Predictive significance of HER2 intratumoral heterogeneity, determined by simultaneous gene and protein analysis, for resistance to trastuzumab-based treatments for HER2-positive breast cancer. Virchows Arch 2021; 479:13-21. [PMID: 33496805 DOI: 10.1007/s00428-021-03036-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 01/01/2021] [Accepted: 01/15/2021] [Indexed: 10/22/2022]
Abstract
Gene-protein assay (GPA), a combination of immunohistochemistry and dual in situ hybridization, allows simultaneous visualization of HER2 protein and gene on a single slide. We aimed to clarify the clinical significance of HER2 intratumoral heterogeneity (ITH) using GPA. We investigated the relationships between various HER2 ITH indicators and clinical course in 102 patients with HER2-positive breast cancer, treated with neoadjuvant trastuzumab and chemotherapy. Five representative microscopic images were captured from each GPA slide of pre-therapeutic biopsy materials. All evaluable cancer cells in the images were individually assessed for HER2 gene copy number and protein expression. Mean and coefficient of variation (CV) of both gene copy number and protein category were calculated, and each was divided into negative, equivocal, and positive. Based on their combined status, cancer cells were classified into nine types. Pathological complete response (pCR) to neoadjuvant treatments showed positive relationships to mean gene copy number (P < 0.001), mean protein category (P < 0.001), and proportion of gene- and protein-positive tumor cells (P < 0.001) and showed negative relationships to the CV of protein category (P < 0.001) and the proportion of gene-amplified but protein-negative tumor cells (P = 0.002). Two diagnostic models, created by combining clinicopathological factors and ITH indicators, showed excellent potential diagnostic ability for pCR (mean gene copy number and protein category CV; AUC = 0.837, proportion of gene- and protein-positive tumor cells; AUC = 0.831). HER2 ITH quantified by GPA is a potential predictive indicator for efficacy of HER2-targeted treatment.
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Yan H, Xiao H, Zhu J, Zhang J, Liu Z. Association Between the HER2 Protein Expression Level and the Efficacy of Neoadjuvant Chemotherapy in HER2-Positive Breast Cancer. Cancer Manag Res 2020; 12:12715-12722. [PMID: 33328766 PMCID: PMC7735715 DOI: 10.2147/cmar.s278694] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 11/26/2020] [Indexed: 01/11/2023] Open
Abstract
Objective This study aimed to assess the relationship between human epidermal growth factor receptor-2 (HER2) protein expression level and clinicopathological features of HER2-positive breast cancer, and to analyze whether the expression level of HER2 protein could predict the response to anti-HER2 therapy. Methods The present study included 296 patients with HER2-positive breast cancer receiving neoadjuvant chemotherapy (NAC) containing trastuzumab between January 2014 and November 2019. The univariate comparisons of the differences in clinicopathological parameters between different HER2 protein expression groups, and the association between HER2 protein expression level and efficacy of NAC, were made using a X2 test or Mann–Whitney U-test. Multivariate analyses of the differences in clinicopathological parameters between different HER2 protein expression groups, and the association between HER2 protein expression level and efficacy of NAC, were performed using logistic regression analysis. Results A total of 110 patients achieved a pathological complete response (pCR) after NAC. The pCR rate was 37.2%. The study showed that patients who were HR-negative, AR-positive, and CK5/6-negative had significantly higher expression level of HER2 protein [odds ratio (OR) = 0.183, P < 0.001; OR = 6.414, P = 0.004; OR = 0.261, P = 0.004, respectively]. Patients with HER2 3+ detected by immunohistochemistry (IHC) had significantly higher pCR rates compared with patients with HER2 2+. The HER2 protein expression level might effectively predict the efficacy of NAC in patients with HER2-positive breast cancer (OR = 3.520, P = 0.003). Conclusion The HER2 protein expression level was related to multiple clinical features in patients with HER2-positive breast cancer. For example, hormone receptor, androgen receptor, cytokeratin5/6, and HER2 protein expression level may be used to predict the response to NAC in patients with HER2-positive breast cancer and may serve as a predictive factor for NAC efficacy.
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Affiliation(s)
- Hui Yan
- Department of Breast Surgery, Breast Cancer Center, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
| | - Hui Xiao
- Department of Breast Surgery, Breast Cancer Center, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
| | - Jiujun Zhu
- Department of Breast Surgery, Breast Cancer Center, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
| | - Jingyang Zhang
- Department of Breast Surgery, Breast Cancer Center, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
| | - Zhenzhen Liu
- Department of Breast Surgery, Breast Cancer Center, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
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Klocker EV, Suppan C. Biomarkers in Her2- Positive Disease. Breast Care (Basel) 2020; 15:586-593. [PMID: 33447232 DOI: 10.1159/000512283] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Accepted: 10/14/2020] [Indexed: 12/11/2022] Open
Abstract
Background Breast cancer is a heterogeneous disease with well-known characteristics such as hormone receptor (HR) status and human epidermal growth factor (Her)2 status. Although Her2 represents an established treatment target, the development of resistance mechanisms during treatment, cardiotoxicity, and a worse response to standard therapies lead to worse outcomes. Summary Therefore, we investigated various biomarkers in breast cancer such as Her2 mutations, Her2 heterogeneity, HR, PIK3CA, PTEN, programmed death receptor ligand 1 (PD-L1), tumor-infiltrating lymphocytes (TIL), micro RNA (miRNA), and BRCA mutations with regard to their clinical impact in Her2-positive disease. HR status and Her2 status, such as the presence of PIK3CA mutations, already play a role in treatment decision-making processes, whereas other biomarkers like PD-L1 status or TIL represent promising future markers. The influence of BRCA mutations in Her2-positive disease, Her2 mutations, and the impact of miRNA is vague to date. Antibody-drug conjugates (ADC) such as T-DM have been established as important treatment strategies, especially in Her2-positive disease. Key Message However, up-to-date biomarkers appropriate for clinical practice are missing. Further studies are needed.
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Affiliation(s)
| | - Christoph Suppan
- Department of Oncology, Medical University of Graz, Graz, Austria
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Grigg CM, Livasy C, He J, Hartman A, Clark PE, Zhu J, Raghavan D, Burgess EF. Human epidermal growth factor receptor 2 overexpression is frequently discordant between primary and metastatic urothelial carcinoma and is associated with intratumoral human epidermal growth factor receptor 2 heterogeneity. Hum Pathol 2020; 107:96-103. [PMID: 33121981 DOI: 10.1016/j.humpath.2020.10.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Revised: 10/18/2020] [Accepted: 10/21/2020] [Indexed: 11/28/2022]
Abstract
Human epidermal growth factor receptor 2 (HER2) overexpression occurs in 5-10% of primary urothelial carcinomas (UCs) but has not reliably predicted benefit from HER2-targeted agents in the metastatic setting. HER2 testing of primary tumors may not reflect the HER2 status of distant metastases. We assessed the concordance of HER2 expression in paired primary and distant metastatic UC lesions. Specimens from 149 patients with metastatic UC underwent immunohistochemical staining for HER2, including 79 paired primary and distant metastatic tumors. HER2 status was defined using 2018 ASCO/CAP guidelines. HER2 intratumoral heterogeneity (ITH) was defined as HER2 3+ expression in 5-50% of tumor cells. The HER2-positive, -equivocal, and -negative rates observed were 10.6%, 24.7%, and 64.7% for primary tumors and 9.8%, 12.6%, and 77.6% for metastatic tumors, respectively. HER2 ITH occurred in 44% of HER2-positive primary tumors. Low agreement of HER2-positive status between primary and metastatic tumors was observed (к = 0.193, P = 0.079). Loss of HER2 overexpression in the metastatic lesion was observed in 55% (5 of 9 cases) of HER2-positive primary cases and was associated with the presence of HER2 ITH in the primary tumor (Fisher's exact P = 0.048). Change from negative primary to positive metastasis was seen in 2% (1 of 50) of cases. No differences in metastasis-free survival or overall survival were observed in accordance with HER2 status defined by either the primary or metastatic lesion. These findings are likely to impact patient selection for HER2 targeted therapies in UC. Confirmation and evaluation of the clinical significance of HER2 discordance is warranted, preferably in the context of a clinical trial.
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Affiliation(s)
- Claud M Grigg
- Levine Cancer Institute, Atrium Health, Charlotte, NC, 28204, USA.
| | - Chad Livasy
- Carolinas Pathology Group, Charlotte, NC, 28203, USA.
| | - Jiaxian He
- Levine Cancer Institute, Atrium Health, Charlotte, NC, 28204, USA.
| | - Aaron Hartman
- Carolinas Pathology Group, Charlotte, NC, 28203, USA.
| | - Peter E Clark
- Levine Cancer Institute, Atrium Health, Charlotte, NC, 28204, USA.
| | - Jason Zhu
- Levine Cancer Institute, Atrium Health, Charlotte, NC, 28204, USA.
| | - Derek Raghavan
- Levine Cancer Institute, Atrium Health, Charlotte, NC, 28204, USA.
| | - Earle F Burgess
- Levine Cancer Institute, Atrium Health, Charlotte, NC, 28204, USA.
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Reduction of Global H3K27me 3 Enhances HER2/ErbB2 Targeted Therapy. Cell Rep 2020; 29:249-257.e8. [PMID: 31597089 DOI: 10.1016/j.celrep.2019.08.105] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 07/12/2019] [Accepted: 08/29/2019] [Indexed: 02/08/2023] Open
Abstract
Monoclonal antibodies (mAbs) targeting the oncogenic receptor tyrosine kinase ERBB2/HER2, such as Trastuzumab, are the standard of care therapy for breast cancers driven by ERBB2 overexpression and activation. However, a substantial proportion of patients exhibit de novo resistance. Here, by comparing matched Trastuzumab-naive and post-treatment patient samples from a neoadjuvant trial, we link resistance with elevation of H3K27me3, a repressive histone modification catalyzed by polycomb repressor complex 2 (PRC2). In ErbB2+ breast cancer models, PRC2 silences endogenous retroviruses (ERVs) to suppress anti-tumor type-I interferon (IFN) responses. In patients, elevated H3K27me3 in tumor cells following Trastuzumab treatment correlates with suppression of interferon-driven viral defense gene expression signatures and poor response. Using an immunocompetent model, we provide evidence that EZH2 inhibitors promote interferon-driven immune responses that enhance the efficacy of anti-ErbB2 mAbs, suggesting the potential clinical benefit of epigenomic reprogramming by H3K27me3 depletion in Trastuzumab-resistant disease.
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