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Kano S, Kawakita D, Honma Y, Takahashi H, Nakaguro M, Utsumi Y, Saigusa N, Hanazawa T, Tsukahara K, Okada T, Okami K, Yamazaki K, Ueki Y, Saito Y, Ozawa H, Arai T, Shimizu A, Hanyu K, Iwaki S, Imaizumi S, Sakai A, Yamauchi M, Tanaka R, Sato Y, Yamamura K, Sekimizu M, Imanishi Y, Hirai H, Sato Y, Urano M, Yamamoto H, Fushimi C, Matsuki T, Nagao T, Tada Y. The impact of HER2-Low expression in salivary duct carcinoma: Clinicopathologic features, survival outcomes, and association with androgen receptor-targeted therapy. Oral Oncol 2025; 165:107280. [PMID: 40252453 DOI: 10.1016/j.oraloncology.2025.107280] [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: 07/06/2024] [Revised: 03/15/2025] [Accepted: 03/25/2025] [Indexed: 04/21/2025]
Abstract
OBJECTIVES Recent advances in systemic therapy for salivary duct carcinoma (SDC) have been driven by the development of HER2- and androgen receptor (AR)-targeted therapies. Trastuzumab deruxtecan has proven effective not only in HER2-positive but also HER2-low breast and gastro-esophageal cancers. However, the significance of HER2-low expression in SDC remains unknown. This study aimed to investigate the clinicopathologic characteristics, prognostic implications, and impact on efficacy to AR-targeted therapy in HER2-low SDC. MATERIALS AND METHODS This was a multi-center, observational study. HER2 status was reclassified as follows: HER2-positive (IHC3+ or 2+/ISH+ ), HER2-low (IHC1+ or 2+/ISH-), and HER2-zero (IHC0). The subjects were compared in three groups: total population, curative treatment cohort, and AR-targeted therapy cohort. RESULTS The total population consisted of 526 patients, of whom, 271 (52 %), 184 (35 %), and 71 (13 %) had HER2-positive, -low, and -zero tumors, respectively. Sex, M category, histological origin, Ki67, and p53 expression differed significantly between the HER2-low and HER2-positive cases. No differences in relapse-free or overall survival were observed for HER2 status in the curative treatment cohort; however, in the AR-targeted therapy cohort, the HER2-low group had significantly better response rates (41.6 % vs. 18.9 %, Odds ratio = 0.30, P = 0.012) and longer median progression-free survival (6.9 vs. 4.2 months, Hazard ratio = 1.61, P = 0.029) than those of the HER2-positive group. CONCLUSION HER2-low showed different clinicopathologic features from HER2-positive cases, with no prognostic differences observed in patients who underwent curative treatment. Still, HER2-low may be associated with the efficacy of AR-targeted therapy.
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Affiliation(s)
- Satoshi Kano
- Department of Otolaryngology - Head and Neck Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Daisuke Kawakita
- Department of Otorhinolaryngology, Head and Neck Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Yoshitaka Honma
- Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Hideaki Takahashi
- Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Masato Nakaguro
- Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya, Japan
| | - Yoshitaka Utsumi
- Department of Anatomic Pathology, Tokyo Medical University, Tokyo, Japan
| | - Natsuki Saigusa
- Division of Dental and Maxillofacial Radiology and Oral Pathology Diagnostic Services, The Nippon Dental University Hospital, Tokyo, Japan
| | - Toyoyuki Hanazawa
- Department of Otorhinolaryngology/Head & Neck Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Kiyoaki Tsukahara
- Department of Otorhinolaryngology, Head and Neck Surgery, Tokyo Medical University, Tokyo, Japan
| | - Takuro Okada
- Department of Otorhinolaryngology, Head and Neck Surgery, Tokyo Medical University Hachioji Medical Center, Hachioji, Japan
| | - Kenji Okami
- Department of Otolaryngology, Head and Neck Surgery, School of Medicine, Tokai University, Isehara, Japan
| | - Keisuke Yamazaki
- Department of Head and Neck Surgery, Niigata Cancer Center Hospital, Niigata, Japan
| | - Yushi Ueki
- Department of Otolaryngology Head and Neck Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Yuki Saito
- Department of Otolaryngology - Head and Neck Surgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hiroyuki Ozawa
- Department of Otorhinolaryngology, Head and Neck Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Tomoyuki Arai
- Department of Otorhinolaryngology/Head & Neck Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Akira Shimizu
- Department of Otorhinolaryngology, Head and Neck Surgery, Tokyo Medical University, Tokyo, Japan
| | - Kenji Hanyu
- Department of Otorhinolaryngology, Head and Neck Surgery, Tokyo Medical University, Tokyo, Japan
| | - Sho Iwaki
- Department of Otorhinolaryngology, Head and Neck Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Sae Imaizumi
- Department of Otorhinolaryngology, Head and Neck Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Akihiro Sakai
- Department of Otolaryngology, Head and Neck Surgery, School of Medicine, Tokai University, Isehara, Japan
| | - Mayu Yamauchi
- Department of Otolaryngology, Head and Neck Surgery, School of Medicine, Tokai University, Isehara, Japan
| | - Ryoko Tanaka
- Department of Head and Neck Surgery, Niigata Cancer Center Hospital, Niigata, Japan
| | - Yuichiro Sato
- Department of Head and Neck Surgery, Niigata Cancer Center Hospital, Niigata, Japan
| | - Koji Yamamura
- Department of Otolaryngology - Head and Neck Surgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan
| | - Mariko Sekimizu
- Department of Otorhinolaryngology, Head and Neck Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Yorihisa Imanishi
- Otorhinolaryngology, Head and Neck Surgery, International University of Health and Welfare, Narita Hospital, Narita, Japan
| | - Hideaki Hirai
- Department of Anatomic Pathology, Tokyo Medical University, Tokyo, Japan
| | - Yukiko Sato
- Division of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Makoto Urano
- Department of Diagnostic Pathology, Bantane Hospital, Fujita Health University, School of Medicine, Nagoya, Japan
| | - Hidetaka Yamamoto
- Pathology and Oncology, Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama University, Okayama, Japan
| | - Chihiro Fushimi
- Department of Head and Neck Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Takashi Matsuki
- Department of Head and Neck Surgery, Kanagawa Cancer Center, Yokohama, Japan
| | - Toshitaka Nagao
- Department of Anatomic Pathology, Tokyo Medical University, Tokyo, Japan
| | - Yuichiro Tada
- Department of Head and Neck Oncology and Surgery, International University of Health and Welfare, Mita Hospital, Tokyo, Japan.
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Heaphy CM, Patel S, Smith K, Wondisford AR, Lynskey ML, O'Sullivan RJ, Fuhrer K, Han X, Seethala RR, Liu TC, Cao D, Ertunc O, Zheng Q, Stojanova M, Zureikat AH, Paniccia A, Lee K, Ongchin MC, Pingpank JF, Zeh HJ, Hogg ME, Geller D, Marsh JW, Brand RE, Chennat JS, Das R, Fasanella KE, Gabbert C, Khalid A, McGrath K, Lennon AM, Sarkaria S, Singh H, Slivka A, Hsu D, Zhang JY, Nacev BA, Nikiforova MN, Wald AI, Vaddi N, De Marzo AM, Singhi AH, Bell PD, Singhi AD. Detection of Alternative Lengthening of Telomeres via Chromogenic In Situ Hybridization for the Prognostication of PanNETs and Other Neoplasms. Mod Pathol 2025; 38:100651. [PMID: 39522643 DOI: 10.1016/j.modpat.2024.100651] [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: 08/02/2023] [Revised: 10/10/2024] [Accepted: 10/25/2024] [Indexed: 11/16/2024]
Abstract
Molecular studies have shown alternative lengthening to telomeres (ALT) to be an important prognostic biomarker of shorter relapse-free survival (RFS) for patients with pancreatic neuroendocrine tumors (PanNETs) and other neoplasms. However, the preferred method of detecting ALT in tissue is by fluorescence in situ hybridization (FISH), which has several clinical limitations. These issues necessitate the creation of a chromogenic ALT assay that can be easily implemented into routine practice. A chromogenic in situ hybridization (CISH) assay was developed using genetically modified osteosarcoma cell lines, 20 normal pancreata, 20 ALT-positive PanNETs, and 20 ALT-negative PanNETs. Thereafter, it was validated on a multiinstitutional cohort of 360 surgically resected PanNETs and correlated with multiple clinicopathologic features, RFS, and FISH results. Separately, 109 leiomyosarcomas (LMS) were evaluated by both CISH and FISH, and, similarly, the prognostic significance of ALT status was assessed. Upon optimization, ALT-CISH was identified in 112 of 360 (31%) primary PanNETs and was 100% concordant with FISH testing. ALT correlated with several adverse prognostic findings and distant metastasis (all P < .004). The 5-year RFS for patients with ALT-positive PanNETs was 35% as compared with 94% for ALT-negative PanNETs. By multivariate analysis, ALT was an independent prognostic factor for shorter RFS. Similarly, ALT was associated with shorter RFS in patients with LMS and, analogous to PanNETs, a negative, independent prognostic factor. ALT-CISH was developed and validated in not only PanNETs but also sarcomas, specifically LMS. CISH testing has multiple advantages over FISH that facilitate its widespread clinical use in the detection of ALT and prognostication of patients with diverse neoplasms.
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Affiliation(s)
- Christopher M Heaphy
- Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.
| | - Simmi Patel
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Katelyn Smith
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Anne R Wondisford
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Michelle L Lynskey
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Roderick J O'Sullivan
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Kimberly Fuhrer
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Xiaoli Han
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Raja R Seethala
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Ta-Chiang Liu
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri
| | - Dengfeng Cao
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri
| | - Onur Ertunc
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Qizhi Zheng
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Marija Stojanova
- Department of Medicine, Boston University School of Medicine, Boston, Massachusetts
| | - Amer H Zureikat
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Alessandro Paniccia
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Kenneth Lee
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Melanie C Ongchin
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - James F Pingpank
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Herbert J Zeh
- Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Melissa E Hogg
- Department of Surgery, NorthShore University Health System, Evanston, Illinois
| | - David Geller
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - James Wallis Marsh
- Department of Surgery, West Virginia University Health Sciences Center, Morgantown, West Virginia
| | - Randall E Brand
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Jennifer S Chennat
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Rohit Das
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Kenneth E Fasanella
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Charles Gabbert
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Asif Khalid
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Kevin McGrath
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Anne Marie Lennon
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Savreet Sarkaria
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Harkirat Singh
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Adam Slivka
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Dennis Hsu
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Janie Y Zhang
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Benjamin A Nacev
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Marina N Nikiforova
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Abigail I Wald
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Neel Vaddi
- Drexel University, Philadelphia, Pennsylvania
| | - Angelo M De Marzo
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Anju H Singhi
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Phoenix D Bell
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Aatur D Singhi
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
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Hu K, Wang Y, Ma Y, Xiu C. Clinical utility of quantitative ultrasonography parameters combined with serum cancer antigen 15‑3, human epidermal growth factor receptor 2 and soluble E‑cadherin in diagnosing mass‑type breast cancer. Oncol Lett 2025; 29:133. [PMID: 39822943 PMCID: PMC11737295 DOI: 10.3892/ol.2025.14879] [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: 07/02/2024] [Accepted: 10/16/2024] [Indexed: 01/19/2025] Open
Abstract
Contrast-enhanced ultrasonography (CEUS), a newly developed imaging technique, holds certain value in differentiating benign from malignant tumors. Additionally, serum tumor markers also exhibit significant clinical importance in the diagnosis and monitoring of malignant tumors. Reports have indicated abnormal expression of HER-2, CA153 and sE-cad in breast cancer. Early diagnosis of breast cancer facilitates early clinical intervention and enhances the overall quality of life for patients. Therefore, this study aims to explore the clinical value of quantitative CEUS parameters combined with serum levels of CA153, HER-2 and sE-cad in diagnosing mass-type breast cancer. In total, 49 patients with breast cancer (breast cancer group) and 56 patients with benign breast tumors (benign group) were selected as the study participants, while 50 healthy women served as the control group. Ultrasonography was performed on the patients in the breast cancer and benign groups using diagnostic color Doppler ultrasonography. The serum CA15-3, HER-2 and sE-cad levels in all three study groups were measured using a fully automated electrochemiluminescence immunoassay. Pearson's correlation test was used to analyze the correlation between the quantitative ultrasonography parameters and serum CA15-3, HER-2 and sE-cad levels. Logistic multivariate regression analysis was performed to analyze the independent risk factors, and a receiver operating characteristic curve was plotted to assess the diagnostic value of these factors. The peak intensity (PI), wash-in slope (WIS), gradient (Grad) and local mean transit time (mTTI), along with the CA15-3, HER-2 and sE-cad levels in the breast cancer group were significantly higher, and the time to peak (TTP) was significantly lower, compared with those values in the benign and control groups. CA15-3, HER-2 and sE-cad were negatively correlated with TTP in the breast cancer group (all P<0.05) and positively correlated with PI, WIS, Grad and mTTI (all P<0.05). The area under the curve (AUC) values for CA15-3, HER-2, sE-cad, PI, WIS, Grad, mTTI and TTP for the diagnosis of malignant breast cancer were 0.640, 0.730, 0.687, 0.683, 0.692, 0.737, 0.697 and 0.671, respectively. The AUC for the combined diagnosis was 0.919, with a sensitivity of 0.857 and a specificity of 0.911, outperforming each index alone for a single diagnosis. Logistic multivariate regression analysis revealed that HER-2, TTP, PI, WI and Grad were independent risk factors for malignant breast cancer. In conclusion, combining the quantitative ultrasonography parameters with the CA15-3, HER-2 and sE-cad levels facilitated the differential diagnosis of benign and malignant breast lesions, and may provide a reference for clinical treatment in the future.
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Affiliation(s)
- Keshuo Hu
- Department of Breast Surgery, The Affiliated Hospital of Beihua University, Jilin, Jilin 132011, P.R. China
| | - Yichun Wang
- Department of Cardiothoracic Vascular Surgery, The Affiliated Hospital of Beihua University, Jilin, Jilin 132011, P.R. China
| | - Yang Ma
- Department of Pain, Jilin Central Hospital, Jilin, Jilin 132011, P.R. China
| | - Chao Xiu
- Department of Imaging, The Affiliated Hospital of Beihua University, Jilin, Jilin 132011, P.R. China
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Mais DD, Nazarullah AN, Guidi AJ, Dintzis S, Blond BJ, Long TA, Coulter SN, Brown RW. Estrogen Receptor, Progesterone Receptor, and Human Epidermal Growth Factor Receptor 2 Expression Rates in Invasive Breast Carcinoma: A Study of 21 Institutions. Arch Pathol Lab Med 2025; 149:8-13. [PMID: 38631690 DOI: 10.5858/arpa.2022-0384-cp] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/09/2024] [Indexed: 04/19/2024]
Abstract
CONTEXT.— Laboratories performing predictive marker testing for breast carcinoma are encouraged to compare patient results to published benchmarks. OBJECTIVE.— To collect expression rates for estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2) in invasive breast carcinoma from multiple laboratories. DESIGN.— Participants submitted data from up to 50 primary cases during the study period. Participants reported ER, PgR, and HER2 results in addition to demographic and histologic information. Participants also provided annual institution-level expression rates. RESULTS.— A total of 21 institutions submitted data for 687 cases. Aggregate positivity rates for ER and PgR were 85.6% and 75.1%, respectively. Receptor positivity rates were higher in well-differentiated (grade 1) tumors (ER, 97.4%; PgR, 88.0%) compared with moderately differentiated (grade 2) tumors (ER, 92.4%; PgR, 84.0%) and poorly differentiated (grade 3) tumors (ER, 61.8%; PgR, 48.0%). Expression rates were higher in postmenopausal women (ER, 87.2%) than premenopausal women (ER, 79.6%) and higher in lobular carcinomas (ER, 98.7%; PgR, 85.3%) than ductal carcinomas (ER, 84.1%; PgR, 74.5%). The aggregate HER2 positivity (score 3+) rate was 9.0%. The aggregate HER2 equivocal (score 2+) rate was 14.5%. Of 81 equivocal (score 2+) cases, 70 (86.4%) were nonamplified. CONCLUSIONS.— The data from this study provide multi-institutional benchmark data to assist laboratories performing periodic comparisons as part of a quality management program. Overall expression rates were generally similar to those of other published reports, with the exception of the ER-negative and HER2-positive rates, both of which were somewhat lower.
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Affiliation(s)
- Daniel D Mais
- From the Department of Pathology, University of Louisville School of Medicine, Louisville, Kentucky (Mais)
| | - Alia N Nazarullah
- the Department of Pathology, University of Texas Long School of Medicine, San Antonio (Nazarullah)
| | - Anthony J Guidi
- the Department of Pathology, Brigham and Women's Faulkner Hospital, Boston, Massachusetts (Guidi)
| | - Suzanne Dintzis
- the Department of Pathology, University of Washington, Seattle (Dintzis)
| | - Barbara J Blond
- the Department of Biostatistics, College of American Pathologists, Northfield, Illinois (Blond, Long, Coulter)
| | - Thomas A Long
- the Department of Biostatistics, College of American Pathologists, Northfield, Illinois (Blond, Long, Coulter)
| | - Suzanne N Coulter
- the Department of Biostatistics, College of American Pathologists, Northfield, Illinois (Blond, Long, Coulter)
| | - Richard W Brown
- the Department of Pathology, Memorial Hermann Hospital, Houston, Texas (Brown)
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Yu QX, Fu PY, Zhang C, Li L, Huang WT. Mesenchymal-epithelial transition factor amplification correlates with adverse pathological features and poor clinical outcome in colorectal cancer. World J Gastrointest Surg 2024; 16:1395-1406. [PMID: 38817281 PMCID: PMC11135301 DOI: 10.4240/wjgs.v16.i5.1395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 02/22/2024] [Accepted: 04/11/2024] [Indexed: 05/23/2024] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is the third most common cancer and the second most common cause of cancer-related mortality worldwide. Mesenchymal-epithelial transition factor (MET) gene participates in multiple tumor biology and shows clinical potential for pharmacological manipulation in tumor treatment. MET amplification has been reported in CRC, but data are very limited. Investigating pathological values of MET in CRC may provide new therapeutic and genetic screening options in future clinical practice. AIM To determine the pathological significance of MET amplification in CRC and to propose a feasible screening strategy. METHODS A number of 205 newly diagnosed CRC patients undergoing surgical resection without any preoperative therapy at Shenzhen Cancer Hospital of Chinese Academy of Medical Sciences were recruited. All patients were without RAS/RAF mutation or microsatellite instability-high. MET amplification and c-MET protein expression were analyzed using fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC), respectively. Correlations between MET aberration and pathological features were detected using the chi-squared test. Progression free survival (PFS) during the two-year follow-up was detected using the Kaplan-Meier method and log rank test. The results of MET FISH and IHC were compared using one-way ANOVA. RESULTS Polysomy-induced MET amplification was observed in 14.4% of cases, and focal MET amplification was not detected. Polysomy-induced MET amplification was associated with a higher frequency of lymph node metastasis (LNM) (P < 0.001) and higher tumor budding grade (P = 0.02). In the survival analysis, significant difference was detected between patients with amplified- and non-amplified MET in a two-year follow-up after the first diagnosis (P = 0.001). C-MET scores of 0, 1+, 2+, and 3+ were observed in 1.4%, 24.9%, 54.7%, and 19.0% of tumors, respectively. C-MET overexpression correlated with higher frequency of LNM (P = 0.002), but no significant difference of PFS was detected between patients with different protein levels. In terms of concordance between MET FISH and IHC results, MET copy number showed no difference in c-MET IHC 0/1+ (3.35 ± 0.18), 2+ (3.29 ± 0.11) and 3+ (3.58 ± 0.22) cohorts, and the MET-to-CEP7 ratio showed no difference in three groups (1.09 ± 0.02, 1.10 ± 0.01, and 1.09 ± 0.03). CONCLUSION In CRC, focal MET amplification was a rare event. Polysomy-induced MET amplification correlated with adverse pathological characteristics and poor prognosis. IHC was a poor screening tool for MET amplification.
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Affiliation(s)
- Qiu-Xiao Yu
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, Guangdong Province, China
| | - Ping-Ying Fu
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, Guangdong Province, China
| | - Chi Zhang
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, Guangdong Province, China
| | - Li Li
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, Guangdong Province, China
| | - Wen-Ting Huang
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, Guangdong Province, China
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Britten K, McAndrew N. New approaches for human epidermal growth factor receptor 2-low and human epidermal growth factor receptor 2-overexpressing metastatic breast cancer. Curr Opin Obstet Gynecol 2024; 36:34-39. [PMID: 38170550 DOI: 10.1097/gco.0000000000000930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2024]
Abstract
PURPOSE OF REVIEW In recent years, there has been a flurry of activity in the human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer space. New, powerful drugs like trastuzumab deruxtecan have challenged our fundamental definition of what HER2 expression means as a predictive biomarker. RECENT FINDINGS Recent approvals of multiple agents in the second line-metastatic setting have given patients access to a variety of new agents, but also raise questions with regard to optimal sequencing. SUMMARY This review will explore current issues with HER2 testing, recently approved drugs in the HER2+ and HER2 low spaces, as well as novel agents/combinations on the horizon.
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Affiliation(s)
- Karissa Britten
- Division of Hematology/Oncology; University of California, Los Angeles, CA, USA
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Popović M, Silovski T, Križić M, Dedić Plavetić N. HER2 Low Breast Cancer: A New Subtype or a Trojan for Cytotoxic Drug Delivery? Int J Mol Sci 2023; 24:ijms24098206. [PMID: 37175916 PMCID: PMC10179462 DOI: 10.3390/ijms24098206] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 04/23/2023] [Accepted: 04/28/2023] [Indexed: 05/15/2023] Open
Abstract
Despite the great progress made in the understanding of the biological behavior of certain types of invasive breast cancer, there is still no single histological or molecular classification that encompasses such diversity and accurately predicts the clinical course of distinct breast cancer subtypes. The long-lasting classification of breast cancer as HER2-positive vs. HER2-negative has recently come into question with the discovery of new antibody drug conjugates (ADC), which are proven to be remarkably efficient in treating HER2-low breast cancer. The HER2-low paradigm has challenged the traditional understanding of HER2 overexpression and emphasized the need for more robust HER2 testing in order to encompass HER2 intratumoral heterogeneity and spatial distribution more accurately. It is yet to be seen if low HER2 will remain merely a marker of HER2-equipped tumors targetable with ADCs or if distinctive molecular and phenotypic groups within HER2-low tumors will eventually be discerned.
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Affiliation(s)
- Marina Popović
- Department of Oncology, University Hospital Centre Zagreb, 10000 Zagreb, Croatia
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Tajana Silovski
- Department of Oncology, University Hospital Centre Zagreb, 10000 Zagreb, Croatia
| | - Marija Križić
- Department of Oncology, University Hospital Centre Zagreb, 10000 Zagreb, Croatia
| | - Natalija Dedić Plavetić
- Department of Oncology, University Hospital Centre Zagreb, 10000 Zagreb, Croatia
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
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Rakha EA, Tan PH, Quinn C, Provenzano E, Shaaban AM, Deb R, Callagy G, Starczynski J, Lee AHS, Ellis IO, Pinder SE. UK recommendations for HER2 assessment in breast cancer: an update. J Clin Pathol 2023; 76:217-227. [PMID: 36564170 DOI: 10.1136/jcp-2022-208632] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 12/09/2022] [Indexed: 12/25/2022]
Abstract
The last UK breast cancer (BC) human epidermal growth factor receptor 2 (HER2) testing guideline recommendations were published in 2015. Since then, new data and therapeutic strategies have emerged. The American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) published a focused update in 2018 that reclassified in situ hybridisation (ISH) Group 2 (immunohistochemistry (IHC) score 2+and HER2/chromosome enumeration probe 17 (CEP17) ratio ≥2.0 and HER2 copy number <4.0 signals/cell), as well as addressed other concerns raised by previous guidelines. The present article further refines UK guidelines, with specific attention to definitions of HER2 status focusing on eight key areas: (1) HER2 equivocal (IHC 2+) and assignment of the ASCO/CAP ISH group 2 tumours; (2) the definition of the group of BCs with low IHC scores for HER2 with emphasis on the distinction between IHC score 1+ (HER2-Low) from HER2 IHC score 0 (HER2 negative); (3) reporting cases showing HER2 heterogeneity; (4) HER2 testing in specific settings, including on cytological material; (5) repeat HER2 testing, (6) HER2 testing turnaround time targets; (7) the potential role of next generation sequencing and other diagnostic molecular assays for routine testing of HER2 status in BC and (8) use of image analysis to score HER2 IHC. The two tiered system of HER2 assessment remains unchanged, with first line IHC and then ISH limited to IHC equivocal cases (IHC score 2+) but emerging data on the relationship between IHC scores and levels of response to anti-HER2 therapy are considered. Here, we present the latest UK recommendations for HER2 status evaluation in BC, and where relevant, the differences from other published guidelines.
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Affiliation(s)
- Emad A Rakha
- Cellular Patthology Department, School of Medicine, University of Nottingham, Nottingham, UK
| | | | - Cecily Quinn
- Department of Histopathology, St Vincent's University Hospital, Elm Park and and UCD School of Medicine, Dublin, Ireland
| | - Elena Provenzano
- Department of Histopathology, Addenbrookes Hospital, Cambridge, UK
| | - Abeer M Shaaban
- Department of Cellular Pathology, University Hospitals Birmingham NHS Foundation Trusts and Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - Rahul Deb
- Cellular Pathology, University Hospitals of Derby and Burton NHS Foundation Trust, Derby, UK
| | - Grace Callagy
- Discipline of Pathology, School of Medicine, Lambe Institute for Translational Research, University of Galway, Galway, Ireland
| | - Jane Starczynski
- Department of Cellular Pathology, University Hospitals Birmingham NHS Foundation Trusts, Birmingham, UK
| | - Andrew H S Lee
- Cellular Pathology Department, City Hospital, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Ian O Ellis
- Cellular Patthology Department, School of Medicine, University of Nottingham, Nottingham, UK
| | - Sarah E Pinder
- School of Cancer & Pharmaceutical Sciences, Kings College London, London, UK
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9
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Zhou Q, Cheng S, Zheng S, Wang Z, Guan P, Zhu Z, Huang X, Zhou C, Li G. ChromLoops: a comprehensive database for specific protein-mediated chromatin loops in diverse organisms. Nucleic Acids Res 2023; 51:D57-D69. [PMID: 36243984 PMCID: PMC9825580 DOI: 10.1093/nar/gkac893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Revised: 09/14/2022] [Accepted: 10/03/2022] [Indexed: 01/29/2023] Open
Abstract
Chromatin loops (or chromatin interactions) are important elements of chromatin structures. Disruption of chromatin loops is associated with many diseases, such as cancer and polydactyly. A few methods, including ChIA-PET, HiChIP and PLAC-Seq, have been proposed to detect high-resolution, specific protein-mediated chromatin loops. With rapid progress in 3D genomic research, ChIA-PET, HiChIP and PLAC-Seq datasets continue to accumulate, and effective collection and processing for these datasets are urgently needed. Here, we developed a comprehensive, multispecies and specific protein-mediated chromatin loop database (ChromLoops, https://3dgenomics.hzau.edu.cn/chromloops), which integrated 1030 ChIA-PET, HiChIP and PLAC-Seq datasets from 13 species, and documented 1 491 416 813 high-quality chromatin loops. We annotated genes and regions overlapping with chromatin loop anchors with rich functional annotations, such as regulatory elements (enhancers, super-enhancers and silencers), variations (common SNPs, somatic SNPs and eQTLs), and transcription factor binding sites. Moreover, we identified genes with high-frequency chromatin interactions in the collected species. In particular, we identified genes with high-frequency interactions in cancer samples. We hope that ChromLoops will provide a new platform for studying chromatin interaction regulation in relation to biological processes and disease.
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Affiliation(s)
- Qiangwei Zhou
- National Key Laboratory of Crop Genetic Improvement, Hubei Hongshan Laboratory, Huazhong Agricultural University, Wuhan 430070, China.,Agricultural Bioinformatics Key Laboratory of Hubei Province, Hubei Engineering Technology Research Center of Agricultural Big Data, Key Laboratory of Smart Farming for Agricultural Animals, 3D Genomics Research Center, College of Informatics, Huazhong Agricultural University, Wuhan 430070, China
| | - Sheng Cheng
- National Key Laboratory of Crop Genetic Improvement, Hubei Hongshan Laboratory, Huazhong Agricultural University, Wuhan 430070, China.,Agricultural Bioinformatics Key Laboratory of Hubei Province, Hubei Engineering Technology Research Center of Agricultural Big Data, Key Laboratory of Smart Farming for Agricultural Animals, 3D Genomics Research Center, College of Informatics, Huazhong Agricultural University, Wuhan 430070, China
| | - Shanshan Zheng
- National Key Laboratory of Crop Genetic Improvement, Hubei Hongshan Laboratory, Huazhong Agricultural University, Wuhan 430070, China.,Agricultural Bioinformatics Key Laboratory of Hubei Province, Hubei Engineering Technology Research Center of Agricultural Big Data, Key Laboratory of Smart Farming for Agricultural Animals, 3D Genomics Research Center, College of Informatics, Huazhong Agricultural University, Wuhan 430070, China
| | - Zhenji Wang
- National Key Laboratory of Crop Genetic Improvement, Hubei Hongshan Laboratory, Huazhong Agricultural University, Wuhan 430070, China.,Agricultural Bioinformatics Key Laboratory of Hubei Province, Hubei Engineering Technology Research Center of Agricultural Big Data, Key Laboratory of Smart Farming for Agricultural Animals, 3D Genomics Research Center, College of Informatics, Huazhong Agricultural University, Wuhan 430070, China
| | - Pengpeng Guan
- National Key Laboratory of Crop Genetic Improvement, Hubei Hongshan Laboratory, Huazhong Agricultural University, Wuhan 430070, China.,Agricultural Bioinformatics Key Laboratory of Hubei Province, Hubei Engineering Technology Research Center of Agricultural Big Data, Key Laboratory of Smart Farming for Agricultural Animals, 3D Genomics Research Center, College of Informatics, Huazhong Agricultural University, Wuhan 430070, China
| | - Zhixian Zhu
- National Key Laboratory of Crop Genetic Improvement, Hubei Hongshan Laboratory, Huazhong Agricultural University, Wuhan 430070, China.,Agricultural Bioinformatics Key Laboratory of Hubei Province, Hubei Engineering Technology Research Center of Agricultural Big Data, Key Laboratory of Smart Farming for Agricultural Animals, 3D Genomics Research Center, College of Informatics, Huazhong Agricultural University, Wuhan 430070, China
| | - Xingyu Huang
- National Key Laboratory of Crop Genetic Improvement, Hubei Hongshan Laboratory, Huazhong Agricultural University, Wuhan 430070, China.,Agricultural Bioinformatics Key Laboratory of Hubei Province, Hubei Engineering Technology Research Center of Agricultural Big Data, Key Laboratory of Smart Farming for Agricultural Animals, 3D Genomics Research Center, College of Informatics, Huazhong Agricultural University, Wuhan 430070, China
| | - Cong Zhou
- National Key Laboratory of Crop Genetic Improvement, Hubei Hongshan Laboratory, Huazhong Agricultural University, Wuhan 430070, China.,Agricultural Bioinformatics Key Laboratory of Hubei Province, Hubei Engineering Technology Research Center of Agricultural Big Data, Key Laboratory of Smart Farming for Agricultural Animals, 3D Genomics Research Center, College of Informatics, Huazhong Agricultural University, Wuhan 430070, China
| | - Guoliang Li
- National Key Laboratory of Crop Genetic Improvement, Hubei Hongshan Laboratory, Huazhong Agricultural University, Wuhan 430070, China.,Agricultural Bioinformatics Key Laboratory of Hubei Province, Hubei Engineering Technology Research Center of Agricultural Big Data, Key Laboratory of Smart Farming for Agricultural Animals, 3D Genomics Research Center, College of Informatics, Huazhong Agricultural University, Wuhan 430070, China
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10
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Hossain MS, Syeed MMM, Fatema K, Hossain MS, Uddin MF. Singular Nuclei Segmentation for Automatic HER2 Quantification Using CISH Whole Slide Images. SENSORS (BASEL, SWITZERLAND) 2022; 22:7361. [PMID: 36236459 PMCID: PMC9571354 DOI: 10.3390/s22197361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Revised: 09/20/2022] [Accepted: 09/22/2022] [Indexed: 06/16/2023]
Abstract
Human epidermal growth factor receptor 2 (HER2) quantification is performed routinely for all breast cancer patients to determine their suitability for HER2-targeted therapy. Fluorescence in situ hybridization (FISH) and chromogenic in situ hybridization (CISH) are the US Food and Drug Administration (FDA) approved tests for HER2 quantification in which at least 20 cancer-affected singular nuclei are quantified for HER2 grading. CISH is more advantageous than FISH for cost, time and practical usability. In clinical practice, nuclei suitable for HER2 quantification are selected manually by pathologists which is time-consuming and laborious. Previously, a method was proposed for automatic HER2 quantification using a support vector machine (SVM) to detect suitable singular nuclei from CISH slides. However, the SVM-based method occasionally failed to detect singular nuclei resulting in inaccurate results. Therefore, it is necessary to develop a robust nuclei detection method for reliable automatic HER2 quantification. In this paper, we propose a robust U-net-based singular nuclei detection method with complementary color correction and deconvolution adapted for accurate HER2 grading using CISH whole slide images (WSIs). The efficacy of the proposed method was demonstrated for automatic HER2 quantification during a comparison with the SVM-based approach.
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Affiliation(s)
- Md Shakhawat Hossain
- Department of CS, American International University-Bangladesh, Dhaka 1229, Bangladesh
- RIoT Research Center, Independent University, Bangladesh, Dhaka 1229, Bangladesh
| | - M. M. Mahbubul Syeed
- RIoT Research Center, Independent University, Bangladesh, Dhaka 1229, Bangladesh
- Department of CSE, Independent University, Bangladesh, Dhaka 1229, Bangladesh
| | - Kaniz Fatema
- RIoT Research Center, Independent University, Bangladesh, Dhaka 1229, Bangladesh
- Department of CSE, Independent University, Bangladesh, Dhaka 1229, Bangladesh
| | - Md Sakir Hossain
- Department of CS, American International University-Bangladesh, Dhaka 1229, Bangladesh
| | - Mohammad Faisal Uddin
- RIoT Research Center, Independent University, Bangladesh, Dhaka 1229, Bangladesh
- Department of CSE, Independent University, Bangladesh, Dhaka 1229, Bangladesh
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11
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Mathew T, Niyas S, Johnpaul C, Kini JR, Rajan J. A novel deep classifier framework for automated molecular subtyping of breast carcinoma using immunohistochemistry image analysis. Biomed Signal Process Control 2022. [DOI: 10.1016/j.bspc.2022.103657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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12
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The Influence of Heavy Metals on Gastric Tumorigenesis. JOURNAL OF ONCOLOGY 2022; 2022:6425133. [PMID: 35669240 PMCID: PMC9167133 DOI: 10.1155/2022/6425133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 05/01/2022] [Accepted: 05/12/2022] [Indexed: 12/24/2022]
Abstract
Objectives This study aimed to observe the relationship among heavy metals concentration, microsatellite instability (MSI), and human epidermal growth factor receptor type 2 (HER2) gene amplification in gastric cancer (GC) patients. Methods The concentrations of 18 heavy metals in the plasma of GC patients and healthy controls were measured by inductive coupled plasma emission spectrometry (ICP-MS). MSI detection was conducted by detecting 5 microsatellite repeat markers by PCR analysis. HER2 gene amplification was detected by fluorescence in situ hybridization (FISH). The relationship among heavy metal elements, tumor biomarkers, HER2 amplification, and MSI status was analyzed by Pearson correlation analysis. Results A total of 105 GC patients and 62 healthy controls were recruited in this study. The concentration of arsenic (As), chromium (Cr), cuprum (Cu), mercury (Hg), manganese (Mn), lead (Pb), stibium (Sb), selenium (Se), stannum (Sn), strontium (Sr), thallium (Tl), vanadium (V), and zinc (Zn) were significantly different between GC patients and controls. Among 105 GC patients, including 87 microsatellite-stable (MSS) samples and 18 MSI samples, the concentration of Ga is significantly higher in the MSI group than that in the MSS group. Meanwhile, in 97 GC patients having detected HER2 gene amplification, 69 of 97 had negative HER2 gene amplification and the rest 28 GC patients had positive HER2 gene amplification. The concentration of Hg, Sn, and Tl is noticeably higher in the HER2 positive group than in the HER2 negative group. Only Sb was positively correlated with MSI, but none of these heavy metals was correlated with HER2 gene amplification. Conclusions The results indicated that Sb has significant positive correlation with the MSI status, which suggests that Sb may cause MSI in GC. However, further research studies are required to elucidate the mechanisms in the near feature.
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13
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Targeting the HER3 pseudokinase domain with small molecule inhibitors. Methods Enzymol 2022; 667:455-505. [PMID: 35525551 DOI: 10.1016/bs.mie.2022.03.044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
HER3 is a potent oncogenic growth factor receptor belonging to the human epidermal growth factor (HER/EGFR) family of receptor tyrosine kinases. In contrast to other EGFR family members, HER3 is a pseudokinase, lacking functional kinase activity. As such, efforts to develop small molecule tyrosine kinase inhibitors against this family member have been limited. In response to HER3-specific growth factors such as neuregulin (NRG, also known as heregulin or HRG), HER3 must couple with catalytically active family members, including its preferred partner HER2. Dimerization of the intracellular HER2:HER3 kinase domains is a critical part of the activation mechanism and HER3 plays a specialized role as an allosteric activator of the active HER2 kinase partner. Intriguingly, many pseudokinases retain functionally important nucleotide binding capacity, despite loss of kinase activity. We demonstrated that occupation of the nucleotide pocket of the pseudokinase HER3 retains functional importance for growth factor signaling through oncogenic HER2:HER3 heterodimers. Mutation of the HER3 nucleotide pocket both disrupts signaling and disrupts HER2:HER3 dimerization. Conversely, ATP competitive drugs which bind to HER3, but not HER2, can stabilize HER2:HER3 dimers, induce signaling and promote cell growth in breast cancer models. This indicates a nucleotide-dependent conformational role for the HER3 kinase domain. Critically, our recent proof-of-concept work demonstrated that HER3-directed small molecule inhibitors can also disrupt HER2:HER3 dimerization and signaling, supporting the prospect that HER3 can be a direct drug target despite its lack of intrinsic activity. In this chapter we will describe methods for identifying and validating small molecule inhibitors against the HER3 pseudokinase.
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14
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Ding J, Jiang L, Xu Z, Chen Y, Wu W, Huang J. Validation of the Prognostic Stage from the American Joint Committee on Cancer 8th Staging Manual in Luminal B-Like Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer. Cancer Manag Res 2022; 14:719-728. [PMID: 35221724 PMCID: PMC8881011 DOI: 10.2147/cmar.s342918] [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: 10/12/2021] [Accepted: 12/24/2021] [Indexed: 11/30/2022] Open
Abstract
PURPOSE The 8th edition American Joint Committee on Cancer (AJCC) prognostic staging system (PS) has been validated numerous times; however, the prognostic value of PS for breast cancer based on molecular subtype has rarely been explored. This study aimed to investigate the prognostic value of PS in Chinese patients with luminal B-like human epidermal growth factor receptor 2 (HER2)-negative breast cancer. METHODS A total of 407 eligible cases were included in the study. All of the cases were restaged using the 8th edition AJCC Anatomic Staging System (AS) and PS. The Kaplan-Meier method was used to calculate estimated survival and the Log rank test was used to compare the survival differences between groups. RESULTS The 5-year disease-specific survival (DSS) and overall survival (OS) rates were 90.3% and 93.5%, respectively, and there were statistically significant differences in the 5-year DSS and 5-year OS rates among the different anatomic and prognostic stage groups. The application of the PS resulted in the assignment of 215 (52.8%) patients to a different group. Different prognostic stage groups restaged from anatomic Stage III had significant differences in both DSS (χ 2 = 4.366, p = 0.037) and OS (χ 2 = 7.549, p = 0.006); additionally, different prognostic stage groups from the anatomic Stage II group had significant differences in DSS (χ 2 = 7.724, p = 0.021) but no significant differences in OS (χ 2 = 5.182, p = 0.075). However, different prognostic stage groups from anatomic Stage I had no significant differences in either DSS (χ 2= 0.159, p = 0.690) or OS (χ 2 = 0.099, p = 0.753). CONCLUSION The 8th edition AJCC PS refined the anatomic stage grouping in luminal B-like HER2-negative breast cancer and could lead to a more personalized approach to breast cancer treatment.
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Affiliation(s)
- Jinhua Ding
- Department of Breast Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, People’s Republic of China
- Department of Breast and Thyroid Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, 315000, People’s Republic of China
| | - Li Jiang
- Department of General Medicine, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, 315000, People’s Republic of China
| | - Zheng Xu
- Ningbo University School of Medicine, Ningbo University, Ningbo, Zhejiang, 315000, People’s Republic of China
| | - Yong Chen
- Ningbo University School of Medicine, Ningbo University, Ningbo, Zhejiang, 315000, People’s Republic of China
| | - Weizhu Wu
- Department of Breast and Thyroid Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, 315000, People’s Republic of China
| | - Jian Huang
- Department of Breast Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, People’s Republic of China
- Key Laboratory of Tumour Microenvironment and Immune Therapy of Zhejiang Province, Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, 310009, People’s Republic of China
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15
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Hwang HW, Hong SA, Nam SJ, Kim SW, Lee JE, Yu JH, Lee SK, Cho SY, Cho EY. Histologic analysis according to HER2 gene status in HER2 2 + invasive breast cancer: a study of 280 cases comparing ASCO/CAP 2013 and 2018 guideline recommendations. Virchows Arch 2022; 480:749-758. [PMID: 35138452 DOI: 10.1007/s00428-022-03280-0] [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: 09/02/2021] [Revised: 12/31/2021] [Accepted: 01/13/2022] [Indexed: 10/19/2022]
Abstract
The American Society of Clinical Oncology and College of American Pathologists guidelines for HER2 testing in breast cancer (BC) have been updated with more stringent criteria regarding immunohistochemistry (IHC) 2 + interpretation. The aim of our study was to determine HER2 status in IHC 2 + cases based on 2013 and 2018 guidelines and to investigate specific histologic characteristics that might predict HER2 status in tumors with equivocal IHC staining. Two hundred eighty BC cases reported as IHC 2 + and 24 cases reported as non-IHC 2 + were reviewed with 12 histologic characteristics. Of the IHC 2 + cases based on 2013 guideline, 21% were reclassified to IHC 1 + when applying the 2018 guidelines. Consequently, it led to an 8% increase of HER2 amplification rate in 2018 IHC 2 + group. Seven characteristics were significantly associated with prediction of HER2 amplification in IHC 2 + BCs, including high tumor-infiltrating lymphocytes (TILs), distinct cellular membrane, no apical snout, large nuclear size, nuclear size variation, high nuclear grade, and tubule formation < 10%. Using these criteria, the presence of four or more characteristics significantly indicates HER2 amplification. Moreover, four characteristics among them, including high TILs, distinct cellular membrane, nuclear size variation, and high nuclear grade, were also associated with HER2 amplification in non-IHC 2 + cases, demonstrating their predictive value as complements to IHC. In conclusion, we provide specific morphologic features that will improve pathologist performance in identifying more HER2-positive BCs. We further suggest an algorithm for trastuzumab therapy decisions using a combination of histomorphologic evaluation and the updated 2018 guidelines.
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Affiliation(s)
- Hye Won Hwang
- Department of Pathology, Chung-Ang University Hospital, Seoul, Republic of Korea
| | - Soon Auck Hong
- Department of Pathology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - Seok Jin Nam
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Seok Won Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jeong Eon Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jong-Han Yu
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Se Kyung Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Soo Youn Cho
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea.
| | - Eun Yoon Cho
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea.
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16
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Grüntkemeier L, Khurana A, Bischoff FZ, Hoffmann O, Kimmig R, Moore M, Cotter P, Kasimir-Bauer S. Single HER2-positive tumor cells are detected in initially HER2-negative breast carcinomas using the DEPArray™-HER2-FISH workflow. Breast Cancer 2022; 29:487-497. [PMID: 35025065 PMCID: PMC9021056 DOI: 10.1007/s12282-022-01330-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 12/22/2021] [Indexed: 02/06/2023]
Abstract
Background In breast cancer (BC), overexpression of HER2 on the primary tumor (PT) is determined by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) to stratify samples as negative, equivocal and positive to identify patients (pts) for anti-HER2 therapy. CAP/ASCO guidelines recommend FISH for analyzing HER2/neu (ERBB2) gene amplification and for resolving equivocal HER2 IHC results. However, pre-analytical and analytical aspects are often confounded by sample related limitations and tumor heterogeneity and HER2 expression may differ between the PT and circulating tumor cells (CTCs), the precursors of metastasis. We used a validation cohort of BC patients to establish a new DEPArray™-PT-HER2-FISH workflow for further application in a development cohort, characterized as PT-HER2-negative but CTC-HER2/neu-positive, to identify patients with PT-HER2 amplified cells not detected by routine pathology. Methods 50 µm FFPE tumor curls from the validation cohort (n = 49) and the development cohort (n = 25) underwent cutting, deparaffinization and antigen retrieval followed by dissociation into a single-cell suspension. After staining for cytokeratin, vimentin, DAPI and separation via DEPArray™, single cells were processed for HER2-FISH analysis to assess the number of chromosome 17 and HER2 loci signals for comparison, either with available IHC or conventional tissue section FISH. CTC-HER2/neu status was determined using the AdnaTest BreastCancer (QIAGEN, Hilden, Germany). Results Applying CAP/ASCO guidelines for HER2 evaluation of single PT cells, the comparison of routine pathology and DEPArray™-HER2-FISH analysis resulted in a concordance rate of 81.6% (40/49 pts) in the validation cohort and 84% (21/25 pts) in the development cohort, respectively. In the latter one, 4/25 patients had single HER2-positive tumor cells with 2/25 BC patients proven to be HER2-positive, despite being HER2-negative in routine pathology. The two other patients showed an equivocal HER2 status in the DEPArray™-HER2-FISH workflow but a negative result in routine pathology. Whereas all four patients with discordant HER2 results had already died, 17/21 patients with concordant HER2 results are still alive. Conclusions The DEPArray™ system allows pure tumor cell recovery for subsequent HER2/neu FISH analysis and is highly concordant with conventional pathology. For PT-HER2-negative patients, harboring HER2/neu-positive CTCs, this approach might allow caregivers to more effectively offer anti-HER2 treatment. Supplementary Information The online version contains supplementary material available at 10.1007/s12282-022-01330-8.
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Affiliation(s)
- Lisa Grüntkemeier
- Department of Gynecology and Obstetrics, University Hospital Essen, Hufelandstrasse 55, 45122, Essen, Germany
| | | | | | - Oliver Hoffmann
- Department of Gynecology and Obstetrics, University Hospital Essen, Hufelandstrasse 55, 45122, Essen, Germany
| | - Rainer Kimmig
- Department of Gynecology and Obstetrics, University Hospital Essen, Hufelandstrasse 55, 45122, Essen, Germany
| | | | | | - Sabine Kasimir-Bauer
- Department of Gynecology and Obstetrics, University Hospital Essen, Hufelandstrasse 55, 45122, Essen, Germany.
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17
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Zhang L, Chen Y, Lv Y, Jiao S, Zhao W. OUP accepted manuscript. Oncologist 2022; 27:245-250. [PMID: 35380719 DOI: 10.1093/oncolo/oyac027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Accepted: 12/28/2021] [Indexed: 11/12/2022] Open
Affiliation(s)
- Li Zhang
- Department of Oncology, PLA General Hospital, Beijing, People's Republic of China
| | - Yimeng Chen
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi, People's Republic of China
| | - Yao Lv
- Department of Oncology, PLA General Hospital, Beijing, People's Republic of China
| | - Shunchang Jiao
- Department of Oncology, PLA General Hospital, Beijing, People's Republic of China
| | - Weihong Zhao
- Department of Oncology, PLA General Hospital, Beijing, People's Republic of China
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18
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Yan Y, Jiang L, Fang J, Dai Y, Chenyu X, Ding J. Interpectoral Lymph Node Dissection Can Be Spared in pN0/N1 Invasive Breast Cancer Undergoing Modified Radical Mastectomy: Single-Institution Experience from Mainland China. Cancer Manag Res 2021; 13:5855-5863. [PMID: 34349558 PMCID: PMC8326277 DOI: 10.2147/cmar.s313971] [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: 04/07/2021] [Accepted: 06/22/2021] [Indexed: 11/29/2022] Open
Abstract
Purpose Interpectoral lymph nodes (IPNs) are one of the lymphatic drainage pathways in breast cancer. However, the clinical significance of IPN dissection is controversial, and there is no international consensus regarding the management of IPN for resectable breast cancer. Our study aims to identify the independent predictors of IPN metastasis in invasive breast cancer (IBC) and provide some evidence for rational decision-making. Methods Data from 214 IBC patients who were treated with modified radical mastectomy (MRM) plus IPN dissection or biopsy in Ningbo Medical Center Lihuili Hospital were retrospectively reviewed. Univariate analysis and multivariate logistic regression analysis were used to analyse the correlations between IPN occurrence or metastasis and clinicopathological characteristics. Results The occurrence rate of IPN in overall population was 75.2%. Univariate analysis showed that tumour size, involvement of axillary lymph nodes (ALNs), histological grading, Ki67 index and molecular subtype were associated with the occurrence of IPN. However, involvement of ALN was the only independent predictor by multivariate logistic regression analysis. In 161 patients whose IPNs were detected, 46 (28.6%) patients had one or more metastatic IPNs. Univariate analysis showed that tumour size, involvement of ALN, oestrogen receptor status and molecular subtype were associated with IPN metastasis. However, involvement of ALN was the only predictor by multivariate logistic regression analysis. In total, 0%, 5.0%, 26.1% and 84.2% of pN0, pN1, pN2, and pN3 patients had metastatic IPNs, respectively. Conclusion The relatively low rate of IPN metastasis in patients with pN0/N1 breast cancer suggests that IPN dissection can be safely spared in patients with low tumour burden in axillary lymph nodes (pN0/N1), when MRM even breast conservation surgery is performed.
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Affiliation(s)
- Yun Yan
- Department of Ultrasound, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, 315000, People's Republic of China
| | - Li Jiang
- Department of General Practice, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, 315000, People's Republic of China
| | - Jianjiang Fang
- Department of General Practice, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, 315000, People's Republic of China
| | - Yi Dai
- Ningbo University School of Medicine, Ningbo, Zhejiang, 315000, People's Republic of China
| | - Xingzi Chenyu
- Ningbo University School of Medicine, Ningbo, Zhejiang, 315000, People's Republic of China
| | - Jinhua Ding
- Department of Breast and Thyroid Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, 315000, People's Republic of China
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19
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Retrospective observational study of HER2 immunohistochemistry in borderline breast cancer patients undergoing neoadjuvant therapy, with an emphasis on Group 2 (HER2/CEP17 ratio ≥2.0, HER2 copy number <4.0 signals/cell) cases. Br J Cancer 2021; 124:1836-1842. [PMID: 33762723 PMCID: PMC8144199 DOI: 10.1038/s41416-021-01351-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Revised: 02/23/2021] [Accepted: 03/04/2021] [Indexed: 02/01/2023] Open
Abstract
BACKGROUND The ASCO/CAP guidance on HER2 testing in breast cancer (BC) has recently changed. Group 2 tumours with immunohistochemistry score 2+ and HER2/CEP17 ratio ≥2.0 and HER2 copy number <4.0 signals/cell were re-classified as HER2 negative. This study aims to examine the response of Group 2 tumours to neoadjuvant chemotherapy (NACT). METHODS 749 BC cases were identified from 11 institutions. The association between HER2 groups and pathological complete response (pCR) was assessed. RESULTS 54% of immunohistochemistry HER2 positive (score 3+) BCs showed pCR, compared to 19% of immunohistochemistry 2+ FISH amplified cases. 27% of Group 2 treated with HER2 targeted therapy achieved pCR, compared to 19 and 11% in the combined Groups 1 + 3 and Groups 4 + 5, respectively. No difference in pCR rates was identified between Group 2 and Group 1 or combined Groups 1 + 3. However, Group 2 response rate was higher than Groups 4 + 5 (p = 0.017). CONCLUSION No difference in pCR was detected in tumours with a HER2/CEP17 ratio ≥2.0 and a HER2 score 2+ by IHC when stratified by HER2 gene copy number. Our data suggest that ASCO/CAP HER2 Group 2 carcinomas should be evaluated further with respect to eligibility for HER2 targeted therapy.
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20
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Memon R, Prieto Granada CN, Harada S, Winokur T, Reddy V, Kahn AG, Siegal GP, Wei S. Discordance Between Immunohistochemistry and In Situ Hybridization to Detect HER2 Overexpression/Gene Amplification in Breast Cancer in the Modern Age: A Single Institution Experience and Pooled Literature Review Study. Clin Breast Cancer 2021; 22:e123-e133. [PMID: 34120846 DOI: 10.1016/j.clbc.2021.05.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 04/26/2021] [Accepted: 05/08/2021] [Indexed: 01/08/2023]
Abstract
BACKGROUND Human epidermal growth factor 2 (HER2) amplification and/or overexpression occurs in 12% to 25% of breast cancers. Accurate detection of HER2 is critical in predicting response to HER2-targeted therapy. Both immunohistochemistry (IHC) and in situ hybridization (ISH) are FDA-approved methods for detecting HER2 status because its protein overexpression is largely attributable to gene amplification. However, variable discordant results between IHC and ISH have been reported. METHODS We determined the frequency of HER2 IHC/ISH discordance in these patients and also performed a pooled literature review analysis. RESULTS Of the 1125 consecutive primary or metastatic breast cancers with HER2 IHC and ISH performed simultaneously between 2015 and 2020, 84.6% had an unequivocal HER2 status. Discordance was found in 30 cases from 26 patients, including 13 IHC-/ISH+ and 17 IHC+/ISH-, representing 1.6% and 11.9% of IHC- and IHC+ cases, respectively. Review of the literature between 2001 and 2020 identified 46 relevant studies, with a total of 43,468 cases with IHC and ISH performed. The IHC-/ISH+ and IHC+/ISH- discordances were seen in all antibody clones and ISH methods used. The IHC+/ISH- discordance was significantly higher than IHC-/ISH+ (13.8% vs. 3%, P < .0001). The overall discordance constituted 4% of all cases and 5.4% of those with an unequivocal IHC status. Significantly lower incongruities for both IHC-/ISH+ and IHC+/ISH- were found in those published after 2018. The discordances probably reflect altered biology of HER2 oncogene/oncoprotein. Routinely performing both IHC and ISH may uncover such cases to prevent denial of potentially beneficial targeted therapy.
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Affiliation(s)
| | | | - Shuko Harada
- Department of Pathology; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL
| | | | | | | | - Gene P Siegal
- Department of Pathology; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL
| | - Shi Wei
- Department of Pathology; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL.
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21
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Cost-effectiveness Analysis of Trastuzumab Emtansine as Second-line Therapy for HER2-Positive Breast Cancer in China. Clin Drug Investig 2021; 41:569-577. [PMID: 33876415 DOI: 10.1007/s40261-021-01035-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/30/2021] [Indexed: 10/21/2022]
Abstract
BACKGROUND AND OBJECTIVE Trastuzumab emtansine (T-DM1) is the standard second-line option for the treatment of patients with human epidermal growth factor receptor-2 (HER2)-positive breast cancer for its superior clinical efficacy in prolonging progression-free survival. The objective of this study was to evaluate the cost effectiveness of T-DM1 from the Chinese healthcare perspective. Capecitabine (Cap), capecitabine + lapatinib (Cap + Lap), capecitabine + trastuzumab (Cap + Tra), capecitabine + trastuzumab + pertuzumab (Cap + Tra + Per) were selected as comparators. METHODS A three-state Markov simulation model was performed. The state transition probabilities were estimated based on the results of a published network meta-analysis, and utilities were derived from the published literature. The costs populated in the model were acquired from the local charge or previously published studies. One-way sensitive analysis and probabilistic sensitivity analyses were performed to test the robustness of the results. RESULTS Compared with Cap, Cap + Lap, Cap + Tra, and Cap + Tra + Per, T-DM1 was estimated to increase the cost by US$109,699.1, $106,019.1, $97,506.3, and $67,121.9, respectively, and yield a gain of 0.544 quality-adjusted life years (QALYs), 0.383 QALYs, 0.367 QALYs, 0.087 QALYs, respectively. Corresponding incremental cost-effectiveness ratios (ICERs) were $201,652.9, $276,812.5, $265,685.0, and $771,516.1 per QALY. The probabilities of T-DM1 as the dominant option were 0% at the willingness-to-pay (WTP) threshold of $31,245.1/QALY. CONCLUSIONS T-DM1, as second-line therapy in the treatment of HER2-positive breast cancer, is not a cost-effective option in China. Given the significant clinical efficacy, an appropriate price reduction of T-DM1 is required to benefit more HER2-positive breast cancer patients.
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22
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Kim YA, Kim YA, Cho SW, Song YS, Min HS, Park IA, Park DJ, Hwang KT, Park YJ. Increased expression of thyroid hormone receptor alpha and estrogen receptor alpha in breast cancer associated with thyroid cancer. Eur J Surg Oncol 2021; 47:1316-1323. [PMID: 33558123 DOI: 10.1016/j.ejso.2021.01.015] [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: 07/07/2020] [Revised: 01/05/2021] [Accepted: 01/17/2021] [Indexed: 11/29/2022] Open
Abstract
INTRODUCTION Breast cancer co-occurred with thyroid cancer might be associated with thyroid hormone receptor (TR) and estrogen receptor (ER), but few have been reported. We aimed to investigate the expression and prognostic significance of ERs and TRs in such settings. MATERIAL AND METHODS Tissue microarrays were constructed from 75 patients with breast and thyroid cancer (BC + TC) who were retrospectively recruited between 1999 and 2012 and 147 with breast cancer only (BC controls). The ERα, ERβ, TRα, and TRβ expression levels were analyzed by immunohistochemistry. RESULTS TRα expression was more frequently observed in the BC + TC group than the BC control group both in the normal (51.5% vs 23.3%, respectively, p = 0.009) and cancer tissues (21.6% vs 6.8%, respectively, p = 0.001). The BC + TC group showed greater ERα-positivity in the cancer tissues (79.7% vs 58.7%, respectively, p = 0.002) than the BC control group. The degree of ERα- and TRα-positivity was unchanged by radioactive treatment or serum thyroid stimulating hormone levels. In the BC + TC group, ERα-positivity was associated with earlier disease stage I/IIA (81.0% vs 50.0%; p = 0.031) and lower recurrence rates (8.5% vs 40.0%; p = 0.002). TRα-positivity alone was not associated with any recurrence-free survival-related differences, and ERα- and TRα-negativity were associated with significantly shorter recurrence-free survival (p < 0.001). CONCLUSION Enhanced ERα and TRα expression in breast cancer is associated with thyroid cancer occurrence, and the observed association with prognosis suggests the possible role of ERs and TRs in the link between breast cancer and thyroid cancer.
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Affiliation(s)
- Ye An Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea; Department of Internal Medicine, Veterans Health Service Medical Center, Seoul, South Korea
| | - Young A Kim
- Department of Pathology, Seoul National University College of Medicine. Seoul, South Korea; Department of Pathology, Seoul National University Boramae Medical Center, Seoul, South Korea
| | - Sun Wook Cho
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea; Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
| | - Young Shin Song
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, South Korea
| | - Hye Sook Min
- Division of Public Healthcare Policy, National Medical Center, Seoul, South Korea; Department of Pathology, Seoul National University Hospital, Seoul, South Korea
| | - In Ae Park
- Department of Pathology, Seoul National University College of Medicine. Seoul, South Korea; Department of Pathology, Seoul National University Hospital, Seoul, South Korea
| | - Do Joon Park
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea; Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
| | - Ki-Tae Hwang
- Department of Surgery, Seoul National University Boramae Medical Center, Seoul, South Korea
| | - Young Joo Park
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea; Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea.
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23
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Mastropasqua MG, Addante F, Pirola S, Ingravallo G, Viale G. Correlation of size and focality with prognosis in small breast carcinoma: a single institution case series. Breast 2020; 54:164-169. [PMID: 33099081 PMCID: PMC7581961 DOI: 10.1016/j.breast.2020.10.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 10/06/2020] [Accepted: 10/14/2020] [Indexed: 11/19/2022] Open
Abstract
AIM OF THE STUDY The clinical behavior and prognosis of small multifocal and microinvasive breast cancers are still debated together with the best method of assessing tumor size in multiple invasive carcinomas. This study evaluates the clinico-pathological features of single and multiple breast cancers up to 0.5 cm in order to evaluate the rate of recurrences. MATERIALS AND METHODS We retrospectively analyzed 170 node-negative patients consecutively treated at European Institute of Oncology from 2001 to 2006. We divided them into Group I (pT1mi) and Group II (pT1a) furtherly divided in subgroups, according to focality and aggregate diameter. For each group we assessed tumor size, (multi)focality, extensive in situ component (EIC), histology, grade, peritumoral vascular invasion (PVI), hormonal receptor status (HR), HER-2 expression, Ki67 expression. RESULTS We observed that the frequency of local recurrences and distant metastases in group I was higher among those with a single focus; whereas in group II, it was higher in multifocal carcinomas. Then, by comparing the two groups, the prognosis was better in multiple pT1mi than in similarly sized unifocal pT1a. CONCLUSIONS Microinvasive carcinomas are associated with a good prognosis, even if they seem to have a more aggressive intrinsic biological behavior. Multifocality seems to be correlated with a worse prognosis in case of invasive carcinomas pT1a. In case of microinvasive carcinomas, by contrast, multifocality per se does not seem to affect the recurrence rate.
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Affiliation(s)
- Mauro G Mastropasqua
- Department of Pathology European Institute of Oncology (IEO), Via Ripamonti, 435, 20141, Milan, Italy; School of Medicine, University of Bari "Aldo Moro", Department of Emergency and Organs Transplantation (DETO) Section of Anatomic Pathology Piazza Giulio Cesare, 11 - 70124, Bari, Italy.
| | - Francesca Addante
- School of Medicine, University of Bari "Aldo Moro", Department of Emergency and Organs Transplantation (DETO) Section of Anatomic Pathology Piazza Giulio Cesare, 11 - 70124, Bari, Italy
| | - Sara Pirola
- Department of Pathology European Institute of Oncology (IEO), Via Ripamonti, 435, 20141, Milan, Italy
| | - Giuseppe Ingravallo
- School of Medicine, University of Bari "Aldo Moro", Department of Emergency and Organs Transplantation (DETO) Section of Anatomic Pathology Piazza Giulio Cesare, 11 - 70124, Bari, Italy
| | - Giuseppe Viale
- Department of Pathology European Institute of Oncology (IEO), Via Ripamonti, 435, 20141, Milan, Italy; School of Medicine, University of Milan, Milan, Italy
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Shamshirian A, Aref AR, Yip GW, Ebrahimi Warkiani M, Heydari K, Razavi Bazaz S, Hamzehgardeshi Z, Shamshirian D, Moosazadeh M, Alizadeh-Navaei R. Diagnostic value of serum HER2 levels in breast cancer: a systematic review and meta-analysis. BMC Cancer 2020; 20:1049. [PMID: 33129287 PMCID: PMC7603697 DOI: 10.1186/s12885-020-07545-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 10/20/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Measurement of serum human epidermal growth factor receptor-2 (HER-2/neu) levels might play an essential role as a diagnostic/screening marker for the early selection of therapeutic approaches and predict prognosis in breast cancer patients. We aimed to undertake a systematic review and meta-analysis focusing on the diagnostic/screening value of serum HER-2 levels in comparison to routine methods. METHODS We performed a systematic search via PubMed, Scopus, Cochrane-Library, and Web of Science databases for human diagnostic studies reporting the levels of serum HER-2 in breast cancer patients, which was confirmed using the histopathological examination. Meta-analyses were carried out for sensitivity, specificity, accuracy, area under the ROC curve (AUC), positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (PLR), and negative likelihood ratio (NLR). RESULTS Fourteen studies entered into this investigation. The meta-analysis indicated the low sensitivity for serum HER2 levels (Sensitivity: 53.05, 95%CI 40.82-65.28), but reasonable specificity of 79.27 (95%CI 73.02-85.51), accuracy of 72.06 (95%CI 67.04-77.08) and AUC of 0.79 (95%CI 0.66-0.92). We also found a significant differences for PPV (PPV: 56.18, 95%CI 44.16-68.20), NPV (NPV: 76.93, 95%CI 69.56-84.31), PLR (PLR: 2.10, 95%CI 1.69-2.50) and NLR (NLR: 0.58, 95%CI 0.44-0.71). CONCLUSION Our findings revealed that although serum HER-2 levels showed low se nsitivity for breast cancer diagnosis, its specificity, accuracy and AUC were reasonable. Hence, it seems that the measurement of serum HER-2 levels can play a significant role as a verification test for initial negative screening test results, especially in low-income regions due to its cost-effectiveness and ease of implementation.
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Affiliation(s)
- Amir Shamshirian
- Department of Medical Laboratory Sciences, Student Research Committee, School of Allied Medical Science, Mazandaran University of Medical Sciences, Sari, Iran
- Gastrointestinal Cancer Research Center, Non-Communicable Diseases Institute, Mazandaran University of Medical Sciences, Sari, Iran
| | - Amir Reza Aref
- Belfer Center for Applied Cancer Science, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA.
| | - George W Yip
- Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117594, Singapore
| | - Majid Ebrahimi Warkiani
- School of Biomedical Engineering, University of Technology Sydney, Sydney, Ultimo, NSW, 2007, Australia
- Institute of Molecular Medicine, Sechenov First Moscow State University, Moscow, 119991, Russia
| | - Keyvan Heydari
- Gastrointestinal Cancer Research Center, Non-Communicable Diseases Institute, Mazandaran University of Medical Sciences, Sari, Iran
- Student Research Committee, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Sajad Razavi Bazaz
- School of Biomedical Engineering, University of Technology Sydney, Sydney, Ultimo, NSW, 2007, Australia
| | - Zeinab Hamzehgardeshi
- Sexual and Reproductive Health Research Center, Mazandaran University of Medical Sciences, Sari, Iran
| | - Danial Shamshirian
- Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahmood Moosazadeh
- Health Sciences Research Center, Addiction Institute, Mazandaran University of Medical Sciences, Sari, Iran
| | - Reza Alizadeh-Navaei
- Gastrointestinal Cancer Research Center, Non-Communicable Diseases Institute, Mazandaran University of Medical Sciences, Sari, Iran.
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Yi Z, Rong G, Guan Y, Li J, Chang L, Li H, Liu B, Wang W, Guan X, Ouyang Q, Li L, Zhai J, Li C, Li L, Xia X, Yang L, Qian H, Yi X, Xu B, Ma F. Molecular landscape and efficacy of HER2-targeted therapy in patients with HER2-mutated metastatic breast cancer. NPJ Breast Cancer 2020; 6:59. [PMID: 33145402 PMCID: PMC7603305 DOI: 10.1038/s41523-020-00201-9] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 10/05/2020] [Indexed: 12/14/2022] Open
Abstract
Human epidermal growth factor receptor 2 (HER2) protein overexpression or gene amplification is an important predictive biomarker for identifying patients with breast cancer, who may benefit from HER2-targeted therapy. However, little is known about the molecular landscape and efficacy of HER2-targeted therapy in patients with HER2-mutated metastatic breast cancer. We analysed the HER2 mutation features of 1184 patients with invasive breast cancer. In addition, a single-arm, prospective, phase-II study (NCT03412383) of pyrotinib was conducted in patient with metastatic HER2 amplification-negative, mutation-positive breast cancer. Peripheral blood was collected from each patient and circulating tumour DNA (ctDNA) sequencing was performed using a 1021 gene panel. HER2 mutations were detected in 8.9% (105/1184) of patients. The HER2 amplification-positive patients had a higher mutation frequency than the HER2 amplification-negative patients (19.5% vs. 4.8%, P < 0.001). A multivariate Cox regression analysis indicated that patients with HER2 mutations had a shorter progression-free survival (PFS) than HER2 wild-type patients (median PFS 4.7 months vs. 11.0 months, hazard ratio 2.65, 95% confidence interval 1.25-5.65, P = 0.011). Ten HER2 amplification-negative, mutation-positive patients who received pyrotinib monotherapy were ultimately included in the efficacy analysis. The median PFS was 4.9 months. The objective response rate (complete response + partial response) was 40.0% and the clinical benefit rate (complete response + partial response + stable disease over 24 weeks) was 60%. In conclusion, a HER2 gene mutation analysis is potentially useful to identify biomarkers of trastuzumab resistance in HER2 amplification-positive patients. Patients with HER2-mutated, non-amplified metastatic breast cancers may benefit from pyrotinib.
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Affiliation(s)
- Zongbi Yi
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021 China
| | - Guohua Rong
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021 China
| | - Yanfang Guan
- Geneplus-Beijing Institute, Beijing, China
- Department of Computer Science and Technology, School of Electronic and Information Engineering, Xi’an Jiaotong University, 28 West Xianning Road, Xi’an, Shanxi 710048 China
| | - Jin Li
- Geneplus-Beijing Institute, Beijing, China
| | | | - Hui Li
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021 China
| | - Binliang Liu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021 China
| | - Wenna Wang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021 China
| | - Xiuwen Guan
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021 China
| | - Quchang Ouyang
- Department of Breast Cancer Medical Oncology, Hunan Cancer Hospital, Changsha, 410013 China
| | - Lixi Li
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021 China
| | - Jingtong Zhai
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021 China
| | - Chunxiao Li
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021 China
| | - Lifeng Li
- Geneplus-Beijing Institute, Beijing, China
| | | | - Ling Yang
- Geneplus-Beijing Institute, Beijing, China
| | - Haili Qian
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021 China
| | - Xin Yi
- Geneplus-Beijing Institute, Beijing, China
- Department of Computer Science and Technology, School of Electronic and Information Engineering, Xi’an Jiaotong University, 28 West Xianning Road, Xi’an, Shanxi 710048 China
| | - Binghe Xu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021 China
| | - Fei Ma
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021 China
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Do M, Kim H, Yeo I, Lee J, Park IA, Ryu HS, Kim Y. Clinical Application of Multiple Reaction Monitoring-Mass Spectrometry to Human Epidermal Growth Factor Receptor 2 Measurements as a Potential Diagnostic Tool for Breast Cancer Therapy. Clin Chem 2020; 66:1339-1348. [DOI: 10.1093/clinchem/hvaa178] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 07/13/2020] [Indexed: 12/23/2022]
Abstract
Abstract
Background
Human epidermal growth factor receptor 2 (HER2) is often overexpressed in breast cancer and correlates with a worse prognosis. Thus, the accurate detection of HER2 is crucial for providing the appropriate measures for patients. However, the current techniques used to detect HER2 status, immunohistochemistry and fluorescence in situ hybridization (FISH), have limitations. Specifically, FISH, which is mandatory for arbitrating 2+ cases, is time-consuming and costly. To address this shortcoming, we established a multiple reaction monitoring-mass spectrometry (MRM-MS) assay that improves on existing methods for differentiating HER2 status.
Methods
We quantified HER2 expression levels in 210 breast cancer formalin-fixed paraffin-embedded (FFPE) tissue samples by MRM-MS. We aimed to improve the accuracy and precision of HER2 quantification by simplifying the sample preparation through predicting the number of FFPE slides required to ensure an adequate amount of protein and using the expression levels of an epithelial cell-specific protein as a normalization factor when measuring HER2 expression levels.
Results
To assess the correlation between MRM-MS and IHC/FISH data, HER2 quantitative data from MRM-MS were divided by the expression levels of junctional adhesion molecule A, an epithelial cell-specific protein, prior to statistical analysis. The normalized HER2 amounts distinguished between HER2 2+/FISH-negative and 2+/FISH-positive groups (AUROC = 0.908), which could not be differentiated by IHC. In addition, all HER2 status were discriminated by MRM-MS.
Conclusions
This MRM-MS assay yields more accurate HER2 expression levels relative to immunohistochemistry and should help to guide clinicians toward the proper treatment for breast cancer patients, based on their HER2 expression.
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Affiliation(s)
- Misol Do
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hyunsoo Kim
- Department of Biomedical Engineering, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Injoon Yeo
- Department of Biomedical Engineering, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jihyeon Lee
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - In Ae Park
- Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Han Suk Ryu
- Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Youngsoo Kim
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
- Department of Biomedical Engineering, Seoul National University College of Medicine, Seoul, Republic of Korea
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La Barbera D, Polónia A, Roitero K, Conde-Sousa E, Della Mea V. Detection of HER2 from Haematoxylin-Eosin Slides Through a Cascade of Deep Learning Classifiers via Multi-Instance Learning. J Imaging 2020; 6:82. [PMID: 34460739 PMCID: PMC8321042 DOI: 10.3390/jimaging6090082] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 08/14/2020] [Accepted: 08/18/2020] [Indexed: 12/28/2022] Open
Abstract
Breast cancer is the most frequently diagnosed cancer in woman. The correct identification of the HER2 receptor is a matter of major importance when dealing with breast cancer: an over-expression of HER2 is associated with aggressive clinical behaviour; moreover, HER2 targeted therapy results in a significant improvement in the overall survival rate. In this work, we employ a pipeline based on a cascade of deep neural network classifiers and multi-instance learning to detect the presence of HER2 from Haematoxylin-Eosin slides, which partly mimics the pathologist's behaviour by first recognizing cancer and then evaluating HER2. Our results show that the proposed system presents a good overall effectiveness. Furthermore, the system design is prone to further improvements that can be easily deployed in order to increase the effectiveness score.
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Affiliation(s)
- David La Barbera
- Department of Mathematics, Computer Science and Physics, University of Udine, 33100 Udine, Italy; (D.L.B.); (K.R.)
| | - António Polónia
- Department of Pathology, Ipatimup Diagnostics, Institute of Molecular Pathology and Immunology, University of Porto, 4169-007 Porto, Portugal;
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4169-007 Porto, Portugal;
| | - Kevin Roitero
- Department of Mathematics, Computer Science and Physics, University of Udine, 33100 Udine, Italy; (D.L.B.); (K.R.)
| | - Eduardo Conde-Sousa
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4169-007 Porto, Portugal;
- INEB—Instituto de Engenharia Biomédica, Universidade do Porto, 4169-007 Porto, Portugal
| | - Vincenzo Della Mea
- Department of Mathematics, Computer Science and Physics, University of Udine, 33100 Udine, Italy; (D.L.B.); (K.R.)
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Comparison of Dako HercepTest and Ventana PATHWAY Anti-HER2 (4B5) Tests and Their Correlation With Fluorescent In Situ Hybridization in Breast Carcinoma. Appl Immunohistochem Mol Morphol 2020; 27:403-409. [PMID: 31233398 DOI: 10.1097/pai.0000000000000646] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVES We compared the performance of two Food and Drug Administration-approved HER2 immunohistochemistry (IHC) tests: HercepTest (Dako) and PATHWAY anti-HER2 (4B5) (Ventana). MATERIALS AND METHODS In total, 180 invasive breast carcinomas previously tested by both HercepTest and fluorescent in situ hybridization (FISH) were retested with 4B5. Three pathologists scored the HER2 IHC using the 2013 American Society of Clinical Oncology/College of American Pathologists guidelines. The HER2 IHC results were correlated with FISH. RESULTS Among 135 equivocal cases by HercepTest, 100 (74.1%) were negative by 4B5. Among 45 positive HercepTest cases 9 (20%) were equivocal by 4B5. Among 135 equivocal HercepTest results, 100 (74.1%) were nonamplified, 18 (13.3%) equivocal, and 17 (12.6%) amplified by FISH. Among the 45 positive results with HercepTest, 2 (4.5%) were nonamplified and 1 (2.2%) was equivocal by FISH. All 37 positive and 3 negative by 4B5 cases were amplified by FISH. The absolute interobserver agreement was high for both tests (Fleiss kappa=0.838 for HercepTest and 0.771 for 4B5). CONCLUSIONS PATHWAY anti-HER2 (4B5) significantly reduced the number of equivocal results that require additional testing. Although HercepTest was positive in a small number of HER2 nonamplified cases, 4B5 failed to detect 3 cases that were interpreted as positive by FISH, all with nonclassic or low levels of amplification.
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Ross C, Szczepanek K, Lee M, Yang H, Qiu T, Sanford JD, Hunter K. The genomic landscape of metastasis in treatment-naïve breast cancer models. PLoS Genet 2020; 16:e1008743. [PMID: 32463822 PMCID: PMC7282675 DOI: 10.1371/journal.pgen.1008743] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 06/09/2020] [Accepted: 03/28/2020] [Indexed: 12/24/2022] Open
Abstract
Metastasis remains the principle cause of mortality for breast cancer and presents a critical challenge because secondary lesions are often refractory to conventional treatments. While specific genetic alterations are tightly linked to primary tumor development and progression, the role of genetic alteration in the metastatic process is not well-understood. The theory of tumor evolution postulated by Peter Nowell in 1976 has yet to be proven in the context of metastasis. Therefore, in order to investigate how somatic evolution contributes to breast cancer metastasis, we performed exome, whole genome, and RNA sequencing of matched metastatic and primary tumors from pre-clinical mouse models of breast cancer. Here we show that in a treatment-naïve setting, recurrent single nucleotide variants and copy number variation, but not gene fusion events, play key metastasis-driving roles in breast cancer. For instance, we identified recurrent mutations in Kras, a known driver of colorectal and lung tumorigenesis that has not been previously implicated in breast cancer metastasis. However, in a set of in vivo proof-of-concept experiments we show that the Kras G12D mutation is sufficient to significantly promote metastasis using three syngeneic allograft models. The work herein confirms the existence of metastasis-driving mutations and presents a novel framework to identify actionable metastasis-targeted therapies.
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Affiliation(s)
- Christina Ross
- Laboratory of Cancer Biology and Genetics, Metastasis Susceptibility Section, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America
| | - Karol Szczepanek
- Laboratory of Cancer Biology and Genetics, Metastasis Susceptibility Section, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America
| | - Maxwell Lee
- Laboratory of Cancer Biology and Genetics, High-Dimension Data Analysis Group, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America
| | - Howard Yang
- Laboratory of Cancer Biology and Genetics, High-Dimension Data Analysis Group, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America
| | - Tinghu Qiu
- Laboratory of Cancer Biology and Genetics, Metastasis Susceptibility Section, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America
| | - Jack D. Sanford
- Laboratory of Cancer Biology and Genetics, Metastasis Susceptibility Section, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America
| | - Kent Hunter
- Laboratory of Cancer Biology and Genetics, Metastasis Susceptibility Section, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America
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Hashemi Bahremani M, Ebrahimi A, Fallahi M. Predicting Effects of Clinicopathological Variables on Her2 Gene Amplification by Chromogenic in situ Hybridization (CISH) in IHC Her2 (2+) Breast Cancer Patients; A Study from Iran. IRANIAN JOURNAL OF PATHOLOGY 2020; 15:217-224. [PMID: 32754217 PMCID: PMC7354073 DOI: 10.30699/ijp.2020.110293.2172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Accepted: 04/10/2020] [Indexed: 11/06/2022]
Abstract
Background & Objective The her2 amplification plays an important role in breast cancer management. Therefore, there is a need for using supplementary molecular methods in IHC equivocal cases. Present study has been conducted to determine the effects of clinicopathological variables on her2 gene amplification by chromogenic in situ hybridization (CISH) in IHC Her2 (2+) breast cancer individuals. Methods A cross-sectional study was conducted in Zaferanyeh Laboratory collaborated with Shahid Beheshti University of Medical Sciences (Tehran-Iran; 2015-2018). All pathological data related invasive breast cancer patients with equivocal IHC results were included. CISH method was performed as a supplementary technique. The associations between histopathologic variables, status of Ki-67 index, progesterone and estrogen receptors (PR & ER) with her2 amplification by CISH were investigated and analyzed. The level of significance was considered as P-value < 0.05. Results Totally, 239 patients with mean age of 53.2 years were studied. CISH identified her2 gene amplification in 51 subjects (21.3%). The type of tumor (invasive ductal carcinoma), the tumor grade, and the value of Ki-67 index were directly correlated with her2 amplification. Significant negative associations were also observed between CISH results and ER and PR expression. Conclusion As her2 gene amplification was identified in 21.3% of invasive breast cancer patients with equivocal IHC results, it is supposed that applying CISH method may consider as a potentially valuable supplementary method. Results have also shown that higher grades of tumor, invasive ductal carcinoma, absences of hormone receptors and high Ki-67 index significantly correlated with the her2 amplification.
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Affiliation(s)
- Mohammad Hashemi Bahremani
- Department of Pathology, Imam Hosein Educational Hospital, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abdolali Ebrahimi
- Department of Pathology, Imam Hosein Educational Hospital, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohaddese Fallahi
- Department of Pathology, Imam Hosein Educational Hospital, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Vincent L, Jankowski C, Arnould L, Coudert B, Rouzier R, Reyal F, Humbert O, Coutant C. [Comparing prediction performances of 18F-FDG PET and CGFL/Curie nomogram to predict pathologic complete response after neoadjuvant chemotherapy for HER2-positive breast cancers]. ACTA ACUST UNITED AC 2020; 48:679-686. [PMID: 32205278 DOI: 10.1016/j.gofs.2020.03.015] [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: 07/09/2019] [Indexed: 10/24/2022]
Abstract
OBJECTIVES The aim of this study was to compare the value of 18F-fluorodesoxyglucose positron emission tomography (18F-FDG PET/CT) with CGFL/Curie nomogram to predict a pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) in women with human epidermal growth factor 2 (HER2)-positive breast cancer treated by trastuzumab. METHODS Fifty-one women with HER2-positive breast cancer treated with trastuzumab plus taxane-based NAC were retrospectively included from January 2005 to December 2015. For 18F-FDG PET/CT, the analyzed predictor was the maximum standardized uptake value of the primary tumor and axillary nodes after the first course of NAC (PET2.SUVmax). pCR was defined by no residual infiltrative tumor but in situ tumor was accepted. Accuracy of CGFL/Curie nomogram and PET2.SUVmax was evaluated measuring sensitivity (Se), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV). Combined prediction was evaluated testing predictor's associations. RESULTS For CGFL/Curie nomogram's performances, Se, Sp, PPV and NPV were respectively: 76% (95%CI: 58-90%), 57% (95%CI: 43-66%), 55% (95%CI: 42-65), 77% (95%CI: 59-90%). For PET2.SUVmax's performances, Se, Sp, PPV and NPV were respectively: 67% (95%CI: 48-81%), 77% (95%CI: 64-97%), 67% (95%CI: 48-82%), 77% (95%CI: 64-87%). ROC curves for these predictors were similar; the areas under the curve were 0.6 (95%CI: 0.56-0.64) for PET2.SUVmax and 0.55 (95%CI: 0.50-0.59) for CGFL/Curie nomogram. Combined prediction was efficient with Se at 80%, VPN at 76%, Sp at 78% and VPP at 81%. CONCLUSIONS CGFL/Curie nomogram and PET2.SUVmax were two efficient predictors of pCR in patients with HER2-positive breast cancer. Combined prediction has an improved accuracy.
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Affiliation(s)
- L Vincent
- Département de chirurgie oncologique, centre Georges-François-Leclerc, 1, rue du Professeur-Marion, 21000 Dijon, France.
| | - C Jankowski
- Département de chirurgie oncologique, centre Georges-François-Leclerc, 1, rue du Professeur-Marion, 21000 Dijon, France
| | - L Arnould
- Département de biologie et pathologie des tumeurs, centre Georges-François-Leclerc, 1, rue du Professeur-Marion, 21000 Dijon, France
| | - B Coudert
- Département d'oncologie médicale, centre Georges-François-Leclerc, 1, rue du Professeur-Marion, 21000 Dijon, France
| | - R Rouzier
- Département de chirurgie oncologique, institut Curie, 26, rue d'Ulm, 75005 Paris, France
| | - F Reyal
- Département de chirurgie oncologique, institut Curie, 26, rue d'Ulm, 75005 Paris, France
| | - O Humbert
- Département de médecine nucléaire, centre Georges-François-Leclerc, 1, rue du Professeur-Marion, 21000 Dijon, France
| | - C Coutant
- Département de chirurgie oncologique, centre Georges-François-Leclerc, 1, rue du Professeur-Marion, 21000 Dijon, France; ImVia, UFR des sciences de santé, 7, boulevard Jeanne-d'Arc, 21000 Dijon, France
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Shui R, Liang X, Li X, Liu Y, Li H, Xu E, Zhang Z, Lian Y, Guo S, Yao M, Yang H, Xu F, Liu Y, Liu J, Guo D, Wang K, Li J, Ma Y, Wang J, Shi J, Bu H, Yang W. Hormone Receptor and Human Epidermal Growth Factor Receptor 2 Detection in Invasive Breast Carcinoma: A Retrospective Study of 12,467 Patients From 19 Chinese Representative Clinical Centers. Clin Breast Cancer 2020; 20:e65-e74. [DOI: 10.1016/j.clbc.2019.07.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 05/06/2019] [Accepted: 07/04/2019] [Indexed: 12/20/2022]
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Ross DS. Breast. Genomic Med 2020. [DOI: 10.1007/978-3-030-22922-1_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
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Ahn S, Woo JW, Lee K, Park SY. HER2 status in breast cancer: changes in guidelines and complicating factors for interpretation. J Pathol Transl Med 2019; 54:34-44. [PMID: 31693827 PMCID: PMC6986968 DOI: 10.4132/jptm.2019.11.03] [Citation(s) in RCA: 154] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Accepted: 11/03/2019] [Indexed: 12/16/2022] Open
Abstract
Human epidermal growth factor receptor 2 (HER2) protein overexpression and/or HER2 gene amplification is found in about 20% of invasive breast cancers. It is a sole predictive marker for treatment benefits from HER2 targeted therapy and thus, HER2 testing is a routine practice for newly diagnosed breast cancer in pathology. Currently, HER2 immunohistochemistry (IHC) is used for a screening test, and in situ hybridization is used as a confirmation test for HER2 IHC equivocal cases. Since the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines on HER2 testing was first released in 2007, it has been updated to provide clear instructions for HER2 testing and accurate determination of HER2 status in breast cancer. During HER2 interpretation, some pitfalls such as intratumoral HER2 heterogeneity and increase in chromosome enumeration probe 17 signals may lead to inaccurate assessment of HER2 status. Moreover, HER2 status can be altered after neoadjuvant chemotherapy or during metastatic progression, due to biologic or methodologic issues. This review addresses recent updates of ASCO/CAP guidelines and factors complicating in the interpretation of HER2 status in breast cancers.
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Affiliation(s)
- Soomin Ahn
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Ji Won Woo
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea.,Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
| | - Kyoungyul Lee
- Department of Pathology, Kangwon National University Hospital, Chuncheon, Korea
| | - So Yeon Park
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea.,Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
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Dumbrava EEI, Balaji K, Raghav K, Hess K, Javle M, Blum-Murphy M, Ajani J, Kopetz S, Broaddus R, Routbort M, Demirhan M, Zheng X, Pant S, Tsimberidou AM, Subbiah V, Hong DS, Rodon J, Shaw KM, Piha-Paul SA, Meric-Bernstam F. Targeting ERBB2 ( HER2) Amplification Identified by Next-Generation Sequencing in Patients With Advanced or Metastatic Solid Tumors Beyond Conventional Indications. JCO Precis Oncol 2019; 3:PO.18.00345. [PMID: 32923865 PMCID: PMC7446516 DOI: 10.1200/po.18.00345] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/06/2019] [Indexed: 12/24/2022] Open
Abstract
PURPOSE Human epidermal growth factor receptor 2 (HER2) is an effective therapeutic target in breast and gastric and gastroesophageal junction cancers. However, less is known about the prevalence of ERBB2 (HER2) amplification and the efficacy of HER2-targeted treatment in other tumors. PATIENTS AND METHODS We assessed HER2 amplification status among 5,002 patients with advanced disease (excluding breast cancer) who underwent next-generation sequencing. We evaluated the clinical benefit of HER2-targeted therapy by measuring the time-dependent overall survival (OS) from the genomic testing results, progression-free survival (PFS), and PFS during HER2-targeted therapy (PFS2) compared with PFS during prior therapy (PFS1). RESULTS Overall, 122 patients (2.4%) had HER2 amplification, including patients with endometrial (5.3%), bladder (5.2%), biliary or gallbladder (4.9%), salivary (4.7%), and colorectal cancer (3.6%). Forty patients (38%) with nongastric, nongastroesophageal junction, or nonesophageal cancers received at least one line of HER2-targeted therapy. Patients receiving HER2-targeted therapy had a median OS of 18.6 months, compared with 10.9 months for patients who did not receive HER2-targeted therapy (P = .070). On multivariable analysis, HER2-targeted therapy was significantly associated with increased OS (hazard ratio, 0.5; 95% CI, 0.27 to 0.93; P = .029), regardless of sex, age, or number of prior lines of treatment. The PFS2-to-PFS1 ratio was 1.3 or greater in 21 (57%) of 37 patients who received HER2-targeted therapy not in the first line of systemic treatment, and the median PFS2 and PFS1 times were 24 and 13 weeks, respectively (P < .001). CONCLUSION HER2 amplifications using next-generation sequencing can be identified in a variety of tumor types. HER2-targeted therapy may confer clinical benefit in tumor types other than those for which HER2 inhibitors are approved.
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Affiliation(s)
| | - Kavitha Balaji
- The University of Texas MD Anderson Cancer Center, Houston, TX
- Lexicon Pharmaceuticals, Houston, TX
| | - Kanwal Raghav
- The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Kenneth Hess
- The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Milind Javle
- The University of Texas MD Anderson Cancer Center, Houston, TX
| | | | - Jaffer Ajani
- The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Scott Kopetz
- The University of Texas MD Anderson Cancer Center, Houston, TX
| | | | - Mark Routbort
- The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Mehmet Demirhan
- The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Xiaofeng Zheng
- The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Shubham Pant
- The University of Texas MD Anderson Cancer Center, Houston, TX
| | | | - Vivek Subbiah
- The University of Texas MD Anderson Cancer Center, Houston, TX
| | - David S. Hong
- The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Jordi Rodon
- The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Kenna M. Shaw
- The University of Texas MD Anderson Cancer Center, Houston, TX
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The role of Ki-67 in Asian triple negative breast cancers: a novel combinatory panel approach. Virchows Arch 2019; 475:709-725. [PMID: 31407032 DOI: 10.1007/s00428-019-02635-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Revised: 07/14/2019] [Accepted: 07/24/2019] [Indexed: 12/23/2022]
Abstract
The proliferation marker Ki-67 is frequently used to assess aggressiveness in the pathological evaluation of cancer, but its role remains uncertain in triple-negative breast cancer (TNBC). We aimed to quantify and localize Ki-67 expression in both epithelial and immune compartments in TNBC and investigate its association with clinicopathological parameters and survival outcomes. A total of 406 TNBC cases diagnosed between 2003 and 2015 at Singapore General Hospital were recruited. Using state-of-the-art, 7-colour multiplex immunofluorescence (mIF) tissue microarrays (TMAs) were stained to assess the abundance, density and spatial distribution of Ki-67-positive tumour cells and immune cells co-decorated with cytokeratin (CK) and leukocyte common antigen (CD45) respectively. Furthermore, MKI67 mRNA profiles were analysed using NanoString technology. In multivariate analysis adjusted for tumour size, histologic grade, age at diagnosis, and lymph node stage, a high Ki-67 labelling index (LI) > 0.3% was associated with improved disease-free survival (DFS; HR = 0.727; p = 0.027). High Ki-67-positive immune cell count per TMA was a favourable prognostic marker for both DFS (HR = 0.379; p = 0.00153) and overall survival (OS; HR = 0.473; p = 0.0482). The combination of high Ki-67 LI and high MKI67 expression was associated with improved DFS (HR = 0.239; p = 0.00639) and OS (HR = 0.213; p = 0.034). This study is among the first to highlight that Ki-67 is associated with favourable prognosis in an adjuvant setting in TNBC, and the mIF-based evaluation of Ki-67 expression on both tumour and immune cells represents a novel prognostic approach.
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Ren C, Zou Y, Zhang X, Li K. Diagnostic value of diffusion-weighted imaging-derived apparent diffusion coefficient and its association with histological prognostic factors in breast cancer. Oncol Lett 2019; 18:3295-3303. [PMID: 31452808 PMCID: PMC6704298 DOI: 10.3892/ol.2019.10651] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 06/26/2019] [Indexed: 12/17/2022] Open
Abstract
Diffusion-weighted imaging (DWI) has been proven to be effective in detecting breast malignancies and has been widely implemented for breast imaging. However, the exact association between certain DWI biomarkers and well-known prognostic factors remains to be fully elucidated. By studying the association between the apparent diffusion coefficient (ADC) and prognostic factors, the present study aimed to explore the diagnostic value and prognostic potential of the ADC in breast lesions. The study included 539 female subjects with histopathologically confirmed breast lesions who underwent DWI of the breast tissue. The diagnoses comprised 307 subjects with malignant breast tumors and 232 with benign breast tumors. The maximum ADC and mean ADC (ADCmean) values of the breast lesions were calculated. For malignant tumors, the association between ADC and major prognostic factors, including histological grade, nuclear grade and lymph node status, as well as estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2) and proliferation marker protein Ki-67.(Ki-67) status, were evaluated. The ADCmean demonstrated the best diagnostic performance in distinguishing between malignant and benign lesions. With the optimum cut-off value at 1.30×10−3 mm2/sec, ADCmean had a sensitivity and specificity of 84.1 and 90.2%, respectively. In those patients with malignant breast lesions, a decreased ADC was associated with breast lesions with high nuclear and histological grades, and lymph node-positive, ER-negative, PR-negative and HER-2-negative status, and Ki-67 ≥14%. In conclusion, the ADC is a useful imaging biomarker for differentiating between benign and malignant breast tumors. The marked association between the ADC and prognostic factors also demonstrated its value in evaluating the malignancy of breast lesions.
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Affiliation(s)
- Congcong Ren
- Department of Radiology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, P.R. China
| | - Yu Zou
- Department of Radiology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, P.R. China
| | - Xiaodan Zhang
- Department of Radiology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, P.R. China
| | - Kui Li
- Department of Radiology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, P.R. China
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The Impact of Partial Weak Staining in Normal Breast Epithelium on the Reliability of Immunohistochemistry Results in HercepTest-positive Breast Cancer. Clin Breast Cancer 2019; 19:340-344. [PMID: 31213407 DOI: 10.1016/j.clbc.2019.04.017] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Revised: 04/24/2019] [Accepted: 04/28/2019] [Indexed: 11/24/2022]
Abstract
INTRODUCTION Although normal epithelial cells do not show human epidermal growth factor receptor-2 (HER2) gene amplification and should lack membrane staining by HER2 immunohistochemistry (IHC), HER2 staining in benign breast epithelium is occasionally encountered. The significance of this occurrence has not yet been adequately studied, and its associated American Society of Clinical Oncology/College of American Pathologists recommendations are vague. Our objective is to assess the correlation between HER2 IHC 3+ breast cancer cases with normal epithelium staining (NES) and their corresponding fluorescence in situ hybridization (FISH) results, and to suggest recommendations for interpretation. MATERIALS AND METHODS A total of 154 breast cancer cases with HER2 IHC 3+ were reviewed. NES, along with other clinicopathologic characteristics, were recorded. NES was scored as present or absent. All study cases were sent for FISH testing. All cases, and particularly those that showed false positivity for IHC (positive IHC, negative FISH) were examined for NES. RESULTS Of the 154 cases, 146 cases were FISH-positive (94.8%) and 2 failed FISH testing (1.3%). Conversely, 22% (34/154) of the cases showed NES for HER2. Of these 34 cases, 23 (67%) were FISH-amplified, 9 (26%) were FISH not amplified, and 2 failed FISH testing. Notably, all of the false-positive (FISH-negative) breast cancer cases showed some degree of positivity in normal breast epithelium. CONCLUSIONS Our findings, though descriptive, show a very strong association between NES and false-positive HER2 IHC. This confirms the need to carefully evaluate IHC-positive breast cancers for NES, and to have a low threshold for confirmatory testing by FISH.
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Abstract
HER2-positive breast cancer is a particularly aggressive type of breast cancer. Indication of HER2 positivity is essential for its treatment. In addition to a few FDA-approved methods such as immunohistochemical (IHC) detection of HER2 protein expression and in situ hybridization (ISH) assessment of HER2 gene amplification, several novel methods have been developed for HER2 testing in recent years. This chapter provides an overview of HER2 testing with emphasis on those new methods.
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Affiliation(s)
- Yun Chen
- School of Pharmacy, Nanjing Medical University, Nanjing, China.
| | - Liang Liu
- School of Pharmacy, Nanjing Medical University, Nanjing, China
| | - Ronghua Ni
- School of Pharmacy, Nanjing Medical University, Nanjing, China
| | - Weixian Zhou
- School of Pharmacy, Nanjing Medical University, Nanjing, China
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Iyer P, Shrikhande SV, Ranjan M, Joshi A, Gardi N, Prasad R, Dharavath B, Thorat R, Salunkhe S, Sahoo B, Chandrani P, Kore H, Mohanty B, Chaudhari V, Choughule A, Kawle D, Chaudhari P, Ingle A, Banavali S, Gera P, Ramadwar MR, Prabhash K, Barreto SG, Dutt S, Dutt A. ERBB2 and KRAS alterations mediate response to EGFR inhibitors in early stage gallbladder cancer. Int J Cancer 2019; 144:2008-2019. [PMID: 30304546 PMCID: PMC6378102 DOI: 10.1002/ijc.31916] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2018] [Accepted: 09/27/2018] [Indexed: 02/05/2023]
Abstract
The uncommonness of gallbladder cancer in the developed world has contributed to the generally poor understanding of the disease. Our integrated analysis of whole exome sequencing, copy number alterations, immunohistochemical, and phospho-proteome array profiling indicates ERBB2 alterations in 40% early-stage rare gallbladder tumors, among an ethnically distinct population not studied before, that occurs through overexpression in 24% (n = 25) and recurrent mutations in 14% tumors (n = 44); along with co-occurring KRAS mutation in 7% tumors (n = 44). We demonstrate that ERBB2 heterodimerizes with EGFR to constitutively activate the ErbB signaling pathway in gallbladder cells. Consistent with this, treatment with ERBB2-specific, EGFR-specific shRNA or with a covalent EGFR family inhibitor Afatinib inhibits tumor-associated characteristics of the gallbladder cancer cells. Furthermore, we observe an in vivo reduction in tumor size of gallbladder xenografts in response to Afatinib is paralleled by a reduction in the amounts of phospho-ERK, in tumors harboring KRAS (G13D) mutation but not in KRAS (G12V) mutation, supporting an essential role of the ErbB pathway. In overall, besides implicating ERBB2 as an important therapeutic target under neo-adjuvant or adjuvant settings, we present the first evidence that the presence of KRAS mutations may preclude gallbladder cancer patients to respond to anti-EGFR treatment, similar to a clinical algorithm commonly practiced to opt for anti-EGFR treatment in colorectal cancer.
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Affiliation(s)
- Prajish Iyer
- Integrated Cancer Genomics LaboratoryAdvanced Centre for Treatment Research Education in Cancer (ACTREC), Tata Memorial CentreNavi MumbaiMaharashtraIndia
- Homi Bhabha National InstituteMumbaiMaharashtraIndia
| | - Shailesh V. Shrikhande
- Homi Bhabha National InstituteMumbaiMaharashtraIndia
- Department of Gastrointestinal and Hepato‐Pancreato‐Biliary Surgical OncologyTata Memorial Centre, Ernest Borges MargMumbaiMaharashtraIndia
| | - Malika Ranjan
- Integrated Cancer Genomics LaboratoryAdvanced Centre for Treatment Research Education in Cancer (ACTREC), Tata Memorial CentreNavi MumbaiMaharashtraIndia
| | - Asim Joshi
- Integrated Cancer Genomics LaboratoryAdvanced Centre for Treatment Research Education in Cancer (ACTREC), Tata Memorial CentreNavi MumbaiMaharashtraIndia
- Homi Bhabha National InstituteMumbaiMaharashtraIndia
| | - Nilesh Gardi
- Integrated Cancer Genomics LaboratoryAdvanced Centre for Treatment Research Education in Cancer (ACTREC), Tata Memorial CentreNavi MumbaiMaharashtraIndia
| | - Ratnam Prasad
- Integrated Cancer Genomics LaboratoryAdvanced Centre for Treatment Research Education in Cancer (ACTREC), Tata Memorial CentreNavi MumbaiMaharashtraIndia
| | - Bhasker Dharavath
- Integrated Cancer Genomics LaboratoryAdvanced Centre for Treatment Research Education in Cancer (ACTREC), Tata Memorial CentreNavi MumbaiMaharashtraIndia
- Homi Bhabha National InstituteMumbaiMaharashtraIndia
| | - Rahul Thorat
- Laboratory Animal FacilityAdvanced Centre for Treatment, Research and Education in Cancer, Tata Memorial CentreNavi MumbaiMaharashtraIndia
| | - Sameer Salunkhe
- Homi Bhabha National InstituteMumbaiMaharashtraIndia
- Shilpee laboratoryAdvanced Centre for Treatment Research Education In Cancer (ACTREC), Tata Memorial CentreNavi MumbaiMaharashtraIndia
| | - Bikram Sahoo
- Integrated Cancer Genomics LaboratoryAdvanced Centre for Treatment Research Education in Cancer (ACTREC), Tata Memorial CentreNavi MumbaiMaharashtraIndia
| | - Pratik Chandrani
- Integrated Cancer Genomics LaboratoryAdvanced Centre for Treatment Research Education in Cancer (ACTREC), Tata Memorial CentreNavi MumbaiMaharashtraIndia
| | - Hitesh Kore
- Integrated Cancer Genomics LaboratoryAdvanced Centre for Treatment Research Education in Cancer (ACTREC), Tata Memorial CentreNavi MumbaiMaharashtraIndia
| | - Bhabani Mohanty
- Small Animal Imaging facilityAdvanced Centre for Treatment Research Education In Cancer (ACTREC), Tata Memorial CentreNavi MumbaiMaharashtraIndia
| | - Vikram Chaudhari
- Department of Gastrointestinal and Hepato‐Pancreato‐Biliary Surgical OncologyTata Memorial Centre, Ernest Borges MargMumbaiMaharashtraIndia
| | - Anuradha Choughule
- Department of Medical OncologyTata Memorial Centre, Ernest Borges MargMumbaiMaharashtraIndia
| | - Dhananjay Kawle
- Integrated Cancer Genomics LaboratoryAdvanced Centre for Treatment Research Education in Cancer (ACTREC), Tata Memorial CentreNavi MumbaiMaharashtraIndia
| | - Pradip Chaudhari
- Small Animal Imaging facilityAdvanced Centre for Treatment Research Education In Cancer (ACTREC), Tata Memorial CentreNavi MumbaiMaharashtraIndia
| | - Arvind Ingle
- Laboratory Animal FacilityAdvanced Centre for Treatment, Research and Education in Cancer, Tata Memorial CentreNavi MumbaiMaharashtraIndia
| | - Shripad Banavali
- Homi Bhabha National InstituteMumbaiMaharashtraIndia
- Department of Medical OncologyTata Memorial Centre, Ernest Borges MargMumbaiMaharashtraIndia
| | - Poonam Gera
- Tissue BiorepositoryAdvanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial CentreNavi MumbaiMaharashtraIndia
| | - Mukta R. Ramadwar
- Homi Bhabha National InstituteMumbaiMaharashtraIndia
- Department of PathologyTata Memorial Centre, Ernest Borges MargMumbaiMaharashtraIndia
| | - Kumar Prabhash
- Homi Bhabha National InstituteMumbaiMaharashtraIndia
- Department of Medical OncologyTata Memorial Centre, Ernest Borges MargMumbaiMaharashtraIndia
| | - Savio George Barreto
- Department of Gastrointestinal and Hepato‐Pancreato‐Biliary Surgical OncologyTata Memorial Centre, Ernest Borges MargMumbaiMaharashtraIndia
| | - Shilpee Dutt
- Homi Bhabha National InstituteMumbaiMaharashtraIndia
- Shilpee laboratoryAdvanced Centre for Treatment Research Education In Cancer (ACTREC), Tata Memorial CentreNavi MumbaiMaharashtraIndia
| | - Amit Dutt
- Integrated Cancer Genomics LaboratoryAdvanced Centre for Treatment Research Education in Cancer (ACTREC), Tata Memorial CentreNavi MumbaiMaharashtraIndia
- Homi Bhabha National InstituteMumbaiMaharashtraIndia
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Zou H, Sevigny MB, Liu S, Madden DT, Louie MC. Novel flexible heteroarotinoid, SL-1-39, inhibits HER2-positive breast cancer cell proliferation by promoting lysosomal degradation of HER2. Cancer Lett 2019; 443:157-166. [PMID: 30503556 DOI: 10.1016/j.canlet.2018.11.022] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 11/21/2018] [Accepted: 11/24/2018] [Indexed: 10/27/2022]
Abstract
SL-1-39 [1-(4-chloro-3-methylphenyl)-3-(4-nitrophenyl)thiourea] is a new flexible heteroarotinoid (Flex-Het) analog derived from the parental compound, SHetA2, previously shown to inhibit cell growth across multiple cancer types. The current study aims to determine growth inhibitory effects of SL-1-39 across the different subtypes of breast cancer cells and delineate its molecular mechanism. Our results demonstrate that while SL-1-39 blocks cell proliferation of all breast cancer subtypes tested, it has the highest efficacy against HER2+ breast cancer cells. Molecular analyses suggest that SL-1-39 prevents S phase progression of HER2+ breast cancer cells (SKBR3 and MDA-MB-453), which is consistent with reduced expression of key cell-cycle regulators at both the protein and transcriptional levels. SL-1-39 treatment also decreases the protein levels of HER2 and pHER2 as well as its downstream effectors, pMAPK and pAKT. Reduction of HER2 and pHER2 at the protein level is attributed to increased lysosomal degradation of total HER2 levels. This is the first study to show that a flexible heteroarotinoid analog modulates the HER2 signaling pathway through lysosomal degradation, and thus further warrants the development of SL-1-39 as a therapeutic option for HER2+ breast cancer.
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Affiliation(s)
- Hongye Zou
- Department of Natural Sciences and Mathematics, Dominican University of California, 50 Acacia Avenue, San Rafael, CA, 94901, USA.
| | - Mary B Sevigny
- Department of Natural Sciences and Mathematics, Dominican University of California, 50 Acacia Avenue, San Rafael, CA, 94901, USA.
| | - Shengquan Liu
- College of Pharmacy, Touro University California, 1310 Club Drive, Vallejo, CA, 94594, USA.
| | - David T Madden
- College of Pharmacy, Touro University California, 1310 Club Drive, Vallejo, CA, 94594, USA; Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA, 94945, USA.
| | - Maggie C Louie
- Department of Natural Sciences and Mathematics, Dominican University of California, 50 Acacia Avenue, San Rafael, CA, 94901, USA; College of Pharmacy, Touro University California, 1310 Club Drive, Vallejo, CA, 94594, USA.
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Periampullary Metastases from Breast Cancer: A Case Report and Literature Review. Case Rep Oncol Med 2019; 2019:3479568. [PMID: 30729053 PMCID: PMC6343154 DOI: 10.1155/2019/3479568] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Accepted: 12/10/2018] [Indexed: 12/25/2022] Open
Abstract
We presented a metastatic breast cancer case who was afflicted with obstructive jaundice caused by an ampullary neoplasm. Since jaundice due to periampullary metastasis from breast cancer was a rare entity, a literature review of similar cases through the PubMed database was done. A total of 23 additional cases were found. Among these 24 cases, 5 presented with periampullary metastasis synchronously with the diagnosis of breast cancer, while 19 had metachronous periampullary metastasis with an interval ranging between 1.3 and 23 years from the initial diagnosis of breast cancer to the emergence of jaundice. It is intriguing to establish a differential diagnosis for common bile tract stricture prior to tissue biopsy, even with diagnostic workups including serum tumor markers, MRI plus MRCP, ERCP with intraductal brushing, and endoscopic ultrasound, in that the clinical, radiological, and endoscopic findings of metastatic lesions overlapped extensively with those found with primary periampullary malignancies. An immunohistochemical portfolio including cytokeratin7/20 (CK7/20), homeobox protein CDX2, human epidermal growth factor receptor 2 (HER2/neu), estrogen receptor alfa (ERα), progesterone receptor (PgR), mammaglobin, gross cystic disease fluid protein-15 (GCDFP-15), and transacting T-cell-specific transcription factor (GATA-3) was helpful for differential diagnosis among cases with ambiguous microscopic features.
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Zare SY, Lin L, Alghamdi AG, Daehne S, Roma AA, Hasteh F, Dell'Aquila M, Fadare O. Breast cancers with a HER2/CEP17 ratio of 2.0 or greater and an average HER2 copy number of less than 4.0 per cell: frequency, immunohistochemical correlation, and clinicopathological features. Hum Pathol 2019; 83:7-13. [PMID: 30121371 DOI: 10.1016/j.humpath.2018.08.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 07/25/2018] [Accepted: 08/01/2018] [Indexed: 11/28/2022]
Abstract
The 2013 American Society of Clinical Oncology and College of American Pathologists (ASCO/CAP) guidelines classified breast cancers with a fluorescence in situ hybridization dual-probe HER2/CEP17 ratio of 2 or greater as "amplified," inclusive of cases with a HER2 copy number less than 4. The 2018 ASCO/CAP update assigns HER2/neu status for the latter group in a fashion that is highly dependent on the associated immunohistochemical findings. Herein, the authors define the frequency, immunohistochemical correlates, and other clinicopathological features of breast cancers with HER2/CEP17 ratio of 2 or greater and HER2/neu copy number less than 4 (group A), based on an analysis of an institutional cohort assessed for HER2/neu status by both florescence in situ hybridization and immunohistochemistry and scored using 2013 ASCO/CAP criteria. Group A cases were compared with a group B of HER2/neu-amplified breast cancers with a HER2/neu copy number of 4 or greater regarding a variety of clinicopathological features. One hundred sixty-nine (14%) of 1201 cases were HER2/neu amplified, 18 (10.7%) in group A and 151 (89.3%) in group B. By immunohistochemistry, 61.1% of group A cases were HER2/neu negative, 7 (38.9%) were equivocal, and none were positive. In contrast, 66.9% of group B cases were HER2 positive (3+). We could not demonstrate statistically significant differences between the 2 groups regarding standard clinicopathological variables. In summary, our group A cases account for 1.5% of breast cancers, and 10.7% of all HER2/neu-amplified cancers classified as such based on 2013 ASCO/CAP criteria. They are predominantly HER2/neu negative by immunohistochemistry, which suggests that they are biologically different from classically HER2/neu-amplified cases and which validates the 2018 ASCO/CAP guideline against automatically classifying such cases as HER2/neu amplified.
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Affiliation(s)
- Somaye Y Zare
- Department of Pathology, University of California San Diego, San Diego, CA, 92037 USA
| | - Leo Lin
- Department of Pathology, University of California San Diego, San Diego, CA, 92037 USA
| | - Abrar G Alghamdi
- Department of Pathology, University of California San Diego, San Diego, CA, 92037 USA
| | - Svenja Daehne
- Department of Pathology, University of California San Diego, San Diego, CA, 92037 USA
| | - Andres A Roma
- Department of Pathology, University of California San Diego, San Diego, CA, 92037 USA
| | - Farnaz Hasteh
- Department of Pathology, University of California San Diego, San Diego, CA, 92037 USA
| | - Marie Dell'Aquila
- Department of Pathology, University of California San Diego, San Diego, CA, 92037 USA
| | - Oluwole Fadare
- Department of Pathology, University of California San Diego, San Diego, CA, 92037 USA.
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Atabati H, Raoofi A, Amini A, Farahani RM. Evaluating HER2 Gene Amplification Using Chromogenic In Situ Hybridization (CISH) Method In Comparison To Immunohistochemistry Method in Breast Carcinoma. Open Access Maced J Med Sci 2018; 6:1977-1981. [PMID: 30559846 PMCID: PMC6290434 DOI: 10.3889/oamjms.2018.455] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 10/27/2018] [Accepted: 10/28/2018] [Indexed: 01/31/2023] Open
Abstract
BACKGROUND: In patients with breast cancer, HER2 gene expression is of a great importance in reacting to Herceptin treatment. To evaluate this event, immunohistochemistry (IHC) has been done routinely on the basis of scoring it and so the patients were divided into 4 groups. Lately, as there have been disagreements about how to treat score 2 patients, chromogenic in situ hybridization (CISH) and florescence in situ hybridization (FISH) are introduced. Since CISH method is more convenient than FISH for gene amplification study, FISH has been substituted by CISH. AIM: The current study is conducted in order to investigate whether using CISH is a better method comparison to IHC method for determines HER2 expression in patients with breast cancer in. METHODS: In this cross-sectional descriptive analytical study, information of 44 female patients with invasive ductal breast cancer were gathered from Imam Reza and Omid Hospital in Mashhad. IHC staining was done for all patients in order to determine the level of HER2 expression, and after scoring them into 4 groups of 0, +1, +2 and +3, CISH staining was carried out for all 4 groups. At the end, results from both methods were statistically evaluated using SPSS software V.22.0. RESULTS: The average age of patients was 50.2 with the standard deviation of 10.96. Using IHC method was observed that 2.6% (1 patient), 26.3% (10 patients), 65.8% (25 patients) and 5.3% (2 patients) percentage of patients had scores of 0, +1, +2 and +3. On the other hand, CISH method showed 36 patients (90%) with no amplifications and 4 (10%) with sever amplifications. In a comparative study using Fisher’s exact test (p = 0.000), we found a significant relation between IHC method and CISH method indicating that all patients showing severe amplifications in CISH method, owned scores of +2 and +3 in IHC method. CONCLUSION: According to the present study and comparing the results with similar previous studies, it can be concluded that CISH method works highly effective in determining HER2 expression level in patients with breast cancer. This method is also able to determine the status of patients with score +2 in IHC for their treatment with herceptin.
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Affiliation(s)
- Hadi Atabati
- Leishmaniasis Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran
| | - Amir Raoofi
- Student Research Committee, Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abdollah Amini
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Reza Masteri Farahani
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Meric-Bernstam F, Johnson AM, Dumbrava EEI, Raghav K, Balaji K, Bhatt M, Murthy RK, Rodon J, Piha-Paul SA. Advances in HER2-Targeted Therapy: Novel Agents and Opportunities Beyond Breast and Gastric Cancer. Clin Cancer Res 2018; 25:2033-2041. [PMID: 30442682 DOI: 10.1158/1078-0432.ccr-18-2275] [Citation(s) in RCA: 233] [Impact Index Per Article: 33.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Revised: 09/10/2018] [Accepted: 11/12/2018] [Indexed: 02/07/2023]
Abstract
The introduction of HER2-targeted therapy for breast and gastric patients with ERBB2 (HER2) amplification/overexpression has led to dramatic improvements in oncologic outcomes. In the past 20 years, five HER2-targeted therapies have been FDA approved, with four approved in the past 8 years. HER2-targeted therapy similarly was found to improve outcomes in HER2-positive gastric cancer. Over the past decade, with the introduction of next-generation sequencing into clinical practice, our understanding of HER2 biology has dramatically improved. We have recognized that HER2 amplification is not limited to breast and gastric cancer but is also found in a variety of tumor types such as colon cancer, bladder cancer, and biliary cancer. Furthermore, HER2-targeted therapy has signal of activity in several tumor types. In addition to HER2 amplification and overexpression, there is also increased recognition of activating HER2 mutations and their potential therapeutic relevance. Furthermore, there is a rapidly growing number of new therapeutics targeting HER2 including small-molecule inhibitors, antibody-drug conjugates, and bispecific antibodies. Taken together, an increasing number of patients are likely to benefit from approved and emerging HER2-targeted therapies.
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Affiliation(s)
- Funda Meric-Bernstam
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas. .,Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.,Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Amber M Johnson
- Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ecaterina E Ileana Dumbrava
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Kanwal Raghav
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Kavitha Balaji
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Michelle Bhatt
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Rashmi K Murthy
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jordi Rodon
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.,Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Sarina A Piha-Paul
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas
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Li R, Chibbar R, Xiang J. Novel EXO-T vaccine using polyclonal CD4 + T cells armed with HER2-specific exosomes for HER2-positive breast cancer. Onco Targets Ther 2018; 11:7089-7093. [PMID: 30410365 PMCID: PMC6200095 DOI: 10.2147/ott.s184898] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Breast cancer is the leading cause of death in women globally. The human epidermal growth factor receptor 2 (HER2)-positive breast cancer is often associated with poor prognosis and high mortality. Even though anti-HER2 monoclonal antibodies have improved the clinical outcome, resistance to the antibody therapy becomes a major obstacle in the treatment of HER2-positive breast cancer patients. Alternative approaches are therefore needed. HER2-specific vaccines have been developed to trigger patient’s immune system against HER2-positive breast cancer. This article describes the development of novel HER2-specific exosome (EXO)-T vaccine using polyclonal CD4+ T cells armed with HER2-specific dendritic cell-released EXO and demonstrates its therapeutic effect against HER2-positive tumor in double-transgenic HER2/HLA-A2 mice with HER2-specific self-immune tolerance. Therefore, our novel HER2-specific EXO-T vaccines are likely to assist in the treatment of HER2-positive breast cancer patients.
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Affiliation(s)
- Rong Li
- Cancer Research Cluster, Saskatchewan Cancer Agency, Saskatoon, SK, Canada, .,Department of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada,
| | - Rajni Chibbar
- Department of Pathology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
| | - Jim Xiang
- Cancer Research Cluster, Saskatchewan Cancer Agency, Saskatoon, SK, Canada, .,Department of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada,
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47
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Koopman T, van der Vegt B, Dijkstra M, Bart J, Duiker E, Wisman GBA, de Bock GH, Hollema H. HER2 immunohistochemistry in endometrial and ovarian clear cell carcinoma: discordance between antibodies and with in-situ hybridisation. Histopathology 2018; 73:852-863. [PMID: 29989198 DOI: 10.1111/his.13704] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2018] [Accepted: 07/09/2018] [Indexed: 11/26/2022]
Abstract
AIMS Treatment with anti-HER2 therapy could be beneficial for patients with HER2-positive endometrial and ovarian clear cell carcinoma (CCC). We studied HER2 overexpression by immunohistochemistry (IHC) using three different antibodies, including concordance with amplification by in-situ hybridisation (ISH). METHODS AND RESULTS IHC and ISH were performed on tissue microarrays of 101 tumours: 58 endometrial pure CCC, 19 endometrial mixed carcinomas with a CCC component and 24 ovarian pure CCC. IHC was performed using SP3, 4B5 and HercepTest antibodies, and was scored by two independent observers. ISH was performed using dual-colour silver ISH. Using IHC, agreement was poor between SP3/4B5 (61.4%), poor between SP3/HercepTest (68.3%) and reasonable between 4B5/HercepTest (75.2%). Interobserver agreement was substantial to almost perfect for all antibodies (SP3: linear weighted κ = 0.89, 4B5: κ = 0.90, HercepTest: κ = 0.76). HER2-positivity by ISH was 17.8% (endometrial pure CCC: 24.1%, endometrial mixed: 0%, ovarian pure CCC: 16.7%). IHC/ISH concordance was poor, with a high false-negative rate of all three IHC antibodies: sensitivity (38.9-50.0%) and positive predictive value (PPV) (37.5-58.3%) were poor; specificity (81.9-94.0%) and negative predictive value (NPV) (87.1-88.3%) were reasonable. When excluding 2+ cases, sensitivity declined (26.7-43.8%) but PPV (80.0-87.5%) and specificity (98.6-98.7%) improved. CONCLUSIONS In ovarian and endometrial CCC, there is considerable difference in HER2 overexpression by different IHC antibodies and marked discordance with ISH. As such, no single antibody can be considered conclusive for determining HER2 status in CCC. Based on these results, the lack of predictive value of different HER2 testing methods, as used in other studies, could be explained.
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Affiliation(s)
- Timco Koopman
- Department of Pathology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Bert van der Vegt
- Department of Pathology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Marcel Dijkstra
- Department of Pathology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Joost Bart
- Department of Pathology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Evelien Duiker
- Department of Pathology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - G Bea A Wisman
- Department of Gynaecologic Oncology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Geertruida H de Bock
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Harry Hollema
- Department of Pathology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
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Comparative Pathologic Analysis of Breast Cancers Classified as HER2/neu-Amplified by FISH Using a Standard HER2/CEP17 Dual Probe and an Alternative Chromosome 17 Control Probe. Am J Surg Pathol 2018; 42:1208-1215. [DOI: 10.1097/pas.0000000000001106] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Hashmi AA, Mahboob R, Khan SM, Irfan M, Nisar M, Iftikhar N, Siddiqui M, Faridi N, Khan A, Edhi MM. Clinical and prognostic profile of Her2neu positive (non-luminal) intrinsic breast cancer subtype: comparison with Her2neu positive luminal breast cancers. BMC Res Notes 2018; 11:574. [PMID: 30103802 PMCID: PMC6090780 DOI: 10.1186/s13104-018-3677-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Accepted: 08/03/2018] [Indexed: 11/10/2022] Open
Abstract
Objective Her2neu receptor is proto-oncogene which can be over-expressed in both luminal and non-luminal breast cancers. In the present study, we aimed to compare the prognostic and predictive factors like tumor grade, T-stage, N-stage and ki67 index in Her2neu intrinsic breast cancer subtype with Her2neu over-expressed luminal breast cancers. Results 801 (41%) cases were Her2neu positive; out of which, 418 cases (52.2%) showed ER positivity and thus were classified as Her2neu positive luminal cancers whereas 383 cases (47.8%) were ER and PR negative and therefore were labeled as intrinsic Her2neu subtype (non-luminal). Her2neu positive (non-luminal) cancers were significantly associated with higher grades and Ki67 proliferative index compared to Her2neu positive luminal cancers. On the other no significant association was noted in T-stage and N-stage. We found a high frequency of her2neu positivity in our studied population of breast cancer. Moreover, association of her2neu positive (non-luminal) breast cancers with higher grade and ki67 index indicates a predictive value of ER/PR positivity in her2neu positive breast cancers. On the other hand, lack of association with respect to T and N stage, signifies no prognostic benefit of ER/PR in her2neu positive breast cancers.
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Affiliation(s)
- Atif Ali Hashmi
- Department of Histopathology, Liaquat National Hospital and Medical College, Karachi, Pakistan
| | - Raeesa Mahboob
- Department of Histopathology, Liaquat National Hospital and Medical College, Karachi, Pakistan
| | - Saadia Mehmood Khan
- Department of Histopathology, Liaquat National Hospital and Medical College, Karachi, Pakistan
| | - Muhammad Irfan
- Department of Histopathology, Liaquat National Hospital and Medical College, Karachi, Pakistan
| | - Mariam Nisar
- Department of Histopathology, Liaquat National Hospital and Medical College, Karachi, Pakistan
| | - Narisa Iftikhar
- Department of Histopathology, Liaquat National Hospital and Medical College, Karachi, Pakistan
| | - Maham Siddiqui
- Department of Histopathology, Liaquat National Hospital and Medical College, Karachi, Pakistan
| | - Naveen Faridi
- Department of Histopathology, Liaquat National Hospital and Medical College, Karachi, Pakistan
| | - Amir Khan
- Department of Medicine, Kandahar University, Kandahar, Afghanistan.
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50
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Guan SS, Wu CT, Chiu CY, Luo TY, Wu JY, Liao TZ, Liu SH. Polyethylene glycol-conjugated HER2-targeted peptides as a nuclear imaging probe for HER2-overexpressed gastric cancer detection in vivo. J Transl Med 2018; 16:168. [PMID: 29921305 PMCID: PMC6009821 DOI: 10.1186/s12967-018-1550-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Accepted: 06/15/2018] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND The human epidermal growth factor receptor 2 (HER2) involved proliferation, angiogenesis, and reduced apoptosis in gastric cancer (GC), which is a common target for tumor therapy. HER2 is usually overexpressed in more than 15% GC patients, developing a reliable diagnostic tool for tumor HER2 detection is important. In this study, we attend to use polyethylene glycol (PEG) linked anti-HER2/neu peptide (AHNP-PEG) as a nuclear imaging agent probe for HER2 detection in GC xenograft animal model. METHODS The HER2 expression of human sera and tissues were detected in GC patients and normal subjects. GC cell lines NCI-N87 (high HER2 levels) and MKN45 (low HER2 levels) were treated with AHNP-PEG to assess the cell viability and HER2 binding ability. The NCI-N87 was treated with AHNP-PEG to observe the level and phosphorylation of HER2. The MKN45 and NCI-N87-induced xenograft mice were intravenous injection with fluorescence labeled AHNP-PEG for detecting in vivo fluorescence imaging properties and biodistribution. The AHNP-PEG was conjugated with diethylenetriaminopentaacetic acid (DTPA) for indium-111 labeling (111In-DTPA-AHNP-PEG). The stability of was assessed in vitro. The imaging properties and biodistribution of 111In-DTPA-AHNP-PEG were observed in NCI-N87-induced xenograft mice. RESULTS The serum HER2 (sHER2) levels in GC patients were significantly higher than the normal subjects. The sHER2 levels were correlated with the tumor HER2 levels in different stages of GC patients. The AHNP-PEG inhibited the cell growth and down-regulated HER2 phosphorylation in HER2-overexpressed human GC cells (NCI-N87) via specific HER2 interaction of cell surface. In addition, the GC tumor tissues from HER2-postive xenograft mice presented higher HER2 fluorescence imaging as compared to HER2-negative group. The HER2 levels in the tumor tissues were also higher than other organs in NCI-N87-induced xenograft mice. Finally, we further observed that the 111In-DTPA-AHNP-PEG was significantly enhanced in tumor tissues of NCI-N87-induced xenograft mice compared to control. CONCLUSIONS These findings suggest that the sHER2 measurement may be as a potential tool for detecting HER2 expressions in GC patients. The radioisotope-labeled AHNP-PEG may be useful to apply in GC patients for HER2 nuclear medicine imaging.
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Affiliation(s)
- Siao-Syun Guan
- Institute of Nuclear Energy Research, Atomic Energy Council, Taoyuan, Taiwan
| | - Cheng-Tien Wu
- Institute of Toxicology, College of Medicine, National Taiwan University, No. 1, Section 1, Jen-Ai Road, Taipei, 10051, Taiwan
| | - Chen-Yuan Chiu
- Institute of Food Safety and Health, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Tsai-Yueh Luo
- Institute of Nuclear Energy Research, Atomic Energy Council, Taoyuan, Taiwan
| | - Jeng-Yih Wu
- Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Tse-Zung Liao
- Institute of Nuclear Energy Research, Atomic Energy Council, Taoyuan, Taiwan
| | - Shing-Hwa Liu
- Institute of Toxicology, College of Medicine, National Taiwan University, No. 1, Section 1, Jen-Ai Road, Taipei, 10051, Taiwan. .,Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan. .,Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
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