HER2 expression is exceedingly rare in anaplastic thyroid carcinoma: an immunohistochemical analysis of 50 surgical cases

HER2 expression is exceedingly rare in anaplastic thyroid carcinoma: an immunohistochemical analysis of 50 surgical cases | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article HER2 expression is exceedingly rare in anaplastic thyroid carcinoma: an immunohistochemical analysis of 50 surgical cases Natalia Timofeeva, Uliana Farafonova, Sergey Vorobjov, Roman Chernikov, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7987311/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Anaplastic thyroid carcinoma (ATC) is one of the most lethal human solid tumors and urgently requires novel therapeutic targets. The HER2/ERBB2 receptor tyrosine kinase is an established biomarker and drug target in breast and gastric cancers, but its relevance in ATC remains uncertain. We performed a retrospective, single‑centre immunohistochemical (IHC) study of 50 consecutive surgical ATC specimens. Formalin‑fixed paraffin‑embedded sections with sufficient viable tumour were stained on the BenchMark ULTRA platform (Ventana, USA) using the Her‑2/neu clone 4B5 rabbit monoclonal antibody. Membranous staining intensity and completeness were scored by two pathologists according to the College of American Pathologists (CAP) guideline for breast carcinoma. All 50 ATC cases were negative for HER2 overexpression. Three tumours showed only focal, granular, intracytoplasmic signal in tumour cells and macrophages; no case demonstrated a strong, complete (3+) membranous pattern. These data indicate that true HER2 protein overexpression is exceedingly rare in ATC. Our results do not support routine HER2 testing or anti‑HER2 monotherapy in unselected patients with ATC. Nevertheless, preclinical studies suggest that pan‑ERBB inhibition may cooperate with BRAF/MEK blockade to prevent pathway reactivation and overcome resistance in BRAFV600E‑mutant thyroid cancer. Prospective trials with molecular stratification are warranted. Health sciences/Biomarkers Biological sciences/Cancer Health sciences/Oncology Introduction Anaplastic thyroid carcinoma (ATC) is one of the most aggressive solid malignancies in humans, characterized by rapid local invasion, early distant spread and dismal survival. Despite recent progress with targeted therapy and immunotherapy, most patients still have no durable systemic treatment options. ATC harbors a complex molecular landscape enriched for alterations in MAPK and PI3K/AKT pathway components (including BRAF, RAS and PIK3CA/PTEN), together with TP53 inactivation and TERT promoter mutations, reflecting a highly dedifferentiated and genomically unstable state. The ERBB/HER receptor tyrosine kinase family (EGFR/HER1, HER2/ERBB2, HER3/ERBB3 and HER4/ERBB4) regulates proliferation, survival and therapy resistance through MAPK/ERK and PI3K/AKT signaling [ 1 ]. HER2 is a ligand‑independent co‑receptor encoded by ERBB2 and is a clinically validated predictive biomarker in breast and gastric cancers, where HER2 amplification and protein overexpression select patients for HER2‑directed therapy [ 2 , 3 ]. In thyroid cancer the clinical significance of HER2 remains unclear, and published frequencies of HER2 positivity vary widely across studies, especially in poorly differentiated and anaplastic tumors [ 4 , 5 ]. This variability likely reflects methodological differences in antibody clones, staining platforms and interpretation criteria, which are usually extrapolated from breast or gastro‑oesophageal guidelines rather than validated for thyroid tissue. At the same time, pan‑ERBB signaling has emerged as a potential bypass pathway that can reactivate MAPK signaling and confer resistance to BRAF/MEK inhibition in BRAFV600E‑mutant thyroid cancer models.5 These observations provide a rationale to reassess HER2 protein expression in ATC specimens in a systematic manner. Here, we performed a single‑center immunohistochemical (IHC) analysis of 50 consecutive ATC resection specimens, scored according to the College of American Pathologists (CAP) guideline for breast carcinoma, to estimate the true prevalence of therapeutically actionable HER2 overexpression in this highly lethal disease. Results All 50 ATC cases were interpretable for HER2 immunohistochemistry. None of the tumours met the criteria for HER2 overexpression. Specifically, no specimen demonstrated strong, complete circumferential membranous staining (3+) in tumour cells according to CAP breast scoring. Three cases showed only focal, granular, intracytoplasmic staining in tumour cells and in macrophages. This staining was variable in intensity and lacked convincing membranous localization; therefore it was interpreted as nonspecific background rather than true HER2 expression. The remaining 47 tumours were completely negative. Taken together, our data indicate that HER2 protein overexpression is exceedingly rare, if present at all, in anaplastic thyroid carcinoma. Discussion In this series of 50 surgically resected ATC specimens, we did not observe membranous HER2 overexpression by IHC. These results reinforce the concept that, unlike breast or gastric carcinoma, ATC is not typically driven by HER2 signalling and is therefore unlikely to benefit from routine HER2‑targeted monotherapy. The wide range of HER2 positivity rates reported in the literature for thyroid malignancies probably reflects several sources of technical and biological heterogeneity. First, pre‑analytical factors such as cold ischaemia time and fixation can strongly influence membrane antigen preservation. Second, different studies have used different antibody clones and staining platforms, often without external quality control. Third, there is no universally accepted HER2 scoring algorithm for thyroid tumours; most groups, including ours, apply breast or gastro‑oesophageal criteria by analogy. Finally, ATC is profoundly heterogeneous at the genomic and phenotypic levels, and extensive dedifferentiation may attenuate or abolish membranous receptor tyrosine kinase expression. From a therapeutic standpoint, our findings argue against routine HER2 testing as a screening tool for anti‑HER2 therapy in unselected ATC patients. Nevertheless, ERBB biology may still be clinically relevant in defined molecular subgroups. In BRAFV600E‑mutant thyroid cancer models, MAPK pathway inhibition with BRAF/MEK inhibitors can induce adaptive ERBB dimerization, reactivate ERK and AKT signalling and thereby limit treatment durability.5 Co‑inhibition of the ERBB family in these models enhances pathway suppression, promotes redifferentiation and increases radioactive iodine uptake [ 5 ]. This raises the hypothesis that combined ERBB and BRAF/MEK inhibition could delay or overcome resistance in selected ATC patients, even in the absence of overt HER2 overexpression. This study has limitations. It is retrospective, single‑centre and based solely on IHC. We did not perform ERBB2 amplification testing by in situ hybridisation (ISH) or next‑generation sequencing, nor did we systematically correlate HER2 status with clinicopathological variables or clinical outcome. Future work should include orthogonal ERBB2 assessment (IHC plus ISH and/or sequencing), explicit molecular stratification (including BRAFV600E status and broader ERBB pathway alterations) and correlative clinical endpoints in prospective trials. In conclusion, HER2 overexpression detectable by standard clinical IHC appears to be exceedingly rare in ATC and does not currently justify incorporation of anti‑HER2 monotherapy into routine management. The ERBB pathway nevertheless remains of interest as a mechanism of adaptive resistance to MAPK pathway inhibition, and deserves prospective evaluation in biomarker‑selected cohorts. Methods Study design and case selection. We performed a retrospective histopathological study of 50 consecutive surgical specimens from patients treated for anaplastic thyroid carcinoma at a single tertiary centre. Formalin‑fixed, paraffin‑embedded (FFPE) tissue blocks containing sufficient viable tumour were retrieved from the pathology archive. Immunohistochemistry. Four‑micrometre FFPE sections were stained on the BenchMark ULTRA automated platform (Ventana, USA) using the Her‑2/neu (clone 4B5) rabbit monoclonal primary antibody. Staining was developed according to the manufacturer’s protocol. Appropriate external positive controls were included in each run. Scoring. HER2 staining intensity and pattern were evaluated by two experienced pathologists in a consensus review. Membranous staining was scored using the College of American Pathologists (CAP) guideline for breast carcinoma, which defines strong, complete circumferential membranous staining in more than 10% of tumour cells as 3+. Cytoplasmic granular staining without convincing membranous accentuation was considered nonspecific. Ethics. The study used only anonymized archival surgical material obtained as part of routine clinical care. No direct patient contact or identifiable clinical data were involved. According to institutional policy, the requirement for formal ethics committee review and informed consent was waived. Declarations Competing interests The authors declare no competing interests. Ethics statement The study was conducted in accordance with institutional guidelines and the Declaration of Helsinki. Because only anonymized archival surgical specimens were used and no identifiable patient information was collected, the institutional ethics committee waived the requirement for formal approval and informed consent. Funding This research received no specific grant from any funding agency in the public, commercial or not‑for‑profit sectors. Author Contribution N.T. conceived and designed the study, drafted the manuscript, provided surgical material and data collection. U.F. conceived and designed the study and provided critical manuscript revisions. S.V. reviewed pathology and performed immunohistochemical staining, optimized and supervised the HER2 staining protocol. R.C. performed data curation and contributed to data interpretation. I.S. provided clinical annotations and critical manuscript revisions. All authors discussed the results, revised the manuscript and approved the final version. Acknowledgement The authors thank Dr. Sergey L. Vorobyev, Head of the Morphological Laboratory at the National Center for Clinical Morphologic Diagnostics, for expert technical assistance and methodological guidance in HER2 immunohistochemistry. Data Availability All data generated or analysed during this study are included in this published article. Additional de‑identified information is available from the corresponding author on reasonable request. References Iqbal, N. & Iqbal, N. Human epidermal growth factor receptor 2 (HER2) in cancers: overexpression and therapeutic implications. Mol. Biol. Int. 2014 , 852748. 10.1155/2014/852748 (2014). Slamon, D. J. et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235 (4785), 177–182. 10.1126/science.3798106 (1987). Press, M. F. et al. Her-2/neu expression in node-negative breast cancer: direct tissue quantitation and association of overexpression with increased risk of recurrent disease. Cancer Res. 53 (20), 4960–4970 (1993). Ciobanu Apostol, D. et al. HER-2/neu expression in different histological subtypes of papillary thyroid carcinoma. Rom J. Morphol. Embryol. 58 (2), 439–444 (2017). Cheng, L. et al. HER inhibitor promotes BRAF/MEK inhibitor-induced redifferentiation in papillary thyroid cancer harboring BRAFV600E. Oncotarget 8 (12), 19843–19854. 10.18632/oncotarget.15773 (2017). Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7987311","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":545986696,"identity":"3707bd44-136d-403a-b106-70378fb3ae5a","order_by":0,"name":"Natalia 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Despite recent progress with targeted therapy and immunotherapy, most patients still have no durable systemic treatment options. ATC harbors a complex molecular landscape enriched for alterations in MAPK and PI3K/AKT pathway components (including BRAF, RAS and PIK3CA/PTEN), together with TP53 inactivation and TERT promoter mutations, reflecting a highly dedifferentiated and genomically unstable state.\u003c/p\u003e\u003cp\u003eThe ERBB/HER receptor tyrosine kinase family (EGFR/HER1, HER2/ERBB2, HER3/ERBB3 and HER4/ERBB4) regulates proliferation, survival and therapy resistance through MAPK/ERK and PI3K/AKT signaling [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. HER2 is a ligand‑independent co‑receptor encoded by ERBB2 and is a clinically validated predictive biomarker in breast and gastric cancers, where HER2 amplification and protein overexpression select patients for HER2‑directed therapy [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn thyroid cancer the clinical significance of HER2 remains unclear, and published frequencies of HER2 positivity vary widely across studies, especially in poorly differentiated and anaplastic tumors [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. This variability likely reflects methodological differences in antibody clones, staining platforms and interpretation criteria, which are usually extrapolated from breast or gastro‑oesophageal guidelines rather than validated for thyroid tissue. At the same time, pan‑ERBB signaling has emerged as a potential bypass pathway that can reactivate MAPK signaling and confer resistance to BRAF/MEK inhibition in BRAFV600E‑mutant thyroid cancer models.5 These observations provide a rationale to reassess HER2 protein expression in ATC specimens in a systematic manner.\u003c/p\u003e\u003cp\u003eHere, we performed a single‑center immunohistochemical (IHC) analysis of 50 consecutive ATC resection specimens, scored according to the College of American Pathologists (CAP) guideline for breast carcinoma, to estimate the true prevalence of therapeutically actionable HER2 overexpression in this highly lethal disease.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eAll 50 ATC cases were interpretable for HER2 immunohistochemistry. None of the tumours met the criteria for HER2 overexpression. Specifically, no specimen demonstrated strong, complete circumferential membranous staining (3+) in tumour cells according to CAP breast scoring.\u003c/p\u003e\u003cp\u003eThree cases showed only focal, granular, intracytoplasmic staining in tumour cells and in macrophages. This staining was variable in intensity and lacked convincing membranous localization; therefore it was interpreted as nonspecific background rather than true HER2 expression. The remaining 47 tumours were completely negative.\u003c/p\u003e\u003cp\u003eTaken together, our data indicate that HER2 protein overexpression is exceedingly rare, if present at all, in anaplastic thyroid carcinoma.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this series of 50 surgically resected ATC specimens, we did not observe membranous HER2 overexpression by IHC. These results reinforce the concept that, unlike breast or gastric carcinoma, ATC is not typically driven by HER2 signalling and is therefore unlikely to benefit from routine HER2‑targeted monotherapy.\u003c/p\u003e\u003cp\u003eThe wide range of HER2 positivity rates reported in the literature for thyroid malignancies probably reflects several sources of technical and biological heterogeneity. First, pre‑analytical factors such as cold ischaemia time and fixation can strongly influence membrane antigen preservation. Second, different studies have used different antibody clones and staining platforms, often without external quality control. Third, there is no universally accepted HER2 scoring algorithm for thyroid tumours; most groups, including ours, apply breast or gastro‑oesophageal criteria by analogy. Finally, ATC is profoundly heterogeneous at the genomic and phenotypic levels, and extensive dedifferentiation may attenuate or abolish membranous receptor tyrosine kinase expression.\u003c/p\u003e\u003cp\u003eFrom a therapeutic standpoint, our findings argue against routine HER2 testing as a screening tool for anti‑HER2 therapy in unselected ATC patients. Nevertheless, ERBB biology may still be clinically relevant in defined molecular subgroups. In BRAFV600E‑mutant thyroid cancer models, MAPK pathway inhibition with BRAF/MEK inhibitors can induce adaptive ERBB dimerization, reactivate ERK and AKT signalling and thereby limit treatment durability.5 Co‑inhibition of the ERBB family in these models enhances pathway suppression, promotes redifferentiation and increases radioactive iodine uptake [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. This raises the hypothesis that combined ERBB and BRAF/MEK inhibition could delay or overcome resistance in selected ATC patients, even in the absence of overt HER2 overexpression.\u003c/p\u003e\u003cp\u003eThis study has limitations. It is retrospective, single‑centre and based solely on IHC. We did not perform ERBB2 amplification testing by in situ hybridisation (ISH) or next‑generation sequencing, nor did we systematically correlate HER2 status with clinicopathological variables or clinical outcome. Future work should include orthogonal ERBB2 assessment (IHC plus ISH and/or sequencing), explicit molecular stratification (including BRAFV600E status and broader ERBB pathway alterations) and correlative clinical endpoints in prospective trials.\u003c/p\u003e\u003cp\u003eIn conclusion, HER2 overexpression detectable by standard clinical IHC appears to be exceedingly rare in ATC and does not currently justify incorporation of anti‑HER2 monotherapy into routine management. The ERBB pathway nevertheless remains of interest as a mechanism of adaptive resistance to MAPK pathway inhibition, and deserves prospective evaluation in biomarker‑selected cohorts.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eStudy design and case selection. We performed a retrospective histopathological study of 50 consecutive surgical specimens from patients treated for anaplastic thyroid carcinoma at a single tertiary centre. Formalin‑fixed, paraffin‑embedded (FFPE) tissue blocks containing sufficient viable tumour were retrieved from the pathology archive.\u003c/p\u003e\u003cp\u003eImmunohistochemistry. Four‑micrometre FFPE sections were stained on the BenchMark ULTRA automated platform (Ventana, USA) using the Her‑2/neu (clone 4B5) rabbit monoclonal primary antibody. Staining was developed according to the manufacturer\u0026rsquo;s protocol. Appropriate external positive controls were included in each run.\u003c/p\u003e\u003cp\u003eScoring. HER2 staining intensity and pattern were evaluated by two experienced pathologists in a consensus review. Membranous staining was scored using the College of American Pathologists (CAP) guideline for breast carcinoma, which defines strong, complete circumferential membranous staining in more than 10% of tumour cells as 3+. Cytoplasmic granular staining without convincing membranous accentuation was considered nonspecific.\u003c/p\u003e\u003cp\u003eEthics. The study used only anonymized archival surgical material obtained as part of routine clinical care. No direct patient contact or identifiable clinical data were involved. According to institutional policy, the requirement for formal ethics committee review and informed consent was waived.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003ch2\u003eCompeting interests\u003c/h2\u003e\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003eEthics statement\u003c/h2\u003e\u003cp\u003eThe study was conducted in accordance with institutional guidelines and the Declaration of Helsinki. Because only anonymized archival surgical specimens were used and no identifiable patient information was collected, the institutional ethics committee waived the requirement for formal approval and informed consent.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003eThis research received no specific grant from any funding agency in the public, commercial or not‑for‑profit sectors.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eN.T. conceived and designed the study, drafted the manuscript, provided surgical material and data collection. U.F. conceived and designed the study and provided critical manuscript revisions. S.V. reviewed pathology and performed immunohistochemical staining, optimized and supervised the HER2 staining protocol. R.C. performed data curation and contributed to data interpretation. I.S. provided clinical annotations and critical manuscript revisions. All authors discussed the results, revised the manuscript and approved the final version.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eThe authors thank Dr. Sergey L. Vorobyev, Head of the Morphological Laboratory at the National Center for Clinical Morphologic Diagnostics, for expert technical assistance and methodological guidance in HER2 immunohistochemistry.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eAll data generated or analysed during this study are included in this published article. Additional de‑identified information is available from the corresponding author on reasonable request.\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eIqbal, N. \u0026amp; Iqbal, N. Human epidermal growth factor receptor 2 (HER2) in cancers: overexpression and therapeutic implications. \u003cem\u003eMol. Biol. Int.\u003c/em\u003e \u003cb\u003e2014\u003c/b\u003e, 852748. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1155/2014/852748\u003c/span\u003e\u003cspan address=\"10.1155/2014/852748\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2014).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSlamon, D. J. et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. \u003cem\u003eScience\u003c/em\u003e \u003cb\u003e235\u003c/b\u003e (4785), 177\u0026ndash;182. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1126/science.3798106\u003c/span\u003e\u003cspan address=\"10.1126/science.3798106\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (1987).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePress, M. F. et al. Her-2/neu expression in node-negative breast cancer: direct tissue quantitation and association of overexpression with increased risk of recurrent disease. \u003cem\u003eCancer Res.\u003c/em\u003e \u003cb\u003e53\u003c/b\u003e (20), 4960\u0026ndash;4970 (1993).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCiobanu Apostol, D. et al. HER-2/neu expression in different histological subtypes of papillary thyroid carcinoma. \u003cem\u003eRom J. Morphol. Embryol.\u003c/em\u003e \u003cb\u003e58\u003c/b\u003e (2), 439\u0026ndash;444 (2017).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCheng, L. et al. HER inhibitor promotes BRAF/MEK inhibitor-induced redifferentiation in papillary thyroid cancer harboring BRAFV600E. \u003cem\u003eOncotarget\u003c/em\u003e \u003cb\u003e8\u003c/b\u003e (12), 19843\u0026ndash;19854. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.18632/oncotarget.15773\u003c/span\u003e\u003cspan address=\"10.18632/oncotarget.15773\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2017).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7987311/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7987311/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eAnaplastic thyroid carcinoma (ATC) is one of the most lethal human solid tumors and urgently requires novel therapeutic targets. The HER2/ERBB2 receptor tyrosine kinase is an established biomarker and drug target in breast and gastric cancers, but its relevance in ATC remains uncertain. We performed a retrospective, single‑centre immunohistochemical (IHC) study of 50 consecutive surgical ATC specimens. Formalin‑fixed paraffin‑embedded sections with sufficient viable tumour were stained on the BenchMark ULTRA platform (Ventana, USA) using the Her‑2/neu clone 4B5 rabbit monoclonal antibody. Membranous staining intensity and completeness were scored by two pathologists according to the College of American Pathologists (CAP) guideline for breast carcinoma. All 50 ATC cases were negative for HER2 overexpression. Three tumours showed only focal, granular, intracytoplasmic signal in tumour cells and macrophages; no case demonstrated a strong, complete (3+) membranous pattern. These data indicate that true HER2 protein overexpression is exceedingly rare in ATC. Our results do not support routine HER2 testing or anti‑HER2 monotherapy in unselected patients with ATC. Nevertheless, preclinical studies suggest that pan‑ERBB inhibition may cooperate with BRAF/MEK blockade to prevent pathway reactivation and overcome resistance in BRAFV600E‑mutant thyroid cancer. Prospective trials with molecular stratification are warranted.\u003c/p\u003e","manuscriptTitle":"HER2 expression is exceedingly rare in anaplastic thyroid carcinoma: an immunohistochemical analysis of 50 surgical cases","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-18 10:02:59","doi":"10.21203/rs.3.rs-7987311/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"92d9078b-1b92-4123-a50e-bfa59597eaac","owner":[],"postedDate":"November 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":58080363,"name":"Health sciences/Biomarkers"},{"id":58080364,"name":"Biological sciences/Cancer"},{"id":58080365,"name":"Health sciences/Oncology"}],"tags":[],"updatedAt":"2025-11-20T07:08:48+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-18 10:02:59","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7987311","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7987311","identity":"rs-7987311","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}