Targeted Therapy Decision in HER2 Exon 20–Mutant Non-Small Cell Lung Cancer with Leptomeningeal Disease: A Case-Based Perspective

Targeted Therapy Decision in HER2 Exon 20–Mutant Non-Small Cell Lung Cancer with Leptomeningeal Disease: A Case-Based Perspective | 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 Case Report Targeted Therapy Decision in HER2 Exon 20–Mutant Non-Small Cell Lung Cancer with Leptomeningeal Disease: A Case-Based Perspective Osama Elzaafarany This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6925753/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 27 Jul, 2025 Read the published version in Cureus → Version 1 posted You are reading this latest preprint version Abstract We report a rare and clinically challenging case of leptomeningeal disease (LMD) secondary to HER2-mutated non-small cell lung cancer (NSCLC), marked by both exon 20 insertion and gene amplification. In the absence of LMD-specific therapeutic guidelines for HER2-driven NSCLC, we initiated treatment with trastuzumab deruxtecan (Enhertu), based on extrapolated evidence from clinical trials in systemic NSCLC and HER2-positive breast cancer with central nervous system involvement. Our patient, a 69-year-old woman with stable performance status, developed LMD following prior systemic therapy and local CNS treatments. MRI and CSF cytology confirmed the diagnosis. Given the lack of approved therapies for HER2-mutant NSCLC with LMD, our treatment strategy was informed by data from DESTINY-Lung02, the DEBRA and ROSET-BM studies, and supporting literature on CNS activity of Enhertu. Other options such as poziotinib and zongertinib were considered but not pursued. This case underscores the urgent need for inclusive clinical trials addressing CNS complications in molecularly defined NSCLC and demonstrates the real-world application of precision oncology beyond trial populations. Oncology non-small cell lung cancer leptomeningeal disease HER2 mutation exon 20 insertion CNS metastases precision oncology Main Text Dear Editor, I am writing to present a rare and therapeutically complex case of leptomeningeal disease (LMD) secondary to HER2-mutated non-small cell lung cancer (NSCLC), characterized by both exon 20 insertion and gene amplification. The coexistence of these alterations, coupled with LMD, presents a clinical dilemma due to the absence of established therapeutic guidelines in this molecular and anatomic context. Our patient is a 69-year-old female diagnosed with T4N2M1c adenocarcinoma of the right lung. She initially presented in early 2024 with respiratory symptoms and cervical adenopathy. Histopathologic analysis confirmed lung adenocarcinoma with PD-L1 expression <1%. Circulating tumor DNA analysis via Guardant360 revealed an HER2 exon 20 insertion along with amplification. She received first-line treatment with carboplatin, pemetrexed, and pembrolizumab, followed by maintenance pemetrexed and pembrolizumab. Additionally, stereotactic radiosurgery (SRS) was administered to multiple brain metastases, along with palliative radiation to osseous lesions. In April 2025, the patient presented with progressive headaches. MRI demonstrated new multifocal leptomeningeal enhancement, with stable parenchymal brain metastases. A subsequent lumbar puncture confirmed positive cerebrospinal fluid cytology, establishing the diagnosis of LMD. At the time of diagnosis, she remained in a good performance status, and she was not receiving corticosteroids or antiepileptic medications. This was a turning point in her care, as no approved therapies exist for HER2-mutant NSCLC with LMD. Given the lack of LMD-specific data for HER2-mutant NSCLC, we initiated treatment with trastuzumab deruxtecan (Enhertu). This decision was informed by data from the DESTINY-Lung02 trial [1], which demonstrated meaningful activity in ERBB2-mutant NSCLC, including exon 20 insertions. Importantly, patients with LMD were excluded from this study. Our rationale was further supported by data from HER2-positive breast cancer, where Enhertu has demonstrated central nervous system (CNS) activity, including in patients with LMD. Specifically, the DEBRA trial and ROSET-BM study have reported responses to trastuzumab deruxtecan in this setting [2,3]. Additional retrospective reports support its CNS penetrance [4]. Alternative therapeutic options were considered. A case report by Fan et al. (2021) described the successful use of poziotinib in HER2 exon 20-mutated NSCLC with LMD [5]. Although poziotinib shows promise, it remains investigational in this context. Another novel agent, zongertinib, has shown preclinical efficacy and blood-brain barrier penetration in HER2 exon 20-altered NSCLC, though no clinical data in LMD currently exist. Intrathecal trastuzumab was not pursued, as the mutation affects the intracellular domain of HER2, limiting the potential efficacy of extracellular-targeting monoclonal antibodies in this case. In summary, this case highlights the urgent need for clinical trials that include patients with LMD, especially within molecularly defined subtypes like ERBB2-mutant NSCLC. Our therapeutic strategy—although extrapolated—reflects the evolving paradigm in precision oncology: the adaptation of robust systemic data to rare, understudied, yet clinically significant scenarios. Sincerely, Osama Elzaafarany, MD Department of Neuro-Oncology Moffitt Cancer Center Email address: [email protected] Declarations Ethics approval: Not applicable. Availability of data and materials: Not applicable. Competing interests: Not applicable. Funding: No funding was received for this work. Authors' contributions: OE collected the clinical data and drafted the manuscript. OE contributed to conceptual design and literature review. OE reviewed and approved the final manuscript. Acknowledgements: Not applicable. Consent to publish: The patient discussed in this case report provided written informed consent for the publication of her clinical details. References Goto, K., Goto, Y., Kubo, T., Ninomiya, K., Kim, S.-W., Planchard, D., Ahn, M.-J., Smit, E. F., de Langen, A. J., Pérol, M., Pons-Tostivint, E., Novello, S., Hayashi, H., Shimizu, J., Kim, D.-W., Kuo, C.-H., Yang, J. C.-H., Pereira, K., Cheng, F.-C., Taguchi, A., Cheng, Y., Feng, W., Tsuchihashi, Z., & Jänne, P. A. (2023). Trastuzumab Deruxtecan in Patients With HER2-Mutant Metastatic Non-Small-Cell Lung Cancer: Primary Results From the Randomized, Phase II DESTINY-Lung02 Trial. Journal of Clinical Oncology, 41(31), 4852-4863. https://doi.org/10.1200/JCO.23.01361 (https://doi.org/10.1200/JCO.23.01361) Pérez-García, J. M., Vaz Batista, M., Cortez, P., Ruiz-Borrego, M., Cejalvo, J. M., de la Haba-Rodriguez, J., Garrigós, L., Racca, F., Servitja, S., Blanch, S., Gion, M., Nave, M., Fernández-Abad, M., Martinez-Bueno, A., Llombart-Cussac, A., Sampayo-Cordero, M., Malfettone, A., Cortés, J., & Braga, S. (2023). Trastuzumab deruxtecan in patients with central nervous system involvement from HER2-positive breast cancer: The DEBBRAH trial. Neuro-Oncology, 25(1), 157-166. https://doi.org/10.1093/neuonc/noac144 (https://doi.org/10.1093/neuonc/noac144) Niikura, N., Yamanaka, T., Nomura, H., Shiraishi, K., Kusama, H., Yamamoto, M., Matsuura, K., Inoue, K., Takahara, S., Kita, S., Yamaguchi, M., Aruga, T., Shibata, N., Shimomura, A., Ozaki, Y., Sakai, S., Kiga, Y., Izutani, T., Shiosakai, K., & Tsurutani, J. (2023). Treatment with trastuzumab deruxtecan in patients with HER2-positive breast cancer and brain metastases and/or leptomeningeal disease (ROSET-BM). npj Breast Cancer, 9, Article 82. https://doi.org/10.1038/s41523-023-00584-5 (https://doi.org/10.1038/s41523-023-00584-5) Rogawski, D., Cao, T., Ma, Q., Roy-O'Reilly, M., Yao, L., Xu, N., & Nagpal, S. (2024). Durable responses to trastuzumab deruxtecan in patients with leptomeningeal metastases from breast cancer with variable HER2 expression. Journal of Neuro-Oncology, 170(1), 209-217. https://doi.org/10.1007/s11060-024-04788-y (https://doi.org/10.1007/s11060-024-04788-y) Fan, Y., Qin, J., Han, N., & Lu, H. (2022). HER2 exon 20 insertion mutations in lung adenocarcinoma with leptomeningeal metastasis: A case report and response to poziotinib. Annals of Palliative Medicine, 11(4), 1582-1588. http://dx.doi.org/10.21037/apm-21-213 (http://dx.doi.org/10.21037/apm-21-213) Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Published Journal Publication published 27 Jul, 2025 Read the published version in Cureus → 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-6925753","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":473263481,"identity":"5f77ae6b-4584-4082-8cd8-cca7bf11e8c7","order_by":0,"name":"Osama Elzaafarany","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0003-3842-9825","institution":"Moffitt Cancer Center","correspondingAuthor":true,"prefix":"","firstName":"Osama","middleName":"","lastName":"Elzaafarany","suffix":""}],"badges":[],"createdAt":"2025-06-18 20:17:23","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-6925753/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6925753/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.7759/cureus.88905","type":"published","date":"2025-07-28T00:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":87867267,"identity":"c0b0f323-e6f6-44b7-8ea3-938a93e18002","added_by":"auto","created_at":"2025-07-29 20:40:33","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":260813,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6925753/v1/ec407960-41e2-4707-bf58-b19ad09cb547.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eTargeted Therapy Decision in HER2 Exon 20–Mutant Non-Small Cell Lung Cancer with Leptomeningeal Disease: A Case-Based Perspective\u003c/p\u003e","fulltext":[{"header":"Main Text","content":"\u003cp\u003eDear Editor,\u003c/p\u003e\n\u003cp\u003eI am writing to present a rare and therapeutically complex case of leptomeningeal disease (LMD) secondary to HER2-mutated non-small cell lung cancer (NSCLC), characterized by both exon 20 insertion and gene amplification. The coexistence of these alterations, coupled with LMD, presents a clinical dilemma due to the absence of established therapeutic guidelines in this molecular and anatomic context.\u003c/p\u003e\n\u003cp\u003eOur patient is a 69-year-old female diagnosed with T4N2M1c adenocarcinoma of the right lung. She initially presented in early 2024 with respiratory symptoms and cervical adenopathy. Histopathologic analysis confirmed lung adenocarcinoma with PD-L1 expression \u0026lt;1%. Circulating tumor DNA analysis via Guardant360 revealed an HER2 exon 20 insertion along with amplification. She received first-line treatment with carboplatin, pemetrexed, and pembrolizumab, followed by maintenance pemetrexed and pembrolizumab. Additionally, stereotactic radiosurgery (SRS) was administered to multiple brain metastases, along with palliative radiation to osseous lesions.\u003c/p\u003e\n\u003cp\u003eIn April 2025, the patient presented with progressive headaches. MRI demonstrated new multifocal leptomeningeal enhancement, with stable parenchymal brain metastases. A subsequent lumbar puncture confirmed positive cerebrospinal fluid cytology, establishing the diagnosis of LMD. At the time of diagnosis, she remained in a good performance status, and she was not receiving corticosteroids or antiepileptic medications. This was a turning point in her care, as no approved therapies exist for HER2-mutant NSCLC with LMD.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGiven the lack of LMD-specific data for HER2-mutant NSCLC, we initiated treatment with trastuzumab deruxtecan (Enhertu). This decision was informed by data from the DESTINY-Lung02 trial [1], which demonstrated meaningful activity in ERBB2-mutant NSCLC, including exon 20 insertions. Importantly, patients with LMD were excluded from this study.\u003c/p\u003e\n\u003cp\u003eOur rationale was further supported by data from HER2-positive breast cancer, where Enhertu has demonstrated central nervous system (CNS) activity, including in patients with LMD. Specifically, the DEBRA trial and ROSET-BM study have reported responses to trastuzumab deruxtecan in this setting [2,3]. Additional retrospective reports support its CNS penetrance [4].\u003c/p\u003e\n\u003cp\u003eAlternative therapeutic options were considered. A case report by Fan et al. (2021) described the successful use of poziotinib in HER2 exon 20-mutated NSCLC with LMD [5]. Although poziotinib shows promise, it remains investigational in this context. Another novel agent, zongertinib, has shown preclinical efficacy and blood-brain barrier penetration in HER2 exon 20-altered NSCLC, though no clinical data in LMD currently exist.\u003c/p\u003e\n\u003cp\u003eIntrathecal trastuzumab was not pursued, as the mutation affects the intracellular domain of HER2, limiting the potential efficacy of extracellular-targeting monoclonal antibodies in this case.\u003c/p\u003e\n\u003cp\u003eIn summary, this case highlights the urgent need for clinical trials that include patients with LMD, especially within molecularly defined subtypes like ERBB2-mutant NSCLC. Our therapeutic strategy\u0026mdash;although extrapolated\u0026mdash;reflects the evolving paradigm in precision oncology: the adaptation of robust systemic data to rare, understudied, yet clinically significant scenarios.\u003c/p\u003e\n\u003cp\u003eSincerely,\u003cbr\u003e\u0026nbsp;\u003cstrong\u003eOsama Elzaafarany, MD\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of Neuro-Oncology\u003c/p\u003e\n\u003cp\u003eMoffitt Cancer Center\u003c/p\u003e\n\u003cp\u003eEmail address: [email protected]\u003c/p\u003e"},{"header":"Declarations","content":"\u003cul type=\"disc\"\u003e\n \u003cli\u003e\u003cstrong\u003eEthics approval:\u003c/strong\u003e Not applicable.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eAvailability of data and materials:\u003c/strong\u003e Not applicable.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e Not applicable.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e No funding was received for this work.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eAuthors' contributions:\u003c/strong\u003e OE collected the clinical data and drafted the manuscript. OE contributed to conceptual design and literature review. OE reviewed and approved the final manuscript.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e Not applicable.\u0026nbsp;\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eConsent to publish: The patient discussed in this case report provided written informed consent for the publication of her clinical details.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGoto, K., Goto, Y., Kubo, T., Ninomiya, K., Kim, S.-W., Planchard, D., Ahn, M.-J., Smit, E. F., de Langen, A. J., P\u0026eacute;rol, M., Pons-Tostivint, E., Novello, S., Hayashi, H., Shimizu, J., Kim, D.-W., Kuo, C.-H., Yang, J. C.-H., Pereira, K., Cheng, F.-C., Taguchi, A., Cheng, Y., Feng, W., Tsuchihashi, Z., \u0026amp; J\u0026auml;nne, P. A. (2023). Trastuzumab Deruxtecan in Patients With HER2-Mutant Metastatic Non-Small-Cell Lung Cancer: Primary Results From the Randomized, Phase II DESTINY-Lung02 Trial. Journal of Clinical Oncology, 41(31), 4852-4863. https://doi.org/10.1200/JCO.23.01361 (https://doi.org/10.1200/JCO.23.01361)\u003c/li\u003e\n\u003cli\u003eP\u0026eacute;rez-Garc\u0026iacute;a, J. M., Vaz Batista, M., Cortez, P., Ruiz-Borrego, M., Cejalvo, J. M., de la Haba-Rodriguez, J., Garrig\u0026oacute;s, L., Racca, F., Servitja, S., Blanch, S., Gion, M., Nave, M., Fern\u0026aacute;ndez-Abad, M., Martinez-Bueno, A., Llombart-Cussac, A., Sampayo-Cordero, M., Malfettone, A., Cort\u0026eacute;s, J., \u0026amp; Braga, S. (2023). Trastuzumab deruxtecan in patients with central nervous system involvement from HER2-positive breast cancer: The DEBBRAH trial. Neuro-Oncology, 25(1), 157-166. https://doi.org/10.1093/neuonc/noac144 (https://doi.org/10.1093/neuonc/noac144)\u003c/li\u003e\n\u003cli\u003eNiikura, N., Yamanaka, T., Nomura, H., Shiraishi, K., Kusama, H., Yamamoto, M., Matsuura, K., Inoue, K., Takahara, S., Kita, S., Yamaguchi, M., Aruga, T., Shibata, N., Shimomura, A., Ozaki, Y., Sakai, S., Kiga, Y., Izutani, T., Shiosakai, K., \u0026amp; Tsurutani, J. (2023). Treatment with trastuzumab deruxtecan in patients with HER2-positive breast cancer and brain metastases and/or leptomeningeal disease (ROSET-BM). npj Breast Cancer, 9, Article 82. https://doi.org/10.1038/s41523-023-00584-5 (https://doi.org/10.1038/s41523-023-00584-5)\u003c/li\u003e\n\u003cli\u003eRogawski, D., Cao, T., Ma, Q., Roy-O\u0026apos;Reilly, M., Yao, L., Xu, N., \u0026amp; Nagpal, S. (2024). Durable responses to trastuzumab deruxtecan in patients with leptomeningeal metastases from breast cancer with variable HER2 expression. Journal of Neuro-Oncology, 170(1), 209-217. https://doi.org/10.1007/s11060-024-04788-y (https://doi.org/10.1007/s11060-024-04788-y)\u003c/li\u003e\n\u003cli\u003eFan, Y., Qin, J., Han, N., \u0026amp; Lu, H. (2022). HER2 exon 20 insertion mutations in lung adenocarcinoma with leptomeningeal metastasis: A case report and response to poziotinib. Annals of Palliative Medicine, 11(4), 1582-1588. http://dx.doi.org/10.21037/apm-21-213 (http://dx.doi.org/10.21037/apm-21-213)\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"Moffitt Cancer Center","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"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":"non-small cell lung cancer, leptomeningeal disease, HER2 mutation, exon 20 insertion, CNS metastases, precision oncology","lastPublishedDoi":"10.21203/rs.3.rs-6925753/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6925753/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eWe report a rare and clinically challenging case of leptomeningeal disease (LMD) secondary to HER2-mutated non-small cell lung cancer (NSCLC), marked by both exon 20 insertion and gene amplification. In the absence of LMD-specific therapeutic guidelines for HER2-driven NSCLC, we initiated treatment with trastuzumab deruxtecan (Enhertu), based on extrapolated evidence from clinical trials in systemic NSCLC and HER2-positive breast cancer with central nervous system involvement. Our patient, a 69-year-old woman with stable performance status, developed LMD following prior systemic therapy and local CNS treatments. MRI and CSF cytology confirmed the diagnosis. Given the lack of approved therapies for HER2-mutant NSCLC with LMD, our treatment strategy was informed by data from DESTINY-Lung02, the DEBRA and ROSET-BM studies, and supporting literature on CNS activity of Enhertu. Other options such as poziotinib and zongertinib were considered but not pursued. This case underscores the urgent need for inclusive clinical trials addressing CNS complications in molecularly defined NSCLC and demonstrates the real-world application of precision oncology beyond trial populations.\u003c/p\u003e","manuscriptTitle":"Targeted Therapy Decision in HER2 Exon 20–Mutant Non-Small Cell Lung Cancer with Leptomeningeal Disease: A Case-Based Perspective","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-27 07:30:31","doi":"10.21203/rs.3.rs-6925753/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":"249fc2b0-5c8f-44c0-858c-b0ccc5efa68b","owner":[],"postedDate":"June 27th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":50262246,"name":"Oncology"}],"tags":[],"updatedAt":"2025-07-29T20:40:25+00:00","versionOfRecord":{"articleIdentity":"rs-6925753","link":"https://doi.org/10.7759/cureus.88905","journal":{"identity":"cureus","isVorOnly":true,"title":"Cureus"},"publishedOn":"2025-07-28 00:00:00","publishedOnDateReadable":"July 28th, 2025"},"versionCreatedAt":"2025-06-27 07:30:31","video":"","vorDoi":"10.7759/cureus.88905","vorDoiUrl":"https://doi.org/10.7759/cureus.88905","workflowStages":[]},"version":"v1","identity":"rs-6925753","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6925753","identity":"rs-6925753","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}