Exceptional response to pembrolizumab in HER2-positive gallbladder carcinoma with high tumor mutational burden

Exceptional response to pembrolizumab in HER2-positive gallbladder carcinoma with high tumor mutational burden | 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 Exceptional response to pembrolizumab in HER2-positive gallbladder carcinoma with high tumor mutational burden Akinori Sasaki, Satoru Nakajima, Yasuaki Motomura This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4855823/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 10 Sep, 2024 Read the published version in Journal of Gastrointestinal Cancer → Version 1 posted 7 You are reading this latest preprint version Abstract Patients with advanced cholangiocarcinoma, including gallbladder cancer, typically have a poor prognosis owing to limited effective chemotherapy options. The field of genotype-directed therapy in patients with cholangiocarcinoma is advancing. However, limited clinical data are currently available to evaluate the efficacy of molecularly targeted therapy. Herein, we report the case of a 67-year-old man diagnosed with human epidermal growth factor receptor-2 (HER2)-positive and tumor mutation burden-high (TMB-H) cholangiocarcinoma. The HER2-positive and TMB-H characteristics were identified using comprehensive genomic profiling after showing resistance to gemcitabine and S-1 therapy. In the absence of clinical trials for HER2-positive cancer at that time, the patient was treated with pembrolizumab, which is used for TMB-H solid tumors in clinical practice. After receiving pembrolizumab, the patient experienced significant shrinkage in the primary tumor and liver metastases. Thus far, the patient has been receiving pembrolizumab for approximately 10 months. To our knowledge, this is the first report showing the efficacy of pembrolizumab in a patient with cholangiocarcinoma harboring both HER2-positive and TMB-H. cholangiocarcinoma gallbladder carcinoma tumor mutational burden-high HER2-positive pembrolizumab Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Cholangiocarcinoma is a malignant tumor classified into intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder carcinoma (GC), and ampullary carcinoma based on the site of origin. Owing to the aggressive growth of cholangiocarcinoma, the cancer often metastasizes to the liver and abdominal lymph nodes, invades major blood vessels, and extends intrahepatically by the time the disease is diagnosed. Therefore, approximately 80% of cholangiocarcinoma cases are considered inoperable [1]. The current standard of care for patients with advanced cholangiocarcinoma is systemic chemotherapy. Recently, the addition of durvalumab, an immune checkpoint inhibitor (ICI), to conventional gemcitabine and cisplatin therapy has shown benefits in overall survival and has been approved [2]. However, the prognosis for advanced cholangiocarcinoma remains poor because no certain chemotherapy regimen consistently extends survival beyond 8 to 15 months when administered alone. In recent years, multigene panel-based comprehensive genomic profiling (CGP) has been widely used to treat patients with malignant solid tumors. CGP enables the identification of patients with targetable alterations who may benefit from targeted therapies. In malignancies with limited chemotherapy regimens, such as cholangiocarcinoma, CGP can be performed early, after the initiation of primary treatment. Approximately 30% of patients with cholangiocarcinoma have targetable mutations in genes such as FGFR2 and IDH1 , as determined by CGP [3, 4]. In addition, several treatments, such as ICIs for microsatellite instability-high and tumor mutation burden-high (TMB-H), can be used regardless of the cancer type [5, 6]. However, it is not currently known which treatment should be selected when multiple genetic alterations with therapeutic indications are detected. Herein, we report the case of a patient with both TMB-H and human epidermal growth factor receptor-2 (HER2)-positive GC who showed an exceptional response to pembrolizumab. The patient provided informed consent for the presentation of anonymized clinical information. Case Report A 67-year-old male patient presenting with fatigue and intermittent epigastric pain for several weeks was referred to Tokyo Bay Urayasu Ichikawa Medical Center. The patient had a medical history of hypertension and dyslipidemia. Laboratory investigations showed elevated levels of liver enzymes. Abdominal computed tomography (CT) revealed GC with multiple lymph node and liver metastases (Fig. 1 ). An endoscopic ultrasound-guided fine-needle biopsy of the primary lesion was performed to collect tissue specimens (Fig. 2 ). Histopathological analysis of the tumor biopsy specimen revealed adenocarcinoma. The patient was diagnosed with stage IV GC (clinical stage T3N1M1 according to the TNM classification, 8th edition). The patient received first-line chemotherapy comprising a reduced dose of gemcitabine (800 mg/m 2 ) and S-1 (60 mg daily) because he refused treatment with cisplatin due to the adverse effects of nausea and vomiting. However, after two cycles of the above chemotherapy, the patient was admitted to the hospital because of fever and stomachache. Laboratory tests showed elevated C-reactive protein (CRP) (11.41 mg/dL) and liver enzyme levels (AST, 83 IU/L; ALT, 116 IU/L; total bilirubin, 2.4 mg/dL). Abdominal CT showed intrahepatic biliary tract obstruction due to GC progression (Fig. 3 ). The patient was diagnosed with acute segmental cholangitis and administered antibiotics (4/0.5 g of piperacillin-tazobactam four times daily). Subsequently, the patient underwent endoscopic retrograde cholangiopancreatography (ERCP) for biliary drainage. A plastic 7Fr-7 cm stent was placed into the bile duct stenosis site using ERCP. The fever decreased, and the patient’s general condition gradually improved after the drainage procedure. In addition, laboratory data, including CRP and liver enzyme levels, normalized (CRP, 1.45 mg/dL; AST, 26 IU/L; ALT, 49 IU/L; total bilirubin, 0.86 mg/dL). The patient was considered refractory to GC treatment. Subsequently, multigene panel-based CGP was performed on tumor tissues from the primary gallbladder carcinoma using FoundationOne CDx (Foundation Medicine, Cambridge, MA, USA). HER2 amplification and TMB-H were identified as actionable genomic alterations. Additionally, alterations in CDK4 , ERBB3 , ERBB4 , and TP53 were detected. Based on the results of the multigene panel-based CGP, a therapeutic strategy was developed by an intra-institutional molecular tumor board called an expert panel. At that time, there were no clinical trials of anti-HER2 drugs for HER2-positive solid tumors; therefore, the patient was treated with pembrolizumab, an ICI, to target the TMB-H characteristic. The patient was administered pembrolizumab (200 mg, every 3 weeks) with no significant adverse events. One to two weeks after treatment initiation, there was a gradual improvement in the patient’s general condition, with an associated reduction in the severity of fatigue. A CT scan on day 56 showed significant shrinkage in the primary and metastatic lesions (Fig. 4 ). Furthermore, the patient showed markedly decreased serum carcinoembryonic antigen and carbohydrate antigen 19 − 9 levels. As of January 2024, the patient has been receiving pembrolizumab without tumor progression. Discussion Herein, we present the case of a patient with TMB-H and HER2-positive GC treated with pembrolizumab. Although pembrolizumab, an ICI, has demonstrated efficacy in TMB-H GC, there have been no reported cases of significant efficacy against GC tumors that are also HER2-positive. To the best of our knowledge, this is the first report of an exceptional response to pembrolizumab treatment in a patient with GC harboring both HER2-positive and TMB-H. Durvalumab, an ICI, was recently approved for cholangiocarcinoma [2]. Thus, a combination of gemcitabine, cisplatin, and durvalumab can be administered as first-line treatment for patients with unresectable cholangiocarcinoma. Additionally, a randomized phase III trial, KEYNOTE-966, demonstrated that adding pembrolizumab to standard treatments provided a survival benefit compared to standard treatments alone [7]. Based on these results, cytotoxic chemotherapy with pembrolizumab is expected to be approved as a first-line treatment for patients with cholangiocarcinoma in the near future. However, chemotherapy regimens after first-line treatment failure are limited, and the prognosis of unresectable cholangiocarcinoma ranges from several to 15 months. Therefore, CGP is recommended as early as possible for patients with cancer with limited or no standard treatment, such as those with cholangiocarcinoma. FoundationOne CDx is mainly used for tissue-based CGP in Japan, and more than 300 cancer-related genes can be analyzed. A CGP study of all cancer types found actionable molecular alterations in approximately 10% of cases. However, actionable molecular alterations have been detected in approximately 30% of cholangiocarcinoma cases [8]. Particularly, FGFR2 mutations are found in 9–16% of cholangiocarcinomas, and pemigatinib, an FGFR2 inhibitor, has shown efficacy and has been approved for clinical use [3, 9]. In addition to FGFR2 mutations, it has been reported that actionable molecular alterations such as BRAF V600E as well as IDH1/2 and HER2 mutations can be detected. The total number of non-inherited mutations in cancer cells is known as TMB. Previous studies confirmed that the higher the TMB, the more likely a patient is to benefit from ICI therapy [10]. A phase II trial was conducted to evaluate the efficacy of pembrolizumab in patients with solid tumors and TMB-H, whose score is 10 mut/Mb or higher [6]. The objective response rate (ORR) to pembrolizumab was 30%, and the median progression-free survival (PFS) was 2.1 months in patients with TMB-H in this study. Twenty-two patients with biliary GC were included in the study and showed better results than the overall population, with an ORR of 40% and a PFS of 4.2 months. The percentage of cases with TMB-H among all cancer types has been reported to be approximately 13%. However, the frequency of TMB-H varies by cancer type; the highest mutational loads are found in melanomas, non-small cell lung carcinomas, and other squamous carcinomas [11]. In contrast, the TMB generally tends to be low in cholangiocarcinoma, and it has been found that only 3 ~ 4% of biliary tract cancers are TMB-H [12]. It has also been reported that the therapeutic response to ICIs differs depending on the cancer type, even if the TMB values are the same. Merkel-cell carcinoma and renal cell cancer have a response to treatment that is better than would be predicted by the TMB score, whereas colorectal cancer with mismatch repair proficiency and gastric cancer have a response that is worse than would be predicted [13]. The HER2 protein is involved in cell proliferation and differentiation. The proliferation of the HER2 gene, which encodes the HER2 protein, is called HER2 amplification. HER2 proliferation is mainly observed in gastric and breast cancers, and anti-HER2 drugs have been used in practice to treat these cancers. Amplification or overexpression of HER2 is often observed in cholangiocarcinoma, especially GC, where it has been reported in 19% of the cases [14]. A phase II trial, MyPathway, was conducted for HER2-positive cholangiocarcinoma. In this study, patients were treated with a combination of trastuzumab and panitumumab, achieving an ORR of 23% and a PFS of 4.0 months [15]. Additionally, the HERB study was conducted in patients with HER2-positive cholangiocarcinoma treated with trastuzumab deruxtecan, an antibody-drug conjugate. In this study, trastuzumab deruxtecan showed an ORR of 36.4% and a PFS of 4.4 months. However, anti-HER2 drugs for HER2-positive cholangiocarcinoma have not been approved by insurance, and their use is still limited to the clinical trials described above. In contrast, it remains unknown whether ICIs are against HER2-positive solid tumors. Although the data are from breast cancer patients, it has been found that tumor-infiltrating lymphocytes (TILs) and PD-L1 expression tend to be increased in HER2-positive breast cancer [16, 17]. TIL count and PD-L1 expression have previously been found to be positively correlated with treatment response in patients with cancer treated with ICIs. Several trials have evaluated the efficacy of ICIs against HER2-positive solid tumors. However, among 26 patients with HER2-positive breast cancer who were treated with avelumab in the JAVELIN Solid Tumor trial, not a single patient showed an objective response [18]. Moreover, in a clinical trial in which patients with HER2-positive non-small cell lung cancer were treated with ICIs alone, the median PFS was 2.0 months, and the ORR was 0% [19]. This study included patients with PD-L1 TPS ≥ 50% and a TMB score of ≥ 10. Thus far, there are no reports of response to treatment with ICIs alone in patients with HER2-positive solid tumors, including cholangiocarcinoma. However, combination therapy with ICIs and anti-HER2 antibodies is expected to be effective in patients with HER2-positive solid tumors. It has been previously reported that treatment with anti-HER2 antibodies such as trastuzumab promotes PD-L1 expression in breast cancer cells. Based on these results, several trials have been conducted to combine anti-HER2 antibodies with ICIs for the treatment of HER2-positive breast cancer. For example, a phase 1b/2 trial was performed to evaluate the efficacy of pembrolizumab plus trastuzumab in patients with pretreated HER2-positive breast cancer [20]. In this study, combination therapy showed an ORR of 15% and demonstrated efficacy in patients who were refractory to trastuzumab. In addition, a phase Ⅲ trial, KEYNOTE-811, confirmed the efficacy of pembrolizumab combined with trastuzumab, a first-line cytotoxic anticancer agent, in patients with HER2-positive gastric cancer [21]. In this trial, the addition of pembrolizumab to standard therapy improved the ORR and yielded a duration of response of over 6 months; the United States Food and Drug Administration approved this regimen for first-line treatment. A case report also described a patient with HER2-positive cholangiocarcinoma who responded to the addition of pembrolizumab after anti-HER2 antibody failure [22]. We look forward to future trials showing the efficacy of anti-HER2 antibodies in combination with ICIs in HER2-positive cholangiocarcinomas or HER2-positive solid tumors. Here, we present the case of a patient with TMB-H and HER2 amplification-positive GC treated with pembrolizumab. Unfortunately, our patient could not be enrolled in a clinical trial of anti-HER2 antibody drugs and was only treated with an ICI. However, the patient responded remarkably to and continued treatment with pembrolizumab alone. If the patient stops responding to pembrolizumab, we will consider enrolling him in clinical trials involving anti-HER2 antibodies. In the future, we hope that the combination of anti-HER2 antibodies and ICIs be applied in clinical practice as first-line treatment in such patients. Declarations Conflict of interest: The authors declare no conflicts of interest regarding the publication of this article. Informed consent: Consent for publication of the case was provided by the patient Funding: Not applicable. Author Contribution SA wrote the main manuscript text and prepared all figures. All authors reviewed the manuscript. Acknowledgments: Not applicable. Availability of data and materials: Not applicable. References Goeppert B, Frauenschuh L, Zucknick M, et al (2013) Prognostic impact of tumour-infiltrating immune cells on biliary tract cancer. Br J Cancer 109(10):2665–2674. https://doi.org/10.1038/bjc.2013.610 Oh DY, He AR, Qin S, et al (2022) A phase 3 randomized, double-blind, placebo-controlled study of durvalumab in combination with gemcitabine plus cisplatin (GemCis) in patients (pts) with advanced biliary tract cancer (BTC): TOPAZ-1. J Clin Oncol 40(4):Suppl.378. https://doi.org/10.1200/JCO.2022.40.4_suppl.378 Abou-Alfa GK, Sahai V, Hollebecque A, et al (2020) Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. 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Cancer Discov 7(9):943–962. https://doi.org/10.1158/2159-8290.CD-17-0245 Javle M, Borad MJ, Azad NS, et al (2021) Pertuzumab and trastuzumab for HER2-positive, metastatic biliary tract cancer (MyPathway): a multicentre, open-label, phase 2a, multiple basket study. Lancet Oncol 22(9):1290–1300. https://doi.org/10.1016/S1470-2045(21)00336-3 Savas P, Salgado R, Denkert C, et al (2016) Clinical relevance of host immunity in breast cancer: from TILs to the clinic. Nat Rev Clin Oncol 13(4):228–241. https://doi.org/10.1038/nrclinonc.2015.215 Cimino-Mathews A, Thompson E, Taube JM, et al. (2016) PD-L1 (B7-H1) expression and the immune tumor microenvironment in primary and metastatic breast carcinomas. Hum Pathol 47(1):52–63. https://doi.org/10.1016/j.humpath.2015.09.003 Dirix LY, Takacs I, Jerusalem G, et al (2018) Avelumab, an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase 1b JAVELIN Solid Tumor study. Breast Cancer Res Treat 167(3):671–686. https://doi.org/10.1007/s10549-017-4537-5 DeMatteo R, Goldman DA, Lin ST, et al. Clinical outcomes of immune checkpoint inhibitors in HER2-amplified non-small cell lung cancers. J Clin Oncol. 2022;40(16):suppl.e21098. https://doi.org/10.1200/JCO.2022.40.16_suppl.e21098 Loi S, Giobbie-Hurder A, Gombos A, et al (2019) Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): a single-arm, multicentre, phase 1b–2 trial. Lancet Oncol 20(3):371–382. https://doi.org/10.1016/S1470-2045(18)30812-X Janjigian YY, Kawazoe A, Yañez P, et al (2021) The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer. Nature 600(7890):727–730. https://doi.org/10.1038/s41586-021-04161-3 Zhang JW, Yang X, Pan B, et al (2023) Clinical response to adding pyrotinib to pembrolizumab and lenvatinib for HER2-positive advanced intrahepatic cholangiocarcinoma: a case report. World J Surg Oncol 21(1):108. https://doi.org/10.1186/s12957-023-02983-1 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 10 Sep, 2024 Read the published version in Journal of Gastrointestinal Cancer → Version 1 posted Editorial decision: Revision requested 11 Aug, 2024 Reviews received at journal 06 Aug, 2024 Reviewers agreed at journal 06 Aug, 2024 Reviewers invited by journal 06 Aug, 2024 Editor assigned by journal 06 Aug, 2024 Submission checks completed at journal 04 Aug, 2024 First submitted to journal 04 Aug, 2024 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. 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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-4855823","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":338853827,"identity":"b757bf08-86da-4fc2-bfce-ff57d027dba7","order_by":0,"name":"Akinori 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1","display":"","copyAsset":false,"role":"figure","size":3177765,"visible":true,"origin":"","legend":"\u003cp\u003eAbdominal computed tomography (CT) images at diagnosis\u003c/p\u003e\n\u003cp\u003eAbdominal CT shows gallbladder carcinoma (a), liver metastasis (b), and lymph node metastasis (c)\u003c/p\u003e","description":"","filename":"HER2TMBHfigure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4855823/v1/494bce8892c5dabf5020f582.jpg"},{"id":64168066,"identity":"e29d4bd0-f4ca-4753-b8e0-4d29508690ba","added_by":"auto","created_at":"2024-09-09 09:56:50","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":3014686,"visible":true,"origin":"","legend":"\u003cp\u003eEndoscopic ultrasound (EUS) imaging at diagnosis\u003c/p\u003e\n\u003cp\u003eGallbladder carcinoma was detected using EUS (a), and a 19-gauge needle (EUS-guided) pierced the targeted lesion (b)\u003c/p\u003e","description":"","filename":"HER2TMBHfigure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4855823/v1/71cbf0515b21556d808baccb.jpg"},{"id":64168069,"identity":"52fd7f83-9d29-4fce-b6eb-6797e4f48a15","added_by":"auto","created_at":"2024-09-09 09:56:50","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":3410047,"visible":true,"origin":"","legend":"\u003cp\u003eAbdominal CT images on admission for cholangitis\u003c/p\u003e\n\u003cp\u003eAbdominal CT revealed obstruction of the common bile duct (a) and aggravation of the gallbladder carcinoma (b) and liver metastasis (c)\u003c/p\u003e","description":"","filename":"HER2TMBHfigure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4855823/v1/c167c9049ca4ae6ea86e959e.jpg"},{"id":64168481,"identity":"1b631281-4f8b-4e52-9fa3-9c2acee35c78","added_by":"auto","created_at":"2024-09-09 10:04:50","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":3344303,"visible":true,"origin":"","legend":"\u003cp\u003eAbdominal CT images after pembrolizumab\u003c/p\u003e\n\u003cp\u003eCT showed marked shrinkage of gallbladder carcinoma (a), liver metastasis (b), and lymph node metastasis (c)\u003c/p\u003e","description":"","filename":"HER2TMBHfigure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4855823/v1/3684f1ac4cb036cfc14472f7.jpg"},{"id":64619736,"identity":"39013ab8-2eae-43e2-9bbd-7259eb826a64","added_by":"auto","created_at":"2024-09-16 16:17:05","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":13195788,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4855823/v1/33716c96-f47c-4741-89c4-8a08179e20c6.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Exceptional response to pembrolizumab in HER2-positive gallbladder carcinoma with high tumor mutational burden","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCholangiocarcinoma is a malignant tumor classified into intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder carcinoma (GC), and ampullary carcinoma based on the site of origin. Owing to the aggressive growth of cholangiocarcinoma, the cancer often metastasizes to the liver and abdominal lymph nodes, invades major blood vessels, and extends intrahepatically by the time the disease is diagnosed. Therefore, approximately 80% of cholangiocarcinoma cases are considered inoperable [1]. The current standard of care for patients with advanced cholangiocarcinoma is systemic chemotherapy. Recently, the addition of durvalumab, an immune checkpoint inhibitor (ICI), to conventional gemcitabine and cisplatin therapy has shown benefits in overall survival and has been approved [2]. However, the prognosis for advanced cholangiocarcinoma remains poor because no certain chemotherapy regimen consistently extends survival beyond 8 to 15 months when administered alone.\u003c/p\u003e \u003cp\u003eIn recent years, multigene panel-based comprehensive genomic profiling (CGP) has been widely used to treat patients with malignant solid tumors. CGP enables the identification of patients with targetable alterations who may benefit from targeted therapies. In malignancies with limited chemotherapy regimens, such as cholangiocarcinoma, CGP can be performed early, after the initiation of primary treatment. Approximately 30% of patients with cholangiocarcinoma have targetable mutations in genes such as \u003cem\u003eFGFR2\u003c/em\u003e and \u003cem\u003eIDH1\u003c/em\u003e, as determined by CGP [3, 4]. In addition, several treatments, such as ICIs for microsatellite instability-high and tumor mutation burden-high (TMB-H), can be used regardless of the cancer type [5, 6]. However, it is not currently known which treatment should be selected when multiple genetic alterations with therapeutic indications are detected.\u003c/p\u003e \u003cp\u003eHerein, we report the case of a patient with both TMB-H and human epidermal growth factor receptor-2 (HER2)-positive GC who showed an exceptional response to pembrolizumab. The patient provided informed consent for the presentation of anonymized clinical information.\u003c/p\u003e"},{"header":"Case Report","content":"\u003cp\u003eA 67-year-old male patient presenting with fatigue and intermittent epigastric pain for several weeks was referred to Tokyo Bay Urayasu Ichikawa Medical Center. The patient had a medical history of hypertension and dyslipidemia. Laboratory investigations showed elevated levels of liver enzymes. Abdominal computed tomography (CT) revealed GC with multiple lymph node and liver metastases (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). An endoscopic ultrasound-guided fine-needle biopsy of the primary lesion was performed to collect tissue specimens (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Histopathological analysis of the tumor biopsy specimen revealed adenocarcinoma. The patient was diagnosed with stage IV GC (clinical stage T3N1M1 according to the TNM classification, 8th edition). The patient received first-line chemotherapy comprising a reduced dose of gemcitabine (800 mg/m\u003csup\u003e2\u003c/sup\u003e) and S-1 (60 mg daily) because he refused treatment with cisplatin due to the adverse effects of nausea and vomiting.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eHowever, after two cycles of the above chemotherapy, the patient was admitted to the hospital because of fever and stomachache. Laboratory tests showed elevated C-reactive protein (CRP) (11.41 mg/dL) and liver enzyme levels (AST, 83 IU/L; ALT, 116 IU/L; total bilirubin, 2.4 mg/dL). Abdominal CT showed intrahepatic biliary tract obstruction due to GC progression (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The patient was diagnosed with acute segmental cholangitis and administered antibiotics (4/0.5 g of piperacillin-tazobactam four times daily). Subsequently, the patient underwent endoscopic retrograde cholangiopancreatography (ERCP) for biliary drainage. A plastic 7Fr-7 cm stent was placed into the bile duct stenosis site using ERCP. The fever decreased, and the patient\u0026rsquo;s general condition gradually improved after the drainage procedure. In addition, laboratory data, including CRP and liver enzyme levels, normalized (CRP, 1.45 mg/dL; AST, 26 IU/L; ALT, 49 IU/L; total bilirubin, 0.86 mg/dL).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe patient was considered refractory to GC treatment. Subsequently, multigene panel-based CGP was performed on tumor tissues from the primary gallbladder carcinoma using FoundationOne CDx (Foundation Medicine, Cambridge, MA, USA). \u003cem\u003eHER2\u003c/em\u003e amplification and TMB-H were identified as actionable genomic alterations. Additionally, alterations in \u003cem\u003eCDK4\u003c/em\u003e, \u003cem\u003eERBB3\u003c/em\u003e, \u003cem\u003eERBB4\u003c/em\u003e, and \u003cem\u003eTP53\u003c/em\u003e were detected. Based on the results of the multigene panel-based CGP, a therapeutic strategy was developed by an intra-institutional molecular tumor board called an expert panel. At that time, there were no clinical trials of anti-HER2 drugs for HER2-positive solid tumors; therefore, the patient was treated with pembrolizumab, an ICI, to target the TMB-H characteristic.\u003c/p\u003e \u003cp\u003eThe patient was administered pembrolizumab (200 mg, every 3 weeks) with no significant adverse events. One to two weeks after treatment initiation, there was a gradual improvement in the patient\u0026rsquo;s general condition, with an associated reduction in the severity of fatigue. A CT scan on day 56 showed significant shrinkage in the primary and metastatic lesions (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Furthermore, the patient showed markedly decreased serum carcinoembryonic antigen and carbohydrate antigen 19\u0026thinsp;\u0026minus;\u0026thinsp;9 levels. As of January 2024, the patient has been receiving pembrolizumab without tumor progression.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eHerein, we present the case of a patient with TMB-H and HER2-positive GC treated with pembrolizumab. Although pembrolizumab, an ICI, has demonstrated efficacy in TMB-H GC, there have been no reported cases of significant efficacy against GC tumors that are also HER2-positive. To the best of our knowledge, this is the first report of an exceptional response to pembrolizumab treatment in a patient with GC harboring both HER2-positive and TMB-H.\u003c/p\u003e \u003cp\u003eDurvalumab, an ICI, was recently approved for cholangiocarcinoma [2]. Thus, a combination of gemcitabine, cisplatin, and durvalumab can be administered as first-line treatment for patients with unresectable cholangiocarcinoma. Additionally, a randomized phase III trial, KEYNOTE-966, demonstrated that adding pembrolizumab to standard treatments provided a survival benefit compared to standard treatments alone [7]. Based on these results, cytotoxic chemotherapy with pembrolizumab is expected to be approved as a first-line treatment for patients with cholangiocarcinoma in the near future. However, chemotherapy regimens after first-line treatment failure are limited, and the prognosis of unresectable cholangiocarcinoma ranges from several to 15 months.\u003c/p\u003e \u003cp\u003eTherefore, CGP is recommended as early as possible for patients with cancer with limited or no standard treatment, such as those with cholangiocarcinoma. FoundationOne CDx is mainly used for tissue-based CGP in Japan, and more than 300 cancer-related genes can be analyzed. A CGP study of all cancer types found actionable molecular alterations in approximately 10% of cases. However, actionable molecular alterations have been detected in approximately 30% of cholangiocarcinoma cases [8]. Particularly, \u003cem\u003eFGFR2\u003c/em\u003e mutations are found in 9\u0026ndash;16% of cholangiocarcinomas, and pemigatinib, an FGFR2 inhibitor, has shown efficacy and has been approved for clinical use [3, 9]. In addition to \u003cem\u003eFGFR2\u003c/em\u003e mutations, it has been reported that actionable molecular alterations such as \u003cem\u003eBRAF\u003c/em\u003eV600E as well as \u003cem\u003eIDH1/2\u003c/em\u003e and \u003cem\u003eHER2\u003c/em\u003e mutations can be detected.\u003c/p\u003e \u003cp\u003eThe total number of non-inherited mutations in cancer cells is known as TMB. Previous studies confirmed that the higher the TMB, the more likely a patient is to benefit from ICI therapy [10]. A phase II trial was conducted to evaluate the efficacy of pembrolizumab in patients with solid tumors and TMB-H, whose score is 10 mut/Mb or higher [6]. The objective response rate (ORR) to pembrolizumab was 30%, and the median progression-free survival (PFS) was 2.1 months in patients with TMB-H in this study. Twenty-two patients with biliary GC were included in the study and showed better results than the overall population, with an ORR of 40% and a PFS of 4.2 months. The percentage of cases with TMB-H among all cancer types has been reported to be approximately 13%. However, the frequency of TMB-H varies by cancer type; the highest mutational loads are found in melanomas, non-small cell lung carcinomas, and other squamous carcinomas [11]. In contrast, the TMB generally tends to be low in cholangiocarcinoma, and it has been found that only 3\u0026thinsp;~\u0026thinsp;4% of biliary tract cancers are TMB-H [12]. It has also been reported that the therapeutic response to ICIs differs depending on the cancer type, even if the TMB values are the same. Merkel-cell carcinoma and renal cell cancer have a response to treatment that is better than would be predicted by the TMB score, whereas colorectal cancer with mismatch repair proficiency and gastric cancer have a response that is worse than would be predicted [13].\u003c/p\u003e \u003cp\u003eThe HER2 protein is involved in cell proliferation and differentiation. The proliferation of the \u003cem\u003eHER2\u003c/em\u003e gene, which encodes the HER2 protein, is called \u003cem\u003eHER2\u003c/em\u003e amplification. \u003cem\u003eHER2\u003c/em\u003e proliferation is mainly observed in gastric and breast cancers, and anti-HER2 drugs have been used in practice to treat these cancers. Amplification or overexpression of HER2 is often observed in cholangiocarcinoma, especially GC, where it has been reported in 19% of the cases [14]. A phase II trial, MyPathway, was conducted for HER2-positive cholangiocarcinoma. In this study, patients were treated with a combination of trastuzumab and panitumumab, achieving an ORR of 23% and a PFS of 4.0 months [15]. Additionally, the HERB study was conducted in patients with HER2-positive cholangiocarcinoma treated with trastuzumab deruxtecan, an antibody-drug conjugate. In this study, trastuzumab deruxtecan showed an ORR of 36.4% and a PFS of 4.4 months. However, anti-HER2 drugs for HER2-positive cholangiocarcinoma have not been approved by insurance, and their use is still limited to the clinical trials described above.\u003c/p\u003e \u003cp\u003eIn contrast, it remains unknown whether ICIs are against HER2-positive solid tumors. Although the data are from breast cancer patients, it has been found that tumor-infiltrating lymphocytes (TILs) and PD-L1 expression tend to be increased in HER2-positive breast cancer [16, 17]. TIL count and PD-L1 expression have previously been found to be positively correlated with treatment response in patients with cancer treated with ICIs. Several trials have evaluated the efficacy of ICIs against HER2-positive solid tumors. However, among 26 patients with HER2-positive breast cancer who were treated with avelumab in the JAVELIN Solid Tumor trial, not a single patient showed an objective response [18]. Moreover, in a clinical trial in which patients with HER2-positive non-small cell lung cancer were treated with ICIs alone, the median PFS was 2.0 months, and the ORR was 0% [19]. This study included patients with PD-L1 TPS\u0026thinsp;\u0026ge;\u0026thinsp;50% and a TMB score of \u0026ge;\u0026thinsp;10. Thus far, there are no reports of response to treatment with ICIs alone in patients with HER2-positive solid tumors, including cholangiocarcinoma.\u003c/p\u003e \u003cp\u003eHowever, combination therapy with ICIs and anti-HER2 antibodies is expected to be effective in patients with HER2-positive solid tumors. It has been previously reported that treatment with anti-HER2 antibodies such as trastuzumab promotes PD-L1 expression in breast cancer cells. Based on these results, several trials have been conducted to combine anti-HER2 antibodies with ICIs for the treatment of HER2-positive breast cancer. For example, a phase 1b/2 trial was performed to evaluate the efficacy of pembrolizumab plus trastuzumab in patients with pretreated HER2-positive breast cancer [20]. In this study, combination therapy showed an ORR of 15% and demonstrated efficacy in patients who were refractory to trastuzumab. In addition, a phase Ⅲ trial, KEYNOTE-811, confirmed the efficacy of pembrolizumab combined with trastuzumab, a first-line cytotoxic anticancer agent, in patients with HER2-positive gastric cancer [21]. In this trial, the addition of pembrolizumab to standard therapy improved the ORR and yielded a duration of response of over 6 months; the United States Food and Drug Administration approved this regimen for first-line treatment. A case report also described a patient with HER2-positive cholangiocarcinoma who responded to the addition of pembrolizumab after anti-HER2 antibody failure [22]. We look forward to future trials showing the efficacy of anti-HER2 antibodies in combination with ICIs in HER2-positive cholangiocarcinomas or HER2-positive solid tumors.\u003c/p\u003e \u003cp\u003eHere, we present the case of a patient with TMB-H and HER2 amplification-positive GC treated with pembrolizumab. Unfortunately, our patient could not be enrolled in a clinical trial of anti-HER2 antibody drugs and was only treated with an ICI. However, the patient responded remarkably to and continued treatment with pembrolizumab alone. If the patient stops responding to pembrolizumab, we will consider enrolling him in clinical trials involving anti-HER2 antibodies. In the future, we hope that the combination of anti-HER2 antibodies and ICIs be applied in clinical practice as first-line treatment in such patients.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eConflict of interest: \u003c/h2\u003e\n\u003cp\u003eThe authors declare no conflicts of interest regarding the publication of this article.\u003c/p\u003e\n\u003ch2\u003eInformed consent:\u003c/h2\u003e\n\u003cp\u003eConsent for publication of the case was provided by the patient\u003c/p\u003e\n\u003ch2\u003eFunding:\u003c/h2\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eSA wrote the main manuscript text and prepared all figures. All authors reviewed the manuscript.\u003c/p\u003e\n\u003ch2\u003eAcknowledgments:\u003c/h2\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003ch2\u003eAvailability of data and materials:\u003c/h2\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGoeppert B, Frauenschuh L, Zucknick M, et al (2013) Prognostic impact of tumour-infiltrating immune cells on biliary tract cancer. Br J Cancer 109(10):2665\u0026ndash;2674. https://doi.org/10.1038/bjc.2013.610\u003c/li\u003e\n\u003cli\u003eOh DY, He AR, Qin S, et al (2022) A phase 3 randomized, double-blind, placebo-controlled study of durvalumab in combination with gemcitabine plus cisplatin (GemCis) in patients (pts) with advanced biliary tract cancer (BTC): TOPAZ-1. 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J Clin Oncol 38(1):1\u0026ndash;10. https://doi.org/10.1200/JCO.19.02105\u003c/li\u003e\n\u003cli\u003eMarabelle A, Fakih M, Lopez J, et al (2020) Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol 21(10):1353\u0026ndash;1365. https://doi.org/10.1016/S1470-2045(20)30445-9\u003c/li\u003e\n\u003cli\u003eKelley RK, Ueno M, Yoo C, et al (2023) Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 401(10391):1853\u0026ndash;1865. https://doi.org/10.1016/S0140-6736(23)00727-4\u003c/li\u003e\n\u003cli\u003eMody K, Jain P, El-Refai SM, et al. (2022) Clinical, genomic, and transcriptomic data profiling of biliary tract cancer reveals subtype-specific immune signatures. JCO Precis Oncol 6:e2100510. https://doi.org/10.1200/PO.21.00510\u003c/li\u003e\n\u003cli\u003eGraham RP, Barr Fritcher EG, Pestova E, et al (2014) Fibroblast growth factor receptor 2 translocations in intrahepatic cholangiocarcinoma. Hum Pathol 45(8):1630\u0026ndash;1638. https://doi.org/10.1016/j.humpath.2014.03.014\u003c/li\u003e\n\u003cli\u003eB\u0026uuml;ttner R, Longshore JW, L\u0026oacute;pez-R\u0026iacute;os F, et al (2019) Implementing TMB measurement in clinical practice: considerations on assay requirements. ESMO Open 4(1):e000442. https://doi.org/10.1136/esmoopen-2018-000442\u003c/li\u003e\n\u003cli\u003eChalmers ZR, Connelly CF, Fabrizio D, et al (2017) Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med 9(1):34. https://doi.org/10.1186/s13073-017-0424-2\u003c/li\u003e\n\u003cli\u003eMody K, Starr J, Saul M, et al (2019) Patterns and genomic correlates of PD-L1 expression in patients with biliary tract cancers. J Gastrointest Oncol 10(6):1099\u0026ndash;1109. https://doi.org/10.21037/jgo.2019.08.08\u003c/li\u003e\n\u003cli\u003eYarchoan M, Hopkins A, Jaffee EM (2017) Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med 377(25):2500\u0026ndash;2501. https://doi.org/10.1056/NEJMc1713444\u003c/li\u003e\n\u003cli\u003eValle JW, Lamarca A, Goyal L, et al (2017) New horizons for precision medicine in biliary tract cancers. Cancer Discov 7(9):943\u0026ndash;962. https://doi.org/10.1158/2159-8290.CD-17-0245\u003c/li\u003e\n\u003cli\u003eJavle M, Borad MJ, Azad NS, et al (2021) Pertuzumab and trastuzumab for HER2-positive, metastatic biliary tract cancer (MyPathway): a multicentre, open-label, phase 2a, multiple basket study. 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Clinical outcomes of immune checkpoint inhibitors in HER2-amplified non-small cell lung cancers. J Clin Oncol. 2022;40(16):suppl.e21098. https://doi.org/10.1200/JCO.2022.40.16_suppl.e21098\u003c/li\u003e\n\u003cli\u003eLoi S, Giobbie-Hurder A, Gombos A, et al (2019) Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): a single-arm, multicentre, phase 1b\u0026ndash;2 trial. Lancet Oncol 20(3):371\u0026ndash;382. https://doi.org/10.1016/S1470-2045(18)30812-X\u003c/li\u003e\n\u003cli\u003eJanjigian YY, Kawazoe A, Ya\u0026ntilde;ez P, et al (2021) The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer. Nature 600(7890):727\u0026ndash;730. https://doi.org/10.1038/s41586-021-04161-3\u003c/li\u003e\n\u003cli\u003eZhang JW, Yang X, Pan B, et al (2023) Clinical response to adding pyrotinib to pembrolizumab and lenvatinib for HER2-positive advanced intrahepatic cholangiocarcinoma: a case report. World J Surg Oncol 21(1):108. https://doi.org/10.1186/s12957-023-02983-1\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-gastrointestinal-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijgc","sideBox":"Learn more about [Journal of Gastrointestinal Cancer](https://www.springer.com/journal/12029)","snPcode":"12029","submissionUrl":"https://submission.nature.com/new-submission/12029/3","title":"Journal of Gastrointestinal Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"cholangiocarcinoma, gallbladder carcinoma, tumor mutational burden-high, HER2-positive, pembrolizumab","lastPublishedDoi":"10.21203/rs.3.rs-4855823/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4855823/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePatients with advanced cholangiocarcinoma, including gallbladder cancer, typically have a poor prognosis owing to limited effective chemotherapy options. The field of genotype-directed therapy in patients with cholangiocarcinoma is advancing. However, limited clinical data are currently available to evaluate the efficacy of molecularly targeted therapy. Herein, we report the case of a 67-year-old man diagnosed with human epidermal growth factor receptor-2 (HER2)-positive and tumor mutation burden-high (TMB-H) cholangiocarcinoma. The HER2-positive and TMB-H characteristics were identified using comprehensive genomic profiling after showing resistance to gemcitabine and S-1 therapy. In the absence of clinical trials for HER2-positive cancer at that time, the patient was treated with pembrolizumab, which is used for TMB-H solid tumors in clinical practice. After receiving pembrolizumab, the patient experienced significant shrinkage in the primary tumor and liver metastases. Thus far, the patient has been receiving pembrolizumab for approximately 10 months. To our knowledge, this is the first report showing the efficacy of pembrolizumab in a patient with cholangiocarcinoma harboring both HER2-positive and TMB-H.\u003c/p\u003e","manuscriptTitle":"Exceptional response to pembrolizumab in HER2-positive gallbladder carcinoma with high tumor mutational burden","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-09-09 09:48:45","doi":"10.21203/rs.3.rs-4855823/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-08-12T01:15:55+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-06T15:56:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"4573135920938180849636374651032855598","date":"2024-08-06T15:50:38+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-08-06T14:19:09+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-08-06T14:16:25+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-08-05T03:59:59+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Gastrointestinal Cancer","date":"2024-08-04T07:38:34+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-gastrointestinal-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijgc","sideBox":"Learn more about [Journal of Gastrointestinal Cancer](https://www.springer.com/journal/12029)","snPcode":"12029","submissionUrl":"https://submission.nature.com/new-submission/12029/3","title":"Journal of Gastrointestinal Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"64f9c93b-824b-4dc2-be0d-42fadc20cf52","owner":[],"postedDate":"September 9th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-09-16T16:11:03+00:00","versionOfRecord":{"articleIdentity":"rs-4855823","link":"https://doi.org/10.1007/s12029-024-01112-9","journal":{"identity":"journal-of-gastrointestinal-cancer","isVorOnly":false,"title":"Journal of Gastrointestinal Cancer"},"publishedOn":"2024-09-10 15:57:30","publishedOnDateReadable":"September 10th, 2024"},"versionCreatedAt":"2024-09-09 09:48:45","video":"","vorDoi":"10.1007/s12029-024-01112-9","vorDoiUrl":"https://doi.org/10.1007/s12029-024-01112-9","workflowStages":[]},"version":"v1","identity":"rs-4855823","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4855823","identity":"rs-4855823","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}