HER2 status based on breast cancer guidelines as a useful prognostic marker of T2 gallbladder cancer

Published:November 01, 2022DOI:



      T2 gallbladder cancer (GBC) is the only stage showing a survival benefit after complete surgical resection, but recurrence rates remain high. Although human epidermal growth factor receptor 2 (HER2) has emerged as a therapeutic target, its role in T2 GBC remains unclear. This study investigated the status and prognostic impact of HER2 expression on T2 GBC.

      Materials and methods

      HER2 expression and amplification were detected by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), respectively, in 90 patients with T2 GBC who underwent radical cholecystectomy. We evaluated HER2 status according to the breast and gastric cancer guidelines and analyzed the effect of relevant prognostic factors on survival.


      HER2 positive status was observed in 11.11% (10/90) and 8.89% (8/90) of cases based on gastric and breast cancer guidelines, respectively. Poor differentiation and a higher level of perineural invasion were independent prognostic factors of disease-free survival (DFS). Old age, male sex, presence of lymph node metastasis, poor differentiation, high levels of perineural invasion, and HER2 positivity based on breast cancer guidelines were identified as independent prognostic factors of overall survival (OS). Patients with HER2-positive T2 GBC according to breast cancer guidelines had worse OS.


      HER2 positivity based on breast- but not gastric-cancer guidelines was associated with poorer survival. These results provide a criterion for the evaluation of HER2 and a rationale for therapeutic strategies targeting HER2 in T2 GBC.


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        • World cancer research fund international
        Worldwide cancer data, Gallbladder cancer statistics.
        • Kang M.J.
        • Yun E.H.
        • Jun K.W.
        • et al.
        Incidence, mortality and survival of gallbladder, extrahepatic bile duct, and pancreatic cancer using Korea central cancer registry database: 1999-2019.
        Ann Hepatobiliary Pancreat Surg. 2022; 26 (Epub 2022 Jul 29): 220-228
        • Park J.S.
        • Yoon D.S.
        • Kim K.S.
        • et al.
        Actual recurrence patterns and risk factors influencing recurrence after curative resection with stage II gallbladder carcinoma.
        J Gastrointest Surg. 2007; 11: 631-637
        • Kim W.S.
        • Choi D.W.
        • You D.D.
        • et al.
        Risk factors influencing recurrence, patterns of recurrence, and the efficacy of adjuvant therapy after radical resection for gallbladder carcinoma.
        J Gastrointest Surg. 2010; 14: 679-687
        • Kim T.G.
        Patterns of initial failure after resection for gallbladder cancer: implications for adjuvant radiotherapy.
        Radiat Oncol J. 2017; 35: 359-367
        • Kim T.H.
        • Woo S.M.
        • Lee W.J.
        • et al.
        Benefit of adjuvant chemoradiotherapy in resected gallbladder carcinoma.
        Sci Rep. 2019; 911770
        • Chan E.
        • Berlin J.
        Biliary tract cancers: understudied and poorly understood.
        J Clin Oncol. 2015; 33: 1845-1848
        • McNamara M.G.
        • Metran-Nascente C.
        • Knox J.J.
        State-of –the art in the management of locally advanced and metastatic gallbladder cancer.
        Curr Opin Oncol. 2013; 25: 425-431
        • Akiyama T.
        • Sudo C.
        • Ogawa H.
        • et al.
        The production of human c-erbB- gene: a 185-kilodalton glycoprotein with tyrosine kinase activity.
        Science. 1986; 232: 1644-1646
        • Slamon D.
        • Eiermann W.
        • Robert N.
        • et al.
        Adjuvant trastuzumab in HER2-positive breast cancer.
        N Engl J Med. 2011; 365: 1273-1283
        • Bang Y.J.
        • Van Cutsem E.
        • Feyereislova A.
        • et al.
        Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial.
        Lancet. 2010; 376: 687-697
        • El-Deiry W.S.
        • Vijayvergia N.
        • Xiu J.
        • et al.
        Molecular profiling of 6,892 colorectal cancer samples suggests different possible treatment options specific to metastatic sites.
        Cancer Biol Ther. 2015; 16: 1726-1737
        • Yochida H.
        • Shimada K.
        • Kosuge T.
        • et al.
        A significant subgroup of resectable bladder cancer patients has an HER2 positive status.
        Virchows Arch. 2016; 468: 431-439
        • Hryciuk B.
        • Peksa R.
        • Bienkowski B.
        • et al.
        Expression of female sex hormone receptors, connective tissue growth factors and HER 2 in gallbladder cancer.
        Sci Rep. 2020; 10: 1871
        • Nakazawa K.
        • Dobashi Y.
        • Suzuki S.
        • et al.
        Amplification and overexpression of c-erbB-2, epithermal growth factor receptor, and c-met in biliary tract cancer.
        J Pathol. 2005; 206: 356-365
        • Harder J.
        • Waiz O.
        • Otto F.
        • et al.
        EGFR and HER2 expression in advanced biliary tract cancer.
        World J Gastroenterol. 2009; 15: 4511-4517
        • Roa I.
        • de Toro G.
        • Schalper K.
        • et al.
        Overexpresion of HER2/neu Gene: a new therapeutic possibility for patients with advanced gallbladder cancer.
        Gastrointest Cancer Res. 2014; 7: 42-48
        • Kumari N.
        • Kapoor V.K.
        • Krishnani N.
        • et al.
        Role of C-erbB2 expression in gallbladder cancer.
        Indian J Pathol Microbiol. 2012; 55: 75-79
        • Singh A.
        • Mishra P.K.
        • Saluja S.S.
        • et al.
        Prognostic significance of HER-2 and p53 expression in gallbladder carcinoma in North Indian patients.
        Oncology. 2016; 91: 354-360
        • Pujani M.
        • Makker I.
        • Makker A.
        • et al.
        Expression of human epidermal growth factor receptor (Her 2/neu) and proliferative marker Ki-67: association with clinicopathological parameters in gallbladder carcinoma.
        Asian Pac J Cancer Prev APJCP. 2016; 17: 3903-3909
        • Chen L.
        • Xu Lei
        • Shen L.
        • et al.
        Her2 positivity is affected by the papillary structure and has a bidirectional prognostic value for gallbladder carcinoma.
        Front Genet. 2022; 13831318
        • Bartley A.N.
        • Washington M.K.
        • Ventura C.B.
        • et al.
        HER2 testing and clinical decision making in gastroesophageal adenocarcinoma: guideline from the college of American pathologists, American society for clinical pathology, and American society of clinical Oncology.
        Arch Pathol Lab Med. 2016; 140: 1345-1363
        • Wolff A.C.
        • Hammond M.E.H.
        • Allison K.H.
        • et al.
        Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline focused update.
        J Clin Oncol. 2018; 36: 2105-2122
        • Dutta U.
        Gallbladder cancer: can newer insights improve the outcome?.
        J Gastroenterol Hepatol. 2012; 27: 642-653
        • Valle J.W.
        • Furuse J.
        • Jitlal M.
        • et al.
        Cisplatin and gemcitabine for advanced biliary tract cancer: a meta-analysis of two randomised trials.
        Ann Oncol. 2014; 25: 391-398
        • Rizzo A.
        • Brandi G.
        First-line chemotherapy in advanced biliary tract cancer ten years after the ABC-02 trial: "and yet it moves.
        Cancer Treat Res Commun. 2021; 27100335
        • Kang H.
        • Choi Y.S.
        • Shu S.
        • et al.
        Prognostic significance of tumor location in T2 Gablladder cancer: a systematic review and meta-analysis.
        J Clin Med. 2021; 10: 3317
        • Hong E.K.
        • Kim K.K.
        • Lee J.N.
        • et al.
        Surgical outcome and prognostic factors in patients with gallbladder carcinoma.
        KJHBPS. 2014; 18: 129-137
        • Jung W.
        • Jang J.Y.
        • Kang M.J.
        • et al.
        Effect of surgical methods and tumor location on survival and recurrence patterns after curative resection in patients with T2 gallbladder cancer.
        Gut Liver. 2016; 10: 140-146
        • Kim D.H.
        • Kim S.H.
        • Choi G.H.
        • et al.
        Role of cholecystectomy and lymph node dissection in patients with T2 gallbladder cancer.
        World J Surg. 2013; 37: 2635-2640
        • chijiiwa K.
        • Nakano K.
        • Ueda J.
        • et al.
        Surgical treatment of patients with T2 gallbladder carcinoma invading the subserosal layer.
        J Am Coll Surg. 2001; 192: 600-607
        • Rakha E.A.
        • Starczynski J.
        • Lee A.H.
        • al er
        The updated ASCO/CAP guideline recommendations for HER2 testing in the management of invasive breast cancer: a critical review of their implications for routine practice.
        Histopathology. 2014; 64: 609-615
        • Hofmann M.
        • Stoss O.
        • Shi D.
        • al er
        Assessment of a HER2 scoring system for gastric cancer: results from a validation study.
        Histopathology. 2008; 52: 797-805
        • Rüschoff J.
        • Hanna W.
        • Bilous M.
        • et al.
        HER2 testing in gastric cancer: a practical approach.
        Mod Pathol. 2012; 25: 637-650
        • Stenzinger a
        • von Winterfeld M.
        • Aulmann S.
        • et al.
        Quantitative analysis of diagnostic guidelines for HER2 status assessment.
        J Mol Diagn. 2012; 14: 199-205
        • Hainsworth J.D.
        • Meric-Bernstam F.
        • Swanton C.
        • et al.
        Targeted therapy for advanced solid tumors on the basis of molecular profiles: results from MyPathway, an open- label, phase IIa multiple basket study.
        J Clin Oncol. 2018; 36: 536-542
        • Hyman D.M.
        • Piha-Paul S.A.
        • Won H.
        • et al.
        HER kinase inhibition in patients with HER2- and HER3-mutant cancers.
        Nature. 2018; 554: 189-194
        • Massa A.
        • Varamo C.
        • Vita F.
        • et al.
        Evolution of the experimental models of cholangiocarcinoma.
        Cancers. 2020; 12: 2308
        • Cai W.
        • Yuan Y.
        • Ge W.
        • et al.
        EGFR target therapy combined with Gemox for advanced biliary tract cancers: a meta-analysis based on RCTs.
        J Cancer. 2018; 9: 1476-1485
        • Saha S.K.
        • Gordan J.D.
        • Kleinstiver B.P.
        • et al.
        Isocitrate dehydrogenase mutations confer dasatinib hypersensitivity and SRC dependence in intrahepatic cholangiocarcinoma.
        Cancer Discov. 2016; 6: 727-739
        • Javle M.
        • Lowery M.
        • Shroff R.T.
        • et al.
        Phase II Study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma.
        J Clin Oncol. 2018; 36: 276-282
        • Rizzo A.
        • Ricci A.D.
        • Brandi G.
        Durvalumab: an investigational anti-PD-L1 antibody for the treatment of biliary tract cancer.
        Expet Opin Invest Drugs. 2021; 30: 343-350
        • Valle J.W.
        • Lamarca A.
        • Goyal L.
        • et al.
        New horizon for precision medicine in biliary tract cancers.
        Cancer Discov. 2017; 7: 943-962
        • Galdy S.
        • Lamarca A.
        • McNamara M.G.
        • et al.
        HER2/HER3 pathway in biliary tract malignancies; systematic review and meta-analysis: a potential therapeutic target?.
        Cancer Metastasis Rev. 2016; 36: 141-157