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  • br Conclusion br Acknowledgments This research was

    2021-11-30


    Conclusion
    Acknowledgments This research was funded by Tianjin Health Institution Key Projects, grant number 15KG148” and “Tianjin Medical University General Hospital Youth Incubation Fund, grant number ZYYFY2017029”. I would like to express my heartfelt gratitude to Professor Hongtao Zhang for his generous gifting of the recombinant pUC57 vector encoding HER2-ScFv.
    Introduction Amplification of HER2 gene and its receptors’ overexpression are recorded in 20–30% of BC and are related to unfavorable prognosis. HER2 overexpressing BC is potentially responsive to monoclonal IOX4 sale (mAb) and small molecule tyrosine kinase inhibitors (TKI) that target different parts of the receptor [1], [2], [3]. Trastuzumab, which is a recombinant humanized mAb, has a high binding affinity to the extracellular domain (ECD) of HER2 [4]. Trastuzumab, when combined with chemotherapy, improves survival outcome in HER2-positive advanced [5] as well as early BC patients [6], [7]. Primary trastuzumab resistance may develop, and about 15% of patients treated with adjuvant trastuzumab-based chemotherapy regimens will develop distant failure [8], [9]. Trastuzumab resistance may be secondary to the expression of truncated forms of HER2 such as p95-HER2 that lacks the ECD [10] resulting in loss of trastuzumab binding target and consequently loss of its effects [11]. Carboxy-terminal fragments (CTF) sized between 90 and 115 kDa are expressed in about thirty percent of HER2-positive BC [12]. These truncated CTF are produced by metalloproteases proteolytic shedding of the HER2 receptor ECD [13] or HER2 mRNA alternative translation [14]. In HER2-positive BC, the p95-HER2 expression is usually associated with higher rate of lymph node metastases and decreased DFS compared with patients overexpressing full-length HER2 [10], [11], [12], [15]. Studies demonstrated that truncated p95-HER2 expressing cells retain their kinase activity and are responsive to lapatinib therapy [3], [16], which has a dual HER2 and HER1 TKI [17]. Geyer et al. [2] reported that combined lapatinib and capecitabine therapy for HER2-positive BC patients who previously progressed on trastuzumab-containing regimens had significantly improved time to progression, compared with capecitabine alone. Moreover, administration of lapatinib as first-line treatment for locally advanced or metastatic HER2-positive BC patients either combined with paclitaxel or as monotherapy resulted in 24% overall response rate [18].
    Patients and methods
    Patients’ samples
    Treatment All patients were treated with trastuzumab-based CT protocol as an adjuvant therapy that consisted of doxorubicin (60 mg/m2 i.v.) plus cyclophosphamide (600 mg/m2 i.v.) on day 1, cycle repeated every 3 weeks for 4 cycles. This was followed by trastuzumab (8 mg/kg i.v.) on day 1 plus paclitaxel (80 mg/m2 i.v.) once weekly for 12 weeks with trastuzumab (6 mg/kg i.v.) every 3 weeks to complete one year.
    HER2 analysis For IHC, the HER2 antibody (Clone CB11, Leica Biosystems, Newcastle-upon-Tyne, UK, 1: 80 dilutions) was utilized. Staining was scored as follow: No staining is observed, or membrane staining is observed in <10% of the tumor cells (0; negative); a faint/barely perceptible membrane staining is detected in >10% of tumor cells or the cells exhibit incomplete membrane staining (1+; negative); weak to moderate complete membrane staining observed in >10% of tumor cells (2+); strong complete membrane staining is observed in malignant cells (3+; positive). The cases that scored 2+ were further evaluated by fluorescence in situ hybridization (FISH) using the PathVysion HER-2 probe kit (Vysis, USA) where specimens with a signal ratio >2.2 were considered positive (Fig. 1a and b).
    Immunohistochemical staining of p95-HER2 According to the intensity of membrane staining and its extension, p95-HER2 expression was classified from 0 to +3 as classic Her2 neu. p95-HER2 expression (+2 and +3) was considered if the samples showing moderate or intense complete membrane IHC staining in >10% of tumor cells [10]. Examples of p95-HER2 staining are shown in Fig. 2(a–d).