Parra-Palau Josep Lluís, Morancho Beatriz, Peg Vicente, Escorihuela Marta, Scaltriti Maurizio, Vicario Rocio, Zacarias-Fluck Mariano, Pedersen Kim, Pandiella Atanasio, Nuciforo Paolo, Serra Violeta, Cortés Javier, Baselga José, Perou Charles M, Prat Aleix, Rubio Isabel T, Arribas Joaquín
*Authors contributed equally to this work.
*Authors contributed equally to this work.Affiliations of authors: Preclinical Research (JLPP, BM, ME, RV, MZF, KP, VS, AP, JA) and Clinical Research Programs (PN, JC, ITR), Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Pathology Department, Vall d'Hebron University Hospital, Barcelona, Spain (VP); Human Oncology and Pathogenesis Program (HOPP) and Memorial Sloan Kettering Cancer Center, New York, NY (MS, JB); Instituto de Biología Molecular y Celular del Cáncer, Campus Miguel de Unamuno, Salamanca, Spain (AP); Lineberger Comprehensive Cancer Center, Chapel Hill, NC (CMP); Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UAB, Bellaterra, Spain (JA); Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain (JA).
J Natl Cancer Inst. 2014 Sep 24;106(11). doi: 10.1093/jnci/dju291. Print 2014 Nov.
Human epidermal growth factor receptor 2 (HER2)-positive breast cancers are currently treated with trastuzumab, an anti-HER2 antibody. About 30% of these tumors express a group of HER2 fragments collectively known as p95HER2. Our previous work indicated that p95HER2-positive tumors are resistant to trastuzumab monotherapy. However, recent results showed that tumors expressing the most active of these fragments, p95HER2/611CTF, respond to trastuzumab plus chemotherapy. To clarify this discrepancy, we analyzed the response to chemotherapy of cell lines transfected with p95HER2/611CTF and patient-derived xenografts (n = 7 mice per group) with different levels of the fragment. All statistical tests were two-sided. p95HER2/611CTF-negative and positive tumors showed different responses to various chemotherapeutic agents, which are particularly effective on p95HER2/611CTF-positive cells. Furthermore, chemotherapy sensitizes p95HER2/611CTF-positive patient-derived xenograft tumors to trastuzumab (mean tumor volume, trastuzumab alone: 906 mm(3), 95% confidence interval = 1274 to 538 mm(3); trastuzumab+doxorubicin: 259 mm(3), 95% confidence interval = 387 to 131 mm(3); P < .001). This sensitization may be related to HER2 stabilization induced by chemotherapy in p95HER2/611CTF-positive cells.
人表皮生长因子受体2（HER2）阳性乳腺癌目前采用抗HER2抗体曲妥珠单抗进行治疗。这些肿瘤中约30%表达一组统称为p95HER2的HER2片段。我们之前的研究表明，p95HER2阳性肿瘤对曲妥珠单抗单药治疗耐药。然而，最近的结果显示，表达这些片段中最具活性的p95HER2/611CTF的肿瘤对曲妥珠单抗联合化疗有反应。为了阐明这种差异，我们分析了转染p95HER2/611CTF的细胞系以及具有不同水平该片段的患者来源异种移植瘤（每组7只小鼠）对化疗的反应。所有统计检验均为双侧检验。p95HER2/611CTF阴性和阳性肿瘤对各种化疗药物表现出不同反应，这些药物对p95HER2/611CTF阳性细胞特别有效。此外，化疗使p95HER2/611CTF阳性的患者来源异种移植瘤对曲妥珠单抗敏感（平均肿瘤体积，单独使用曲妥珠单抗：906 mm³，95%置信区间 = 1274至538 mm³；曲妥珠单抗 + 阿霉素：259 mm³，95%置信区间 = 387至131 mm³；P <.001）。这种敏感性可能与化疗在p95HER2/611CTF阳性细胞中诱导的HER2稳定有关。
