BACKGROUND: In an attempt to identify markers of resistance to trastuzumab, we evaluated both the profiling of human epidermal growth factor receptor 2 (HER2)-positive tumor cells measuring the relative levels of EGFR, pMAPK, pAkt and PTEN and their correlations with clinical outcome in HER2-positive metastatic breast cancer patients treated with trastuzumab. PATIENTS AND METHODS: Tumor tissues for this retrospective analysis were available from 45 out of 76 patients with metastatic breast cancer treated from April 1999 to March 2006 with trastuzumab-based therapy at our Institution. Evaluations of EGFR, pMAPK, pAkt and PTEN status by immunohistochemistry (IHC) were carried out on all 45 tissue samples and their correlations with response to trastuzumab, incidence of central nervous system (CNS) metastases, time to progression (TTP), overall survival from diagnosis of breast cancer (OS1), from diagnosis of metastatic disease (OS2) and from the start of trastuzumab (OS3) were analyzed. RESULTS: We observed that TTP (P = 0.001) and median OS2 and OS3 were significantly longer in patients responsive to trastuzumab-based regimen compared with nonresponsive patients. EGFR, pMAPK, pAkt and PTEN status by IHC were not significantly associated with response to trastuzumab, TTP, overall survival (OS1, OS2, OS3) and CNS metastases incidence. A trend for shorter OS3 was observed for pMAPK-positive patients compared with pMAPK-negative patients (22.8 versus 31.2 months; P = 0.076). Median OS1 resulted shorter in 22 pAkt-positive patients (69.8 months) compared with 23 pAkt-negative patients (108.2 months); P = 0.091. It is likely that high expression of pMAPK (pMAPK-positive status) or pAkt (pAkt-positive status) could identify a subgroup of HER2-positive tumors with high activity of proliferation and survival pathways and with resistance to trastuzumab. CONCLUSIONS: In HER2-positive metastatic breast cancers, EGFR, pMAPK, pAkt and PTEN status evaluated by IHC was not significantly associated with response to trastuzumab, TTP, OS and CNS metastases incidence. However, HER2 status determined by IHC and/or FISH assays may not be sufficient to predict response to trastuzumab-based therapy.
BACKGROUND: In an attempt to identify markers of resistance to trastuzumab, we evaluated both the profiling of humanepidermal growth factor receptor 2 (HER2)-positive tumor cells measuring the relative levels of EGFR, pMAPK, pAkt and PTEN and their correlations with clinical outcome in HER2-positive metastatic breast cancerpatients treated with trastuzumab. PATIENTS AND METHODS: Tumor tissues for this retrospective analysis were available from 45 out of 76 patients with metastatic breast cancer treated from April 1999 to March 2006 with trastuzumab-based therapy at our Institution. Evaluations of EGFR, pMAPK, pAkt and PTEN status by immunohistochemistry (IHC) were carried out on all 45 tissue samples and their correlations with response to trastuzumab, incidence of central nervous system (CNS) metastases, time to progression (TTP), overall survival from diagnosis of breast cancer (OS1), from diagnosis of metastatic disease (OS2) and from the start of trastuzumab (OS3) were analyzed. RESULTS: We observed that TTP (P = 0.001) and median OS2 and OS3 were significantly longer in patients responsive to trastuzumab-based regimen compared with nonresponsive patients. EGFR, pMAPK, pAkt and PTEN status by IHC were not significantly associated with response to trastuzumab, TTP, overall survival (OS1, OS2, OS3) and CNS metastases incidence. A trend for shorter OS3 was observed for pMAPK-positive patients compared with pMAPK-negative patients (22.8 versus 31.2 months; P = 0.076). Median OS1 resulted shorter in 22 pAkt-positive patients (69.8 months) compared with 23 pAkt-negative patients (108.2 months); P = 0.091. It is likely that high expression of pMAPK (pMAPK-positive status) or pAkt (pAkt-positive status) could identify a subgroup of HER2-positive tumors with high activity of proliferation and survival pathways and with resistance to trastuzumab. CONCLUSIONS: In HER2-positive metastatic breast cancers, EGFR, pMAPK, pAkt and PTEN status evaluated by IHC was not significantly associated with response to trastuzumab, TTP, OS and CNS metastases incidence. However, HER2 status determined by IHC and/or FISH assays may not be sufficient to predict response to trastuzumab-based therapy.
Authors: Howard M Stern; Humphrey Gardner; Tomasz Burzykowski; Wafaa Elatre; Carol O'Brien; Mark R Lackner; Gary A Pestano; Angela Santiago; Ivonne Villalobos; Wolfgang Eiermann; Tadeusz Pienkowski; Miguel Martin; Nicholas Robert; John Crown; Paolo Nuciforo; Valerie Bee; John Mackey; Dennis J Slamon; Michael F Press Journal: Clin Cancer Res Date: 2015-02-03 Impact factor: 12.531
Authors: Edith A Perez; Amylou C Dueck; Ann E McCullough; Beiyun Chen; Xochiquetzal J Geiger; Robert B Jenkins; Wilma L Lingle; Nancy E Davidson; Silvana Martino; Peter A Kaufman; Leila A Kutteh; George W Sledge; Lyndsay N Harris; Julie R Gralow; Monica M Reinholz Journal: J Clin Oncol Date: 2013-05-06 Impact factor: 44.544
Authors: Francisco J Esteva; Hua Guo; Siyuan Zhang; Cesar Santa-Maria; Steven Stone; Jerry S Lanchbury; Aysegul A Sahin; Gabriel N Hortobagyi; Dihua Yu Journal: Am J Pathol Date: 2010-09-02 Impact factor: 4.307
Authors: Guanglei Zhuang; Dana M Brantley-Sieders; David Vaught; Jian Yu; Lu Xie; Sam Wells; Dowdy Jackson; Rebecca Muraoka-Cook; Carlos Arteaga; Jin Chen Journal: Cancer Res Date: 2009-12-22 Impact factor: 12.701
Authors: Nandini Dey; Yuliang Sun; Jennifer H Carlson; Hui Wu; Xiaoqian Lin; Brian Leyland-Jones; Pradip De Journal: Am J Cancer Res Date: 2016-03-15 Impact factor: 6.166