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      Impact of HER2 copy number in IHC2+/FISH-amplified breast cancer on outcome of adjuvant trastuzumab treatment in a large UK cancer network

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          Abstract

          Background:

          Adjuvant trastuzumab with chemotherapy is standard treatment for HER2-positive breast cancer, defined as either HER2 IHC3+ or IHC2+ and FISH amplified. The aim of this study was to investigate the degree to which HER2 amplification in terms of HER2 gene copy numbers in HER2+IHC2+ cancers affected the outcome in a community setting.

          Methods:

          Case records of 311 consecutive patients with early breast cancer presenting between 1st January 2005 and 31st December 2008 were reviewed. Progression-free survival and overall survival were calculated with the Kaplan–Meier method using STATA 13.

          Results:

          Among 3+ cases ( n=230) 163 received T vs 67 no-T. Among 2+ cases ( n=81) 59 received T vs 22 no-T. Among 59 IHC2+-treated cases n=28 had an average of >12, n=13 had >6 to <12, and n=18 had >2 to <6 HER2 gene copies, respectively. The time of progression and overall survival of high and low copy number patients was similar and better than the intermediate copy number and the untreated cohorts.

          Conclusions:

          High HER2 copy number (>12) appears to be associated with consistently better response compared with patients with intermediate HER2 copy numbers (6–12). In light of emerging data of patients showing insensivity to trastuzumab therapy, we propose that the HER2 gene copy number value should be included as an additional indicator for stratifying both the management and the follow-up of breast cancer patients.

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          Most cited references 10

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          HER2 status and benefit from adjuvant trastuzumab in breast cancer.

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            Quantitative association between HER-2/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer.

            HER-2/neu, which encodes a receptor tyrosine kinase, is amplified and overexpressed in 20%-25% of human breast cancers. Such tumors are often resistant to hormone therapy. Despite a general inverse association between HER-2/neu amplification/overexpression and estrogen receptor (ER) and/or progesterone receptor (PR) expression, a fraction of patients are both HER-2/neu- and hormone receptor (HR)-positive. The efficacy of hormone therapy in this group is currently a matter of debate. To better understand the relationship between HER-2/neu positivity and HR expression, we analyzed HER-2/neu, ER, and PR as continuous variables in breast cancer cell lines and two cohorts of primary breast cancer patients. HER-2/neu and ER/PR expression was analyzed by enzyme-linked immunosorbent assay (ELISA) and enzyme immunoassay (EIA), respectively, in 14 human breast cancer cell lines, some of which had been transfected with the HER-2/neu gene. For the clinical study population, HER-2/neu protein levels were assessed by ELISA (cohort A, n = 665), and HER-2/neu gene copy number was determined using fluorescence in situ hybridization (cohort B, n = 894). ER/PR expression was analyzed by EIA (cohort A) or radioligand binding (cohort B). Associations between HER-2/neu and ER/PR expression were analyzed using Spearman's rho correlation and the chi-square test, and absolute levels were compared using the Mann-Whitney U test. All statistical tests were two-sided. HR-positive human breast cancer cell lines transfected with the HER-2/neu gene expressed statistically significantly lower levels of ER and PR than parental lines. In the clinical cohorts, levels of HER-2/neu overexpression and gene amplification were inversely correlated with ER/PR levels (Cohort A [n = 112]: for ER, r = -0.34, P<.001; for PR, r = -0.24, P =.010. Cohort B [n = 188]: for ER, r = -0.39, P<.001; for PR, r = -0.26, P<.001). Among patients with HR-positive tumors, HER-2/neu-positive tumors had statistically significantly lower ER/PR levels than HER-2/neu-negative ones (Cohort A: for ER, median = 25 fmol/mg [interquartile range [IQR] = 13-78] versus median = 38.5 fmol/mg [IQR = 17-99] and P =.031; for PR, median = 35 fmol/mg [IQR = 12-119] versus median = 88.5 fmol/mg [IQR = 22-236] and P<.001. Cohort B: for ER, median = 44 fmol/mg [IQR = 13-156] versus median = 92 fmol/mg [IQR = 35-235] and P<.001; for PR, median = 36 fmol/mg [IQR = 13-108] versus median = 84 fmol/mg [IQR = 24-250] and P<.001). Patients with higher levels of HER-2/neu overexpression or amplification had statistically significantly lower levels of ER/PR than patients with lower levels of HER-2/neu overexpression or amplification. Because absolute HR levels are strongly related to response to hormone therapy in primary and advanced breast cancer, reduced ER/PR expression may be one mechanism to explain the relative resistance of HER-2/neu-positive:HR-positive tumors to hormone therapy.
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              Disease-free survival according to degree of HER2 amplification for patients treated with adjuvant chemotherapy with or without 1 year of trastuzumab: the HERA Trial.

              To determine whether (1) immunohistochemical (IHC) HER2 status (ie, 2+ or 3+), (2) degree of fluorescence in situ hybridization (FISH) amplification according to (2a) HER2/CEP17 ratio or (2b) HER2 gene copy number, or (3) polysomy significantly influenced clinical outcome for patients with human epidermal growth factor receptor 2 (HER2) -positive breast cancer enrolled in the Herceptin Adjuvant trial of trastuzumab versus no trastuzumab administered after completion of chemotherapy. IHC and/or FISH analyses were performed locally and required central confirmation as indicating HER2 positivity for trial entry. FISH data from the central HER2 analysis on patients in the 1-year trastuzumab and no trastuzumab arms were assessed in relation to disease-free survival (DFS) after a median 2 years of follow-up. Central FISH results were available for 2,071 (61%) of the 3,401 patients randomized to the 2 arms. Among patients with FISH-positive disease, (1) the hazard ratios for trastuzumab versus no trastuzumab were 0.56 (95% CI, 0.32 to 0.99) for locally IHC2+ cases (n = 340) and 0.80 (95% CI, 0.40 to 1.61) for centrally IHC2+ cases (n = 299). There was no significant prognostic relationship between (2a) HER2 FISH ratio, (2b) HER2 copy number, or (3) polysomy and DFS in the control arm or predictive relationship defining differential benefit from trastuzumab. There was no evidence for reduced benefit of trastuzumab in HER2 IHC2+FISH+ cases. The degree of HER2 amplification does not influence prognosis or benefit from adjuvant trastuzumab in patients treated with prior adjuvant chemotherapy.
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                Author and article information

                Journal
                Br J Cancer
                Br. J. Cancer
                British Journal of Cancer
                Nature Publishing Group
                0007-0920
                1532-1827
                15 April 2014
                01 April 2014
                : 110
                : 8
                : 2139-2143
                Affiliations
                [1 ]Velindre Cancer Centre, Whitchurch , Cardiff CF14 2TL, UK
                [2 ]Cardiff University School of Medicine, Heath Park , Cardiff CF14 4YU, UK
                [3 ]Department of Cellular Pathology, University Hospital of Wales, Heath Park , Cardiff CF14 4YU, UK
                [4 ]Wales Cancer Trials Unit, Neuadd Meirionnydd, Heath Park , Cardiff CF14 4YS, UK
                [5 ]Department of Pathology and Diagnostic, University of Verona , Verona 37134, Italy
                [6 ]Institute of Cancer & Genetics, Cardiff University School of Medicine, Heath Park , Cardiff CF14 4XN, UK
                Author notes
                Article
                bjc2014147
                10.1038/bjc.2014.147
                3992505
                24691421
                Copyright © 2014 Cancer Research UK

                From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/

                Categories
                Genetics & Genomics

                Oncology & Radiotherapy

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