***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Purpose : To critically assess the accuracy and reproducibility of  human epidermal growth factor receptor type 2 ( HER-2 ) testing in outside/local community-based hospitals versus two central ized reference laboratories and its effect on selection of women for  trastuzumab (Herceptin)–based clinical trials . Experimental Design : Breast cancer specimens from 2,600 women were prospect ively evaluated by fluorescence in situ hybridization ( FISH ) for entry into Breast Cancer International Research Group ( BCIRG ) clinical trials for HER-2-directed therapies . Results : HER-2 gene amplification by FISH was observed in 657 of the 2,502 ( 26 % ) breast cancers successfully analyzed . Among 2,243 breast cancers with central laboratory immunohistochemistry ( 10H8-IHC ) analysis , 504 ( 22.54 % ) showed overexpression ( 2 + or 3 + ) . Outside/local laboratories assessed HER-2 status by immunohistochemistry in 1,536 of these cases and by FISH in 131 cases . Overall , the HER-2 alteration status determined by outside/local immunohistochemistry showed a 79 % agreement rate [ κ statistic , 0.56 ; 95 % confidence interval ( 95 % CI ) , 0.52 - 0.60 ] , with FISH done by the central laboratories . The agreement rate comparing BCIRG central laboratory 10H8-IHC and outside/local laboratory immunohistochemistry was 77.5 % ( κ statistic , 0.51 ; 95 % CI , 0.46 - 0.55 ) . Finally , HER-2 status , determined by unspecified FISH assay methods at outside/local laboratories , showed a 92 % agreement rate ( κ statistic , 0.83 ; 95 % CI , 0.73 - 0.93 ) , with FISH done at the BCIRG central laboratories . Conclusions : Compared with the HER-2 status determined at central ized BCIRG reference laboratories , these results indicate superiority of FISH to accurately and reproducibly assess tumors for the HER-2 alteration at outside/local laboratories for entry to clinical trials BACKGROUND Women with HER2-overexpressing breast cancer have an unfavorable prognosis . Trastuzumab improves survival when combined with chemotherapy in the first-line treatment of patients with HER2-overexpressing metastatic breast cancer and decreases the rate of disease relapse by 52 % and the rate of death by 33 % in women with HER2-overexpressing early-stage breast cancer . HER2 testing can be performed using immunohistochemistry ( IHC ) or fluorescence in situ hybridization ( FISH ) and can be performed at local pathology laboratories or at central /reference laboratories . Because of the significant benefit seen with trastuzumab , it is critical to accurately identify women most likely to benefit . The method and the location of HER2 testing contribute to the accuracy of test results . PATIENTS AND METHODS HER-First , a prospect i ve , community-based , phase IV study of first-line trastuzumab/taxane therapy , enrolled patients with HER2-overexpressing metastatic breast cancer . Retesting of all tumor specimens by HER2 IHC and FISH at a high-volume , experienced laboratory was required . RESULTS Concordance between local and central laboratory HER2 IHC testing was highest for local IHC 3 + sample s ( n = 377 ; 77 % ) and lowest for IHC 2 + sample s ( n = 184 ; 26 % ) . Thirty-three percent of sample s testing IHC 2 + at a local laboratory tested FISH-positive at the central laboratory . Concordance between HER2 IHC and FISH results was higher when both tests were performed at the central laboratory . CONCLUSION Accurate HER2 test results are critical to identify patients who are appropriate c and i date s for trastuzumab , a therapy with significant clinical benefits in HER2-overexpressing breast cancer . These data show that HER2 testing is most accurate when performed at a high-volume reference laboratory BACKGROUND The HER2/neu proto-oncogene is frequently over-expressed in breast cancer and serves as a biological target for trastuzumab therapy . However , there is no consensus regarding the technical aspects to be used to define HER2/neu status in clinical practice . METHODS The present study was conducted to address this critical issue by prospect ively analysing a large cohort of breast cancer patients ( n = 222 ) and using a variety of methods . To define HER2/neu expression , detection of its encoded protein ( p185 ) was performed by comparative immunohistochemical ( IHC ) analysis using two mouse monoclonal antibodies ( mAb CB11 and mAb TAB250 ) . To assess HER2/neu gene amplification , fluorescent in situ hybridisation ( FISH ) assays with gene-specific probes were conducted . All procedures were applied to de-paraffinised tissue sections of breast tumour sample s. RESULTS Results showed that mAb CB11 had increased sensitivity and specificity ( 62.5 % and 93.4 % , respectively ) compared to mAb TAB250 ( 40 % and 76.4 % , respectively ) in defining HER2/neu amplification . We conclude that HER2/neu measurement by IHC using mAb CB11 is an appropriate strategy which provides a high negative predictive value ( 95.5 % ) for HER2/neu amplification in cases with low or undetectable p185 expression . Conversely , mAb CB11 has a high positive predictive value ( 96.2 % ) for HER2/neu amplification in cases with p185 overexpression . However , cases with moderate p185 expression need to be considered as inconclusive . In such cases , it is necessary to use FISH measurement to evaluate HER2/neu amplification . It is also advisable to conduct FISH if there is discordance between p185 expression and the histopathology classification of the lesion , or molecular profile of the tumour . Finally , even though the false positive rate of IHC assay is < 5 % , the toxicity and cost of trastuzumab therapy suggest that FISH be used systematic ally prior to implementation of treatment . CONCLUSION We suggest the use of a molecular protocol for HER2/neu analysis in this type of tumor PURPOSE To evaluate concordance between local and central laboratory HER2 testing results in patients from the North Central Cancer Treatment Group ( NCCTG ) N9831 adjuvant trial of trastuzumab . PATIENTS AND METHODS NCCTG N9831 is a r and omized , phase III clinical trial comparing three drug regimens : doxorubicin/cyclophosphamide followed by paclitaxel with trastuzumab added concurrently , sequentially , or not at all as adjuvant therapy for women with HER2-positive resected breast cancer . Originally , patients were eligible if their tumors were HER2 positive by either local laboratory immunohistochemistry ( IHC ) or fluorescence in situ hybridization ( FISH ) . A protocol modification in 2002 made central laboratory testing m and atory , with additional testing of discordant cases conducted by a reference laboratory . Concordance between local and central laboratory , and level of agreement between central and reference laboratory HER2 findings in discordant cases were examined . RESULTS HER2 positivity was confirmed in 85.8 % of 2,535 patients registered since March 2002 . When local and central evaluation used the same methodology , concordance was 88.1 % for FISH and 81.6 % for a diagnostic test for presence of the HER2 protein . Among discordant cases examined at the reference laboratory , there was 94.3 % agreement for IHC ( 0 , 1 + , 2 + ) and 95.2 % agreement for FISH ( not gene amplified ) . CONCLUSION There was a high degree of discordance between local and central testing for IHC and FISH , but a high degree of agreement between central and reference laboratories . These findings support the importance of using high-volume , experienced laboratories for HER2 testing to improve the process of selecting patients likely to benefit from trastuzumab therapy PURPOSE To investigate the impact of human epidermal growth factor receptor ( HER ) 1 and HER2 gene amplification on endocrine therapy responsiveness , a fluorescence in situ hybridization ( FISH ) study was conducted on tumor sample s from 305 postmenopausal patients with stage II and III estrogen receptor ( ER ) -positive ( ER > or = 10 % ) breast cancers treated on two independent neoadjuvant endocrine therapy trials . PATIENTS AND METHODS FISH analysis focused on HER1 and /or HER2 immunohistochemistry ( IHC ) -positive patients and a r and om selection of HER1/2 IHC-negative patients . HER2 FISH status was correlated with response and changes in the proliferation marker Ki67 . RESULTS HER1 was rarely amplified ( < 1 % ) , and HER2 amplification was observed in 9.2 % of patients . Letrozole response by clinical measurement ( 71 % HER2 FISH positive v 71 % HER2 FISH negative ) , mammogram ( 44 % HER2 FISH positive v 47 % HER2 FISH negative ) , or  ultrasound  ( 47 % HER2 FISH positive v 54 % HER2 FISH negative ) was not impaired by HER2 FISH-positive status . In contrast , HER2 FISH-positive tumors showed higher histologic grade ( P = .009 ) , higher pretreatment Ki67 ( P = .005 ) , and less Ki67 suppression after letrozole when compared with HER2 FISH-negative tumors ( P = .0001 ) . Similar observations regarding Ki67 were made in a smaller cohort of tamoxifen-treated tumors . CONCLUSION Neoadjuvant letrozole is clinical ly effective in ER-positive HER2 FISH-positive tumors , indicating sensitivity to short-term estrogen deprivation . However , continued proliferation despite ongoing letrozole or tamoxifen treatment in the majority of ER-positive HER2 FISH-positive sample s ( 88 % ) could imply therapeutic resistance that may manifest later in the clinical course of the disease . Discordance between clinical and biomarker findings in this study serves to emphasize the need for surrogate end point validation in neoadjuvant endocrine trials through correlation with information on long-term outcomes 
    Output:
    
Our findings have shown high concordance rates between IHC and FISH in tumors IHC0 and IHC1 + , and discordance rates among cases with IHC2 + and IHC3 + .
In these cases , FISH is considered gold st and ard for confirming or excluding HER2 amplification