Indian J Med Res 132, September 2010, pp
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1 Indian J Med Res 2, September 2, pp Assessment of HER-2/neu status in breast cancer using fluorescence in situ hybridization & immunohistochemistry: Experience of a tertiary cancer referral centre in India Poonam Panjwani, Sridhar Epari, Arti Karpate, Hemlata Shirsat, Preetha Rajsekharan, Ranjan Basak, Tanuja Shet, Roshni Chinoy, Roy Chacko, Sampada Gursale, Nayana Baraskar, Sudeep Gupta *, Rohini Hawaldar ** & Sangeeta Desai Department of Pathology, Tata Memorial Hospital (TMH) & Advanced Centre for Training, Research & Education in Cancer (ACTREC), * Department of Medical Oncology & ** Clinical Research Secretariat, Tata Memorial Centre, Mumbai, India Received March 8, 29 Background & objective: Determination of HER2 status in breast cancer has become important to identify potential candidates for anti-her2 therapy. In this study we compared fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) for the determination of HER2 status in breast cancer patients referred to a tertiary care referral centre. Methods: A total of 2 cases of invasive breast cancer were evaluated for HER2 status using IHC and FISH and results were compared. Results: The IHC + (9.9%) and IHC negative (85.9%) cases showed good concordance with the corresponding FISH results; while 66.6 per cent of IHC 2+ cases showed gene amplification by FISH. In addition, hormone receptor expression and HER2 gene status showed a statistically significant inverse association (P<.5). Interpretation & conclusion: These findings reaffirm IHC as a prudent first-step to screen tissue samples for HER2 status and to determine suitability for technically demanding FISH test and the dual coloured FISH as a gold standard for determination of HER2/neu status in IHC equivocal cases of breast carcinoma. Key words Breast cancer - fluorescent in situ hybridization (FISH) - HER2/neu - immunohistochemistry (IHC) - trastuzumab Among the various prognostic and predictive factors of breast cancer,2, the most widely studied biomarker is the human epidermal growth factor receptor 2 (HER2) gene, also referred to as ERBB2 or HER2/neu, which is amplified in approximately 8-2 per cent of all breast cancers. Amplification of this gene is associated with the rapid progression of the disease, increased metastatic potential, increased resistance to tamoxifen and better response to anthracycline-based chemotherapy. The discovery of targeted therapy 287
2 288 INDIAN J MED RES, SEPTEMBER 2 against the HER2 gene in the form of the humanized anti-her2 monoclonal antibody trastuzumab (Herceptin, Genentech, South San Francisco, CA) and HER/HER2 dual receptor inhibitor, lapatinib, has brought forward an effective treatment modality for patients having the gene amplification 4-6. However, the treatment is expensive and carries certain serious adverse effects like cardiotoxicity with trastuzumab. Both drugs have been found to be effective only in tumours showing true gene amplification. Hence, it is of utmost importance to correctly identify the subset of patients who would benefit from this novel mode of therapy. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) are the most commonly used diagnostic procedures for determining the HER2 status in breast carcinoma. Though numerous studies,7- have been done to compare the results of these methods to arrive at a gold standard for the HER2 status testing, the existing literature is still unclear about the most ideal and specific test for determination of the HER2 status. It is estimated that 2 per cent of the current HER2 testing may be inaccurate,7. The present study was undertaken to test the HER2 status in patients diagnosed with invasive breast carcinoma using both IHC and the FISH techniques with an aim to compare the results of the two techniques. Material & Methods A total of 2 (wherein either tissue or paraffin blocks were available) histologically proven breast cancer cases (including both in-hospital and referral cases) received from April 26 till September 28 in the Division of Molecular Pathology, Advanced Centre for Training, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Mumbai, were included in the study. The study protocol was approved by the institutional review board. Clinical and histological parameters: Clinical and demographic data - including age, sex, tumour size, histologic type, grade, status of nodal and distant metastasis, wherever available, were noted for each case. Immunohistochemical evaluation: All the cases were immunohistochemically evaluated for estrogen and progesterone hormone receptor status (ER and PR), and c-erbb-2 protein expression using standard immunoperoxidase method i.e., avidin-biotin complex peroxidase method (Vector peroxidase ABC kit - PK4 and PK42, Burlingame, CA, USA) and pressure cooking for antigen retrieval. Adequate tissue fixation in per cent neutral buffered formalin for 6-48 h was ensured. Paraffin sections (-4 mm thick) with maximum invasive tumour component were selected for IHC. The antibodies used for ER, PR and c-erbb2 were monoclonal mouse anti-human estrogen receptor, DAKO, Carpinteria, CA, USA (Clone D5; dilution :5), monoclonal mouse anti-human progesterone receptor, DAKO, Carpinteria, CA, USA (Clone PgR 66; dilution :5) and B5 monoclonal antibody (Immunotech, Marseilles, France, dilution :) respectively. HER2 scoring of IHC slides was done on light microscopy as per the recommended American Society of Clinical Oncology (ASCO) guidelines 27. Scores and were considered as negative while scores 2 and were considered as equivocal and positive respectively. Sections which showed strong membrane staining of normal epithelia of breast were rejected and subjected to a repeat IHC. ER and PR scoring was done by assigning a score from to 9 based on percentage distribution of immunoreactive tumour cells and intensity of staining. Cases in which internal control was negative were repeated. All the tests were interpreted in conjunction with positive and negative controls and if required, were repeated. The controls were previously tested positive and negative test samples. Fluorescence in-situ hybridization (FISH) evaluation: FISH was performed using the US FDA approved PathVysion (Abbott Molecular Inc., Des Plaines, IL, USA) HER2 DNA Probe kit, a dual-coloured probe comprising locus specific identifier (LSI) HER2/neu SpectrumOrange and centromere enumeration probe (CEP) 7 SpectrumGreen.4. The test was carried out on paraffin sections taken on acid-treated double poly-l-lysine coated glass slides. FISH procedure was carried out manually as per manufacturer s instructions in package insert. Slides were scored immediately using a Axio Imager Z (Carl Zeiss Ltd, Germany) upright fluorescence microscope equipped with appropriate excitation and emission filters allowing visualization of the signals, Axio Cam MRc5 camera, and Axio Vision Rel 4.5 software. Subjective interpretation was independently done by three pathologists. The results were then compared and
3 PANJWANI et al: HER2 BY FISH & IHC 289 consensus score was recorded. In case of variable result, the assay was repeated. The fields containing invasive tumour component with non-overlapping tumour nuclei were chosen for interpretation. A minimum of 4 tumour nuclei for each case were counted and only those nuclei showing at least green and red signal were selected. The total number of red and green signals counted in the tumour nuclei was recorded and then ratio of the HER2 (red) to CEP 7 (green) signals for the 4 tumour nuclei was calculated. Other feature like polysomy 7 was also noted. Fields showing excess background signals or auto-fluorescence masking the nuclear signals were not evaluated. The interpretation of the FISH assay was done following the ASCO/College of American Pathologists (CAP) guidelines. A ratio of HER2 to CEP7 signals higher than 2.2 was reported as amplification, a ratio less than.8 was reported as non-amplification, while a ratio between.8 and 2.2 was taken as an equivocal result. A recounting of additional 2 tumour nuclei (i.e. total 6) was done for the equivocal cases. The assay was repeated in the case of failure of test due to technical problems like excess paraffin in the tissue, excess background auto-fluorescence, no gene signal or improper protease digestion. Normal and amplified control slides, ProbeChek, were run simultaneously with the test cases. The slides were then stored in the dark at -2 o C. Statistical evaluation: The results of HER2 status by FISH and IHC were compared and sensitivity, specificity, negative and positive predictive values, concordance and accuracy were evaluated considering FISH as gold standard. In addition, correlation of HER2 status with ER and PR status along with various aforementioned clinical and histologic parameters was done using Chi square test, P<.5 was considered significant. Results Of the 2 breast cancer samples evaluated by IHC and FISH, showed failed IHC or FISH results due to various reasons - depletion of invasive tumour during IHC resulting in residual DCIS only (n=), failed FISH test due to inappropriate tissue processing or excess paraffin in the tissues (n=4 referral cases), no appreciable signals in the FISH test due to prolonged storage of paraffin blocks (n=4), no signals on FISH even on repeated tests (n=2). In addition, 4 cases represented metastatic sites and all these cases viz., (+4=25) were excluded from the analysis. Thus the final study group comprised 75 primary invasive tumour samples. Clinical and histological parameters: All except one were female patients and were of wide age range (29-78 yr). Ninety one patients were of < 5 yr while 84 were >5 yr in age. Tumour size could be recorded in 99 cases on gross examination. Of these, 7 (7.8%) had tumour size of 2-5 cm, while in 4 cases (4.4%) the tumour size was less than 2 cm (pt) and 5 (5.5%) cases showed the tumour size of more than 5 cm (pt). One hundred and fifty eight cases (9.29%) were high grade (grade ), 6 (9.4%) were grade 2 and only one case was of low grade (grade ). Regional nodal metastasis was documented in 82 cases. Immunohistochemical evaluation: Immunohistochemical evaluation was performed on all the 75 primary cases for ER, PR and c-erbb-2. Estrogen receptor (ER) and progesterone receptor (PR) - One hundred and ten cases were ER negative and 9 cases were PR negative. Of the 65 ER positive cases, 2 (.7 %) were of score + to +, 9 cases (6%) were of score 4+ to 6+ and six (9.2 %) were of score 8+ to 9+. On the other hand, of the 56 PR positive cases, 9 (5.7%) had score + to +, 24 cases (42.8%) had score 4+ to 6+ and (2.2%) score 8+ to 9+. HER2 protein - Eighty two cases (46.8%) showed score + reactivity (Fig. ), 6 cases (2.7%) showed score 2+ reactivity (Fig. 2) and 57 (2.5%) were negative. FISH evaluation: Of the 75 cases tested for HER2 gene amplification, 8 cases (6.7%) were amplified (Fig. ). The result was equivocal in 4 cases and Fig.. Strong and complete membrane staining in > per cent of cells (IHC score +) (4X).
4 29 INDIAN J MED RES, SEPTEMBER 2 6 (6%) were non-amplified by FISH (Fig. 4). In addition, polysomy 7 was noted in 25 cases, of whom 4 were amplified, nine were not amplified and 2 were equivocal. Comparison of HER 2 status by IHC and FISH: Considering FISH as gold standard, both the tests were compared. The IHC + (9.9%) and IHC negative (85.96%) cases correlated well with FISH results; while a significant 66.6 per cent IHC 2+ group cases showed gene amplification. The comparison between the IHC scores and FISH results is shown in Table I. Fig. 2. Moderate or weak complete membrane staining in - per cent of tumour cells (IHC score 2+) (4X). Fig.. Detection of HER-2/neu DNA amplification in breast carcinoma by FISH. Each tumour cell nucleus demonstrated HER-2/neu signals/cep 7 signals ratio of > 2.2. (X). For the purpose of analyzing the correlation between HER2 gene status and various parameters, 4 cases with equivocal amplification on FISH, were excluded from the analysis. On statistical evaluation, HER2 status did not show any significant correlation with age, tumour size and regional nodal status. A majority viz., 2 of 58 grade tumours (64.5%) showed HER2/neu amplification (P<.). HER 2 amplification was noted in 29 of 65 ER positive cases (44.6%) and 24 of 56 (42.8%) PR positive cases. A statistically significant inverse association (P<.5) was noted between hormonal and HER2 gene status. The correlation of the HER2 status with clinical, ER/ PR status and other histological parameters is depicted in Table II. The data were further analysed in two ways by first combining the IHC 2+ and IHC + cases as positive cases and later only IHC + as positive group. Then, comparative results between each of these two groups (combined 2+, + and + alone) and FISH amplified cases were obtained separately (Tables III and IV). For this purpose, FISH was taken as the gold standard. Comparison of the two groups revealed a significantly higher sensitivity of 9 per cent in the Table I. Comparison of IHC results with FISH (n=75) HER2 protein expression by IHC Negative (/+) n=57 Equivocal (2+) n=6 Positive (+) n=82 n=75 Fig. 4. Non-amplified HER-2/neu DNA as demonstrated by HER2/ CEP7 ratio <.8 (X). HER2 testing by FISH No. Amplified Non-amplified Equivocal 7 (2.2) 49 (85.96) (.75) 24 (66.66) (.55) (2.77) 77 (9.9) (.65) 2 (2.2) IHC, indicates immunohistochemistry; FISH, fluorescent in situ hybridization
5 PANJWANI et al: HER2 BY FISH & IHC 29 combined group of IHC 2+ and IHC + cases than 7 per cent of IHC + alone. The difference was mainly due to the fact that in our study, 24 of 6 cases (66.6%) of the IHC 2+ cases were amplified by FISH. Table II. Correlation of HER 2 status with clinical, ER, PR status and histological parameters Parameter. Age (yr): <5 (n=9) > 5 (n=84) 2. T size (cm): < 2 (n=4) 2-5 (n=7) > 5 (n=5) Not known (n=76). Histologic grade: I (n=) II (n=6) III (n=58) 4. Regional LN metastasis: Present (n=82) Absent (n=45) Not known (n=48) 5. ER status: Positive (n=65) Negative (n=) 6. PR status: Positive (n=56) Negative (n=9) Amplified HER2 testing by FISH Nonamplified Equivocal FISH, fluorescent in situ hybridization; T size, tumour size; LN, lymph node; ER, estrogen receptor; PR, progesterone receptor A total of 25 (4.2%) cases showed polysomy 7. Of these, 4 showed gene amplification by FISH (n=2 for IHC +, n=2 for IHC 2+), nine cases were nonamplified (n=4 for IHC negative, n= for IHC 2+ and n=2 for IHC +), while two showed an equivocal result (n= for IHC negative and n= for IHC +). Of the nine polysomy 7 HER 2 non-amplified cases, two were IHC +. Discussion HER2 amplification is reported in various studies in the range of 8-2 to 25- per cent of breast cancers,9. In the present study, 6.7 per cent cases showed amplification by FISH. Younger breast cancer patients were reported to have higher frequency of HER2 gene amplification but no significant association between the age and HER2 gene amplification was seen in the present study. No statistically significant association between HER2 gene status with tumour size and regional nodal metastasis was seen in the present study. These observations are consonant with those reported by Prati et al 2. Tumour grade showed positive correlation with HER2 amplification in the present study which is concordant with the existing literature,2. A majority i.e per cent of high grade (grade ) tumours were associated with HER2 amplification (P<.). A significant inverse association was noted between hormone receptor status and HER2 gene amplification in the present study, as reported earlier 2,. The reason for the inverse relation between hormone receptor and HER2 amplification is postulated to be due to complex interactive Study Table III. Comparison of combined IHC 2+ and + groups with FISH Sensitivity Specificity Positive predictive value Negative predictive value Concordance Yaziji et al Tsuda et al Present study IHC, immunohistochemistry Study Table IV. Comparison of IHC + (after excluding IHC 2+ group) with FISH Sensitivity Specificity Positive predictive value Negative predictive value Concordance Yaziji et al Tsuda et al Present study IHC, immunohistochemistry
6 292 INDIAN J MED RES, SEPTEMBER 2 signaling between ER and other growth factor signaling pathways in breast cancer cells 4. Sixteen per cent cases showed both expression of ER and HER2 amplification. HER2 amplification in these tumours is reported to be associated with resistance to tamoxifen therapy 5. It is postulated that in these tumours, tamoxifen functions as an estrogen agonist to enhance growth in breast cancer cells which express high levels of HER2 and estrogen receptor co-activator resulting in de novo resistance for tamoxifen 4,6. Triple negatives i.e., negativity to ER, PR hormone receptors and non-amplified HER2 gene, made up 4.8 per cent. It is now evident that triple negative patients are resistant to chemotherapy and also have a rapidly progressive clinical course 7. Three cases of IHC score of + did not show gene amplification by FISH in the present study. Two of these had polysomy 7 and thus a false positivity by IHC 8 ; whereas, the reasons for the other case could be due to one of the following reasons, viz. excess antigen retrieval 9, single copy over-expression of HER2 gene at the mrna transcriptional level or beyond without actual gene amplification, gene amplification below the detection level of the FISH assay A vast majority of our cases with IHC score + showed amplification by FISH. The ASCO/CAP guidelines reported a concordance rate of 82 per cent while Jacobs et al 2 have reported a concordance rate of 9 per cent. Gene amplification by FISH was noted in 2.2 per cent IHC negative cases. Press et al 9 have reported an incidence of 7.4 per cent of gene amplification in IHC negative cases. One of the possible reasons for this discrepancy may be insufficient tissue preservation leading to low levels of protein detection, cases with low level gene amplification, gene transcription and post-transcriptional or post-translational events could be downregulated or could be abnormal, leading to low HER2 protein levels or abnormal epitope production thus resulting in nonreactivity on IHC 2. For patients having discordant results (IHC +/ FISH negative or IHC negative/fish positive), though clinical trials with trastuzumab have been done, clinical outcome data are yet not available. The equivocal FISH result was shown 2.2 per cent cases in the present study. This is in keeping with the ASCO/CAP 27 guidelines, which recommend that equivocal results by FISH should be < per cent of all samples tested. Patients in this category would also be likely to benefit from trastuzumab therapy. In the present study, a substantially higher percentage (66.6%) with IHC score 2+ cases was found to have gene amplification on FISH. Previous studies reported 6-25 per cent incidence of IHC 2+/FISH amplified cases,2-25. The ASCO/CAP guidelines report an incidence of 2.9 per cent. To determine the significance of the indeterminate score on IHC in our patients, sensitivity and specificity were determined first by combining the IHC 2+ with the IHC + group and then analyzing IHC + group exclusively. Tsuda et al 25 reported a rise in the concordance rate from 9 to 95 per cent when the 2+ group was excluded. Yaziji et al reported a significant rise in the concordance rate from 64.9 to 96. per cent when the 2+ group was excluded from the analysis. This significant rise in the concordance rate was due to the fact that in their study, though a large set of tumour sections scored 2+ on IHC (52%), on FISH analysis, only 7.2 per cent of these cases were truly amplified. On the contrary, we noted a drop in sensitivity from 9 to 7 per cent and a drop in the concordance rate from 87.7 to 8. per cent when the 2+ group was excluded from the analysis. This is because, we found that a higher number of cases (66.6%) having a score of 2+ on IHC had gene amplification on the FISH assay. Most of the studies including the present one showed an overall high concordance between IHC +/ FISH amplified and IHC negative/fish non-amplified groups. The discordant results between IHC and FISH have been mostly attributed to 2+ scores on IHC indicating that IHC 2+ connotes uncertainty and is an indicator of undetermined HER2 status 7,25,26. The main problem appears to be underscoring of HER2 on IHC. The high degree of amplified cases in score 2+ category in the present study can be explained by a high load of referral material (56 cases), where there was no control over time and quality of tissue fixation, the method of tissue processing, duration of storage. The incidence of polysomy of chromosome 7 varies from -5 per cent depending on criterion used to define the polysomic state 27. In the present study, 4.2 per cent primary breast tumours (25 out of 75) expressed polysomy 7. Several studies have confirmed that protein overexpression without gene amplification might be secondary to an increased chromosome 7 copy number and resultant increase in the copies of HER2/neu per cell in the absence of true amplification of HER2/neu gene 27,28. It is stated in the ASCO/CAP guidelines that around 8 per cent of equivocal cases
7 PANJWANI et al: HER2 BY FISH & IHC 29 on FISH exhibit polysomy of the chromosome 7. In the present study, a single case with an equivocal HER2 status by FISH and one case with high protein expression by IHC (+) had polysomy 7. IHC assays could not detect polysomy 7, thus cannot eliminate the false positivity. In conclusion, the present results emphasize the importance and gold standard nature of dual coloured FISH for determination of HER2/neu status in invasive breast carcinoma. With most authorities agree upon FISH to be more reliable than IHC for determining the HER2 status; FISH is an expensive, time consuming and labour intensive procedure, which requires training for interpretation. These constraints make IHC the most common method used for testing HER2. However, IHC is a prudent first-step to screen tissue samples and determine suitability for the technically demanding FISH test, which is employed as reflex testing for confirmation of IHC results. Acknowledgment The authors thank the Indian Council of Medical Research (ICMR), New Delhi, for supporting this research work with a financial grant to Dr Panjwani. The authors are also grateful to Shrimati Vaishali and Shrimati Tanuja, ACTREC, Mumbai, for providing technical assistance during analysis of FISH slides on Axio Imager Z. References. Walker RA. Use and assessment of diagnostic and predictive markers in breast pathology. Curr Diagn Pathol 27; : Henry NL, Hayes DF. Uses and abuses of tumor markers in the diagnosis, monitoring and treatment of primary and metastatic breast cancer. Oncologist 26; : Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cole RJ, et al. American Society of Clinical Oncology/ College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 resting in breast cancer. J Clin Oncol 27; 25 : Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metatstatic breast cancer that overexpresses HER2. N Engl J Med 2; 44 : Baselga J, Perez EA, Pienkowski T, Bell R. Adjuvant trastuzumab: a milestone in the treatment of HER-2 positive early breast cancer. Oncologist 26; (Suppl ): Bilancia D, Rosati G, Dinota A, Germano D, Romano R, Manzione L. Lapatinib in breast cancer. Ann Oncol 27; 8 (Suppl 6): vi Paik S, Bryant J, Tan-Chiu E. Romond E, Hiller W, Park K, et al. Real-world performance of HER2 testing-national Surgical Adjuvant Breast and Bowel Project experience. J Natl Cancer Inst 22; 94 : Payne SJ, Bowen RL, Jones JL, Wells CA. Predictive markers in breast cancer - the present. Histopathology 28; 52 : Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 989; 244 : Yaziji H, Goldstein LC, Barry TS, Werling R, Hwang H, Ellis GK, et al. HER-2 testing in breast cancer using parallel tissuebased methods. JAMA 24; 29 : Crowe JP, Patrick RJ, Rybicki LA, Escobar PF, Weng D, Budd GT, et al. A data model to predict HER2 status in breast cancer based on the clinical and pathologic profiles of a large patient population at a single institution. Breast 26; 5 : Prati R, Apple SK, He J, Gornbein JA, Chang HR. Histopathologic characteristics predicting HER-2/neu amplification in breast cancer. Breast J 25; : Huang HJ, Neven P, Drijkoningen M, Paridaens R, Wildiers H, Limbergen V, et al. Hormone receptors do not predict the HER2/neu status in all age groups of women with an operable breast cancer. Ann Oncol 25; 6 : Massarweh S, Schiff R. Resistance to endocrine therapy in breast cancer: exploiting estrogen receptor/growth factor signaling crosstalk. Endocr Relat Cancer 26; (Suppl ): S5-S Pinto AE, André S, Pereira T, Nóbrega S, Soares J. c-erbb-2 oncoprotein overexpression identifies a subgroup of estrogen receptor positive (ER+) breast cancer patients with poor prognosis. Ann Oncol 2; 2 : Shou J, Massarweh S, Osborne CK, Wakerling AE, Ali S, Weiss H, et al. Mechanisms of Tamoxifen resistance: increased estrogen receptor-her2/neu cross-talk in ER/HER2-positive breast cancer. J Natl Cancer Inst 24; 96 : Rakha EA, Reis-Filho JS, Ellis IO. Basal-like breast cancer: a critical review. J Clin Oncol 28; 26 : Merola R, Mottolese M, Orlandi G, Vico E, Cognetti F, Sperduti I, et al. Analysis of aneusomy level and HER-2 gene copy number and their effect on amplification rate in breast cancer specimens read as 2+ in immunohistochemical analysis. Eur J Cancer 26; 42 : Press MF, Sauter G, Bernstein L, Villalobos IE, Mirlacher M, Zhou JY, et al. Diagnostic evaluation of HER-2 as a molecular target: an assessment of accuracy and reproducibility of laboratory testing in large, prospective, randomized clinical trials. Clin Cancer Res 25; : Jacobs TW, Gown AM, Yaziji H, Barnes MJ, Schnitt SJ. Comparison of fluorescence in situ hybridization and immunohistochemistry for the evaluation of HER-2/neu in breast cancer. J Clin Oncol 999; 7 : Birner P, Oberhuber G, Stani J, Reithofer C, Samonigg H, Hausmaninger H, et al. Evaluation of the United States Food and Drug Administration-approved scoring and test system of HER-2 protein expression in breast cancer. Clin Cancer Res 2; 7 : Tubbs RR, Pettay JD, Roche PC, Stoler MH, Jenkins RB, Grogan TM. Discrepancies in clinical laboratory testing of eligibility of trastuzumab therapy: apparent Immunohistochemical false-positives do not get the message. J Clin Oncol 2; 9 :
8 294 INDIAN J MED RES, SEPTEMBER 2 2. Hammock L, Lewis M, Phillips C, Cohen C. Strong HER-2/ neu protein overexpression by immunohistochemistry often does not predict oncogene amplification by fluorescence in situ hybridization. Hum Pathol 2; 4 : Perez EA, Suman VJ, Davidson NE, Martino S, Kaufman PA, Lingle WL, et al. HER2 testing by local, central, and reference laboratories in specimens from the North Central Cancer Treatment Group N98 intergroup adjuvant trial. J Clin Oncol 26; 24 : Tsuda H, Akiyama F, Terasaki H, Hasegawa T, Kurosumi M, Shimadzu M, et al. Detection of HER-2/neu (c-erbb-2) DNA amplification in primary breast carcinoma: interobserver reproducibility and correlation with immunohistochemical HER-2 overexpression. Cancer 2; 92 : Barrett C, Magee H, O Toole D, Daly S, Jeffers M. Amplification of the HER2 gene in breast cancers testing 2+ weak positive by HercepTest immunohistochemistry: falsepositive or false-negative immunohistochemistry? J Clin Pathol 27; 6 : Downs-Kelly E, Yoder BJ, Stoler M, Tubbs RR, Skacel M, Grogan T, et al. The influence of polysomy 7 on HER2 gene and protein expression in adenocarcinoma of the breast: a fluorescent in situ hybridization, immunohistochemical, and isotopic mrna in situ hybridization study. Am J Surg Pathol 25; 29 : Ma Y, Lespagnard L, Durbecq V, Paesmans M, Desmedt C, Gomez GM, et al. Polysomy 7 in HER-2/neu status elaboration in breast cancer: effect on daily practice. Clin Cancer Res 25; : Reprint requests: Dr Sangeeta Desai, Professor & Pathologist, Tata Memorial Hospital, Dr E. Borges Road Parel, Mumbai 4 2, India sangeetabdesai@rediffmail.com
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