Determination of HER2 Amplification by In Situ Hybridization. When Should Chromosome 17 Also Be Determined?

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1 Anatomic Pathology / FISH f o r HER2: Wh e n to Use Ch r o m o s o m e 17 Determination of HER2 Amplification by In Situ Hybridization When Should Chromosome 17 Also Be Determined? John M.S. Bartlett, PhD, FRCPath, 1 Fiona M. Campbell, MSc, 1 and Elizabeth A. Mallon, MD 2 Key Words: HER2; Breast; Fluorescence in situ hybridization; FISH; In situ hybridization; Amplification; Copy number; Chromosome 17; Aneusomy; Trastuzumab Abstract Our purpose was to determine the accuracy of diagnosis of HER2 amplification by analysis of HER2 copy number. HER2 and chromosome 17 were measured by dual-color fluorescence in situ hybridization in breast cancer samples. At a HER2 copy number of 2 to less than 3, 16 (3.3%) of 488 cases had HER2 amplification; and at a copy number of 3 to less than 4, 32 (16.4%) of 195 cases were amplified. The proportion of cases with HER2 amplification increased considerably at HER2 copy numbers of 4 to less than 7: 50.0% at 4 to less than 5; 67.5% at 5 to less than 6, and 77.3% at 6 to less than 7. Virtually all cases were amplified at HER2 copy numbers of 7 or more. We recommend that all breast cancer cases with a HER2 copy number of 2 to 7 determined by singlecolor in situ hybridization should also be analyzed for chromosome 17 to obtain a more accurate diagnosis of HER2 amplification. Accurate diagnostic testing of HER2 expression and/ or gene amplification is an important aspect of breast cancer management and is required for treatment decisions in breast cancer, in particular relating to treatment with trastuzumab (Herceptin). 1-4 Guidelines for breast cancer management in the United Kingdom, European Union, United States, and many other countries require that all patients with breast cancer be tested accurately for HER2 status at initial diagnosis or at the time of recurrence. 1,2 No rationale for excluding patients from HER2 testing has been established. 5 Establishing tumor HER2 status may also be of value for guidance in predicting responses to other agents such as tamoxifen, taxanes, and anthracyclines. 2-5 Amplification of the HER2 gene drives overexpression of the oncoprotein 6,7 ; however, the majority of laboratories rely on a 2-tier testing procedure of immunohistochemical analysis followed by fluorescence in situ hybridization (FISH) for equivocal (predominantly with an immunohistochemical score of 2+) cases, according to UK, US, and Canadian guidelines. 1,2,8-11 Good correlation between immunohistochemical analysis and FISH for HER2 tumors (immunohistochemical score of 0 or 1+; no amplification) and for tumors with high levels of HER2 overexpression (immunohistochemical score of 3+; 90%-95% amplification) can be achieved with care, but the performance of FISH on the population with immunohistochemical scores of 2+ is essential for accurate identification of HER2+ tumors. 12 Previous studies have shown that FISH is the most accurate, reproducible, and precise predictor of HER2 overexpression in routine diagnostic laboratories. 6,7,13 Molecular testing based on in situ hybridization (ISH) is increasingly regarded as more predictive of response to trastuzumab and other agents Am J Clin Pathol 2008;130: Downloaded 920 from

2 Anatomic Pathology / Original Article ISH tests measure HER2 copy number using FISH or chromogenic ISH (CISH) detection methods. 1,14 Dual-probe FISH or CISH, with HER2 and chromosome 17 probes, determines the ratio of the HER2 gene to the chromosome 17 copy number and provides an accurate means of assessing gene amplification (an increase in copies of HER2 per chromosome) rather than increases in copy number due to chromosomal duplication. Aberrations of chromosome 17 (aneusomy) are common in breast cancer 15 and, therefore, have a critical impact on the assessment and reporting of HER2 gene amplification in a significant subset of cases. There is an ongoing debate as to the proportion of cases for which assessment of chromosome 17 copy number may be important. This debate is centered around 2 questions: first, the frequency of aneusomy of chromosome 17 in breast cancer, and second, the impact of such aneusomy on diagnosis of gene amplification. Misunderstandings relating to the determination of chromosomal copy number in tissue sections underpin the majority of false assumptions made regarding the frequency of aneusomy of chromosome 17 in breast cancer and, therefore, the impact this aberration has on the diagnosis of HER2 gene amplification. These misunderstandings have led to widespread inappropriate use of single-color ISH techniques for testing HER2 gene amplification, which rely on the false assumption that aneusomy of chromosome 17 is infrequent and rarely impacts on the diagnosis of HER2 gene amplification. The purpose of this article is to provide data to refute this assumption and to provide advice on the inclusion of chromosome 17 copy number testing for laboratories performing diagnostic testing for HER2 gene amplification. According to current guidelines, 1,2 amplification of HER2 is considered to be a HER2/chromosome 17 ratio of 2.0 or more, and a ratio less than 2.0 is regarded as nonamplified. For HER2 gene copy number assays, it has been assumed that copy numbers of more than 6.0 reflect amplification, and results of less than 4.0 HER2 gene copies per nucleus is always associated with lack of amplification; cases with 4 to 6 copies per cell are thought to require validation by testing of a parallel section for chromosome 17. 1,2 To our knowledge, this assumption has not been verified experimentally. If cases with fewer than 4 observed copies of HER2 per cell have fewer than 2 copies of chromosome 17 per cell, they may be amplified. Similarly, cases with 6 or more HER2 copies may be nonamplified if they exhibit more than 3 copies of chromosome 17. Hitherto, the assumption has been made that such cases do not exist. If this assumption is incorrect, a proportion of cases will be incorrectly diagnosed. Previous data from our group have shown that owing to nuclear truncation in thin tissue sections and incomplete hybridization of ISH probes in diagnostic specimens, the observed mean chromosomal copy number (MCCN) falls significantly below the theoretical value of 2 copies per cell. By using normal breast tissues, Watters et al 15 have demonstrated that the observed MCCN for chromosome 17 in diagnostic tissue sections is 1.61 ± 0.08 (mean ± SD). By using this value, a normal range for disomy 17 can be calculated using the 99% confidence intervals for the mean value; the calculated range is, thus, 1.35 to 1.85 observed copies per cell. Observed values from diagnostic breast cancer specimens beyond this range must, therefore, reflect monosomy (values <1.35) or polysomy (values >1.85). This principle, which has been validated by using other tissues and chromosomal probes, underpins much of the work on detection of chromosomal aneusomy by ISH methods By using the definition of 1.35 to 1.85 copies per cell for disomy, Watters et al 15 have shown that more than 50% of breast cancers exhibit chromosome 17 aneusomy, which may result in a higher copy number of HER2, owing to chromosome 17 polysomy, in the absence of HER2 amplification. These observations have been repeated by others (verbal communication, Kirsten van Neilsen, PhD, DAKO, Glostrup, Denmark, December 2007), but the implication of this high rate of chromosomal aneusomy for single-color ISH assays has not been explored. However, one immediate consequence can be predicted: because the observed MCCN for chromosome 17 falls within the range of 1.35 to 1.85 copies, a tumor with an observed mean HER2 copy number of 3 and an observed MCCN of 1.4 for chromosome 17 would, in fact, be amplified. Under current guidelines, however, there is no requirement for these low copy tumors to be tested for chromosome 17. Therefore, measurement of the chromosome 17 copy number in conjunction with HER2 gene copy number is critically important for the accurate diagnosis of HER2 gene amplification. The aim of this study was to analyze the frequency of HER2 amplification (determined by dual-color FISH) relative to the HER2 copy number in a large population of breast cancer patients to determine the accuracy of diagnosis of HER2 amplification as determined by using current guidelines. We provide evidence to support the requirement for measurement of chromosome 17 for a broader range of HER2 copy number determined by single-color ISH to obtain a more accurate diagnosis of HER2 amplification. We also highlight the significant risk of misdiagnosis of HER2 gene amplification by using current guidelines for single-probe HER2 assays. Materials and Methods Study Cases In an audit of HER2 testing, HER2 and chromosome 17 were measured by FISH in breast cancer samples referred between 2000 and 2008 from external hospitals to 1 author s (J.M.S.B.) laboratory, an established UK reference laboratory. Data on pathologic type, grade, and other such variables are not included because these were not required for referral of HER2 cases from external sources. Downloaded from Am J Clin Pathol 2008;130:

3 Bartlett et al / FISH f o r HER2: Wh e n to Use Ch r o m o s o m e 17 Determination of HER2 by Immunohistochemical Analysis HER2 was determined by immunohistochemical analysis using the HercepTest (DakoCytomation, Carpinteria, CA), as previously described. 7 The HercepTest scoring protocol assigns overall HER2 scores of 1+, 2+, or 3+ if 10% or more of carcinoma cells attain weak, moderate, or intense HER2 membrane staining, respectively. Determination of HER2 and Chromosome 17 by FISH HER2 and chromosome 17 were determined by dual-color FISH using the PathVysion detection kit (Vysis, Downers Grove, IL), as previously described. 7 This is an established method used routinely for clinical diagnosis. 1,8 FISH-stained sections were scanned at 1,000 magnification, and 3 separate carcinoma areas identified. The numbers of chromosome 17 and HER2 signals were counted in 20 to 60 nonoverlapping nuclei using at least 3 distinct tumor fields, or more if there was heterogeneity. The mean HER2/chromosome 17 copy ratio was calculated, and the mean HER2 and mean chromosome 17 copy numbers observed were recorded. For the purposes of this audit, the mean HER2 copy number from the PathVysion system was used to stratify cases by observed HER2 copy number. Analysis of Results The HER2 status of all cases measured by immunohistochemical analysis during this period is included. HER2 was measured by FISH (dual color) in all cases referred for FISH testing because they had immunohistochemical scores of 2+ 8,9 and also in a cohort in which all samples were screened by dual-color FISH. FISH data were analyzed by the number of cases categorized by the observed mean HER2 copy number per cell (as in single-color FISH ). For each HER2 copy number, the number of cases with HER2 amplification relative to chromosome 17 (as with dual-color FISH) was determined. Based on these values, the potential for misdiagnosis of HER2 gene amplification if chromosome 17 was not measured was calculated. Underdiagnosis was calculated as the proportion of HER2-amplified cases (by HER2/chromosome 17 ratio) that would be recorded as HER2 based on the HER2 copy number if chromosome 17 was not measured. Overdiagnosis was calculated as the number of HER2 nonamplified (by ratio) cases that would be considered amplified based only on the HER2 copy number if chromosome 17 was not measured. Results The HER2 status of 4,903 breast cancer patients was evaluated by immunohistochemical analysis between 2000 and Of the 4,903 cases, 63.2% were HER2 (immunohistochemical score, 0 or 1+), 11.4% were scored as 2+, 18.9% were 3+, and 6.3% had missing immunohistochemical data. The HER2/chromosome 17 copy ratio was measured by dual-color FISH in 1,711 of these cases, including all scored 2+ immunohistochemically (593 cases) and also in a cohort in which all samples were screened by dual-color FISH irrespective of immunohistochemical status. Data on chromosome 17 were missing for 1 case. The patient population with measurement of HER2 by FISH in this study was clearly biased toward cases scored 2+ immunohistochemically. The mean HER2 copy number per cell was fewer than 2 in 40.4% of cases, 2 to fewer than 4 in 39.9% of cases, 4 to fewer than 6 in 6.5% of cases, 6 to fewer than 7 in 1.3% of cases, and 7 or more in 11.8% of cases zfigure 1z. In this study population of breast cancer patients, the chromosome 17 copy number (recorded from dual-color FISH) was defined Percentage of Cases <2 2<3 3<4 4<5 5<6 6<7 7<8 8<9 9<10 10<15 15<20 20<25 >25 HER2 Copy Number zfigure 1z Distribution of HER2 copy number across the total patient study population. The percentage of cases by observed mean HER2 copy number per cell is shown. The HER2 copy number was recorded from dual-color fluorescence in situ hybridization in 1,711 cases. 922 Am J Clin Pathol 2008;130: Downloaded 922 from

4 Anatomic Pathology / Original Article as monosomic (<1.35) in 9.1% of cases, disomic ( ) in 51.7% of cases, and polysomic (>1.85) in 39.2% of cases zfigure 2z. zfigure 3z shows the frequency of HER2 gene amplification (defined by the HER2/chromosome 17 ratio) as a function of observed mean HER2 copy number per cell. zimage 1z illustrates examples of low HER2 copy amplified and high HER2 copy nonamplified cases. Even at a HER2 copy number of 2 to fewer than 3, 16 (3.3%) of 488 cases exhibited HER2 amplification; and at a copy number of 3 to fewer than 4, 32 (16.4%) of 195 cases were amplified. The proportion of cases with HER2 amplification increased considerably at HER2 copy numbers of 4 to fewer than 7: 50.0% at copy numbers of 4 to fewer than 5; 67.5% at 5 to fewer than 6, and 77.3% at 6 to fewer than 7. Virtually all cases were amplified at HER2 copy numbers of 7 or more. Percentage of Cases < > >2-3 >3 Chromosome 17 Copy Number zfigure 2z Distribution of chromosome 17 copy number across the total patient study population. The percentage of cases by chromosome 17 copy number per cell is shown. Chromosome 17 copy number was recorded from dualcolor fluorescence in situ hybridization measurements in 1,710 cases. Of the 816 cases with a HER2 copy number between 2 and 8, there were 291 cases (35.7%) referred for FISH testing only that, therefore, have no immunohistochemical result available for analysis; 277 cases (33.9%) with an immunohistochemical score of 2+, reflecting the enrichment of these cases in this series, of which 27.4% were HER2 amplified; 198 immunohistochemically negative cases (24.3%), of which only 6 (3.0%) were HER2 amplified; 33 cases (4.0%) with an immunohistochemical score of 1+, of which 12% were amplified; and 17 cases (2.1%) with an immunohistochemical score of 3+, of which 82.4% were amplified. Discussion Although it is now universally accepted that the vast majority of patients with early breast cancer require testing for expression, or preferably amplification, of the HER2 oncogene, debate continues about the appropriate methods to be used. 1-4 A key area of debate is related to when or, indeed, if chromosome 17 should be evaluated for the determination of HER2 gene amplification. HER2 gene amplification is now recognized as the key driver of HER2 overexpression in breast cancer. 6,7 Gene amplification for HER2 has been defined as a ratio of observed HER2/chromosome 17 copy numbers in invasive breast cancer cells, which would seem to mandate inclusion of chromosome 17 for all cases. However, there are clear hypothetical cases in which exclusion of chromosome 17 may be valid: cases with observed HER2 copy numbers less than 2.0 are, almost by definition, never amplified, whereas cases with very high HER2 copy numbers (>20 signals/cell) are frequently assumed to be amplified. As a result, many national guidelines have provided estimated HER2 copy number ranges for which testing of chromosome 17 is perceived Percentage of Patients With HER2 Amplification <2 2<3 3<4 4<5 5<6 6<7 7<8 8<9 9<10 10<15 15<20 20<25 >25 HER2 Copy Number (copies per cell) zfigure 3z Frequency of HER2 gene amplification (defined by HER2/chromosome 17 ratio) as a function of HER2 copy number. The HER2/chromosome 17 ratio was recorded in 1,711 cases by dual-color fluorescence in situ hybridization. Downloaded from Am J Clin Pathol 2008;130:

5 Bartlett et al / FISH f o r HER2: Wh e n to Use Ch r o m o s o m e 17 to be important. 1,2,8-11 However, the major weakness of these guidelines has been the lack of an evidence base for the selection of cases for chromosome 17 testing in centers that use single-color ISH to assess the HER2 copy number rather than dual-color ISH for the HER2 ratio. We have addressed this gap by auditing cases diagnosed in our laboratories by FISH and using the HER2 gene copy number (derived from dualcolor ISH testing) to estimate the frequency of HER2 gene amplification (defined by the HER2/chromosome 17 ratio) relative to HER2 copy number. This analysis suggests that all guidelines have been excluding a significant proportion of cases that require chromosome 17 copy number testing to adequately define HER2 gene amplification. The potential impact, in terms of misdiagnosis of HER2 gene amplification in this study population, if adhering to current guidelines is illustrated in ztable 1z. Current guidelines recommend that an observed HER2 copy number of fewer than 4 should be considered nonamplified 1,2 without the need for chromosome 17 copy number determination. However, our data show that HER2 is amplified in 16.4% of cases with an observed mean HER2 copy number of 3 to 4, and 11.4% of the total patient population tested falls within this group, which would represent a 1.87% underdiagnosis of HER2 gene amplification in the total patient study population. In fact, HER2 is amplified in 3.28% of cases with an observed HER2 copy number of 2 to 3, and 28.5% of the study population falls A B C D zimage 1z Low HER2 copy amplified and high HER2 copy nonamplified cases. A (Case 1), Average HER2 copy number, 2.33 per cell. B (Case 1), Average HER2 copy number, 2.33 per cell; average chromosome 17 copy number, 1.00; ratio, Case is amplified according to the ratio. C (Case 2), Average HER2 copy number per cell, D (Case 2), Average HER2 copy number per cell, 5.05; average chromosome 17 copy number, 3.77 per cell; ratio, Case is not amplified according to the ratio. 924 Am J Clin Pathol 2008;130: Downloaded 924 from

6 Anatomic Pathology / Original Article ztable 1z Potential Percentage of Misdiagnosis in Patient Study Population (N = 1,711) When Adhering to Current Guidelines Percentage of Percentage of Cases Percentage of Misdiagnosis Mean HER2 Copy Number Total Population With HER2 Amplification in Total Population < to < to < to < NA 5 to < NA 6 to < Virtually NA, current guidelines require chromosome 17 testing in this population, which excludes the potential for misdiagnosis. within this group, which would represent a further 0.94% of cases misdiagnosed as HER2 nonamplified when calculated as a proportion of the total study patient population. No HER2 amplification was observed in tumors with an observed HER2 copy number fewer than 2. Therefore, based on the current guidelines for fewer than 4 HER2 copies per cell being considered negative, 1,2 2.81% of the total patient population in this study (ie, 1 in 36 patients) would have been given a misdiagnosis of nonamplified if the chromosome 17 copy number had not been determined. Conversely, a diagnosis of HER2 amplification based on a HER2 copy number of more than 6 to fewer than 7 represents a 22.7% chance of misdiagnosis because the present study has shown that only 77.3% of these cases have true amplification of HER2 when the chromosome 17 copy number is measured. Although this is only 1.29% of the total patient population within this group (copy number 6 to <7), it still represents a misdiagnosis rate of 0.3% in the total patient population in this study. Virtually all cases were amplified at HER2 copy numbers of 7 or more. Therefore, based on the current guidelines for fewer than 4 HER2 copies per cell being considered negative and 6 or more HER2 copies per cell being considered positive, 1,2 3.1% of cases in this study population (ie, 1 in 32 patients) would have received an incorrect diagnosis with respect to HER2 gene amplification (Table 1). Current guidelines recommend that a HER2 copy number of 4 to 6 should be validated by measurement of chromosome 17. 1,2 HER2 is amplified in 50.0% of cases with a HER2 copy number of 4 to fewer than 5, and 4.2% of the study population falls within this group (Table 1). Similarly, HER2 is amplified in 67.5% of cases with a HER2 copy number of 5 to fewer than 6, and 2.34% of the study population falls within this group. If all cases with a copy number of 4 to 6 were considered positive, as is the case in some centers that ignore the importance of measuring chromosome 17, this would represent a further significant population of cases with an incorrect diagnosis with respect to HER2 gene amplification (2.9%). For centers using single-probe ISH (FISH or CISH) for the detection of amplification of the HER2 gene, current guidelines mandate testing for chromosome 17 copy number for cases with an observed HER2 gene copy number between 4 and 6 copies per cell. 1,2 An audit of almost 1,700 cases, for which FISH was performed in our laboratories, demonstrates that these guidelines are important and prevent the misdiagnosis of a significant group of HER2-amplified breast cancers in laboratories using single-color ISH assays (2.9% of cases; ie, 1/34 of all cases). However, we also showed that an equal proportion of cases (3.1%; 1/32) are at risk of misdiagnosis even in laboratories adhering to current guidelines for chromosome 17 testing following single-color ISH for HER2. Extending the use of chromosome 17 analysis to all cases with observed HER2 copy numbers between 2.0 and 7.0 per cell would avoid the current misdiagnosis of HER2 gene amplification for these cases. Even in this population with low copy numbers, there seems to be a strong relationship between gene amplification and HER2 protein expression. However, these data are compromised by the large proportion of cases scored immunohistochemically as 2+ and cases for which no immunohistochemical result was available for analysis. We, therefore, recommend that all cases with observed HER2 copy numbers of 2 to 7 should also be analyzed for chromosome 17 to accurately determine HER2 gene amplification. ztable 2z illustrates the impact of this recommendation, which would require analysis of chromosome 17 in 48.3% of all breast cancer cases based on the study population. Current guidelines 1,2 recommend chromosome 17 measurement only in cases with a HER2 copy number of 4 to fewer than 6, which represents only 6.6% of all breast cancer cases in the present study. Although single-color ISH is becoming more widely used with the availability of CISH, the importance of chromosome 17 measurement cannot be ignored. It is essential that HER2 testing is of high quality, so that optimal patient management can be provided. Because HER2+ status correlates with clinical efficacy of trastuzumab, it is necessary to accurately identify patients who will benefit from this treatment and to avoid unnecessary treatment of patients who are unlikely to benefit. False-positive HER2 results can give rise to overtreatment of patients, raise false Downloaded from Am J Clin Pathol 2008;130:

7 Bartlett et al / FISH f o r HER2: Wh e n to Use Ch r o m o s o m e 17 ztable 2z Percentage of Total Patient Study Population (N = 1,711) Requiring Chromosome 17 Measurement if Chromosome 17 Was Measured in All Cases HER2 Copy Number 4 to < to < to < to < hope, and waste resources, whereas false-negative results may result in undertreatment and deny women with breast cancer potentially life-extending treatment. The issue of the potential for misdiagnosis and requirement for greater accuracy has recently been highlighted in the press. 20 We recommend that all breast cancer cases with a HER2 copy number of 2 to 7 determined by single-color ISH also be analyzed for chromosome 17 to obtain a more accurate diagnosis of HER2 amplification. From the 1 Endocrine Cancer Group, Edinburgh University Cancer Research Centre, Western General Hospital, Edinburgh, Scotland; and 2 Department of Pathology, Western Infirmary, Glasgow, Scotland. Diagnostic HER2 testing supported in part by Roche Products, Welwyn Garden City, England. J. Merritt, PhD, Merritt Science, St Albans, England, a professional medical writer, drafted the manuscript and was paid by Roche Products. Address reprint requests to Dr Bartlett: Endocrine Cancer Group, Edinburgh University Cancer Research Centre, Western General Hospital, Crewe Rd South, Edinburgh EH4 2XR, Scotland. References Percentage of Total Population Requiring Chromosome 17 Measurement 1. Walker RA, Bartlett JMS, Dowsett M, et al. HER2 testing in the UK: further update to recommendations J Clin Pathol. 2008;61: Wolff AC, Hammond EH, Schwartz JN, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol. 2007;25: Bartlett JMS. Pharmacodiagnostic testing in breast cancer: focus on HER2 and trastuzumab therapy. Am J Pharmacogenomics. 2005;5: Faratian D, Bartlett J. Predictive markers in breast cancer: the future. Histopathology. 2008;52: Bartlett JMS, Ellis IO, Dowsett M, et al. Human epidermal growth factor receptor 2 status correlates with lymph node involvement in patients with estrogen receptor (ER)-negative, but with grade in those with ER-positive early-stage breast cancer suitable for cytotoxic chemotherapy. J Clin Oncol. 2007;28: Bartlett J, Mallon E, Cooke T. The clinical evaluation of HER-2 status: which test to use? J Pathol. 2003;199: Bartlett JMS, Going JJ, Mallon EA, et al. Evaluating HER2 amplification and overexpression in breast cancer. J Pathol. 2001;195: Ellis IO, Dowsett M, Bartlett J, et al. Recommendations for HER2 testing in the UK. J Clin Pathol. 2000;53: Ellis IO, Bartlett J, Dowsett M, et al. Best Practice No. 176: updated recommendations for HER2 testing in the UK. J Clin Pathol. 2004;57: Dowsett M, Hanby AM, Laing R, et al. HER2 testing in the UK: consensus from a national consultation. J Clin Pathol. 2007;60: Hanna W, O Malley FP, Barnes P, et al. Updated recommendations from the Canadian National Consensus Meeting on HER2/neu testing in breast cancer. Curr Oncol. 2007;14: Dowsett M, Bartlett J, Ellis IO, et al. Correlation between immunohistochemistry (HercepTest) and fluorescence in situ hybridization (FISH) for HER-2 in 426 breast carcinomas from 37 centres. J Pathol. 2003;199: Bartlett JMS, Ibrahim M, Miller K, et al. External quality assurance of HER2 fluorescence in situ hybridisation testing: results of a UK NEQAS pilot scheme. J Clin Pathol. 2007;60: Dietel M, Ellis IO, Höfler H, et al. Comparison of automated silver enhanced in situ hybridisation (SISH) and fluorescence ISH (FISH) for the validation of HER2 gene status in breast carcinoma according to the guidelines of the American Society of Clinical Oncology and the College of American Pathologists. Virchows Arch. 2007;451: Watters AD, Going JJ, Cooke TG, et al. Chromosome 17 aneusomy is associated with poor prognostic factors in invasive breast cancer. Breast Cancer Res Treat. 2003;77: Bartlett JMS, Watters AD, Ballantyne SA, et al. Is chromosome 9 loss a marker of disease recurrence in transitional cell carcinoma of the urinary bladder? Br J Cancer. 1998;77: Bartlett JMS, Adie L, Watters AD, et al. Chromosomal aberrations in transitional cell carcinoma that are predictive of disease outcome are independent of polyploidy. BJU Int. 1999;84: Watters AD, Ballantyne SA, Going JJ, et al. Aneusomy of chromosomes 7 and 17 predicts the recurrence of transitional cell carcinoma of the urinary bladder. BJU Int. 2000;85: Watters AD, Going JJ, Grigor KM, et al. Progression to detrusor-muscle invasion in bladder carcinoma is associated with polysomy of chromosomes 1 and 8 in recurrent pta/pt1 tumours. Eur J Cancer. 2002;38: Wilde-Mathews A. Bad cancer tests drawing scrutiny. The Wall Street Journal. January 4, 2008:B Am J Clin Pathol 2008;130: Downloaded 926 from

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