A Study Comparing Conventional Brightfield Microscopy, Image Analysis-Assisted Microscopy, and Interobserver Variation

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1 Effects of the Change in Cutoff Values for Human Epidermal Growth Factor Receptor 2 Status by Immunohistochemistry and Fluorescence In Situ Hybridization A Study Comparing Conventional Brightfield Microscopy, Image Analysis-Assisted Microscopy, and Interobserver Variation Roscoe Atkinson, MD; Jens Mollerup, PhD; Anne-Vibeke Lænkholm, MD; Mark Verardo, PhD; Debra Hawes, MD; Deborah Commins, MD, PhD; Birte Engvad, MD; Adrian Correa, MD, MBA; Charlotte Cort Ehlers, MD; Kirsten Vang Nielsen, PhD N Context. New guidelines for HER2 testing have been introduced. Objectives. To evaluate the difference in HER2 assessment after introduction of new cutoff levels for both immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) and to compare interobserver agreement and time to score between image analysis and conventional microscopy. Design. Samples from 150 patients with breast cancer were scored by 7 pathologists using conventional microscopy, with a cutoff of both 10% and 30% IHC-stained cells, and using automated microscopy with image analysis. The IHC results were compared individually and to HER2 status as determined by FISH, using both the approved cutoff of 2.0 and the recently introduced cutoff of 2.2. Results. High concordance was found in IHC scoring among the 7 pathologists. The 30% cutoff led to slightly fewer positive IHC observations. Introduction of a FISH equivocal zone affected 4% of the FISH scores. If cutoff for FISH is kept at 2.0, no difference in patient selection is found between the 10% and the 30% IHC cutoff. Among the 150 breast cancer samples, the new 30% IHC and 2.2 FISH cutoff levels resulted in one case without a firm diagnosis because both IHC and FISH were equivocal. Automated microscopy and image analysis-assisted IHC led to significantly better interobserver agreement among the 7 pathologists, with an increase in mean scoring time of only about 30 seconds per slide. Conclusions. The change in cutoff levels led to a higher concordance between IHC and FISH, but fewer samples were classified as HER2 positive. (Arch Pathol Lab Med. 2011;135: ) The HER2 gene, with the official gene name ERBB2, is amplified 1 and overexpressed 2 in 15% to 25% of breast cancers. 3 The highest frequency is found among patients eligible for chemotherapy, 3 whereas frequencies as low as Accepted for publication December 2, From the Department of Pathology, University of Southern California, Los Angeles (Drs Atkinson, Hawes, Commins, and Correa); the Departments of Clinical Affairs (Dr Mollerup) and Research and Development (Dr Nielsen), Dako Denmark A/S, Glostrup, Denmark; the Department of Pathology, Rigshospitalet, Copenhagen, Denmark (Dr Lænkholm); Dako North America, Inc, Carpentaria, California (Drs Atkinson and Verardo); the Department of Pathology, Odense University Hospital, Odense, Denmark (Dr Engvad); and the Department of Pathology, Hillerød Hospital, Hillerød, Denmark (Dr Ehlers). Drs Mollerup, Verardo, and Nielsen are fulltime employees at Dako, the company producing and distributing the products used in the study. Dr Atkinson is on contract to Dako by the University of Southern California. Drs Lænkholm, Hawes, Commins, Engvad, Correa, and Ehlers have received minor honoraria from Dako for scoring the tissue sections for the study. Reprints: Kirsten Vang Nielsen, PhD, Research and Development, Dako Denmark A/S, Produktionsvej 42, DK-2600 Glostrup, Denmark ( kirsten.vang@dako.com). 7% have been reported among patients receiving endocrine treatment. 4 The efficacy of HER2-targeting therapy was first demonstrated in metastatic breast cancer, 5 and later, the adjuvant effect in early breast cancer was established. 6,7 With the introduction of trastuzumab (Herceptin) in 1998, accurate assessment of HER2 status became essential for the clinical management of patients with breast cancer. The companion diagnostic test, the HercepTest (Dako Denmark A/S, Glostrup, Denmark), classifies the HER2 membrane staining into 4 categories: 3+ is a positive result, with strong, complete membrane staining; 2+ is weakly positive or equivocal, with weak to moderate, complete membrane staining; 1+ is a negative result, with faint incomplete membrane staining; and 0 is negative, with no membrane staining. Initially, treatment with trastuzumab was recommended in the United States to patients with both immunohistochemistry (IHC) scores of 2+ and 3+, but retrospective analyses have suggested that only patients with 3+ score by IHC, and/or gene amplification, benefited. 5 The debate about the accuracy of HER2 assessment was initiated by reports on the lack of 1010 Arch Pathol Lab Med Vol 135, August 2011 HER2 Assessment in Breast Cancer Atkinson et al

2 HER2 amplification in most 2+ cases. 8 When trastuzumab was later registered in the European Union, the recommendation was restricted to patients with an HER2 IHC score of 3+ or 2+ with confirmed HER2 gene amplification. 9,10 Several methods can be used to determine HER2 overexpression or gene amplification 11 but the 2 most relevant diagnostic methods currently in use are IHC and fluorescence in situ hybridization (FISH). There is still no consensus on which of these methods is the most predictive Since 1998, HER2 testing has been based on the HercepTest guidelines approved by the US Food and Drug Administration (FDA). Other IHC tests have been approved by concordance to the HercepTest. The FISH scoring guidelines for selection of patients for trastuzumab treatment was later approved by the FDA using a HER2 gene to centromere 17 ratio (HER2/CEN-17) cutoff for HER2 gene amplification of 2.0. Almost 10 years after the introduction of HER2 testing, joint guidelines were introduced by the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) for the laboratory evaluation of HER2 assessment. The new guidelines were introduced because of discordant testing results among local and central laboratories and to achieve a higher concordance between IHC and FISH results. 13 These new guidelines recommended validation of the assays, use of standard operating procedures, use of proficiency testing and laboratory accreditation standards, 15 and importantly, new cutoff values for considering a tumor HER2 positive. The new ASCO/CAP guidelines redefine a HER2- positive result as 3+ staining by IHC of greater than 30% of invasive tumor cells, as compared with the 10% cutoff used in the clinical trials leading to approval of trastuzumab. The earlier FISH cutoff of 2.0 has been substituted with an equivocal zone of 1.8 to 2.2 that requires additional testing. However, it is not known how many patients the new guidelines will affect by providing either a different, or a double equivocal, diagnosis To investigate the effect of part of these new guidelines, and especially the new cutoff values (ie, 3+ at 30%), we initiated a study of 150 invasive breast cancer specimens, interpreted by the FDA-approved HER2 FISH pharmdx assay (Dako) and the HercepTest, and scored by 7 different pathologists. The results were compared with the ASCO/CAP criteria for HER2 FISH and to a 30% cutoff (30% cutoff for all scores: 1+,2+, and 3+). Although we are not advocating the use of a general 30% cutoff, it was useful to investigate the 3+ cutoff at the 30% level. Additional information was gathered, including the (1) concordance between the HercepTest and the HER2 FISH pharmdx assays, (2) comparison of manual analysis versus image analysis-aided scoring, and (3) comparison of the time taken for image analysis scoring versus manual slide scoring. MATERIALS AND METHODS Tumor Specimens Routine, formalin-fixed, paraffin-embedded breast cancer specimens from 150 patients were included in this study. Full serial sections were cut at 4 mm to5mm. Breast cancer specimens were selected to get a distribution of HER2 protein expression levels close to that observed in women newly diagnosed with primary breast cancer. 19 Fluorescence In Situ Hybridization The HER2 FISH pharmdx assay was used according to the manufacturer s recommendations. Scoring was performed by an experienced technologist using an Olympus BX51 fluorescence microscope (Olympus Denmark A/S, Ballerup, Denmark), equipped with appropriate filters for 496-diamidino-2-phenylindole (DAPI), fluorescein isothiocyanate (FITC), and Texas Red. All borderline cases were rescored by a more-experienced technologist. Verification was done through random sample checks by an experienced pathologist on a separate microscope system. Immunohistochemistry Preparation and staining of sections were performed according to the package insert of the HercepTest. Pretreatment and staining of HercepTest slides were performed using PT Link and Autostainer Plus Link (Dako). One section of every specimen was stained with hematoxylin-eosin and was available for inspection during the scoring of FISH and HercepTest slides. Conventional and Image Analysis-Assisted Slide Scoring Using Different Guidelines Seven pathologists, representing different levels of experience in reading HercepTest slides, scored the HercepTest-stained breast cancer slides using conventional brightfield microscopy. Before scoring, all pathologists were instructed on the study setup and were trained using a training set. The HercepTest was scored according to the FDA-approved manufacturer guidelines, with a cutoff of 10% and a cutoff of 30% of the invasive cancer cells having positive membrane staining. Both cutoff levels were applied for all scores: 1+, 2+, and 3+. Pathologists were also allowed to comment on each slide, if applicable. The HER2 slides were also scanned on an Automated Cellular Imaging System (ACIS III; Dako). These digitized HER2 slides were saved and preloaded onto ACIS systems or ACIS workstations. Pathologists were first given an introduction to the ACIS, including the use of a training set if they were unfamiliar with the ACIS. Following this, the slides were scored. Briefly, areas of interest were selected in the low-resolution images, and the high-resolution images were displayed in the viewer box. The display magnification could be adjusted to the desired magnification, and a hot-spots function could be used. The 403-circle drawing tool was used to demarcate the area of interest on a high-resolution image, which was then automatically scored. The pathologists were instructed to always examine the image to verify the ACIS results. At least 6 regions per slide were to be scored in this manner. The pathologists were instructed to examine the ACIS overview; to place a checkmark in a box corresponding to less than 10%, greater than 10%, less than 30%, and/or greater than 30% membrane staining; and to make comments, if appropriate, for each slide on a report form. This also allowed the pathologist to put in a score different from the ACIS-generated fractional score if he or she did not agree with the ACIS fractional score. If a pathologist did not score a minimum of 6 regions, the results were not used in the analysis. If a pathologist put in a score different from the ACIS score, that pathologist s score was used for the final analysis. Following a pathologist s scoring, the ACIS region scores were imported to an Excel (Microsoft Corporation, Redmond, Washington) spreadsheet and used for data analysis. Average scores were generated in Excel. Scoring time per batch of 10 slides for manual microscopy (2 scorings) and scoring time with the ACIS III were tracked using a digital stopwatch and recorded. Conversion of HER2 IHC Scores and HER2:CEN-17 Ratios to HER2 Status Manual HercepTest and HER2 FISH pharmdx scores were converted to HER2 status as shown in Table 1. Additionally, the population with HER2-positive status was defined either as positive with the HercepTest (using a 10% cutoff according to the Arch Pathol Lab Med Vol 135, August 2011 HER2 Assessment in Breast Cancer Atkinson et al 1011

3 Table 1. Human Epidermal Growth Factor Receptor 2 (HER2) Status and Positive and Negative Score Results as Defined by the 2 Methods and 2 Guidelines HER2 Status Test Method and Guideline Negative Equivocal a Positive b HercepTest FDA-approved Dako guidelines 10% cutoff 0 or HercepTest 30% cutoff 0 or HER2/CEN-17 ratio FDA-approved Dako guidelines,2.0 NA $2.0 HER2/CEN-17 ratio by ASCO/CAP guidelines, Positive scores NA NA IHC, 3+; or FISH ratio, $2.0 Negative scores IHC, 0 or 1+; or FISH ratio, NA NA,2.0 Abbreviations: ASCO/CAP, American Society of Clinical Oncology/College of American Pathologists; CEN-17, centromere 17; FDA, US Food and Drug Administration; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry. a The term weakly positive is used in the HercepTest package insert. b The term strongly positive is used in the HercepTest package insert. manufacturer guidelines or a 30% cutoff according to the ASCO/ RESULTS CAP guidelines for a 3+ score) or as positive by FISH (following Dako guidelines; ie, a HER2/CEN-17 score $2.0). In addition, the Concordance Between the HercepTest and the HER2 FISH population with HER2-negative status was defined as those PharmDx Assays samples that were negative either by having a negative Samples from 150 patients with breast cancer were HercepTest result (manufacturer guidelines or using a 30% analyzed by 7 pathologists using manual HercepTest cutoff; ie, a 0 or 1+ score by any of the pathologists) or by having a scoring and both a 10% cutoff and a 30% cutoff, which negative FISH results (Dako guidelines; ie, a HER2/CEN-17 were compared with the FISH scoring according to score,2.0). Fractional scores from the ACIS III system were manufacturer and ASCO/CAP guidelines. Each pathologist was able to score between 136 and 150 samples by converted to ACIS scores according to the application guide. In short, the fractional scores were rounded to the nearest whole number (ie, ACIS III fractional scores $2.5 represented 3+ result). manual IHC and slightly fewer by ACIS-assisted scoring ( ). Of 1050 possible scores, 997 data points (95%) Data Handling and Statistical Analyses were available (Table 2), and 53 scores (5%) were removed Scoring from the 7 pathologists was checked against the from the data sets and analysis. Table 2 shows the guidelines in the HercepTest working procedures. During that comparison between HER2 status obtained by manual check, reported scores associated with comments like pure IHC using the cutoffs from the 2 guidelines. The overall ductal carcinoma in situ (DCIS), no invasive cancer, only agreement is 94.4% (941 of 997). When excluding the cytoplasmic staining, or only carcinoma in situ were not equivocal or 2+ cases (n 5 192) from these 997 scores, there included in the data set (n 5 53; 5%). Therefore, there are missing values from the pathologists in the data set, and the final number was 100% agreement. The 30% cutoff caused more negative HER2 status scores, and fewer scores were of total observations used was 997. Data entry was performed by positive or had equivocal status (Table 2). one person, and verification was done with 100% proofreading The ASCO/CAP guidelines have introduced an equivocal range from 1.8 to 2.2 in HER2 FISH scores. According by a second person. For statistical analysis, a standard 2-tailed significance level of.05 was used. Overall, the percentage of to the guidelines, cases in the range of 2.0 to 2.2, which are agreement (concordance) was calculated, and k statistics were positive using the FDA-approved Dako guidelines, are also used to assess agreement between the 2 methods and to describe agreement among the different pathologists. 12 All equivocal using the ASCO/CAP guidelines. Introducing a statistical analyses were done using SPSS 17 or 18 for Windows 2.2 cutoff for positivity instead of 2.0 influenced 5 (SPSS Inc, Chicago, Illinois). specimens (3%) that could potentially have their results changed. If FISH had been the entry test, those 5 samples Ethical Issues All specimens were fully anonymous, and no data were collected on patient demographics or medical history. The study would have been classified HER2 positive, with a ratio in the range of 2.0 to 2.2. When compared by IHC, only 3 discordant scores (0.03%) were identified, and they were was performed in agreement with local ethical regulations and not systematic because they represented 3 different the Helsinki declaration. samples scored by 3 different pathologists. Using the criteria for positive scores and negative scores defined in Table 1 (ie, cutoff for a positive HER2 FISH result, 2.0), the number of IHC-positive-and-FISHnegative results and the number of IHC-negative-and- Table 2. Cross-Tabulation of Human Epidermal Growth Factor Receptor 2 Status Results Obtained by FISH-positive scores were investigated using the 2 Manual Immunohistochemistry (10% and 30% Cutoff) different IHC cutoff values. Among the 262 positive for all Pathologists scores, a high concordance was found between the 10% Results at 10% Cutoff and the 30% cutoff (96.2% agreement; k value, 0.92; Table 3). Applying a 30% cutoff, instead of a 10% cutoff, 5 Results at 30% Negative Positive Equivocal observations changed from a positive to an equivocal Cutoff (0 and 1+) (3+) (2+) Total HER2 status result. These observations would have been Negative (0 and 1+) redirected to HER2 FISH and thereby assigned to the Positive (3+) appropriate category of positive cases eligible for trastuzumab treatment. Table 3 also shows that a high concor- Equivocal (2+) Total dance is found among the 803 negative scores (93.3% 1012 Arch Pathol Lab Med Vol 135, August 2011 HER2 Assessment in Breast Cancer Atkinson et al

4 Table 3. Comparison of Positive and Negative Scores in Human Epidermal Growth Factor Receptor 2 (HER2) Status for Manual Microscopy Using 10% and 30% Cutoff Manual IHC Results, 30% Cutoff HER2 Status, 10% Cutoff Negative (0 and 1+) Positive (3+) Equivocal (2+) Total Negative (0/1+) Positive (3+) Equivocal (2+) Total positive scores Negative (0/1+) Positive (3+) Equivocal (2+) Total negative scores Abbreviation: IHC, immunohistochemistry. agreement; k value, 0.78). The main difference is that 50 assessments scored as equivocal results with a 10% cutoff are scored as negative results with a 30% cutoff. The overall agreement between manual IHC and FISH can be seen in Table 4. Cases with an equivocal IHC (2+) are not included, and in the ASCO/CAP guidelines, equivocal FISH scores are not included. Apparently a slightly better agreement (95.0% agreement; k value, 0.85), using the 30% cutoff and 2.2 FISH ratio cutoff, is obtained by manual scoring compared with the agreement (92.1% agreement; k value, 0.78) obtained when applying the FDA-approved manufacturer guidelines of 10% stained cells and 2.0 FISH ratio cutoff. However, these results were caused by the exclusion of a few difficult cases that ranged between 1.8 and 2.2 using FISH (excluded according to ASCO/CAP guidelines) and by the exclusion of more 2+ cases when the cutoff for a 3+ result was increased to 30%. Consensus IHC Scoring Compared With FISH A consensus IHC score was defined as a concordant result from at least 4 of the pathologists, which lead to 140 (93%) and 138 (92%) consensus IHC scores for manual IHC with 10% and 30% cutoffs, respectively. One hundred thirty-one cases (87%) were evaluated with agreement among all 7 pathologists, whereas in only 6 (4%) of the Table 4. Overall Agreement of the Pathologists Individual Observations of Human Epidermal Growth Factor Receptor 2 (HER2) Results Between Fluorescence In Situ Hybridization (FISH) and Immunohistochemistry (IHC) Using Manual and Image Analysis-Assisted Scoring a FISH and IHC Guidelines Used Manual Scoring Overall Agreement k Value Image Analysis- Assisted Scoring Overall Agreement k Value FDA-approved Dako guidelines 92.1% % 0.79 ASCO/CAP FISH guidelines and 30% cutoff for manual scoring b 95.0% % 0.86 Abbreviations: ASCO/CAP, American Society of Clinical Oncology/ College of American Pathologists; FDA, US Food and Drug Administration. a IHC 2+ equivocal cases were excluded. b FISH equivocal cases ( ) were excluded. Table 5. Consensus of 7 Pathologists on Human Epidermal Growth Factor Receptor 2 (HER2) Status Using Manufacturer Cutoffs for Manual Immunohistochemistry (IHC) a and Fluorescence In Situ Hybridization (FISH) b Manual IHC Status a HER2 FISH Statusb Negative Positive Equivocal Total Negative (0 and 1+) Positive (3+) Equivocal (2+) Total a Dako guidelines for manual IHC of 10% of cells stained. b Dako guidelines for HER2 FISH cutoff of 2.0. evaluated cases did 1, 2, or 3 pathologists disagree. The remaining 13 cases (9%) did not have a consensus IHC score (,4 pathologists agreed). Those that lacked a consensus IHC score were primarily caused by most of the pathologists failing to provide a score for those cases. Table 5 shows the IHC HER2 status using the Dako guidelines, compared with the HER2 FISH status using the Dako guidelines. Table 6 shows the IHC HER2 status using the 30% cutoff levels, compared with the HER2 FISH status (using ASCO/CAP guidelines). Overall, 24.3% of the cases were amplified using the Dako/FDA cutoff of 2.0, whereas only 21.0% were amplified using the ASCO/CAP cutoff of 2.2. According to the Dako guidelines and 10% cutoff value, 28 patients would have been eligible for treatment with trastuzumab (ie, 3+ IHC and/or FISH amplified) if IHC was the entry analysis, and an additional 6 patients would have been eligible for treatment if FISH was chosen for the initial analysis (Table 5). A negative HER2 FISH status was given to 106 and 103 cases, respectively; both guidelines were associated with only one IHC-positive-FISH-negative assessment, with a FISH ratio of 1.06 (Tables 5 and 6). According to the ASCO/CAP FISH guidelines and the 30% cutoff, 26 patients would have been eligible for treatment with trastuzumab if IHC was the entry analysis, and an additional 3 patients would have been eligible for treatment if FISH was chosen as the entry analysis (Table 6). This influences the HER2 assessment of at least one case with a FISH ratio of 2.0 and classified as an IHCpositive result with the Dako guidelines, but an IHC- and FISH-equivocal result using the ASCO/CAP FISH guidelines and the 30% cutoff (Table 7). Overall, 90 cases were negative and 24 cases were positive, when comparing the consensus IHC HER2 status Table 6. Consensus of 7 Pathologists on Human Epidermal Growth Factor Receptor 2 (HER2) Status Using New Cutoffs for Manual Immunohistochemistry (IHC) a and Fluorescence In Situ Hybridization (FISH) b Manual IHC Status a HER2 FISH Statusb Negative Positive Equivocal Total Negative (0 and 1+) Positive (3+) Equivocal (2+) Total a Cutoff for manual IHC of 30% of cells stained. b American Society of Clinical Oncology/College of American Pathologists guidelines for HER2 FISH cutoff with results of as equivocal. Arch Pathol Lab Med Vol 135, August 2011 HER2 Assessment in Breast Cancer Atkinson et al 1013

5 Table 7. Possible Change in Fluorescence In Situ Hybridization (FISH) Positive Results in Human Epidermal Growth Factor Receptor 2 (HER2) Status by Changes in Cutoff Values FISH Ratio IHC 10% a IHC 30% a 2.0 FISH Cutoff obtained by manual IHC (Table 8). The overall agreement was 95.6%, and the k value was An equivocal or weakly positive status by IHC was found in 17 samples using both cutoff values, and 3 of those samples were positive using FISH (FISH ratio of 2.33, 3.02, and 5.29, respectively). There were 3 IHC-negative-and-FISH-positive samples (FISH ratio of 2.26, 2.27, and 2.32, respectively) that both cutoff values classified as negative by IHC (Table 7). Additionally, the FISH status of 4 negative samples results by IHC changed from positive to equivocal when applying the ASCO/CAP FISH guidelines (Table 7). Interobserver Agreement Using Conventional Microscopy and Image Analysis-Assisted HercepTest Scoring Investigation of the interobserver agreement was done by pairwise comparisons of the 3 score groups (0 and 1+, 2+, and 3+) for all possible pathologist pairs. This was done for data obtained using conventional microscopy with the 10% cutoff and the 30% cutoff and with image analysis-assisted microscopy. For the 7 pathologists, 21 comparisons were possible. The mean (SD) interobserver k value found in the scores using conventional microscopy and the Dako HercepTest guidelines was 0.72 (0.12) versus 0.84 (0.05) for image analysis-assisted microscopy and 0.72 (0.09) for conventional microscopy using the 30% cutoff. To test for a difference among these mean interobserver k values, paired 2-tailed t tests were employed. The mean interobserver k value for image analysis-assisted microscopy was significantly different from the means for conventional microscopy (P,.001), whereas the mean interobserver k values found in conventional microscopy using 10% or 30% cutoff were not significantly different FISH Cutoff 2.2 Effect of Change in FISH Cutoff 2.00 Pos Equ (2+) Pos Equ No firm HER2 status because of double-equivocal diagnoses 2.03 Neg Neg Pos Equ The 4 negative results by IHC (both cutoffs) are changed from 2.06 Neg Neg Pos Equ FISH-positive to FISH-equivocal results 2.13 Neg Neg Pos Equ 2.20 Neg Neg Pos Equ 2.26 Neg Neg Pos Pos No change: 3 results are negative by IHC and positive by FISH 2.27 Neg Neg Pos Pos (both cutoffs) 2.32 Neg Neg Pos Pos 8.44 Equ (2+) Neg Pos Pos FISH-positive finding that might be overlooked by a 30% cutoff Abbreviations: Equ, equivocal; IHC, immunohistochemistry; Neg, negative; Pos, positive. a The IHC status is based on consensus of scores by 7 pathologists. Table 8. Consensus of 7 Pathologists on Human Epidermal Growth Factor Receptor 2 (HER2) Status Using Manual Microscopy and the 10% and 30% Cutoffs HER2 Consensus Status, 10% Cutoff (P 5.70). Therefore, interobserver agreement was not affected by the choice of cutoff value when scoring with a conventional microscope, whereas interobserver agreement was significantly better when pathologists used image analysis as an aid, compared with manual scoring. Concordance in HER2 Status Using FISH Scoring Is Similar With Conventional Microscopy and Image Analysis- Assisted HercepTest Scoring Agreement between HER2 status determined using image analysis-assisted scoring or conventional microscopy is shown in Table 4. When using image analysisassisted microscopy with a cutoff of 10%, overall agreement was very similar (Table 4) to the overall agreement obtained by manual microscopy. A paired t test showed no significant difference between conventional microscopy and image analysis-assisted microscopy in concordance between HER2 status (positive/negative) obtained using HercepTest (10% cutoff) and HER2 FISH (2.0 cutoff; P 5.70) when 2+ equivocal cases were excluded. This paired t test analysis was performed by comparing the 2 sets of k values obtained from the stratified comparisons of conventional microscopy versus HER2 FISH and image analysis-assisted microscopy versus HER2 FISH (the averages of the k values are shown in Table 4). Comparison of Scoring Time of HercepTests Between Automated Image Analysis and Conventional Microscopy A difference in the scoring time for HercepTests was found among pathologists and between conventional microscopy and image analysis-assisted microscopy. The mean scoring times for the individual pathologists are plotted in the Figure. The mean (SD) scoring time (minutes:seconds) was 1:01 (0:26) using conventional microscopy and 1:31 (0:38) using ACIS-assisted scoring. The range was from 0:17 to 2:22 for manual scoring and from 0:37 to 2:58 for image analysis-assisted microscopy. A 2-tailed paired t test of the mean scoring times revealed a significant difference (P,.001). For one pathologist, a shorter scoring time using image analysis was observed, and for another, no difference in time to score was observed. HER2 Consensus Negative Positive Equivocal Status, 30% Cutoff (0 and 1+) (3+) (2+) Total COMMENT Negative (0 and 1+) The present study revealed a good concordance in the Positive (3+) IHC scores among the 7 pathologists with both the 10% Equivocal (2+) and a 30% cutoff values, and a consensus HER2 IHC Total assessment could be given to 140 (93%) and 138 (92%) of 1014 Arch Pathol Lab Med Vol 135, August 2011 HER2 Assessment in Breast Cancer Atkinson et al

6 Comparison of the mean time used to score a manual HercepTest result for one slide according to both the 10% and 30% cutoff, compared with the mean time used to score an Automated Cellular Imaging System (ACIS III) result (hour:minutes:seconds) stratified by pathologist. The error bars indicate the 95% confidence interval. the 150 patient samples in the 2 series, respectively. The study revealed 7 IHC-negative-and-FISH-positive cases (5%) out of the 140 cases that were assessed from a crosstabulation of HER2 status obtained using IHC and HER2 FISH according to the FDA-approved Dako guidelines. These cases had negative HercepTest results (IHC 0 or 1+) but were amplified by FISH. Such HER2 FISH-amplified and IHC-negative cases are well described in the literature 12 and have recently been found to represent 3.5% of IHC 0 and 5.8% of IHC 1+ cases. 20 Considering the frequency of IHC 0 and 1+ cases in this study, between 4 and 5 IHC-negative-and-FISH-positive samples would be expected. Therefore, the frequency of observed IHCnegative-and-FISH-positive cases is close to what would be expected in a study with 150 specimens. The data presented showed that there were fewer IHCnegative-and-FISH-positive instances observed when using the 30% cutoff. The FISH status of 4 IHC-negative samples changed from positive to equivocal when applying ASCO/CAP guidelines. Therefore, if the entry test method was IHC, the HER2 status would not change, but if FISH was the entry test, the ASCO/CAP guidelines might prevent the offering of trastuzumab to these 4 patients. It has been debated whether low-level HER2- amplified tumors benefit to the same extent from trastuzumab treatment as those tumors from patients with high-level amplification, 14,21 but limited data have been available. However, 2 recent studies have clarified that the benefit of HER2-targeted therapy is not related to the level of amplification, 3,22 thus, the clinical benefit for increasing the cutoff for positive FISH results seems to be lacking. The new cutoff of 2.2 has indirectly been challenged 23 by data on the prognostic value of HER2 from 1400 patients showing that low-level amplification ( ) is associated with a distinct, intermediate outcome, compared with patients with HER2 ratios of less than 1.5 and to patients with HER2 ratios greater than 2.2. Arguably, these data indicate that the cutoff for FISH should be decreased rather than increased; however, that study was done before Herceptin therapy was available. The new guidelines have further been challenged 24 by a group that considers FISH as the gold standard, suggesting FISH as the primary testing modality. One additional aspect of the ASCO/CAP guidelines that is not presently clear is the use of the new ASCO/CAP guidelines for the new FISH equivocal range. Because ASCO/CAP introduced an equivocal HER2 FISH range of 1.8 to 2.2, it is tempting to ask how a decision should be made in the clinic in cases of equivocal HER2 FISH ( ). If performed by a highly experienced laboratory, repeated testing would be expected to lead to the same result. Importantly, our study revealed that the new ASCO/CAP guidelines might have resulted in the lack of appropriate treatment for at least one patient. That patient, with a FISH ratio of 2.0, had equivocal IHC results with the 30% cutoff and positive IHC results with the 10% cutoff. Therefore, the introduction of the new guidelines may leave this patient without a firm HER2 status because both methods changed the results from positive to equivocal. Even if the same sample is stained and scored several times with both IHC and FISH, a double-equivocal finding is possible (equivocal for both IHC and FISH). For patient care, the oncologist and the patient need a yes or a no answer, and they should be confident that the most appropriate therapy is being offered. Concern regarding whether a test is the most accurate or decisions about what to do with an equivocal result are problematic. Our data also support the conclusion that there is only a limited difference in HER2 agreement between IHC and FISH when changing the cutoff levels because both the cutoff levels for IHC and FISH were increased. However, the use of the 30% cutoff raises the agreement to greater than the 95% concordance limit for positive and negative assay values 15 because an increased number of 2+ equivocal cases are excluded. The cutoff of 30% was chosen to cover the term uniformly positive 25 by the authors of the ASCO/CAP guidelines, 15 but the cutoff is not related to a specific FISH ratio. The methods (IHC and FISH) are, however, not always expected to show identical results because different biological features are being measured (DNA or protein). Instead, the methods should be considered supplementary, meaning that a patient having either a HER2 3+ score or HER2 amplification should be considered as having a positive finding. Further, even if an equivocal zone for the FISH ratio can be an advantage as a guideline for retesting or additional counting, the rationale for moving the cutoff is lacking. If the cutoff is kept at 2.0 in accordance with clinical trial data there will be no difference in patient selection between the 10% and the 30% IHC cutoff, except for more FISH analyses being required because of the larger number of 2+ cases identified when the 30% cutoff is used for 3+ scores. The time it takes to score a HercepTest result using image analysis-assisted microscopy is significant longer than it takes for manual scoring for most of the pathologists, although there were exceptions. However, the mean difference was about 30 seconds per slide. Additional observations made during this study lead to the conclusion that there is no observed difference in the concordance of HER2 status between HercepTest results and HER2 FISH pharmdx results when using conventional microscopy or image analysis-assisted microscopy. The observations showed that the use of image analysis did not impose an overall improvement or hindrance in the concordance of HER2 findings. In other words, the use of image analysis-assisted microscopy in this study did Arch Pathol Lab Med Vol 135, August 2011 HER2 Assessment in Breast Cancer Atkinson et al 1015

7 not give better overall concordance with HER2 FISH status. This might simply reflect exceptional conventional HER2 scoring by the pathologists who scored the slides in this study (eg, there was a 92.1% overall agreement between FISH and manual scoring by the Dako guidelines, excluding 2+ cases, even though the pathologists had a range of experience). The benefit of digital microscopy to pathologist accuracy has been documented. 26 Interobserver agreement was significantly higher using image analysis-assisted microscopy compared with conventional microscopy. In conclusion, this study showed that a 30% cutoff value could mean higher concordance between the testing methods for 3+ cases. However, the 30% cutoff for 3+ IHC and 2.2 for HER2 FISH ratio could mean that fewer patients would be offered treatment with HER2-targeted therapy, especially if double equivocal HER2 results (both IHC and FISH) are obtained. The use of image analysisassisted scoring increased the interobserver concordance. We thank technologists Arman Vahebzadeh and Signe Lykke Nielsen for performing the HER2 FISH analyses and R. Lee Ryan, BS, for the data collection. References 1. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235(4785): Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2/neu protooncogene in human breast and ovarian cancer. Science. 1989;244(4905): Dowsett M, Procter M, McCaskill-Stevens W, et al. 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. J Clin Oncol. 2009;27(18): Rasmussen BB, Regan MM, Lykkesfeldt AE, et al. Adjuvant letrozole versus tamoxifen according to centrally-assessed ERBB2 status for postmenopausal women with endocrine-responsive early breast cancer: supplementary results from the BIG 1-98 randomised trial. Lancet Oncol. 2008;9(1): Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11): Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005; 353(16): Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005; 353(16): Bose S, Mohammed M, Shintaku P, Rao PN. Her-2/neu gene amplification in low to moderately expressing breast cancers: possible role of chromosome 17/ Her-2/neu polysomy. Breast J. 2001;7(5): Tubbs RR, Pettay JD, Roche PC, Stoler MH, Jenkins RB, Grogan TM. Discrepancies in clinical laboratory testing of eligibility for trastuzumab therapy: apparent immunohistochemical false-positive do not get the message. J Clin Oncol. 2001;19(10): European Medicines Agency (EMEA). Herceptin: product information. human/000278/wc pdf. Published October 21, Accessed October 28, European Public Assessment Report WC Ross JS, Slodkowska EA, Symmans WF, Pusztai L, Ravdin PM, Hortobagyi GN. The HER-2 receptor and breast cancer: ten years of targeted anti-her-2 therapy and personalized medicine. Oncologist. 2009;14(4): Cuadros M, Villegas R. Systematic review of HER2 breast cancer testing. Appl Immunohistochem Mol Morphol. 2009;17(1): Hicks DG, Kulkarni S. HER2+ breast cancer: review of biologic relevance and optimal use of diagnostic tools. Am J Clin Pathol. 2008;129(2): McCormick SR, Lillemoe TJ, Beneke J, Schrauth J, Reinartz J. HER2 assessment by immunohistochemical analysis and fluorescence in situ hybridization: comparison of HercepTest and PathVysion commercial assays. Am J Clin Pathol. 2002;117(6): Wolff AC, Hammond ME, 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(1): Vang Nielsen K, Jorgensen JT, Schonau A, Oster A. Human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol. 2007;25(25):4020; author reply Yaziji H, Taylor CR. Begin at the beginning, with the tissue!: the key message underlying the ASCO/CAP task-force guideline recommendations for HER2 testing. Appl Immunohistochem Mol Morphol. 2007;15(3): Chibon F, de Mascarel I, Sierankowski G, et al. Prediction of HER2 gene status in Her2 2+ invasive breast cancer: a study of 108 cases comparing ASCO/ CAP and FDA recommendations. Mod Pathol. 2009;22(3): Dendukuri N, Khetani K, McIsaac M, Brophy J. Testing for HER2-positive breast cancer: a systematic review and cost-effectiveness analysis. CMAJ. 2007; 176(10): Brunelli M, Manfrin E, Martignoni G, et al. HER-2/neu assessment in breast cancer using the original FDA and new ASCO/CAP guideline recommendations: impact on selecting patients for Herceptin therapy. Am J Clin Pathol. 2008; 129(6): Pauletti G, Dandekar S, Rong H, et al. Assessment of methods for tissuebased detection of the HER-2/neu alteration in human breast cancer: a direct comparison of fluorescence In situ hybridization and immunohistochemistry. J Clin Oncol. 2000;18(21): Press MF, Finn RS, Cameron D, et al. HER-2 gene amplification, HER-2 and epidermal growth factor receptor mrna and protein expression, and lapatinib efficacy in women with metastatic breast cancer. Clin Cancer Res. 2008;14(23): Jensen KC, Turbin DA, Leung S, et al. New cutpoints to identify increased HER2 copy number: analysis of a large, population-based cohort with long-term follow-up. Breast Cancer Res Treat. 2008;112(3): Sauter G, Lee J, Bartlett JM, Slamon DJ, Press MF. Guidelines for human epidermal growth factor receptor 2 testing: biologic and methodologic considerations. J Clin Oncol. 2009;27(8): Moeder CB, Giltnane JM, Harigopal M, et al. Quantitative justification of the change from 10% to 30% for human epidermal growth factor receptor 2 scoring in the American Society of Clinical Oncology/College of American Pathologists guidelines: tumor heterogeneity in breast cancer and its implications for tissue microarray based assessment of outcome. J Clin Oncol. 2007;25(34): Bloom K, Harrington D. Enhanced accuracy and reliability of HER-2/neu immunohistochemical scoring using digital microscopy. Am J Clin Pathol. 2004; 121(5): Arch Pathol Lab Med Vol 135, August 2011 HER2 Assessment in Breast Cancer Atkinson et al

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