Editorials
Progress in Implementing HER2 Testing Guidelines Patrick L. Fitzgibbons, MD; David G. Hicks, MD
P
ublication of the 2007 American Society of Clinical Oncology/College of American Pathologists (CAP) guideline recommendations for human epidermal growth factor receptor 2 (HER2) testing in breast cancer represented a significant development in cancer biomarker testing that links the analysis of human tumor samples to specific therapies.1 The recommendations addressed preanalytic and analytic variables, such as fixation time and assay validation, which had not previously been standardized across clinical laboratories. Although hormone receptor and HER2 testing had been in routine practice long before that publication, the guidelines helped to (1) focus attention on the need for more stringent control of assay conditions and interpretation criteria, and (2) change how pathologists view predictive factor testing vis-a-vis ` non-predictive factor (lineage) testing. Pathologists had substantial experience in testing different specimen and tumor types, but the guidelines heightened awareness of the differences between lineage markers with qualitative results, where individual results are only relevant within the context of the clinical and histologic features, and quantitative predictive marker tests, where a single test result drives a treatment decision. A 2008 CAP survey of laboratories indicated that few laboratories had been able to fully comply with all HER2 testing recommendations.2 This was not unexpected because the survey was created not long after the guidelines’ publication, and the time was insufficient for the substantial changes to the institutional (eg, changing how surgical cases are scheduled and transported) and accreditation processes needed to comply. That initial survey was expected to be a baseline with which improvements could be compared. The survey was repeated in 2011 to assess progress in implementation and is published in this issue of Archives of Pathology & Laboratory Medicine.3 The results of the latest survey suggest that laboratories face challenges in meeting the requirements specified in the guidelines, particularly those related to assay validation; however, other evidence Accepted for publication February 18, 2014. From the Department of Pathology, St Jude Medical Center, Fullerton, California (Dr Fitzgibbons); and the Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York (Dr Hicks). The authors have no relevant financial interest in the products or companies described in this article. doi: 10.5858/arpa.2014-0064-ED Reprints: Patrick L. Fitzgibbons, MD, Department of Pathology, St Jude Medical Center, 101 E Valencia Mesa Dr, Fullerton, CA 92835 (e-mail; [email protected]). Arch Pathol Lab Med—Vol 138, July 2014
suggests that laboratories have actually made substantial progress in improving test performance. There are few data on how laboratories have addressed the guidelines since 2007, but substantial progress in complying with some elements is relatively easy to document. The effect of the guidelines is most easily measured by the response to the requirement for laboratory participation in an external proficiency testing (PT) program. In 2006, the year the guidelines were being written, the CAP PT program for HER2 by immunohistochemistry (IHC) had 157 participants. At the end of 2007, there were 508 participating laboratories, and by the end of 2013, the number had risen to 1269. Results from that program also show that 7% of laboratories in 2007 were using something other than 10% neutral-buffered formalin, but by 2013, only 2.6% were still using an alternative fixative. Also see p. 876. Although the latest survey indicates that implementation of the testing guideline remains incomplete and that more progress is needed, it would be a mistake to conclude that the testing community has failed to address issues outlined in the guidelines. Indeed, there is ample evidence that laboratories have improved HER2 testing since the publication of the guidelines. For example, participating laboratories have shown excellent performance on external PT challenges since 2011. In the A mailing of the 2011 HER2 (IHC) Survey, 1044 of 1066 laboratories (97.9%) that returned completed result forms had satisfactory performance (90% correct responses). In 2013, satisfactory PT performance was achieved by 98.6% (1210 of 1227) of the laboratories that returned completed result forms. Survey results suggesting failure of a significant number of laboratories to address guideline elements are also not reflected in the findings of the CAP Laboratory Accreditation Program (LAP). On-site inspection is a more objective means of assessing laboratory performance than selfreported surveys, and the results of the LAP inspections have not revealed the types of problems suggested in the 2011 survey. The LAP checklist item ANP.22997, introduced in 2007 after publication of the guidelines, assesses whether the laboratory had documented appropriate validation for its HER2 assays. In 2012, only 0.3% of inspected laboratories were cited for a deficiency on that item. Those voluntary surveys relied on self-reported metrics and are necessarily incomplete assessments of laboratory practices. In addition, there were likely differences in how questions were interpreted by those completing the survey. Editorial—Fitzgibbons & Hicks 863
When the guidelines were first published, it was anticipated that some pathologists would choose to send cases to reference laboratories for staining because of difficulty in complying with the analytic requirements set out in the recommendations. It is not known how many laboratories that offered HER2 testing by IHC in 2007 decided because of the guidelines to discontinue staining inhouse (or to discontinue both staining and interpretation), but the surveys suggest that did occur: 18.6% (137 of 735) of the respondents in the 2008 survey reported that they sent blocks to another laboratory for staining, but that increased to 25.5% (243 of 954) in the 2011 survey. An interesting finding in the most recent survey is that ‘‘new’’ survey respondents—those who were not part of the 2008 survey— were significantly more likely to send blocks to an outside laboratory for staining than were existing participants (36% [43 of 118] versus 24% [200 of 936]). Because those laboratories were not part of the original survey, we cannot say with certainty that the guidelines were the reason for the difference, but it is indirect evidence that laboratories having difficulty complying with guideline elements often decide to discontinue staining. Laboratories are still working to achieve full compliance with the testing recommendations, which is not surprising given the complexity of the test process and the variety of laboratory settings. Laboratories differ dramatically in the source(s) of tissue specimens, the ability to control specimen handling, the availability of validation materials, and, of course, financial and human resources; all of this can lead to differences in how laboratories address compliance. Reference laboratories, for example, generally cannot control fixative type and time of fixation, 2 of the most important guideline elements. Incomplete compliance may also be related to issues not easily addressed through standardized guidelines. Better understanding of some of those difficulties led to changes in the LAP checklist requirements and to the recently updated HER2 testing guidelines.4 For instance, recommendations on initial assay validation were changed to address differences between the procedures for verification of assay performance required for US Food and Drug Administration (FDA)-approved tests and the assay validation requirements for laboratory-developed tests. The limitations notwithstanding, these 2 surveys provide useful information for those interested in working toward achieving optimal laboratory testing for this important, predictive biomarker. Recognizing the challenges to achiev-
864 Arch Pathol Lab Med—Vol 138, July 2014
ing full compliance with the guidelines, the CAP continues to develop a variety of programmatic and educational tools to assist pathologists and laboratories, including courses at annual meetings, online and faculty-led programs in breast predictive factors and multidisciplinary breast pathology, HER2-related Webinars (the last having more than 1000 registrants), and a dedicated HER2 resource page. The CAP Pathology and Laboratory Quality Center recently convened an expert panel to develop evidence-based guidelines on initial validation for IHC assays.5 Although those validation guidelines do not encompass hormone receptor and HER2 tests, they will provide laboratories with the framework needed for ensuring that all assays are properly validated. The assessment of HER2 status in breast cancer is critical for the management of this disease and is, therefore, a priority for standardization.6 The selection of the most appropriate adjuvant treatment regimen depends on reliable and accurate laboratory results to determine whether the patient is a candidate for anti-HER2 therapy. Among the most important lessons learned from HER2 testing is the need to standardize all testing parameters regardless of test method. Laboratories have made great strides in improving HER2 testing, but continued support is needed to ensure that progress continues. References 1. 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. Arch Pathol Lab Med. 2007;131(1):18–43. 2. Nakhleh RE, Grimm EE, Idowu MO, Souers RJ, Fitzgibbons PL. Laboratory compliance with the American Society of Clinical Oncology/College of American Pathologists guidelines for human epidermal growth factor receptor 2 testing: a College of American Pathologists survey of 757 laboratories. Arch Pathol Lab Med. 2010;134(5):728–734. 3. Dyhdalo KS, Fitzgibbons PL, Goldsmith JD, Souers R, Nakhleh RE. Laboratory compliance with the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) Human Epidermal Growth Factor Receptor 2 Testing Guidelines: a 3-year comparison of validation procedures. Arch Pathol Lab Med. 2014;138(5). In press. 4. Wolff AC, Hammond ME, Hicks DG, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update [published online ahead of print October 7, 2013]. Arch Pathol Lab Med. 2014;138(2):241–256. doi:10.5858/arpa.2013-0953-SA. 5. Fitzgibbons PL, Bradley LA, Fatheree LA, et al. Principles of analytic validation of immunohistochemical assays: guideline from the CAP Pathology and Laboratory Quality Center [published ahead of print March 19, 2014]. Arch Pathol Lab Med. doi:10.5858/arpa.2013-0610-CP. 6. Hicks, DG, Kulkarni S. Trastuzumab as adjuvant therapy for early breast cancer: the importance of accurate human epidermal growth factor receptor 2 testing. Arch Pathol Lab Med. 2008;132(6):1008–1015.
Editorial—Fitzgibbons & Hicks
Copyright of Archives of Pathology & Laboratory Medicine is the property of College of American Pathologists and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Progress in Implementing HER2 Testing Guidelines Patrick L. Fitzgibbons, MD; David G. Hicks, MD
P
ublication of the 2007 American Society of Clinical Oncology/College of American Pathologists (CAP) guideline recommendations for human epidermal growth factor receptor 2 (HER2) testing in breast cancer represented a significant development in cancer biomarker testing that links the analysis of human tumor samples to specific therapies.1 The recommendations addressed preanalytic and analytic variables, such as fixation time and assay validation, which had not previously been standardized across clinical laboratories. Although hormone receptor and HER2 testing had been in routine practice long before that publication, the guidelines helped to (1) focus attention on the need for more stringent control of assay conditions and interpretation criteria, and (2) change how pathologists view predictive factor testing vis-a-vis ` non-predictive factor (lineage) testing. Pathologists had substantial experience in testing different specimen and tumor types, but the guidelines heightened awareness of the differences between lineage markers with qualitative results, where individual results are only relevant within the context of the clinical and histologic features, and quantitative predictive marker tests, where a single test result drives a treatment decision. A 2008 CAP survey of laboratories indicated that few laboratories had been able to fully comply with all HER2 testing recommendations.2 This was not unexpected because the survey was created not long after the guidelines’ publication, and the time was insufficient for the substantial changes to the institutional (eg, changing how surgical cases are scheduled and transported) and accreditation processes needed to comply. That initial survey was expected to be a baseline with which improvements could be compared. The survey was repeated in 2011 to assess progress in implementation and is published in this issue of Archives of Pathology & Laboratory Medicine.3 The results of the latest survey suggest that laboratories face challenges in meeting the requirements specified in the guidelines, particularly those related to assay validation; however, other evidence Accepted for publication February 18, 2014. From the Department of Pathology, St Jude Medical Center, Fullerton, California (Dr Fitzgibbons); and the Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York (Dr Hicks). The authors have no relevant financial interest in the products or companies described in this article. doi: 10.5858/arpa.2014-0064-ED Reprints: Patrick L. Fitzgibbons, MD, Department of Pathology, St Jude Medical Center, 101 E Valencia Mesa Dr, Fullerton, CA 92835 (e-mail; [email protected]). Arch Pathol Lab Med—Vol 138, July 2014
suggests that laboratories have actually made substantial progress in improving test performance. There are few data on how laboratories have addressed the guidelines since 2007, but substantial progress in complying with some elements is relatively easy to document. The effect of the guidelines is most easily measured by the response to the requirement for laboratory participation in an external proficiency testing (PT) program. In 2006, the year the guidelines were being written, the CAP PT program for HER2 by immunohistochemistry (IHC) had 157 participants. At the end of 2007, there were 508 participating laboratories, and by the end of 2013, the number had risen to 1269. Results from that program also show that 7% of laboratories in 2007 were using something other than 10% neutral-buffered formalin, but by 2013, only 2.6% were still using an alternative fixative. Also see p. 876. Although the latest survey indicates that implementation of the testing guideline remains incomplete and that more progress is needed, it would be a mistake to conclude that the testing community has failed to address issues outlined in the guidelines. Indeed, there is ample evidence that laboratories have improved HER2 testing since the publication of the guidelines. For example, participating laboratories have shown excellent performance on external PT challenges since 2011. In the A mailing of the 2011 HER2 (IHC) Survey, 1044 of 1066 laboratories (97.9%) that returned completed result forms had satisfactory performance (90% correct responses). In 2013, satisfactory PT performance was achieved by 98.6% (1210 of 1227) of the laboratories that returned completed result forms. Survey results suggesting failure of a significant number of laboratories to address guideline elements are also not reflected in the findings of the CAP Laboratory Accreditation Program (LAP). On-site inspection is a more objective means of assessing laboratory performance than selfreported surveys, and the results of the LAP inspections have not revealed the types of problems suggested in the 2011 survey. The LAP checklist item ANP.22997, introduced in 2007 after publication of the guidelines, assesses whether the laboratory had documented appropriate validation for its HER2 assays. In 2012, only 0.3% of inspected laboratories were cited for a deficiency on that item. Those voluntary surveys relied on self-reported metrics and are necessarily incomplete assessments of laboratory practices. In addition, there were likely differences in how questions were interpreted by those completing the survey. Editorial—Fitzgibbons & Hicks 863
When the guidelines were first published, it was anticipated that some pathologists would choose to send cases to reference laboratories for staining because of difficulty in complying with the analytic requirements set out in the recommendations. It is not known how many laboratories that offered HER2 testing by IHC in 2007 decided because of the guidelines to discontinue staining inhouse (or to discontinue both staining and interpretation), but the surveys suggest that did occur: 18.6% (137 of 735) of the respondents in the 2008 survey reported that they sent blocks to another laboratory for staining, but that increased to 25.5% (243 of 954) in the 2011 survey. An interesting finding in the most recent survey is that ‘‘new’’ survey respondents—those who were not part of the 2008 survey— were significantly more likely to send blocks to an outside laboratory for staining than were existing participants (36% [43 of 118] versus 24% [200 of 936]). Because those laboratories were not part of the original survey, we cannot say with certainty that the guidelines were the reason for the difference, but it is indirect evidence that laboratories having difficulty complying with guideline elements often decide to discontinue staining. Laboratories are still working to achieve full compliance with the testing recommendations, which is not surprising given the complexity of the test process and the variety of laboratory settings. Laboratories differ dramatically in the source(s) of tissue specimens, the ability to control specimen handling, the availability of validation materials, and, of course, financial and human resources; all of this can lead to differences in how laboratories address compliance. Reference laboratories, for example, generally cannot control fixative type and time of fixation, 2 of the most important guideline elements. Incomplete compliance may also be related to issues not easily addressed through standardized guidelines. Better understanding of some of those difficulties led to changes in the LAP checklist requirements and to the recently updated HER2 testing guidelines.4 For instance, recommendations on initial assay validation were changed to address differences between the procedures for verification of assay performance required for US Food and Drug Administration (FDA)-approved tests and the assay validation requirements for laboratory-developed tests. The limitations notwithstanding, these 2 surveys provide useful information for those interested in working toward achieving optimal laboratory testing for this important, predictive biomarker. Recognizing the challenges to achiev-
864 Arch Pathol Lab Med—Vol 138, July 2014
ing full compliance with the guidelines, the CAP continues to develop a variety of programmatic and educational tools to assist pathologists and laboratories, including courses at annual meetings, online and faculty-led programs in breast predictive factors and multidisciplinary breast pathology, HER2-related Webinars (the last having more than 1000 registrants), and a dedicated HER2 resource page. The CAP Pathology and Laboratory Quality Center recently convened an expert panel to develop evidence-based guidelines on initial validation for IHC assays.5 Although those validation guidelines do not encompass hormone receptor and HER2 tests, they will provide laboratories with the framework needed for ensuring that all assays are properly validated. The assessment of HER2 status in breast cancer is critical for the management of this disease and is, therefore, a priority for standardization.6 The selection of the most appropriate adjuvant treatment regimen depends on reliable and accurate laboratory results to determine whether the patient is a candidate for anti-HER2 therapy. Among the most important lessons learned from HER2 testing is the need to standardize all testing parameters regardless of test method. Laboratories have made great strides in improving HER2 testing, but continued support is needed to ensure that progress continues. References 1. 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. Arch Pathol Lab Med. 2007;131(1):18–43. 2. Nakhleh RE, Grimm EE, Idowu MO, Souers RJ, Fitzgibbons PL. Laboratory compliance with the American Society of Clinical Oncology/College of American Pathologists guidelines for human epidermal growth factor receptor 2 testing: a College of American Pathologists survey of 757 laboratories. Arch Pathol Lab Med. 2010;134(5):728–734. 3. Dyhdalo KS, Fitzgibbons PL, Goldsmith JD, Souers R, Nakhleh RE. Laboratory compliance with the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) Human Epidermal Growth Factor Receptor 2 Testing Guidelines: a 3-year comparison of validation procedures. Arch Pathol Lab Med. 2014;138(5). In press. 4. Wolff AC, Hammond ME, Hicks DG, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update [published online ahead of print October 7, 2013]. Arch Pathol Lab Med. 2014;138(2):241–256. doi:10.5858/arpa.2013-0953-SA. 5. Fitzgibbons PL, Bradley LA, Fatheree LA, et al. Principles of analytic validation of immunohistochemical assays: guideline from the CAP Pathology and Laboratory Quality Center [published ahead of print March 19, 2014]. Arch Pathol Lab Med. doi:10.5858/arpa.2013-0610-CP. 6. Hicks, DG, Kulkarni S. Trastuzumab as adjuvant therapy for early breast cancer: the importance of accurate human epidermal growth factor receptor 2 testing. Arch Pathol Lab Med. 2008;132(6):1008–1015.
Editorial—Fitzgibbons & Hicks
Copyright of Archives of Pathology & Laboratory Medicine is the property of College of American Pathologists and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
