TRANSCRIPT
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Welcome to the ASCO Guidelines episode of the ASCO University weekly podcast. My name is Alexander Drilon, and I'm the clinical director of the early drug development service at Memorial Sloan-Kettering Cancer Center, and editorial board member for ASCO University. Today, we feature an ASCO guideline published in the Journal of Clinical Oncology. The episode you are about to hear was originally aired on the ASCO Guidelines podcast series. The ASCO Guidelines podcast series features interviews with panelists of recently published ASCO clinical practice guidelines products, highlighting recommendations and noteworthy qualifying statements made by the expert panel.
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Hello, and welcome to the ASCO Guidelines podcast series. My name is Shana McKernan, and today, I'm interviewing Dr. Antonio Wolff from Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, an author on HER2 Testing in Breast Cancer, American Society of Clinical Oncology College of American Pathologists Clinical Practice Guideline Focus Update. Thank you for being here, Dr. Wolff.
Thank you for the opportunity. It is really a privilege to be here today on behalf of all of my colleagues in the ASCO/CAP HER2 testing panel, which truly represents not just a multi-disciplinary, but a multi-society effort over many years.
First, can you give us a general overview of what this guideline covers?
The recommendations by the ASCO/CAP HER2 testing expert panel were first released in 2007 and updated in 2013. And this is now a 2018 focus update. The aim was to improve the analytic validity of HER2 testing and the utility of HER2 as a predictive biomarker for potential responsiveness to therapies targeting the HER2 protein.
In fact, in late 2017 at the San Antonio Breast Cancer Symposium, we finally had data from the NRG trial B-47, which confirmed the lack of benefit from adjuvant trastuzumab for patients whose tumors lack gene amplification and were IHC 1+ or 2+. As a result, HER2 gene amplification assessed by In Situ Hybridization-- ISH, or I-S-H, or protein overexpression assessed by immunohistochemistry, IHC, remained the primary predictors of responsiveness to HER2-targeted therapy in breast cancer.
We have seen over the years a great communication among health care providers, especially pathologists and oncologists, but also much-needed infrastructure support by administrative teams regarding specimen handling in lab facilities. And they have resulted in meaningful improvements in the analytic performance and accuracy of HER2 testing.
We also have had greater clinical experience with the efficacy and safety of HER2-targeted therapies that resulted in a meaningful reduction in the high frequency of false-positive HER2 test results that were observed in the mid 2000s. And this led to the 2013 guideline update panel to provide further guidance regarding less-common clinical scenarios to allow greater discrimination between positive and negative results.
Since 2013, since the 2013 update, several labs and clinical investigators have reported on the practical implications of the guideline update and the observed frequency of equivocal cases. And these results have allowed the panel recently to evaluate the observed frequency of less-common HER2 testing patterns, the apparent prognostic and predictive value when retrospectively analyzed within clinical trial data sets, and the critical need to understand the underlying distribution of HER2 immunohistochemistry test results in cases that were submitted for additional tests, specifically In Situ Hybridization by a reference lab. This all led to the ASCO/CAP HER2 testing panel to prepare and now issue this 2018 HER2 testing focus update that includes five key recommendations.
What are the key recommendations of this guideline?
The HER2 testing guideline panel identified five clinical questions that formed the core of the 2018 focus update. Clinical question one is, what is the most appropriate definition of IHC 2+ or IHC equivocal. And clinical question two asks whether HER2 testing must be repeated on a surgical specimen if initially negative tests on a core biopsy. And these two questions were addressed in a previous correspondence by the panel that was published in the JCO in 2015. And they referred specifically to Figure 1, the algorithm for immunohistochemistry testing, and Table 2, the histopathologic features suggestive of possible test discordance.
Clinical questions three, four, and five address less-common patterns observed when performing dual-probe In Situ Hybridization testing, and are now graphically summarized in four different figures, Figures 3 to 6, that focus on the algorithm for dual-probe In Situ Hybridization testing. And these three questions help clarify the 2013 recommendations that led some labs to adopt the use of multiple alternative chromosome 17 probe testing as the sole strategy to resolve equivocal HER2 test results by In Situ Hybridization, despite limited evidence on analytical and clinical validity of such strategy.
The three additional questions of the 2018 focus updates are clinical question three, should invasive cancers with HER2/CEP17 ratio of 2.0 or higher, but an average HER2 copy number of less than 4 signals per cell, be considered ISH-positive. Clinical question four, should the invasive cancers with an average HER2 copy number of 6.0 or greater signals per cell, but a HER2/CEP17 ratio of less than 2.0 be considered ISH-positive? And finally, clinical question five, what is the appropriate diagnostic workup for invasive cancers with an average HER2 copy number 4.0 or higher, but less than 6.0 signals per cell, and a HER2/CEP17 ratio less than 2.0, and initially found to have an equivocal HER2 ISH test result.
The recommendations regarding dual-probe ISH testing also led to a change in figure 2 that describes the algorithm for single-probe ISH testing, and includes a new footnote with a recommendation that concomitant immunohistochemistry review should become part of the interpretation of single-probe In Situ Hybridization results.
The 2018 HER2 testing focus update also includes a new Table 3 that describes the patterns of HER2 ISH testing using dual probe assays showing a clear impact of the underlying distribution of HER2 immunohistochemistry test results on the frequency of these less common patterns of In Situ Hybridization.
As we expect, in total, groups 2, 3, and 4 will represent no more than 5% of all cases tested by In Situ Hybridization. And the majority, 95% of cases, tested for HER2 by dual-probe In Situ Hybridization will consist of group 1, which are clearly HER2-positive , and group 5, HER2-negative. And ultimately, the available clinical outcome data from related trials, although of limited statistical power, have allowed the panel to more carefully define this expected prognostic and predictive behavior of cases tested by dual-probe In Situ Hybridization that will fall in groups 2, 3, or 4.
What are the major changes from the 2013 version of this guideline?
Most important, after consideration of the available evidence and expert opinions, the ASCO/CAP HER2 testing panel revised the diagnostic approach to groups 2, 3, and 4 to include more rigorous interpretation criteria for dual-probe In Situ Hybridization testing, and to require concomitant immunohistochemistry review to arrive at the most accurate HER2 status designation, positive or negative, based on the combined interpretation of the ISH and the IHC assays.
The panel therefore recommends that such concomitant review be performed in the same institution to ensure parallel interpretation and quality of the two assays. As a result, most group 2 specimens will not be confirmed as HER2-positive, as very few will be immunohistochemistry 3+, and most group 4 specimens will be confirmed HER2-negative without the need for additional testing, use alternative probes, which happen a lot since 2013.
At the same time, group 3 specimens will be a mixed group of results with a small number of cases shown to be amplified, and a larger number shown not to be amplified. And so for these dual-probe ISH group 3 cases, the panel allows specimens that are IHC 2+ to be considered HER2-positive. And the rationale is described in greater detail in the manuscript.
And finally, how will these guideline recommendations affect patients?
While the main focus was to clarify the less common test results observed with the two-probe ISH assays, the recommendations do impact users of single-probe ISH assays. As such, the panel now recommends that concomitant immunohistochemistry review should become part of the interpretation of single-probe In Situ Hybridization results to allow a more accurate HER2 designation. And this is nicely described in Figure 2.
And the panel also preferentially recommends the use of dual-probe instead of single-probe ISH assays, while it recognizes that several single-probe ISH assays have regulatory approval in many parts of the world. At the end, and to conclude, these actions, we hope, will reduce the already small number of cases that have HER2 test results that are unresolved, will reduce the frequency of alternative group testing, and will remind us all of the importance of integrating the information provided by both types of assay platforms, IHC and ISH, in difficult cases, as we expect these results to be concordant in the vast majority of cases, when expertly performed.
Thank you for your insights on this guideline, and thank you for your time today, Dr. Wolff.
Thank you so much.
And thank you to all of our listeners for tuning in to the ASCO guidelines podcast series. If you've enjoyed what you've heard today, please rate and review the podcast and refer the show to a colleague.
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The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
