Clinical and Health Economic Outcomes of Alternative HER2 Test Strategies for Guiding Adjuvant Trastuzumab Therapy

James A Lee; Megan Shaheen; Thomas Walke; Matt Daly


Expert Rev Pharmacoeconomics Outcomes Res. 2011;11(3):325-341. 

In This Article


Di Palma et al. concluded in 2007 when comparing CISH and IHC in the UK, "Therefore, a frontline ISH test would be a more favourable option".[34] Di Palma et al. further point out the importance of appropriate use of chromosome 17 correction when using CISH. Our results also demonstrate that using a primary ISH test is clinically superior in terms of expected QALYs and is cost effective relative to using IHC as a primary test. Furthermore, our results support the importance of adequate use of dual-probe CISH, as all studies that failed to have greater than 95% negative and positive concordance relative to FISH used single-probe CISH alone or very rarely. Di Palma et al. conclude that CISH is more cost effective than FISH based on a lower assay cost, but did not compare therapy response and clinical outcomes when making this conclusion.

While other recent studies only considered FISH and IHC, both Lidgren et al.[24] and Blank et al.[23] also concluded that primary FISH is a cost-effective strategy relative to primary IHC testing with confirmation of equivocal IHC results. Dendukuri et al. stands out as one study of HER2 test strategies that considered economics and outcomes and concluded that confirmation of IHC 2+ and 3+ was cost effective versus confirmation of IHC 2+ only.[10] Our further analysis of the Dendukuri data confirms their conclusion and also shows that primary FISH would be a cost-effective alternative to their recommended strategy at an incremental cost of approximately US$27,250 per QALY. Note that none of the health economic and outcome studies that were identified concluded that primary IHC testing with confirmation of IHC 2+ results is an optimal test strategy.

Additional research, with direct observation of therapy response and clinical outcomes, is necessary to fully understand the relative clinical and economic outcomes of AT therapy guided by alternative ISH tests. Our analyses, however, demonstrate that predicting response to therapy, rather than assay price, is the primary determining factor in selecting an optimal test strategy. A concordance rate of 98% or higher relative to a validated reference assay appears to be warranted based on the observed AT therapy benefits and costs. Concordance below 98% favors a reference assay, even if it is US$400 more expensive, when therapy benefits and costs are considered along with test costs.

Given the substantial benefit observed in accurately guided AT therapy and the high cost and risk of side effects of AT therapy, it is imperative that highly accurate test protocols be used. As additional anti-HER2 therapies are evaluated in clinical trials and introduced into standard clinical practice, one can only expect test accuracy to become more important, since therapy benefit and cost are both likely to increase, as in the case of lapatinib.[35]

The aforementioned analysis has limitations, in particular with regard to the economic analysis, the foremost being the assumption that patients whose test result is negative with an alternative assay, yet positive with a reference assay, will achieve the same clinical benefit, measured in QALYs, as the typical patient. In the case of IHC and FISH, it is assumed that patients with an IHC 0/1+ result but FISH+ result will benefit from therapy like the average patient. Likewise, a patient with an IHC 3+ result yet FISH-negative result will not benefit from AT therapy at all.

Few studies have directly compared IHC and FISH test results for predicting AT therapy response. As summarized by Sauter et al.,[36] evidence supports the assumption that patients with IHC 3+ but FISH-negative results are unlikely to respond to therapy.[36] Owing to the fact that the pivotal trials did not include patients with IHC 0/1+ results, there is little direct evidence to support, nor refute, the assumption that patients with IHC 0/1+ and FISH-positive results will respond to AT therapy like the typical patient. That said, IHC 0/1+ and FISH+ patients can and do show significant responsiveness to some HER2-targeted therapy.[37] The same limitations apply to comparisons of CISH and SISH relative to FISH.

Furthermore, the analysis of HER2 test strategies depends on well-measured clinical costs and benefits of AT. Numerous studies have found AT therapy to be cost effective under a broad set of assumptions regarding costs, benefits and patient populations.[25] This analysis also finds that the conclusions are not dependent on reasonable assumptions of costs and benefits of AT therapy, but instead are highly dependent on the assumed accuracy of the HER2 test protocol.

Lastly, the publication of the ASCO/CAP guidelines recommending both concordance analysis and proficiency testing was subsequent to many of the studies evaluated, and test performance may have improved relative to the past. On the other hand, many of the studies represent controlled clinical trials or comparisons under relatively ideal conditions and may not be fully representative of the practice community.

In conclusion, primary ISH-based test algorithms appear to be cost saving or, at a minimum, cost effective, relative to primary IHC-based test algorithms. Differentiating between gene-based tests requires direct evaluation of response to therapy in terms of clinical and economic outcomes.


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