al., 2010; Phillips et al., 2009). At least seven tests to detect HER2 gene amplification and protein overexpression have Food and Drug Administration (FDA) approval for use as effect modifier markers for tumor response to trastuzumab (reviewed by Allison, 2010, and Shah and Chen, 2010). In addition, some companies have received FDA clearance for imaging analysis tools accompanying FDA-approved HER2 tests (FDA, 2011a). However, despite more than 20 years of research and development, difficulties remain in defining optimal implementation of this single-marker test (De et al., 2010), illustrating some of the profound challenges confronting developers of multianalyte, omics-based tests.

These difficulties include the number of modalities for evaluating HER2 (IHC [immunohistochemistry], FISH [fluorescent in situ hybridization], and others), the subjectivity of test results, lab-to-lab variability (central or reference laboratory versus smaller laboratories), laboratory errors leading to false positives and false negatives, differences in cut-off recommendations, and some uncertainty regarding clinical benefit of trastuzumab for patients with borderline HER2-positive results. Accurate selection of patients for therapy targeting HER2, or conversely, identification of those patients who are not likely to benefit from HER2-targeted therapy, depends on reliable HER2 testing and appropriate cut-off criteria (Kroese et al., 2007).

HER2 Testing in Clinical Practice

In 2007, a panel established by the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) recommended HER2 status determination for all invasive breast cancers (Wolff et al., 2007a,b) and clarified some of the technical limitations of both IHC and FISH (Schmitt, 2009). In 2002, substantial discordance was reported for both IHC and FISH results performed in community laboratories versus a central reference laboratory in the course of two clinical trials (Paik et al., 2002; Roche et al., 2002). In response, the ASCO/CAP panel issued recommendations for the HER2 testing process (e.g., ways to reduce lab-based errors) and interpretation (Wolff et al., 2007a,b). These guidelines alleviated some lab effects within a single HER2 testing modality, though interlab reproducibility continues to be an area of substantial concern for HER2 testing.

The choice of HER2 testing modality is also debated (Sauter et al., 2009; Schmitt, 2009). Historically, IHC has been the primary method for HER2 testing, and FISH has been used to confirm these findings, when IHC testing is equivocal. However, some assert that FISH should be the primary HER2 testing platform (Sauter et al., 2009), while others have advised that IHC alone should never be relied on for selecting anti-HER2 treatment (De et al., 2010). The ASCO/CAP recommendations did not recommend one



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