Concordance Between Local and Central Laboratories

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Data published by Perez et al. showed that in the North Central Cancer Treatment Group (NCCTG) N9831 trial, when local and central evaluation used the same methodology, the level of concordance was 80.6% for HercepTest IHC and 87% for FISH. Concordance between local testing by non-HercepTest IHC and central testing by IHC or FISH was 73.9%. Among the discordant cases examined at the reference laboratory, there was 94.5% agreement for IHC (0, 1+, and 2+) and 95.1% agreement for FISH regarding nonamplified samples. Paik et al. had reported high level of discordance between local and central IHC testing. But when IHC is performed in experienced laboratories (those performing more than 100 tests per month), the concordance rate of local versus central IHC increased to 98% (8). These data indicate discordance between local and central testing for both IHC and FISH but a high degree of agreement between the central and reference laboratories regarding the discordant cases and support the importance of using highvolume, experienced laboratories for HER2 testing to improve the process of selecting patients likely to benefit from trastuzumab therapy (8a).

The predictability of different testing methods has been evaluated in various studies, including an analysis conducted by the FDA utilizing the data from the original and pivotal H0648 g trial, which evaluated chemotherapy versus chemotherapy and trastuzumab in patients with HER2-positive breast cancer (at that time defined as 2+ or 3+ via the clinical trial assay).

Sponsor analysis of the H0648 g trial in data presented to the FDA shows that IHC 3+ benefited irrespectively of FISH status (i.e., both FISH+ and FISH-derived benefit with trastuzumab). However, 2+ did not derive benefit, again irrespective of FISH status. Similarly, FISH+ patients (regardless of IHC scores) derived greater clinical benefit from the addition of trastuzumab to chemotherapy than did patients with FISH- tumors.

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