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HER2 Testing and Correlation With Efficacy of Trastuzumab Therapy

HER2 Testing and Correlation With Efficacy of Trastuzumab Therapy

This excellent review by Drs. Fornier, Risio, Van
Poznak,
and Seidman provides an explanation of the regulatory pathways of cell
proliferation that involve the epidermal growth factor receptor (EGFR) family.
Ultimately, the authors focus on the differences in HER2 testing methods and,
most importantly, the correlation between immunohistochemistry, fluorescence in
situ hybridization (FISH), and clinical response. Unfortunately, in most of the
reported studies, the concordance between immunohistochemistry and FISH may not
reflect the real world of HER2 testing, because they use the results of both
immunohistochemistry and FISH testing performed in experienced reference
laboratories.

The need for accurate determination of HER2 status is becoming more apparent,
as therapeutic decisions are based mainly on testing in the advanced setting,
and now on clinical trials evaluating trastuzumab (Herceptin) in combination
with polychemotherapy in the adjuvant setting. Which test should be used to
determine eligibility for therapy? Of greater concern and controversy, however,
is the level of concordance between local and central laboratories.

Concordance Between Assays

Consistently, multiple reports have demonstrated high concordance between
FISH and immunohistochemistry for cases scored as 0 and 3, especially when the
testing was performed in highly experienced laboratories. In contrast, low
concordance has been found for immunohistochemistry scores of 1+ or 2+.

One such important concordance study was presented by Mass and colleagues,
who detected gene amplification in 3%, 7%, 24%, and 89% of samples with 0, 1+,
2+, 3+ HER2 overexpression by immunohistochemistry, respectively.[1] Of note,
this study had an artificially selected equal number of patients scored as
negative (0 or 1+) and positive (2+ or 3+) by immunohistochemistry. This
arbitrary division does not reflect the actual proportion of patients with these
immunohistochemistry levels in the general breast cancer population. Tubbs et
al[2] have reached the same conclusions and have determined that the largest
source of discordance involves HercepTest scores of 2+, again with a high rate
of false-positive results.

A large cohort of patients analyzed by Perez and collaborators demonstrated
that among patients with HER2 overexpression scores of 2+, only a minority had
high levels of gene amplification.[3] This information should be seriously
considered, because both of the large single-agent trastuzumab trials included
patients with 2+ or 3+ HER2 overexpression by immunohistochemistry. As will be
discussed later, retrospective analysis showed that only 1 of 65
immunohistochemistry-positive but FISH-negative patients derived clinical
benefit from trastuzumab therapy.

Another important concordance study of 117 breast cancer specimens was
recently reported.[4] Press et al found that the accuracy of the FISH assays was
high—97.4% for the Vysis PathVision and 95.7% for the Ventana INFORM test. The
immunohistochemistry assay with the highest accuracy was the R60 polyclonal
antibody with 96.6% and 95.7% for the 10H8 monoclonal immunohistochemistry antibody. Interestingly, the lowest accuracy was for the two commercially
available immunohistochemistry tests, the Dako Hercep
Test (88.9%) and the Ventana C11 monoclonal antibody (89.7%).

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