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Reproducibility <strong>of</strong> Her-/2neu analysis: analytical and clinical<br />
implications<br />
Angelo Paradiso1, Paolo Verderio2<br />
1Scientific Direction, National Cancer Institute, Bari, Italy; 2Medical Statistics and Biometry, Fondazione<br />
IRCCS, Istituto Nazionale dei Tumori, Milan, Italy<br />
The clinical interest in HER-2/neu is related to Trastuzumab, a drug used to treat patients<br />
with invasive breast carcinoma overexpressing the HER-2/neu protein. As suggested by<br />
the Food and Drug Administration (FDA) guidelines, the eligibility <strong>of</strong> breast cancer<br />
patients for treatment with Trastuzumab is based on the accuracy <strong>of</strong> the assessment <strong>of</strong> the<br />
HER-2/neu status <strong>of</strong> the tumor (Lidgren, 2007). However, the specificity <strong>of</strong> Her-2/neu<br />
immunohistochemical analysis remains still unsatisfactory. Several attempts have been<br />
done to improve the performances <strong>of</strong> the assay.<br />
Recently, the using <strong>of</strong> higher cut-<strong>of</strong>f for the percentage <strong>of</strong> positive cells has been proposed<br />
with interesting results (Hameed, 2007). However, the quality <strong>of</strong> the assessment <strong>of</strong> the<br />
HER-2/neu status has been stressed as a crucial point to correctly identify patients who<br />
may benefit from Trastuzumab.<br />
The results <strong>of</strong> several Quality Control (QC) programs for IHC determination <strong>of</strong> HER-<br />
2/neu have been published and among them, the programs <strong>of</strong> UK-NEQAS (United<br />
Kingdom National External Quality Assessment Service) are perhaps the longest lasting<br />
and involving the largest number <strong>of</strong> laboratories. In particular, the UK-NEQAS program<br />
focused its attention on pre-analytical aspects <strong>of</strong> the IHC assay. Conversely, the INQAT<br />
Group (Italian Network for Quality Assessment <strong>of</strong> Tumour Biomarkers) developed a<br />
QC program concerning the analytical phase <strong>of</strong> HER-2/neu determination in Italy.<br />
The INQAT program investigated inter-intra laboratory reproducibility <strong>of</strong> the optical<br />
microscope analysis on a set <strong>of</strong> IHC slides.<br />
The combined analysis <strong>of</strong> these two QC programs permit to make interesting comments:<br />
the need for each laboratory to have an overall picture <strong>of</strong> the quality <strong>of</strong> the whole process<br />
<strong>of</strong> the biomarker<br />
l34<br />
determination and a better understanding <strong>of</strong> the possible reasons <strong>of</strong> its<br />
questionable performance during the different phases <strong>of</strong> the biomarker determination; the<br />
need to implement quality control programs focused on the whole process <strong>of</strong> biomarker<br />
determination moving from standardization <strong>of</strong> reagents and techniques to reproducibility<br />
<strong>of</strong> biomarker analysis at optical microscope. These items are relevant in clinical practice<br />
where the treatment choice is based on categories defined by this assay, suggesting the need<br />
<strong>of</strong> adopting educational programs and/or new reference materials to improve the assay<br />
performance.<br />
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