Quantitative justification of the change from 10% to 30% for human epidermal growth factor receptor 2 scoring in the American Society of Clinical Oncology/College of American Pathologists guidelines: tumor heterogeneity in breast cancer and its implications for tissue microarray based assessment of outcome.

Author(s): Moeder CB, Giltnane JM, Harigopal M, Molinaro A, Robinson A, Gelmon K, Huntsman D, Camp RL, Rimm DL

Publication: J Clin Oncol, 2007, Vol. 25, Page 5418-25

PubMed ID: 18048824 PubMed Review Paper? No

Purpose of Paper

Conclusion of Paper

Studies

1. Study Purpose

   Tumor heterogeneity was assessed by examinging variability in biomarker expression (ER, PR, HER-2) among tissue microarray (TMA) cores by immunohistochemistry. Four to five TMA cores (0.6 mm diameter) were collected from donor paraffin blocks for each of the 676 cases examined, and organized into five arrays representing identical populations. Of note, breast tumor specimens were procured 30-45 years prior to TMA construction.

   Summary of Findings:

   Correlations in biomarker expression between the five replicate TMAs were influenced by construction order, with the lowest correlation coefficients associated with the first TMA constructed. For ER, correlation coefficients ranged between 0.65 and 0.70 when comparisons to the first TMA were drawn, and 0.79 and 0.86 when comparisons among second, third, fourth, and fifth TMAs were made. A similar trend was observed for PR, while for HER-2 correlation coefficients were higher when third, fourth, and fifth TMAs were compared (0.68-0.74) as opposed to comparisons with first and second TMAs (0.40-0.63). The authors hypothesize that comparisons between later TMAs represent true heterogeneity in marker expression. To better assess the magnitude of heterogeneity, patients were ranked by the mean AQUA score for each marker and the range of expression for each patient was examined. Plots for all three markers illustrate that variability was greater in those patients with high mean AQUA scores compared to those with low scores. In order to determine whether high or low AQUA scores were more predictive of tumor behavior, risk ratios and ten-year survival plots were examined and data suggested that prognosis was best when ER and PR scores were high, and HER-2 scores were low.

   Biospecimens

   • Tissue - Breast

   Preservative Types

   • Formalin

   Diagnoses:

   • Neoplastic - Carcinoma

   Platform:

   Analyte	Technology Platform
   Protein	Immunohistochemistry
   Protein	Tissue microarray

   Pre-analytical Factors:

   Classification	Pre-analytical Factor	Value(s)
   Biospecimen Aliquots and Components	Biospecimen heterogeneity	Intratumoral sampling (exact positions not specified)
   Immunohistochemistry Specific	Targeted peptide/protein	ER PR HER-2
   Tissue microarray Specific	Construction order	1st 2nd 3rd 4th 5th

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