Abstract
BackgroundHER2/Neu (ErbB-2) overexpression, which occurs in 15–20% of breast cancer cases, is associated with better response to treatment with the drug trastuzumab. PhosphoHER2 (pHER2) has been evaluated for prediction of response to trastuzumab. Both markers are heterogeneously detected and are potentially subject to loss as a consequence of delayed time to fixation. Here, we quantitatively assess both markers in core needle biopsies (CNBs) and matched tumor resections to assess concordance between the core and the resection and between HER2 and pHER2.MethodsA selected retrospective collection of archival breast cancer cases yielded 67 cases with both core and resection specimens. Both HER2 and pTyr1248HER2 were analyzed by the AQUA® method of quantitative immunofluorescence on each specimen pair.ResultsBoth HER2 immunoreactivity (P<0.0001) and pTyr1248HER2 immunoreactivity (P<0.0001) were lower in resections relative to CNB specimens. However, clinical implications of this change may not be evident since no case changed from 3+ (CNB) to negative (resection). Assessment of pTyr1248HER2 showed no direct correlation with HER2 in either CNB or resection specimens.ConclusionsThe data suggest that measurement of both HER2 and phospho- Tyr1248HER2, in formalin-fixed tissue by immunological methods is significantly affected by pre-analytic variables. The current study warrants the adequate handling of resected specimens for the reproducible evaluation of HER2 and pHER2. The level of pTyr1248HER2, was not correlated to total HER2 protein. Further studies are required to determine the significance of these observations with respect to response to HER2 directed therapies.
Highlights
Immunohistochemistry (IHC) as a method to measure HER2 expression is a standard part of the assessment of breast cancer specimens
Cohorts Formalin-fixed paraffin-embedded (FFPE) primary invasive breast cancer tumors were obtained from 67 patients with infiltrating ductal carcinoma or Ductal Carcinoma in Situ (DCIS) of the breast who underwent core needle biopsies and subsequent surgeries at Yale University/New Haven Hospital from 2001 to 2009
CB11 AQUA was positive for both BT474 and SKBR3 cell lines, which are known to over-express HER2
Summary
Immunohistochemistry (IHC) as a method to measure HER2 expression is a standard part of the assessment of breast cancer specimens. Other studies have confirmed this discordance rate, including a prospective study showing that up to 20% of HER2 tests were not reproducible [1]. These observations raised questions about the source of discordance and the relative contributions of true tumor heterogeneity versus artifactual variation as a result of delayed time to fixation or other technical variables. PhosphoHER2 (pHER2) has been evaluated for prediction of response to trastuzumab Both markers are heterogeneously detected and are potentially subject to loss as a consequence of delayed time to fixation. We quantitatively assess both markers in core needle biopsies (CNBs) and matched tumor resections to assess concordance between the core and the resection and between HER2 and pHER2
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