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 Immunohistochemical Markers  ER PR HER2 and others from Genzyme

ER and PR stain the nucleus of the cell. HER2 on the other hand, extends through the cell membrane and carries signals from the outside to the inside of the cell. Genzyme also recommends the prognostic indicators Ki-67 and p53.

ER and PR (estrogen and progesterone) nuclear levels are positively correlated with response to hormonal therapy and clinical outcome. Genzyme reports a sample as postive for ER/PR when nuclear receptors are detected at or above 5% total nuclear receptor composition.

HER2 cell membrane content is assessed by immunohistochemistry (IHC) and by Fluorescent In-Situ Hybridization (FISH).
HER2 IHC assessment is reported positive when "uniform and intense staining of the complete cell membrane is observed in > 30% of tumor cells" (Genzyme). Genzyme's HER2 IHC positivity status indicates they believe Trastuzumab (Herceptin) may be beneficial.

According to FDA standards, HER2 composition is actually stratified by composition, with level "0" equal to < 20,000 receptors per cell and less than 10% of cells overexpressing HER2, up to level 3+ which is defined as 2 million receptors per cell and > 10% of cells overexpressing HER2. The FDA considers 3+ status as indication for Trastuzumab. Genzyme's conservative approach to recommendation of Trastuzumab is likely due to reports that Trastuzumab is only therapeutic when it reverses the effects of overactive HER2 receptors, and is not beneficial or may cause harm when HER2 is not overexpressed.

HER2 FISH amplification tests are used in predicting resistance to chemotherapy and likely beneficial response to anthracycline agents (adriamycin), and to Trastuzumab. HER2 FISH is considered the "gold standard" in determining response to Trastuzumab, but it is expensive as compared to IHC methods and is indicated when IHC methods produce an equivocal response (equivocal defined as FDA IHC score of less than 3+ but greater than 1+).  It should also be noted that IHC is considered to have other limitations including accuracy and reproducibility, as compared with FISH.  Many oncologists will order both regardless of IHC outcome if the financial resources are available. As a note, a history of heart disease can be a contraindication for Trastuzumab therapy. Large studies have shown that when all-cause morbidity is considered, 25 to 100 patients must be treated to save a single life with Trastuzumab. For each life saved 10-25 patients will develop heart disease, and some will die despite appropriate therapy. Trastuzumab is no "cure all" in patients who meet therapy criteria [1]. Trastuzumab is also very expensive, in the range of $100,000 per year.

Ki-67 is a nuclear protein associated with ribosomal RNA transcription produced by the MKI67 gene and is utilized to count the number of cells in phases G1, S, G2 and Mitosis / Cytokenesis. Inactivation leads to inhibition of ribosomal RNA synthesis. Ki-67 is absent from cells resting in G0. Ki-67 levels have been proven as prognostic for survival and tumor recurrence in breast cancer (and also prostate and brain). Genzyme reports an unfavorable result if > 20% of the cell nuclei in the sample stain positive for Ki-67.

The p53 tumor suppressor gene is well-known and also provided as part of the standard panel by Genzyme in the assessment of breast cancer. p53 inhibits the G1-to-S transition in it's hypophosphorylated (active) state, and mutations are correlated with increased risk of progression. Genzyme will report an unfavorable p53 status when > 10% of the cells in the sample demonstrate mutated p53.