Identification of HER-2

  • The evaluation of HER-2:
    • Is recommended in all cases of breast cancer at the time of initial diagnosis and / or at the time of recurrence to guide therapy
  • A number of methods are used for HER-2 testing. including
    • Immunohistochemistry (IHC)
    • Florescence in situ hybridization (FISH)
    • Enzyme-linked immunosorbent assay (ELISA) analysis of serum and tumor
    • Western blot
    • Southern blot
    • Chromogenic in situ hybridization (CISH)
    • Silver in situ hybridization (SISH)
    • Polymerase chain reaction (PCR)
  • IHC and FISH:
    • Are currently the main testing modalities for HER-2-positive breast cancer
  • HER-2 expression in breast cancer:
    • Is primarily assessed semiquantitatively by IHC
  • The 2013 American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) guidelines:
    • Outline an IHC scoring method based on four classes:
      • 0
      • 1+
      • 2+
      • 3+
    • A score of 0 is negative:
      • Indicating no observed staining in invasive tumor cells
    • A score of 1+ is negative:
      • Indicates weak, incomplete membrane staining in any proportion of invasive tumor cells or weak, complete membrane staining in less than 10% of invasive tumor cells
    • A score of 2+ is equivocal:
      • Indicating circumferential membrane staining that is incomplete and / or weak / moderate and in more than 10% of invasive tumor cells or complete and circumferential membrane staining that is intense and in 10% or less of invasive tumor cells
      • All 2+ equivocal cases undergo subsequent testing by FISH
    • A score of 3+ is positive:
      • Indicates circumferential membrane staining that is complete and intense in a homogeneous and contiguous population, present in more than 10% of invasive tumor cells, and readily appreciated using a low-power objective
  • FISH is a sensitive and accurate method of scoring invasive breast tumor tissue for HER-2 expression:
    • Initial gene amplification studies by FISH assessment used chromosome 17 centromere (CEP17) or another gene on the same chromosome as an internal control:
      • With a ratio of 2.0 or greater considered evidence of HER-2 amplification:
        • These criteria were used as the cutoff for enrollment in trials evaluating HER-2 targeted therapies
    • In 2007, the ASCO / CAP guidelines were changed to define HER-2 amplified as:
      • A ratio of 2.2 or greater
  • More recent guidelines have changed the ratio cutoff back to:
    • A ratio of 2.0 or greater with the inclusion of criteria to account for HER-2 copy number per tumor cell:
      • Based on the recent guidelines, HER-2 is amplified in cases where the HER-2 / CEP17 ratio is 2.0 or greater with an average HER-2 copy number of more than 4.0 signals/cell or the HER-2 / CEP17 ratio is less than 2.0 with an average HER-2 copy number of 6.0 or more signals/cell using a dual probe or a HER-2 copy number of 6.0 or more copies/cell using a single probe
    • FISH testing is negative for HER-2 amplification with a HER-2 / CEP17 ratio of less than 2.0 with an average HER-2 copy number of less than 4.0 signals/cell or an average HER-2 copy number of less than 4.0 signals/cell using a single probe

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