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Drugs relevant to surgical pathology
Trastuzumab


Topic Completed: 30 December 2019

Minor changes: 30 December 2019

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PubMed Search: Trastuzumab[TI] Herceptin[TI] free full text[sb]

Y. Albert Yeh, M.D., Ph.D.
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Cite this page: Yeh YA. Trastuzumab. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/drugsherceptin.html. Accessed September 20th, 2020.
Definition / general
  • Humanized IgG1 kappa monoclonal antibody targets HER2 / neu receptor (human epidermal receptor 2)
  • Discovered by scientists including Dr. Axel Ullrich and Dr. H. Michael Shepard at Genentech, Inc., South San Francisco, CA
  • Synonym: anti-HER2 (N Engl J Med 2007;357:39)
Trade name
  • Herceptin®
Clinical information
  • Approved by U.S. Food and Drug Administration on September 25, 1998 (Oncology (Williston Park) 1998;12:1727)
  • Biosimilars (Ther Adv Med Oncol 2019;11:1758835919887044):
    • Trastuzumab-dkst (Ogivri): FDA approved, 2017
    • Trastuzumab-pkrb (Herzuma): FDA approved, 2018
    • Trastuzumab-dttb (Ontruzant): FDA approved, 2019
    • Trastuzumab-qyyp (Trazimera): FDA approved, 2019
    • Trastuzumab-anns (Kanjinti): FDA approved, 2019
  • Indications and usage (National Cancer Institute: Trastuzumab [Accessed 18 December 2019]):
    • Breast cancer with HER2 receptor positive
    • Gastric adenocarcinoma and gastroesophageal junction adenocarcinoma with HER2 receptor positive
  • Clinical pharmacokinetics (Oncologist 2011;16:800):
    • Route of administration: intravenous
    • Elimination: predominantly in epithelial cells; renal elimination very low
    • Half life: 28 days
  • Side effects (Ann Pharmacother 2019 Oct 9 [Epub ahead of print]):
    • Infusion related reactions if occurring < 24 hours after first infusion: fever, chills, rash, headache, dizziness; (severe) angioedema, respiratory distress syndrome, severe hypotension, anaphylaxis (Oncologist 2007;12:601)
    • Cardiotoxicity: hypotension, congestive heart failure, ventricular dysfunction
    • Respiratory: dyspnea, bronchospasm, hypoxia, asthma
    • Gastrointestinal: diarrhea, vomiting, dyspepsia
    • Hematologic: anemia, leukopenia, thrombocytopenia
  • Mechanism of drug resistance (Front Oncol 2012;2:62):
    • Loss of phosphatase and tensin homologue (pTEN)
    • Activation of the phosphoinositide 3 kinase pathway
    • Overexpression of other surface receptors (insulin-like growth factor)
  • Trastuzumab costs about U.S. $70,000 for a full course of treatment, U.S. $1,800 - $1,955 per 440 mg vial (Wikipedia: Trastuzumab [Accessed 18 December 2019])
Pathophysiology
  • HER2, a member of HER family, does not have a receptor specific ligand binding site
  • HER2 / neu signaling in cancer cells:
    • HER2 heterodimerizes with HER1, HER3 or HER4, phosphorylates and activates intracellular tyrosine kinase domain
    • Activated tyrosine kinase on HER2 activates PI3K-Akt pathway and induces cellular survival
    • Activated tyrosine kinase activates SOS, induces a cascade of activation of RAS-RAF-MAPK-MEK and MAPK, eventually promotes cellular proliferation
    • Cleavage of HER2 extracellular domain produces phosphorylated P95 that could activate downstream signal transduction
  • Mechanism of action:
    • Upon binding the extracellular domain of HER2, trastuzumab reduces cleavage of HER2 receptor, blocks the activation ability of P95 residue and eventually decreases signaling
    • Binding of trastuzumab to extracellular domain of HER2 inhibits homo or heterodimerization of HER2 to HER1, HER2, HER3 or HER4 and reduces signaling
    • Trastuzumab binds to immune effector cells and activates antibody dependent cell mediated cytotoxicity, eventually leads to tumor cell lysis
    • Endocytosis of HER2 is increased and leads to intracellular HER2 degradation
  • Reference: N Engl J Med 2007;357:39, see Diagrams / tables, figure 8
Diagrams / tables

Images hosted on other servers:

HER2 IHC testing in breast carcinoma

HER2 single probe ISH in breast carcinoma

HER2 dual probe ISH in breast carcinoma

HER2/CEP17 ≥ 2.0, HER2 < 4 signals/cell


HER2/CEP17 < 2.0, HER2 copy number ≥ 6.0 signals/cell

HER2/CEP17 < 2.0,
HER2 copy number
≥ 4.0 and < 6.0
signals/cell

HER2 IHC
testing in gastric &
gastroesophageal
adenocarcinoma

Mechanism of action

Uses by pathologists
  • Identify HER2 positive tumors to identify candidates for treatment
    • Primary breast carcinomas
    • Gastric and gastroesophageal adenocarcinomas
    • Metastatic diseases (test performed in a metastatic site)
  • HER2 immunohistochemistry in breast carcinoma (see Diagrams / tables, figure 1):
    • ASCO-CAP HER2 Test 2013 and 2018 Guideline Recommendation (Arch Pathol Lab Med 2014;138:241, Arch Pathol Lab Med 2018;142:1364)
      • Negative (score 0):
        • No staining
        • Incomplete faint membrane staining ≤ 10% invasive tumor cells
      • Negative (score 1+):
        • Incomplete faint membrane staining > 10% invasive tumor cells
      • Equivocal (score 2+): perform HER2 ISH (see Diagrams / tables, figure 2)
        • Incomplete, weak / moderate membrane staining > 10% invasive tumor cells
        • Complete, intense membrane staining ≤ 10% invasive tumor cells
      • Positive (score 3+):
        • Complete, intense circumferential membrane staining
  • HER2 single probe in situ hybridization (ISH) in breast carcinoma (see Diagrams / tables, figure 2)
    • ISH negative (not amplified)
      • Single probe HER2 copy number < 4.0
    • ISH positive (amplified)
      • Single probe HER2 copy number ≥ 6.0 signals/cell
    • ISH equivocal: perform HER2/CEP17 dual probe ISH (see Diagrams / tables, figure 3)
      • Single probe HER2 copy number ≥ 4.0 and < 6.0 signals/cell
  • HER2 dual probe ISH in breast carcinoma (see Diagrams / tables, figure 3)
    • Negative:
      • Dual probe HER2/CEP17 < 2.0, HER2 copy number < 4.0 signals/cell
    • Positive:
      • Dual probe HER2/CEP17 ≥ 2.0, HER2 copy number ≥ 4.0 signals/cell
    • Equivocal (see Diagrams / tables, figures 4, 5 and 6):
      • HER2/CEP17 ≥ 2.0, with HER2 copy number < 4.0 signals/cell
      • HER2/CEP17 < 2.0, HER2 copy number ≥ 6.0 signals/cell
      • HER2/CEP17 < 2.0, HER2 copy number ≥ 4.0 and < 6.0 signals/cell
  • HER2 immunohistochemistry testing in gastric and gastroesophageal adenocarcinoma (see Diagrams / tables, figure 7):
    • 2017 CAP / ASCP / ASCO guidelines (J Clin Oncol 2017;35:446, Virchows Arch 2010;457:299):
      • Representative surgical samples or at least 6 to 8 biopsy samples
      • Score 0: negative
        • No membranous staining or staining in < 10% of tumor cells (surgical specimen) or < 5 cohesive tumor cells (biopsy)
      • Score 1+: negative
        • Weak staining in only one part of the membrane in ≥ 10% of tumor cells (surgical specimen) or at least 5 cohesive tumor cells (biopsy)
      • Score 2+: equivocal, perform HER2 ISH
        • Moderate / weak complete or basolateral membranous staining in ≥ 10% of tumor cells (surgical specimen) or at least 5 cohesive tumor cells (biopsy)
      • Score 3+: positive
        • Strong or complete or basolateral membranous staining in ≥ 10% of tumor cells (surgical specimen) or at least 5 cohesive tumor cells (biopsy)
  • HER2 ISH in gastric and gastroesophageal adenocarcinoma (Mod Pathol 2012;25:637):
    • Positive: HER2/CEP17 ratio ≥ 2.0
    • Positive: HER2 copy number > 6.0 (using single probe)
    • HER2 copy number 4 to 6: use dual probe testing and recount 20 cells
Board review style question #1
Which of the following drugs target HER2 / neu on cancer cells?

  1. Dabrafenib
  2. Larotrectinib
  3. Trametinib
  4. Trastuzumab
Board review answer #1
D. Trastuzumab

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Board review style question #2
Which of the following results is interpreted as positive staining (score 3+) for HER2 in gastric and gastroesophageal adenocarcinoma?

  1. Intense nuclear and cytoplasmic staining > 10% of tumor cells
  2. Intense luminal membranous staining > 10% of tumor cells
  3. Intense basolateral membranous staining > 10% of tumor cells
  4. Intense luminal and lateral membranous staining > 10% of tumor cells
Board review answer #2
C. Intense basolateral membrane staining > 10% of tumor cells

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