Trastuzumab

Companion diagnostic testing
Drugs relevant to surgical pathology
Trastuzumab

Editor-in-Chief: Debra L. Zynger, M.D.

Topic Completed: 30 December 2019

Minor changes: 11 December 2020

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

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Table of Contents

Cite this page: Yeh YA. Trastuzumab. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/drugsherceptin.html. Accessed January 15th, 2021.

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 2

Diagrams / tables

Images hosted on other servers:

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:
- 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
    - 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
- 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
  - Single probe HER2 copy number ≥ 4.0 and < 6.0 signals/cell
HER2 dual probe ISH in breast carcinoma
- 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:
  - 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 1):
- 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

Additional references

Am J Clin Pathol 2019;152:17, N Engl J Med 2019;381:1284, Cell 2019;179:8, J Hematol Oncol 2019;12:50, Cancer Treat Rev 2019;75:12, Br J Cancer 2019;121:199, J Clin Med 2019;8:E254, Exp Hematol Oncol 2019;8:25, Clin Cancer Res 2019;25:2033, Breast Cancer Res 2014;16:209, ISRN Oncol 2012;2012:428062, N Engl J Med 2012;366:664, N Engl J Med 2012;366:663, Hum Pathol 2010;41:304, Oncogene 2007;26:3637, Oncogene 2007;26:6577

Board review style question #1

Which of the following drugs target HER2 / neu on cancer cells?

Dabrafenib
Larotrectinib
Trametinib
Trastuzumab

Board review style 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?

Intense nuclear and cytoplasmic staining > 10% of tumor cells
Intense luminal membranous staining > 10% of tumor cells
Intense basolateral membranous staining > 10% of tumor cells
Intense luminal and lateral membranous staining > 10% of tumor cells

Board review style answer #2

C. Intense basolateral membrane staining > 10% of tumor cells

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