Trastuzumab (Herceptin)

Overview & History

Trastuzumab represents one of the first and most successful examples of targeted cancer therapy - drugs designed to attack specific molecular abnormalities in cancer cells while sparing normal tissue.

Revolutionary Impact

• FDA approval: September 1998 (metastatic breast cancer), November 2006 (adjuvant breast cancer), October 2010 (gastric cancer)
• Developed by: Genentech (now part of Roche)
• Transformed outcomes: HER2-positive breast cancer went from worst prognosis to favorable outcomes
• Survival benefit: Reduced risk of death by 33% in early-stage disease, 20% in metastatic disease
• Disease-free survival: Improved by approximately 40% in adjuvant setting

Understanding HER2

To understand how trastuzumab works, it's important to understand HER2.

What is HER2?

• Full name: Human Epidermal growth factor Receptor 2 (HER2/neu, ErbB2)
• Function: Protein receptor on cell surface that sends growth signals
• Normal role: Regulates normal cell growth and division
• In cancer: Can be overexpressed (too many copies on cell surface)

HER2 Overexpression in Cancer

• Breast cancer: Overexpressed in 15-20% of cases
• Gastric/GEJ cancer: Overexpressed in 15-25% of cases
• Mechanism: Gene amplification (multiple copies of HER2 gene) leads to too many receptors
• Effect: Excessive growth signals cause rapid, uncontrolled cancer cell division
• Before treatment: Associated with aggressive disease, higher recurrence, shorter survival

Why HER2 Status Matters

Critical point: Trastuzumab ONLY works for HER2-positive cancers. Accurate HER2 testing is absolutely essential before starting treatment.

Mechanism of Action

Trastuzumab is a humanized monoclonal antibody that works through multiple mechanisms to fight HER2-positive cancer:

How Trastuzumab Works

1. HER2 Receptor Binding: Trastuzumab binds specifically to the extracellular domain (domain IV) of the HER2 receptor on cancer cell surface
2. Signal Blockade: Prevents HER2 from sending growth signals into the cell, slowing cancer cell division
3. Receptor Downregulation: Causes HER2 receptors to be removed from cell surface and degraded
4. Antibody-Dependent Cellular Cytotoxicity (ADCC): The "tail" of the antibody recruits immune cells (NK cells, macrophages) to attack and destroy the cancer cell - this is thought to be the most important mechanism
5. Prevents Receptor Cleavage: Stops enzymatic cleavage of HER2 receptor that would create constitutively active fragments
6. Inhibits Angiogenesis: May reduce new blood vessel formation that tumors need to grow
7. Cell Cycle Arrest: Prevents cells from entering S phase of cell cycle

Approved Uses

Trastuzumab is FDA-approved for HER2-positive cancers only. HER2 testing is mandatory before treatment.

Primary Indications

1. HER2-Positive Breast Cancer

Adjuvant Treatment (After Surgery)

• Indication: Early-stage HER2+ breast cancer as part of treatment regimen containing doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel
• Alternative: With docetaxel and carboplatin
• Duration: Total of 1 year (52 weeks) of trastuzumab
• Benefit: Reduces risk of recurrence by ~40%, risk of death by ~33%
• Eligibility: Node-positive or node-negative disease (if high risk)

Neoadjuvant Treatment (Before Surgery)

• Indication: Locally advanced, inflammatory, or early-stage HER2+ breast cancer >2 cm
• Regimen: Combined with chemotherapy before surgery
• Benefit: Increases pathologic complete response (pCR) rates, may allow breast conservation
• Post-surgery: Continue to complete 1 year total

Metastatic Disease

• First-line: Combined with paclitaxel
• Single agent: After failure of chemotherapy for metastatic disease
• Duration: Until disease progression or unacceptable toxicity
• Benefit: Median survival increased from 20 to 25 months

2. HER2-Positive Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma

• Indication: Metastatic HER2+ gastric or GEJ cancer not previously treated for metastatic disease
• Regimen: Combined with cisplatin and a fluoropyrimidine (capecitabine or 5-FU)
• Standard regimen: Every 3 weeks until disease progression
• Benefit: Median overall survival increased from 11.1 to 13.8 months in ToGA trial

Off-Label and Investigational Uses

• HER2+ colorectal cancer: Emerging data in trastuzumab combinations
• HER2+ uterine serous carcinoma: Case reports and small studies
• HER2+ ovarian cancer: Under investigation
• HER2+ bladder cancer: Clinical trials ongoing

HER2 Testing Requirements

HER2 testing is mandatory before starting trastuzumab. The drug will not work in HER2-negative cancers.

Testing Methods

Immunohistochemistry (IHC)

• Method: Stains tissue to detect HER2 protein on cell surface
• Results: Scored as 0, 1+, 2+, or 3+
• Interpretation:
  • 0 or 1+: HER2-negative (no trastuzumab)
  • 2+: Equivocal - requires FISH testing
  • 3+: HER2-positive (treat with trastuzumab)

Fluorescence In Situ Hybridization (FISH)

• Method: Detects HER2 gene amplification (number of copies)
• Results: HER2/CEP17 ratio and HER2 copy number
• HER2-positive criteria:
  • HER2/CEP17 ratio ≥2.0, OR
  • HER2 copy number ≥6.0 signals/cell (if ratio <2.0), OR
  • HER2/CEP17 ratio <2.0 with HER2 copy number ≥4.0 and <6.0 signals/cell (requires additional testing)
• Considered gold standard for equivocal cases

When to Test

• All invasive breast cancers: At diagnosis (ASCO/CAP guidelines)
• Gastric/GEJ cancer: When metastatic disease is diagnosed
• Recurrent/metastatic disease: Retest on biopsy - HER2 status can change
• Quality control: Ensure testing done at CAP-accredited laboratory

Borderline/Equivocal Results

Approximately 15-20% of cases fall into equivocal zone:

• IHC 2+: Must perform FISH or other ISH method
• Discordant results: May need repeat testing or expert pathology review
• When in doubt: Multidisciplinary tumor board discussion recommended

Dosing and Administration

Trastuzumab can be given intravenously (IV) or subcutaneously (SC). Dosing varies by indication and schedule.

Standard IV Dosing Regimens

Weekly Dosing

• Loading dose: 4 mg/kg IV over 90 minutes (first dose)
• Maintenance dose: 2 mg/kg IV over 30 minutes weekly
• Common use: When combined with weekly paclitaxel, or patient preference

Every 3 Weeks (Q3W) Dosing - MOST COMMON

• Loading dose: 8 mg/kg IV over 90 minutes (first dose)
• Maintenance dose: 6 mg/kg IV over 30-90 minutes every 3 weeks
• Common use: Adjuvant therapy, with 3-weekly chemotherapy regimens
• Advantage: Fewer infusion center visits

Subcutaneous (SC) Dosing

• Fixed dose: 600 mg subcutaneously over 2-5 minutes every 3 weeks
• No loading dose required
• Administration: Injected into thigh using provided injection device
• Bioequivalent to IV: Achieves same blood levels as IV dosing
• Advantages: Much faster (2-5 minutes vs. 30-90 minutes), no IV access needed, convenient
• Availability: Widely used in Europe, available in US as Herceptin Hylecta

Duration of Treatment

Dose Modifications

Cardiac Toxicity

Infusion Reactions

• Mild to moderate: Slow or interrupt infusion; treat symptoms; resume at slower rate
• Severe (dyspnea, hypotension): Interrupt infusion; treat symptoms
• Life-threatening: Discontinue permanently

Pulmonary Toxicity

• Severe pulmonary symptoms: Discontinue permanently

Administration Guidelines

IV Preparation and Infusion

• Reconstitution: Use sterile water for injection (NOT bacteriostatic water)
• Dilution: Add to 250 mL 0.9% sodium chloride (do NOT use D5W)
• Stability: Use within 24 hours if refrigerated
• Filters: Use 0.22 micron in-line filter
• First infusion: 90 minutes with close monitoring
• Subsequent infusions: 30 minutes if prior doses tolerated (some give over 90 min per institutional protocol)
• Do NOT give IV push or bolus

Missed Doses

• Missed by ≤1 week: Give usual maintenance dose; do not wait
• Missed by >1 week: Give loading dose, then resume maintenance schedule

Special Considerations

• No premedication required: Unlike some other monoclonal antibodies
• Can be mixed with chemotherapy: Often given same day as chemotherapy (not in same bag)
• Sequence: Typically given after chemotherapy when combined
• Anthracycline combination: Do NOT give concurrently - allow ≥3 weeks washout after anthracycline completion before starting trastuzumab

Side Effects

Trastuzumab is generally better tolerated than traditional chemotherapy, but can cause serious side effects, particularly cardiac toxicity.

Most Common Side Effects (>30%)

Fatigue

• Incidence: 40-50%
• Usually mild to moderate
• May be cumulative
• Management: Energy conservation, light exercise, rule out contributing factors (anemia, thyroid)

Headache

• Incidence: 25-35%
• Usually mild
• Management: Acetaminophen, hydration

Diarrhea

• Incidence: 20-30%
• Usually mild
• Management: Loperamide, hydration, dietary modifications

Nausea

• Incidence: 25-35%
• Usually mild - trastuzumab has LOW emetogenic potential
• Often attributable to concurrent chemotherapy
• Management: Ondansetron, metoclopramide as needed

Infection (Upper Respiratory)

• Incidence: 20-30%
• Types: Nasopharyngitis, sinusitis, influenza
• Risk: Mild immunosuppression

Serious Side Effects Requiring Close Monitoring

Cardiomyopathy (Heart Damage) - MOST SERIOUS

• Incidence: 2-7% (monotherapy), up to 27% (with anthracyclines)
• Mechanism: HER2 plays role in cardiac myocyte survival; blockade may impair cardiac function
• Presentation:
  • Asymptomatic decline in LVEF (most common)
  • Symptomatic heart failure (dyspnea, edema, fatigue)
  • Usually develops within first 3 months but can occur anytime
• Risk factors:
  • Prior or concurrent anthracycline use (highest risk)
  • Age >60 years
  • Pre-existing cardiac disease
  • Hypertension
  • Previous chest radiation
  • Low baseline LVEF
• Important distinction: Usually reversible upon discontinuation (unlike anthracycline cardiotoxicity)
• Recovery: Most patients recover cardiac function within 1-6 months after stopping
• Management: ACE inhibitors, beta-blockers, diuretics; cardiology referral
• Rechallenge: May be possible after recovery in metastatic setting with close monitoring

Infusion Reactions

• Incidence: 40% during first infusion, <5% with subsequent doses
• Timing: During or within 24 hours of infusion (usually during or immediately after)
• Symptoms:
  • Mild to moderate: Fever, chills, flushing, nausea, headache, weakness
  • Severe (rare <1%): Dyspnea, hypotension, wheezing, bronchospasm, angioedema, urticaria
• Management:
  • Interrupt infusion for dyspnea or significant hypotension
  • Acetaminophen, diphenhydramine for mild symptoms
  • Epinephrine, bronchodilators, oxygen for severe reactions
• Prevention: Slower first infusion (90 minutes), close monitoring
• Note: Much less common with SC formulation

Pulmonary Toxicity

• Incidence: Rare (<1%) but serious
• Types: Interstitial pneumonitis, pulmonary infiltrates, pleural effusions, ARDS
• Symptoms: Dyspnea, cough, pulmonary infiltrates on imaging
• Risk: Higher in patients with lung disease or concurrent lung metastases
• Management: Discontinue trastuzumab, supportive care, may require corticosteroids

Common Side Effects (10-30%)

Musculoskeletal Pain

• Incidence: 20-25%
• Types: Myalgia, arthralgia, back pain
• Management: NSAIDs, acetaminophen

Insomnia

• Incidence: 15-20%
• Management: Sleep hygiene, short-term sleep aids if needed

Neutropenia (Low White Blood Cells)

• Incidence: 10-30% (higher when combined with chemotherapy)
• Severity: Usually mild with trastuzumab alone
• Risk: Increased infection risk if severe

Peripheral Edema

• Incidence: 10-15%
• Usually mild - ankle swelling
• May indicate cardiac dysfunction - evaluate LVEF if new or worsening

Less Common but Notable Side Effects

Anemia

• Incidence: 10-15%
• Usually mild
• May require iron supplementation or ESAs

Rash

• Incidence: 5-10%
• Usually mild maculopapular rash
• Management: Topical corticosteroids, antihistamines

Nail Changes

• Paronychia (nail fold infection/inflammation)
• More common when combined with chemotherapy

Rare but Serious Side Effects

• Hypersensitivity/anaphylaxis: Very rare, most reactions are infusion-related, not true allergy
• Tumor lysis syndrome: Rare, in patients with high tumor burden
• Renal failure: Rare case reports

Side Effects Trastuzumab Does NOT Cause

Unlike traditional chemotherapy:

• No alopecia (hair loss): Trastuzumab alone does not cause hair loss
• No severe nausea/vomiting: Low emetogenic potential
• No mucositis: Does not damage GI tract lining
• No peripheral neuropathy: No nerve damage
• No nephrotoxicity: No kidney damage

Cardiac Monitoring

Regular cardiac monitoring is mandatory due to risk of cardiotoxicity. This is the most important monitoring requirement for trastuzumab.

LVEF (Left Ventricular Ejection Fraction) Monitoring Schedule

Baseline (Before Starting)

• Required: LVEF assessment via ECHO (echocardiogram) or MUGA scan
• Minimum LVEF to start: Within normal institutional limits (typically ≥50-55%)
• Also assess: History of cardiac disease, risk factors

During Treatment

• Every 3 months during treatment (standard recommendation)
• More frequently if:
  • Prior anthracycline exposure
  • Pre-existing cardiac disease
  • Borderline baseline LVEF
  • Development of cardiac symptoms

After Treatment Completion

• At completion: LVEF assessment
• 6 months after: Repeat LVEF
• Annually thereafter: Consider ongoing surveillance, especially if received anthracyclines

Criteria for Holding or Stopping Trastuzumab

ECHO vs. MUGA Scan

Recommendation: Use same method consistently for each patient to improve serial comparisons.

Managing Cardiac Toxicity

If Asymptomatic LVEF Decline

1. Hold trastuzumab for at least 4 weeks
2. Cardiology referral for evaluation and management
3. Consider cardiac medications: ACE inhibitors (lisinopril, enalapril) or ARBs, beta-blockers (carvedilol, metoprolol)
4. Repeat LVEF in 4 weeks
5. If improves: May cautiously resume trastuzumab with more frequent monitoring (monthly LVEF)
6. If persists or worsens: Discontinue permanently

If Symptomatic Heart Failure

1. Discontinue trastuzumab permanently
2. Immediate cardiology referral
3. Treat heart failure: ACE inhibitor/ARB, beta-blocker, diuretics, dietary sodium restriction
4. Most patients recover cardiac function within weeks to months

Risk-Benefit in Metastatic Disease

In metastatic breast cancer where trastuzumab offers survival benefit:

• May consider continuing trastuzumab with close monitoring and cardiac management if LVEF decline is modest
• Multidisciplinary discussion with patient, oncologist, cardiologist essential
• Alternative: Switch to T-DM1 (ado-trastuzumab emtansine) which may have lower cardiac risk

Other Monitoring Parameters

Before Each Dose

• Vital signs: Blood pressure, heart rate, temperature
• Symptom assessment: Cardiac symptoms, respiratory symptoms, signs of infection
• Complete blood count (CBC): If given with chemotherapy; less critical with trastuzumab alone

During Infusion (IV)

• Continuous monitoring during first infusion (especially first 30 minutes)
• Vital signs: Every 15-30 minutes during first infusion, less frequent for subsequent doses if tolerated
• Infusion reaction monitoring: Fever, chills, dyspnea, hypotension

After Infusion

• Observation: At least 30-60 minutes after first infusion
• Patient education: Report delayed symptoms (up to 24 hours)

Periodic Monitoring

• LVEF: Every 3 months (see Cardiac Monitoring section)
• Imaging for disease response: Every 2-3 months in metastatic setting, after completion in adjuvant

Pregnancy Testing

• Before starting: Verify pregnancy status in women of reproductive potential
• During treatment: Monthly pregnancy testing recommended

Drug Interactions

Major Interactions

Anthracyclines (Doxorubicin, Epirubicin) - MOST IMPORTANT

• Interaction: Significantly increased risk of cardiac toxicity
• Cardiotoxicity rate: Up to 27% when given concurrently vs. 2-7% with trastuzumab alone
• Mechanism: Additive cardiac damage - anthracyclines cause permanent damage, trastuzumab causes functional impairment
• Management:
  • Do NOT give concurrently
  • Allow ≥3 weeks washout after completing anthracycline before starting trastuzumab
  • Sequential administration (anthracycline-containing regimen first, then trastuzumab) is standard in adjuvant therapy
  • More frequent cardiac monitoring required (every 3 months or more often)

Paclitaxel and Docetaxel

• Interaction: Increased paclitaxel levels when given with trastuzumab
• Clinical significance: Minimal - commonly used combination
• Management: No dose adjustment needed; monitor for increased taxane toxicity
• Sequence: Typically give chemotherapy first, then trastuzumab on same day

Moderate Interactions

Other Cardiotoxic Agents

• Cyclophosphamide: May increase cardiac toxicity risk (though commonly combined)
• Chest radiation: Increased cardiac risk - more frequent monitoring
• Other targeted agents with cardiac effects: Pertuzumab (usually given together safely), lapatinib

No Significant Interactions

• Not metabolized by CYP450: No interactions with CYP inducers/inhibitors
• Platinum agents (carboplatin, cisplatin): Commonly combined without issues
• Fluoropyrimidines (5-FU, capecitabine): No interaction
• Immunotherapy (pembrolizumab): Being studied in combination; early data suggest safety

Other Considerations

• Live vaccines: Avoid during treatment due to immunosuppression
• Warfarin: Monitor INR; antibodies may affect coagulation

Biosimilars

Biosimilars are highly similar versions of biologic drugs like trastuzumab. They are NOT identical (like generics) but are approved based on demonstrating no clinically meaningful differences.

FDA-Approved Trastuzumab Biosimilars

What are Biosimilars?

• Highly similar: No clinically meaningful differences in safety, purity, and potency
• NOT generic: Biologics are large, complex molecules that cannot be exactly copied
• Approved for all indications: If reference product (Herceptin) is approved for multiple uses, biosimilar gets all approvals
• Interchangeable status: Some biosimilars may receive "interchangeable" designation allowing pharmacy substitution (like generics)

Efficacy and Safety

• Equivalent efficacy: Clinical trials show similar response rates, progression-free survival
• Similar safety profiles: Side effect rates comparable to Herceptin
• Immunogenicity: Similar rates of antibody formation
• Switching studies: Patients can safely switch from Herceptin to biosimilar and vice versa

Cost Considerations

• Lower cost: Biosimilars typically 15-35% less expensive than reference product
• Herceptin cost: ~$5,000-7,000 per dose (varies by dose and setting)
• Annual cost: ~$90,000-126,000 for 1 year adjuvant treatment
• Biosimilar savings: Potentially $15,000-40,000+ per year
• Insurance coverage: Most plans cover biosimilars; may incentivize use through lower copays

Should You Use a Biosimilar?

Advantages

• Lower cost (for patients and healthcare system)
• Equivalent efficacy and safety
• FDA-approved based on rigorous standards
• Increased access to treatment

Considerations

• Patient/provider preference and comfort level
• Insurance formulary requirements
• Availability at treatment center

Warnings and Precautions

Contraindications

• HER2-negative cancer: Will not work; do not use
• No absolute contraindications if HER2-positive, but use with extreme caution if:
• Severe pre-existing cardiac disease or heart failure
• Baseline LVEF below normal limits
• History of hypersensitivity to trastuzumab or murine proteins

Pregnancy and Breastfeeding

• Pregnancy Category D: Can cause fetal harm
• Known risk: Oligohydramnios (low/absent amniotic fluid) in second and third trimesters
• Consequences: Pulmonary hypoplasia, skeletal abnormalities, neonatal death
• Pregnancy testing: Required before starting and monthly during treatment
• Contraception: Effective contraception required during and for 7 months after last dose
• If pregnancy occurs: Immediately report to healthcare provider; close fetal monitoring required
• Registry: MotHER Pregnancy Registry (1-800-690-6720) for exposed pregnancies
• Breastfeeding: Not recommended during treatment and for 7 months after last dose

Special Populations

Elderly Patients (≥65 years)

• No dose adjustment needed based on age alone
• Increased risk of cardiac toxicity due to age-related cardiac changes
• More frequent cardiac monitoring may be warranted
• Similar efficacy as in younger patients

Renal Impairment

• No dose adjustment required
• Not significantly renally eliminated
• Can be used safely in patients with kidney disease

Hepatic Impairment

• No dose adjustment required
• Not significantly hepatically metabolized
• No specific studies in severe hepatic impairment

Patients with Pulmonary Disease

• Increased risk of pulmonary toxicity
• Use with caution in patients with symptomatic lung disease
• Close monitoring for dyspnea and pulmonary symptoms

Drug-Specific Warnings

Anthracycline Exposure

• Prior anthracycline: Highest cardiac risk group - aggressive monitoring essential
• Cumulative doxorubicin dose matters: Risk increases with higher cumulative anthracycline doses
• Consider cardioprotection: Dexrazoxane during anthracycline phase (controversial)

Prior Chest Radiation

• Increases cardiac toxicity risk
• More frequent cardiac monitoring recommended
• Consider lower threshold for holding drug if LVEF declines

Frequently Asked Questions