Herceptin (Trastuzumab)
trastuzumab — humanised IgG1 monoclonal antibody
Indications for Trastuzumab
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| HER2-overexpressing breast cancer — adjuvant | Adults; node-positive or node-negative with high-risk features (ER/PR-negative, or ≥1 high-risk feature) | Combination with AC→T, TCH, or single-agent post-anthracycline | FDA Approved |
| HER2-overexpressing metastatic breast cancer — first-line | Adults | Combination with paclitaxel | FDA Approved |
| HER2-overexpressing metastatic breast cancer — previously treated | Adults who received ≥1 prior chemo regimen for metastatic disease | Monotherapy | FDA Approved |
| HER2-overexpressing metastatic gastric / GEJ adenocarcinoma | Adults; previously untreated metastatic disease | Combination with cisplatin + capecitabine or 5-FU | FDA Approved |
Trastuzumab fundamentally changed the treatment landscape for HER2-positive cancers following its landmark approval in 1998. It was among the first targeted biologic therapies and remains a backbone of HER2-directed treatment in both early-stage and advanced settings. Patient selection requires confirmed HER2 overexpression (IHC 3+ or IHC 2+ with FISH amplification) using an FDA-approved companion diagnostic performed by a laboratory with demonstrated proficiency.
HER2-positive esophageal / esophagogastric junction cancer — used in combination with chemotherapy, supported by NCCN guidelines. Evidence quality: Moderate.
HER2-positive uterine serous carcinoma — in combination with carboplatin and paclitaxel, with maintenance monotherapy. Evidence quality: Moderate (based on a randomised phase II trial).
HER2-amplified, RAS/BRAF wild-type colorectal cancer — in combination with pertuzumab or other HER2-targeted agents. Evidence quality: Moderate.
Intra-CSF trastuzumab for leptomeningeal carcinomatosis — used in HER2-positive breast cancer with CNS involvement. Evidence quality: Low (case series and small prospective studies).
Dosing for Trastuzumab
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose (Loading) | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Early breast cancer — adjuvant, weekly schedule (with taxane phase) | 4 mg/kg IV over 90 min | 2 mg/kg IV over 30 min weekly during chemo (12–18 wk), then 6 mg/kg IV q3wk | 52 weeks total | Weekly during paclitaxel (12 wk) or docetaxel/carboplatin (18 wk), then q3wk to complete 1 year Do not extend beyond 52 weeks (no added benefit, more toxicity) |
| Early breast cancer — adjuvant, q3-weekly schedule (post-anthracycline single agent) | 8 mg/kg IV over 90 min | 6 mg/kg IV over 30–90 min q3wk | 52 weeks total | Used when given as single agent following completion of multi-modality anthracycline-based chemotherapy |
| Metastatic breast cancer — first-line or beyond (with or without paclitaxel) | 4 mg/kg IV over 90 min | 2 mg/kg IV over 30 min weekly | Until progression | Continue until disease progression or unacceptable toxicity Paclitaxel given concurrently at 175 mg/m² q3wk when used in combination |
| Metastatic gastric / GEJ adenocarcinoma — first-line | 8 mg/kg IV over 90 min | 6 mg/kg IV over 30–90 min q3wk | Until progression | Given with cisplatin 80 mg/m² + capecitabine or 5-FU; chemotherapy for 6 cycles, trastuzumab continues Steady-state exposure is lower in gastric cancer vs. breast cancer at same dose |
Missed Dose Management
| Clinical Scenario | Starting Dose (Re-loading) | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Missed dose ≤1 week (weekly schedule) | Not required | 2 mg/kg as soon as possible | N/A | Resume usual maintenance; next dose 7 days later |
| Missed dose >1 week (weekly schedule) | 4 mg/kg IV over 90 min | 2 mg/kg weekly thereafter | N/A | Re-load required due to long washout kinetics |
| Missed dose >1 week (q3wk schedule) | 8 mg/kg IV over 90 min | 6 mg/kg q3wk thereafter | N/A | Re-load required; resume 21-day cycle from re-load date |
Withhold trastuzumab for at least 4 weeks if LVEF decreases ≥16% absolute from baseline, or falls below institutional normal limits with ≥10% absolute decrease. Trastuzumab may be resumed if LVEF recovers to normal limits and the absolute decrease from baseline is ≤15% within 4–8 weeks. Permanently discontinue if LVEF decline persists >8 weeks or if dosing has been held for cardiomyopathy more than 3 times (FDA PI).
Pharmacology of Trastuzumab
Mechanism of Action
Trastuzumab is a recombinant humanised IgG1 kappa monoclonal antibody that binds with high affinity to subdomain IV of the extracellular domain of the human epidermal growth factor receptor 2 (HER2/ErbB2). HER2 is a transmembrane tyrosine kinase receptor that, when overexpressed, drives tumour cell proliferation through activation of the PI3K/AKT and RAS/MAPK signalling cascades. By binding HER2, trastuzumab blocks receptor dimerisation and downstream signalling, leading to cell cycle arrest primarily through upregulation of the cyclin-dependent kinase inhibitor p27Kip1. Trastuzumab also mediates antibody-dependent cellular cytotoxicity (ADCC), recruiting natural killer cells and macrophages to lyse HER2-overexpressing tumour cells. This dual mechanism — signal blockade plus immune-mediated killing — accounts for its selective activity against HER2-amplified cancers while largely sparing normal tissues that express low basal levels of HER2.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | IV only; 100% bioavailability; Cmax at end of infusion; steady state reached by week 12 (q3wk) or week 16–32 (weekly) | First infusion given over 90 minutes; subsequent infusions may be shortened to 30 minutes if tolerated |
| Distribution | Vd ~44 mL/kg (~2.95 L central compartment); does not cross the blood-brain barrier in appreciable concentrations | Limited CNS penetration explains poor activity against brain metastases; intrathecal delivery explored investigationally |
| Metabolism | Target-mediated disposition: HER2 binding → intracellular lysosomal degradation to peptides and amino acids; parallel non-specific IgG clearance via reticuloendothelial system. No CYP450 involvement | No hepatic enzyme-based drug interactions; clearance increases with higher tumour burden (more HER2 antigen sink) |
| Elimination | t½ ~28 days; total CL 0.173–0.337 L/day at steady state; renal excretion minimal; ~97% washout by 7 months | 7-month washout period relevant for: (1) contraception duration after stopping, (2) timing of anthracycline use post-trastuzumab |
Trastuzumab exhibits nonlinear, dose-dependent kinetics owing to target-mediated drug disposition. Patients with higher tumour burden and more metastatic sites show increased clearance and lower serum trough concentrations. Increased body weight and reduced serum albumin are also associated with higher clearance, though these effects are modest compared with overall interpatient variability (~43% CV).
Side Effects of Trastuzumab
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Fever / chills (infusion-related) | ~40% (first infusion) | Most common with first dose; drops to 21–35% on subsequent infusions; managed with paracetamol and diphenhydramine pre-medication |
| Headache | 10–36% | More common in combination therapy; usually mild and self-limiting |
| Nausea | 33% (monotherapy) | Higher rates when combined with AC chemotherapy (≥76%); anti-emetic regimen guided by chemotherapy backbone |
| Fatigue / asthenia | 35–62% | Dose-related in combination regimens; counsel about activity pacing |
| Diarrhoea | 25–45% | Increased in combination with paclitaxel; monitor hydration |
| Infection | 20–47% | Upper respiratory tract most common; increased with chemotherapy; febrile neutropenia up to 23% with myelosuppressive chemo |
| Cough / dyspnoea | 22–43% | Usually mild; must be distinguished from pulmonary toxicity (see Serious tier) |
| Rash | 18–38% | Higher with paclitaxel combination; usually mild, treat symptomatically |
| Pain (including tumour-site pain) | 47–62% | Generalised body pain; more frequent in metastatic setting |
| Insomnia | 14–29% | Higher in combination with AC |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Arthralgia / myalgia | 6–8% (adjuvant) | More common in combination with taxanes |
| Peripheral oedema | 5–10% | Differentiate from fluid retention due to cardiac dysfunction |
| Hypertension | 4% | Monitor blood pressure at each cycle |
| Ejection fraction decrease (asymptomatic) | 3.5–8.6% | Requires serial LVEF monitoring; see cardiac monitoring protocol |
| Nail disorders | 2% | Higher frequency with taxane combination (up to 11.5%) |
| Constipation / dyspepsia | 2% | Usually mild; manage symptomatically |
| Paresthesia | 2–9% | Differentiate from taxane-related neuropathy |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Cardiomyopathy / CHF (NYHA III–IV) | 0.4–4% (adjuvant); 4–19% (metastatic with AC) | Weeks to months; highest risk during concurrent anthracycline | Withhold or permanently discontinue based on LVEF decline criteria; cardiology consultation; initiate heart failure treatment |
| Severe infusion reactions (anaphylaxis, angioedema, bronchospasm) | <1% (severe); fatal events reported post-marketing | During or within 24 hours of infusion; variable onset | Stop infusion immediately; administer epinephrine, corticosteroids, bronchodilators as indicated; permanently discontinue for severe reactions |
| Pulmonary toxicity (interstitial pneumonitis, ARDS, pulmonary fibrosis) | 0.2–0.7% | Variable; may be acute (infusion-related) or subacute | Permanently discontinue; initiate corticosteroids; pulmonology consultation; rule out infection |
| Embryo-fetal toxicity (oligohydramnios) | Reported in post-marketing; frequency not quantified | Any trimester | Verify pregnancy status before treatment; effective contraception during and for 7 months after last dose |
| Febrile neutropenia | 5% (gastric); up to 23% with myelosuppressive chemotherapy | During chemotherapy phase | G-CSF support; antimicrobial therapy; hold chemotherapy as indicated |
| Nephrotic syndrome / glomerulopathy | Rare (post-marketing) | 4–18 months | Discontinue trastuzumab; nephrology referral; renal biopsy may be indicated |
| Tumour lysis syndrome | Very rare (post-marketing) | First cycles; risk highest with bulky disease | Monitor uric acid, phosphate, potassium, calcium; aggressive hydration; rasburicase if indicated |
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Cardiac dysfunction / LVEF decline | 2.6–15% | Highest in AC→TH regimen (NSABP B31); lower in non-anthracycline regimens (TCH ~2.9%) |
| Severe infusion reactions | <1% | Most patients successfully re-treated with premedication; rare permanent d/c |
| Pulmonary toxicity | <1% | Interstitial pneumonitis, ARDS |
| Infection (metastatic gastric) | ~2% | In combination with cisplatin/fluoropyrimidine (ToGA) |
Trastuzumab-related cardiomyopathy is generally reversible with early detection and treatment. In the NSABP B31 long-term follow-up, approximately 24% of patients who developed CHF recovered to a normal LVEF (≥50%) with ongoing medical management. The risk is substantially lower when trastuzumab is combined with non-anthracycline regimens (TCH: CHF rate 0.4% vs. AC→TH: 2%). Consider TCH over AC→TH for patients with borderline cardiac function or additional cardiovascular risk factors.
Drug Interactions with Trastuzumab
Trastuzumab does not undergo hepatic metabolism via cytochrome P450 enzymes, and no formal drug interaction studies have identified clinically significant pharmacokinetic interactions with chemotherapy agents used in combination. Interaction concerns are primarily pharmacodynamic, centred on additive cardiotoxicity with other cardiotoxic agents.
Monitoring for Trastuzumab
-
LVEF (echo or MUGA)
Baseline, then every 3 months during treatment, and every 6 months for ≥2 years after completion
Routine The most critical monitoring parameter. Withhold for ≥16% absolute decrease from baseline, or LVEF below institutional limits with ≥10% absolute decrease. Repeat LVEF at 4-week intervals during holds. -
HER2 Status
Before treatment initiation
Routine Confirm HER2 overexpression (IHC 3+ or IHC 2+/FISH-amplified) via FDA-approved companion diagnostic. IHC 2+ alone requires FISH or CISH confirmation. -
Pregnancy Status
Before treatment initiation
Routine Verify pregnancy status in females of reproductive potential prior to first dose. Counsel regarding contraception during and for 7 months after treatment. -
Vital Signs (during infusion)
Every infusion; especially first infusion
Routine Monitor for infusion reactions: fever, chills, dyspnoea, hypotension. First infusion given over 90 minutes with 60-minute post-infusion observation. -
CBC with Differential
Per chemotherapy schedule
Routine Trastuzumab exacerbates chemotherapy-induced neutropenia. Monitor for febrile neutropenia, especially with anthracycline-based regimens. -
Signs of Heart Failure
Each cycle & as symptoms arise
Trigger-based Assess for dyspnoea on exertion, orthopnoea, peripheral oedema, weight gain, or new-onset cough. Obtain urgent LVEF and cardiology review if symptomatic CHF suspected. -
Respiratory Symptoms
Each cycle & as symptoms arise
Trigger-based Promptly investigate new cough, dyspnoea, or hypoxia to rule out interstitial pneumonitis or ARDS. CT chest and pulmonology consultation if suspected. -
Renal Function
If proteinuria develops
Trigger-based Rare cases of nephrotic syndrome reported (onset 4–18 months). Monitor urinalysis if clinically indicated; nephrology referral for significant proteinuria.
Contraindications & Cautions for Trastuzumab
Absolute Contraindications
- Pregnancy — Boxed warning for embryo-fetal toxicity. Oligohydramnios, pulmonary hypoplasia, skeletal abnormalities, and neonatal death have been reported.
- Prior severe hypersensitivity reaction to trastuzumab — including anaphylaxis or angioedema. No safe re-challenge protocol established.
Relative Contraindications (Specialist Input Recommended)
- Pre-existing cardiac dysfunction (LVEF <50%) — patients with baseline impaired cardiac function were excluded from pivotal trials. If trastuzumab is considered essential, joint oncology-cardiology decision required with intensified monitoring.
- Prior cumulative anthracycline exposure exceeding recommended limits — increased risk of irreversible cardiomyopathy when followed by trastuzumab.
- Symptomatic intrinsic lung disease — patients with extensive pulmonary tumour involvement and dyspnoea at rest appear to have more severe pulmonary toxicity.
- Concurrent anthracycline therapy — synergistic cardiotoxicity precludes simultaneous administration in current standard-of-care protocols.
Use with Caution
- Elderly patients (≥65 years) — increased risk of cardiac dysfunction compared with younger patients in both adjuvant and metastatic settings.
- Patients with cardiovascular risk factors (prior radiation to chest, hypertension, diabetes, obesity) — may increase baseline cardiac risk.
- Patients with bulky metastatic disease — rare cases of tumour lysis syndrome reported; ensure adequate hydration.
- Breastfeeding — manufacturer recommends discontinuing breastfeeding during treatment and for 7 months after the last dose due to insufficient safety data.
Trastuzumab can result in subclinical and clinical cardiac failure, including CHF and decreased LVEF. The incidence and severity are highest when administered concurrently with anthracycline-containing chemotherapy. A 4–6-fold increase in symptomatic myocardial dysfunction has been observed. Evaluate cardiac function prior to and during treatment. Discontinue for cardiomyopathy.
Serious and fatal infusion reactions and pulmonary toxicity have been reported. Symptoms usually occur during or within 24 hours of administration. Interrupt infusion for dyspnoea or clinically significant hypotension. Monitor until symptoms completely resolve. Discontinue for anaphylaxis, angioedema, interstitial pneumonitis, or ARDS.
Exposure during pregnancy can result in oligohydramnios and oligohydramnios sequence, including pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Verify pregnancy status before initiation. Advise effective contraception during treatment and for 7 months after the last dose.
Patient Counselling for Trastuzumab
Purpose of Therapy
Trastuzumab targets a specific protein (HER2) that is overproduced by the cancer cells. By blocking this protein, trastuzumab slows tumour growth and helps the immune system recognise and destroy cancer cells. It is used alongside or after chemotherapy, and in early breast cancer, treatment typically lasts one year. For advanced cancer, treatment continues as long as it is working and tolerable.
How to Receive Treatment
Trastuzumab is given as an intravenous infusion in a clinical setting. The first infusion takes approximately 90 minutes, and if well tolerated, subsequent infusions may be shortened to 30 minutes. Patients will need regular heart function monitoring (echocardiograms or MUGA scans) throughout treatment and for two years after completion. Blood tests will also be performed regularly.
Sources
- Herceptin (trastuzumab) for injection. Full Prescribing Information. Genentech, Inc. Revised June 2024. FDA Label Primary source for all dosing, boxed warnings, adverse reactions, pharmacokinetics, and drug interaction data in this monograph.
- FDA Approval Letter. Herceptin (trastuzumab). September 25, 1998. FDA Approval Historical regulatory milestone as one of the first targeted cancer therapies approved by the FDA.
- Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353(16):1673-1684. doi:10.1056/NEJMoa052122 Joint NSABP B31/NCCTG N9831 analysis establishing adjuvant trastuzumab as standard of care, demonstrating DFS hazard ratio of 0.48.
- Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer (HERA). N Engl J Med. 2005;353(16):1659-1672. doi:10.1056/NEJMoa052306 HERA trial demonstrating benefit of 1-year adjuvant trastuzumab over observation, and that 2 years offered no additional benefit over 1 year.
- Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783-792. doi:10.1056/NEJM200103153441101 Pivotal H0648g trial in metastatic breast cancer showing improved TTP and OS with trastuzumab plus chemotherapy versus chemotherapy alone.
- Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer (BCIRG 006). N Engl J Med. 2011;365(14):1273-1283. doi:10.1056/NEJMoa0910383 BCIRG 006 trial comparing AC-TH vs. TCH, establishing TCH as an effective lower-cardiotoxicity alternative.
- Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA). Lancet. 2010;376(9742):687-697. doi:10.1016/S0140-6736(10)61121-X Landmark trial extending trastuzumab indications to HER2-positive gastric cancer, showing median OS of 13.8 vs. 11.1 months.
- National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology: Breast Cancer. Version 4.2024. NCCN Current NCCN guidelines for HER2-positive breast cancer management, incorporating adjuvant and metastatic trastuzumab regimens.
- National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology: Gastric Cancer. Version 2.2024. NCCN NCCN recommendations for HER2-directed therapy in gastric and GEJ adenocarcinoma.
- Hudis CA. Trastuzumab — mechanism of action and use in clinical practice. N Engl J Med. 2007;357(1):39-51. doi:10.1056/NEJMra043186 Comprehensive review of trastuzumab’s mechanism of action, including ADCC, receptor downregulation, and anti-angiogenic effects.
- Greenblatt K, Khaddour K. Trastuzumab. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; Updated June 22, 2024. StatPearls Current comprehensive review of trastuzumab pharmacology, indications, adverse effects, and monitoring requirements.
- Bruno R, Washington CB, Lu JF, et al. Population pharmacokinetics of trastuzumab in patients with HER2+ metastatic breast cancer. Cancer Chemother Pharmacol. 2005;56(4):361-369. doi:10.1007/s00280-005-1026-z Population PK model establishing t½ of 28.5 days, CL of 0.225 L/day, and influence of tumour burden on clearance.
- Leveque D, Gigou L, Bergerat JP. Clinical pharmacology of trastuzumab. Curr Clin Pharmacol. 2008;3(1):51-55. doi:10.2174/157488408783329931 Review of trastuzumab pharmacokinetics characterising low clearance, low Vd (~4 L), and long half-life comparable to endogenous IgG.