What are the side effects and management considerations for trastuzumab and pertuzumab in HER2‑positive breast cancer?

Side Effects of Trastuzumab and Pertuzumab

The most common side effects of trastuzumab and pertuzumab combination therapy include diarrhea (67%), alopecia (61%), neutropenia (53%), nausea (42%), fatigue (37%), rash (34%), and peripheral neuropathy (32%), with cardiac toxicity being the most critical safety concern requiring systematic monitoring. 1

Cardiac Toxicity (Most Critical Safety Concern)

Trastuzumab Cardiac Effects

• Cardiac dysfunction is the primary concern with trastuzumab therapy, occurring in 4% of patients receiving monotherapy and up to 27% when combined with anthracyclines. 2, 3
• The American Heart Association notes that trastuzumab-induced cardiotoxicity differs fundamentally from anthracyclines—it does not cause myocyte loss and appears reversible after discontinuation, resulting in a good cardiovascular prognosis. 4
• The FDA mandates evaluating left ventricular ejection fraction (LVEF) prior to and every 3 months during treatment. 2, 3
• The mechanism involves inhibition of HER2 in cardiomyocytes, blocking an important protective, growth-promoting, and anti-apoptotic pathway in the myocyte. 4

Pertuzumab Cardiac Safety

• Critically, the CLEOPATRA trial demonstrated no significant increase in symptomatic or asymptomatic cardiac dysfunction when pertuzumab was added to trastuzumab and docetaxel. 5
• The NCCN strongly advises against administering pertuzumab and trastuzumab concurrently with anthracyclines due to the 27% risk of significant cardiac dysfunction. 5, 6

Hematologic Toxicity

Neutropenia and Febrile Neutropenia

• Neutropenia occurs in 53% of patients receiving pertuzumab plus trastuzumab plus docetaxel (Grade 3-4 in 49%), compared to 50% with placebo plus trastuzumab plus docetaxel (Grade 3-4 in 46%). 1
• Febrile neutropenia occurs in 14% of patients on the pertuzumab-containing regimen versus 8% without pertuzumab, with Asian patients experiencing higher rates (26% versus 12%). 1
• The NCCN notes that per-patient incidences of Grade 3-4 neutropenia and febrile neutropenia are higher when trastuzumab is combined with myelosuppressive chemotherapy, though septic death rates remain similar. 3

Anemia and Leukopenia

• Anemia occurs in 23% of patients (Grade 3-4 in 2%) with pertuzumab combination therapy. 1
• Leukopenia affects 18% of patients (Grade 3-4 in 12%) with pertuzumab-containing regimens. 1

Gastrointestinal Side Effects

• Diarrhea is the most common adverse reaction, occurring in 67% of patients receiving pertuzumab plus trastuzumab plus docetaxel (Grade 3-4 in 8%), compared to 46% without pertuzumab (Grade 3-4 in 5%). 1
• Nausea affects 42% of patients in both treatment arms. 1
• Vomiting occurs in 24% of patients with pertuzumab combination versus 24% without. 1
• Stomatitis and mucosal inflammation occur in 19-28% of patients. 1

Infusion-Related Reactions

Trastuzumab Infusion Reactions

• The FDA warns that trastuzumab can cause severe infusion reactions including fever, chills, nausea, vomiting, pain, headache, dizziness, dyspnea, hypotension, rash, and asthenia. 3
• Prior to resuming trastuzumab infusion after severe reactions, the majority of patients were pre-medicated with antihistamines and/or corticosteroids, though some experienced recurrent severe reactions despite pre-medications. 3

Pertuzumab Infusion Reactions

• Infusion-related reactions and hypersensitivity reactions including anaphylaxis are recognized adverse reactions requiring monitoring. 1

Dermatologic Side Effects

• Alopecia occurs in 61% of patients receiving pertuzumab combination therapy versus 60% without pertuzumab. 1
• Rash affects 34% of patients (Grade 3-4 in 0.7%) with pertuzumab versus 24% without (Grade 3-4 in 0.8%). 1
• Nail disorders occur in 23% of patients with pertuzumab combination. 1
• Pruritus and dry skin affect 14% and 11% of patients respectively. 1

Neurologic Side Effects

• Peripheral neuropathy occurs in 32% of patients (Grade 3-4 in 3%) receiving pertuzumab plus trastuzumab plus docetaxel. 1
• Headache affects 21% of patients with pertuzumab combination versus 17% without. 1
• Dysgeusia (taste disturbance) occurs in 18% of patients. 1
• Dizziness affects 13% of patients. 1

Pulmonary Toxicity

• The FDA warns that trastuzumab can result in serious and fatal pulmonary toxicity including dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, pulmonary insufficiency, hypoxia, acute respiratory distress syndrome, and pulmonary fibrosis. 3
• Patients with symptomatic intrinsic lung disease or extensive tumor involvement of the lungs resulting in dyspnea at rest appear to have more severe toxicity. 3
• These events can occur as sequelae of infusion reactions. 3

Constitutional Symptoms

• Fatigue affects 37% of patients (Grade 3-4 in 2%) with pertuzumab combination versus 37% without (Grade 3-4 in 3%). 1
• Asthenia occurs in 26% of patients (Grade 3-4 in 2%) with pertuzumab versus 30% without (Grade 3-4 in 2%). 1
• Pyrexia (fever) affects 19% of patients with pertuzumab combination versus 18% without. 1

Musculoskeletal Side Effects

• Myalgia occurs in 23% of patients with pertuzumab combination versus 24% without. 1
• Arthralgia affects 15% of patients in both treatment arms. 1

Embryo-Fetal Toxicity

• Both trastuzumab and pertuzumab can cause fetal harm when administered during pregnancy, with post-marketing reports documenting oligohydramnios, oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. 3, 1
• The FDA mandates verifying pregnancy status prior to initiation and advising females of reproductive potential to use effective contraception during treatment and for 7 months following the last dose. 3, 1

Infections

• Upper respiratory tract infections occur in 17% of patients with pertuzumab combination versus 13% without. 1
• Nasopharyngitis affects 12-13% of patients in both arms. 1

Critical Management Considerations

• Adverse reactions requiring interruption or discontinuation include congestive heart failure, significant decline in left ventricular cardiac function, severe infusion reactions, and pulmonary toxicity. 3
• The most common adverse reactions (>1%) leading to discontinuation of all study therapy in the CLEOPATRA trial was left ventricular dysfunction (1% with pertuzumab versus 2% without). 1
• The safety profile of pertuzumab remained unchanged with an additional 2.75 years of follow-up (median total follow-up of 50 months). 1