	There have been remarkable advances in the field of anti-HER2 biologic agents. The benefits of trastuzumab, pertuzumab, lapatinib, and ado-trastuzumab emtansine (T-DM1) have all been well studied, but each drug also has its own set of complications and toxicities. Most concerning for trastuzumab is cardiotoxicity; understanding how to monitor for and treat cardiotoxicity is paramount. Diarrhea and rash are potentially troubling side effects seen with lapatinib. Pertuzumab has not been shown to have a high frequency of cardiotoxicity, but cytopenias, diarrhea, and rash can be seen with this medication. With T-DM1, rash and diarrhea are less-common side effects, but thrombocytopenia and transaminitis can be problematic. It is important to know what side effects to monitor for and how to properly manage them in order to best support patients through these biologic treatments. In this review, we discuss the main adverse-event profile of each biologic agent and provide concise management recommendations.

Targeted biologic agents may increase efficacy with less toxicity as compared with traditional cytotoxic chemotherapy. Currently there are four targeted agents that are US Food and Drug Administration (FDA)-approved for clinical use for human epidermal growth factor receptor 2 (HER2)-positive breast cancer: trastuzumab, pertuzumab, lapatinib, and ado-trastuzumab emtansine (T-DM1). However, these agents have potentially serious toxicities (

). Knowledge of common complications or adverse events (AEs) will enable oncologists to make more informed treatment decisions for each individual patient. The objectives of this review are to provide a current description of the safety profiles of anti- HER2-targeted agents used in breast cancer, and to outline practical recommendations for management of toxicities.

		Table 1. Common or Severe Toxicities of Anti-HER2 Biologic Agents

					Common or Serious Grade 3/4 Adverse Events

 gene is localized to chromosome 17q. It encodes a transmembrane tyrosine kinase receptor protein that belongs to the epidermal growth factor receptor (EGFR) or HER family of four transmembrane receptor tyrosine kinases that mediate cell growth, differentiation, and survival.

 protein, amplification of the HER2/neu gene, or both occur in 20%-25% of breast cancers.

 Prior to the development of anti-HER2 agents, HER2- positive breast cancer was known to be aggressive and have high recurrence rates and short disease-free intervals after adjuvant chemotherapy.

Trastuzumab is a humanized monoclonal antibody and was the first anti-HER2 agent to be approved in 1998, and then in 2006 for HER2-positive breast cancer in the metastatic and adjuvant settings, respectively.

 It has been proven to be effective in several neoadjuvant, adjuvant, and metastatic clinical trials. It was first noted in a phase III trial in the metastatic setting that the addition of trastuzumab compared with chemotherapy alone (doxorubicin or epirubicin plus cyclophosphamide or paclitaxel) increased progression-free survival (PFS) by almost 3 months, prolonged overall survival (OS) from 20.3 to 25.1 months, and resulted in a 20% reduction in death.

New York Heart Association (NYHA) class III or IV cardiac dysfunction occurred in 16% of patients in the anthracycline/trastuzumab arm compared with 3% in the arm without trastuzumab.

 In the adjuvant setting there have been four large, randomized clinical trials and one smaller randomized Finnish trial of trastuzumab: the NSABP B-31/N9831 joint analysis,

 Breast International Group (BIG) Herceptin Adjuvant (HERA),

 Breast Cancer International Research Group (BCIRG)-006,

 Comparisons between studies of trastuzumab-related cardiotoxicity in the adjuvant setting are difficult because there were different entry criteria, different definitions of cardiovascular risk, and different cardiac safety parameters.

Cardiac toxicity is defined as per BCIRG-006 and N9831 as congestive heart failure (CHF), which is defined as NYHA class III/IV symptoms with either decline in left ventricular ejection fraction (LVEF) >10% from baseline to <55%, or decline in LVEF >5% to < lower limit of normal (LLN).

 These trials demonstrated that the addition of trastuzumab to chemotherapy decreased the risk of recurrence by 50% and improved survival by 30%. The incidence of NYHA class III/ IV CHF ranged from 0.5% in the HERA trial

There is a clear benefit for trastuzumab, but not insignificant cardiotoxicity.

		Table 2. Recommendations for Withholding Trastuzumab Treatment in Patients Based on Serial LVEF Measurements

					Asymptomatic Decrease in LVEF from Baseline

					Asymptomatic Decrease in LVEF from Baseline Decrease of <10 Percentage Points

					Withhold trastuzumab and repeat cardiac imaging after 4 weeks

					Withhold trastuzumab and repeat cardiac imaging after 4 weeksc,

					Continue trastuzumab and repeat cardiac imaging after 4 weeks

					Withhold trastuzumab and repeat cardiac imaging after 4 weeks 

 Revised to include recommendations for initiating cardioprotective medications and obtaining a cardiology consult as per Canadian Trastuzumab Working Group and Saad et al1

 and withholding trastuzumab for symptomatic heart failure.

 Consider both a cardiac work-up and angiotensin-converting enzyme (ACE) inhibitor therapy.

 After 2 holds and no improvement, consider discontinuation of trastuzumab.

 Recommend to initiate ACE inhibitor and/or beta blocker therapy and cardiology consultation. If LVEF <40%, highly recommend ACE inhibitor treatment.

 Recommend cardiology referral and urgent treatment for heart failure.

		“Cardiac imaging” refers to either echocardiogram or multiple-gated acquisition scan.

		LLN = lower limit of normal; LVEF = left ventricular ejection fraction.

The cardiotoxicity associated with trastuzumab is not completely understood, but unlike anthracyclines, is not dose-related, does not cause ultrastructural damage, often presents as asymptomatic LVEF declines, and is potentially reversible by stopping the drug and initiating cardioprotective medications.

 Risk factors for developing cardiac dysfunction secondary to trastuzumab administration include previous or concurrent use of anthracycline, age greater than 50 years, and decreased baseline LVEF <50%. Other risk factors include increased body mass index and hypertension.

 The LVEF should be normal prior to initiating trastuzumab, or at least ≥50%, or as per institutional guidelines.

 Recommendations for monitoring for cardiac toxicity in the adjuvant setting are included in Table 2.

It is recommended to check LVEF at baseline, then every 3 months until treatment completion, and every 6 months for 2 years. Either a multiple- gated acquisition (MUGA) scan or echocardiogram can be used to determine LVEF, but it is recommended to use the same modality each time for better comparisons. There are advantages and disadvantages to each: MUGAs have less interobserver variability, but echocardiograms better describe the structure of the heart. Management of cardiotoxicity consists of withdrawal of trastuzumab chemotherapy and medical treatment of cardiac dysfunction.

 Table 2 outlines when it is recommended to withhold trastuzumab, obtain a cardiology referral, or initiate cardioprotective medications.

Trastuzumab should be withheld if there is a >16% absolute decrease in LVEF from pretreatment values, or if the LVEF is below institutional limits of normal and there is a >10% absolute decrease in LVEF from pretreatment values.

 Resuming the biologic is permitted if within 4 to 8 weeks the LVEF returns to normal limits and the absolute decrease from baseline is <15%. Permanent discontinuation of trastuzumab is recommended for a persistent ( >8 weeks) LVEF decline or if trastuzumab dosing is suspended on more than 2 occasions.

Trastuzumab should also be discontinued if symptomatic heart failure develops. Symptomatic (clinical) heart failure is defined by symptoms such as dyspnea, orthopnea, and pedal edema, and by objective signs such as elevated jugular venous pressure, sinus tachycardia, tachypnea, S3 gallop, crackles, and LVEF declines or by chest radiograph findings of pulmonary edema or increased vascular markings. Treatment of trastuzumab-related cardiotoxicity is controversial, since patients in the adjuvant trials were not treated in a uniform manner. The Canadian Trastuzumab Working Group has perhaps been the most prolific in publishing recommendations (

Symptomatic LV dysfunction should be treated as per institutional guidelines. Generally, angiotensin-converting enzyme (ACE) inhibitors should be initiated at an LVEF below 40% and should be considered below an ejection fraction (EF) of 50%, especially if symptomatic. Beta blockers should be considered in patients with asymptomatic LV dysfunction and LVEF below 40%.

 The Canadian Working Group recommends an accelerated schedule for pharmacotherapy because the normal schedules for titration can take several months to reach optimal therapeutic goals.

 Consultation with a cardiologist familiar with these medications would be useful.

Trastuzumab infusion-related reactions occur in up to 40% of patients,

 but the incidence of severe infusion-related reactions is rare at <1%.

 Infusion reactions usually occur during the first infusion or within 24 hours of the infusion, and generally do not occur subsequently. The reaction includes fever, chills, dyspnea, hypotension, bronchospasm, and respiratory distress.

 Caution is recommended in those patients with severe pulmonary conditions or with clinically relevant dyspnea and hypoxia secondary to tumor burden or advanced malignancy. For infusion reactions manifesting as anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome, it is recommended to discontinue trastuzumab.

Premedications are not necessary, but it is recommended to have emergency medications on standby. The safety of rechallenge is unknown. In one retrospective review, 85% of patients with a severe hypersensitivity reaction were safely rechallenged.

Lapatinib is an orally administered small-molecule inhibitor of tyrosine kinase domains of both HER2 and HER1/EGFR type 1. The most common side effects reported in a phase I study were diarrhea (42%) and rash (31%). Five grade 3 drug-related toxicities (gastrointestinal events and rash) were experienced by four patients. No grade 4 drug-related AEs were reported. The incidence of diarrhea was dose-related, whereas the incidence of rash was not.

 In the phase III study comparing capecitabine and lapatanib to capecitabine alone, diarrhea and rash occurred more frequently in the combination-therapy group, with the difference due to an increase in grade 1 events.

The mainstay of treatment for this toxicity is antidiarrheal preparations. For mild-to-moderate (grade 1 or 2) diarrhea, the patient should hydrate aggressively, eat small meals, avoid irritants such as lactose-containing products, and take loperamide at an initial dose of 4 mg followed by 2 mg every 4 hours or after every unformed stool. Loperamide should be continued until the patient is without diarrhea for at least12 hours.

 Lapatinib should be withheld for grade 3 diarrhea or grade 1 or 2 diarrhea with complicating features such as moderate to severe abdominal cramping, nausea or vomiting, decreased performance status, fever, sepsis, neutropenia, frank bleeding, or dehydration. Admission for intravenous fluids, octreotide, and antibiotics may be warranted.

 When the diarrhea resolves to grade 1 or less, lapatinib can be reintroduced at a lower dosage (reduced from 1250 mg/day to 1000 mg/day or from 1500 mg/day to 1250 mg/day). Lapatinib should be permanently discontinued in patients with grade 4 diarrhea.

The skin rash associated with lapatinib is typical of drugs that target the ErbB-1 receptor, presenting as an erythematous, papular eruption on the face, chest, and back, and sometimes resembling folliculitis or acneiform drug rash.

 There are no clear guidelines for management. In most patients, temporary interruption or cessation of lapatinib resolves the rash. Commonly used treatments include aggressive moisturization and topical or oral antibiotics. Colloidal oatmeal lotion and emollients can be effective. Either clindamycin phosphate 1% gel or a combination of clindamycin 1% and benzoyl peroxide 5% gel is favored for inflammatory and pustular lesions. Oral antibiotics include tetracycline (250 mg four times daily) or minocycline (100 mg two times daily). Patients with widespread or persistent skin involvement should be referred to a dermatologist. were safely rechallenged. 

Pertuzumab is a humanized anti-HER2 monoclonal antibody that binds to the extracellular dimerization subdomain of the HER2 receptor, thereby preventing heterodimer formation and reducing intracellular signaling. Pertuzumab and trastuzumab bind to different sites on the HER2 receptor and have complementary antitumor activities. In the randomized, double-blind, placebo-controlled, multinational, phase III CLEOPATRA trial, pertuzumab in combination with trastuzumab and docetaxel compared with placebo plus trastuzumab and docetaxel significantly increased median PFS (primary endpoint) from 12.4 to 18.5 months and objective response rate from 69% to 80% in the first-line setting of HER2-positive metastatic breast cancer.

 In the latest interim analysis, there was a trend toward overall survival in the pertuzumab arm, but it did not achieve statistical significance.

 Pertuzumab also had an acceptable tolerability profile.

 The incidence of most grade ≥3 AEs was comparable between the two groups. Most notable, the incidence of febrile neutropenia was 13.8% versus 7.6%, and the incidence of diarrhea was 7.9% vs 5%, respectively, in the pertuzumab and placebo arms. There were no reported cardiac AEs, and grade 3 left ventricular systolic dysfunction (LVSD) was 1.2% versus 2.8% in the pertuzumab and placebo arms respectively.

T-DM1 is an antibody-drug conjugate that combines the HER2-targeted antitumor properties of trastuzumab with the cytotoxic activity of the microtubule-inhibitory agent DM1 (derivative of maytansine). The pivotal phase III, randomized, open-label, international EMILIA trial compared lapatinib and capecitabine to T-DM1 in patients with HER2-positive, unresectable, locally advanced or metastatic breast cancer who were previously treated with trastuzumab and a taxane. There was a significantly prolonged median PFS of 6.4 to 9.6 months and OS of 25.1 to 30.9 months with T-DM1.

 T-DM1 also had a more favorable toxicity profile. The incidence of grade ≥3 AEs was higher in the lapatinib-capecitabine group than in the T-DM1 group (57.0% vs 40.8%).

 The most commonly reported grade 3 or 4 events with T-DM1 were thrombocytopenia (12.9%) and elevated serum concentrations of aspartate aminotransferase (AST) (4.3%) and alanine aminotransferase (ALT) (2.9%).

 For the majority of patients, the primary occurrence of grade 3 or 4 thrombocytopenia occurred during the first two cycles of T-DM1 treatment. Only 2% had to discontinue treatment secondary to thrombocytopenia.

The rates of grade 3 or 4 bleeding events were 1.4% and 0.8% in the T-DM1 and lapatinib-capecitabine arms, respectively. In a population pharmacokinetic/pharmacodynamic model of thrombocytopenia, the short-term platelet nadir during cycle 1 was captured in addition to 46% of patients experiencing variable degrees of downward drifting platelets with multiple treatment cycles that were predicted to stabilize by the 8th cycle.

 Any increases in AST and ALT were commonly observed by day 8 of each cycle and generally returned to baseline by day 21. Only three patients discontinued T-DM1 due to grade 3 elevations in AST levels, because with dose modifications, most patients with grade 3 or 4 elevations were able to continue treatment. In the EMILIA protocol, T-DM1 was permanently discontinued in patients with ALT >3 × upper limit of normal (ULN) and a subsequent increase in total bilirubin to >2 × ULN within 21 days. For patients with AST > 3 × ULN (without ALT > 3 × ULN) and a subsequent increase of total bilirubin to >2 × ULN within 21 days, treatment with T-DM1 was permitted to be continued with one dosage level reduction after recovery of AST to ≤2.5 × ULN and total bilirubin to ≤1.5 × ULN. The starting dosage was 3.6 mg/kg with a first dosage reduction to 3.0 mg/kg and a second dosage reduction to 2.4 mg/kg. It is recommended to check serum transaminases and bilirubin prior to each dose of T-DM1.

The development of targeted biologics has been a major milestone in the treatment of HER2-positive breast cancer. Survival outcomes have been markedly improved with these agents. However, these medications all have potential adverse effects, and specific management may be necessary. Preparing in advance for expected side effects and appropriate management during treatment can help maintain compliance and quality of life for patients.

: Aarti S. Bhardwaj, MD, is a clinical fellow at the Icahn School of Medicine at Mount Sinai/Mount Sinai Medical Center, New York City. Amy D. Tiersten, MD, is associate professor at Icahn School of Medicine aand Tisch Cancer Institute at Mount Sinai.

: Drs. Bhardwaj and Tiersten report no conflicts of interest to disclose.

 Aarti S. Bhardwaj, MD, Icahn School of Medicine, Mount Sinai Medical Center, One Gustave L. Levy Place, Box 1079, New York, NY 10029. Email: aarti.bhardwaj@mountsinai.org.

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