	Human epidermal growth factor receptor 2 (HER2)-positive breast cancer is an aggressive type of breast cancer with an inferior prognosis. Trastuzumab, a human monoclonal anti-HER2 antibody, was the first targeted agent for this breast cancer subtype. However, de novo and acquired trastuzumab resistance does occur, resulting in the need for other HER2-directed therapies. One approach has been the use of antibody drug conjugates (ADCs), which are cytotoxic drugs connected by chemical linkers to monoclonal antibodies that are specific for a tumor-associated antigen. This results in the preferential delivery of a drug to cancer cells while minimizing exposure to normal tissues. Ado-trastuzumab emtansine (T-DM1) is a novel ADC that consists of trastuzumab bound via a thioether linker to the cytotoxic agent, DM1, a highly potent antimitotic drug. Currently, T-DM1 is approved for patients with HER2-positive metastatic breast cancer who have previously received trastuzumab and a taxane, progressed on their most recent treatment in the locally advanced or metastatic setting, or are within 6 months of adjuvant trastuzumab for early-stage disease. It is currently being investigated in the neoadjuvant and adjuvant settings. This article provides a concise review of the clinical development, use, safety, and pharmacokinetics of T-DM1, as well as future research directions of T-DM1 in the field of HER2-directed therapies.

Human epidermal growth factor receptor 2 (HER2)-positive disease accounts for 20% to 25% of breast cancers, as represented by amplification of the HER2 gene and/or HER2 protein overexpression. This breast cancer subtype has an aggressive clinical course and inferior outcome.

 Trastuzumab is a humanized monoclonal anti-HER2 antibody that binds to the extracellular domain of HER2 and has significantly improved outcomes for patients with both early-stage and metastatic HER2-positive disease.

 Despite these significant advances, both de novo and acquired trastuzumab resistance occurs. Approximately 15% of women develop metastatic breast cancer (MBC) despite trastuzumab-based adjuvant therapy.

 This has led to the development of other HER2-directed therapies. Lapatinib, a potent small molecule dual tyrosine kinase inhibitor of HER2 and epidermal growth factor receptor (EGFR), was approved by the FDA in 2007 either in combination with capecitabine or trastuzumab for patients with HER2-positive MBC following disease progression on trastuzumab.

 In 2012, pertuzumab, a monoclonal antibody that binds subdomain II of the HER2 extracellular domain and blocks HER2 dimerization and signaling, was approved in combination with trastuzumab and docetaxel in the first-line setting for HER2-positive MBC (

 Most recently, the FDA provided accelerated drug approval for dual HER2 blockade in the neoadjuvant setting using pertuzumab and trastuzumab in combination with chemotherapy.

		Figure. Mechanisms of Action of HER2-Directed Agents for Breast Cancer

		Human epidermal growth factor (EGF) receptors HER1, HER2, HER3, and HER4 are receptor tyrosine kinases that are involved in the signal transduction pathways that lead to cell survival and differentiation. Each of these receptors consists of three components: an extracellular binding domain, a transmembrane lipophilic segment, and a functional intracellular tyrosine kinase domain (with the exception of HER3). When a ligand of an EGF receptor binds to the extracellular binding domain, the tyrosine kinase domains are activated by both homodimerization and heterodimerization. The HER2 receptor is an orphan receptor and does not require the binding of a ligand for activation. HER2 is also the preferential dimerization partner of other members of the EGF family, and dimerization can be induced by receptor overexpression and mutation. Homo- and heterodimerization of the HER family leads to phosphorylation of the tyrosine kinase domain and activation of downstream signaling pathway, including the PI3K-AKT-mTOR and the RAF-MEK-MAPK pathways. Downstream effects include survival, proliferation, and increased vascular endothelial growth factor (VEGF). Anti-HER2 strategies include: (A) Trastuzumab is a monoclonal antibody that binds to the extracellular domain IV of the HER2 receptor. (B) Lapatinib is a dual tyrosine kinase inhibitor against HER2 and EGFR (HER1). (C) Pertuzumab is a monoclonal antibody that binds to extracellular domain II of HER2 and inhibits the dimerization of HER2 with other HER family receptors, especially HER3. The HER2-HER3 heterodimer is a strong activator of signaling through the PI3K-AKT-mTOR pathway. (D) T-DM1 is a novel antibody-drug conjugate of trastuzumab and DM1, a derivative of maytansine and a highly potent antimitotic drug. The drug binds to the extracellular domain of HER2, allowing for the selective delivery of DM-1 to HER2-overexpressing cells.

One novel approach in the development of new HER2-targeted therapies has been the development of HER2-directed antibody-drug conjugates (ADCs).

 ADCs are cytotoxic drugs that are connected by chemical linkers to monoclonal antibodies specific for a tumor-associated antigen. ADCs are designed to preferentially deliver a cytotoxic drug to cancer cells while minimizing exposure to normal tissues, thus improving the therapeutic index.

 The use of ADCs in oncology first began with the development of gemtuzumab ozogamicin, an anti-CD33 antibody linked to the cytotoxic antibiotic, calicheamicin, for CD33-positive acute myelogenous leukemia (AML).

 Subsequently, brentuximab vedotin, a CD30-specific ADC, was developed and is approved for use in Hodgkin lymphoma and anaplastic large cell lymphoma.

Ado-trastuzumab emtansine (T-DM1) is an ADC that was developed to treat HER2-positive MBC. T-DM1 consists of trastuzumab covalently bound via a thioether linker, (N-maleimidomethyl) cyclohexane-1-carboxylate (MCC), to the cytotoxic agent, DM1, a derivative of maytansine. DM1 is a highly potent antimitotic drug that binds to microtubules in a similar way to that of vinca alkaloids.

 Vinca alkaloids have demonstrated synergy with trastuzumab.

 T-DM1 binds to the extracellular domain of HER2, and the complex is then internalized into the cell. The antibody is degraded by proteases and the active metabolite, lysine-Nε—MCC-DM1, is released into the cytoplasm (

 This metabolite is a charged molecule and is relatively membrane impermeable. This reduces the chance that DM1 can enter a neighboring cell and limits the possibility of nonspecific toxicity.19 T-DM1 also retains the effector functions of trastuzumab: inhibition of HER2-mediated signal transfusion and activation of antibody-dependent cellular cytotoxicity.

T-DM1 was initially evaluated as a single agent in a phase I dose escalation study in 24 patients with trastuzumab-refractory HER2-positive MBC (TDM3569g).

 Weekly and every-3-week dosing schedules were tested. The maximum tolerated dose (MTD) for the 3-week regimen was determined to be 3.6 mg/ kg. T-DM1 was well tolerated and the most common adverse events (AEs) were thrombocytopenia, elevated transaminases, fatigue, anemia, and nausea.

 In the 3-week regimen, the objective response rate (ORR) was 44% in patients treated at the MTD and was comparable to patients treated on the weekly regimen (40%). Subsequently, the every-3-week schedule has been utilized in the majority of subsequent studies, largely due to the convenience for patients.

T-DM1 monotherapy was then studied in two single arm phase II trials (TDM4258g and TDM4374g). TDM4258g evaluated T-DM1 at 3.6 mg/kg every 3 weeks for patients with HER2-positive MBC who had progressed on at least one line of HER2-directed therapy. A total of 112 patients with a median of 8 (range 2-19) prior anticancer agents in all settings were enrolled. The primary endpoint, ORR, was 25.9% (95% confidence interval [CI], 18.4% to 34.4%). Median progression free survival (PFS) was 4.6 months (95% CI, 3.9 to 8.6 months), and median duration of response (DOR) was not reached. In a post hoc exploratory analysis, the ORR in patients who had received prior lapatinib and trastuzumab was not significantly different than the overall ORR, suggesting that T-DM1 has activity after progression on prior HER2-directed therapies.

TDM4374g enrolled 110 patients who had previously received trastuzumab, lapatinib, capecitabine, a taxane, and an anthracycline for HER2-positive breast cancer and had progressed on at least two HER2-directed agents in the metastatic or locally advanced setting.

 This was in contrast to TDM4258g, which only required that patients had received and progressed on at least one prior HER2-directed therapy and had received at least one chemotherapy regimen in the metastatic setting.

 In TDM4374g, all patients were heavily pretreated with a median of 7 (range 3-17) anticancer agents in the metastatic setting. The ORR was 34.5% (95% CI, 26.1% to 43.9%) with a median PFS of 6.9 months (95% CI, 4.2 to 8.4 months) and a clinical benefit rate (CBR) of 48.2% (95% CI, 38.8% to 57.9%). This confirmed the single agent activity of T-DM1 in the metastatic setting.

T-DM1 was subsequently evaluated in several large, randomized studies. The pivotal EMILIA study was a phase III, international trial in patients with locally advanced or metastatic, centrally confirmed, HER2-positive breast cancer. Patients had previously received a taxane and trastuzumab and had progressed on their most recent treatment in the locally advanced or metastatic setting or within 6 months of completion of adjuvant trastuzumab for early-stage disease. A total of 991 patients were randomized 1:1 to T-DM1 (3.6 mg/kg every 3 weeks) or to lapatinib (1250 mg daily) and capecitabine (2000 mg/m

 days 1-14). The primary endpoints were PFS and overall survival (OS). Treatment with T-DM1 significantly improved median PFS compared with lapatinib plus capecitabine (9.6 vs 6.4 months; hazard ratio [HR] 0.65; 95% CI, 0.55 to 0.77; 

<.001). OS also favored T-DM1 (30.9 vs 25.1 months, HR 0.68; 95% CI, 0.55 to 0.85; 

<.001). ORR and DOR were superior in patients treated with T-DM1. Serious AEs were reported for 18% of patients in the lapatinib-capecitabine group versus 15.5% in the T-DM1 group. There were more grade ≥3 AEs in the lapatinib-capecitabine group versus in the T-DM1 group (57% vs 40.8%). The most commonly reported grade 3 or 4 AEs were diarrhea and palmar-plantar erythrodysesthesia in the lapatinib-capecitabine group and thrombocytopenia and elevated transaminases in the T-DM1 group.

 The results of the EMILIA study led to the FDA approval of T-DM1 in February 2013 for patients with HER2-positive MBC.

The TH3RESA trial is another phase III trial, which evaluated the efficacy and safety of T-DM1 in comparison with treatment of physician’s choice (TPC) in 602 patients with MBC or unresectable locally advanced/recurrent HER2-positive breast cancer who had received at least two prior HER2-directed therapies, including trastuzumab and lapatinib (NCT01419197).

 The first results from this trial, presented at the 2013 European Cancer Congress, showed that median PFS increased by nearly 3 months (6.2 vs 3.3 months; HR 0.528; 95% CI, 0.422-0.661; 

<.0001) in patients receiving T-DM1 compared with patients receiving TPC.

T-DM1 has also been evaluated in the first-line metastatic setting. The TDM4450g study was a phase II trial in which 137 patients with previously untreated HER2-positive metastatic or locally advanced breast cancer were randomized to T-DM1 or trastuzumab plus docetaxel. The primary endpoints were PFS and safety. PFS was significantly longer in patients receiving T-DM1 compared with those receiving trastuzumab plus docetaxel (14.2 months vs 9.2 months, HR 0.59; 95% CI, 0.36 to 0.97; 

=.035). Patients receiving T-DM1 had fewer grade ≥3 AEs compared with the trastuzumab plus docetaxel group (46.4% vs 90%). Of note, only 27.1% of the patients in the trastuzumab plus docetaxel group and 17.9% of the patients in the T-DM1 group had received trastuzumab in the neoadjuvant or adjuvant setting.

Encouraged by the synergistic activity noted in xenograft models, the combination of T-DM1 plus pertuzumab was then evaluated in a phase Ib/II clinical trial (TDM4373g). The safety and efficacy of T-DM1 plus pertuzumab in 67 patients with HER2-positive locally advanced or MBC was assessed. Patients received the combination either in the first-line or relapsed setting (defined as progression on prior HER2 therapy for MBC). All patients in the relapsed setting (n=46) had received prior trastuzumab and 75% had received prior lapatinib; of these 46 patients, 16 had confirmed responses. Interim results showed ORRs of 34.8% and 57.1% in the relapsed and first-line settings, respectively. The combination was deemed to be safe and tolerable.

Notably, the combination regimen did result in a 24% incidence of peripheral sensory neuropathy, and one patient was discontinued from the trial due to a decrease in left ventricular ejection fraction. However, the peripheral neuropathy was mild and it is not known if it was noted specifically in the patients treated with T-DM1 in the first-line setting versus those treated in the relapsed setting. In the 4374g phase II trial of single agent T-DM1, there was 18% incidence of peripheral neuropathy. However, these patients were heavily pretreated. The incidence of neuropathy will perhaps be further elucidated in the MARIANNE study.

The MARIANNE study is a randomized, 3-arm, multicenter, phase III study that is evaluating the efficacy and safety of T-DM1 with pertuzumab in patients with HER2-positive progressive or recurrent locally advanced or previously untreated MBC (NCT01120184). Patients were randomized to one of the three cohorts: T-DM1 with pertuzumab, T-DM1 with pertuzumab-placebo (blinded for pertuzumab), or trastuzumab combined with a taxane. This trial has completed enrollment and results are eagerly awaited later in 2014.

An additional phase 1b study of T-DM1 and paclitaxel with or without pertuzumab showed that the combination was feasible, and updated results regarding dosing schedules and safety are awaited.

					T-DM1 + capecitabine in HER2+ MBC and HER2+ locally advanced or metastatic gastric cancer (followed by phase II component)

					T-DM1 in HER2+ MBC and normal or reduced hepatic function

					Neoadjuvant T-DM1 with or without standard endocrine therapy vs trastuzumab with standard endocrine therapy for 12 weeks in patients with operable HER2+/HR+ breast cancer

					Pertuzumab + trastuzumab with or without chemotherapy both followed by T-DM1 in case of progression in patients with HER2+ MBC

					Pertuzumab + trastuzumab vs pertuzumab + trastuzumab + metronomic chemotherapy in the elderly HER2+ MBC population who may continue on T-DM1 alone following disease progression

					T-DM1 + pertuzumab + standard chemotherapy in women with HER2+ locally advanced breast cancer

					Assessing cardiac safety of trastuzumab vs pertuzumab vs T-DM1 in adjuvant or metastatic setting in patients with LVEF between 40% and 50%

					Cardiac events or asymptomatic worsening of cardiac function

					T-DM1 vs paclitaxel + trastuzumab for stage I HER2+ breast cancer

					T-DM1 in HER2+ locally advanced or MBC patients who have received prior anti-HER2 and chemotherapy-based treatment

					Adjuvant T-DM1 vs trastuzumab in HER2+ breast cancer with residual tumor in breast or axillary lymph nodes following neoadjuvant therapy

		DFS, disease-free survival; HR, hormone receptors; LVEF, left ventricular ejection fraction; MTD, maximum tolerated dose; MBC, metastatic breast cancer; ORR, overall response rate; OS, overall survival; pCR, pathologic complete response; PFS, progression free survival.

In addition to evaluating T-DM1 in the metastatic setting, T-DM1 is also being studied in the neoadjuvant and adjuvant settings. The I-SPY 2 study is evaluating T-DM1 and pertuzumab in the neoadjuvant setting.

 The KATHERINE trial is an adaptive trial design wherein patients with HER2-positive primary breast cancer with residual disease in the breast or axillary lymph nodes following neoadjuvant therapy are being randomized to T-DM1 versus trastuzumab.

Overall, T-DM1 is well tolerated with a relatively low rate of clinically significant AEs (

 A pooled analysis of toxicity data from 882 patients treated in seven clinical trials with single agent T-DM1 at 3.6 mg/kg every 3 weeks found that the most common AEs of any grade were fatigue (45.4%), nausea (42.3%), headache (28.7%), thrombocytopenia (28.7%), and constipation (25.5%).

 Grade ≥3 AEs occurring in ≥2% of patients were thrombocytopenia, increased transaminases, fatigue, hypokalemia, and anemia.

 It is important to note that up to two dose modifications (3 mg/kg and 2.4 mg/kg) are allowed with T-DM1 treatment. After two dose reductions, any further requirements for dose reductions should result in discontinuation of T-DM1.

The most common AEs of special interest are thrombocytopenia, hepatic toxicity, and cardiotoxicity. Thrombocytopenia is typically grade 1 or 2 and rapidly reversible, and has generally not been associated with clinically significant bleeding.

Platelet counts can start to decline as soon as 24 hours after dosing, nadir around day 8, and recover by day 15.20 In approximately 20% of patients, platelet counts do not completely recover to baseline after repeated dosing.

 Hepatic toxicity typically presents as transient and asymptomatic transaminase elevations.

 Serious hepatobiliary disorders, including two fatal cases of severe drug-induced liver injury and associated hepatic encephalopathy, have been reported; as such, the prescribing information for T-DM1 includes a boxed warning for hepatotoxicity.

 Rare cases of nodular regenerative hyperplasia (NRH) have also been described (3 cases out of 882 treated patients).

 NRH is a rare liver disorder characterized by a widespread transformation of the hepatic parenchyma into small regenerative nodules and can result in noncirrhotic portal hypertension.

NRH can only be diagnosed by a liver biopsy, which should be considered in any patient receiving T-DM1 who develops signs and/or symptoms of portal hypertension.

		Table 2. Most Common Adverse Events (>20% incidence in at least one single agent trial) Reported in Clinical Trials of T-DM1

Patients were treated with 0.3-4.8 mg/kg every 3 weeks. This trial also included a separate cohort of a weekly regimen, which is not reported here.

 TDM4450g compared T-DM1 (n=67) versus trastuzumab plus docetaxel (HT) (n=70). Only the T-DM1 arm is reported here. 67 patients were enrolled in the T-DM1 arm but two patients in the HT arm mistakenly received a dose of T-DM1 and were included in the T-DM1 safety analyses.

 TDM4373g compared T-DM1 with pertuzumab. The AEs reported here are of the combination regimen.

EMILIA compared T-DM1 (n=490) versus lapatinib plus capecitabine (n=488). Only the T-DM1 arm is reported here. NR, not reported.

 One patient required a dose reduction for neuropathy but exact grade was not recorded.

T-DM1 should be discontinued if NRH develops.

 For both thrombocytopenia and hepatic toxicity, patients can typically continue on T-DM1 with dose modifications.

 Cardiotoxicity has been carefully studied in patients receiving T-DM1 because of the cardiac toxicity of trastuzumab, and a boxed warning for left ventricular dysfunction exists for T-DM1.

 In the pooled safety analysis, there were 13 cardiac AEs (1.5%) and all but 2 of the events were grade 1 or 2.

 Rare AEs of special interest include interstitial lung disease and pneumonitis, infusion-related reactions and hypersensitivity reactions, and peripheral neuropathy. T-DM1 is pregnancy category D and carries a boxed warning for embryo-fetal toxicity

The half-life of T-DM1 is approximately 3.5-4 days and there is no significant accumulation of T-DM1 when given every 3 weeks.

 The level of free DM1 in the plasma is very low (average of approximately 5 ng/mL) throughout the treatment cycle, which is likely related to the favorable toxicity profile of T-DM1. Pretreatment residual levels of trastuzumab have not been shown to influence the pharmacokinetics or clinical efficacy of T-DM1.

As the therapeutic armamentarium of HER2-directed therapies has expanded in the past decade, it has become imperative to identify patients who are most likely to respond to a specific agent or be resistant to it. The mechanisms that contribute to the frequent development of resistance to trastuzumab are only beginning to be understood.

 One mechanism of resistance to trastuzumab is the development of mutations in the phosphoinositide 3-kinase/protein kinase B /mammalian target of rapamycin (PI3K/AKT/mTOR) pathway.

 Preclinical studies have shown potent T-DM1 activity in breast cancer cells with PIK3CA mutations.

 T-DM1 inhibits the growth of lapatinib-resistant breast cancer cells with an activated PI3K pathway.

 A recent analysis performed on archival tumor tissue from the EMILIA study showed that patients with PIK3CA mutations who were assigned to the lapatinib-capecitabine arm had a shorter PFS and OS compared with patients with wild-type cancers in the lapatinib-capecitabine arm. However, patients treated with T-DM1 had a similar PFS and OS, regardless of the presence of a PIK3CA mutation.

 These results need further validation but highlight the need for identification of biomarkers of response to help identify which patients are specifically likely to benefit from T-DM1.

 Future steps also include identifying mechanisms of resistance to T-DM1. Currently, potential mechanisms include downregulating HER2 expression and upregulating expression of drug efflux pumps, such as multidrug resistance 1 (MDR1), and thus, reduction of intracellular exposure to DM1.

Overall, T-DM1, a novel ADC, is an attractive HER2-directed therapy given its favorable toxicity profile and clinical efficacy in the locally advanced and metastatic settings. Ongoing and future trials, as demonstrated in 

, will help elucidate the efficacy in the neoadjuvant and early disease settings. Research efforts are also focused on best selecting patients who are most likely to benefit from this therapy.

Given that there are now four approved agents in the field of HER2-directed therapy with various others under investigation, identifying biomarkers of response and/or resistance to these agents and determining the exact sequence of these promising therapies to best optimize the outcomes of patients is critical. Cost-effectiveness and toxicity profiles of these agents will come to play a significant role. Nevertheless, the future is bright and exciting, and evolving data bear further hope for the improvement of outcomes in this patient population.

Articles

Human epidermal growth factor receptor 2 (HER2)-positive disease accounts for 20% to 25% of breast cancers, as represented by amplification of the HER2 gene and/or HER2 protein overexpression

Antibody-Drug Conjugates and T-DM1

	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.

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.

Common Adverse Effects of Anti-HER2 Therapies and Practical Management Recommendations

	Brain metastases represent the most common intracranial malignancy. The management of brain metastases is often complex, multidisciplinary, and highly individualized. In this review, the role of radiotherapy in the management of brain metastases is considered from a historical perspective, in the context of other treatment modalities, and with regard to different radiotherapy techniques. Data regarding coordination of systemic therapy with radiotherapy is reviewed, outlining historical findings and a paucity of data in the context of novel systemic cytotoxic and biologic therapies with whole brain radiotherapy and stereotactic radiosurgery. Controversial aspects of patient management are considered, including multifactorial patient, tumor, and treatment factors that inform treatment recommendations for individual patients. Current clinical controversies and research endeavors are reviewed as they relate to maximization of therapeutic efficacy, minimization of toxicity, and optimization of quality of life. General evidence-based approaches to management of brain metastases are considered and published guidelines are addressed in this review.

Brain metastases represent the most common intracranial malignancy in adults and are reported to develop in 10% to 40% of patients with a known extracranial primary malignancy.

 While the exact incidence is uncertain, present estimates suggest that approximately 180,000 patients in the United States are diagnosed with brain metastases annually.

 With advances in systemic therapies and the potential increased longevity of cancer patients, the absolute incidence of brain metastases may increase, as may survival following therapeutic intervention for brain metastases. Thus, more than ever before, therapeutic strategies are urgently needed that offer effective, durable control of brain metastases with a favorable toxicity profile.

The management of brain metastases has evolved over the past several decades but has continued to rely on radiotherapy and neurosurgical resection as the predominant treatment modalities. Most systemic therapies including chemotherapy have demonstrated poor penetration of the blood brain barrier and have had limited efficacy against brain metastases. As such, whole brain radiotherapy (WBRT) has been the classic treatment for brain metastases for decades, and includes irradiation of the entire cerebrum, cerebellum, and brainstem.

The techniques utilized in the delivery of WBRT are generally straightforward but beyond the scope of this review. For the purposes of this review, the treatment may be thought of as one lateral x-ray delivered from the patient’s left and one lateral x-ray delivered from the patient’s right. Throughout the 1960s to 1980s several studies evaluating different WBRT dosing and fractionation schemes were performed.

 In recent decades, most institutions have used WBRT regimens involving between 5 and 20 daily fractions of radiotherapy treatment, with 10 fractions being the most common. Landmark randomized controlled trials in the 1990s evaluated the role of WBRT, surgery, and various combinations of WBRT and surgery for patients with a single brain metastasis.

For patients treated with WBRT, the addition of neurosurgical resection to WBRT in patients with a single brain metastasis resulted in decreased rates of local recurrence (20% recurrence with WBRT and surgery vs 52% recurrence with WBRT and no surgery) and improved overall survival (OS; 40 weeks with surgery vs 15 weeks with WBRT alone).

 Multiple studies suggest the survival benefit is most pronounced in young patients with a single brain metastasis, good performance status, and absent/controlled extracranial disease.

 Of note, one study evaluating the role of surgery in patients with a Karnofsky Performance Score (KPS) of 50% or greater and one cerebral metastasis undergoing WBRT failed to show a survival benefit to the addition of surgery.

Additional factors influencing recommendation for surgical resection include the rapidity of onset of symptoms, size of a metastasis, location (eloquent vs non-eloquent location), number of metastases, and whether a histopathologic diagnosis has previously been established. In a study evaluating the role of WBRT following upfront neurosurgical intervention for patients with a single brain metastasis, the addition of WBRT resulted in no increase in OS but did demonstrate decreased rates of local failure (10% with WBRT and surgery vs 46% with surgery alone) and decreased rates of any intracranial failure (18% with WBRT and surgery vs 70% with surgery alone).

 While no OS benefit was appreciated, the addition of WBRT to surgery reduced the rate of neurologic death in patients with a single brain metastasis (14% with surgery and WBRT vs 44% with surgery alone).

The findings of this study were supported by an additional multiinstitutional randomized trial by the European Organization for Research and Treatment of Cancer (EORTC) evaluating the role of WBRT after surgical resection or stereotactic radiosurgery (SRS) for patients with 1-3 brain metastases.

 The authors found that regardless of the local treatment modality (surgery or SRS), the addition of WBRT decreased rates of recurrence at the site of index lesion(s) (27% with WBRT and surgery vs 59% with surgery alone; 19% with WBRT with SRS vs 31% with SRS alone) and reduced the likelihood of patients developing new brain metastases (23% with WBRT and surgery vs 42% with surgery alone; 33% with WBRT and SRS vs 48% with SRS alone).

As in the prior study of neurosurgical resection with/ without WBRT, no OS advantage was appreciated, though rates of neurologic death were reduced (44% without WBRT vs 28% with WBRT). The potential advantages of adjuvant WBRT must be weighed against potential drawbacks of WBRT, including potential neurologic toxicity and a recently reported transient reduction in health-related quality of life in patients treated with WBRT in the EORTC phase III study of SRS or surgery followed by WBRT or observation.

At the same time that the roles of WBRT and surgery were being evaluated regarding their relative benefits in the management of brain metastases, a more recently developed radiotherapeutic technique, SRS, was being developed and refined as a mechanism for conformal, ablative high-dose radiation treatment of individual metastatic lesions, instead of irradiation of the entire brain.

Though SRS was developed by Lars Leksell in the early 1950s, it was not widely utilized in the United States until the mid-1990s and early 2000s, when radiographic imaging techniques caught up with treatment delivery systems, allowing for improved visualization of intracranial radiotherapy targets with CT- and MRI-based imaging. Presently, several SRS platforms exist. Treatment may be delivered with: 1) a standard linear accelerator (LINACbased SRS) with adequate stereotactic capabilities; 2) the CyberKnife® system, which is a photon-only single-energy LINAC mounted on a robotic arm; 3) TomoTherapy®, which is helical delivery LINAC-based SRS; 4) the GammaKnife® system, which delivers SRS using highly focused photons from 192- 201 60Co radionuclide sources; and 5) particle-therapy SRS, most commonly utilizing protons (see 

). The intricacies of the different SRS treatment delivery techniques are beyond the scope of this review. However, all of these systems deliver multiple small photon beams from a large number of angles. The contribution of each beam (or beamlet) is very small and delivers an exceedingly low dose of radiation, but, at the point where all of the individual beams (or beamlets) converge, a very large dose of radiation is delivered. Protons may also be used in delivery of SRS, though in the United States SRS is generally delivered with photons.

		Table. Stereotactic Radiosurgery Treatment Platforms

					Stereoscopic x-rays and/or cone-beam CT

					Able to perform stereotactic and nonstereotactic radiotherapy to other parts of the body; electron therapy

					Alignment must be checked and verified before each isocentric treatment; requires intense physics assessment before each patient’s treatment

					CyberKnife® (Single energy linear accelerator)

					Small linear accelerator mounted on a robotic arm

					Linear accelerator on robotic arm allows treatment delivery with nearly unlimited treatment angles

					Single energy photon; no electrons; no portal imaging

					Linear accelerator with helical delivery of x-rays

					Capable of treating very long fields in a continuous fashion

					Treatment plan does not have traditional review

					192-201 radioactive cobalt-60 sources

					Multiple isocenters easily treated in same session; daily quality assurance allows treatment of multiple lesions and multiple patients

					Radioactive source/ regulations; if patient undergoes multiple fractions (SRT), often requires overnight stay with frame in place; treatment is limited to high cervical spine and above

					No exit dose permits targeting of lesions near critical structures

Upon completion of an SRS dose-finding study,

 randomized controlled trials evaluated the role of SRS alone, WBRT alone, SRS with/without addition of WBRT (evaluating whether WBRT added any benefit to SRS), and WBRT with/without SRS (conversely evaluating whether SRS added any benefit in addition to WBRT). Patients with 1-3 brain metastases treated with SRS in addition to WBRT were noted to have better rates of local control at one year (82% for WBRT + SRS) than patients treated with WBRT alone (71% for patients treated with WBRT alone).

 The same study also noted a survival benefit in patients with favorable histology (squamous cell or nonsmall cell carcinoma of the lung) and in patients <65 years of age with KPS of ≥ 70%, controlled primary disease, and no extracranial metastases.

 Conversely, when WBRT was added to SRS in patients with 1-4 brain metastases, investigators found improved local control with the addition of WBRT (89% local control with SRS and WBRT vs 73% local control with SRS alone) as well as reduced rates of development of new brain metastases (42% developed new brain metastases with SRS and WBRT vs 64% with SRS alone).

 No difference in preservation of neurologic function was noted between patients treated with SRS alone and with SRS and WBRT.

 These studies echoed the findings of the previously discussed studies that demonstrated a survival benefit for the addition of local therapy to WBRT and a decrease of both local recurrence and in the rate of patients developing additional brain metastases when WBRT is added to surgery.

 In this review, the role of radiotherapy in the management of brain metastases is considered from a historical perspective, in the context of other treatment modalities, and with regard to different radiotherapy techniques.

February 2014 | Contemporary Oncology®

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Common Adverse Effects of Anti-HER2 Therapies and Practical Management Recommendations

The Role of Radiation in the Management of Brain Metastases

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