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The Breast 22 (2013) 1009e1018

Contents lists avai

The Breast

journal homepage: www.elsevier .com/brst

Review

Biological therapies in breast cancer: Common toxicities andmanagement strategies

Romualdo Barroso-Sousa, Iuri A. Santana, Laura Testa, Débora de Melo Gagliato,Max S. Mano*

Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina, Universidade de São Paulo, Av. Dr. Arnaldo, 251, 5� andar,CEP 01246-000 São Paulo, SP, Brazil

a r t i c l e i n f o

Article history:Received 21 May 2013Received in revised form14 September 2013Accepted 21 September 2013

Keywords:Breast cancerAdverse eventsTrastuzumabPertuzumabLapatinibBevacizumabTrastuzumab-emtansineEverolimus

Abbreviations: ABC, advanced breast cancer; QoLevent; HER2, human epidermal growth factor receptoejection fraction; EGFR, epidermal growth factor reemtansine; FDA, Food and Drug Administration; VEGFfactor; mTOR, the mammalian target of rapamycin; CTrenal cell cancer.* Corresponding author. Tel.: þ55 11 3893 2686; fa

E-mail addresses: max.mano@usp.br, max.mano@

0960-9776/$ e see front matter � 2013 Elsevier Ltd.http://dx.doi.org/10.1016/j.breast.2013.09.009

a b s t r a c t

In recent years, a number of new molecules e commonly known as biological therapies e have beenapproved or are in late stages of regulatory evaluation for the treatment of advanced breast cancer. Theseinnovative compounds have improved treatment efficacy and have probably contributed to the increasein survival length observed in some breast cancer subtypes. However, these agents are not deprived oftoxicity, which can impair quality of life and may occasionally be life-threatening. In this article, wereviewed the most common toxicities associated with these drugs and provided a number of practicalrecommendations on their optimal clinical management.

� 2013 Elsevier Ltd. All rights reserved.

Introduction

Currently, six drugs entitled targeted or ‘biological’ agents areapproved for clinical use in distinct disease scenarios in breastcancer (BC) management. The medications include trastuzumab,pertuzumab, lapatinib, trastuzumab-emtansine, bevacizumab andeverolimus. These drugs are changing survival outcomes in meta-static BC patients and are largely used in clinical practice.

However, treating patients for longer periods with potentiallytoxic agents raises new challenges, such as managing their poten-tial adverse events (AEs). Clinicians must be aware that gains indisease control and/or survival must be weighed against potentialdetrimental effects in quality of life (QoL). Some of these molecules

, quality of life; AE, adverser type 2; LVEF, left ventricularceptor; T-DM1, Trastuzumab, vascular endothelial growth, computed tomography; RCC,

x: þ55 11 3893 2690.gmail.com (M.S. Mano).

All rights reserved.

can cause unusual AEs even for an experienced oncologist. Also,potentially life-threatening AEs can also occur. A recent meta-analysis showed that new anticancer agents approved since 2000increasedmorbidity and treatment-relatedmortality [1]. Therefore,community oncologists must become fully familiar with the po-tential toxicity associated with these agents and must have theexpertise for their appropriate management.

The objectives of this review are to provide 1) an updateddescription of the safety profile of novel targeted agents used in themanagement of breast cancer; 2) practical recommendations onthe management of these AEs and patient monitoring.

Search criteria

We conducted an English-language MEDLINE (last 10 years) andproceedings of ASCO Annual Meetings and San Antonio AnnualMeeting (last 5 years). We gave priority to phase III studies whenthose were available, but also included Phase II trials, when PhaseIII were not available. The search terms included six agents nowapproved or under evaluation from regulatory authorities. The lastsearch was updated on 03 March 2013.

R. Barroso-Sousa et al. / The Breast 22 (2013) 1009e10181010

Trastuzumab

Risk of cardiac dysfunction

Approximately 15e20% of breast cancers have amplification oroverexpression of the human epidermal growth factor receptortype 2 (HER2) and are characterized by an aggressive clinicalbehavior and a worse prognosis [2]. Trastuzumab, a humanizedmonoclonal antibody against HER2 was proven to be effective inseveral clinical trials in the neoadjuvant, adjuvant and metastaticsetting [3]. However, in the Pivotal Trial that evaluated this drug,Trastuzumab use was associated with cardiac dysfunction, espe-cially in the cohort of patients that were treated concurrently withanthracyclines [3]. Of note, cardiac monitoring was not mandatoryin this trial and the actual risk of trastuzumab-related cardiacdysfunction remained unclear.

Subsequent studies demonstrated symptomatic heart failure(HF) in approximately 4% of patients [4e6]. An important adjuvanttrial evaluated trastuzumab given sequentially to anthracyclines (4cycles of Doxorubicin plus Cyclophosphamide followed by Doce-taxel and Trastuzumab: AC-TH). This study included an arm ofpatients treated with Docetaxel plus Carboplatin plus Trastuzumab(TCH) and a third one with AC-T. The actual risk of symptomaticcongestive heart failure was 2% for the AC-TH group and 0.7% forthe TCH group of patients (p < 0.001). A subclinical asymptomaticloss of mean LVEF (defined as>10% relative loss) was found in 18.6%and 9.4% for the group that received AC-TH and TCH, respectively.This is showed in Table 1 [7].

Of note, Quality of Life data was collected in a portion of thepatients from BCIRG006. Patients answered The European Organi-zation for Research and Treatment of Cancer (EORTC) Quality of LifeQuestionnaire C30 and BR-23 at baseline, in cycle 4 and in the endof chemotherapy. The questionnaire was also answered at month 6,12, and 24 after chemotherapy. Systemic side effect change scoreswere significantly improved for the group treated with TCH,compared with AC-TH and AC-T. All patients recovered from dete-rioration of systemic side effects by one year. This analysis suggestsTCH as a more tolerable treatment [8]. Although TCH was associ-ated with few cardiac events and better quality of life, one cannotconclude that this is a preferable regimen over AC-TH, as the trialwas not designed to demonstrate it.

Asymptomatic impairment of left ventricular ejection fraction(LVEF) of 10e15% or more was seen in up 18% of patients as sum-marized in Table 1 [7,9e11]. The clinical significance of this findingremains unknown. Whether or not the cardiac toxicity rates can begeneralized to the real world is still a matter of debate, sincewomen included in these clinical trials were usually highlyselected, with limited comorbidities. In addition, many studiessimply excluded patients with suboptimal cardiac function. Forinstance, two recent retrospective studies performed in patientstreated in the community setting suggested that risk oftrastuzumab-associated cardiac dysfunction could be slightly

Table 1Reported asymptomatic LVEF and CHF in pivotal trastuzumab-based adjuvant trialsin breast cancer.

Trial Number of patients LVEF decreasing CHF

NSABP-31 [11,16] 1736 14.0% 4.1%NCCTG 9831 [11] 1633 NR 2.9%HERA [10] 3387 7.1% 1.7%BCIRG 006a [7] 3222 18.6% � 9.4% 2.0% � 0.4%FinHer [9] 332 3.5% 0.0%

Abbreviations: LVEF, left ventricular ejection fraction (defined as a drop in LeftVentricular Ejection Fraction of more than 10 units percent or a drop below 50%);CHF, congestive heart failure.

a Trastuzumab-based chemotherapy including or not anthracyclines.

higher than reported in the adjuvant trials [12,13]. It is alsoimportant to point out that LVEF decrease criteria can vary and themethods currently used to evaluate LVEF are quite heterogeneousamong the clinical trials, As a consequence Trastuzumab CardiacToxicity can be over or underestimated depending on the criteriaadopted.

Trastuzumab-related cardiotoxicity, differently fromanthracycline-related, commonly presents as asymptomaticimpairment of LVEF, does not appear to be related to cumulativedose and is often partially reversible with treatment interruption.Resuming treatment with trastuzumab after cardiac function re-covery is often feasible. However it can also be associated withrelapse of LVEF decrease [14]. To date, other anti-HER2 targetedagents have not been associated with significant cardiotoxicity.

Recommendations for the management of trastuzumab-relatedcardiotoxicity

The most important risk factors for trastuzumab-related car-diotoxicity are previous or concurrent use of anthracycline and agegreater than 50 years [12,15,16]. Elderly patients (�70 years), whichhave been traditionally excluded from clinical trials, are at espe-cially high risk for Trastuzumab related Cardiotoxity. A retrospec-tive study that evaluated patients with 70 years old or more treatedwith Trastuzumab, showed an incidence of 8.9% in the develop-ment of symptomatic congestive heart failure for the metastaticpatients cohort [17].

Other risk factors include decreased baseline LVEF, increasedbody mass index and previous hypertension [14]. A recent studyevaluated troponin 1 levels before and after each Trastuzumabcycle in women with early stage or advanced BC. TrastuzumabCardiac Event, defined as LVEF decrease of 10 units and below 50%,was more commonly seen in patients with elevated levels oftroponin 1 (62% versus 5%; p < 0.001). Also, LVEF recovery occurredless frequently in patients with elevated troponin 1 (35% versus100%; P < 0.001) [18].

Surveillance for trastuzumab-related cardiotoxicity is largelyempirical [19,20]. Cardiac function should be assessed prior totrastuzumab therapy. Clinical Oncologists should determine pre-vious cardiac events and risk factors for each patient. Also, we feelthat a 12-lead electrocardiogram (ECG) e looking for possiblemarkers of structural heart disease is recommended. Additionally, abaseline exam to obtain the Left ventricular ejection fractionmeasurement, using echocardiogram or radionucleotide multiple-gated acquisition (MUGA) scan is also extremely important.Repeat echocardiogram or MUGA every three months of therapyand also at the end of Adjuvant Trastuzumab treatment. For themetastatic patients, we recommend repeating echo or MUGA every3 months.

Patients with a normal baseline LVEF and no signs or symptomsof heart failure are able to start therapy. Patients with a modestlyincreased risk for cardiotoxicity (include those with borderlineLVEF between 50 and 55 percent, age >50 years and hypertension)should also be considered for treatment with trastuzumab, aftercareful consideration of the potential harms and benefits. In thisgroup of patients, one should consider the use of non-anthracyclinecontaining trastuzumab schedules [7].

Although the late onset of cardiac dysfunction seems to be un-common, it is advisable to continue LVEF assessments every 6months for at least 2 years after completion of treatment [14,16]. Inthe metastatic setting, the routine assessment is less clearlydefined. Nevertheless, we believe that there is no reason not topropose the same schedule as in the adjuvant setting. Some of thesepatients can become long-term survivors, and cardiac function is animportant part of the quality of life [18].

R. Barroso-Sousa et al. / The Breast 22 (2013) 1009e1018 1011

If a Cardiac Event related to Trastuzumab use occurs, this agentshould be initially halted for 4 weeks. Cardiac dysfunction shouldbe managed according to established guidelines for treatment ofheart failure [19]. Treatment should include anti-hypertensivedrugs (especially angiotensin converting enzyme inhibitors orangiotensin receptors blocks) until LVEF recovery [19,21]. Sincemost cases of trastuzumab-related cardiotoxicity are reversible andLVEF improves after treatment withdrawal, it is recommended thata new assessment of LVEF be performed after 4 weeks. If cardiacfunction restores to the previous normal baseline from the patient,re-challenge with trastuzumab can be considered [22e24]. If asecond event occurs, trastuzumab should be permanently dis-continued. Table 2 summarizes the recommendations for patientmonitoring and management of cardiac dysfunction during treat-ment with anti-HER2 therapies.

Trastuzumab-related infusion reactions

Common trastuzumab related AE include infusional reactions,can be occasionally severe and are described in up to 40% of thepatients receiving the drug. However, they rarely lead to treatmentdiscontinuation and tend not to recur with repeated exposure.Caution is recommended in patients with severe pulmonary con-ditions and/or tumor involvement especially those with clinicallyrelevant dyspnea and hypoxemia. Other side effects have beendescribed but are usually mild with no clinical impact.

Lapapatinib and pertuzumab

Lapatinib is an orally administered small-molecule inhibitor ofthe tyrosine kinase domains of both HER2 and HER1/epidermalgrowth factor receptor type 1 (EGFR). The Phase I trial that evalu-ated lapatinib demonstrated that the most common side effectsassociated with this drug are diarrhea, rash, nausea, and fatigue.The great majority of side effects were grade 1 or 2 (135 from 140drug-related AE) [25]. Table 3 shows the common clinically rele-vant toxicity in lapatinib treated patients.

From the patient’s perspective, one of the most compromisingAE is the skin rash, manifested by an erythematous papular

Table 2Monitoring and management of cardiac dysfunction in patients undergoing adjuvant an

Therapy phase Recommendations Patient p

Before startingtreatment

Clinical assessment with detailed historyand physical examination

No risk fPositive cfactor wiImpaired

During treatment Monitoring LVEF repeated at 3-monthsintervals until the end of anti-HER2therapy or when clinically indicated

First dec

Second dof cardia

After completionof treatment

Repeat LVEF at 6-months intervals untilat least 2 years have elapsed since thelast dose of trastuzumab

No changDecreasesymptom

LVEF: left ventricular ejection fraction.a Decrease in LVEF was defined as a decrease in the ejection fraction of 10 percentage

*the onset of cardiac symptoms including: symptoms (dyspnea, orthopnea, pedal edemtachypnea, S3 gallop, crackles) and concomitant LVEF decline or chest radiograph findin

eruption, most often seen on the face, chest, and back. In the largephase III trial of lapatinib plus capecitabine versus capecitabinealone for metastatic BC patients, 28% of patients in the combinationarm experienced rash, versus 15% in the capecitabine alone arm[26]. This type of rash is an AE typically seen in drugs that target theErbB-1 receptor. The possible mechanism of skin rash is not fullycompletely understood. One possible explanation is the inhibitionof EGFR receptor from the keratinocytes in the skin itself [27]. Also,a systemic immunological reaction is another possible theory forthe rash, as a neutrophilic infiltrate is often seen in the skin tissueand corticosteroids are usually effective in the rash treatment [28].

Although skin rash can considerably compromise QoL, the PhaseIII Trial that evaluated capecitabine and Lapatinib versus capecita-bine alone published an important QoL assessment [27]. Patientscompleted Functional Assessment of Cancer Therapy Breast (FACT-B) and EuroQoL (EQ-5D) questionnaires during efficacy and safetyassessment visits. Surprisingly, the combination group had betterQol scores, although not statistically significant. Patients with anobjective response rate or stable disease had clinically meaningfuldifferences in QoL scores compared to patients with progressivedisease. This may have contributed to the better QoL scores foundin the combination group, as this treatment was associated with abetter Progression Free survival. Thus, this combination proved thatQoL was not compromised with the addition of the biological agent[29].

Nevertheless, the toxicity profile from lapatinib is not negligibleand a new drug was proven better tolerated. A recent randomizedPhase III study evaluated the combination of lapatinib and capeci-tabine against a novel drug in this setting, Trastuzumab emtansine(T-DM1). This trial demonstrated that T-DM1 significantly pro-longed progression-free and overall survival compared to lapatiniband capecitabine. Also, it was associated with a more favorabletoxicity profile. Grade 3 or above AE were much higher withlapatinib plus capecitabine, compared with T-DM1 (57% vs. 41%).Lapatinib treated patients experienced more diarrhea, nausea,vomiting, and palmareplantar erythro-dysesthesia. After data fromthis study, T-DM1 is the preferable option over capecitabine andlapatinib combination in the second line treatment of metastatic BCpatients with overexpression of HER2 [30].

ti-HER2 therapy.

rofile Recommendations

actors with normal LVEF 1. Start trastuzumab-based therapyardiac history and/or riskth normal LVEF

1. Start trastuzumab-based therapy

LVEF 1. Treat heart failure with standard therapies(ACE-1 or ARB, BB).

2. Reassess LVEF to decide if starting therapywill be possible/appropriate.

rease in LVEFa 1. Interrupt trastuzumab for 4 weeks2. Start treatment for heart failure and after

4 weeks reassess LVEF- If LVEF returns to baseline, resumetrastuzumab if clinically appropriate.

- If LVEF remains impaired, trastuzumabshould be discontinued

ecrease in LVEF or onsetc symptoms*

1. Discontinue trastuzumab

e in LVEF 1. Stop monitoring after 2 yearsin LVEF or cardiovasculars

1. Start treatment for heart failure2. After 4 weeks reassess LVEF

points or more from baseline to an LVEF of less than 50 percent at any time [10,19];a) and/or objective findings (elevated jugular venous pressure, sinus tachycardia,gs of pulmonary edema or increased vascular markings.

Table 3Reported adverse events in pivotal phase III of biological therapies in advanced breast cancer.

Everolimus (plusexemestane; n ¼ 485)[Baselga et al. [56]]

Pertuzumab (plustrastuzumab anddocetaxel; n ¼ 402)[Baselga et al. [32]]

Lapatinib (pluscapecitabine; n ¼ 163)[Geyer et al. [26]]

Lapatinib (pluscapecitabine; n ¼ 496)[Verma et al. [30]]

TD-M1 (n ¼ 495)[Verma et al. [30]]

Bevacizumab (pluspaclitaxel; n ¼ 722)[Miller et al. [40]]

Bevacizumab (plusdocetaxel; n ¼ 736)[Miles et al. [41]]

Bevacizumab (pluschemotherapya; n ¼ 1237)[Robert et al. [39]]

All grades Grade3 or 4

All grades Grade3 or 4

All grades Grade3 or 4

All grades Grade3 or 4

All grades Grade3 or 4

Grade 3 or 4 Grade 3 or 4 Grades 2e5

General (%)Fatigue 33 4 37 3 18 2 28 4 35 3 9 7 e

Decreased weight 19 1 e e e e e e e e e e e

Pyrexia 14 <1 e e e e e e e e e e e

Infections e e e e e e e e e e 9 <1 e

Metabolic disorders (%)Hyperglycemia 13 5 e e e e e e e e e e e

Cardiovascular and pulmonary toxicities (%)Hypertension e e e e e e e e e e 15 e 8.9e10.5LVEF decreasing e 2.8 e e e e e e <1 e 1.5e6.2Peripheral edema 14 1 e e e e e e e e e <1 e

Hemorrhage e e e e e e e e e e <1 e 0.2e5.4Thrombosis/embolism e e e e e e e e e e 2 e 2e5Cerebral ischemia e e e e e e e e e e 2 e 0.5e1.5Dyspnea 18 4 e 2 11 3 e e e e e 3 e

Pneumonitis 12 3 e e e e e e e e e e e

Hematological, %Neutropenia e e 50 46 e e 9 4 6 2 <1 e 1.2e9.4Febrile Neutropenia e e 8 8 e e e e e e e e 0e8.4Anemia 16 6 e 4 e e 8 2 10 3 <1 2 e

Thrombocytopenia 12 3 e e e e 3 <1 28 13 0 e e

Gastrointestinal and hepatic toxicities (%)Anorexia 29 1 26 e 15 <1 e e e e <1 2 e

Dysgeusia 21 <1 e e e e e

Nausea 27 1 42 e 44 2 45 3 39 <1 3 2 e

Vomiting 14 1 e e 26 2 29 5 19 <1 3 2 e

Diarrhea 30 3 46 5 60 13 80 21 23 2 e 7 e

Constipation 13 <1 25 10 0 e e e e e e e

Proteinuria e e e e e e e e e e 4 e 2.2e3.9Perforation e e e e e e e e e e <1 e 0e2.5ALT level increased 11 3 e e e e 9 1 17 3 e e e

AST level increased 13 3 e e e e 9 <1 22 4 2 e e

Dermatological toxicity (%)Stomatitis 56 8 e e 15 0 e e e e 1 3 e

Rash 36 1 24 e 27 1 e e e e e 2 e

Abbreviations:LVEF: left ventricular ejection fraction; ALT: alanine aminotrasferase; AST: aspartate aminotransferase.a chemotherapy regimens were choosed by investigators and included: capecitabine (Cape; 2000 mg/m2 for 14 days), taxane (Tax) -based (nab-paclitaxel 260 mg/m2, docetaxel 75 or 100 mg/m2), or anthracycline (Anthra)

-based (doxorubicin or epirubicin combinations [doxorubicin/cyclophosphamide, epirubicin/cyclophosphamide, fluorouracil/epirubicin/cyclophosphamide, or fluorouracil/doxorubicin/cyclophosphamide]) chemotherapyadministered every 3 weeks [39].

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Pertuzumab is a humanized monoclonal antibody that binds toHER 2 receptor domain II (dimerization domain), differently fromtrastuzumab, that binds HER2 at subdomain IV [31]. Recently,CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab)phase III trial has confirmed the benefit of pertuzumab, trastuzu-mab and docetaxel combination as first-line therapy in HER2-positive metastatic breast cancer patients compared with thestandard combination of trastuzumab and docetaxel [32]. The mostcommon AE (any grade) were diarrhea, rash, mucosal inflamma-tion, febrile neutropenia, and dry skin (Table 3). The events weremostly grade 1 or 2 and occurred during the period of docetaxeladministration. Grade 3 or higher febrile neutropenia and diarrheawere also more frequently seen in the pertuzumab group. Neo-adjuvant trials demonstrated similar results: Pertuzumab use wasassociated with markedly increased efficacy, with a good safetytrack [33,34]. Currently, a registration phase III study is ongoing inthe adjuvant setting with patients newly diagnosed with HER2-positive breast cancer [35].

Management of diarrhea associated to lapatinib and pertuzumab

Management of lapatinib or pertuzumab-associated diarrhea isempirical. Practical management recommendations are similar tothose established for diarrhea associated to capecitabine. If a pa-tient experiences mild to moderate (grade 1 or 2) diarrhea, alactose-containing free diet should be oriented, as well as oral fluidsintake and small portions meals. Anti diarrheal drugs are indicated,such as loperamide. Start with an initial dose of 4 mg followed by2mg every 4 h or after every unformed stool until the patient is freefrom diarrhea for at least 12 h [36].

If a patient experiences moderate to severe diarrhea or has signsof potential complications, such as severe cramping, nausea, vom-iting, fever, or dehydration, further doses of lapatinib or pertuzu-mab should be held. Intravenous fluids and inpatienthospitalization should be considered. Repeat administration of theanti-HER2 drugs should be delayed until the patient recovers andsubsequent doses should be decreased.

Management of rash associated to lapatinib and pertuzumab

There are no clear evidence-based recommendations for themanagement of lapatinib or pertuzumab-associated rash. However,there is considerable experience in managing dermatologic erup-tions from other EGFR-targeted agents. In most patients, rashattributable to lapatinib resolves during treatment, following atemporary interruption in treatment, or after treatment cessation.

Clindamycin phosphate 1% gel can be used with good effect forinflammatory pustular lesions. A combination of clindamycin 1%and benzoyl peroxide 5% gel can also be effective. Oral antibiotics

Table 4Graduation and management of hepatotoxicity associated to T-DM1.

Grade 1 Grade 2

Increased Serum Transaminases (AST/ALT)- Definition: �2.5 � ULN >2.5 to �5 � ULN- Intervention recommended: None Treat at same dose level.

Hyperbilirubinemia- Definition: <1.5 � ULN >1.5 to �3 � ULN- Intervention recommended: None Do not administer T-DM1 un

total bilirubin recovers to Grand then treat at same dose

a Starting dose: 3.6 mg/kg; first dose reduction: 3.0 mg/kg; second dose reduction: 2.4transaminase; AST: aspartate transferase; ULN: upper limit of normality.

can also be used, including doxycycline (100 mg twice daily) ortetracycline (500 mg twice daily). Colloidal oatmeal lotion has alsobeen shown to be effective. Emollients should be used to reduce dryskin component of this. The treatment for cutaneous toxicitiesneeds to be maintained evenwhen EGFRI therapy is decreased or isinterrupted as EGFRI-associated toxicities can last a very longduration period. Patients with extensive or persistent skininvolvement should be referred to a dermatologist [36].

Trastuzumab-DM1

Trastuzumab emtansine (T-DM1) is an antibodyedrug conju-gate that incorporates the HER2- targeted antitumor properties oftrastuzumab with the cytotoxic activity of the microtubule-inhibitory agent DM1 (derivative of maytansine) [37]. T-DM1 wasdeveloped to deliver the intracellular drug specifically to HER2-overexpressing cells, thereby improving the therapeutic indexand minimizing exposure of normal tissue. The pivotal phase 3study ‘EMILIA’was described above, in the lapatinib section [30]. Asmentioned, T-DM1 treatment was associated with fewer grade 3 orhigher AE, compared with Lapatinib and Capecitabine.

Although with a more favorable toxicity profile, grade 3 or 4thrombocytopenia (12.9%), elevated serum concentrations ofaspartate aminotransferase (4.3%) and alanine aminotransferase(2.9%) were important side effects associated with T-DM1 use.However, the great majority of patients were able to continue thetreatment after briefly interruption of T-DM1, when returning tonormal levels of platelets and serum aminotransferases. Table 3shows AE associated with T-DM1.

The hepatoxicity associated with T-DM1 administration raisesserious concerns. It was previously reported two fatal cases of se-vere drug-induced liver injury and associated hepatic encepha-lopathy. Thus, the packet insert of T-DM1 contains a boxed warningregarding the risk of serious liver injury. There is a formal recom-mendation for monitoring serum transaminases and bilirubinbefore each dose. Table 4 summarizes the dose adjustments in T-DM1 regimen in the case of hepatotoxicity exhibited as increases inserum transaminases and/or hyperbilirubinemia.

Anti-VEGF monoclonal antibody e bevacizumab

Angiogenesis plays a critical role in progression of breast cancer.After publication of E2100 trial, the Food and Drug Administration(FDA) approved the bevacizumab in combinationwith paclitaxel forthe first-line treatment of metastatic HER-2 negative breast cancer.Of note, bevacizumab is a humanized monoclonal antibodydirected against circulating vascular endothelial growth factor A(VEGF-A).

Grade 3 Grade 4

>5 to �20 � ULN >20 � ULNDo not administer T-DM1 untilAST/ALT recovers to Grade �2,and then reduce one dose levela

Discontinue treatment

>3 to �10 � ULN >10 � ULNtilade �1,levela

Do not administer T-DM1 untiltotal bilirubin recovers to Grade �1,and then reduce one dose levela

Discontinue treatment

mg/kg; requirement for further dose reduction: discontinue treatment. ALT: alanine

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However, ever since its approval for the management of meta-static BC, bevacizumab has generated discussion and controversies.On July 2010 the Oncologic Drugs Advisory Committee votedagainst its use in BC. At the same year, FDA revoked the approval ofbevacizumab for this indication [38]. Despite that, bevacizumabremains approved and is used in many countries in combinationwith chemotherapy for metastatic BC treatment.

Safety analyses from the three phase III randomized clinicaltrials that evaluated bevacizumab in the first line treatment formetastatic BC demonstrated an expected AE profile. The mostcommon side effects were hypertension, proteinuria, bleedingdisorders, cardiovascular events, gastrointestinal perforation andthromboembolic events [39e41] (Table 3).

It is important to point out that in view of the borderline efficacygains and safety issues, the license for bevacizumab in combinationwith docetaxel has been withheld in many countries.

Hypertension

Hypertension is by far the most common AE associated withbevacizumab. Previous studies have shown its multifactorial cause.However, the inhibition of nitric oxide production causing vaso-constriction is the major pathway. Other described mechanism isthe reduction of density in the microvascular beds, increasingsystemic vascular resistance [42]. There are two meta-analysesshowing a raise in the risk of hypertension of 3e7.5 fold for pa-tients receiving bevacizumab [43,44].

Management of antiangiogenic related hypertension isfrequently based on the current guidelines from the AmericanHeart Association [45], but should be individualized for each pa-tient. Women should be advised to periodically monitor bloodpressure during bevacizumab use. This may detect early changesand should promptly trigger treatment [46].

There are no clear recommendations for specific antihyperten-sive agents, but one should consider that Angiotensin ConversionEnzyme Inhibitors and Angiotensin Receptor Blockers are able toreduce proteinuria, which may contribute for renal function pro-tection. Drugs that increase nitric oxide, such as nitrates, nebivololand phophodiesterase inhibitors, might be of particular interestand should be evaluated in prospective clinical trials. Among Cal-cium Channel Blockers, verapamil and diltiazem inhibit CYP3A4and nifedipine induces VEGF. However, amlodipine and felodipinedo not share those issues and can be used safely [47]. Thiazide di-uretics should be used cautiously, particularly in patients prone todehydration or hypercalcemia.

A panel expert from the National Cancer Institute published aguideline for the management of hypertension induced by VEGFsignaling pathway inhibitors. It can be summarized in four rec-ommendations: (1) conduct and document a formal risk assess-ment for potential cardiovascular complications; (2) recognize thatpreexisting hypertension will be common in cancer patients andshould be identified and addressed before initiation of VSP inhib-itor therapy; (3) actively monitor BP throughout treatment withmore frequent assessments during the first cycle of treatment; (4)manage BP with a goal of less than 140/90 mmHg for most patients

Table 5Graduation and management of proteinuria related to bevacizumab.

Proteinuria Grade 1 Grade 2

- Definition: 1þ proteinuria;urinary protein <1.0 g/24 h

2þ proteinuriaUrinary protei

- Interventionrecommended:

Dose adjustment: No interventionis required

Dose adjustmen

(and to lower, pre specified goals in patients with specific preex-isting cardiovascular risk factors [48].

Proteinuria

Proteinuria is a common dose-related AE occurring with inhi-bition of VEGF signaling and may reflect glomerular damage. Hy-pertension is a strong risk factor for bevacizumab-associatedproteinuria, leading to the hypothesis that increasing intra-glomerular pressure secondary to hypertension produces thisproteinuria. Besides, it is well known that VEGF is responsible formaintaining glomerular integrity. Podocytes constitutively expressVEGF and are found on glomerular capillary endothelial cells [49].

Since there are no interventional studies addressing the man-agement of proteinuria, no evidence-based recommendations canbe made at the present time. However, following specialists’ ori-entations all patients prior to the start of an anti-VEGF drug shouldbe evaluated for existing kidney disease. This includes a screeningurine analysis for proteinuria, blood pressure measurement and anestimated renal function. After bevacizumab initiation, all patientsshould have their urine analyzed by dipstick before each infusion.Key recommendations for management of bevacizumab-associatedproteinuria are summarized in Table 5 [49].

Bleeding disorders

Minor hemorrhagic events are relatively common in patientstreated with targeted agents. The most common event reported inpatients treated with bevacizumab is epistaxis, which usually re-solves without medical attention [50,51]. Life-threatening hemor-rhagic events are very rare in breast cancer patients.

The risk of serious hemorrhage can be minimized by goodcontrol of hypertension. Clearly, with any agent that increases therisk of bleeding, care should be taken in patients who requireconcomitant treatment with anticoagulants or who for any reasondevelop thrombocytopenia.

Thromboembolic events

Two meta-analyses showing an increased risk of arterial andvenous thromboembolic events are published. Patients withdifferent types of solid tumors using bevacizumab were included[52,53]. Whether this increased risk requires some form of pro-phylaxis remains unclear. The great issue of this discussion isfinding a balance of risk between thromboembolic and hemor-rhagic complications. For now, there is no evidence to support theindication of primary prophylactic anticoagulation for patientsreceiving bevacizumab.

When a patient develops a venous thromboembolism while onBevacizumab therapy, it is of extreme importance graduation of theevent. If a deep vein thrombosis with intervention necessity occurs,or a pulmonary embolus is incidentally discovered, bevacizumabshould be held for at least two weeks while anticoagulant treat-ment is initiated. The decision to continue the drug should beindividualized. If the patient has a clinically meaningful benefit

Grade 3 or higher

; 24 h urinary protein analysis indicated;n 1.0e3.4 g/24 h

Urinary protein �3.5 g/24 h

t: Hold dose until recovery to �2 g/24 h Dose adjustment: Discontinuetreatment

R. Barroso-Sousa et al. / The Breast 22 (2013) 1009e1018 1015

with the treatment, is clinically stable and adequate anti-coagulation is achieved, bevacizumab may be re started. We do notrecommend Bevacizumab use if any life-threatening thromboem-bolism occurs.

If an arterial thromboembolism occurs, such as cerebrovascularaccident, myocardial infarction, unstable angina, transient ischemicattack or any other arterial embolic events, we recommend bev-acizumab discontinuation.

Cardiotoxicity

Another rare but serious AE related to bevacizumab is car-diotoxicity. Heart failure has been rarely reported in some trialswith bevacizumab use in different tumors. However, this is ofspecial importance in patients with BC due to prior or concurrentexposure to other cardiotoxic agents. In a meta-analysis, Choueiriand cols demonstrated an overall relative risk of development ofhigh-grade congestive heart failure for patients receiving bev-acizumab of 4.74 (95% CI, 1.84 to 12.19 p¼ 0.001) compared to thosewho did not receive bevacizumab [54]. Guidelines for the man-agement of cardiotoxicity related to bevacizumab are not welldefined. However, it is recommended holding the drug and acardiologist evaluation [54].

Everolimus

Everolimus is an oral sirolimus (formerly called rapamycin)derivative that inhibits the mammalian target of rapamycin(mTOR). This complex is located at a central point for a number ofintracellular signaling pathways, linking growth factors, nutrientsand energy availability to cell survival, growth, proliferation, andmotility [55].

Recently, BOLERO-2 (the Breast Cancer Trials of Oral Everolimus-2), a multicenter, phase III, randomized, placebo-controlled clinicaltrial confirmed the substantial benefit of mTOR blockage in post-menopausal womenwith advanced estrogen receptorepositive BC.Of note, this was a cohort of patients resistant to first-line endo-crine therapy with anastrozole or letrozole [56].

Of relevance, the addition of everolimus to hormonal therapytreatment was accompanied by a significant increase in side effects.A higher percentage of patients discontinued everolimus in thecombination-therapy group than discontinued placebo in thecontrol group. This was mostly due to AE (19% vs. 4%). The maingrade 3 or 4 AE were stomatitis, anemia, dyspnea, hyperglycemia,fatigue and pneumonitis. In clinical practice, we recommend acareful monitoring of patients receiving exemestane with ever-olimus, since there are some important and potentially serious AEassociated with this drug combination.

Pneumonitis

Non-infectious pneumonitis is a class effect of rapamycin ana-logues, including everolimus, and is characterized by a non-malignant infiltration of the lungs. The exact mechanism fromthe pneumonitis related to mTOR inhibitors remains unclear,although data suggests that is immunologically mediated [57]. Theexperience acquired with everolimus use in renal cell cancer (RCC)patients, reveals that the typical onset of pneumonitis (any grade)occurred within 2e6 months of treatment initiation with a mediantime to occurrence of 108 days [58]. The majority of patients wereasymptomatic despite the radiographic abnormalities. The mostfrequent radiological findings observed were ground-glass opaci-ties, parenchymal consolidation and pleural effusion. Whensymptomatic, patients typically present with dyspnea on exertion

and dry cough. Systemic symptoms of fever and fatigue can bepresent in some cases.

BOLERO2 trial demonstrated that approximately 12% of patientsin the everolimus arm had a diagnosis consistent with non-infectious pneumonitis (3% had a grade 3 and none of them had agrade 4 event). This diagnosis was determined by routinecomputed tomography (CT) scans performed every 6 weeks, asrecommended in the study protocol for tumor assessment. A cen-tral radiology panel reviewed those CT scans [56]. The frequency ofthis pneumonitis in the everolimus arm was consistent with pre-vious clinical experience [59].

The use of systemic corticosteroids is recommended in severecases. Thus, it is important to rule out alternative diagnoses, such asinfection and tumor progression before starting treatment. Keyrecommendations for the management of everolimus-relatedpneumonitis are summarized in Table 6.

The appropriate monitoring of patients receiving everolimus iscurrently unclear. Chest X-rays have low sensitive and are probablyunhelpful. In a retrospective analysis from CT scans of the ‘RECORD-1’ trial, up to 50% of the exams were found to fulfill criteria for non-infectious pneumonitis. The reported incidence of clinical pneu-monitis was much lower, suggesting that routine monitoring ofthese patients with serial CTs may be excessive [58]. However,physicians should be aware that even minimal symptoms poten-tially indicative of pneumonitis (usually dry cough and dyspnea onexertion e sometimes described by patients as ‘fatigue’) should bepromptly investigated.

Stomatitis/mucositis

Although oral AE associated with everolimus are sometimesunderestimated, stomatitis is one of the most frequent dose-limiting toxicities in practice. The clinical findings resemble athrush stomatitis rather than the mucositis seen with conventionalcytotoxic chemotherapy [60]. Although the etiology of this sto-matitis is not fully understood, some data suggest involvement of T-cell mediated inflammatory reaction [61]. It generally presents asan inflammation of the mucous membranes in the oral cavity, innersurface of the lips, or tongue. Most cases are associated with ery-thema, edema, burning sensation and occasionally bleeding. Inaddition, other symptoms can also be present, such as oral mucosalpain, dysgeusia, and dysphagia, in the absence of clinical lesions.The stomatitis has a rapid onset being usually seen within the firstweek therapy, however, the incidence decreases with subsequentcycles [60]. In BOLERO-2 trial, the incidence of stomatitis in theeverolimus group was 56% (grade 3, 8%; none grade 4) [56].

The management of everolimus-associated stomatitis is empir-ical and derives from the experience with cytotoxic chemotherapy.A good oral hygiene and treatment of anticipated infectious foci(e.g. periodontal diseases) should be encouraged. Patients shouldalso be evaluated for herpes and/or fungal infections, with anantiviral agent (e.g. acyclovir) or antifungal agent (e.g. fluconazole)treatment. Laser therapy can be considered for the occasional casesof severe stomatitis. Key recommendations for the management ofeverolimus-associated stomatitis are summarized in Table 6.

In clinical practice, physicians are used to empirical managethose side effects with dose reductions to 5 mg or they starttreatment with half of the recommended dose. Nevertheless, thePhase Ib study that evaluated letrozol in combination with 5 or10 mg of everolimus recommended the dose of 10 mg. Also, thiswas the dose used in BOLERO2 and in the neoadjuvant Phase II trialthat evaluated everolimus in combination with letrozol [59,62].Therefore, we recommend initiating with a 10 mg dose of ever-olimus. Dose reducing is acceptable in clinical practice, but is notgrounded by clinical trials.

Table 6Graduation and management of adverse events related to everolimus.

Grade 1 Grade 2 Grade 3 Grade 4

Pneumonitis- Definition: Asymptomatic; Symptomatic; medical intervention

indicated; limiting instrumental ADLSevere symptoms; limiting selfcare ADL; oxygen indicated

Life-threatening respiratorycompromise; urgentintervention indicated(tracheotomy or intubation)

- Interventionrecommended:

No intervention requiredclinical and/or radiologicsurveillance only

� Consult pulmonologist as appropriateConsider diagnostic procedures torule out infectious causes or tumorprogression

� Consider corticosteroids

Dose adjustment:� Hold dose until recovery to grade �1

and consider reescalation� If no recovery to grade �1, discontinue

treatment

� High dose corticosteroids ifinfectious cause ruled out

For impending respiratorydistress: concomitant treatmentwith antibiotics andcorticosteroids is recommended

Dose adjustment:� Hold dose until recovery to

grade �1, then restart atreduced dose

� Same as grade 3

Dose adjustment:� Discontinue treatment

Stomatitis- Definition: Asymptomatic or mild

symptoms;Moderate pain; not interfering with oralintake; modified diet Indicated

Severe pain; interfering withoral intake

Life-threatening consequences

- Interventionrecommended:

� Non-alcoholic mouth washor 0.9% saline solution(Avoid agents containinghydrogen peroxide, iodineand thyme derivatives)

Dose adjustment:Not required

� Same as Grade 1 plus:� Topical analgesic mouth treatments� Topical corticosteroids� Antiviral therapy if herpetic infection

confirmed� Antifungal therapy (topical preferred),

if fungal infection suspectedDose adjustment: Maintain dose if tolerable� Hold dose if intolerable until recovery

to grade �1, then restart at same dose

� Same as Grade 2

Dose adjustment:Hold dose until recovery tograde �1, then restart atreduced dose

� Same as Grade 2

Dose adjustment: Discontinuetreatment

Rash- Definition: � Papules and/or pustules

covering <10% BSA, whichmay or may not beassociated with symptomsof pruritus or tenderness

� Papules and/or pustules covering 10e30%BSA, which may or may not be associatedwith symptoms of pruritus or tenderness;associated with psychosocial impact;limiting instrumental ADL

� Papules and/or pustulescovering >30% BSA, whichmay or may not be associatedwith symptoms of pruritusor tenderness; limiting selfcare ADL; associated withlocal superinfection withoral antibiotics indicated

� Papules and/or pustulescovering any % BSA,which may or may not beassociated with symptomsof pruritus or tendernessand are associated withextensive superinfectionwith IV antibiotics indicated;life-threatening consequences

- Interventionrecommended:

� Mild lesions may resolvespontaneously; no specifictherapy

Dose adjustment:� No change

� Topical treatment with corticosteroidsand products containing benzoylperoxide and antibiotic initially

� Some patients with acne before startingeverolimus benefit from topical as wellas oral antibiotic therapy (i.e., tetracycline;avoid strong CYP3A4 inhibitors suchas clarithromycin)

Dose adjustment:� If patient is able to tolerate the toxicity,

maintain same dose;� If patient is unable to tolerate the toxicity,

hold dose until recovery to grade �1, thenrestart at same dose;

� If toxicity returns to grade 2, hold doseuntil recovery to grade �1, then restartat lower dose level.

� Proceed the sameinterventions cited for grade 2

Dose adjustment:� Everolimus dose modification:

Interrupt dose until recoveryto grade �1, then restart atlower dose level

� Proceed the sameinterventions cited for grade 2

Dose adjustment:� Everolimus dose

modification: discontinueeverolimus

Metabolic abnormalities- Definition: Glucose: >ULN e 160 mg/dL

Colesterol: >ULN e 300 mg/dLTGC: >ULN e 2.5 � ULN

Glucose: >160e250 mg/dLColesterol: >300e400 mg/dLTGC: >2.5e5.0 � ULN

Glucose: >250e500 mg/dLColesterol:>400e500 mg/dLTGC: >5.0e10$ULN

Glucose: >500 mg/dLColesterol: >500 mg/dLTGC:>10$ULN

- Interventionrecommended:

None intervention is required � Treat hyperglycaemia and hyperlipidemiaaccording to the ADA and EASD consensus

� Triglycerides �500 mg/dL present risk ofpancreatitis; treat urgently with fibrates

Dose adjustment: Maintain dose if tolerable� Hold dose if intolerable until recovery

to grade �1, then restart at same dose

� Same as Grade 2

Dose adjustment:Hold dose until recovery tograde �1, then restart atreduced dose or discontinueas per clinical judgment

� Same as Grade 2

Dose adjustment: Discontinuetreatment

ADL: Activities of Daily Living; ULN: Upper Limit of Normal; TGC: Triglycerides; ADA: American Diabetes Association; EASD: European Association for the Study of Diabetes.

R. Barroso-Sousa et al. / The Breast 22 (2013) 1009e10181016

R. Barroso-Sousa et al. / The Breast 22 (2013) 1009e1018 1017

Metabolic abnormalities e hyperglycemia and dyslipidemia

Hyperglycemia is a class effect common to all mTOR inhibitors.Most cases occur in patients with abnormal fasting glucose levelsbefore treatment. Insulin-induced up-regulation of GLUT1 mRNAtranslation is reduced bymTOR inhibitors, resulting in the failure ofinsulin to stimulate glucose uptake [63]. Hyperglycemia wasobserved in BOLERO-2 in 13% of patients (grade 3, 4%; grade 4,<1%)who received everolimus. Although hypercholesterolemia isanother potential AE of mTOR inhibitors, there was no mentionabout it in BOLERO-2. This AE has been probably underestimated, asserum lipid checks were not planned in most trials. In the RCC trialRECORD-1, the incidence of hypercholesterolemia was based onlaboratory results instead of a record by investigators. In this trialthe incidence was higher and occurred approximately in 75% ofpatients that used everolimus. However, this side effect is generallymarked by mild increases in cholesterol levels [60,64].

Patients with preexistent lipid metabolic abnormalities shouldbe adequately treated according to general practice guidelines toachieve optimal glycemic and lipids control before starting ever-olimus. Patients with underlying diabetes require careful moni-toring and may require modifications of their anti-hyperglycemicregimen. Treatment of hyperglycemia and hypercholesterolemiashould follow the established guidelines, such as the AmericanDiabetes Association and American Heart Association. Key recom-mendations for the management of everolimus-associated meta-bolic abnormalities are summarized in Table 6.

Rash

Everolimus has been associated with a high incidence of skinrash (39% all grades) in BOLERO-2. This AE is defined as drug-induced acneiform dermatitis and usually starts as an inflamma-tory lesion (papule or pustule), while comedones (blackheads) mayappear thereafter [65,66]. The distribution is frequently unusual,typically in acne-free areas (e.g., upper extremities, trunk, neck)[65e68]. There are no evidence-based guidelines for its manage-ment. Treatment includes topical treatments (with products con-taining corticosteroids, benzoyl peroxide, and antibiotics), systemicantibiotics, and dose adjustments. Key recommendations for themanagement of everolimus-associatedmetabolic abnormalities aresummarized in Table 6. Patients with extensive or persistent skininvolvement should be referred to a dermatologist.

Infections

Everolimus has been associated with a higher risk of infectiondue to its immunosuppressive properties. Everolimus can predis-pose patients to opportunistic infections and/or reactivation oflatent infections. Thereby, patients should be screened for active orlatent infections at baseline and when possible, should be appro-priately treated prior to treatment initiation. In some circum-stances, everolimus treatment might not be appropriate, such as inpatients with a history of hepatitis B/C, HIV, tuberculosis and fungalinfections. Local endemic infections should also be considered.

Contrary to the phase III trials in renal and neuroendocrine can-cer, no increase in the rate of severe infections was reported in ABC(BOLERO-2 trial) [56]. The rationale for this discrepancy is unclearbut may reflect the severity from the underlying malignant disease.Of note, an earlier phase II trial evaluated two schedules of ever-olimus (daily vs. weekly) in heavily pretreated patients, the authorsreported an incidence of infections of 11% (2% grades 3e4) [69].

Therefore, we recommend an aggressive and early infectiontreatment in patients being treated with everolimus and a clinicalsuspicion of infection.

Conclusion

The development of novel targeted agents represents a majorprogress to patients with BC. Survival outcomes have been mark-edly improved of these agents. However, many of them are alsoassociated with a wide range of side effects, and specific manage-ment is required. The resulting side effects can also be associatedwith potential detrimental effects in QoL and decrease treatmentcompliance, making the management of side effects a keycomponent of treatment. In this review, we illustrated the maintoxic profile related with each target agent and provided a numberof practical recommendations in this regard.

Authorship

All the authors have made substantive contributions to thestudy, endorse the data and conclusions, declare that all material inthis assignment is our own work and do not involve plagiarism.

Conflict of interest statement

None declared.

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