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Vol. 42. Núm. 12.
Páginas 961-984 (dezembro 2023)
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Vol. 42. Núm. 12.
Páginas 961-984 (dezembro 2023)
Systematic review
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Is dyslipidemia a risk factor for trastuzumab-induced cardiotoxicity in breast cancer patients? A systematic review and meta-analysis
É a dislipidemia um fator de risco para cardiotoxicidade do trastuzumab em pacientes com cancro da mama? Uma revisão sistemática e meta-análise
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Jaime Pinhoa,1,
Autor para correspondência
jaimefranciscopinho@gmail.com

Corresponding author.
, Miguel Carvalhob,1, Mariana Paivaa,b, Nuno Teixeira-Tavaresa, Cristina Costa-Santosa, Carla Sousaa,b
a Faculdade de Medicina da Universidade do Porto, Porto, Portugal
b Centro Hospitalar e Universitário de São João, Porto, Portugal
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Table 1. Main features of the included studies.
Table 2. Characterization of cardiotoxicity events.
Table 3. Assessment of article quality according to the method used by Haffar et al.18
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Abstract
Introduction

Breast cancer patients undergoing trastuzumab therapy have greater risk of cardiovascular disease. Risk factors for this effect have been proposed. However, the role of dyslipidemia is not completely understood. This systematic review aimed to explore the role of dyslipidemia in trastuzumab-induced cardiotoxicity.

Methods

The investigators searched MEDLINE, Scopus, and Web of Science up to October 25, 2020. A random-effects model was used to determine pooled estimates of the results. The primary endpoint was trastuzumab-induced cardiotoxicity in patients with and without dyslipidemia.

Results

A total of 39 studies were selected for inclusion in our systematic review assessing 21079 patients. One study demonstrated a statistically significant association between dyslipidemia and cardiotoxicity (OR=2.28, 95% CI 1.22–4.26, p=0.01). In all other studies, no such association was observed. Twenty-one studies including 6135 patients were eligible for meta-analysis. In this meta-analysis of unadjusted data, dyslipidemia was significantly associated with cardiotoxicity (OR=1.25, 95% CI 1.01–1.53, p=0.04, I2=0%), however, a subgroup analysis of studies reporting adjusted measures did not demonstrate a significant association (OR=0.89, 95% CI 0.73–1.10, p=0.28, I2=0%).

Conclusion

This systematic review and meta-analysis did not demonstrate a significant association between dyslipidemia alone and the development of cardiotoxicity. In the absence of other relevant cardiovascular risk factors, review of lipid profile may not be obligatory, and management of patients could be performed without referral for cardio-oncology assessment. Further investigation of risk factors for trastuzumab-induced cardiotoxicity is required to confirm these results.

Keywords:
Breast cancer
Cardiotoxicity
Chemotherapy
Trastuzumab
Dyslipidemia
Resumo
Introdução

Pacientes com cancro da mama sob tratamento com trastuzumab apresentam maior risco de doença cardiovascular. Fatores de risco têm sido propostos. No entanto, o papel da dislipidemia não é completamente conhecido. Esta revisão sistemática destinou-se a explorar o papel da dislipidemia na cardiotoxicidade induzida por trastuzumab.

Métodos

Os investigadores pesquisaram publicações na MEDLINE, Scopus e Web of Science até 25 de outubro de 2020. Um modelo de efeitos aleatórios foi utilizado para determinar as estimativas combinadas dos resultados. A variável de resultado primária foi a cardiotoxicidade induzida por trastuzumab em pacientes com e sem dislipidemia.

Resultados

Foram selecionados 39 estudos para inclusão na nossa revisão sistemática, avaliando 21.079 pacientes. Um estudo demonstrou associação significativa entre dislipidemia e cardiotoxicidade (OR=2,28, 95% CI=1,22-4,26, p=0,01). Em todos os restantes não foram observadas semelhantes associações. Foram elegíveis 21 estudos para a meta-análise incluindo 6135 pacientes. Na meta-análise de dados não ajustados a dislipidemia esteve associada significativamente a cardiotoxicidade (OR=1,25, 95% CI=1,01-1,53, p=0,04, I2=0%). No entanto, a análise de subgrupos de estudos que reportaram as medidas ajustadas não demonstrou uma associação significativa (OR=0,89, 95% CI=0,73-1,10, p=0,28, I2=0%).

Conclusão

Esta revisão sistemática e meta-análise não demonstrou uma associação significativa entre dislipidemia isolada e o desenvolvimento de cardiotoxicidade. Na ausência de outros fatores de risco cardiovasculares relevantes, a análise do perfil lipídico nestes pacientes pode não ser obrigatória e a vigilância poderá ser realizada sem referenciação para avaliação por cardio-oncologia. Investigação adicional sobre fatores de risco para cardiotoxicidade induzida por trastuzumab é necessária para confirmar estes resultados.

Palavras-chave:
Cancro da mama
Cardiotoxicidade
Quimioterapia
Trastuzumab
Dislipidemia
Texto Completo
Introduction

Treatment of breast cancer has progressed greatly due to advances in systemic therapies, and survival rates have increased.1 Trastuzumab is a monoclonal antibody that targets the human epidermal growth factor receptor 2 (HER-2)/neu oncogene. It is used in combination with chemotherapy in metastatic and (neo)adjuvant settings in breast cancer, demonstrating improvement in survival outcomes and clinical benefit compared to chemotherapy alone.2,3

Trastuzumab therapy causes an increase in lifetime risk of heart failure (HF),4 the incidence of which is higher when combined with anthracyclines.5,6 Although rare (5% in the NSABP B-31 trial and 2.5% in the HERA trial),7 this has important prognostic implications.

In contrast to the well-recognized effect of anthracyclines,8 which have been the focus of research on cancer therapy-related cardiac dysfunction, trastuzumab-induced cardiotoxicity (TIC) is still the subject of debate,9 as it appears not to be dose-dependent, and discontinuation of treatment can often reverse the condition.10,11

Although current guidelines encourage modification of cardiovascular risk factors for patients in this setting,12 the real incidence of TIC, especially in breast cancer patients, is still largely unknown.13

Several potential risk factors for TIC have been proposed. However, their real weight and role as independent predictors are still debated.13

Dyslipidemia is a known risk factor for cardiovascular disease.14 However, the actual susceptibility for TIC of patients with dyslipidemia is not well documented and to our knowledge, there has to date been no systematic review assessing this link.

This systematic review and meta-analysis aimed to explore whether dyslipidemia could be used as a predictor for the development of TIC in breast cancer patients and to quantify its impact.

Methods

The PRISMA guidelines were followed for the systematic review design.15,16 Patients and the public were not involved in this review.

Search strategy

Three electronic databases were searched (MEDLINE, Scopus, and ISI Web of Science) to identify potentially eligible articles using a pre-defined search strategy (Appendix A).

The search encompassed all articles from inception to October 25, 2020.

This process resulted in 857 articles in the MEDLINE database, 1048 articles in ISI Web of Science, and 840 in Scopus (Figure 1). A further 19 articles were later identified, mainly through manual searches and citations.

Figure 1.

Flowchart of study selection using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram to illustrate the study selection process.

(0,46MB).
Eligibility criteria

We considered only human studies assessing the effects of HER-2 directed agents in breast cancer patients undergoing chemotherapy and reporting on independent risk factors. This strategy ensured that articles that did not mention dyslipidemia in their title or abstract due to non-significant results were included. The included studies assessed the impact of risk factors for cardiotoxicity, analyzing at least two study arms, comparing either patients with cardiotoxicity to those without or patients with a given factor to those without. Subsequently, the studies were screened for the role of dyslipidemia in the development of TIC.

Our primary outcome was cardiotoxicity, defined according to the criteria used in the HERA trial17 as symptomatic (e.g. HF and/or dyspnea, and/or referral to a cardiologist) or asymptomatic (e.g. decline in left ventricular ejection fraction [LVEF] >10% from baseline or LVEF <50%). We did not, however, exclude articles that diverged slightly from this definition for the qualitative and quantitative synthesis.

Secondary outcomes consisted of symptomatic cardiotoxicity, discontinuation of trastuzumab due to cardiac causes, recovery of cardiac function after a cardiac event and reintroduction of therapy after discontinuation.

Exclusion criteria

We excluded (1) studies that mainly focused on anthracycline effects rather than trastuzumab; (2) studies that analyzed outcomes in a pediatric population; (3) non-human studies; (4) studies that followed patients for less than six months; and (5) guidelines, systematic reviews and meta-analyses, case reports, editorials, letters, and/or review articles with no original data.

No articles were excluded based on population size, publication date, or language.

Study selection

After removal of duplicates, two reviewers (JFP and MMC) independently screened the articles at title/abstract level according to the predefined inclusion and exclusion criteria. Afterward, the two reviewers (JFP and MMC) independently analyzed the full texts of studies not previously excluded using the same inclusion and exclusion criteria. Disagreements were resolved by consensus with a third reviewer (CDS) serving as final arbitrator. Efforts were made to contact investigators in order to obtain publications not accessible by other means.

Data extraction

Two reviewers (JFP and MMC) independently analyzed the full texts that had met the inclusion criteria and extracted data into a pre-established spreadsheet.

The full text of short-listed articles was systematically appraised for the following items: first author, year of publication, nationality, study setting, study design, number of patients with breast cancer, number of patients treated with anthracyclines and/or trastuzumab, duration of follow-up, patients’ median age and age at diagnosis, method of LVEF assessment, and number of patients developing or not developing cardiotoxicity (or number of patients with and without a given cardiovascular risk factor).

Quality assessment and risk of bias

The risk of bias was assessed at the study level according to the method used by Haffar et al.,18 given that for the most part, the studies included are observational. This method was also used to classify sub-analyses of randomized controlled trials (RCTs) since the primary subject of these studies was not the effect of dyslipidemia. Two reviewers (JFP and MMC) independently analyzed the studies. Any disagreements were resolved by consensus.

Statistical analysis

Review Manager® (version 5.4.1)19 was used for statistical analysis and to derive forest plots.

Summary measures and synthesis of results

The frequency of a given risk factor was assessed using absolute and relative frequencies. If these were not present, they were calculated.

Odds ratios (ORs) were used as a summary measure. The precision of effect sizes was measured using 95% confidence intervals (CIs) and corresponding p-values for both. We chose the OR since relative estimates are more comparable than absolute effects between studies with different designs, populations, and lengths of follow-up.20

The Cochran Q test (I2)21,22 was used to assess heterogeneity and statistical inconsistency. Small study effects and reporting bias were explored with a visual inspection of asymmetry in funnel plots.23 We classified heterogeneity as 0%, signifying absence of detected heterogeneity; 0–10%, indicating low heterogeneity; 10–50%, indicating moderate heterogeneity; and over 50%, indicating high heterogeneity.

A random-effects model was used to pool data owing to the anticipated heterogeneity in the included trials. In fact, adjusted indirect comparisons that use a fixed-effects model tend to underestimate the standard errors of pooled estimates.24

To better understand the specific effect of dyslipidemia alone as a risk factor for cardiotoxicity, we also performed a pre-planned subgroup analysis involving only studies reporting the most adjusted measures.

ResultsGeneral characteristics of the included studies

The search returned 2745 records, of which 1407 remained after removal of duplicates. After title and abstract screening, followed by full-text appraisal, 39 articles matched our eligibility criteria and were included in our systematic review.25–63 Afterward, 18 records were excluded from the meta-analysis because of data duplication (n=5), missing data (n=8) or being sub-analyses of large RCTs (n=5), and were thus not suitable for use in pooled estimates in conjunction with observational studies. Hence, 21 studies were further examined by meta-analysis (Figure 1). Table 1 summarizes the characteristics of the included studies.

Table 1.

Main features of the included studies.

Study  Design  Year  Sample size  Type of BC  Setting  CT rate  AC use rate  T use rate  DLP rate, n (%)  CT definition  DLP role 
Abd Alghafar et al.25  Retrospective  2020  146  HER-2 BC all stages  Anthracyclines >>1-year adjuvant trastuzumab (when possible)In MBC, trastuzumab continued beyond progressionAC (doxorubicin plus cyclophosphamide) or FEC or other chemo regimen;Palliative, adjuvant, neoadjuvant, pseudoadjuvant trastuzumab  24%  67%  100%  32 (21.92%)  LVEF drop >10% or LVEF <50% or symptomatic HF  Dyslipidemia:Calculated OR=0.68 CI (0.25–1.81) p=0.44 
Abdel-Razaq et al.26  Retrospective  2019  146  BC all stages  Adjuvant/neoadjuvant or palliative trastuzumabWith or without anthracycline/taxanes/endocrine therapy  21.9%  32.9%  100%  30 (20.5%)  LVEF drop ≥10% or a drop to LVEF <50% or symptomatic HF even without decline in LVEF  Dyslipidemia:Calculated OR=1.12 (0.43–2.88) p=0.8335Multivariate OR=0.45 CI (0.11–1.93) p=0.23 
Aldiab27  Retrospective  2010  98  HER-2 BC  Adjuvant trastuzumab after TAC (docetaxol, cyclophosphamide, F-FU) or AC (doxorubicin, cyclophosphamide) followed by taxotere  11.2%  89%  100%  24 (24%)  LVEF drop >10% or a drop to LVEF <50%  Insufficient data 
Ayres et al.28  Retrospective  2015  79  HER-2 EBC  Pre-treatment >>1-year trastuzumabAdjuvant/neoadjuvant chemotherapyECT or FEC or FEC+T or otherECT (epirubicin plus cyclophosphamide plus docetaxel), FEC (fluorouracil plus epirubicin plus cyclophosphamide), FEC+T (fluorouracil plus epirubicin plus cyclophosphamide plus docetaxel)  32.9%  91.1%  100%  7 (8.9%)  LVEF drop ≥10% or to <50% at any time or symptomatic HF  Hypercholesterolemia:Calculated OR=1.60 CI (0.33–7.73) p=0.56Crude OR=1.6 CI (0.3–7.7)Multivariate OR 0.7 CI (0.1–4.3) 
Baron et al.29  Retrospective  2014  76  HER-2 all stages  Pre-treatment+(1-year trastuzumab) with or without prior anthracyclineAdjuvant or palliative  28%  58%  100%  14 (18%)  ≥16% decrease in LVEF or ≥10% decrease in LVEF to <50%.  Hyperlipidemia:Calculated OR 1.84 CI (0.52–6.43) p=0.34 
Ben Kridis et al.30  Prospective  2020  50  HER-2 BC including metastatic  With/without anthracycline >>taxane and trastuzumabNeoadjuvant, adjuvant or palliative  14%  76%  100%  6 (12%)  Asymptomatic decrease in LVEF of 10–15% from baseline to a below <50% or a decrease >15% of the LV LMS (peak systolic left ventricular longitudinal myocardial strain)  Hyperlipidemia:Calculated OR=0.38 CI (0.02–7.58) p=0.53Adjusted OR=0.91 (0.74–1) p=0.67 
Bergamini et al.31  Retrospective  2016  227  HER-2 EBC or locally advanced (stages I–IIIC)  Adjuvant/neoadjuvant trastuzumab with or without anthracyclines and/or taxanes  17.62%  50%  100%  33 (14%)  LVEF drop to <50% or >10% with or without signs and/or symptoms of HF  Hypercholesterolemia:Calculated OR=0.81 CI (0.29–2.249) p=0.69Univariate OR=0.81 CI (0.29–2.24) p=NA 
Bergamini et al.32  Retrospective  2018  90  HER-2 EBC or locally advanced (stages I–IIIC)  Adjuvant/neoadjuvant trastuzumab with or without anthracyclines and/or taxanes  21.1%  50%  100%  16 (17.8%)  LVEF drop to <50% or >10% with or without signs and/or symptoms of HF  Hypercholesterolemia:Calculated OR=0.21 CI (0.02–1.69) p=0.14 
Blancas et al.33  Retrospective  2020  66  HER-2 all stages  Trastuzumab: neoadjuvant/adjuvant/bothWith or without anthracyclines and/or taxanes or other drugs  27.3%  87.9% no total  100%  29 (43.9%)  Asymptomatic drop in baseline LVEF≤10% with a final value <50%, or any drop in LVEF accompanied by signs or symptoms of CHF or other cardiac symptom suggestive of CT  Hypercholesterolemia:Calculated OR=1.91 CI (0.88–4.12) p=0.10 
Bonifazi et al.34  Retrospective  2013  2046  EBC  Adjuvant trastuzumab+chemotherapyYes 1845 (90.2)Adjuvant/neoadjuvant/undefined  2.6%  Insufficient data  100%  285 (14%)  ICD-9 code referring to possibly drug-induced cardiac disease in the main diagnosis (hospitalization)  Dyslipidemia:Calculated OR=2.28 CI (1.22–4.26) p<0.01 
Eiger et al.35  Post-hoc analysis of the ALTTO trial*  2020  4190  HER-2 EBC  Adjuvant trastuzumabTrastuzumab vs. Trastuzumab+L (apatinib)  8.6% total*(7.9%) of patient in T+L arm vs. 197 (9.3%) in T arm  95% vs. 95%  100%  339 (8%)  Asymptomatic CE (cardiac event)=asymptomatic significant LVEF drop, defined as an absolute decline of at least 10 percentage points from baseline and to below 50% symptomatic CE=NYHA class II, III or IV HF associated with a significant LVEF drop. Cardiac death: death due to CHF, myocardial infarction or documented arrhythmia, or probable cardiac death within 24 h of a CE  Hypercholesterolemia:Calculated OR=0.99 CI (0.66–1.46) p=0.94Adjusted OR=0.99 CI (0.66–1.46) p=0.94Multivariate OR=0.90 CI (0.60–1.36) p=0.63 
Farolfi et al.36  Retrospective  2013  179  HER-2 EBC  Adjuvant trastuzumab with or without anthracycline and/or taxane  44%  90%  100%  16 (9%)  LVEF drop ≥15% or a drop to LVEF<50%  Hypercholesterolemia:Calculated OR=0.76 CI (0.26–2.19) p=0.61Univariate OR=0.76 CI (0.26–2.19) p=0.61 
Fried et al.37  Retrospective  2013  124  HER-2 EBC  Adjuvant or neoadjuvant treatmentAnthracycline cyclophosphamide (AC), followed by taxol+trastuzumab (TH) OR taxotere, carboplatin, and trastuzumab (TCH) OR cyclophosphamide, anthracycline and fluouracil (CAF)  7%  90%  100%  12 (10%)  LVEF drop >10%  Insufficient data 
Ganz et al.38  Post-hoc analysis of NSABP B-31*  2017  407 complete LVEF assessments: 110 in the control group and 297 in the trastuzumab group  HER-2 EBC  AC→P vs. AC→PH (trastuzumab)AC, doxorubicin and cyclophosphamide; H, trastuzumab; P, paclitaxel  3.7%  100%  72.2% of total  28/313 (eligible, consented) (9%)  LVEF drop >10% to a value <50% along with patient-reported outcomes  Hyperlipidemia:Calculated OR=2.89 CI (1.41–5.91) p=<0.01Multivariable model for predicting low DASI score (<43) – baseline elevated lipid profile medication use: OR=1.92 CI 0.85–4.36 p=0.12 
Gong et al.39  Retrospective  2016  3134  EBC  Adjuvant trastuzumab with or without anthracycline/taxane  9.3% events composite  78.9%  100%  55 (1.75%)  Composite endpoints: hospitalization/emergency room visit for HF or death  DyslipidemiaVarious composite outcomes – composite of HF event or death: adjusted HR 0.65 CI (0.21–1.99) p=0.45 
Grazziotin et al.40  Prospective  2017  109  EBC or MBC  Adjuvant or palliative trastuzumabWith or without anthracycline/taxane/hormone therapy  53.2%  8.3%  100%  17 (15.6%)  (1) LVEF drop ≥10%, (2) drop to <50% or (3) trastuzumab discontinuation without significant decrease in LVEF, due to important symptoms or signs of HFThe secondary outcomes were hospitalization rate, emergency-seeking rate and trastuzumab discontinuation due to CT  Dyslipidemia:Calculated OR=0.76 CI (0.27–2.12) p=0.61Univariate HR 1.47 CI (0.74–2.93) p=0.27 
Guglin et al.41  Retrospective  2019  118 (adjuvant)38 (metastatic)156 (combined group)  HER-2 BC  >1-Year trastuzumab  48% total*33.1% percent of adjuvant group vs. 34.2% combined group  93.2% adjuvant group36.8% metastatic group  100%  12 (10.2%)  Time to development of cardiomyopathy (decline of LVEF by ≥10%, decline of LVEF to <50%, symptoms and physical signs of HF)  DyslipidemiaCalculated OR for EF<50 in adjuvant=0.56 CI (0.07–4.59)RR segregated for cardiomyopathy, LVEF <50, LVEF drop >10, HF symptoms=1.00 p=0.98; 0.57 p=0.84; 1.22 p=0.74, N/A p=0.60 
Gunaldi et al.42  Retrospective  2016  111  Metastatic and non-metastatic BC  Adjuvant or palliative trastuzumab  16.21%  91.9%  100%  25 (22.52)  LVEF drop to <50% or drop >10% or any indication of HF  Hyperlipidemia (LVEF):Calculated OR=2.65 CI (0.90–7.79) p=0.08 
Kaboré et al.43  Prospective  2019  929  EBC  Anthracycline and/or trastuzumab  3.2%  93%  43%  92 (9.9%)  Reduction in LVEF >10% to LVEF<50%  Dyslipidemia:Calculated OR=2.47 CI (0.98–6.23) p=0.06Univariate OR=2.46 CI (0.97–6.23) p=0.05 
Kosalka et al.44  Retrospective  2019  243  HER-2 BC all stages  Trastuzumab with or without previous anthracycline  13.6% hospitalizatio  76.3  100%  28 (11.5%)  Asymptomatic drop in LVEF of more than 10% to <53%, or cardiac hospitalization  Insufficient data 
Matos et al.45  Prospective  2016  92  HER-2 BC  Anthracycline+adjuvant 1-year trastuzumab+taxane concomitantly when indicated  23.9%  100%  100%  9 (9.8%)  Clinical signs and/or symptoms of HF or a drop in LVEF ≥10% in asymptomatic patients  Insufficient data 
Piotrowski et al.46  Prospective  2012  253  HER-2 BC, no metastasis  AC (anthracycline cyclophosphamide)/FEC (fluorouracil plus epirubicin plus cyclophosphamide)/docetaxel/endocrine when indicatedAdjuvant trastuzumab for 1 year  20.6%  Insufficient data  100%  87 (34.4%)  (1) LVEF drop >15% (2) LVEF drop of 10% and below 50%, (3) any symptoms or signs of HF.  Hypercholesterolemia:Calculated OR=0.91 CI (0.48–1.74) p=0.77OR=1.03 CI (0.53–2.01) p=0.93 
Piotrowski et al.47  Prospective  2013  253  HER-2 BC, no metastasis  AC (anthracycline cyclophosphamide)/FEC (fluorouracil plus epirubicin plus cyclophosphamide)/docetaxel/endocrine when indicatedAdjuvant trastuzumab for 1 year  31.7%  Insufficient data  100%  87 (34.4%)  (1) Left ventricular size (left ventricular end diastolic volume index, and left ventricular end systolic volume index), (2) LVEF, (3) left ventricular mass and structure, (4) left atrial size  Hypercholesterolemia:Multivariate OR=Hypercholesterolemia (i) changes after 6-month follow-up ≥SD of baseline value in at least one echo parameter (model I); (ii) changes after 6-month follow-up ≥2 SD of baseline value in at least one echo parameter (model II)I OR=0.76 CI (0.31–1.84) p=0.54II OR=1.49 CI (0.70–3.19) p=0.31 
Romond et al.48  Post-hoc analysis of NSABP B-31*  2012  944 trastuzumab arm and 743 in control arm  HER-2 BC, no metastasis  AC+trastuzumab with at least 1 dose of post-AC therapy  5% total* 4.0% trastuzumab vs. 1.3% control arm  100%  Arm with vs. arm without  70 (7.5%)  Time to cardiac toxicityA CE was defined as a definite or probable cardiac death or congestive HF manifested by dyspnea with normal activity or at rest and associated with an absolute decrease in LVEF of >10 percentage points from baseline to a value less than 55% or a decrease of more than 5% to a value below the lower limit of normal  Lipid medication:p=0.61 HR=0.69 CI (0.17–2.86)Calculated OR=0.69 CI (0.16–2.94) p=0.62 
Rossi et al.49  Retrospective  2016  681  MBC  Palliative  4.7%  Insufficient data  100%  90 (13.2%)  Hospitalization for one of the following conditions: myocardial infarction/ischemia, HF, rhythm disorders, or other cardiac disease after the first trastuzumab administration  Insufficient data 
Russo et al.50  Retrospective  2012  499  HER-2 EBC  Adjuvant trastuzumab  26%  88%  100%  75 (15%)  Experience of at least one episode of CT  Dyslipidemia 
Russo et al.51  Retrospective  2014  499  EBC  Previously treated with chemotherapy (anthracyclines, cyclophosphamide, taxanes, 5-fluorouracil, neoadjuvant)+trastuzumab (18 doses)  26.6%  88%  100%  75 (15%)  Onset of congestive HF  Dyslipidemia:Calculated OR=1.90 CI (0.60–6.10) p=0.28 
Sato et al.52  Retrospective  2019  119  BC  Trastuzumab every 3 weeks with or without previous anthracycline  10.8%  60.5%  100%  24 (20%)  Overt HF or ≥10% LVEF drop to LVEF <55% in asymptomatic patients.  Dyslipidemia:Calculated OR=0.69 CI (0.14–3.36) p=0.65Univariate OR=0.672 CI (0.16–2.89) p=0.59 
Serrano et al.53  Retrospective  2012  45  Early or advanced BC  >1 dose trastuzumab-based regimen  17.8%  40%  100%  13 (28.9%)  Onset of symptomatic CT (drop ≥10% resulting in a final LVEF <50% or absolute drop >20%)  Dyslipidemia:Calculated OR=2.23 CI (0.55–9.02) p=0.26Univariate p=0.25Multivariate p=0.76 
Suter et al.54  Post-hoc analysis of HERA trial*  2007  16931678 used in trastuzumab safety analysis  HER-2 BC early stage invasive  1 vs. 2 years of trastuzumab every 3 weeks  3.04% vs. 0.53%  100%  94%  74(4.4)  Disease-free survival and cardiac adverse event  Hyperlipidemia:Calculated OR=0.3525 CI (0.05–2.58) p=0.30Difference in incidence=−2.39 CI (−5.87 to 1.09) 
Tan-Chiu et al.55  Post-hoc analysis of NSABP B-31*  2005  814  HER-2 node-positive BC  Doxorubicin and cyclophosphamide (AC) followed by paclitaxel vs. AC followed by paclitaxel plus 52 weeks of trastuzumab  0.6% control vs. 3.6% trastuzumab  100%  Arm with vs. arm without  60 (7.4%)  Time to cardiac event  Elevated fasting lipid profile medications:Calculated OR CI (0.41–0.06) p=0.39Elevated fasting lipid profile medications: Relative risk=0.44 CI (0.06–3.2) p=0.52 
Tang et al.56  Retrospective  2017  160  HER-2 EBC  Adjuvant trastuzumab  21.3%  48.1%  100%  25 (15.6%)  Symptomatic HF or asymptomatic [decline in LVEF by ≥10% or LVEF ≤50%]  Hyperlipidemia:Calculated OR=1.21 CI (0.44–3.31) p=0.71 
Tarantini et al.57  Retrospective  2012  499  EBC treated with trastuzumab  Adjuvant trastuzumab  27%  87%  100%  75 (15%)  Time to cardiac dysfunction LVEF/HF  Dyslipidemia (LVEF)Calculated OR 1.17 CI (0.68–2.01) p=0.57 
Tarantini et al.58  Retrospective  2012  499  EBC treated with trastuzumab  Adjuvant trastuzumab  27%  87%  100%  75 (15%)  Drop of LVEF classified into five grades  Insufficient data 
Ürun et al.59  Prospective  2015  52  HER-2 EBC+MBC  Trastuzumab either single-agent or combined with chemotherapy agents  9.6%  75%  100%  6 (11.5%)  Symptomatic HF or LVEF drop >10%  Hyperlipidemia:Calculated OR=0.58 CI (0.03–11.78) p=0.72 
Vicente et al.60  Retrospective  2009  61  HER-2 BC  Adjuvant trastuzumab (excluding neoadjuvant)  32.8%  Insufficient data  100%  Insufficient data  LVEF <50% or ≥10% LVEF drop  Insufficient data 
Wadhwa et al.61  Retrospective  2009  152  HER-2 BC  Adjuvant trastuzumab after FEC or ACAC adriamycin, cyclophophamide.  23.7%  100%  100%  20 (13.2%)  Onset of cardiac dysfunction (decline of 10% in LVEF)  Hyperlipidemia:Calculated OR=0.53 CI (0.15–1.92) p=0.33 
Yoon et al.62  Retrospective  2016  712  BC all stages  Neoadjuvant/adjuvant anthracycline based, taxane-based, or combined regimens followed by adjuvant trastuzumab in some cases  11.5%  68%  15,7%  Not specified  LVEF <55% or LVEF drop >10%  Low triglyceride level:RR=0.995 CI (0.99–1.00) p=0.11 
Yu et al.63  Retrospective  2015  573  HER-2 EBC  Adjuvant trastuzumab with or without previous adjuvant anthracyclines  16.1%  81.5%  100%  125 (21.8%)  LVEF drop ≥16% or LVEF drop of ≥10% to <55% with or without symptoms of HF  Hyperlipidemia:Calculated OR=1.15 CI (0.68–1.95) p=0.60OR=1.15 CI (0.68–1.95) p=0.595 

>>: followed by; AC: doxorubicin plus cyclophosphamide; AC rate: anthracycline use rate; BC: breast cancer; CT: cardiotoxicity; CE: cardiac event; CI: confidence interval; DASI: Duke Activity Status Index; DLP: dyslipidemia; EBC: early breast cancer; echo: echocardiographic; FEC: 5-fluorouracil plus epirubicin plus cyclophosphamide; HF: heart failure; HR: hazard ratio; ICD-9: International Classification of Diseases, Ninth Revision; LVEF: left ventricular ejection fraction; MBC: metastatic breast cancer; NYHA: New York Heart Association functional class; OR: odds ratio; RR: risk ratio; SD: standard deviation; T: trastuzumab.

*

Studies that analyzed risk factor data in databases provided by large randomized clinical trials. Data were collected referring specifically to dyslipidemia.

Of the 39 articles included in the qualitative analysis, most were Italian31–36,49–51,57,58 (n=9) or American29,38,41,48,54,55,63 (n=7), and all were published between 200555 and 2020.25,30,33,35 The shortest follow-up time was six months47,61 and the longest was 9.5 years.33 Seven studies were prospective and observational,30,43,45–47,59 27 were retrospective and observational,29,31–34,36,37,39,41,42,44,49–53,56–58,60–63 and five were subanalyses of large trials35,38,48,54,55 (of the ALTTO trial,35 NSABP B-31,38,48,55 and HERA.54 The studies included a total of 21079 patients (17998 excluding those based on the same population32,38,46,48,50,51,57), with ages ranging from 2027 to 9253 years, and one study focused on the elderly population.53 No mentions of male patients were found. The median sample size was 179 patients, ranging from 4553 to 4190.35

Patients were treated in both (neo)adjuvant and palliative settings. Only 11 studies did not analyze HER-2 confirmed breast cancer.26,34,39,40,42,43,49,51,52,58,62 Some studies had higher rates of anthracycline use and lower rates of trastuzumab therapy. This was most evident in Kaboré et al.43 (43% patients treated with trastuzumab) and Yoon et al.32 (15.7%). We tried to keep this bias to a minimum by excluding three articles in which trastuzumab use was less than 5% and were therefore judged to have inadequate intervention. These characteristics and other several variations in the treatment for adjuvant/neoadjuvant therapy, dosing, and regimen are further described in Table 1.

Dyslipidemia

The definition of dyslipidemia was similar between studies. Alghafar et al.25 and Farolfi et al.36 defined it as total plasma cholesterol >5.2 mmol/l or use of lipid-lowering medications, while Ganz et al.,38 Romond et al.48 and Tan-Chiu et al.55 used only lipid medications as the marker for dyslipidemia. Matos et al.45 defined dyslipidemia as a combination of low-density lipoprotein cholesterol >3 mmol or total cholesterol >5 mmol/l. Piotrowski et al.,47 Russo et al.50,51 and Tarantini et al.57 defined dyslipidemia as total serum cholesterol >190 mg/dl or lipid-lowering therapy or triglycerides >150 mg/dl. Bonifazi et al.34 used International Classification of Diseases, Ninth Revision (ICD-9) codes to identify patients diagnosed with dyslipidemia.

In our systematic review, after excluding articles dealing with the same populations,32,38,46,48,50,51,57 lacking information on dyslipidemia prevalence,60,62 and large subanalyses of RCTs,35,38,48,54,55 we found the overall prevalence of dyslipidemia to be 11.32%, ranging between studies from 1.75%39 to 43.9%.33 In the meta-analysis this figure was 15.84% and in RCTs only, it was 7.01%.

Trastuzumab-induced cardiotoxicity

Most studies included in this systematic review defined cardiotoxicity as a ≤10–16% decline in LVEF, a decline in LVEF to <50–55%, or patients exhibiting signs and symptoms of heart failure.25–33,35–38,40–46,48–63 All these studies used either echocardiography or multigated acquisition (MUGA) scan as a tool to serially assess LVEF. However, outcome definitions and assessment of results differed widely between different studies, with a vast array of descriptive terminology being used. Bonifazi et al.34 defined the primary outcome as ICD-9 code reports referring to possibly drug-induced cardiac hospitalization in the main diagnosis, while Gong et al.39 and Rossi et al.49 defined it as hospitalizations due to cardiac events, and it was defined as use of medication in Ganz et al.,38 Romond et al.,48 and Tan-Chiu et al.55 We also included other studies in which there were slight variations in the percentages of LVEF decrease29,36,44,46,62,63 (Table 1), such as asymptomatic cardiotoxicity defined as LVEF drop ≥16%29,63 or LVEF drop ≥15%,36,46 or for symptomatic cardiotoxicity, LVEF drop ≥10% to LVEF <55%62,63 or LVEF <53%.44

A detailed characterization of cardiotoxicity-related parameters is presented in Table 2. In this systematic review, excluding RCTs,35,38,48,54,55 we found the overall incidence of TIC to be 11.94%, with 5.59% of patients presenting symptoms of heart failure. Performing the same calculation only for RCTs, we found these values to be 9.18% and 2.4%, respectively. In the primary meta-analysis, the cardiotoxicity rate was 13.55%.

Table 2.

Characterization of cardiotoxicity events.

Study  Reintroduction of trastuzumab  Recovery  Discontinuation of trastuzumab due to CT  Cardiac death  CT rate  DLP patients  DLP rate  CT  Symptomatic CT  Total patients treated with trastuzumab 
Abd Alghafar et al.25  13  22  29  24%  32  21.92%  35  15  146 
Abdel-Razaq et al.26  No data  No data  No data  No data  21.90%  30  20.5%  32  24  146 
Aldiab27  No data  No data  11  11.20%  24  24%  11  98 
Ayres et al.28  No data  No data  13  No data  32.9%  8.9%  26  12  79 
Baron et al.29  12  17  No data  28%  14  18.00%  21  76 
Ben Kridis et al.30  No data  14%  12.00%  50 
Bergamini et al.31  No data  No data  No data  No data  17.62%  33  14.00%  40  227 
Blancas et al.33  No data  No data  No data  No data  27.30%  29  43.9%  18  12  66 
Bonifazi et al.34  No data  No data  No data  2.60%  285  14.00%  53a  28b  2046 
Farolfi et al.36  24  24  30  No data  44%  16  9.00%  78c  179 
Fried et al.37  No data  22.4%  12  10.00%  26  124 
Gong et al.39  No data  No data  No data  No data  9.3% composite HF/death events compositea  55  1.75%  291  291d  3134 
Grazziotin et al.40  22    34  53.20%  17  15.6%  58  10  109 
Guglin et al.41  11    23  48% total 33.1% of adjuvant group vs. 34.2% combined group  12  10.2%  39  11  118 
Gunaldi et al.42  18  No data  16.21%  25  22.52%  18  111 
Kaboré et al.43  No data  No data  No data  No data  3.20%  92  9.9%  29  No data  929 
Kosalka et al.44  No data  No data  No data  No data  13.6%  28  11.5%  33e  33  243 
Matos et al.45  No data  No data  23.90%  9.8%  22  92 
Piotrowski et al.46  13  33  52    20.60%  87  34.4%  52  9f  253 
Rossi et al.49  No data  No data  No data  Unspecified cardiac death  4.7%  90  13.2%  32g  32  681 
Sato et al.52    13  13  10.80%  24  20.00%  13  119 
Serrano et al.53  11  12  No data  17.80%  13  28.9%  12  45 
Tang et al.56      No data  21.3%  25  15.6%  34  160 
Tarantini et al.58  13  13  24  27%  75  15.00%  133  15  499 
Ürun et al.59    No data  9.60%  11.5%  52 
Vicente et al.60  14  32.8%  No data  No data  19  12  61 
Wadhwa et al.61  20  36  No data  23.70%  20  13.2%  36  152 
Yoon et al.62    14  Unspecified cardiac death  11.50%  No data  No data  82  59  712 
Yu et al.63  27  57  57  No data  16.10%  125  21.8%  92  18  573 

CT: cardiotoxicity; DLP: dyslipidemia; HF: heart failure.

The table does not include studies in which different analyses of the same samples were performed.32,38,46,48,50,51,57

a

Hospitalizations due to cardiac events.

b

Heart failure.

c

Cardiac events: four cases of heart failure (New York Heart Association class III or above).

d

Refers to composite heart failure/death in both columns, since information on asymptomatic cardiotoxicity was not provided.

e

Refers to cardiac hospitalizations in both columns.

f

Six severe, symptomatic heart failure, one left bundle branch block, two negative T waves V1-6 on the electrocardiogram.

g

Refers to cardiac hospitalizations in both columns.

In observational studies that provided data concerning discontinuation of trastuzumab, 11.13% of 3808 patients discontinued treatment temporarily or permanently due to cardiac complications. The figure was 6.61% when only RCTs were considered.

Furthermore, in studies that provided data concerning recovery of cardiac function after trastuzumab discontinuation, recovery was observed in 72.12% of patients discontinuing trastuzumab due to cardiac reasons.

Also, in studies reporting reintroduction of trastuzumab after discontinuation, we observed that 43.65% presented significant recovery of cardiac function that enabled continuation of therapy.

Association between dyslipidemia and trastuzumab-induced cardiotoxicity

Six of the included studies28,31,36,43,52,53 presented univariate estimations of ORs concerning the role of dyslipidemia in trastuzumab-induced cardiotoxicity, while another six presented multivariate data.26,28,35,38,47,53 In all other studies, we calculated ORs based on demographic data found in the reports.

Of the latter studies, only Bonifazi et al.34 found a significant association (OR=2.28, 95% CI 1.22–4.26, p=0.01). The study's original summary measure was the hazard ratio (HR). This study identified the rate of severe cardiac adverse events among 2046 women treated with trastuzumab for early breast cancer, through a record linkage between health care databases and searches for records concerning ICD-9 codes referring to cardiac events and cardiovascular risk factors. A cumulative risk of cardiotoxicity was then estimated using the Kaplan-Meier method over a follow-up of three years. The predictors found were age and history of cardiac disease.

Other studies were close to the significance threshold. Gunaldi et al.42 retrospectively assessed a sample of 111 women, however, a significant association between hyperlipidemia and LVEF decrease was not found (OR=2.65, 95% CI 0.90–7.79, p=0.08). Kaboré et al.43 used prospective data in a French national multicenter study aiming to examine the association of body mass index (BMI) and cardiotoxicity defined as a decrease in LVEF in a total of 929 patients. In multivariate analysis, obesity was independently associated with cardiotoxicity. However, no significant association was found for dyslipidemia on univariate analysis (OR=2.46, 95% CI 0.97–6.23, p=0.05). This proximity to significance may also be in part explained by the low rates of trastuzumab use (43%).

Furthermore, studies that performed subanalyses of large RCTs,35,38,48,54,55 including studies reporting multivariate measures,35,38 did not observe such an association either: OR=0.90, 95% CI 0.60–1.36, p=0.63 as observed in Eiger et al.35 and OR=1.92, 95% CI 0.85–4.36, p=0.12 for the association between baseline elevated lipid profile medication use and low Duke Activity Index Status score in Ganz et al.38

Other studies were not included in the meta-analysis because of unavailability of data to calculate OR. These studies used other summary measures such as risk ratio (RR)41,55,62 or HR,39,40,48 however, they also failed to find an association. Of note that one of these studies performed rigorous adjustments for HR.39

Our random-effects meta-analysis encompassed 21 studies5,25,26,28–31,33,34,36,40–43,46,53,56,58,59,61,63 and included 6135 patients. The prevalence of dyslipidemia was 15.84%. The pooled estimate for the OR of cardiotoxicity for individuals with dyslipidemia undergoing trastuzumab treatment for breast cancer was 1.25 (95% CI 1.01–1.53, p=0.04, I2=0%) (Figure 2).

Figure 2.

Forest plot representing the effect on cardiotoxicity of dyslipidemia compared with the absence of a diagnosis of dyslipidemia in trastuzumab-based breast cancer treatment (odds ratio with 95% confidence interval, random effects meta-analysis). CI: confidence interval; OR: odds ratio; SE: standard error.

(0,47MB).

We also performed a subgroup analysis by selecting only studies reporting the most adjusted results,26,28,30 which resulted in a pooled estimate for the OR of cardiotoxicity for individuals with dyslipidemia undergoing trastuzumab treatment for breast cancer of 0.89 (95% CI 0.73–1.10, p=0.28, I2=0%) (Figure 3). However, one study30 demonstrated a disproportionate weight in the pooled result, but it did cause significant heterogeneity.

Figure 3.

Forest plot representing the effect on cardiotoxicity of dyslipidemia compared with the absence of a diagnosis of dyslipidemia in trastuzumab-based breast cancer treatment only in studies reporting adjusted data (odds ratio with 95% confidence interval, random effects meta-analysis). CI: confidence interval; OR: odds ratio; SE: standard error.

(0,16MB).
Heterogeneity and risk of bias

There were no significant differences between individual studies in the magnitude of the association between dyslipidemia and cardiotoxicity in our primary meta-analysis, as indicated by the statistical test for heterogeneity (tau2=0.00; chi-square=17.21, df=20 [p=0.64]; I2=0%).

However, across studies, the treatment was heterogeneous due to the use of different regimens (Table 1), which makes it difficult to define the effect specifically caused by dyslipidemia in the setting of trastuzumab therapy.

The quality of the studies and the risk of bias were assessed at the study level using the method of Haffar et al.18 Overall, we judged 13 studies to be of moderate quality, 1227,29,33,36,40–42,44,52,53,59,61 due to incomplete exclusion of pre-existing LVEF impairment and one due to lack of specification of the tool used for outcome assessment.34 One study was deemed to be of low quality49 because of failure to collect diagnosis details and unclear diagnostic method. The results of this assessment are shown in Table 3.

Table 3.

Assessment of article quality according to the method used by Haffar et al.18

Study  Did the patients represent the whole experience of the medical center?  Was the diagnosis correctly made?  Were other important diagnoses excluded?  Were all important data cited in the report?  Was the outcome correctly ascertained?  Overall quality assessment 
Abd Alghafar et al.25  Yes  Yes  Yes  Yes  Yes  Good 
Abdel-Razaq et al.26  Yes  Yesa  Yes  Yes  Yes  Good 
Aldiab27  Yes  Yesa  No  Insufficient data to calculate OR  Yes  Moderate 
Ayres et al.28  Yes  Yesa  Yes  Yes  Yes  Good 
Baron et al.29  Yes  Yesa  No  Yes  Yes  Moderate 
Ben Kridis et al.30  Yes  Yesa  Yes  Yes  Yes  Good 
Bergamini et al.31  Yes  Yesa  Yes  Yes  Yes  Good 
Bergamini et al.32  Yes  Yesa  Yes  Yes  Yes  Good 
Blancas et al.33  Yes  Yesa  No  Yes  Yes  Moderate 
Bonifazi et al.34  Yes  Yes  Yes  Yes  No  Moderate 
Eiger et al.35  Yes  Yesa  Yes  Yes  Yes  Good 
Farolfi et al.36  Yes  Yes  No  Yes  Yes  Moderate 
Fried et al.37  Yes  Yesa  Yes  Insufficient data to calculate OR  Yes  Good 
Ganz et al.38  Yes  Yes  Yes  Yes  Yes  Good 
Gong et al.39  Yes  Yesa  Yes  Insufficient data to calculate OR  Yes  Good 
Grazziotin et al.40  Yes  Yesa  No  Yes  Yes  Moderate 
Guglin et al.41  Yes  Yesa  No  Yes  Yes  Moderate 
Gunaldi et al.42  Yes  Yesa  No  Yes  Yes  Moderate 
Kabore et al.43  Yes  Yesa  Yes  Yes  Yes  Good 
Kosalka et al.44  Yes  Yesa  No  Insufficient data to calculate OR  Yes  Moderate 
Matos et al.45  Yes  Yes  Yes  Insufficient data to calculate OR  Yes  Good 
Piotrowski et al.46  Yes  Yes  Yes  Yes  Yes  Good 
Piotrowski et al.47  Yes  Yes  Yes  Yes  Yes  Good 
Romond et al.48  Yes  Yes  Yes  Yes  Yes  Good 
Rossi et al.49  Yes  Yesa  Yes  No+insufficient data to calculate OR  No  Low 
Russo et al.50  Yes  Yes  Yes  Yes  Yes  Good 
Russo et al.51  Yes  Yes  Yes  Yes  Yes  Good 
Sato et al.52  Yes  Yesa  No  Yes  Yes  Moderate 
Serrano et al.53  Yes  Yesa  No  Yes  Yes  Moderate 
Suter et al.54  Yes  Yesa  Yes  Yes  Yes  Good 
Tan-Chiu et al.55  Yes  Yes  Yes  Yes  Yes  Good 
Tang et al.56  Yes  Yesa  Yes  Yes  Yes  Good 
Tarantini et al.57  Yes  Yes  Yes  Yes  Yes  Good 
Tarantini et al.58  Yes  Yes  Yes  Yes  Yes  Good 
Ürun et al.59  Yes  Yesa  No  Yes  Yes  Moderate 
Vicente et al.60  Yes  Yesa  Yes  Insufficient data to calculate OR  Yes  Good 
Wadhwa et al.61  Yes  Yesa  No  Yes  Yes  Moderate 
Yoon et al.62  Yes  Yesa  Yes  Insufficient data to calculate OR  Yes  Good 
Yu et al.63  Yes  Yesa  Yes  Yes  Yes  Good 

OR: odds ratio.

aNot specified, probably adequate.

Publication bias and small-study effects were assessed for all collected variables, as demonstrated by the funnel plot of data from the 21 studies included in the meta-analysis of raw ORs, which was asymmetrical (Figure 4). These data indicate that included studies with small sample sizes appear to underestimate the effect of dyslipidemia.

Figure 4.

Funnel plot of included studies. OR: odds ratio; SE: standard error.

(0,09MB).
Discussion

To our knowledge, this is the most comprehensive and up-to-date systematic review and meta-analysis studying the effect of dyslipidemia on TIC. Overall, most studies (38 out of 39), adjusted or otherwise, did not observe an association between dyslipidemia and cardiac events. The quantitative analysis using random-effects model meta-analysis of raw demographic data yielded an OR of 1.25 (95% CI 1.01–1.53, p=0.04, I2=0%). However, subgroup analysis using only the most adjusted measures failed to observe this association (OR=0.89, 95% CI 0.73–1.10, p=0.28, I2=0%).

Is dyslipidemia a predictor of trastuzumab-induced cardiotoxicity?

Despite the existence of a plethora of studies on the mechanisms and characteristics of TIC, there remains ambiguity concerning robust clinical predictors for this complication. The systematic review by Jawa et al.13 identified hypertension, diabetes, age, and previous anthracycline use as risk factors for a cardiac event, but failed to prove other associations with known risk factors, including dyslipidemia. Attempts have also been made to develop risk scores that will predict rates of heart failure and cardiotoxicity to enable appropriate monitoring in this group,48,64 considering such factors as baseline LVEF,48 age,48,64 adjuvant chemotherapy, coronary artery disease, atrial fibrillation or flutter, diabetes, hypertension, and renal failure.65

Dyslipidemia is linked with heart failure and coronary heart disease in the general population.14 There have been several animal and human studies that point to the beneficial effect of statins in the context of TIC,66–68 and a study has shown that rats fed a high-lipid diet are more sensitive to anthracycline-induced cardiotoxicity.65 We therefore hypothesized that dyslipidemia may play a role in TIC. A previous meta-analysis13 failed to show such an association; however, most of the literature had been based on small samples and there was a lack of studies presenting formal multivariate adjustment, hence the need for an up-to-date and comprehensive systematic review on this topic.

This systematic review was planned and designed to assess the association between dyslipidemia and TIC in breast cancer patients and included 39 studies found by a systematic search regarding this topic.

We found the overall prevalence in this systematic review of dyslipidemia in observational studies to be 11.32%, ranging between studies from 1.75%39 to 43.9%.33 This wide range may be explained because a large proportion of patients excluded in our primary analysis were in subanalyses of data from large RCTs,35,38,48,54,55 in which the dyslipidemia prevalence was 7.01%. These trials included relatively healthier and younger patients. Consequently, there is a risk that it may inadequately represent the real-world breast cancer population, who may present with a higher prevalence of risk factors, including dyslipidemia. Indeed, a major research concern in oncology is the lack of information on elderly populations.69 This question was addressed in a study included in our review that included a population with a median age of 75.9 years53 and that presented a higher prevalence of dyslipidemia (28.9%) than most included studies.

We documented a significant rate of TIC in this population, around 12.0% in the overall review of observation studies, which is consistent with previously reported data.13,70 A recent pooled analysis of adjuvant trials investigated the incidence of TIC and its impact on treatment completion.70 The incidence of symptomatic heart failure in our meta-analysis was 3.18%, which was slightly higher than the figure reported by these authors (2.3%). This suggests that cardiotoxicity may be more frequent outside clinical trials, as observed in recent retrospective cohorts.4

In the qualitative and quantitative synthesis of the data, only one study, Bonifazi et al.,34 showed a clear association between dyslipidemia and trastuzumab-induced cardiotoxicity (OR=2.28, 95% CI 1.22–4.26, p=0.01). This study had the third largest sample size (2046 patients); however, ICD codes were used for both identification of patients diagnosed with dyslipidemia and the incidence of cardiac events (defined as hospitalization). Hence, we judged this study to be at moderate risk of bias for our meta-analysis, and thus the results in the meta-analysis of unadjusted measures may be overestimated due to the weight of this study. Other studies appear to suggest an association; however, in none did it achieve statistical significance.33,42,43 These findings are further supported by the absence of association found in our subgroup analysis, which only took into consideration adjusted measures. However, it is of note that studies were also unclear about their methods of adjustment, with only Ayres et al.28 specifying that their adjustments controlled for age and BMI.

In our meta-analysis, an association of dyslipidemia with TIC was observed in the pooled data from raw ORs in observational studies. This association was not supported by a subgroup analysis of studies reporting the most adjusted measures. This suggests that the role of dyslipidemia may merit further attention, since it is a condition that often exists in interplay with other comorbidities in a synergistic interaction. Indeed, obesity,35,42,43,59,71 diabetes,13,35,59,65 and hypertension13,30,38,42,47,49 are factors reported to be associated with TIC, which suggests that metabolic syndrome as a whole could be linked to this complication. A study by Kosalka et al.44 found that, compared with any risk factor alone, the combination of two or three comorbidities (such as diabetes, dyslipidemia, and obesity) is associated with a significant increase in the incidence of symptomatic cancer therapy-related cardiotoxicity.

Strengths and limitations

This systematic review was conducted according to the PRISMA guidelines.15,16 Data selection was rigorous, and the analysis was thorough. We were also conservative in our analysis, as undefined data were not considered and the most precise and adjusted measures were extracted for a subgroup analysis.

However, this study has all the limitations inherent to systematic reviews and meta-analyses, particularly of observational studies. Overall, we judged thirteen studies to be of moderate quality27,29,33,34,36,40–42,52,53,59,61 and one of low quality.49 There is considerable heterogeneity between the included studies concerning sample size, therapeutic regimens, cancer stages and molecular profiles, patient demographics, and inclusion/exclusion criteria and follow-up in each study.

The fact that advanced cancer predisposes to further doses of treatment should be taken into consideration, since it may enhance the risk for cardiac harm and consequently overestimate the incidence of cardiotoxicity. Furthermore, different imaging modalities were used, particularly MUGA scans as opposed to echocardiography, which is currently considered the preferred imaging modality for surveillance.72 We should also bear in mind that there is still no clear consensus on the correct definition of cardiotoxicity, hence our outcome aggregates subclinical and clinical cardiotoxicity as a single endpoint. This highlights the need to create a universally acceptable definition of cardiotoxicity in this setting that could be uniformly used in future trials.

Although we tried to minimize the risk of selection bias by performing a wider initial search for all possible risk factors for TIC, the studies included were not specifically designed to address this question and the definitions of dyslipidemia were not always stated and differed between studies. This led to bias in data collection, as we were only able to extract data from studies in which the authors considered dyslipidemia to be a relevant factor.

Clinical relevance

Although our systematic review and meta-analysis found an association between dyslipidemia and cardiotoxicity in a pooled estimation of unadjusted data, the same did not apply for the meta-analysis of multivariate measures. Hence, in the absence of other relevant cardiovascular risk factors, routine review of these patients’ lipid profile may not be as important as previously thought. Also, breast cancer patients who are candidates for trastuzumab therapy and who present isolated dyslipidemia should probably not be considered at high risk for the development of cardiotoxicity and can be managed in the same way as patients with no dyslipidemia, without referral for cardio-oncology assessment.

Conclusion

TIC is responsible for a significant burden in breast cancer treatment, causing an increase in morbidity and mortality. Although there is concern about the role of dyslipidemia in TIC, our study was not able to provide conclusive evidence to identify dyslipidemia as a risk factor for TIC. These findings, however, should not be taken as definitive, as the data are insufficient and extracted from observational studies at risk of various biases.

As such, a low-bias, adequately powered RCT designed to clarify this question and additional systematic reviews on the topic of the real predictive value of cardiovascular risk factors in the development of TIC would be of significant scientific and clinical value.

Even so, this review may provide valuable support for stratifying the risk for this effect, and help to manage and avoid adverse outcomes in these patients, particularly if integrated into a system to predict the risk of this complication in each patient. These questions and the role of other specific factors should be addressed in future studies.

Funding

None declared.

Conflicts of interest

The authors have no conflicts of interest to declare.

Acknowledgment

The authors wish to thank Professor José Nunes for his assistance in the editing of the manuscript and advice given throughout the development of this project.

Appendix A
Queries used in the electronic database search

Our search was performed using the following queries:

MEDLINE:

((“trastuzumab”[MeSH Terms] OR “trastuzumab”[Title/Abstract] OR “pertuzumab”[Title/Abstract] OR “lapatinib”[Title/Abstract] OR “neratinib”[Title/Abstract]) AND (“cardiotoxicity”[MeSH Terms] OR “cardiotox*”[Title/Abstract] OR (“cardiac”[Title/Abstract] AND “toxi*”[Title/Abstract]) OR “LVEF”[Title/Abstract] OR “cardiomyopathy”[Title/Abstract])) NOT (animal[mh] NOT human [mh]) NOT ((Review[pt]) OR (meta-analysis[pt]) OR (practice-guideline[pt]))

Scopus:

(TITLE-ABS (trastuzumab) OR TITLE-ABS (pertuzumab) OR TITLE-ABS (lapatinib) OR TITLE-ABS (neratinib)) AND (TITLE-ABS (cardiotoxicity) OR TITLE-ABS (cardiotox*) OR (TITLE-ABS (cardiac) AND TITLE-ABS (toxi*)) OR TITLE-ABS (lvef) OR TITLE-ABS (cardiomyopathy)) AND NOT (TITLE-ABS (animal) AND NOT TITLE-ABS (human)) AND (LIMIT-TO (DOCTYPE, “ar”))

Web of Science:

TS=(trastuzumab OR pertuzumab OR lapatinib OR neratinib) AND TS= (cardiotoxicity OR cardiotox* OR (cardiac AND toxicity) OR Cardiomyopathy OR LVEF) NOT TS=(animal NOT human) Refined by: DOCUMENT TYPES: (ARTICLE)

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