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Pertuzumab Cardiotoxicity in Patients With HER2-Positive Cancer: A Systematic Review and Meta-analysis

Background Human epidermal growth factor receptor 2 (HER2) overexpressing malignancies, including breast and gastro-esophageal, are associated with a poor prognosis. The cardiotoxicity of trastuzumab, a HER2-targeting monoclonal antibody, is well established. However, the cardiotoxic effect of pertuzumab, another HER2-directed therapy, is less well documented. The objective of this systematic review and meta-analysis was to determine the risk of cardiac events in patients with HER2-positive cancer who are receiving pertuzumab. Methods We performed a systematic review of phase 2 and 3 randomized controlled trials in which the addition of pertuzumab to other standard therapies in patients with stage I-IV HER2-positive cancer was evaluated, and cardiac adverse effects reported. We searched MEDLINE (1946-2020), Embase (1974-2020), and CENTRAL. Two independent reviewers assessed the risk of bias and extracted the data. Risk ratios (RRs) with 95% confidence intervals (CIs) were calculated from the pooled data using the inverse variance method and random-effects models. Results Eight randomized controlled trials (8420 patients) were included: 1 was gastro-esophageal; 7 were breast cancer trials. Participants’ median age ranged from 49 to 61.5 years. All participants received trastuzumab and chemotherapy in addition to pertuzumab or placebo. Compared with placebo, pertuzumab increased the risk of clinical heart failure (HF; RR [95% CI]: 1.97 [1.05-3.70]; I2 = 0%). However, pertuzumab had no demonstrable effect on asymptomatic/minimally symptomatic left ventricular systolic dysfunction (RR [95% CI]: 1.19 [0.89-1.61]; I2 = 19%). Conclusions Pertuzumab increases the risk of clinical HF, but not asymptomatic/minimally symptomatic left ventricular systolic dysfunction, in HER2-positive cancer patients. Further research into the mechanisms underlying pertuzumab-related HF is needed to understand its clinical spectrum of cardiotoxicity.

Human epidermal growth factor receptor 2 (HER2) is overexpressed in 15%-20% of breast cancers, 1 and its presence is associated with poor prognosis. 2 A variety of other cancers may also express HER2, including ovarian, cervical, endometrial, salivary gland, gastroesophageal junction, gastric, biliary, pancreatic, colorectal, bladder, head and neck, and nonesmall cell lung cancers. [3][4][5][6] Targeting the HER2 receptor has been associated with improved disease-free survival and overall survival, with 7 anti-HER2 agents currently approved (trastuzumab, pertuzumab, T-DM1, lapatinib, neratinib, famtrastuzumab deruxtecan-nxki, and tucatinib) for clinical use. [7][8][9] The first HER2 antibody, trastuzumab, has been in clinical use since 1998, and it is approved for the treatment of HER 2-positive breast, gastric, and gastroesophageal cancer. 7 This drug has dramatically changed the natural history of these malignancies. 10,11 However, its main adverse effect is cardiac dysfunction, which develops in 8% who are treated with trastuzumab alone, and 29% of those treated with trastuzumab in combination with anthracycline. 12,13 The incidence of cardiotoxicity in clinical practice is known to exceed that in clinical trials, especially in older populations and patients with cardiovascular risk factors. [14][15][16] Therefore, cardiotoxicity is the major dose-limiting toxicity of trastuzumab, potentially leading to its premature and unwanted discontinuation despite its anticancer benefits.
Pertuzumab is a recombinant humanized monoclonal antibody that targets HER2, preventing the dimerization of HER2 with HER3, thus blocking oncogenic signaling. 17 It has demonstrated promising efficacy in both metastatic and early breast cancer and is an integral part of HER2-positive breast cancer therapy. The synergistic activity of pertuzumab with trastuzumab has led to the approval of the combination of these 2 drugs with taxane-based chemotherapy (including either paclitaxel or docetaxel) for the first-line treatment of patients with HER2-positive metastatic breast cancer 18,19 and for the treatment of patients with early-stage HER2-positive breast cancer who are at high risk for recurrence, 20,21 for whom it improves invasive disease-free survival 22 and pathologic complete response. 23 Pertuzumab generally has been considered to be less cardiotoxic than trastuzumab. In an analysis of pooled data from 14 phase II studies (n ¼ 598), which in many cases were nonrandomized, asymptomatic left ventricular systolic dysfunction(LVSD, defined as 10% reduction in left ventricular ejection fraction [LVEF] to a value of < 50%) occurred in 6.9% of patients receiving pertuzumab as monotherapy and in 6.5% of patients receiving the combination of pertuzumab and trastuzumab. In this study, the incidence rates of symptomatic heart failure (HF) were 0.3% and 1.1%, respectively. 24 Since this study, more data on pertuzumab, from randomized, placebo-controlled studies, have been published. However, to our knowledge, these data have not been systematically summarized. We therefore undertook a systematic review, with the objective of evaluating the risk of HF or left ventricular dysfunction associated with pertuzumab use as compared with cancer treatment strategies that did not include pertuzumab.

Methods
This systematic review and meta-analysis were performed in accordance with MECIR (Methodological Expectations for Cochrane Intervention Reviews) standards for conducting and reporting intervention reviews, 25 and in accordance with the Preferred Reporting Items for Systematic Reviews and Metaanalyses (PRISMA) guidelines. 26

Search strategy
We searched the following electronic databases: Ovid MEDLINE (1946 to week 10 of 2020); Ovid Embase (1974 to week 10 of 2020); and the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 4 of 12, accessed February 2020). 27 No restrictions based on language or date of publication were used. The MEDLINE and Embase search strategies are available in Supplemental Table S1.
Other sources. We conducted a search of clinical trial registries, including clinicaltrials.gov and the World Health Risk ratios (RRs) with 95% confidence intervals (CIs) were calculated from the pooled data using the inverse variance method and randomeffects models. Results: Eight randomized controlled trials (8420 patients) were included: 1 was gastro-esophageal; 7 were breast cancer trials. Participants' median age ranged from 49 to 61. 5  Conclusions : Le pertuzumab fait augmenter le risque de manifestations cliniques de l'IC, mais pais la dysfonction systolique du ventricule gauche asymptomatique/minimalement symptomatique, chez les patients atteints d'un cancer HER2 positif. Des recherches plus approfondies sur les m ecanismes sous-jacents à l'IC li ee au pertuzumab sont n ecessaires pour comprendre son spectre de manifestations cliniques de cardiotoxicit e.
Organization (WHO) International Clinical Trials Registry Platform. We also searched the electronic abstract databases of the major international congresses' proceedings (the American Society of Clinical Oncology annual meeting and the San Antonio Breast Cancer Symposium). The lists of references of relevant articles and reviews were scanned.

Study selection
Two reviewers (M.M.A. and A.M.) independently screened the titles, abstracts, and descriptors of identified studies for possible inclusion.
Criteria for considering studies for this review Types of studies. Eligible papers were abstracts or full-length manuscripts describing phase II or III randomized controlled trials that reported on the addition of pertuzumab to other therapies and reported on the cardiotoxicity of pertuzumab. We excluded nonrandomized trials, phase I randomized trials, and observational studies. When more than one publication was identified from the same clinical trial, we used the most recent or complete report of that trial.
Types of participants. This review included adult patients (age > 18 years) with stage I-IV HER2-positive cancers of any tumour type, in any treatment settings: neoadjuvant, adjuvant, and metastatic.

Types of interventions and comparisons.
To assess the cardiotoxic effect of pertuzumab, we considered randomized controlled trials in which use of pertuzumab was the only systematic difference between the 2 arms of the studies.
Types of outcome measures. Each of the following binary outcomes was considered to indicate pertuzumab cardiotoxicity: 3. Cardiac death. 4. If adequately reported, we documented the incidence of the following cardiovascular adverse events, to detect any harmful signal that was not previously reported owing to limited data: cardiac ischemia, arrhythmias, QT prolongation, and hypertension.

Data collection and analysis
Data extraction and management. Two authors (M.M.A. and A.M.) independently reviewed the full texts of the potentially related articles and extracted the data from eligible articles. Any disagreement was resolved by discussion and consensus. Data were extracted into a standardized Microsoft Excel spreadsheet.
Assessment of risk of bias in the included studies. For each outcome, dual (M.M.A. and A.M.) independent assessment of risk of bias of the included studies was conducted using the Cochrane Collaboration risk of bias tool (Cochrane's Handbook, version 5.1.0). 30 Disagreements were resolved by discussion. The assessed domains included the sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), and selective outcome reporting. Risk of bias was rated as high/low/unclear (Supplemental Table S2). As this review is concerned with side effects (cardiotoxicity), special interest was given to  attrition bias (incomplete outcome data), which was estimated according to the following factors: (i) whether the outcome of interest (cardiotoxicity) was measured in all trial participants; (ii) whether the proportion of missing outcome data was low (< 5%) or high (> 20%); (iii) the difference between the proportions of missing outcome data in the pertuzumab vs placebo arms; and (iv) the reasons the outcome data are missing.
Measures of treatment effect and data synthesis. The outcomes of interest were dichotomous variables reported as number of events in each trial arm. A summary statistic (risk ratio) was calculated, along with 95% confidence intervals (CIs). A P value of 0.05 was considered statistically significant for the comparison between the groups. The data were pooled in a meta-analysis for each reported outcome if there were 2 or more studies reporting this outcome. For an outcome that could not be pooled in the meta-analysis, it was represented in the narrative results. Absolute effects were calculated using the baseline risk from the placebo arm, where baseline risk ¼ number of events number participants . We then estimated the risk in the pertuzumab group by multiplying the pooled relative risk for pertuzumab by the baseline risk. The absolute risk difference ¼ pertuzumab risk e baseline risk. These estimates were presented with their 95% CIs.
Analysis and pooling of the results were done according to the recommendations in the Cochrane Handbook for Systematic Reviews of Interventions. All statistical analyses were performed with Review Manager Version 5.3 (The Cochrane Collaboration, Software Update, Oxford, UK). We pooled the results of trials using the inverse variance method and the random-effects model. Heterogeneity between studies was evaluated by visual inspection of forest plots, the c 2 with statistical significance set at P < 0.10, and the I 2 statistic. 31 Subgroup and sensitivity analysis. We prespecified subgroup analyses to compare the risk of cardiotoxicity of pertuzumab in different treatment settings (early vs metastatic cancer), and in different cancers. Three sensitivity analyses were performed. The first was performed using the Peto statistical method, which is proposed to be less biased for rare events. The second and third were to explore the impact of removing studies with T-DM1 or studies that had 2 or more domains of high risk of bias.
Quality of evidence. We used the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) system approach to assess the quality of evidence related to each of the key outcomes (asymptomatic/minimally symptomatic LVSD; HF). 30 A ''summary of findings'' table for our main comparisons, including the GRADE level of certainty of evidence, was created using GRADEpro software (McMaster University and Evidence Prime, 2021; gradepro.org).

Search results
The last search was performed in March 2020. The search yielded 2158 records, of which 2064 were screened after removing duplicates. After screening, we retrieved the full text of 103 potential articles. We excluded 95 articles, for reasons outlined in Figure 1. Ultimately, 8 studies were included in the meta-analysis, 22,23,[32][33][34][35][36][37][38][39] There was a high agreement between reviewers (kappa was 0.89).

Brief description of study characteristics
The characteristics of the 8 studies included in the metaanalysis are displayed in Table 1, and a brief description of the excluded studies is shown in Supplemental Table S3. All studies included adult patients (median age range: 49-61.5 years) with HER2-positive malignancy (7 studies included patients with breast cancer, and one study included patients with gastric and gastro-esophageal cancer). The duration of pertuzumab treatment was not consistently reported (5 of 8 studies (63%) reported the median duration, one reported the mean, and 2 did not report on duration). Four studies were in the metastatic setting. Among these, the median (range) number of pertuzumab cycles reported in 2 studies were: 15 (1-68) and 24 (1-96) 37,38 ; one study reported a mean (standard deviation) number of pertuzumab cycles of 13.1 (10.7), 35 and one study did not report the pertuzumab duration. 33 The median (range) number of pertuzumab cycles was 4 (1-4) in both studies in the neoadjuvant setting, 22 and those in the neoadjuvant/adjuvant setting. 36 In the study in which patients from all treatment settings (neoadjuvant, adjuvant, and metastatic) were eligible, 34 the median (range) number of pertuzumab cycles was 18 (1-65).
In 7 of the 8 studies (88%), the addition of pertuzumab to trastuzumab and chemotherapy was compared with placebo, trastuzumab, and chemotherapy. 22,23,[33][34][35][36]38 In one study, the combination of pertuzumab and T-DM1 was compared with placebo and T-DM1 alone. 37 Six of the 8 studies reported the use of concomitant or previous anthracyclines (NeoSphere [ 22,23,36 or in prior exposure in the case of metastatic disease (3 studies). 34,37,38 Only one trial (APHINITY), which was the largest, reported adverse events data stratified according to anthracycline use. In this trial, 13 of 15 patients (87%) who had HF in the pertuzumab arm, and 5 of 6 patients (83%) in the placebo arm received anthracyclines. Four trials reported the proportion of participants exposed to anthracycline in each arm. The respective percentages of participants prescribed anthracycline in the pertuzumab vs the placebo arm were 96.3% vs 95.3% in NeoSphere, 46 reported that all 5 patients who developed HF were exposed to anthracyclines, but it did not mention whether the placebo group was exposed to * The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
y Imprecise results as the CIs include both no effect and appreciable harm.
anthracycline. 33 The last study in the metastatic setting (JACOB [Pertuzumab Plus Trastuzumab and Chemotherapy for HER2-Positive Metastatic Gastric or Gastro-Oesophageal Junction Cancer]) did not explicitly report whether participants had anthracycline exposure. 35 In all 8 studies (8420 participants), asymptomatic/minimally symptomatic LVSD events were reported. In 7 of 8 studies (7693 participants), HF events were reported. Most studies did not report other outcomes (ie, cardiac death or other cardiovascular adverse effects); however, when given, we have summarized these data.

Risk of bias in the included studies
Our assessment of the risk of bias in the individual included studies is shown in Figure 2 (and in Supplemental Table S2; see also Supplemental Figure S1). The domains judged to have low risk of bias in all 8 studies were random-sequence generation, allocation concealment, and selective outcome reporting. The domains judged to have a high risk of bias were blinding of the participants and the personnel (in 3 studies), attrition bias (in 3 studies), and "other bias" related to industry-funded trials (in 2 studies). For the blinding of outcome assessors, 7 studies had low risk of bias, and in 1 study the risk was unclear.

Effects of pertuzumab
Effect of pertuzumab on asymptomatic/minimally symptomatic LVSD. The definition of LVEF reduction was generally consistent among studies (LVEF decline 10% from baseline and/or below 50%), except for one study 37 that defined it as a drop of > 15% from baseline ( Table 1). The pooled incidence of asymptomatic/minimally symptomatic LVSD was 3.5% in the pertuzumab group, compared to 3.1% in the placebo group. Pooling the data from 8 studies (8420 participants) showed that the risk of asymptomatic/minimally symptomatic LVSD among patients prescribed pertuzumab was no higher than the effect of placebo (risk ratio [RR]: 1.19; 95% CI: 0.89-1.61; Fig. 3), an absolute risk increase of 6 more patients per 1000 (95% CI, from 3 less, to 19 more patients).
Overall, according to the GRADE system, the quality of the evidence was moderate ( Table 2; Supplemental Table S4). Among the studies included, there was only a modest level of heterogeneity (I 2 ¼ 19%; P ¼ 0.25).
Effect of pertuzumab on HF. One study did not report the incidence of HF. Pooling the data from the 7 remaining studies (7693 participants) revealed that patients using pertuzumab were at significantly higher risk of HF than patients in the placebo arm (RR 1.97; 95% CI: 1.05-3.70; Fig. 4). This difference represents an absolute risk increase of 4 more patients per 1000 (95% CI: 0 to 10 more per 1000 patients) developing HF while taking pertuzumab, as compared with placebo (the absolute risks in the pertuzumab and placebo groups were 8 per 1000, and 4 per 1000, respectively). Of the 34 HF events across the pooled pertuzumab groups, there was previous/concurrent anthracycline exposure in 13 cases (38%), no anthracycline exposure in 2 cases, and no report regarding anthracycline exposure in the remaining 19 cases. Of the 14 HF events in the placebo group, there was previous/concurrent anthracycline exposure in 4 cases (29%), no anthracycline exposure in 1 case, and no report regarding anthracycline exposure in the remaining 9 cases.
According to the GRADE system, the evidence quality was moderate ( Table 2; Supplemental Table S5). There was no heterogeneity among the included studies (I 2 ¼ 0; P ¼ 0.43).
Of participants who developed HF, recovery was noted in 1 of 2 cases in the pertuzumab arm in NeoSphere (with no HF noted in the placebo arm), 7 of the 15 cases (47%) reported in the pertuzumab arm of APHINITY at the time of trial closure (as compared with 4 of 6 cases in the placebo arm), and 4 (80%) of 5 cases in the pertuzumab arm of the trial by Urruticoechea et al. 33 (with no HF noted in the placebo arm). In the trial by Swain et al., 38 reductions in LVEF of 10% from baseline to an absolute value < 50% occurred in 24 of 394 individuals (6.1%) in the pertuzumab arm and 28 of 378 participants (7.4%) in the control group. These declines reversed in 21 of the 24 affected participants (87.5%) in the pertuzumab group and 22 of the 28 affected individuals (78.6%) in the control group. Other cardiovascular effects of pertuzumab. Only one study reported cardiac death: there were 2 deaths (1%) in each study arm. 23 One study reported incidence rates of hypertension of 5.5% and 4.7% in the pertuzumab and placebo arm, respectively. 37 In a substudy of 37 patients in one trial, the effects of pertuzumab on the corrected QT interval and other echocardiographic parameters were evaluated. No clinically relevant changes relative to placebo were identified. 40 Cardiotoxicity of pertuzumab in different subgroups. Comparing patients according to treatment settings. There were 4 trials in the metastatic setting, and 3 trials in the adjuvant and/ or neoadjuvant setting; one trial included patients from all treatment settings (Supplemental Fig. S2). There was insufficient evidence to suggest differences in the risk of asymptomatic/minimally symptomatic LVSD between those with metastatic vs non-metastatic disease (I 2 ¼ 0 for heterogeneity). The respective RRs (95% CI) were 1. 30 43,5.77]), there was insufficient evidence to confirm heterogeneity of effect between the subgroups (I 2 ¼ 0; Supplemental Fig. S3).
Comparing patients according to type of cancer. The first subgroup included breast cancer (7 studies), and the second included gastric and gastro-esophageal cancers (one study) (Supplemental Figs. S4 and S5). Between the 2 subgroups, there was no evidence of heterogeneity of the effect of pertuzumab for either outcome: asymptomatic/minimally symptomatic LVSD, and HF. The respective I 2 values were 0 (P ¼ 0.61 and P ¼ 0.98). For asymptomatic/minimally symptomatic LVSD among breast and gastric/gastroesophageal cancers, the respective RRs (95% CI) were: 1.29 (0.88-1.90) and 1.07 (0.56-2.04). For HF, the respective RRs (95% CI) in breast and gastric/gastro-esophageal cancer, respectively, were 2.07 (0.93-4.61) and 2.02 (0. 18-22.14). A sensitivity analysis was performed to explore the impact of excluding the studies that had at least 2 domains with high risk of bias (3 studies) from the analysis. In this sensitivity analysis, pertuzumab did not result in significant risk of asymptomatic/minimally symptomatic LVSD (RR [95% CI] 1.03 (0.80-1.33) of HF (RR [95% CI] 1.63 [0.71-3.73]). In a second sensitivity analysis, we excluded the single study in which TDM-1 was used. Again, pertuzumab had no significant increased risk of asymptomatic/minimally symptomatic LVSD, with a RR (95% CI) of 1.08 (0.84-1.37); this study did not report HF outcomes.

Discussion
In this systematic review and meta-analysis, pertuzumab was associated with an approximately 2-fold increased risk of HF, with no detectable effect on asymptomatic/minimally symptomatic LVSD. These findings are in contrast with those of previous reports that suggest no major risk of cardiotoxicity when pertuzumab is used alone or in combination with other anti-HER2 agents. 24,[41][42][43] In a meta-analysis of cardiotoxicity incidence using data pooled from 598 patients from 14 different studies published in 2012, Lenihan et al. found that patients treated with pertuzumab had a relatively low incidence of asymptomatic left ventricular dysfunction, or symptomatic HF, when pertuzumab was given alone or in combination with either chemotherapy or trastuzumab. 24 In this analysis, a decrease in LVEF of 10% to < 50% occurred in 6.5% of pertuzumab recipients, and HF occurred in 1.1%. In Lenihan's paper, no data on cardiovascular outcomes from a control group were reported, so the relative risk of adverse cardiovascular outcomes among pertuzumab recipients was not identified.
Since the publication of Lenihan's analysis, only a few more papers on the efficacy and safety of pertuzumab have been published. In 2013, Valachis et al. 41 published a systematic review in which they identified randomized trials of trastuzumab, pertuzumab, and lapatinib up to July 2012. Their study was limited to trials comparing anti-HER2 monotherapy with anti-HER2 combination therapy. They reported no significant difference between these treatment groups with respect to the outcomes of HF (although the numbers of outcome events were low) or asymptomatic/ minimally symptomatic LVSD. The respective incidence rates of congestive HF in the groups that received the anti-HER2 therapy in combination and as monotherapy were 0.88% (95% CI: 0.47%-1.64%) and 1.49% (95% CI: 0.98%-2.23%); the respective rates of asymptomatic/minimally symptomatic LVSD were 3.1% (95% CI: 2.2%-4.4%) and 2.9% (95% CI: 2.1%-4.1%). 41 Our study represents an important update to, and extension of, the systematic review performed by Valachis et al. With more data and broader study eligibility criteria, we found, in contrast to previous research, that the risk of HF is increased with pertuzumab use.
We found a surprising discordance between the effect of pertuzumab on asymptomatic/minimally symptomatic LVSD and its effect on HF risk. One possible explanation is that pertuzumab may lead to predominantly diastolic, rather than systolic, left ventricular dysfunction, hence resulting in HF with preserved ejection fraction. In one observational study, diastolic dysfunction developed frequently after the initiation of trastuzumab. 44 However, the biologic mechanisms underlying this observation are unknown, and no direct evidence was found in the included papers to confirm this hypothesis. In the largest trial included in our metaanalysis (APHINITY), although there was an excess of moderateesevere HF with impaired systolic left ventricular function in the pertuzumab group, there was no difference in the rate of asymptomatic/minimally symptomatic LVSD between the pertuzumab and placebo groups. This unexpected finding warrants further research to understand how pertuzumab leads to an excess of HF but with no excess of asymptomatic/minimally symptomatic HF with reduced LVEF. Furthermore, this finding highlights the importance of clinical outcomes over surrogate outcomes because surrogate outcomes may not always correlate with clinical events, and clinical events are ultimately what most affects patients' well-being.
The definition of HF varied between the studiesdsome have included only patients with NYHA class III-IV, whereas others have also included NYHA class I-II, and some did not explicitly mention NYHA class, but used grade 3 or more HF according to the National Cancer Institute (CTCAE). Consequently, this variability may have led to an underestimate of the effect of HF, since not all degrees of NYHA class were included. The other concern is that patients with cancer can have symptoms that could erroneously be attributed to HF, and this might lead to overestimation of HF events. On the other hand, although there was one study that differed in the definition of asymptomatic/minimally symptomatic LVSD, this study was excluded in the sensitivity analysis for TDM-1, with no significant change in the effect estimate.
The event rates reported in the studies we identified were lower than those that have been reported previously in trastuzumab studies. Although we found that pertuzumab (generally used in combination with trastuzumab) was associated with an absolute risk of 8 HF cases per 1000 patients, the HF risk reported in other studies of trastuzumab monotherapy was between 24 and 30 cases per 1000 patients). 14,45 Similarly, the incidence of asymptomatic/minimally symptomatic LVSD in the control group treated only with trastuzumab was 3.1% in our study, a proportion much lower than that previously reportedd7.66% to 11.2%din different meta-analyses. 45,46 The difference may be because the patients in the population represented in our pooled data are highly selected and at low cardiac risk.

Strengths and limitations
Our study represents the largest pooled experience from randomized clinical trials of pertuzumab. However, this review has several limitations. First, the outcomes of our analysis were not the primary endpoints of the included studies; in fact, they were reported as adverse events. Second, not all cardiac adverse effects of interest were reported in the trials (e, cardiac death), restricting our analysis to 2 main outcomes. We are uncertain whether other cardiac outcomes or indicators of cardiac function, such as diastolic echocardiographic parameters, differed between pertuzumab recipients and controls. Finally, although we specifically included randomized trials, as this study design minimizes the risk of bias and confounding, a number of other phase II nonrandomized trials evaluating pertuzumab monotherapy have also provided data about cardiotoxicity but were not included.

Implications
Our findings suggest that surveillance for HF may be important in individuals treated with pertuzumab, and that LVEF alone may not be sufficient to identify those at risk of developing HF. Other echocardiographic tools, including global longitudinal strain and diastolic function assessment, and/or monitoring of cardiac biomarkers, such as troponin and N-terminal prohormone of brain natriuretic peptide (NTproBNP), have shown promise in the early detection of cardiotoxicity. 47,48 Further research is needed to determine their value in identifying those who will develop HF related to pertuzumab use.

Conclusion
In patients with HER2 overexpressing cancers who took part in clinical trials and underwent frequent cardiac monitoring, pertuzumab use was associated with an increased risk of HF but was not associated with an increased risk of asymptomatic LVSD. The incidence of HF was very low in these trials; therefore, despite the increased risk of HF, we do not recommend against using pertuzumab in eligible patients with low cardiac risk.