Abstract
Background
Breast cancer is the most common cancer in women. Although anti-human epidermal growth factor receptor 2 (HER2) therapy is effective in patients with HER2-positive breast cancer, it occasionally induces cancer therapy-related cardiac dysfunction (CTRCD). This study aimed to determine the factors associated with CTRCD in patients with HER2-positive breast cancer treated with trastuzumab.
Methods and Results
We retrospectively analyzed the data of 286 patients with breast cancer who received trastuzumab. Accordingly, patients were categorized into CTRCD (+) and CTRCD (−) groups to elucidate the factors associated with cardiotoxicity. The median age of patients was 54 years. CTRCD was observed in 13 (4.5%) patients, and 2 (0.7%) patients had severe symptomatic heart failure, with a New York Heart Association class ≥III. All patients with CTRCD had a history of epirubicin use, and patients receiving both trastuzumab and pertuzumab had significantly higher rates of CTRCD (P=0.003); the history of pertuzumab administration was an independent predictor of CTRCD development. The median duration from trastuzumab initiation to CTRCD onset and from CTRCD onset to recovery was 244 (interquartile range [IQR] 164–333) and 122 ([IQR] 38–186) days, respectively.
Conclusions
In HER2-positive breast cancer, CTRCD occurred more frequently in patients using anthracycline followed by trastuzumab and pertuzumab simultaneously. Systolic dysfunction was reversible in all patients, and normalization of cardiac function took approximately 4 months from CTRCD onset.
Key Words: Breast cancer, Cancer therapy-related cardiac dysfunction, Human epidermal growth factor receptor 2, Pertuzumab, Trastuzumab
Breast cancer is the most common cancer among women and is classified based on hormone receptors, including estrogen and progesterone receptors as well as human epidermal growth factor receptor 2 (HER2). In 2020, breast cancer accounted for incidence and mortality rates of 24.5% and 15.5%, respectively. Furthermore, the incidence of breast cancer is expected to continue to increase.1 HER2 gene amplification or HER2 protein overexpression occurs in 14.9–28.2% of breast cancers, and the prognosis for patients with HER2-positive breast cancer without anti-HER2 therapy is poor.2 HER2 targeting therapy improves outcomes, and several anti-HER2 agents are currently in clinical use.3 Trastuzumab, which is the most common monoclonal antibody that targets HER2, has been shown to be very effective in treating HER2-positive breast cancer. Moreover, the disease-free and overall survival rates have improved by 34–50% and 30–34%, respectively, with the administration of trastuzumab combined with standard chemotherapy.4 However, trastuzumab is known to cause cardiotoxicity, asymptomatic cardiac dysfunction, and congestive heart failure (CHF), particularly in cases in which an anthracycline is used simultaneously or sequentially.5 Furthermore, pertuzumab, a monoclonal antibody targeting HER2 has recently been recommended in combination with trastuzumab, as a dual HER2 inhibition therapy. However, a report from the Cleveland Clinic has demonstrated that anti-HER2 therapy occasionally induces cancer therapy-related cardiac dysfunction (CTRCD) and dual anti-HER2 therapy results in hemodynamic abnormalities and systolic dysfunction.6
In the present study, we investigated the factors associated with the development and course of CTRCD in patients with HER2-positive breast cancer treated with trastuzumab according to the prior use of anthracycline and combination therapy.
Methods
Study Design and Population
We retrospectively reviewed the medical records of consecutive patients for whom trastuzumab was first prescribed for HER2-positive breast cancer at Nagoya University Hospital from January 2009 to March 2022 and who had undergone ultrasound echocardiography (UCG) evaluations more than 4 times per year (at baseline performed before trastuzumab was administered and at 3, 6, and 12 months).
Collected Data
The following data at the point trastuzumab was administered were collected: age, body mass index, smoking status, comorbidities, medication history, details regarding the breast cancer, preceding or combined therapy, vital signs (blood pressure and heart rate), and clinical test results (laboratory measurements, electrocardiogram, chest radiography and UCG). Comorbidities were noted based on the presence of a prior diagnosis or receipt of therapy thereof, which included hypertension, dyslipidemia, diabetes, coronary artery disease (CAD), and atrial fibrillation.
Assessment and Cancer Details
Details regarding the breast cancer included advanced or stage IV cancer, recurrence, site, hormone receptor status, and preceding or combined therapy. HER2-positivity was defined as 3+ staining on immunohistochemistry or 2+ staining with HER2 gene amplification based on fluorescence in situ hybridization. Estrogen and progesterone hormone receptor positivity was defined as an Allred score >2.7,8 The preceding or combined therapy included surgical and radiation therapy, as well as anthracycline and other cytotoxic regimens.
Trastuzumab was administered to patients as follows: (1) initially received trastuzumab at 8 mg/kg body weight, followed by 6 mg/kg every 3 weeks; or (2) initially received trastuzumab at 4 mg/kg, followed by 2 mg/kg per week. Trastuzumab was administered as adjuvant, neo-adjuvant, or progression-inhibition therapy. The initial dose of pertuzumab was 840 mg, followed by 420 mg every 3 weeks with trastuzumab.
Definition of CTRCD
CTRCD was defined as a ≥10% decline in left ventricular ejection fraction (LVEF) to a value <50% or symptomatic heart failure with New York Heart Association (NYHA) classification ≥III, which corresponds to asymptomatic or symptomatic CTRCD of moderate or greater in the 2022 European Society of Cardiology (ESC) guideline.9 Accordingly, patients were categorized into CTRCD (+) or CTRCD (−) groups. Recovery from cardiotoxicity was defined as >50% increase in LVEF after cardiotoxicity. Cardiac adverse events in the CTRCD group were then graded according to the Common Terminology Criteria for Adverse Events (CTCAE; version 5.0).
Outcome
The primary outcome was incidence of CTRCD in patients with HER2-positive breast cancer treated with trastuzumab. The secondary outcomes were the factors associated with the development of CTRCD and the duration from trastuzumab administration to CTRCD development and recovery times from CTRCD onset.
Statistical Analyses
Continuous data are presented as median with interquartile range (IQR) and were compared using the Wilcoxon rank-sum test. Categorical variables are expressed as frequency (percentage) and were compared using the chi-square or Fisher’s exact tests.
The cumulative incidence of all-cause mortality based on the occurrence of CTRCD risks was calculated, and differences between the time-to-event curves were compared using log-rank statistics. In multivariate analysis for the CTRCD, odds ratios (ORs) were obtained from logistic regression analysis using registered risk factors, such as age, hypertension, and prior radiotherapy to the left chest, as predictors.10–12 JMP software (version 14.2.0; SAS Institute Inc., Cary, NC, USA) was used for the statistical analyses. Statistical significance was set at P<0.05. Figures were generated using Prism (GraphPad Software, San Diego, CA, USA).
Ethics Approval
This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Nagoya University Graduate School of Medicine and adhered to the principles of the Declaration of Helsinki (September12, 2019/No. 2019-0176).
Consent to Participate
Participant consent was obtained using an ‘opt-out’ method.
Results
Patient Demographic and Clinical Characteristics at Baseline
A flow diagram depicting the enrolment process of patients is shown in Figure 1. During the study period, 400 patients with breast cancer were treated with trastuzumab, and 286 were included in this study. Of these patients, 114 were excluded for the following reasons: (1) received trastuzumab beyond the observation period (n=40); (2) received trastuzumab at another hospital (n=9); (3) had deficient UCG data (n=56); (4) had an LVEF of <55% at baseline (n=3); (5) received epirubicin within 1 year following trastuzumab administration (n=3); (6) received doxorubicin before trastuzumab administration (n=2); and (7) had a history of cardiomyopathy (n=1).
Figure 1.
Study protocol. Of the 400 patients who received trastuzumab, 114 were excluded for the following reasons: (1) received trastuzumab beyond the observation period (n=40); (2) received trastuzumab at another hospital (n=9); (3) had deficient ultrasound echocardiography (UCG) data (n=56); (4) had a left ventricular ejection fraction (LVEF) of <55% at baseline (n=3); (5) received epirubicin within 1 year following trastuzumab administration (n=3); (6) received doxorubicin before trastuzumab administration (n=2); and (7) had a history of cardiomyopathy (n=1). CTRCD, cancer therapy-related cardiac dysfunction.
Overall, 279 patients received trastuzumab every 3 weeks, and 7 received it every week. Trastuzumab was administered as adjuvant, neo-adjuvant, and progression-inhibition therapies in 175, 81, and 30 patients, respectively.
The median follow-up period was 2,137 ([IQR] 1,288–3,445) days. Baseline demographic characteristics and the clinical data of patients are presented in Table 1. The median age was 54 ([IQR] 46–64) years. Among the patients, 46 (16.1%), 44 (15.4%), 21 (7.3%), 4 (1.4%), and 3 (1.0%) patients had hypertension, dyslipidemia, diabetes, CAD, and atrial fibrillation, respectively, as comorbidities. Furthermore, 29 (10.1%), 6 (2.1%), and 32 (11.2%) patients were taking angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin II receptor blockers (ARBs), β-blockers (βBs), and calcium-channel blockers, respectively. Twenty (7.0%) patients had advanced stage IV cancer, and 22 (7.9%) had recurrent cancer. Prior to or in combination with trastuzumab, surgery and radiotherapy were performed in 271, and 122 cases, respectively. Epirubicin was administered with a total dose of 360.7 ([IQR] 354.2–375.3) mg/m2. Moreover, 74 patients received pertuzumab plus taxane, and 105 received taxane as chemotherapy plus trastuzumab. Comparing the CTRCD (+) and CTRCD (−) groups, statistically significant differences were not observed in the body mass index, comorbidities, current medications, and preceding treatments such as surgery and radiation to the chest. No statistically significant differences were found in epirubicin dosage between the CTRCD (+) and CTRCD (−) groups, and significantly more patients in the CTRCD (+) group received prior anthracycline therapy (P=0.020) and combination therapy with pertuzumab (P=0.003) than those in the CTRCD (−) group.
Table 1.
Patient Profiles at Baseline
| All (n=286) |
CTRCD (+) (n=13) |
CTRCD (−) (n=273) |
P value | |
|---|---|---|---|---|
| Age (years) | 54 [46–64] | 58 [48–65] | 54 [46–64] | 0.655 |
| Sex, female | 285 (99.7) | 13 (100) | 272 (99.6) | 0.827 |
| BMI (kg/m2) | 21.5 [19.5–24.2] | 21.4 [19.8–23.4] | 21.6 [19.6–24.3] | 0.980 |
| Current smoking | 12 (6.5) | 0 (0.0) | 12 (6.8) | 0.419 |
| SBP (mmHg) | 126 [113–137] | 131 [121–143] | 125 [112–137] | 0.083 |
| HR (beats/min) | 83 [74–92] | 89 [81–97] | 82 [74–91] | 0.069 |
| Comorbidity | ||||
| HTN | 46 (16.1) | 1 (7.7) | 45 (16.5) | 0.399 |
| DL | 44 (15.4) | 2 (15.4) | 42 (15.4) | 1.000 |
| Diabetes | 21 (7.3) | 0 (0.0) | 21 (7.7) | 0.299 |
| Coronary artery disease | 4 (1.4) | 0 (0.0) | 4 (1.5) | 0.660 |
| Atrial fibrillation | 3 (1.0) | 0 (0.0) | 3 (1.1) | 0.704 |
| Medication | ||||
| ACE-I/ARB | 29 (10.1) | 0 (0.0) | 29 (10.6) | 0.215 |
| βB | 6 (2.1) | 0 (0.0) | 6 (2.2) | 0.589 |
| Calcium channel blocker | 32 (11.2) | 2 (15.4) | 31 (11.4) | 0.682 |
| Diuretic | 8 (2.8) | 0 (0.0) | 8 (2.9) | 0.531 |
| Aspirin | 3 (1.0) | 0 (0.0) | 3 (1.1) | 0.704 |
| Oral anticoagulant | 3 (1.0) | 0 (0.0) | 3 (1.1) | 0.704 |
| Statin | 35 (12.2) | 2 (15.4) | 33 (12.9) | 0.723 |
| Insulin | 5 (1.7) | 0 (0.0) | 5 (1.8) | 0.623 |
| Oral hypoglycemic agent | 14 (4.9) | 0 (0.0) | 14 (5.1) | 0.403 |
| Cancer details | ||||
| Stage IV | 20 (7.0) | 0 (0.0) | 20 (7.4) | 0.311 |
| Recurrence | 22 (7.9) | 1 (7.7) | 21 (7.9) | 0.982 |
| Position | ||||
| Right breast | 125 (43.7) | 5 (38.5) | 120 (44.0) | 0.696 |
| Left breast | 146 (51.0) | 8 (61.5) | 138 (50.5) | 0.439 |
| Bilateral breast | 11 (3.8) | 0 (0.0) | 11 (4.0) | 0.461 |
| Hormone receptor | ||||
| ER positive | 172 (60.1) | 8 (61.5) | 164 (60.1) | 0.916 |
| PgR positive | 126 (44.1) | 5 (38.5) | 121 (44.3) | 0.678 |
| HER2 positive | 286 (100) | 13 (100) | 273 (100) | NA |
| Laboratory measurements | ||||
| Alb (g) | 4.0 [3.7–4.2] | 4.1 [3.8–4.2] | 4.0 [3.7–4.2] | 0.984 |
| Cre (mg) | 0.56 [0.50–0.64] | 0.56 [0.54–0.65] | 0.56 [0.50–0.64] | 0.712 |
| Hb (g/dL) | 11.1 [10.1–12.3] | 10.5 [9.5–12.0] | 11.1 [10.1–13.4] | 0.439 |
| LDL-C (g/dL) | 119 [98–144] | 141 [138–175] | 119 [98–143] | 0.082 |
| Chest radiography | ||||
| CTR (%) | 45.4 [42.3–49.4] | 43.7 [41.3–50.3] | 45.5 [42.4–49.5] | 0.656 |
| Electrocardiogram | ||||
| QRS (ms) | 93 [87–98] | 87 [83–94] | 93 [87–98] | 0.055 |
| QTc (ms) | 421 [407–434] | 417 [408–431] | 421 [407–434] | 0.692 |
| Ultrasound echocardiography | ||||
| LVEF (%) | 67.3 [63.6–70.6] | 66.2 [62.9–69.5] | 67.4 [63.7–70.7] | 0.281 |
| LVDd (mm) | 45.0 [42.4–47.5] | 45.4 [42.4–49.8] | 45.0 [42.4–47.5] | 0.570 |
| LVDs (mm) | 28.1 [26.0–30.5] | 28.3 [26.2–33.4] | 28.1 [26.0–30.5] | 0.310 |
| E/e′ | 9.4 [7.5–11.3] | 8.9 [8.1–11.3] | 9.4 [7.5–11.3] | 0.770 |
| Prior/combination treatment | ||||
| Operation | 271 (94.8) | 13 (100) | 258 (94.5) | 0.385 |
| Chest radiation | 122 (42.7) | 5 (38.5) | 117 (42.9) | 0.754 |
| L-radiation | 69 (24.1) | 3 (23.1) | 66 (24.2) | 0.928 |
| R-radiation | 50 (17.5) | 2 (15.4) | 48 (17.6) | 0.839 |
| B-radiation | 2 (0.7) | 0 (0.0) | 2 (0.7) | 0.757 |
| Prior chemotherapy | ||||
| EC | 145 (50.7) | 9 (69.2) | 136 (49.8) | 0.171 |
| FEC | 36 (12.6) | 2 (15.4) | 34 (12.5) | 0.756 |
| EC+PTX/DTX | 2 (0.7) | 0 (0.0) | 2 (0.7) | 0.757 |
| FEC+PTX/DTX | 22 (7.7) | 2 (15.4) | 20 (7.3) | 0.287 |
| EPI | 205 (71.7) | 13 (100) | 192 (70.3) | 0.020* |
| Cumulative dose of EPI (mg/m2) | 360.7 [354.2–375.3] | 361.1 [356.6–381.5] | 360.7 [354.1–376.6] | 0.936 |
| interval from EPI to Tmab (days) | 21 [15–28] | 21 [14–29] | 21 [15–28] | 0.740 |
| Combination chemotherapy | ||||
| PER+PTX/DTX | 74 (25.9) | 8 (61.5) | 66 (24.2) | 0.003* |
| PTX/DTX | 105 (36.7) | 3 (23.1) | 102 (37.4) | 0.297 |
Unless indicated otherwise, data are presented as n (%), or median [IQR]. Missing data (n): current smoking (100); SBP (2); HR (2); stage IV (1); reccurence (6); LDL (190); CTR (55); QRS (35); QTc (35); E/e′ (10); cumulative dose of EPI (82); interval from EPI to Tmab (82). *P<0.05. ACE-I, angiotensin-converting enzyme inhibitor; Alb, albumin; ARB, angiotensin II receptor blocker; βB, β-blocker; BMI, body mass index; B-radiation, radiation on both sides of chest; Cre, creatinine; CTR, cardiothoracic ratio; CTRCD, cancer therapy-related cardiac dysfunction; DL, dyslipidemia; EC, epirubicin+cyclophosphamide; EPI, epirubicin; ER, estrogen receptor; FEC, epirubicin+cyclophosphamide+5-fluorouracil; Hb, hemoglobin; HER2, human epidermal growth factor receptor 2; HR, heart rate; HTN, hypertension; LDL-C, low-density lipoprotein cholesterol; L-radiation, radiation on the left chest; LVDd, left ventricular end-diastolic diameter; LVDs, left ventricular end-systolic diameter; LVEF, left ventricular ejection fraction; NA, not applicable; PER, pertuzumab; PgR, progesterone receptor; PTX/DTX, paclitaxel/docetaxel; QTc, corrected QT; R-radiation, radiation on the right chest; SBP, systolic blood pressure; Tmab, trastuzumab.
In multiple logistic regression analysis, pertuzumab was an independently associated factor for the development of CTRCD after adjustment for other conventional CTRCD risk factors, including age, hypertension, and radiation therapy on the left chest (Table 2). These results were similar when analyzed for the group of patients with a history of anthracycline use only (n=205) (Supplementary Table 1).
Table 2.
Multiple Logistic Regression Analysis for CTRCD (n=286)
| Variable | Univariate analysis | Multivariate analysis† | ||||||
|---|---|---|---|---|---|---|---|---|
| OR | 95% CI | β | P value | OR | 95% CI | β | P value | |
| Age | 1.007 | 0.96–1.057 | 0.007 | 0.760 | – | – | – | – |
| HTN | 0.422 | 0.054–3.329 | –0.862 | 0.413 | – | – | – | – |
| L-radiation | 1.000 | 0.267–3.746 | 0.000 | 1.000 | – | – | – | – |
| PER | 4.730 | 1.498–14.943 | 1.554 | 0.008 | 4.700 | 1.48–14.92 | 1.548 | 0.009 |
†The final model included all univariate variables. CI, confidence interval; OR, odds ratio. Other abbreviations as in Table 1.
Anthracycline could not be included in the logistic regression analysis because anthracycline was used for all patients in the CTRCD (+) group; however, pertuzumab was significantly associated with CTRCD regardless of anthracycline use (odds ratio 6.277; 95% confidence interval 1.946–20.252; P=0.002) in the Mantel-Haenszel test.
Kaplan-Meier Survival Analysis for the All-Cause Mortality Rate
Although treatment strategies and prognosis varied greatly depending on the advanced stage of breast cancer, CTRCD onset had no prognostic impact (log-rank test, P=0.714)(Supplementary Figure).
LVEF Fluctuations
The LVEF fluctuations are shown in Figure 2. A statistically significant difference was not observed in the LVEF at baseline between the CTRCD (+) and CTRCD (−) groups (P=0.281), with median percentages of 66.2% and 67.4%, respectively. However, LVEF in the CTRCD (+) group was 60.2% at 3 months, 49.6% at 6 months, and 51.9% at 12 months, while LVEF in the CTRCD (−) group was 67.4% at 3 months, 65.1% at 6 months, and 64.7% at 12 months.
Figure 2.
Ejection fraction fluctuation. This shows the change in left ventricular ejection fraction (LVEF) over time in the CTRCD (+) and CTRCD (−) groups. A statistically significant difference has not been observed in the LVEF at baseline between the CTRCD (+) and CTRCD (−) groups, with median percentages of 66.2% and 67.4%, respectively. However, the LVEF in the CTRCD (+) and CTRCD (−) groups is statistically significantly different at 3 (60.2%; 65.8% [P<0.001]), 6 (49.6%; 65.1% [P<0.001]), and 12 months (51.9%; 64.7% [P<0.001]), respectively. CTRCD, cancer therapy-related cardiac dysfunction.
Summary of Patients With CTRCD
A summary of patients with CTRCD is shown in Table 3. CTRCD was observed in 13 (4.5%) patients. Furthermore, 2 (0.7%) patients had severe symptomatic heart failure with NYHA ≥III. Cardiac dysfunction improved in all cases; the duration from trastuzumab administration to CTRCD was 244 ([IQR] 164–333) days, and the duration from CTRCD to recovery was 122 ([IQR] 38–186) days. Three patients had comorbidities: 1 patient was treated for hypertension, and 2 patients were treated for dyslipidemia. Supplementary Table 2 shows the prescription history of cardioprotective drugs and diuretics. Of the 2 patients with NYHA ≥III, 1 initially required intravenous furosemide and was subsequently administered an ACE-I, βB, loop diuretic, and mineralocorticoid receptor antagonist (MRA). The patient was discharged on the ninth day of hospitalization. The second patient initially required intravenous furosemide and was administered an MRA, loop diuretic, ACE-I, and βB, sequentially. The patient was discharged on the 14th day of hospitalization. The median LVEF at baseline and at the point of CTRCD was 66.2%, and 47.0%, respectively. Furthermore, improvement in cardiac dysfunction was confirmed in all patients. In the 13 cases of CTRCD, only 3 patients were able to complete the initial planned treatment with trastuzumab, and none experienced a cancer recurrence during the median observation period of 1,554 ([IQR] 1,253–2,674) days.
Table 3.
Summary of CTRCD
| Case no. |
Age (years) |
BMI | Comorbidity | Administration of trastuzumab post CTRCD |
Total cycle of trastuzumab |
Total dose of anthracycline (mg/m2) |
EF at baseline (%) |
EF at CTRCD onset (%) |
ΔEF (%) | Time from trastuzumab to CTRCD (days)† |
Time from CTRCD to recovery (days)‡ |
CTCAE§ | Medication for CTRCD |
Recovery | NYHA ≥3 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 35 | 18.5 | (−) | Discontinuation | 6 | 367 | 56.8 | 47.8 | –15.8 | 126 | 21 | Grade 1 | None | ○ | – |
| 2 | 61 | 22.8 | (−) | Completed | 18 | 411 | 65.4 | 49.0 | –25.1 | 244 | 63 | Grade 1 | None | ○ | – |
| 3 | 38 | 19.8 | (−) | Completed | 18 | 396 | 64.2 | 47.0 | –26.8 | 364 | 21 | Grade 1 | None | ○ | – |
| 4 | 66 | 19.2 | (−) | Discontinuation | 11 | 364 | 62.1 | 47.0 | –24.3 | 267 | 133 | Grade 1 | βB | ○ | – |
| 5 | 57 | 20.4 | HTN | Discontinuation | 8 | 411 | 66.9 | 35.0 | –47.7 | 147 | 175 | Grade 2 | ACE-I, βB | ○ | – |
| 6 | 68 | 27.6 | (−) | Discontinuation | 12 | 357 | 70.6 | 31.2 | –55.8 | 322 | 232 | Grade 3 | ACE-I, βB, MRA | ○ | ○ |
| 7 | 59 | 23.3 | DL | Discontinuation | 12 | 358 | 66.3 | 48.4 | –26.9 | 91 | 42 | Grade 1 | ACE-I, βB | ○ | – |
| 8 | 71 | 21.4 | DL | Discontinuation due to another adverse event |
17 | 361 | 66.2 | 42.8 | –35.3 | 203 | 33 | Grade 1 | βB | ○ | – |
| 9 | 58 | 26.7 | (−) | Discontinuation | 10 | 343 | 63.7 | 35.2 | –44.7 | 261 | 169 | Grade 1 | ACE-I, βB, MRA | ○ | – |
| 10 | 51 | 19.8 | (−) | Discontinuation | 14 | 362 | 72.6 | 33.2 | –54.3 | 343 | 196 | Grade 1 | ACE-I, βB (MRA) | ○ | – |
| 11 | 48 | 23.3 | (−) | Discontinuation due to another adverse event |
11 | 181 | 60.0 | 48.8 | –18.7 | 181 | 196 | Grade 1 | ACE-I, βB | ○ | – |
| 12 | 63 | 23.6 | (−) | Completed | 18 | 356 | 70.9 | 49.6 | –30.0 | 231 | 84 | Grade 1 | None | ○ | – |
| 13 | 47 | 20.4 | (−) | Discontinuation | 16 | 357 | 68.4 | 30.3 | –55.7 | 382 | 122 | Grade 3 | ACE-I, βB, MRA | ○ | ○ |
†Median [IQR], 244 [164–333]. ‡Median [IQR], 122 [38–186]. §Grading of heart failure based on Common Terminology Criteria for Adverse Events (CTCAE; version 5.0). EF, ejection fraction; MRA, mineralocorticoid receptor antagonist; NYHA, New York Heart Association. Other abbreviations as in Table 1.
Discussion
We identified the duration from trastuzumab administration to CTRCD development or its onset to recovery in patients with HER2-positive breast cancer treated with trastuzumab. In this retrospective study, cardiac function declined within 1 year of trastuzumab administration in 13 (4.5%) patients, and cardiotoxicity occurred in patients who received anthracycline previously, and more frequently in those who concurrently received pertuzumab.
Trastuzumab-Induced Cardiotoxicity
Trastuzumab is a monoclonal antibody targeting HER2 and effectively improves the prognosis of patients with HER2-positive breast cancer. Cardiotoxicity is regarded as a significant adverse event, although the effects are usually reversible.13,14 While the pathological mechanism of trastuzumab-induced cardiotoxicity has not been completely clarified, the mechanism for the action of HER2 is reported to involve the activation of signal pathways on the myocardial cell membrane. First, neuregulin-1 (NRG-1), a member of the epidermal growth factor-like family, binds to and activates HER4 to bind to HER2. This leads to the activation of cell survival signals such as mitogen-activated protein kinase/extracellular signal-regulated kinase, phosphoinositide 3 kinase/AKT, and focal adhesion kinase/Src. Consequently, the myofibrillar structure is stabilized, mitochondrial changes are induced, reactive oxygen species (ROS) are reduced, and sarcomere structure and function are maintained, leading to cell survival. Other mechanisms, such as the mediation of antibody-dependent cell-mediated cytotoxicity (ADCC), inhibition of angiogenesis, degradation of HER2 receptors, and inhibition of DNA repair, are also reported. Trastuzumab binds to HER2 and blocks its downstream signaling pathway, inducing apoptosis and causing cardiac dysfunction.15–17
Combined Trastuzumab- and Anthracycline-Induced Cardiotoxicity
Sequential or concurrent use of trastuzumab and anthracyclines is associated with an increased risk of cardiotoxicity. The mechanism is considered to be the dependence of anthracycline stress on the HER2 pathway and the involvement of angiopoietin (ANG) II. First, the administration of anthracyclines increases ROS production, upregulates ANG II expression, and induces apoptosis, although some cells undergo repair. During this process, the HER signaling pathway is stimulated and upregulated as a signal to promote cell survival; however, the increased dependence on HER2 makes the cells more susceptible to damage caused by HER2 inhibition. Second, ANG II, whose expression is upregulated by anthracyclines, is an inhibitor of NRG-1 and therefore inhibits the binding of NRG-1 to the HER family, suppressing the cell survival signaling pathway. Thus, inhibition of the HER2 pathway further increases ROS production, induces cardiomyocyte apoptosis, and reduces myocardial contractility.16–19
When trastuzumab is administrated as a single agent, cardiotoxicity is reported to be 2.6–7%; the cardiotoxicity risk of trastuzumab combined with standard chemotherapy with or without anthracycline is reported as 7.7–27.0%,5,20–22 and development of CHF associated with the combination of trastuzumab and standard chemotherapy is reported as 1.44%, which is 3 times more than that of standard therapy alone.23
Dual-HER2 Therapy-Induced Cardiotoxicity
Dual HER2 inhibition regimens, such as lapatinib/pertuzumab/neratinib plus trastuzumab, in the treatment of HER2-positive breast cancer are more effective than single-targeted treatments solely comprising trastuzumab.24 Pertuzumab is efficacious in both metastatic and early stage breast cancers. Pertuzumab is a cytotoxic, recombinant, humanized monoclonal antibody that binds to the extracellular dimerization domain II of HER2, at an epitope different from that of trastuzumab, and inhibits the heterodimerization of HER2, with other HER family members, blocking downstream tumor signaling of other HER family members and enhancing ADCC-mediated antitumor effects. As pertuzumab acts in a complementary manner to trastuzumab, the combination of these 2 drugs has been postulated to synergistically inhibit the growth of HER2-positive tumor cells, which may induce more myocardial injury.15,25,26
Several large clinical trials of HER2 dual therapy (CLEOPATRA, NeoSphere, and TRYPHAENA) reported that the addition of pertuzumab to trastuzumab significantly improved disease-free survival, while cardiac toxicity was not significantly increased compared with trastuzumab alone.27–30 Canino et al. reported no significant difference in cardiotoxicity between treatment with standard chemotherapy and trastuzumab vs. standard chemotherapy and trastuzumab plus pertuzumab.31
However, Cai et al. reported that dual-targeted therapy including trastuzumab and pertuzumab is an effective regimen with an improved survival rate compared with other treatment regimens for breast cancer. Nonetheless, they have cautioned that this combination has demonstrated the highest cardiac event risk.32 In the Adjuvant Pertuzumab and Herceptin IN Initial Therapy in Breast Cancer (APHINITY) study, a phase III trial involving 4,805 patients, the findings demonstrated no significant increase in the incidence of cardiac dysfunction, due to the administration of pertuzumab plus trastuzumab (3.5%), as opposed to that of a placebo plus trastuzumab (3.2%); however, symptomatic heart failure incidence was higher in the pertuzumab group 16 (0.7%) than in the placebo group 6 (0.2%).14 Multivariate analysis revealed a 3.92-fold higher risk of cardiac dysfunction for anthracycline and trastuzumab/pertuzumab with or without radiation compared with radiotherapy alone.33 Another meta-analysis showed that the addition of pertuzumab was associated with an increased risk of heart failure.34 Bao et al. found that the presence of cardiovascular risk increased the incidence of cardiotoxicity when pertuzumab was added to trastuzumab in a real-world clinical setting similar to the CLEOPATORA trial.35
Our results revealed that all patients with CTRCD had a history of receiving anthracycline previously, and some patients receiving a combination of trastuzumab and pertuzumab had a temporary, albeit reversible, decline in cardiac function. The difference was not sufficiently clinically significant to cause major adverse cardiovascular events, such as hospitalization for heart failure. Nonetheless, cardiac dysfunction can lead to several interruptions of antitumor therapy, and may warrant caution, especially in patients with pre-existing myocardial dysfunction. Although some reports deny the risk of cardiotoxicity in pertuzumab, the higher rate of anthracycline use (72%) in this study compared with previous reports may be related to the fact that 5% of the patients had transient CTRCD. Therefore, further studies are needed to confirm this hypothesis.
Study Limitations
This study had some limitations. First, the number of patients enrolled was small, the analysis was performed in a single center, and no data on biomarkers, such as B-type natriuretic peptide, were available. In addition, the involvement of ischemic cardiomyopathy was not differentiated. Owing to our retrospective analysis, selection bias may have occurred, because we included patients who were deemed suitable for trastuzumab administration and who underwent routine UCG. In particular, patients with a poor prognosis may have been excluded from the 1-year follow up, during which UCGs were routinely performed. Last, global longitudinal strain is known to be a highly sensitive early marker of myocardial dysfunction, but was not analyzed due to the lack of data in this study.
Conclusions
In HER2-positive breast cancer, the rate of CTRCD was 4.5%, and CTRCD occurred more frequently in patients using anthracycline followed by trastuzumab and pertuzumab, simultaneously. Systolic dysfunction in all cases was found to be reversible; however, normalization of cardiac function took approximately 1 year from drug initiation and 4 months from CTRCD. In patients with CTRCD with reversible asymptomatic cardiac decompensation only, discontinuation of chemotherapy may lead to stagnation of tumor treatment. We expect that further experience with pertuzumab will clarify the issue of cardiotoxicity. Appropriate monitoring of cardiac function during chemotherapy should help to detect cardiac dysfunction early enough to allow adequate anti-tumor therapy with the necessary intervention.
Disclosures
Y.K.B. and T.M. are members of Circulation Reports’ Editorial Team. R.M. is supported by a grant (No. 22 K08178) from Grant-in-Aid for Scientific Research. T. Kondo has received speaker fees from Abbott, OnoPharma, Otsuka Pharma, Novartis, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, and Abiomed, and is supported by a grant (No. 20 K17112) from Grant-in-Aid for Scientific Research. T.S. received honoraria for writing promotional material for Chugai Pharmaceutical. Y.A. received grants from Chugai Pharmaceutical, Taiho Pharmaceutical, Kyowa Kirin, Daiichi Sankyo, Nippon Kayaku, BeiGene, Mochida Pharmaceutical, and lecture fees from Chugai Pharmaceutical, Eli Lilly, Kyowa Kirin, Ono Pharmaceutical, Nippon Kayaku, Taiho Pharmaceutical, Novartis Pharma, Bayer Holding, Daiichi Sankyo, MSD, SymBio Pharceuticals, Alfresa Pharma, Scohia Pharma, AstraZeneca, Nippon Boehringer Ingelheim, Guardant Health Japan, Hisamitsu Pharmaceutical, Incyte Biosciences, and GlaxoSmithKline. T.M. received lecture fees and unrestricted research grants from Bayer, Daiichi-Sankyo, Dainippon Sumitomo, Kowa, MSD, Mitsubishi Tanabe, Boehringer Ingelheim, Novartis, Pfizer, Sanofi-Aventis, Takeda, Astellas, Otsuka, and Teijin. The other authors have no conflicts of interest to disclose.
IRB Information
The Ethics Committee of Nagoya University Graduate School of Medicine (reference no. 2019-0176).
Supplementary Files
Supplementary Table 1. Supplementary Table 2. Supplementary Figure.
Acknowledgments
This work was supported by the Japan Society for the Promotion of Science (JP) KAKENHI Grant JP22K08178 (to R.M.).
Data Availability
The deidentified participant data will not be shared due to concerns that the information contained could compromise the privacy of research participants.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary Table 1. Supplementary Table 2. Supplementary Figure.
Data Availability Statement
The deidentified participant data will not be shared due to concerns that the information contained could compromise the privacy of research participants.