Cardiac function in women receiving dual anti-Her2 antibodies (trastuzumab and pertuzumab) combined with chemotherapy for breast cancer

Abstract

Background:

Chemotherapy regimens containing a combination of anti-Her2 antibodies are effective but can be associated with cardiac toxicity.

Objectives:

We evaluate the outcome with a particular focus on the cardiac function of patients with Her2 over-expressed breast cancer receiving Chemotherapy regimens combined with Trastuzumab and Pertuzumab in routine clinical practice settings.

Design and methods:

The initial cohort of patients who started Chemotherapy regimens in combination with Trastuzumab and Pertuzumab before September 2019 in four cancer units were reviewed retrospectively. All patients had regular measurements of left ventricular ejection fraction by Doppler ultrasound.

Results:

Sixty-seven patients were identified. Chemotherapy regimens in combination with Trastuzumab and Pertuzumab treatment were administered in the neoadjuvant and palliative settings in 28 (41.8%) and 39 (58.2%) patients, respectively. All patients underwent left ventricular ejection fraction assessment prior to starting Chemotherapy regimens in combination with Trastuzumab and Pertuzumab treatment and at 3 and 6 months later. Subsequently, left ventricular ejection fraction was measured at 9, 12, 15, 18, 21, and 24 months as long as patients are still receiving any of the treatment components. Compared to baseline, the mean left ventricular ejection fraction was not significantly different at any of the subsequent time points (range; decrease by 0.936% to increase by 1.087%: T-test P value not statistically significant for all comparisons). Trastuzumab and Pertuzumab administration was withheld temporarily for two patients due to clinically suspected cardiac toxicity which was excluded upon further investigations. In the neoadjuvant cohort, 82.3% of patients were relapse free at 3 years. The median progression-free survival was 20 months, and the median overall survival was 41 months in the palliative cohort.

Conclusion:

In this cohort describing our limited initial experience, dual anti-Her2 antibodies (Trastuzumab and Pertuzumab) combined with chemotherapy is effective and not associated with significant cardiac toxicity when the left ventricular ejection fraction is measured every 3 months. This may suggest that previous concerns about cardiotoxicity may have been overemphasized. Further studies investigating less frequent left ventricular ejection fraction monitoring may be warranted.

Keywords

cardiac function ejection fraction heart failure pertuzumab trastuzumab

Introduction

HER2 is overexpressed/gene-amplified in 15%–20% of breast cancer (BC).¹ Higher rates of up to 30% have been reported in certain ethnic communities.² Anti-Her2 antibodies such as Trastuzumab (T), Pertuzumab (P), and Ado-Trastuzumab emtansine (TDM-1) improve the outcome of patients with Her2 over-expressed (Her2OE) BC in the adjuvant, neoadjuvant and palliative treatment settings.^3,4 Chemotherapy (C) regimens containing anti-Her2 antibodies are associated with a risk of cardiac toxicity.⁵ More recent land-mark trials confirmed that combining both T and P with chemotherapy regimens improves pathological response rates (RR) and relapse-free survival (RFS) in the neoadjuvant and adjuvant settings and improves progression-free survival (PFS) and overall survival (OS) in the palliative settings.^6–8 The cardiac function was regularly monitored in these trials and the results did not raise additional significant cardiac toxicity for C in combination with TP (CTP) compared to CT.⁹ Patients enrolled in observational and cohort studies more closely reflect women treated in real-life settings and were reported to experience higher rates of T induced cardiac toxicity than those enrolled in randomized controlled trials.¹⁰

The primary aim of our study is to evaluate the cardiac function of patients with Her2 over-expressed (Her2OE) BC receiving C combined with TP in routine clinical practice settings. The secondary aim is to explore the clinical outcome in the neoadjuvant and palliative settings.

Methods

The initial cohort of patients with Her2OE BC who started CTP in standard doses and schedules before September 2019 in the neoadjuvant or palliative settings at four cancer units (three in the Kingdom of Saudi Arabia and one in the United Kingdom) were included. Patients started treatment between April 2015 and March 2019. Those with prior exposure to P were excluded. Patients received subsequent adjuvant Anti-Her2 therapy in the form of T and/or P as appropriate and as per the treating physician’s choice.

All patients underwent a baseline pre-treatment and 3 monthly post-treatment measurements of left ventricular ejection fraction (LVEF) by Doppler ultrasound studies. LVEF values were retrieved retrospectively for a maximum of 24 months post-treatment initiation for each subject as long as the patient is on T and/or P within the line of treatment of interest. LVEF data were not collected in this study context if the line of treatment was changed due to disease progression. Data collection cut-off was April 2021. The endpoints of the study were: (1) Changes in the mean LVEF while the patient is on anti-Her2-based therapy. (2) Decrease in LVEF of ⩾ 10% points from baseline and to below 50%. (3) RR and RFS in the neoadjuvant cohort and PFS and OS in the palliative cohort.

The sample size is not based on statistical considerations but represents the total number of eligible patients who started treatment with the regimens of interest within the defined study period. The study was approved by the king Faisal Specialist Hospital and Research Centre (Jeddah) institutional review board (IRB 2019-72). The informed consent from the patients was waived by the Institutional Review Board/Ethics Committee.

Statistical Considerations: Statistical Package for the Social Sciences Version 20 (SPSS.20) software was used for statistical analysis. The paired sample T-test was used to test the significance of the differences in LVEF while survival outcomes (RFS, PFS, and OS) were estimated using the Kaplan-Meier function.

Results

Sixty-seven female patients were eligible and are the subject of this report. The median age was 50 (21–79) years. Chemotherapy treatment regimens are depicted in Table 1. None of the patients received concomitant anthracycline with TP. In the neoadjuvant cohort and after surgery, combination adjuvant TP was continued in 5 (18%) patients while single agent adjuvant T was continued for the remaining 23 (82%) patients.

Table 1.

Patients and treatment characteristics.

	Number (%)
Female gender	67 (100)
Median age (range) in years	50 (21–79)
Tumor estrogen receptor expression
Positive	33 (49)
Negative	34 (51)
Treatment intention
Neoadjuvant	28 (41.8%)
Palliative	39 (58.2%)
Neoadjuvant chemotherapy regimens	28
AC followed by DTP	16/28 (57%)
DCHP	12/28 (43%)
Palliative chemotherapy regimen	39
DTP	38/39 (97)
NTP	1/39 (3)

AC: doxorubicin and cyclophosphamide; DTP: Docetaxel, Trastuzumab and Pertuzumab; DCHP: Docetaxel, Carboplatin Trastuzumab and Pertuzumab; NTP: Navelbine, Trastuzumab and Pertuzumab.

All patients underwent a baseline LVEF assessment prior to starting CTP treatment and at 3 and 6 months later. Subsequently, LVEF was measured at 9, 12, 15, 18, 21 and 24 months as long as patients are still receiving any of the CTP treatment components and within the data cutoff period (Table 2). LVEF was measured in 11 patients for 24 months.

Table 2.

Baseline and subsequent mean left ventricular ejection fraction.

Follow up time points	Number of patients	Mean baseline LVEF	Mean LVEF at different Follow up time points	Difference	Two-tailed P value of paired T-test
0 month	67	57.5045	///	///	///
3 months	67	57.5045	57.1836	−0.3209	0.310
6 months	67	57.5045	56.9896	−0.51493	0.276
9 months	48	57.7771	58.4667	0.68958	0.368
12 months	31	58.4484	58.6839	0.23548	0.799
15 months	24	57.4750	57.2875	−0.18750	0.839
18 months	22	57.3591	56.4227	−0.93636	0.297
21 months	15	56.9600	58.0467	1.08667	0.414
24 months	11	56.2636	56.3364	0.07273	0.950

LVEF: left ventricular ejection fraction.

Compared to baseline, mean LVEF was not significantly different at any of the subsequent time points (range; decrease by 0.936% to increase by 1.087%) (Table 2). Dual anti-Her2 antibodies (TP) administration was omitted temporarily once for two patients each due to clinically suspected cardiac toxicity which was excluded upon further investigations. One of these patients was treated in the neoadjuvant setting when she presented with subjective cardiac symptoms. TP was omitted for one cycle and appropriate investigations including LVEF excluded cardiac impairment. Subsequently, the patient continued chemotherapy combined with TP in both neoadjuvant and later in adjuvant settings. The second patient was treated in the palliative setting for lung and bone metastases when right-side pleural effusion was identified. TP was omitted for one cycle and then reinstituted as appropriate investigations excluded cardiac diseases. No patient experienced a decrease in LVEF of ⩾ 10% points from baseline and to below 50%.

CTP treatment was administered in the neoadjuvant and palliative settings in 28 (41.8%) and 39 (58.2%) patients, respectively. After a median follow-up of 15 months, two patients (7.1%) treated in the neoadjuvant setting experienced disease relapse and died. The median RFS was not reached (Figure 1). Tumor characteristics and response to neoadjuvant treatment are illustrated in Table 3. Twenty-three patients (59%) treated in the palliative setting experienced progression of disease on CTP treatment and 18 patients died after a median follow-up of 37 months. The median PFS was 20 months (95% confidence interval (CI): 4.5–35.5) and the median OS was 41 months (95% CI: 33.4–48.6).

Figure 1.

Relapse-free survival of patients treated in the neoadjuvant setting (n = 28).

Table 3.

Tumor characteristics and response to neoadjuvant treatment (n = 28 patients).

	All neoadjuvant cohort (%)	Estrogen receptors negative (%)	Estrogen receptors positive
Number	28	14 (50)	14 (50)
Baseline tumor size
Mean (mm)	33.4	38	28.7
Median (mm)	31.5	39	27.5
Range (mm)	11–83	11–83	12–77
Pretreatment axillary LNs involvement	19 (67.9)	10 (71.4)	9 (64.3)
Clinical response
CR	8 (28.6)	6 (42.9)	2 (14.3)
PR	18 (64.3)	7 (50)	11 (78.6)
PD	2 (7.1)	1 (7.1)	1 (7.1)
Surgery
Mastectomy	21 (75)	12 (85.7)	9 (64.3)
BCS	7 (25)	2 (14.3)	5 (35.7)
Pathological response
CR (breast)	16 (57.1)	9 (64.3)	7 (50%)
CR (axilla)	19 (67.9)	12 (85.7)	7 (50)
CR (breast and axilla)	15 (53.6)	9 (64.3)	6 (42.9)

LNs: lymph nodes; CR: complete response; PR: partial response; PD: progressive disease; BCS: breast conservative surgery.

Discussion

Over the recent few years, dual anti-Her2 antibodies (TP) treatment established its role compared to single agent T, raising concerns of increased cardiac toxicity. The results of landmark clinical trials showed that anti-Her2 antibodies and chemotherapy are associated with cardiotoxicity. Therefore, real-world data (RWD) are much needed to highlight, complement, or confirm these results. Our data indicate that the combination of non-anthracyline chemotherapy, T and P (CTP) was not associated with significant changes in cardiac LVEF in the routine clinical practice settings. Our results are not unexpected as landmark trials showed that cardiac toxicity is not increased with CTP compared to CT. In fact, the addition of P to CT was at times associated with slightly more favorable cardiac tolerability compared to CT. Left ventricular systolic dysfunction (LVSD) defined as a reduction of LVEF by ⩾ 10% points from baseline was reported in 4.42% versus 8.31% in the CTP versus CT arms (chemotherapy component was Docetaxel) in metastatic BC (MBC) in the phase 3 CLEOPATRA trial.^11,12

In the adjuvant APHINITY trial, patients with early BC were randomized to standard adjuvant chemotherapy and 1 year of T or the same with 1 year of P. Primary cardiac events were defined as heart failure (HF) of New York Heart Association (NYHA) class III or IV and a substantial decrease in LVEF, defined as a decrease of at least 10% points from baseline and to below 50%, or cardiac death. Secondary cardiac events were defined as asymptomatic or mildly symptomatic (NYHA class II) substantial decrease in LVEF. Primary cardiac events were infrequent (<1%) in both arms (0.7% in CTP versus 0.3% in CT arms). Secondary cardiac events occurred in 2.7% and 2.8% in the CTP and CT arms, respectively.⁷ The neoadjuvant phase II NeoSphere trial randomized patients to CT, CTP, TP or CP. LVSD or ⩾ grade III HF was reported in 0%, 0%, 1%, and 0% while LVSD defined as a reduction of LVEF by ⩾ 10% points from baseline was reported in 1%, 3%, 1% and 1%, respectively.¹³ BERENICE is a non-randomized, phase II study. In the neoadjuvant period, patients received four cycles of an anthracycline-based regimen followed by a Taxane chemotherapy agent (cohort A: weekly paclitaxel and cohort B: three weekly Docetaxel) with four cycles of TP. Patients received four cycles of dose-dense doxorubicin and cyclophosphamide, then 12 doses of standard paclitaxel plus 4 standard T and P cycles. Cohort B patients received 4 standard fluorouracil/epirubicin/cyclophosphamide cycles, then 4 docetaxel cycles with 4 standard T and P cycles. Only three patients (1.5%) in cohort “A” experienced New York Heart Association class III/IV heart failure events.¹⁴

The literature is rich with large reports documenting the cardiac toxicity of T in patients treated in the real-world routine clinical practice setting. For example, 6208 patients received T as part of their anti-cancer therapy experienced a significant short-term risk of cardiovascular diseases (hazard ratio (HR): 4.55; 95% CI: 2.58–8.01) compared to 12,416 matched patients who received chemotherapy without T or any other anti-Her2 treatment.¹⁵ The OHERA prospective observational real-world study followed up 3733 patients with early BC on T-based adjuvant therapy. Symptomatic HF was reported in 2.8% of patients.¹⁶

A UK-based RWD study recorded a decline of LVEF by ⩾10% and a reduction to <50% in 15.72% of 388 patients.¹⁷ Other relatively large RWD studies reported higher rates of cardiac toxicity associated with T in a routine clinical setting. Twenty of the 230 patients (8.7%) had symptomatic cardiotoxicity, defined as a drop in LVEF of at least 10 percentage points and to below 50%, accompanied by symptoms of congestive heart failure. Fifteen out of 20 patients required permanent discontinuation of the treatment according to the guidelines. In the majority of these patients (84.8%) treatment was stopped in the first 6 months and the first LVEF drop was seen at a median of 2.5 months.¹⁸ Other studies that assessed the timing of cardiotoxicity suggest that the first 3 months of T treatment is the most precarious period, counting for most of the cardiotoxic events, and that cardiotoxicity occurring more than 6 months after start of T is rare.¹⁹

In contrast, there are only limited RWD reports with smaller numbers of patients receiving TP investigating cardiac toxicity in this practice setting. This relative scarcity of data was the main impetus that encouraged our group to conduct the study. A group from the Memorial Sloan Kettering Cancer Center (MSKCC), New York, USA reported the cardiac safety data from a single institutional retrospective cohort study of 57 patients with HER2OE BC treated with dose-dense doxorubicin and cyclophosphamide (AC) followed by paclitaxel with TP (THP; AC-THP) in the neoadjuvant setting followed by 1 year of adjuvant anti-HER2 therapy. The median LVEF was 65% at baseline and 64% after AC, and decreased to 60%, 60%, 61%, and 58% after 3, 6, 9, and 12 months. They concluded that the frequency of NYHA class III/IV HF in these patients is comparable to rates reported in trials of sequential doxorubicin and T. They commented that their findings do not suggest an increased risk of cardiotoxicity from TP following a doxorubicin-based regimen.²⁰ Single center RWD from India reported no cases of HF among 45 patients treated with TP in combination with docetaxel and carboplatin in the neoadjuvant setting.²¹ A multi-center retrospective study from China reported no significant difference in the mean LVEF changes from baseline in 72 patients treated with neoadjuvant THP and TCHP (with carboplatin;−5.62% ± 2.26% vs −4.30% ± 3.12%, P = 0.206). Only one patient in the THP group experienced an LVEF decline of ⩾ 10% from baseline. That patient had a history of coronary heart disease and symptomatic treatment normalized the LVEF with the subsequent continuation of anti-Her2 therapy.²²

On one hand, supported by the above results, our observation suggests that anti-Her2-associated cardiac toxicity is mostly caused by T and that the addition of P may not be detrimental in this context. Certainly, a meta-analysis of eight studies comparing T (n = 5122) with combination anti-Her2 agents (n = 7146) confirmed this notion (HR: 1.14; 95% CI: 0.63–2.05).²³ Based on protocols in clinical trials, the US Food and Drug Administration label of T recommends LVEF monitoring prior to initiation of T and every 3 months during treatment. These recommendations have been adopted into clinical practice guidelines by the European Society of Medical Oncology, European Society of Cardiology and American Society of Clinical Oncology.^24–26 Based on our results and those of other groups (as discussed above), we raise questions about the value of strict regular on-treatment monitoring of LVEF every 3 months when HF is not clinically suspected in these patients. A review by a group from the MSKCC Center in New York, listed the historical events that led to the development of these guidelines and highlighted critical knowledge gaps with regard to the benefits of such cardiac monitoring and subsequent intervention. The authors raised the following questions: (1) Is asymptomatic LVEF decline a predictor of HF in these patients? (2) Does intervention for asymptomatic patients prevent subsequent HF? (3) Is there potential harm and cost in over screening? (4) Does Adherence to current guidelines improve outcomes? The review concluded by questioning the utility of the existing one-size-fits-all cardiotoxicity screening.²⁷ The SAFE-HEART is a pilot Study assessing the cardiac safety of anti-Her2 therapy (T±P, or TDM-1) in patients with Her2OE BC and mildly compromised cardiac function (LVEF 40%–49%). The primary endpoint was completion of anti-Her2 therapy without cardiac events or worsening of LVEF. Thirty patients were recruited and started on cardioprotective medications. The study met its primary endpoint with 27 patients (90%) completing therapy without cardiac issues. One patient developed symptomatic HF with no change in LVEF. There were no cardiac deaths. The mean LVEF improved to 52.1% from 44.9% at study baseline, including patients who remained on anti-Her2 therapy, and those who received prior anthracyclines.²⁸

On the other hand, it might be relevant to appreciate that LVEF may have a limited scope of assessing the global contractile cardiac function. Certainly, a recent systematic review of 8 phase 2 and 3 randomized controlled trials (8420 patients) in which the addition of P to T was investigated in patients with stage I-IV Her2OE BC showed that P increased the risk of clinical HF (RR: 1.97; 95% CI: 1.05–3.70]). However, P had no demonstrable effect on asymptomatic and minimally symptomatic LVSD (RR 1.19; 95% CI: 0.89–1.61). The authors acknowledged that their findings were in contrast with those of previous reports that suggested no major risk of cardiotoxicity when P is used alone or in combination with other anti-Her2 agents. They suggested that P may lead to predominantly diastolic, rather than systolic left ventricular dysfunction, hence resulting in HF with preserved ejection fraction. They concluded that their findings highlight the importance of clinical outcomes (such as clinical HF) over surrogate outcomes (such as LVEF) because surrogate outcomes may not always correlate with clinical events, and clinical events are ultimately what most affects patients’ well-being.²⁹ It may be worth mentioning here that false positive echocardiographic results might influence the number of reported cases as there is evidence that echocardiography underestimates LVEF compared to cardiac magnetic resonance imaging (CMR).³⁰

Other echocardiographic tools, including global longitudinal strain and diastolic function assessment, and/or monitoring of cardiac biomarkers, have shown promise in the early detection of cardiotoxicity. Additional echocardiographic parameters are being studied as potential tools to assess the left ventricular (LV) performance in patients undergoing cancer therapy.

Conventional 2D transthoracic echocardiography (TTE) is currently the first choice tool for assessing cardiac function among oncology patients due to its widespread availability, convenience and lack of ionizing radiation exposure. However, a 10% temporal inter- and intra-observer variability in the assessment of LVEF by 2D TTE has been reported compared to 3D TTE with and without contrast in oncology patients.³¹

Myocardial work (MW) reflects LV function, integrating simultaneously LV deformation and LV afterload data. Evaluating LV MW using pressure-strain loop demonstrated that LV mechanics are affected in all MW components during chemotherapy and anti-Her2 treatment in patients with BC. More specifically global work index and global work efficiency had a more pronounced variation in patients with treatment-induced cardiac dysfunction.^32,33

The authors suggested that measuring MW may identify high-risk sub-groups of patients who may benefit of closer monitoring and earlier initiation of cardioprotective therapies, even before LVEF impairment.

Often considered the reference standard for the assessment of cardiac volume and function, CMR with its high spatial and temporal resolution demonstrated superior reproducibility and accuracy compared to other conventional methods.³⁴ Certainly, CMR identified trastuzumab-mediated cardiotoxicity characterized by concurrent LV and right ventricle dysfunction and reversible myocardial inflammation and edema in a randomized controlled clinical trial that recruited 94 patients.³⁵

The extent of myocardial deformation which occurs following the application of contractile and relaxation forces can be quantified as strain, defined as the percent change in myocardial length from the relaxed to the contractile state.

Further research is needed to determine the value of the above different cardiac function assessment tools in monitoring patients receiving anti-Her2 therapies.^36,37

More than half of patients (53.6%) treated in the neoadjuvant setting achieved pCR in the breast and axilla. This is similar to the pCR rate reported in the I-SPY2 trial (56%) and higher than the rates reported in the Neosphere (45.8%) and PEONY (39.9%) trials.^6,38,39 Consistent with findings in previous studies, more pathological complete responses were noted in hormone receptor-negative compared to hormone receptor-positive tumors (64.3% vs 42.9%).^6,40 pCR was associated with better long-term survival outcome in a pooled analysis of 12 international trials including 11,955 patients in particular those with triple-negative BC and in those with HER2-positive, hormone-receptor-negative tumors.⁴¹ Despite the relatively short follow-up of our patients treated in the neoadjuvant setting, the estimated RFS is 82.3% (Figure 1), which is similar to (84%) that was reported in the group of patients who received docetaxel and TP in the Neosphere trial.¹³

The CLEOPATRA trial was a randomized phase 3 trial that evaluated the addition of P to T and docetaxel for patients with HER2OE BC who had not received previous chemotherapy or biologic therapy for their metastatic disease. The median PFS was 18.7 months in both analyses after a median follow-up of 30 and 50 months.^12,42 In patients treated in the palliative setting in our study and after a median follow-up of 37 months, the median PFS was 20 months which is similar to that reported in the CLEOPATRA trial.^12,42 The median OS in our study was 41 months which is less than the 56.5 months reported in the CLEOPATRA trial that had stringent inclusion criteria limited to patients with excellent performance status (0–1) treated in the first-line setting. This difference in survival is not unexpected as patients treated in daily clinical practice are less stringently selected, more heterogeneous, and can have worse performance status compared to those included in landmark registration trials.

Patients treated in routine day-to-day practice can be different from those treated in clinical trials under securitized inclusion and exclusion criteria. Therefore, we investigated the cardiac and clinical outcomes of patients treated in routine practice in an effort to achieve relatively generalizable results that reflect daily practice. This may be considered a point of strength, however, such approach posed a number of limitations including; (a) a relatively small sample size, (b) the study describes our early experience, and thus the sample size is based on the number of patients treated within a specified period of time rather than on formal statistical considerations and (c) the reproducibility of LVEF measurements can not be guaranteed as the study was conducted in four hospitals by different personnel.

Conclusion

In this cohort describing our limited early experience in routine clinical practice, dual anti-Her2 antibodies (TP) combined with chemotherapy is effective and not associated with significant cardiac toxicity. Finding a safe, practical, and cost-effective approach to cardiac monitoring remains elusive until the knowledge gaps in cardio-oncology are addressed and filled or negated through well-designed clinical research. Therefore, further studies investigating less frequent on-treatment LVEF monitoring may be warranted in the absence of clinical HF. In addition, other more specific means of cardiac monitoring may need to be studied.

Footnotes

Acknowledgements

Not applicable.

Declarations

ORCID iD

Jamal Zekri

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