Int J Clin Pharm DOI 10.1007/s11096-015-0070-y
RESEARCH ARTICLE
Trastuzumab induced cardiotoxicity in HER2 positive breast cancer patients attended in a tertiary hospital Lorena Rocha Ayres • Marı´lia Silveira de Almeida Campos • Thais de Oliveira Gozzo • Edson Zangiacomi Martinez • Andrea Queiro´z Ungari • Jurandyr Moreira de Andrade Leonardo Re´gis Leira Pereira
•
Received: 2 May 2014 / Accepted: 13 January 2015 Koninklijke Nederlandse Maatschappij ter bevordering der Pharmacie 2015
Abstract Background The use of trastuzumab is associated with an increased survival rate in HER2 positive breast cancer patients. However, it is related to different levels of cardiotoxicity leading to treatment discontinuation, which can deprive patients of the benefits of this therapy. Objective This study aimed to identify the incidence of trastuzumab induced cardiotoxicity (TIC) and the rate of discontinuation of trastuzumab in clinical practice. Possible factors associated with TIC were also investigated. Setting This study was conducted in the General Hospital of the School of Medicine of Ribeira˜o Preto, University of Sa˜o Paulo. Methods We retrospectively reviewed the medical records of patients without distant metastasis that started trastuzumab between 2007 and 2011 in the tertiary hospital. TIC was defined as symptomatic heart failure or a decrease in left ventricular ejection fraction (LVEF) by C10 % compared to the first
L. R. Ayres (&) M. S. de Almeida Campos L. R. L. Pereira Departamento de Cieˆncias Farmaceˆuticas, Faculdade de Cieˆncias Farmaceˆuticas de Ribeira˜o Preto, Centro de Pesquisa em Assisteˆncia Farmaceˆutica e Farma´cia Clı´nica (CPAFF), Universidade de Sa˜o Paulo, Avenida do Cafe´, s/n8. Campus Universita´rio da USP, Ribeira˜o Preto, SP 14040-903, Brazil e-mail: [email protected] T. de Oliveira Gozzo Escola de Enfermagem de Ribeira˜o Preto, Universidade de Sa˜o Paulo, Ribeira˜o Preto, Brazil E. Z. Martinez J. M. de Andrade Faculdade de Medicina de Ribeira˜o Preto, Universidade de Sa˜o Paulo, Ribeira˜o Preto, Brazil A. Q. Ungari Hospital das Clı´nicas da Faculdade de Medicina de Ribeira˜o Preto, Universidade de Sa˜o Paulo, Ribeira˜o Preto, Brazil
echocardiography measurement or to \50 % at any time. Logistic regression models were used to estimate odds ratios and their respective 95 % confidence intervals for TIC associated with variables such as age, body mass index, smoking history, cardiac risks, type of surgery, presence of positive lymph nodes, chemotherapy regimen and epirubicin cumulative dose. Main outcome measure The incidence and factors associated with TIC and the rate of discontinuation of trastuzumab in clinical practice. Results We analyzed the records of 79 patients. TIC developed in 26 (32.9 %) patients, being the LVEF decline by C10 % observed in 21 (26.6 %), a decreased to \50 % in four (5.1 %) and one (1.2 %) was symptomatic without LVEF decline. Thirteen (16.4 %) patients discontinued permanently the treatment, three (3.8 %) discontinued temporarily and 10 (12.6 %) finished it without interruption. None of the covariates influenced on the incidence of TIC in this population. Conclusion Although most patients finished their treatment, TIC led to trastuzumab discontinuation in a significant proportion of patients suggesting the need of a closer cardiac monitoring. None of the covariates influenced on the incidence of TIC, which can be due to the relatively small sample. Thus, larger scale studies should be conducted in order to establish which specific factors are associated with the development of TIC in order to avoid it. Keywords Brazil Cardiotoxicity HER2 positive breast cancer Trastuzumab
Impact of findings on practice •
There is a need of a closer monitoring to prevent cardiac complications in HER2 positive breast cancer patients who receive trastuzumab.
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•
To outweigh the risks and benefits of therapy, cardiologists and oncologists need to collaborate closely in cases of cancer patients receiving trastuzumab.
Introduction Breast cancer is the second most common type of cancer worldwide, with approximately 1.4 million new cases and 458,000 deaths each year [1]. In Brazil, it was estimated 52,680 new cases in 2012 and approximately 13,000 women died from the disease in 2010 [2, 3]. In 20–30 % of these women with breast cancer, the human epidermal growth factor receptor 2 (HER2) is amplified and/or over expressed, which is known as HER2 positive breast cancer [4, 5]. HER2 or ErbB-2 oncogene encodes a transmembrane glycoprotein receptor and belongs to the ErbB family, which comprises four transmembrane growth factor receptors, HER1, HER2, HER3, and HER4 with intrinsic tyrosine kinase activity [6]. The receptors have partial homology and regulate a wide range of cell functions such as cell growth and survival, differentiation, and migration [7]. This breast cancer subtype is associated with poor prognosis, decreased overall survival and higher probability of disease recurrence [8, 9]. However, with the development of therapies that target HER2, patients have benefited from a reduced risk of recurrence and increased survival rate. Among the therapies that target HER2, trastuzumab is a recombinant humanized monoclonal antibody of the IgG1 type, which binds with high affinity to the extracellular domain of the HER2 receptor [8]. Clinical trials demonstrated that trastuzumab combined with standard chemotherapy is capable to decrease in approximately 50 % the chance of recurrence and 33 % the risk of death [10, 11]. Trastuzumab is generally well tolerated, presenting few side effects. Unfortunately, some patients may experience different levels of cardiotoxicity, leading to treatment discontinuation, which can deprive patients of the benefits of the pharmacotherapy [5]. Trastuzumab induced cardiotoxicity (TIC) is recognized as a symptomatic heart failure (HF) and/or asymptomatic left ventricular ejection fraction (LVEF) reduction, which occurs due to a blockade of HER2 receptor signaling in cardiomyocytes [12]. It is important to highlight that the cardiotoxicity appears to be reversible when trastuzumab is discontinued [12]. Although there are various studies that investigate the incidence of TIC in clinical practice [13–15], they were performed only in more developed countries. To date, there is no published study that addresses the incidence of TIC and discontinuation of trastuzumab among Brazilian patients.
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Aim of the study The main objective of this study is to identify the incidence of TIC and the rate of discontinuation of trastuzumab in HER2 positive breast cancer patients in a Brazilian routine clinical setting. The secondary objective is to investigate possible factors associated with the incidence of TIC since it can be a useful tool to identify patients at higher risks of developing LVEF decrease.
Ethical approval The study protocol was approved by the Research Ethics Committee of the School of Pharmaceutical Sciences of Ribeira˜o Preto, University of Sa˜o Paulo (FCFRP/USP), protocol no. 226/2011.
Methods Setting This retrospective descriptive study was conducted in the Brazilian city of Ribeira˜o Preto, state of Sa˜o Paulo. We reviewed the medical records of HER2 positive breast cancer patients assisted by Brazilian Public Health System called SUS in the outpatient clinic of the General Hospital of the School of Medicine of Ribeira˜o Preto, University of Sa˜o Paulo (HCFMRP/USP). Every day, this hospital attends 2,500 outpatients from a wide range of medical specialties and performs 60 surgical procedures [17]. It covers an estimated population of 3,000,000 from 26 municipalities from the state of Sa˜o Paulo. Besides, since the hospital is classified as a high complexity center for oncologic treatment, it also attends patients from other states and even other countries [18]. Population Patients that started the treatment with trastuzumab as part of that treatment for breast cancer between 01 January 2007 and 31 December 2011 were eligible to this study. Trastuzumab was approved by the Brazilian National Surveillance Agency (ANVISA) in 1999 [19]. However, its use became available in the HCFMRP-USP in 2007 and only in the neoadjuvant setting. Therefore, we revised patients’ medical records since that year. The inclusion criteria were female patients with diagnosis of HER2 positive breast cancer that had at least one dose of trastuzumab and two LVEF results during treatment. HER2 positive was defined as 3? by immunohistochemistry and/or gene amplification by chromogenic in situ
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hybridization, according to the American Society of Clinical Oncology/College of American Pathologists [8]. The exclusion criteria were recurrent breast cancer, previous history of another primary cancer and the presence of distant metastasis before or during trastuzumab treatment. Data collection We collected data from patients’ medical records. We collected information about the selected patients from the moment they were diagnosed with breast cancer until their last LVEF after the end of the treatment with trastuzumab. Patients received a dose of 8 mg per kilogram of body weight intravenously initially, followed by maintenance doses of 6 mg per kilogram given every 3 weeks. Patients that completed the treatment without interruption received 17 doses and the total length was approximately 1 year. We collected socio-demographic data (age and marital status) and clinical data (body mass index (BMI), tumor location, type of surgery, hormonal receptor status, staging, histological type, presence of positive lymph nodes, cardiovascular medications used before and during the treatment, chemotherapy regimen, epirubicin cumulative dose, LVEF results and HF symptoms). It was considered cardiovascular medication, medicines classified using the first level of anatomical therapeutical chemical (ATC) classification C Cardiovascular System. Data related to cardiac risk factors such as hypertension, hypercholesterolaemia, diabetes mellitus, hypo/hyperthyroidism smoking history and previous radiotherapy were also collected. The chemotherapy regimens used to treat the participants in adjuvant or neoadjuvant setting were: fluorouracil, epirubicin and cyclophosphamide (FEC), epirubicin, cyclophosphamide and docetaxel (ECT) and, fluorouracil, epirubicin, cyclophosphamide and docetaxel (FEC ? T). Trastuzumab induced cardiotoxicity definition Trastuzumab induced cardiotoxicity was defined according to the criteria followed by Herceptin Adjuvant (HERA) clinical trial [10], being LVEF as a minimum of 10 % decrease in LVEF from baseline and/or a LVEF \ 50 % at any time or symptoms of HF without LVEF decline. The LVEF measurement was performed with two-dimensional (2D) transthoracic echocardiography. The symptoms of HF were classified following the New York Heart Association (NYHA) classification. The NYHA categories are: class I (cardiac disease without symptoms and/or limitations); class II (mild shortness of breath and/or angina); class III (marked limitation in activity due to symptoms); and class IV (severe limitations).
Data analysis Descriptive statistics were used to characterize most variables. Results are presented in absolute and relative frequencies, means and standard deviations (SD). The association between TIC (the dependent variable) and a set of independent variables (age, BMI, smoking history, hypertension, diabetes mellitus, hyperlipidemia, hypo/ hyperthyroidism, cardiovascular medications, radiotherapy, presence of positive lymph nodes, chemotherapy scheme, epirubicin cumulative dose and type of surgery) was analyzed by odds ratios (OR) with their respective 95 % confidence intervals (95 % CI). The multiple logistic regression was used to obtain adjusted OR, controlling by age and BMI. Confidence intervals for OR that include the value 1.0 indicate absence of evidence between the respective exposition and TIC, similar to p [ 0.05. We used the SASTM software, version 9.2, for all statistical analyses [20].
Results During the study period 125 patients were treated with trastuzumab, being excluded 14 with recurrent breast cancer, 18 with distant metastasis, 13 with only one LVEF measurement and one with previous history of another primary cancer. Thus, we included and analyzed the records of 79 HER2 positive breast cancer patients treated with trastuzumab. The mean age at the start of the therapy was 49.8 years (SD = 11.1), ranging from 24 to 71 years. The mean BMI was 28.0 (SD = 6.1), being the range from 15.6 to 53.4. The majority of the patients had mastectomy (54.5 %) and disease stages II and III (93.7 %). Seventytwo patients (91.1 %) were treated previously with epirubicin and 54 (68.4 %) with epirubicin and docetaxel. The characteristics of this group are described in Table 1. Trastuzumab induced cardiotoxicity developed in 26 (32.9 %) patients, LVEF decline by 10 % occurred in 21 (26.6 %) and reduced to \50 % in four patients (5.1 %) and only one patient had HF symptoms without LVEF reduction (Table 2). Eleven patients with LVEF decline experienced HF symptoms totalizing 12. Considering the NYHA classification, seven patients had class II HF symptoms and five had class III, none have class IV. Thirteen patients completed the whole treatment, being 10 (12.6 %) without interruption and three (3.8 %) with temporary discontinuation (Table 2). The same amount of patients, 13 (16.4 %), discontinued the treatment and, among them, the mean number of trastuzumab doses was approximately 12, ranging from 4 to 16. None of the patients received cardiovascular medication after the development of TIC.
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Int J Clin Pharm Table 1 Sociodemographic and clinical characteristics of the studied population n (%) Total patients
79
Age group (years) \35 35–49
7 (18.9) 28 (35.4)
50–59
27 (34.2)
[60
17 (21.5)
BMI \20
4 (5.1)
Discussion
20–24
23 (29.1)
25–29
28 (35.4)
C30
24 (30.4)
Tumor location Left
43 (54.4)
Right
35 (44.3)
Bilateral
1 (1.3)
Type of surgery Tumorectomy Quadrantectomy Mastectomy Other
29 (36.7) 5 (6.3) 43 (54.5) 2 (2.5)
Hormone receptor status ER - PRER ? PR-
38 (48.1) 13 (16.5)
ER ? PR?
28 (35.4)
Stage I
2 (2.5)
II
35 (44.3)
III
39 (49.4)
Unknown
3 (3.8)
Histological type Invasive ductal carcinoma Others
75 (94.9) 4 (5.1)
Chemotherapy regimen ECT
39 (49.4)
FEC
18 (22.8)
FEC ? T Others
8 (10.1) 14 (17.7)
BMI body mass index, ER estrogen receptor, PR progesterone receptor, ECT epirubicin plus cyclophosphamide plus docetaxel, FEC fluorouracil plus epirubicin plus cyclophosphamide, FEC ? T fluorouracil plus epirubicin plus cyclophosphamide plus docetaxel
The total number of LVEF results available was 284, being a median of three measurements per patient. About 22 (27.8 %) patients did not have their baseline LVEF result, therefore we considered the first available for comparison. All patients had their first LVEF measure above 55 %. The average LVEF decline was 15.3 %,
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ranging from 10 to 28 % among patients that had LVEF decline by 10 %. None of the covariates influenced on the incidence of TIC in this population (Table 3). Considering all patients, 49.4 % of them showed at least one cardiac risk factor before the start of trastuzumab: hypertension (n = 23; 29.1 %), smoking history (n = 21; 26.6 %), hypo/hyperthyroidism (n = 3; 3.8 %), hypercholesterolemia (n = 7; 8.9 %), diabetes mellitus (n = 6; 7.6 %).
To our knowledge, this investigation is the first retrospective study conducted in Brazil to assess the incidence of TIC, the rate of trastuzumab discontinuation and to investigate possible factors associated with TIC in clinical practice. We found that 32.9 % of the patients developed TIC (Table 2), which is similar to the results of studies performed in developed countries [13, 15]. Another study conducted in Italy showed higher incidence of cardiac events, which was 44 % [16]. Our results from a routine clinical practice is different from those found in randomized controlled clinical trials, which showed that TIC occurs in up to 7 % of patients when trastuzumab was given in monotherapy and in 28 % of patients when associated with cyclophosphamide and anthracyclines such as doxorubicin and epirubicin, whereas epirubicin was used only previously to trastuzumab in our study [10, 21]. This difference can be justified by the fact that clinical trials have a strict monitoring of LVEF, which may not reflect the routine clinical practice. The majority of the patients from our study (91.1 %) were treated previously with epirubicin, which seems to be associated with a lower risk of cardiotoxicity compared to trastuzumab plus doxorubicin [22, 23]. Anthracyclines are incorporated in most chemotherapies schemes against breast cancer since it improves the efficacy of the therapy [24]. Only 7 (8.9 %) patients were treated with trastuzumab without previous epirubicin use. Among them, one (14.3 %) patient developed TIC that is lower than the percentage of patients treated previously with epirubicin that developed TIC, which was 25 out of 72 (34.7 %) (Table 3). However, a larger sample is needed to verify the occurrence of TIC among patients that used trastuzumab alone. Trastuzumab induced cardiotoxicity is different from anthracycline cardiotoxicity. Cardiotoxicity associated with the use of anthracycline based regimens seems to occur because of the generation of free radicals and the reduced levels of antioxidant enzymes in the heart may explain this tissue-specific toxicity [25]. It is also related to the cumulative dose of the agent and rapid intravenous infusion [26].
Int J Clin Pharm Table 2 Incidence of trastuzumab induced cardiotoxicity and treatment discontinuation n (%)
Presence of HF symptoms
Permanent treatment discontinuation
Temporary treatment discontinuation
Treatment without discontinuation
TIC
26 (32.9)
12 (15.2)
13 (16.4)
3 (3.8)
10 (12.6)
LVEF decline by C10 %
21 (26.6)
7 (8.9)
8 (10.1)
3 (3.8)
10 (12.6)
LVEF decline to \50 %
4 (5.1)
4 (5.1)
4 (5.1)
–
–
HF symptoms without LVEF decline
1 (1.2)
1 (1.2)
1 (1.2)
–
–
TIC trastuzumab induced cardiotoxicity, LVEF left ventricular ejection fraction, HF heart failure
The mechanism of cardiac events associated with trastuzumab needs to be clarified, but it is related to a blockade of HER2 receptor signaling in cardiomyocytes [12]. Previous use of chemotherapy such as anthracycline based regimens increases the expression of HER2 and/or activates HER2/HER4 signaling by neuregulin in the heart conferring protection against oxidative stress and preventing apoptosis [27]. However, trastuzumab inhibits HER2 depriving the heart of the response of cardiomyocytes to oxidative stress causing the cardiac damage [27]. Studies showed that TIC seems to be reversible when trastuzumab is withdrawn [28]. Three (3.8 %) patients from our study that had discontinued the treatment recovered from the cardiac events (Table 2). Another study showed a slightly higher percentage (9.4 %) of recovery [13]. However, both studies lacked a more rigorous investigation of the long-term effects of this anticancer therapy in order to verify TIC reversibility. In relation to the symptoms of HF, most studies considered of importance the presence of class III and class IV symptoms according to NYHA classification. Five (6.3 %) patients had class III HF, which is higher than other studies that report 2 % HF class III [14] and a meta-analysis showed a mean of 1.9 % of HF class III and IV from ten randomized clinical trials [29]. Treatment discontinuation and/or management of cardiovascular side effects with cardioprotective agents such as angiotensin-converting enzyme inhibitors, beta blockers or diuretics are recommended strategies to revert TIC. From the 13 (16.4 %) patients that discontinued permanently and three (3.8) that discontinued temporary the treatment, none received cardiovascular medication after the development of TIC. An explanation for this is that clinical studies showed that the discontinuation of trastuzumab alone is able to restore cardiac function and/or prevent cardiac events in patients with a decrease in LVEF lower than 40 % [21]. This finding suggests there is a need to combine efforts between oncologists and cardiologists to determine which patient that developed TIC the cardiovascular medication is required. Our study found that 93.7 % of the patients were diagnosed with breast cancer stages II and III (Table 1). This
finding is different from that of studies conducted in developed countries where more than 70 % of the patients were diagnosed with stage I and II [16, 30]. This contrast exists because trastuzumab was first provided by the public health system in this hospital for the neoadjuvant setting, which means that only patients with advanced breast cancer received the treatment. Only in 2010 Sa˜o Paulo state started to provide it also for the adjuvant setting.10. Regarding the age range, the majority of patients (69.6 %) have between 35 and 59 years old (Table 1). The older patient included was 71 since the treatment protocol excludes patients older than 75 years. Elderly breast cancer patients treated with trastuzumab have increased chance of developing TIC, specially if they present a history of cardiac disease and/or diabetes [31]. The median of three LVEF determinations per patient is small, which shows a poor cardiac monitoring. Another study showed a median of 6 measurements per subject, which is twice the number found in our study [32]. The lack of baseline measurements in some patients together with the few LEVF results is unable alter the incidence of TIC and apparently it did not impaired patients’ treatment. However a regular cardiac monitoring is able to anticipate TIC diagnosis and consequently trastuzumab discontinuation, which may contribute to prevent serious cardiac complications. Currently, the standard recommendation for monitoring cardiac function is an echocardiography conducted before the beginning the administration of trastuzumab and every 3 months until the end of this therapy [33]. The huge amount of patients that depends on public system combined with limited financial resources might be the cause of this poor monitoring since patients have to deal with delays to perform the echocardiography examination. Considering the factors associated with TIC in our study, none of the covariates influenced on the incidence of TIC in this population (Table 3) while some studies showed the some association. The American Adjuvant Study found the risk of TIC was attributed to pre-existing hypertension, advanced age and lower levels of LVEF after athracycline based regimens [22]. In addition, patients receiving cumulative doses of more than 240 mg/m2 of
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Int J Clin Pharm Table 3 Factors associated with Trastuzumab induced cardiotoxicity Trastuzumab induced cardiotoxicity Yes (n = 26)
Crude OR (95 % CI)
Adjusted OR (95 % CI)a
Reference
–
2.0 (0.2, 19.6)
–
No (n = 53)
Age group (years) \35
1 (3.8)
6 (11.3)
35–49
7 (26.9)
21 (39.6)
50–59
10 (38.5)
17 (32.1)
3.5 (0.3, 33.7)
–
8 (30.8)
9 (17.0)
5.3 (0.5, 54.3)
–
\20 20–24
2 (7.7) 4 (15.4)
2 (3.8) 19 (35.8)
Reference 0.2 (0.02, 2.0)
Reference 0.2 (0.02, 2.4)
25–29
11 (42.3)
17 (32.1)
0.7 (0.08, 5.3)
0.6 (0.06, 5.0)
9 (34.6)
15 (28.3)
0.6 (0.07, 5.0)
0.6 (0.06, 4.9)
[60 BMI
C30 Smoking history Non-smoker
23 (88.5)
35 (66.0)
Reference
Reference
Smoker
1 (3.8)
12 (22.6)
0.1 (0.01, 1.1)
0.1 (0.01, 1.2)
Ex-smoker
2 (7.7)
6 (11.3)
0.5 (0.09, 2.7)
0.4 (0.07, 2.7)
10 (38.5)
13 (24.5)
1.9 (0.7, 5.3)
1.4 (0.4, 4.8)
4 (15.4)
2 (3.8)
4.6 (0.7, 27.2)
3.5 (0.5, 23.5)
Cardiac risks Hypertension Diabetes mellitus Hypercholesterolemia
3 (11.5)
4 (7.8)
1.6 (0.3, 7.7)
0.7 (0.1, 4.3)
Hypo/hyperthyroidism
1 (3.8)
2 (3.8)
1.0 (0.08, 11.8)
0.6 (0.04, 7.7)
Cardiovascular medications
9 (34.6)
13 (24.5)
1.6 (0.5, 4.5)
1.1 (0.3, 3.6)
Radiotherapy
16 (61.5)
33 (62.3)
1.0 (0.3, 2.5)
1.1 (0.3, 3.3)
Lymph node Chemotherapy regimen
13 (50.0)
20 (37.7)
1.7 (0.6, 4.3)
2.4 (0.8, 7.0)
ECT
19 (73.1)
20 (37.5)
Reference
Reference
FEC
6 (23.1)
12 (22.6)
FEC ? T
0.5 (0.1, 1.7)
0.3 (0.08, 1.3)
8 (15.1)
b
b
1 (3.8)
13 (24.5)
b
b
Reference
Reference
0
Others Epirubicin cumulative dose Treatment without epirubicin
1 (3.8)
6 (11.3)
2
11 (42.3)
23 (43.4)
2.9 (0.3, 26.8)
6.2 (0.5, 67.2)
[500 mg/m2
14 (53.8)
24 (45.3)
3.5 (0.3, 32.1)
5.5 (0.5, 57.9)
Tumorectomy
9 (34.6)
20 (37.7)
Quadrantectomy
3 (11.5)
2 (3.8)
12 (46.2)
31 (58.5)
B500 mg/m
Type of surgery
Mastectomy Other
2 (7.7)
0
Reference
Reference
3.3 (0.4, 23.5)
2.5 (0.3, 19.8)
0.9 (0.3, 2.4)
0.7 (0.2, 2.4)
b
b
BMI body mass index, ECT epirubicin plus cyclophosphamide plus docetaxel, FEC fluorouracil plus epirubicin plus cyclophosphamide, FEC ? T fluorouracil plus epirubicin plus cyclophosphamide plus docetaxel a
Adjusted by age and BMI
b
Not estimated due to small sample size
doxorubicin or 500 mg/m2 of epirubicin had higher incidence of TIC [16]. The lack of correlation between the covariates and the incidence of TIC in this population can be due to the relatively small sample. Trastuzumab became available for the entire country in the Brazilian Public Health System only in 2012 [19, 34]. Although the hospital HCFMRP/
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USP provided it for the patients since 2007, not all the patients routinely attended in the hospital received the treatment and some of them had to deal with long delays and/or had to use legal means to acquire the medication. In addition, since Brazil is a large country, oncology treatment is spread into health institutions located in diverse regions unlike European countries that have one or more
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reference centers that attends the whole country. These observations explain the limited number of patients included in this study. This study has some limitations. The retrospective nature of the study may lead to information bias, since some data may be missing. The lack of LVEF baseline measurements of some patients and of LVEF regular monitoring did not allow us to compare when TIC developed in each patient. The short follow-up period make it difficult to verify if a long-term recovery from the cardiotoxicity after the end of treatment occurred or if the reversibility persists and also, to investigate if some patients developed HF after completing the treatment. The relatively small number of patients included in this study did not help establishing which specific factors are associated with the development of TIC. Conclusion This study showed a moderate incidence of TIC among HER2 positive breast cancer patients (32.9) and that there is a need of a closer cardiac monitoring to prevent cardiac complications in this population. Although 10 (12.6) patients finished the treatment without interruption, TIC led to permanent trastuzumab discontinuation in a significant number of patients (16.4) suggesting that it is important to stimulate collaboration between cardiologists and oncologists to outweighs the risks and benefits of this anticancer therapy and to identify patients that need cardiovascular medication after developing TIC. In addition, none of the covariate analyzed were associated with TIC in this population, which can be due to the relatively small sample. Thus, larger studies should be conducted in order to confirm which specific factors are associated with the development of TIC to early identify potential cardiovascular injury and to establish strategies to prevent TIC among this population. Acknowledgments The authors would like to thank the School of Pharmaceutical Sciences of Ribeira˜o Preto—University of Sa˜o Paulo for its support during the research and the General Hospital of the Faculty of Medicine of Ribeira˜o Preto of the University of Sa˜o Paulo (HCFMRP-USP) for its support during data collection. Funding National Council for Scientific and Technological Development (CNPq). Conflicts of interest of interest.
The authors declare that they have no conflict
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3. Lee BL, Liedke PE, Barrios CH, et al. Breast cancer in Brazil: present status and future goals. Lancet Oncol. 2012;13:e95–102. 4. Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER2-2/neu oncogene. Science. 1987;235:177–82. 5. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344: 789–92. 6. Murphy CG, Modi S. HER2 breast cancer therapies: a review. Biologics. 2009;3:289–301. 7. Yarden Y. The EGFR family and its ligands in human cancer: signalling mechanisms and therapeutic opportunities. Eur J Cancer. 2001;37(Suppl 4):S3–8. 8. Wolff AC, Hammond ME, Schwartz JN, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol. 2007;25: 118–45. 9. Ross JS, Slodkowska EA, Symmans WF, et al. The HER-2 receptor and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine. Oncologist. 2009;14:320–68. 10. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353:1659–72. 11. Procter M, Suter TM, de Azambuja E, et al. Longer-term assessment of trastuzumab-related cardiac adverse events in the Herceptin Adjuvant (HERA) trial. J Clin Oncol. 2010;28:3422–8. 12. de Azambuja E, Bedard PL, Suter T, Piccart-Gebhart M. Cardiac toxicity with anti-HER-2 therapies: what have we learned so far? Target Oncol. 2009;4:77–88. 13. Guglin M, Hartlage G, Reynolds C, et al. Trastuzumab-induced cardiomyopathy: not as benign as it looks? A retrospective study. J Card Fail. 2009;15:651–7. 14. Wadhwa D, Fallah-Rad N, Grenier D, et al. Trastuzumab mediated cardiotoxicity in the setting of adjuvant chemotherapy for breast cancer: a retrospective study. Breast Cancer Res Treat. 2009;117:357–64. 15. Tarantini L, Cioffi G, Gori S, et al. Trastuzumab adjuvant chemotherapy and cardiotoxicity in real-world women with breast cancer. J Card Fail. 2012;18:113–19. 16. Farolfi A, Melegari E, Aquilina M, et al. Trastuzumab-induced cardiotoxicity in early breast cancer patients: a retrospective study of possible risk and protective factors. Heart. 2013;99: 634–9. 17. Hospital das Clı´nicas da Faculdade de Medicina de Ribeira˜o Preto, Universidade de Sa˜o Paulo (HCFMRP/USP). http://www. hcrp.fmrp.usp.br/sitehc/informacao.aspx?id=5&ref=1&refV=1. Last accessed 26 May 2013. 18. Brasil. Portaria n8 741 de 19 de dezembro de 2005. http://portal. anvisa.gov.br/wps/wcm/connect/ 3092aa80474594909c3fdc3fbc4c6735/PORTARIA?N%C2% BA?741-2005.pdf?MOD=AJPERES. Last accessed 26 May 2013. 19. Ministe´rio da Sau´de. http://portal.saude.gov.br/portal/arquivos/ pdf/Trastuzumabe_caavancado_final.pdf. Last accessed 26 May 2013. 20. Allison PD. Logistic regression using the SAS system: theory and application. Cary: SAS Books; 2001. 21. Guarneri V, Lenihan DJ, Valero V, et al. Long-term cardiac tolerability of trastuzumab in metastatic breast cancer: the MD Anderson Cancer Center experience. J Clin Oncol. 2006;24: 4107–15. 22. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 1995;353:1673–84.
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Int J Clin Pharm 23. Aogi K, Saeki T, Nakamura S, et al. A multicenter, phase II study of epirubicin/cyclophosphamide followed by docetaxel and concurrent trastuzumab as primary systemic therapy for HER-2 positive advanced breast cancer (the HER2NAT study). Int J Clin Oncol. 2012;. doi:10.1007/s10147-012-0437-1. 24. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Peto R, Davies C, et al. Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trial. Lancet. 2012;379:432–44. 25. Roca-Alonso L, Pellegrino L, Castellano L, et al. Breast cancer treatment and adverse cardiacevents: what are the molecular mechanisms? Cardiology 2012;122:253–59. 26. Singal PK, Iliskovic N. Doxorubicin-induced cardiomyopathy. N Engl J Med. 1998;339:900–5. 27. Di Cosimo S. Heart to heart with trastuzumab: a review on cardiac toxicity. Target Oncol. 2011;6:189–95. 28. Ewer MS, Vooletich MT, Durand JB, et al. Reversibility of trastuzumab-related cardiotoxicity: new insights based on clinical course and response to medical treatment. J Clin Oncol. 2005;23:7820–6.
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29. Chen T, Xu T, Li Y, et al. Risk of cardiac dysfunction with trastuzumab in breast cancer patients: a meta-analysis. Cancer Treat Rev. 2011;37:312–20. 30. Dent S, Hopkins S, Graham N. The experience of a multidisciplinary clinic in the management of early-stage breast cancer patients receiving trastuzumab therapy: an observational study. Cardiol Res Pract. 2012;2012:135819. doi:10.1155/2012/135819. 31. Serrano C, Corte´s J, De Mattos-Arruda L, et al. Trastuzumabrelated cardiotoxicity in the elderly: a role for cardiovascular risk factors. Ann Oncol. 2012;23:897–902. 32. van Hasselt JG, Boekhout AH, Beijnen JH, et al. Population pharmacokinetic-pharmacodynamic analysis of trastuzumabassociated cardiotoxicity. Clin Pharmacol Ther. 2011;90:126–32. 33. Fox KF. The evaluation of left ventricular function for patients being considered for, or receiving trastuzumab (Herceptin) therapy. Br J Cancer. 2006;95:1454. 34. Ministe´rio da Sau´de. http://portal.saude.gov.br/portal/arquivos/ pdf/Relatorio_Trastuzumabe_ca_inicial.pdf. Last accessed 26 May 2013.
RESEARCH ARTICLE
Trastuzumab induced cardiotoxicity in HER2 positive breast cancer patients attended in a tertiary hospital Lorena Rocha Ayres • Marı´lia Silveira de Almeida Campos • Thais de Oliveira Gozzo • Edson Zangiacomi Martinez • Andrea Queiro´z Ungari • Jurandyr Moreira de Andrade Leonardo Re´gis Leira Pereira
•
Received: 2 May 2014 / Accepted: 13 January 2015 Koninklijke Nederlandse Maatschappij ter bevordering der Pharmacie 2015
Abstract Background The use of trastuzumab is associated with an increased survival rate in HER2 positive breast cancer patients. However, it is related to different levels of cardiotoxicity leading to treatment discontinuation, which can deprive patients of the benefits of this therapy. Objective This study aimed to identify the incidence of trastuzumab induced cardiotoxicity (TIC) and the rate of discontinuation of trastuzumab in clinical practice. Possible factors associated with TIC were also investigated. Setting This study was conducted in the General Hospital of the School of Medicine of Ribeira˜o Preto, University of Sa˜o Paulo. Methods We retrospectively reviewed the medical records of patients without distant metastasis that started trastuzumab between 2007 and 2011 in the tertiary hospital. TIC was defined as symptomatic heart failure or a decrease in left ventricular ejection fraction (LVEF) by C10 % compared to the first
L. R. Ayres (&) M. S. de Almeida Campos L. R. L. Pereira Departamento de Cieˆncias Farmaceˆuticas, Faculdade de Cieˆncias Farmaceˆuticas de Ribeira˜o Preto, Centro de Pesquisa em Assisteˆncia Farmaceˆutica e Farma´cia Clı´nica (CPAFF), Universidade de Sa˜o Paulo, Avenida do Cafe´, s/n8. Campus Universita´rio da USP, Ribeira˜o Preto, SP 14040-903, Brazil e-mail: [email protected] T. de Oliveira Gozzo Escola de Enfermagem de Ribeira˜o Preto, Universidade de Sa˜o Paulo, Ribeira˜o Preto, Brazil E. Z. Martinez J. M. de Andrade Faculdade de Medicina de Ribeira˜o Preto, Universidade de Sa˜o Paulo, Ribeira˜o Preto, Brazil A. Q. Ungari Hospital das Clı´nicas da Faculdade de Medicina de Ribeira˜o Preto, Universidade de Sa˜o Paulo, Ribeira˜o Preto, Brazil
echocardiography measurement or to \50 % at any time. Logistic regression models were used to estimate odds ratios and their respective 95 % confidence intervals for TIC associated with variables such as age, body mass index, smoking history, cardiac risks, type of surgery, presence of positive lymph nodes, chemotherapy regimen and epirubicin cumulative dose. Main outcome measure The incidence and factors associated with TIC and the rate of discontinuation of trastuzumab in clinical practice. Results We analyzed the records of 79 patients. TIC developed in 26 (32.9 %) patients, being the LVEF decline by C10 % observed in 21 (26.6 %), a decreased to \50 % in four (5.1 %) and one (1.2 %) was symptomatic without LVEF decline. Thirteen (16.4 %) patients discontinued permanently the treatment, three (3.8 %) discontinued temporarily and 10 (12.6 %) finished it without interruption. None of the covariates influenced on the incidence of TIC in this population. Conclusion Although most patients finished their treatment, TIC led to trastuzumab discontinuation in a significant proportion of patients suggesting the need of a closer cardiac monitoring. None of the covariates influenced on the incidence of TIC, which can be due to the relatively small sample. Thus, larger scale studies should be conducted in order to establish which specific factors are associated with the development of TIC in order to avoid it. Keywords Brazil Cardiotoxicity HER2 positive breast cancer Trastuzumab
Impact of findings on practice •
There is a need of a closer monitoring to prevent cardiac complications in HER2 positive breast cancer patients who receive trastuzumab.
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Int J Clin Pharm
•
To outweigh the risks and benefits of therapy, cardiologists and oncologists need to collaborate closely in cases of cancer patients receiving trastuzumab.
Introduction Breast cancer is the second most common type of cancer worldwide, with approximately 1.4 million new cases and 458,000 deaths each year [1]. In Brazil, it was estimated 52,680 new cases in 2012 and approximately 13,000 women died from the disease in 2010 [2, 3]. In 20–30 % of these women with breast cancer, the human epidermal growth factor receptor 2 (HER2) is amplified and/or over expressed, which is known as HER2 positive breast cancer [4, 5]. HER2 or ErbB-2 oncogene encodes a transmembrane glycoprotein receptor and belongs to the ErbB family, which comprises four transmembrane growth factor receptors, HER1, HER2, HER3, and HER4 with intrinsic tyrosine kinase activity [6]. The receptors have partial homology and regulate a wide range of cell functions such as cell growth and survival, differentiation, and migration [7]. This breast cancer subtype is associated with poor prognosis, decreased overall survival and higher probability of disease recurrence [8, 9]. However, with the development of therapies that target HER2, patients have benefited from a reduced risk of recurrence and increased survival rate. Among the therapies that target HER2, trastuzumab is a recombinant humanized monoclonal antibody of the IgG1 type, which binds with high affinity to the extracellular domain of the HER2 receptor [8]. Clinical trials demonstrated that trastuzumab combined with standard chemotherapy is capable to decrease in approximately 50 % the chance of recurrence and 33 % the risk of death [10, 11]. Trastuzumab is generally well tolerated, presenting few side effects. Unfortunately, some patients may experience different levels of cardiotoxicity, leading to treatment discontinuation, which can deprive patients of the benefits of the pharmacotherapy [5]. Trastuzumab induced cardiotoxicity (TIC) is recognized as a symptomatic heart failure (HF) and/or asymptomatic left ventricular ejection fraction (LVEF) reduction, which occurs due to a blockade of HER2 receptor signaling in cardiomyocytes [12]. It is important to highlight that the cardiotoxicity appears to be reversible when trastuzumab is discontinued [12]. Although there are various studies that investigate the incidence of TIC in clinical practice [13–15], they were performed only in more developed countries. To date, there is no published study that addresses the incidence of TIC and discontinuation of trastuzumab among Brazilian patients.
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Aim of the study The main objective of this study is to identify the incidence of TIC and the rate of discontinuation of trastuzumab in HER2 positive breast cancer patients in a Brazilian routine clinical setting. The secondary objective is to investigate possible factors associated with the incidence of TIC since it can be a useful tool to identify patients at higher risks of developing LVEF decrease.
Ethical approval The study protocol was approved by the Research Ethics Committee of the School of Pharmaceutical Sciences of Ribeira˜o Preto, University of Sa˜o Paulo (FCFRP/USP), protocol no. 226/2011.
Methods Setting This retrospective descriptive study was conducted in the Brazilian city of Ribeira˜o Preto, state of Sa˜o Paulo. We reviewed the medical records of HER2 positive breast cancer patients assisted by Brazilian Public Health System called SUS in the outpatient clinic of the General Hospital of the School of Medicine of Ribeira˜o Preto, University of Sa˜o Paulo (HCFMRP/USP). Every day, this hospital attends 2,500 outpatients from a wide range of medical specialties and performs 60 surgical procedures [17]. It covers an estimated population of 3,000,000 from 26 municipalities from the state of Sa˜o Paulo. Besides, since the hospital is classified as a high complexity center for oncologic treatment, it also attends patients from other states and even other countries [18]. Population Patients that started the treatment with trastuzumab as part of that treatment for breast cancer between 01 January 2007 and 31 December 2011 were eligible to this study. Trastuzumab was approved by the Brazilian National Surveillance Agency (ANVISA) in 1999 [19]. However, its use became available in the HCFMRP-USP in 2007 and only in the neoadjuvant setting. Therefore, we revised patients’ medical records since that year. The inclusion criteria were female patients with diagnosis of HER2 positive breast cancer that had at least one dose of trastuzumab and two LVEF results during treatment. HER2 positive was defined as 3? by immunohistochemistry and/or gene amplification by chromogenic in situ
Int J Clin Pharm
hybridization, according to the American Society of Clinical Oncology/College of American Pathologists [8]. The exclusion criteria were recurrent breast cancer, previous history of another primary cancer and the presence of distant metastasis before or during trastuzumab treatment. Data collection We collected data from patients’ medical records. We collected information about the selected patients from the moment they were diagnosed with breast cancer until their last LVEF after the end of the treatment with trastuzumab. Patients received a dose of 8 mg per kilogram of body weight intravenously initially, followed by maintenance doses of 6 mg per kilogram given every 3 weeks. Patients that completed the treatment without interruption received 17 doses and the total length was approximately 1 year. We collected socio-demographic data (age and marital status) and clinical data (body mass index (BMI), tumor location, type of surgery, hormonal receptor status, staging, histological type, presence of positive lymph nodes, cardiovascular medications used before and during the treatment, chemotherapy regimen, epirubicin cumulative dose, LVEF results and HF symptoms). It was considered cardiovascular medication, medicines classified using the first level of anatomical therapeutical chemical (ATC) classification C Cardiovascular System. Data related to cardiac risk factors such as hypertension, hypercholesterolaemia, diabetes mellitus, hypo/hyperthyroidism smoking history and previous radiotherapy were also collected. The chemotherapy regimens used to treat the participants in adjuvant or neoadjuvant setting were: fluorouracil, epirubicin and cyclophosphamide (FEC), epirubicin, cyclophosphamide and docetaxel (ECT) and, fluorouracil, epirubicin, cyclophosphamide and docetaxel (FEC ? T). Trastuzumab induced cardiotoxicity definition Trastuzumab induced cardiotoxicity was defined according to the criteria followed by Herceptin Adjuvant (HERA) clinical trial [10], being LVEF as a minimum of 10 % decrease in LVEF from baseline and/or a LVEF \ 50 % at any time or symptoms of HF without LVEF decline. The LVEF measurement was performed with two-dimensional (2D) transthoracic echocardiography. The symptoms of HF were classified following the New York Heart Association (NYHA) classification. The NYHA categories are: class I (cardiac disease without symptoms and/or limitations); class II (mild shortness of breath and/or angina); class III (marked limitation in activity due to symptoms); and class IV (severe limitations).
Data analysis Descriptive statistics were used to characterize most variables. Results are presented in absolute and relative frequencies, means and standard deviations (SD). The association between TIC (the dependent variable) and a set of independent variables (age, BMI, smoking history, hypertension, diabetes mellitus, hyperlipidemia, hypo/ hyperthyroidism, cardiovascular medications, radiotherapy, presence of positive lymph nodes, chemotherapy scheme, epirubicin cumulative dose and type of surgery) was analyzed by odds ratios (OR) with their respective 95 % confidence intervals (95 % CI). The multiple logistic regression was used to obtain adjusted OR, controlling by age and BMI. Confidence intervals for OR that include the value 1.0 indicate absence of evidence between the respective exposition and TIC, similar to p [ 0.05. We used the SASTM software, version 9.2, for all statistical analyses [20].
Results During the study period 125 patients were treated with trastuzumab, being excluded 14 with recurrent breast cancer, 18 with distant metastasis, 13 with only one LVEF measurement and one with previous history of another primary cancer. Thus, we included and analyzed the records of 79 HER2 positive breast cancer patients treated with trastuzumab. The mean age at the start of the therapy was 49.8 years (SD = 11.1), ranging from 24 to 71 years. The mean BMI was 28.0 (SD = 6.1), being the range from 15.6 to 53.4. The majority of the patients had mastectomy (54.5 %) and disease stages II and III (93.7 %). Seventytwo patients (91.1 %) were treated previously with epirubicin and 54 (68.4 %) with epirubicin and docetaxel. The characteristics of this group are described in Table 1. Trastuzumab induced cardiotoxicity developed in 26 (32.9 %) patients, LVEF decline by 10 % occurred in 21 (26.6 %) and reduced to \50 % in four patients (5.1 %) and only one patient had HF symptoms without LVEF reduction (Table 2). Eleven patients with LVEF decline experienced HF symptoms totalizing 12. Considering the NYHA classification, seven patients had class II HF symptoms and five had class III, none have class IV. Thirteen patients completed the whole treatment, being 10 (12.6 %) without interruption and three (3.8 %) with temporary discontinuation (Table 2). The same amount of patients, 13 (16.4 %), discontinued the treatment and, among them, the mean number of trastuzumab doses was approximately 12, ranging from 4 to 16. None of the patients received cardiovascular medication after the development of TIC.
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Int J Clin Pharm Table 1 Sociodemographic and clinical characteristics of the studied population n (%) Total patients
79
Age group (years) \35 35–49
7 (18.9) 28 (35.4)
50–59
27 (34.2)
[60
17 (21.5)
BMI \20
4 (5.1)
Discussion
20–24
23 (29.1)
25–29
28 (35.4)
C30
24 (30.4)
Tumor location Left
43 (54.4)
Right
35 (44.3)
Bilateral
1 (1.3)
Type of surgery Tumorectomy Quadrantectomy Mastectomy Other
29 (36.7) 5 (6.3) 43 (54.5) 2 (2.5)
Hormone receptor status ER - PRER ? PR-
38 (48.1) 13 (16.5)
ER ? PR?
28 (35.4)
Stage I
2 (2.5)
II
35 (44.3)
III
39 (49.4)
Unknown
3 (3.8)
Histological type Invasive ductal carcinoma Others
75 (94.9) 4 (5.1)
Chemotherapy regimen ECT
39 (49.4)
FEC
18 (22.8)
FEC ? T Others
8 (10.1) 14 (17.7)
BMI body mass index, ER estrogen receptor, PR progesterone receptor, ECT epirubicin plus cyclophosphamide plus docetaxel, FEC fluorouracil plus epirubicin plus cyclophosphamide, FEC ? T fluorouracil plus epirubicin plus cyclophosphamide plus docetaxel
The total number of LVEF results available was 284, being a median of three measurements per patient. About 22 (27.8 %) patients did not have their baseline LVEF result, therefore we considered the first available for comparison. All patients had their first LVEF measure above 55 %. The average LVEF decline was 15.3 %,
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ranging from 10 to 28 % among patients that had LVEF decline by 10 %. None of the covariates influenced on the incidence of TIC in this population (Table 3). Considering all patients, 49.4 % of them showed at least one cardiac risk factor before the start of trastuzumab: hypertension (n = 23; 29.1 %), smoking history (n = 21; 26.6 %), hypo/hyperthyroidism (n = 3; 3.8 %), hypercholesterolemia (n = 7; 8.9 %), diabetes mellitus (n = 6; 7.6 %).
To our knowledge, this investigation is the first retrospective study conducted in Brazil to assess the incidence of TIC, the rate of trastuzumab discontinuation and to investigate possible factors associated with TIC in clinical practice. We found that 32.9 % of the patients developed TIC (Table 2), which is similar to the results of studies performed in developed countries [13, 15]. Another study conducted in Italy showed higher incidence of cardiac events, which was 44 % [16]. Our results from a routine clinical practice is different from those found in randomized controlled clinical trials, which showed that TIC occurs in up to 7 % of patients when trastuzumab was given in monotherapy and in 28 % of patients when associated with cyclophosphamide and anthracyclines such as doxorubicin and epirubicin, whereas epirubicin was used only previously to trastuzumab in our study [10, 21]. This difference can be justified by the fact that clinical trials have a strict monitoring of LVEF, which may not reflect the routine clinical practice. The majority of the patients from our study (91.1 %) were treated previously with epirubicin, which seems to be associated with a lower risk of cardiotoxicity compared to trastuzumab plus doxorubicin [22, 23]. Anthracyclines are incorporated in most chemotherapies schemes against breast cancer since it improves the efficacy of the therapy [24]. Only 7 (8.9 %) patients were treated with trastuzumab without previous epirubicin use. Among them, one (14.3 %) patient developed TIC that is lower than the percentage of patients treated previously with epirubicin that developed TIC, which was 25 out of 72 (34.7 %) (Table 3). However, a larger sample is needed to verify the occurrence of TIC among patients that used trastuzumab alone. Trastuzumab induced cardiotoxicity is different from anthracycline cardiotoxicity. Cardiotoxicity associated with the use of anthracycline based regimens seems to occur because of the generation of free radicals and the reduced levels of antioxidant enzymes in the heart may explain this tissue-specific toxicity [25]. It is also related to the cumulative dose of the agent and rapid intravenous infusion [26].
Int J Clin Pharm Table 2 Incidence of trastuzumab induced cardiotoxicity and treatment discontinuation n (%)
Presence of HF symptoms
Permanent treatment discontinuation
Temporary treatment discontinuation
Treatment without discontinuation
TIC
26 (32.9)
12 (15.2)
13 (16.4)
3 (3.8)
10 (12.6)
LVEF decline by C10 %
21 (26.6)
7 (8.9)
8 (10.1)
3 (3.8)
10 (12.6)
LVEF decline to \50 %
4 (5.1)
4 (5.1)
4 (5.1)
–
–
HF symptoms without LVEF decline
1 (1.2)
1 (1.2)
1 (1.2)
–
–
TIC trastuzumab induced cardiotoxicity, LVEF left ventricular ejection fraction, HF heart failure
The mechanism of cardiac events associated with trastuzumab needs to be clarified, but it is related to a blockade of HER2 receptor signaling in cardiomyocytes [12]. Previous use of chemotherapy such as anthracycline based regimens increases the expression of HER2 and/or activates HER2/HER4 signaling by neuregulin in the heart conferring protection against oxidative stress and preventing apoptosis [27]. However, trastuzumab inhibits HER2 depriving the heart of the response of cardiomyocytes to oxidative stress causing the cardiac damage [27]. Studies showed that TIC seems to be reversible when trastuzumab is withdrawn [28]. Three (3.8 %) patients from our study that had discontinued the treatment recovered from the cardiac events (Table 2). Another study showed a slightly higher percentage (9.4 %) of recovery [13]. However, both studies lacked a more rigorous investigation of the long-term effects of this anticancer therapy in order to verify TIC reversibility. In relation to the symptoms of HF, most studies considered of importance the presence of class III and class IV symptoms according to NYHA classification. Five (6.3 %) patients had class III HF, which is higher than other studies that report 2 % HF class III [14] and a meta-analysis showed a mean of 1.9 % of HF class III and IV from ten randomized clinical trials [29]. Treatment discontinuation and/or management of cardiovascular side effects with cardioprotective agents such as angiotensin-converting enzyme inhibitors, beta blockers or diuretics are recommended strategies to revert TIC. From the 13 (16.4 %) patients that discontinued permanently and three (3.8) that discontinued temporary the treatment, none received cardiovascular medication after the development of TIC. An explanation for this is that clinical studies showed that the discontinuation of trastuzumab alone is able to restore cardiac function and/or prevent cardiac events in patients with a decrease in LVEF lower than 40 % [21]. This finding suggests there is a need to combine efforts between oncologists and cardiologists to determine which patient that developed TIC the cardiovascular medication is required. Our study found that 93.7 % of the patients were diagnosed with breast cancer stages II and III (Table 1). This
finding is different from that of studies conducted in developed countries where more than 70 % of the patients were diagnosed with stage I and II [16, 30]. This contrast exists because trastuzumab was first provided by the public health system in this hospital for the neoadjuvant setting, which means that only patients with advanced breast cancer received the treatment. Only in 2010 Sa˜o Paulo state started to provide it also for the adjuvant setting.10. Regarding the age range, the majority of patients (69.6 %) have between 35 and 59 years old (Table 1). The older patient included was 71 since the treatment protocol excludes patients older than 75 years. Elderly breast cancer patients treated with trastuzumab have increased chance of developing TIC, specially if they present a history of cardiac disease and/or diabetes [31]. The median of three LVEF determinations per patient is small, which shows a poor cardiac monitoring. Another study showed a median of 6 measurements per subject, which is twice the number found in our study [32]. The lack of baseline measurements in some patients together with the few LEVF results is unable alter the incidence of TIC and apparently it did not impaired patients’ treatment. However a regular cardiac monitoring is able to anticipate TIC diagnosis and consequently trastuzumab discontinuation, which may contribute to prevent serious cardiac complications. Currently, the standard recommendation for monitoring cardiac function is an echocardiography conducted before the beginning the administration of trastuzumab and every 3 months until the end of this therapy [33]. The huge amount of patients that depends on public system combined with limited financial resources might be the cause of this poor monitoring since patients have to deal with delays to perform the echocardiography examination. Considering the factors associated with TIC in our study, none of the covariates influenced on the incidence of TIC in this population (Table 3) while some studies showed the some association. The American Adjuvant Study found the risk of TIC was attributed to pre-existing hypertension, advanced age and lower levels of LVEF after athracycline based regimens [22]. In addition, patients receiving cumulative doses of more than 240 mg/m2 of
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Int J Clin Pharm Table 3 Factors associated with Trastuzumab induced cardiotoxicity Trastuzumab induced cardiotoxicity Yes (n = 26)
Crude OR (95 % CI)
Adjusted OR (95 % CI)a
Reference
–
2.0 (0.2, 19.6)
–
No (n = 53)
Age group (years) \35
1 (3.8)
6 (11.3)
35–49
7 (26.9)
21 (39.6)
50–59
10 (38.5)
17 (32.1)
3.5 (0.3, 33.7)
–
8 (30.8)
9 (17.0)
5.3 (0.5, 54.3)
–
\20 20–24
2 (7.7) 4 (15.4)
2 (3.8) 19 (35.8)
Reference 0.2 (0.02, 2.0)
Reference 0.2 (0.02, 2.4)
25–29
11 (42.3)
17 (32.1)
0.7 (0.08, 5.3)
0.6 (0.06, 5.0)
9 (34.6)
15 (28.3)
0.6 (0.07, 5.0)
0.6 (0.06, 4.9)
[60 BMI
C30 Smoking history Non-smoker
23 (88.5)
35 (66.0)
Reference
Reference
Smoker
1 (3.8)
12 (22.6)
0.1 (0.01, 1.1)
0.1 (0.01, 1.2)
Ex-smoker
2 (7.7)
6 (11.3)
0.5 (0.09, 2.7)
0.4 (0.07, 2.7)
10 (38.5)
13 (24.5)
1.9 (0.7, 5.3)
1.4 (0.4, 4.8)
4 (15.4)
2 (3.8)
4.6 (0.7, 27.2)
3.5 (0.5, 23.5)
Cardiac risks Hypertension Diabetes mellitus Hypercholesterolemia
3 (11.5)
4 (7.8)
1.6 (0.3, 7.7)
0.7 (0.1, 4.3)
Hypo/hyperthyroidism
1 (3.8)
2 (3.8)
1.0 (0.08, 11.8)
0.6 (0.04, 7.7)
Cardiovascular medications
9 (34.6)
13 (24.5)
1.6 (0.5, 4.5)
1.1 (0.3, 3.6)
Radiotherapy
16 (61.5)
33 (62.3)
1.0 (0.3, 2.5)
1.1 (0.3, 3.3)
Lymph node Chemotherapy regimen
13 (50.0)
20 (37.7)
1.7 (0.6, 4.3)
2.4 (0.8, 7.0)
ECT
19 (73.1)
20 (37.5)
Reference
Reference
FEC
6 (23.1)
12 (22.6)
FEC ? T
0.5 (0.1, 1.7)
0.3 (0.08, 1.3)
8 (15.1)
b
b
1 (3.8)
13 (24.5)
b
b
Reference
Reference
0
Others Epirubicin cumulative dose Treatment without epirubicin
1 (3.8)
6 (11.3)
2
11 (42.3)
23 (43.4)
2.9 (0.3, 26.8)
6.2 (0.5, 67.2)
[500 mg/m2
14 (53.8)
24 (45.3)
3.5 (0.3, 32.1)
5.5 (0.5, 57.9)
Tumorectomy
9 (34.6)
20 (37.7)
Quadrantectomy
3 (11.5)
2 (3.8)
12 (46.2)
31 (58.5)
B500 mg/m
Type of surgery
Mastectomy Other
2 (7.7)
0
Reference
Reference
3.3 (0.4, 23.5)
2.5 (0.3, 19.8)
0.9 (0.3, 2.4)
0.7 (0.2, 2.4)
b
b
BMI body mass index, ECT epirubicin plus cyclophosphamide plus docetaxel, FEC fluorouracil plus epirubicin plus cyclophosphamide, FEC ? T fluorouracil plus epirubicin plus cyclophosphamide plus docetaxel a
Adjusted by age and BMI
b
Not estimated due to small sample size
doxorubicin or 500 mg/m2 of epirubicin had higher incidence of TIC [16]. The lack of correlation between the covariates and the incidence of TIC in this population can be due to the relatively small sample. Trastuzumab became available for the entire country in the Brazilian Public Health System only in 2012 [19, 34]. Although the hospital HCFMRP/
123
USP provided it for the patients since 2007, not all the patients routinely attended in the hospital received the treatment and some of them had to deal with long delays and/or had to use legal means to acquire the medication. In addition, since Brazil is a large country, oncology treatment is spread into health institutions located in diverse regions unlike European countries that have one or more
Int J Clin Pharm
reference centers that attends the whole country. These observations explain the limited number of patients included in this study. This study has some limitations. The retrospective nature of the study may lead to information bias, since some data may be missing. The lack of LVEF baseline measurements of some patients and of LVEF regular monitoring did not allow us to compare when TIC developed in each patient. The short follow-up period make it difficult to verify if a long-term recovery from the cardiotoxicity after the end of treatment occurred or if the reversibility persists and also, to investigate if some patients developed HF after completing the treatment. The relatively small number of patients included in this study did not help establishing which specific factors are associated with the development of TIC. Conclusion This study showed a moderate incidence of TIC among HER2 positive breast cancer patients (32.9) and that there is a need of a closer cardiac monitoring to prevent cardiac complications in this population. Although 10 (12.6) patients finished the treatment without interruption, TIC led to permanent trastuzumab discontinuation in a significant number of patients (16.4) suggesting that it is important to stimulate collaboration between cardiologists and oncologists to outweighs the risks and benefits of this anticancer therapy and to identify patients that need cardiovascular medication after developing TIC. In addition, none of the covariate analyzed were associated with TIC in this population, which can be due to the relatively small sample. Thus, larger studies should be conducted in order to confirm which specific factors are associated with the development of TIC to early identify potential cardiovascular injury and to establish strategies to prevent TIC among this population. Acknowledgments The authors would like to thank the School of Pharmaceutical Sciences of Ribeira˜o Preto—University of Sa˜o Paulo for its support during the research and the General Hospital of the Faculty of Medicine of Ribeira˜o Preto of the University of Sa˜o Paulo (HCFMRP-USP) for its support during data collection. Funding National Council for Scientific and Technological Development (CNPq). Conflicts of interest of interest.
The authors declare that they have no conflict
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