Abstract
Aim: The aim of the present study was to assess metastasis-free survival of 134 patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer treated with chemotherapy, radiotherapy and trastuzumab in an adjuvant setting, according to sub-clinical cardiac side-effects (parameters not tested previously) evaluated before, during and after trastuzumab therapy, as well as selected clinicopathological parameters. Results: In our series, left ventricular ejection fraction decreased significantly from 68.1% before trastuzumab treatment to 66.7% after therapy (p<0.001). Further analysis revealed that this decrease was significant only in patients who received radiotherapy and developed valve insufficiency during or after (but not before) trastuzumab therapy (p<0.001). Cox multivariate analysis revealed that both pN2a tumor stage and valve regurgitation during/after trastuzumab therapy (vs. lack of valve insufficiency or insufficiency before trastuzumab therapy) were significant independent factors for a negative prognosis. Conclusion: Valve insufficiency diagnosed during or after trastuzumab application might be cancer-unrelated indicator of decreased sensitivity to trasuzumab.
In the absence of trastuzumab therapy, patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer present poorer disease-free and overall survival compared to HER2-negative ones. Clinical trials revealed that the addition of trastuzumab to standard chemotherapy was associated with a decreased risk of breast cancer progression and cancer-related deaths (1). Despite optimistic results, treatment schedules applied for HER2-positive breast cancer are associated with increased cardiovascular comorbidities (1, 2).
This is not surprising because trastuzumab, chemotherapy and radiotherapy influence the physiology of cardiac myocytes and heart-supportive tissue (2). Both anthracyclines and irradiation induce production of reactive oxygen species, which cause DNA damage, and promote p53 expression and cell-cycle arrest (2, 3). The aforementioned processes influence cardiac stem cells and endothelial cells (3). Radiation-induced damage of endothelium is responsible for increased permeability of vessels and inflammation, which additionally activates cascades leading to fibrosis of vessel wall and heart connective tissue, as well as damage to myocardial cells. Anthracycline-induced cardiotoxicity comprises of left ventricular dysfunction, heart failure, myocarditis, and arrhythmia (4). The mechanism for this is not fully-understood, however, it is accepted that anthracycline-induced free radical formation plays a vital role. Oxidative stress in cardiomyocytes causes the following adverse effects: DNA damage, sarcomere degradation with de-regulation of Ca2+ levels, and mitochondrial dysfunction (5, 6). Among mechanisms of trastuzumab-related cardiotoxicity (left ventricular dysfunction, heart failure, arrhythmia), which is thought to be reversible (4), one can list: (i) direct effect on HER2, which is expressed on the myocardium and has a protective role on cardiac function (4); (ii) regulation of mitochondrial integrity through B cell lymphoma-extra large (BCL-X) proteins, leading to ATP depletion and contractile dysfunction (5); and (iii) immune-mediated destruction of cardiomyocytes. Irrespective of the mechanisms involved, acute or sub-acute cardiac dysfunction develops between initiation of treatment up to two weeks, while chronic dysfunction up to one year after treatment completion (4).
There is a difficulty in comparing the frequency of cardiac complications between different clinical trials because of different definitions of cardiotoxicity and discrepancies in inclusion/exclusion criteria (1). Moreover, symptoms of cardiac complications recorded in clinical studies often comprised of only severe side-effects such as cardiac death, severe (grade III/IV) congestive heart failure according to the New York Heart Association (NYHA) scale (7), or significant decrease in the left ventricular ejection fraction (LVEF) (1). Since, as described above, all agents applied for eradication of HER2-positive breast cancer cells might affect cardiac function, recording even small and sub-clinical symptoms of cardiotoxicity might be valuable for understanding the mechanisms of this process and for planning future clinical and experimental studies.
This prompted us to investigate early and sub-clinical cardiac complications in the form of valvular regurgitation of any grade and changes in LVEF. This approach has not been previously adopted. Moreover, taking into account the existence of biomarkers of treatment efficiency not related to cancer, such as a rash predicting clinical response to targeted therapy against epidermal growth factor receptor (8) and arterial hypertension indicating efficiency of tyrosine kinase inhibitors (9), we analyzed metastasis-free survival (MFS) of patients with HER2-positive breast cancer treated with chemotherapy, radiotherapy and trastuzumab in an adjuvant setting, according to the aforementioned sub-clinical cardiac side-effects (parameters not tested previously) and selected clinicopathological parameters.
Patients and Methods
Patients. The study included 134 patients with breast carcinoma characterized by: (i) HER2 overexpression, (ii) tumor diameter of over 1 cm (pT1c), or (iii) metastasis to the axillary lymph nodes, with the exception of patients with pT4 tumors (stage IIIB) or metastases in 10 or more lymph nodes (stage IIIC) (10). We excluded patients who presented an LVEF below 50%, or with any serious cardiac disorders or significant deviations from the norm in the blood count and biochemical tests.
All patients included in the study underwent adjuvant treatment with trastuzumab at the Center and Institute of Oncology, Krakow Branch, between 2007 and 2011. The mean age of patients was 53.5±0.8 (standard error) years; range=33-77 years. All patients completed radical surgical treatment as modified radical mastectomy (102/134 patients, 76.1%) or breast-conserving surgery (32/134, 23.9%), which was followed by adjuvant chemotherapy, and, as individually indicated (description below), by radiotherapy with/without hormonal therapy (in the case of hormone receptor positivity) (Table I). After radiotherapy (RT), the patients received trastuzumab for 12 months, every 3 weeks.
Clinical and therapeutic characteristics of 134 patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer.
Changes in number of cases of valvular insufficiency, before during and after trastuzumab therapy.
RT was applied after completing chemotherapy and it was followed by trastuzumab therapy. RT was executed with a linear accelerator with the application of megavoltage photon and electron beams. The energy of beams was individually established depending on the patient's anatomy. All RT plans were prepared on a basis of computed tomographic scans as a 3D RT technique with delineation of target and organ-at-risk volumes. The target volume received a total dose of 45 Gy in 20 fractions given once a day, 5 days a week.
In RT performed after breast-conserving surgery, the technique of tangential fields was used to irradiate the whole breast. In patients with nodal involvement (9 out of 32 patients), the monoisocenctric technique was used to irradiate the whole breast and regional lymph nodes. Additionally, all patients received amended boost of 10 Gy given in four fractions to the tumor bed.
In RT given after mastectomy, the technique of monocentric mixed photon-electron beam was used to irradiate target volume. It covered the chest wall with the postoperative scar and internal mammary nodes, which were irradiated with the electron beam and the remaining lymph nodes (axillary, supra- and subclavicular), which were irradiated with the photon beam.
LVEF and heart valve function were evaluated by echocardiography using the method of Teichholz or Simpson (11). The grade of valve insufficiency was assessed by color Doppler, using a semiquantitative scale based on the range of regurgitant flow. In cases of aortic regurgitation, grade I, the wave of regurgitation was below the aortic valve leaflets; in grade II, the wave reached the edges of the mitral valve; in grade III, it reached the level of the papillary muscles; while in grade IV, it was below the level of the papillary muscles. The grade of mitral and tricuspid regurgitation was determined based on the following criteria: grade I, wave of regurgitation just below the mitral valve; grade II, wave does not exceed one-third of the depth of the left atrium; grade III, mitral wave reaches to the middle of the left atrium; grade IV, mitral wave reaches beyond the midpoint of the left atrium (Table II) (12). The above-mentioned diagnostic procedures were performed in all patients before trastuzumab therapy, every 3 months during the treatment and up to 3 months after its completion. The NYHA Functional Classification was used to determine the extent of heart failure (7). Moreover, before trastuzumab therapy, medical history and physical examination were performed to assess body mass index (BMI) and coexisting diseases including: arterial hypertension, ischemic heart disease and diabetes mellitus.
Trastuzumab therapy was suspended for 3 weeks and echocardiography was repeated if the following cardiac side-effects were noted: (i) LVEF decreased either by more than 10 percentage points as compared to its initial value or fell below 50%; (ii) grade III/IV cardiovascular failure; (iii) grade III/IV valve insufficiency; (iv) cardiac conduction disorders; or (v) exacerbation of coronary artery disease. In cases of high severity or persistence of the above-mentioned symptoms, trastuzumab therapy was not continued.
The study is in accordance with the Helsinki Declaration. The Ethical Committee at the Regional Medical Chamber in Krakow approved the study (decision from 04.12.2013). No specific consent was needed as this was a retrospective study performed on archived data with no direct patient contact, no modification of diagnostic or treatment procedures, and no personal patient data revealed.
Tissue. The histological sub-type was assessed according to the WHO classification (13), while tumor grade according to the Bloom-Richardson scale with Elston-Ellis modification (14).
Estrogen (ER) and progesterone (PR) receptors and HER2 testing. Steroid receptor expression was evaluated on the basis of immunohistochemistry (15). Expression of ER or PR in >1% of tumor cells was considered as immunopositivity. Overexpression of HER2 protein was tested using immunohistochemistry (HercepTest; Dako Denmark A/S, Glostrup/Denmark) and, in cases of an unclear result (expression assessed as +2), amplification of HER2 gene was verified using fluorescence in situ hybridization– PathVysion HER2 DNA Probe (Abbot Molecular, Abbott Laboratories. Abbott Park, Illinois, USA). Finally, overexpression of HER2 protein/amplification of HER2 gene was established according to recommended standards (16).
Statistical analysis. STATISTICA v.10 software (StatSoft, Inc., Tulsa, OK, USA) was used for all calculations. A p-value of less than 0.05 was considered significant.
The following tests were applied: (i) Pearson or NW χ2 for independence of categorical variables expressed in a cross-tab; (ii) repeated measures ANOVA (within-subjects ANOVA or ANOVA for correlated samples) for differences in mean scores of LVEF measured six times [before, during (every 3 months), and after trastuzumab therapy] according to the presence of valve insufficiency (dependent variable).
The median follow-up was 50.6 (range=11.4-80.5) months. Nineteen patients were followed-up for ≤36 months, 107 patients for 36-72 months, while seven patients for over 72 months. MFS was defined as the time (number of months) from surgery to the occurrence of metastases. Only MFS was analyzed because only 14 deaths occurred. Cumulative survival probabilities were calculated using the Kaplan–Meier method. Differences between survival rates were evaluated with the log-rank test.
All variables related to MFS in the univariate analysis were entered into the Cox multivariate analysis. The joint effect of the remaining covariates was analyzed using Cox proportional hazard model with stepwise regression procedure.
Results
Trastuzumab therapy was discontinued in 24/129 (18.6%) patients who developed the following persistent side-effects: (i) the reduction of LVEF by more than 10 percentage points of initial value or decrease below 50%, which did not increase or was reduced after three weeks: 10/129 patients (7.7%); (ii) decrease of LVEF plus grade III/IV cardiovascular failure: 2/129 patients (1.5%); (iii) decrease of LVEF plus arrhythmia: 1/129 cases (0.8%); (iv) decrease of LVEF plus arrhythmia and grade III/IV cardiovascular failure: 1/129 woman (0.8%); (v) grade III/IV cardiovascular failure: 3/129 patients (2.3%); (vi) arrhythmia (supraventricular tachycardia): 1/129 cases (0.8%); (vii) arrhythmia and grade III/IV cardiovascular failure: 1/129 cases (0.8%); (viii) grade III or IV valvular insufficiency: 2/129 patients (1.5%); (ix) cardiac conduction disorders (atrial-ventricular third-degree block: 1/129 woman (0.8%); and (x) exacerbation of coronary artery disease: 2/129 patients (1.5%). In 14/129 (10.8%) women, because of high severity or persistence of the above-mentioned symptoms, trastuzumab therapy was not continued.
Cardiac complications that resulted in discontinuation of treatment were more frequent in older patients (p=0.051) and patients who received a high dose of anthracyclines (>300 mg/m2) or both anthracyclines and docetaxel (p=0.050), with correlations at borderline significance (Table III). Other parameters (BMI and comorbidities before treatment, application of radiotherapy and hormonotherapy) were not related to the frequency of cardiac complications (Table III). No relationship was found between the frequency of valvular regurgitation and age, BMI and comorbidities before treatment, chemotherapy schedule, application of radiotherapy and hormonotherapy (Table III). Except for severe and persistent cardiac side-effects, we described asymptomatic sub-clinical cardiac complications. Before the aforementioned therapy, valvular regurgitation was present in 32/127 (26.0%) patients, during therapy it was found in 84/126 (66.7%) patients, while after the completion of therapy in 71/115 (61.7%) patients (Table II). In 37/117 (31.6%) cases, no valve insufficiency was diagnosed before, during or after trastuzumab therapy. On the other hand, valve insufficiency was found only during trastuzumab treatment in 5/117 (4.3%) patients; only after trastuzumab treatment in 1/117 (0.8%); during and after trastuzumab treatment in 41/117 (36.0%); before, during and after trastuzumab treatment in 28/117 (23.9%); and, finally, before and during trastuzumab treatment in 2/117 (1.7%) patients (Table III).
Asymptomatic mitral regurgitation of grade III or more was observed in one patient before trastuzumab therapy, as well as in 23 cases at least once during or after this treatment. Asymptomatic tricuspid regurgitation was diagnosed in nine women during or after the period in which trastuzumab was applied. Asymptomatic mitral or tricuspid regurgitation of grade III or more was more frequent in older patients (p=0.070) and those who received >300 mg/m2 of anthracyclines and docetaxel (p=0.005) as compared to younger patients and those who received ≤300 mg/m2 of anthracyclines without docetaxel (Table III).
The mean LVEF prior to the initiation of trastuzumab therapy was 68.1±0.4% (n=131), while in five subsequent measurements it was: 67.2%±0.6 (n=131), 67.1%±0.4 (n=129), 67.4%±0.4 (n=129), 66.7%±0.5 (n=124), and 66.7%±0.4 (n=120), respectively. With repeated-measures ANOVA, we found a significant decrease in LVEF during trastuzumab treatment (p<0.0001). The decrease of LVEF was most significant in patients who received RT and additionally developed valvular insufficiency during or after (but not before) trastuzumab therapy (p<0.001, Figure 1). In women who received RT but did not develop valvular regurgitation or developed it before treatment implementation (trastuzumab-unrelated valvular regurgitation), the decrease was less pronounced (p=0.028, Figure 1). The LVEF did not change in individuals who did not receive RT (p=0.595, Figure 1). Other studied parameters were not related to changes in LVEF during treatment.
Relationship between some clinical parameters and cardiac complications/valvular regurgitation developed during trastuzumab therapy.
Survival analysis. Metastases were found in 17/134 patients in: lungs: four cases, central nervous system: two cases, bones: two cases, lungs and liver: three cases, lungs and bones: two cases, liver and orbit: one case, bones and cervical lymph nodes: one case, liver and supraclavicular lymph nodes: one case, supraclavicular and mediastinal lymph nodes: one case. We noted 14 cancer-related deaths. Out of 120 women who were alive at the time of study end, six had developed metastases.
Changes in left ventricular ejection fraction (LVEF) during and after trastuzumab treatment in sub-groups of patients with HER2-positive breast cancer identified based on radiotherapy application and valvular insufficiency. Points are mean value of the LVEF, while whiskers represent the 95% confidence interval.
We found poorer MFS in patients with pN2a (vs. patients with pN0 and pN1a) carcinomas (p=0.041, Figure 2a) and patients who developed valvular regurgitation during and/or after trastuzumab therapy (vs. women without valve insufficiency or insufficiency before trastuzumab therapy) (p=0.001, Figure 2b). The following parameters did not influence survival: type of surgery, ER/PR expression, chemotherapy schedule, coexisting type 2 diabetes, arterial hypertension, ischemic heart disease, BMI before treatment (≤25 vs. >25).
Cox multivariate analysis revealed that both pN 2a [relative risk [(RR)=3.7, 95% CI=1.2-10.9; p=0.020] and valvular regurgitation during and/or after trastuzumab therapy [(RR=7.6, 95% CI=1.7-34.4, p=0.008)] were independent negative prognostic parameters.
Discussion
In our study, in patients with pN0 or pN1 carcinomas, lower risk of distant metastasis formation was observed compared to patients with pN2a carcinomas. This is consistent with other studies, such as N988831 and B-31, which used trastuzumab in the adjuvant setting (17).
We found poorer MFS in patients who developed clinically asymptomatic valvular insufficiency during trastuzumab therapy. This parameter was significant in both univariate and multivariate analyses. To the best of our knowledge, this finding has not been reported before. It may indicate that valvular insufficiency diagnosed during/after trastuzumab application (early effect) might be an indicator of a decreased sensitivity to this drug (or possibly also to chemotherapy) and, hence, of an increased risk of metastasis formation in patients with HER2-positive breast cancer who received chemotherapy, RT and trastuzumab in an adjuvant setting. This might seem surprising but similar cancer-unrelated predictors for targeted-therapies exist: a rash is a candidate predictive clinical biomarker for cetuximab in front-line therapy of non-small cell lung cancer (8), while arterial hypertension indicates sensitivity to tyrosine kinase inhibitors (9).
The relationship between the development of clinically asymptomatic valvular regurgitation diagnosed de novo during/after trastuzumab therapy and risk of metastasis formation might suggest the existence of a factor (or factors) stimulating both cardiac valvular insufficiency and metastasis formation. The following substances, which are involved in pathogenesis of de-generation of cardiac valves and the breast cancer progression, may be potentially responsible for the relationship between poor MFS and valvular insufficiency during trastuzumab therapy: transforming growth factor-beta (TGFβ) (18-23), serotonin (23, 24), angiotensin (23, 25), and nitric oxide (23, 26). It is possible that in some patients included in our study, elevated levels of TGFβ1 (or other aforementioned factors) occurred, or genetic variants of this growth factor existed, which could be responsible for both higher susceptibility to treatment-induced valvular regurgitation (diagnosed during treatment) and metastasis formation (observed after therapy). It is worth mentioning that in patients exposed to potentially cardiotoxic drugs/therapies (trastuzumab, RT, anthracyclines) elevated levels of a cardiotoxicity-related factor may increase the risk of valvular insufficiency. Furthermore, this might result in a correlation between poorer MFS and valvular regurgitation diagnosed during/after trastuzumab therapy that was found in our study.
Survival of patients with HER2-positive breast cancer according to nodal status (a) and valvular insufficiency before, during and after trastuzumab therapy (b).
From the above-mentioned factors which potentially may induce cardiac complications (27) and progression of breast cancer, TGFβ1 seems to be the most interesting. As suggested by experimental studies, TGFβ1 signaling might be involved in promotion of cancer progression, as well as inhibition of cancer growth (18-20). This is reflected by translational studies in which a high serum level of TGFβ1 predicted both favorable (21) and poor survival (22). The aforementioned discrepancies might be explained by the heterogeneity of the analyzed groups. It was suggested that crosstalk between HER2 and TGFβ signaling can enhance the metastatic potential of cancer cells (19, 20). Therefore, it is possible that the progression-promoting effect of TGFβ1 might be particularly strong in HER2-overexpressing breast cancer.
In our study, severe and persistent early cardiac complications were observed in 18.6% (24/129) of patients. In 10.8% (14/129) of women, such complications resulted in discontinuation of trastuzumab therapy. Compared to adjuvant trastuzumab trials, the frequencies found in our study are generally higher than the frequencies of cardiac deaths and severe congestive heart failure, but comparable to the frequency of LVEF decrease (1, 28-30). In NSABP B-31 and NCCTG N9831 trials, in the trastuzumab-treated arm, NYHA III/IV congestive heart failure or cardiac-related deaths at 3 years were found in 4.1% and 3.5% of cases, respectively, while asymptomatic decrease occurred in LVEF in 14% and 10.8% of patients, respectively (29, 30). Meanwhile, in the trastuzumab-treated arm of the HERA study, severe congestive heart failure (NYHA III/IV and LVEF <50% with a decrease of ≥10 percentage points from baseline at any time) and decrease in LVEF were described in 0.6% and 7.4% of cases, respectively (31). Another adjuvant trastuzumab trial (BCIRG 006) reported grade III/IV congestive heart failure in 1.6% of patients treated with doxorubicin, cyclophosphamide, docetaxel and trastuzumab; in 0.4% of women treated with docetaxel, carboplatin and trastuzumab; as well as in 0.3% of patients who received adjuvant chemotherapy (doxorubicin, cyclophosphamide, docetaxel) without trastuzumab. In that trial, the frequency of decrease in LVEF (>10% relative LVEF decline from baseline) was also the highest (17.3%) in individuals who received doxorubicin, cyclophosphamide, docetaxel and trastuzumab (32). Our results are in concordance with the results of these studies. We noted both cardiac complications, which resulted in discontinuation of treatment, and grade III or more valvular insufficiency more frequently in individuals who were administered a high dose of anthracyclines (>300 mg/m2) or anthracyclines and docetaxel (p=0.050). As indicated above, the difficulty in comparing the frequency of cardiac complications between trials results from differences in applied definitions of cardiotoxicity and discrepancies in inclusion/exclusion criteria (1, 28, 31, 32).
In the present study, LVEF was assessed before, during (approximately every 3 months) and after trastuzumab treatment. This means that the measurements were performed after RT and chemotherapy, which gave us the possibility to study not only decrease to below the cut-off value (the reduction of LVEF by more than 10 percentage points of its initial value) but also differences in mean LVEF before, during (every 3 months), and after trastuzumab therapy. We observed a significant decrease in LVEF during trastuzumab treatment, from 68.1% before therapy through 67.2%, 67.1%, 67.4%; 66.7% and 66.7% in five subsequent measurements during and early after this therapy. The decrease in LVEF was also reported by others (33). In their study, the mean LVEF before trastuzumab therapy (after doxorubicin) was 61%; it decreased to 43% during the treatment and increased to 56% after withdrawal of the drug (33). We will continue to observe patients included in our study to assess potential reversibility of LVEF decrease and other cardiac side-effects.
We found that the decrease of LVEF was most pronounced in patients who received RT and additionally developed valvular insufficiency during trastuzumab therapy or thereafter (but not before). This seems to be inconsistent with the Frank-Starling hypothesis, according to which LVEF values should be higher in patients who developed valvular regurgitation. However, as discussed earlier, valvular regurgitation which developed during treatment (treatment-related regurgitation) might be associated with individual susceptibility, which might be the effect of interpersonal differences in the level of cancer-related TGFβ1 (21, 22) (or other growth factors), or the existence of its genetic variants. In such cases, application of RT, stimulating TGFβ1 signaling (34, 35, 36), may increase TGFβ1-related pathological de-regulation of homeostasis of extracellular matrix building heart connective tissue. The above-mentioned process comprises of the synthesis of matrix-catabolic enzymes, exuberant deposition of proteoglycan and glycosaminoglycan, fragmentation of elastin and disorganization of collagen. In these circumstances, the decrease of LVEF may be the effect of TGFβ1-induced ECM protein production inducing dysfunction of cardiac muscle (27).
In other words, the results discussed above suggest that the employment of adjuvant RT may increase individual susceptibility to chemotherapy and early trastuzumab-related cardiac complications. The fact that LVEF decreases during trastuzumab therapy (an early effect) were observed only in patients who received RT and concurrently developed valvular insufficiency during/after trastuzumab application is not surprising because radiation-associated cardiac disease is a consequence of damage to the following heart structures: valves, pericardium, myocardium, coronary arteries, and conduction pathways (37). Cardiotoxicity resulting from RT is a multifactorial process. Early changes result from radiation-induced cell damage (as a consequence of formation of reactive oxygen species) which is related to the activation of apoptosis, necrosis and damage of vascular endothelium. The aforementioned phenomenon leads to an increase in vascular permeability and stromal edema. Late radiation-induced lesions are irreversible and they are associated with the occurrence of epithelial nuclear atypia and activation of fibroblasts in the stroma. Moreover, they produce changes in vessel intima, fibrinoid necrosis, hyalinization of vessel wall, multiple thrombosis and, finally, parenchymal atrophy. Thus, RT can cause cardiac fibrosis (involving the pericardium and myocardium) or endothelial fibrosis, causing valvular disease or coronary artery disease (38). The clinical presentation of these pathologies is not specific and it comprises the spectrum of RT-induced heart diseases including: perfusion defects, wall motion abnormality, myocardial fibrosis, coronary artery disease, myocardial infarction, and valvular disease (39). Valvular dysfunction is observed particularly when RT volume includes internal mammary nodes (hazard ratio is 3.17 in comparison to a group without RT) (40). The mechanism of RT-induced valvular injury is probably based on apoptosis of endocardial cells, as well as platelet and fibrin deposits on the surface of the leaflets. Such changes impedes valve closure, inducing early-phase regurgitation (39). Later, valvular stenosis is developed as a consequence of fibrosis with or without calcification (39). Clinical observations showed that the left-sided valves are more involved than right-sided ones. To sum up, it is not surprising that RT, which reduces the risk of local recurrence and breast cancer-related deaths (41-43), also increases non-breast cancer mortality. The Early Breast Cancer Trialists' Collaborative Group proved in an updated meta-analysis that relative risk of cardiovascular mortality in patients treated with RT (in comparison to untreated patients) is 1.27 (41).
Longer observation of patients included in our study will provide the answer to the following questions: Are the early cardiac complications observed during trastuzumab therapy reversible, irreversible or progressive? Is the relationship between valvular insufficiency and MFS maintained on longer observation? Does this parameter influence overall survival? Do changes in LVEF (increase, decrease) differ in sub-groups according to RT application and valvular insufficiency on longer observation?
Acknowledgements
The study was financed by the National Science Centre, based on decision numbered DEC-2013/09/B/NZ5/00764.
Footnotes
This article is freely accessible online.
- Received April 8, 2015.
- Revision received May 3, 2015.
- Accepted May 6, 2015.
- Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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