|Year : 2018 | Volume
| Issue : 12 | Page : 1183-1187
Influence of pharmorubicin on the left ventricular ejection fraction of patients with breast cancer: A mechanism study
Hu Liu1, Ming-rui Xie2, Hui Gao3, Jian Li4
1 Xi'an JiaoTong University, Xi'an; Cardiovascular Center, Affiliated Hospital of Yan'an University, Yan'an, ShaanXi, China
2 Department of Oncology, Yulin Second Hospital, Yulin, ShaanXi, China
3 Department of Radiology, Affiliated Hospital Yan'an University, Yan'an, ShaanXi, China
4 Department of Gland Vascular Surgery, Affiliated Hospital of Yan'an University, Yan'an, ShaanXi, China
|Date of Web Publication||11-Dec-2018|
Department of Gland Vascular Surgery, Affiliated Hospital of Yan'an University, No. 43 North Street, Yan'an 716000, ShaanXi
Source of Support: None, Conflict of Interest: None
Aims: Breast cancer is a great public health problem. It remains unclear how pharmorubicin induces cardiac dysfunction in patients with breast cancer. Our study was aimed to explore the influence of pharmorubicin on the left ventricular ejection fraction (EF) of patients with breast cancer and its potential mechanism.
Materials and Methods: Patients with breast cancer were enrolled at the same hospital. Group I consisted of 135 samples, who were under treatment of pharmorubicin (200 mg/m2). Group II consisted of 144 samples, who were under treatment the of pharmorubicin (360 mg/m2). Group III was used as control group, which consists of 120 samples without treatment of pharmorubicin. Color Doppler ultrasonic inspection and measurement were performed to examine EF. Flow cytometry was performed to assess oxygen free radical level in hemocytes. Further combination therapy (N-acetylcysteine [NAC] + pharmorubicin) was provided for patients, and the same examinations were performed for the assessment of cardiac function and oxygen free radical level.
Results: The ultrasound results showed that pharmorubicin treatment significantly jeopardized cardiac function, verified by decrease of both EF and fractional shortening (FS) (P < 0. 05). Moreover, such effect was dose-dependent. Oxygen free radical level was remarkably increased after pharmorubicin treatment (P < 0. 05), verified by flow cytometry. Adjunctive therapy of NAC decreased oxygen free radical level and improved cardiac function of patients with breast cancer, suggesting NAC ameliorated side effect of pharmorubicin treatment.
Conclusions: Pharmorubicin treatment decreased EF and FS of patients with breast cancer through increasing oxygen free radical level in hemocytes. Adjunctive therapy of NAC could be a potential treatment to ameliorated side effect pharmorubicin treatment.
Keywords: Cardiac function, left ventricular ejection fraction, N-acetylcysteine, oxygen free radical, pharmorubicin
|How to cite this article:|
Liu H, Xie Mr, Gao H, Li J. Influence of pharmorubicin on the left ventricular ejection fraction of patients with breast cancer: A mechanism study. J Can Res Ther 2018;14, Suppl S5:1183-7
|How to cite this URL:|
Liu H, Xie Mr, Gao H, Li J. Influence of pharmorubicin on the left ventricular ejection fraction of patients with breast cancer: A mechanism study. J Can Res Ther [serial online] 2018 [cited 2020 Aug 9];14:1183-7. Available from: http://www.cancerjournal.net/text.asp?2018/14/12/1183/247189
| > Introduction|| |
As the main type of cancer occurring in female patients, breast cancer is a global public problem which puts greats threat on female health., Mortality of breast cancer presents a descend trend due to scientific and technological progress., To be specific, early screening of breast cancer increases sensitivity and accuracy of early diagnosis, and comprehensive therapy of breast cancer improves efficacy., Therapeutic methods of breast cancer include surgical treatment, chemical treatment, drug treatment, and molecular targeting treatment whereas chemical treatment is the most common treatment for breast cancer., First-line drugs of chemical treatment are anthracyclines and tamoxifen, and pharmorubicin, a novel kind of anthracyclines, seems to have promising efficacy.,
The therapeutic mechanism of pharmorubicin is that pharmorubicin induces intercalation into DNA sequence and inhibits transcription so as repress gene expression of cancer cells. Although pharmorubicin treatment makes breast cancer become a kind of solid tumor with promising prognosis, increasing studies report defects and shortcomings of novel drug., For example, bleeding events always result from chemical treatment. Moreover, long-term use of pharmorubicin seems to cause cardiac dysfunction despite of its promising efficacy., In addition, it remains unclear how pharmorubicin induces cardiac dysfunction in patients with breast cancer. The previous study indicated increased oxygen free radical level was associated with worsen cardiac function, whereas anthracyclines were reported with such effect. However, no report was about effect of pharmorubicin on oxygen free radical level.
Reported with eliminating effect of oxygen free radical, N-acetylcysteine (NAC) plays a pivotal role in treatments of cancer and cardiovascular diseases and has get approval of the USA Food and Drug Administration., Thus, combination therapy of NAC and pharmorubicin may improve cardiac function of patients with breast cancer.
In summary, we hypothesized that pharmorubicin worsened cardiac function of patients with breast cancer through increasing oxygen free radical. Our study was aimed to explore the influence of pharmorubicin on the left ventricular ejection fraction (LVEF) of patients with breast cancer and its potential mechanism.
| > Materials and Methods|| |
Research object and grouping
The inclusion criteria and exclusion criteria are reported previously., Three hundred and ninety-nine patients with breast cancer were enrolled for our trial (age ranging from 30 to 70 years, average: 45. 1 ± 9. 4 years). Group I consisted of 135 samples, who were under treatment of pharmorubicin (200 mg/m2). Group II consisted of 144 samples, who were under treatment of pharmorubicin (360 mg/m2). Group III was used as control group, which consists of 120 samples without treatment of pharmorubicin. This study was under the approval of Local Ethics Committee.
Ultrasonic inspection and measurement
According to routine protocols, color Doppler ultrasonic inspection and measurement were performed to examine the index of cardiac function, including EF and fractional shortening (FS).
Collection of blood Sample
Venous blood was drawn from patients with breast cancer, and separation of hemocytes was performed as reported previously. Hemocytes samples for flow cytometry were prepared.
Flow cytometer detection for oxygen free radical
Oxygen free radical was assessed by flow cytometry with routine protocol. Details were as follows citrate anticoagulation was performed for blood sample. Centrifuge after mixing samples (2100 rpm/min, 5 min). Harvest hemocytes precipitation and resuspend hemocytes in coagulocytes (CGS) buffer solution. Fluorescein isothiocyanate-dichlorofluorescein solution was added and incubated away from light at room temperature. Flow cytometer was performed and examine at absorbance value at exciting wave 488 nm and absorption wave 625 nm.
Data analysis and statistics
SPSS 19.0 software (SPSS, Chicago, IL, USA) was used for data processing. Measurement data are normal distribution to X ± S. T-test was performed for statistical significance. P < 0.05 was considered to be statistically significant.
| > Results|| |
Ultrasonic findings of three groups
As showed in [Figure 1], color Doppler ultrasonic examination was performed for three groups, which included 399 samples. Among three groups, patients in Group III had ideal cardiac function, whereas Group I had worst cardiac function. Compared with Group I, Adjunctive therapy of NAC in Group II improved cardiac function, including increased LVEF and FS.
|Figure 1: Ultrasonic findings of three groups. Group number were marked on the top of graphs|
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Analysis of the left ventricular ejection fraction and fractional shortening
Analysis results showed that pharmorubicin treatment indeed jeopardized cardiac function, verified by decreased LVEF and FS. Moreover, NAC abrogated such side effect of pharmorubicin on cardiac function [Figure 2] and [Table 1].
|Figure 2: Analysis of the left ventricular ejection fraction and fractional shortening in three groups. White bar represents prior treatment of N-acetylcysteine, and black bar represents posttreatment of N-acetylcysteine. **P < 0. 05|
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|Table 1: Comparison of the left ventricular ejection fraction and fractional shortening in three groups|
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Detection of oxygen free radical levels in three groups
As described previously, we hypothesized pharmorubicin damaged heart through increasing oxygen free radical level. The results of flow cytometer were showed in [Figure 3] and [Table 2]. Compared with Group III, pharmorubicin treatment significantly increased oxygen free radical level in hemocytes.
N-acetylcysteine alleviated increased oxygen free radical
We further explored the effect of NAC, and offer additional NAC treatment for patients (showed as II + NAC group). As showed in [Table 3] and [Figure 3], NAC alleviated worsen oxygen free radical induced by pharmorubicin (P < 0. 05), suggesting adjunctive therapy of NAC might abrogate side effect of pharmorubicin through decreasing oxygen free radical.
|Table 3: Analysis of flow cytometer findings of N-acetylcysteine treatments|
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N-acetylcysteine alleviated cardiac dysfunction induced by pharmorubicin
Further ultrasonic examination proved that NAC indeed alleviated cardiac dysfunction induced by pharmorubicin [Table 4].
|Table 4: Analysis of further ultrasonic examination of N-acetylcysteine treatments|
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| > Discussion|| |
Our study proved that pharmorubicin treatment indeed worsen cardiac function in patients with breast cancer, which was consistent with the previous report. In addition, we demonstrated that pharmorubicin cause heart damage through increasing oxygen free radical level while NAC can be an ideal adjunctive drug for pharmorubicin to alleviate its side effect, suggesting that combination therapy of NAC and pharmorubicin should be considered in treatment of breast cancer.
Pharmorubicin was a first-line drug for the treatment of breast cancer with promising tumor-restricted efficacy, but some clinical study indicated pharmorubicin treatment was associated with poor prognosis of cardiovascular diseases, and observed in patients with breast cancer., Despite of unclear mechanisms, recent studies have provided some hints on how pharmorubicin influenced heart. For example, aberrant accumulation of pharmorubicin was found in heart, and in vitro experiment showed that pharmorubicin-induced dysfunction and excessive oxidative stress in both cardiomyocytes and hemocytes. However, there were no reports about how pharmorubicin induced side effects in vivo. Our study found that, in patients with breast cancer, oxygen free radical level of blood was significantly increased after pharmorubicin treatment, and excessive oxidative stress in peripheral blood has been thoroughly proved as a risk factor for cardiomyocytes. Thus, we proved in vivo that pharmorubicin treatment jeopardized cardiac function of patients with breast cancer through increasing oxygen free radical level in hemocytes. Further, we explore potential therapy to alleviated side effect of pharmorubicin. The previous study suggested that NAC was an alternative antioxidant for multiple diseases., Considering its characteristics, we used NAC as an adjunctive drug for patients. We are pleased to find that NAC indeed reduced oxidative stress in patients with breast cancer. Moreover, such treatment improved cardiac function, verified by color Doppler ultrasonic inspection, and measurement. All these findings indicated that side effect of pharmorubicin on cardiac function should be emphasized in clinical treatment, and NAC was recommend as adjunctive drug of pharmorubicin.
Another innovation point of our study is that we demonstrated color Doppler ultrasonic examination could be used as diagnosis tool to assess the cardiac function of patients with breast cancer. In summary, there are three main findings in our study. (1) Pharmorubicin influenced cardiac function of patients with breast cancer, verified by decreased LVEF, and FS. (2) Pharmorubicin increased oxygen free radical level of blood, which resulted in cardiac dysfunction. (3) Application of NAC abrogated side effect of pharmorubicin, and improved cardiac function.
Our study still has some shortcomings, which need further research. (1) Our study is based on a relatively small sample. (2) Direct evidence was warranted for better understanding of how pharmorubicin influenced cardiac function through oxygen free radical level. (3) Knockout mouse models should be established to test our findings.
Pharmorubicin treatment decreased EF and FS of patients with breast cancer through increasing oxygen free radical level in hemocytes. Adjunctive therapy of NAC could be a potential treatment to ameliorated side effect pharmorubicin treatment.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Bertucci F, Fekih M, Autret A, Petit T, Dalenc F, Levy C, et al.
Bevacizumab plus neoadjuvant chemotherapy in patients with HER2-negative inflammatory breast cancer (BEVERLY-1): A multicentre, single-arm, phase 2 study. Lancet Oncol 2016;17:600-11.
Yamaguchi N, Fujii T, Aoi S, Kozuch PS, Hortobagyi GN, Blum RH. Comparison of cardiac events associated with liposomal doxorubicin, epirubicin and doxorubicin in breast cancer: A Bayesian network meta-analysis. Eur J Cancer 2015;51:2314-20.
de Azambuja E, Ameye L, Diaz M, Vandenbossche S, Aftimos P, Bejarano Hernández S, et al.
Cardiac assessment of early breast cancer patients 18 years after treatment with cyclophosphamide-, methotrexate-, fluorouracil- or epirubicin-based chemotherapy. Eur J Cancer 2015;51:2517-24.
Vulsteke C, Pfeil AM, Maggen C, Schwenkglenks M, Pettengell R, Szucs TD, et al.
Clinical and genetic risk factors for epirubicin-induced cardiac toxicity in early breast cancer patients. Breast Cancer Res Treat 2015;152:67-76.
Hanusch C, Schneeweiss A, Loibl S, Untch M, Paepke S, Kümmel S, et al.
Dual Blockade with AFatinib and Trastuzumab as NEoadjuvant treatment for patients with locally advanced or operable breast cancer receiving taxane-anthracycline containing chemotherapy-DAFNE (GBG-70). Clin Cancer Res 2015;21:2924-31.
Krop IE, Suter TM, Dang CT, Dirix L, Romieu G, Zamagni C, et al.
Feasibility and cardiac safety of trastuzumab emtansine after anthracycline-based chemotherapy as (neo)adjuvant therapy for human epidermal growth factor receptor 2-positive early-stage breast cancer. J Clin Oncol 2015;33:1136-42.
Leonardi MC, Morra A, Santoro L, Balduzzi A, Ivaldi GB, Vischioni B, et al.
Nonrandomized comparison between concomitant and sequential chemoradiotherapy with anthracyclines in breast cancer. Tumori 2015;101:64-71.
Ayres LR, de Almeida Campos MS, de Oliveira Gozzo T, Martinez EZ, Ungari AQ, de Andrade JM, et al.
Trastuzumab induced cardiotoxicity in HER2 positive breast cancer patients attended in a tertiary hospital. Int J Clin Pharm 2015;37:365-72.
Watanabe N, Otsuka S, Sasaki Y, Shimojima R, Wani Y, Uchino K. Cardiac tolerability of concurrent administration of trastuzumab and anthracycline-based regimen as adjuvant chemotherapy for breast cancer. Breast Care (Basel) 2014;9:46-51.
Vivenza D, Feola M, Garrone O, Monteverde M, Merlano M, Lo Nigro C. Role of the renin-angiotensin-aldosterone system and the glutathione S-transferase Mu, Pi and Theta gene polymorphisms in cardiotoxicity after anthracycline chemotherapy for breast carcinoma. Int J Biol Markers 2013;28:e336-47.
Joensuu H, Kellokumpu-Lehtinen PL, Huovinen R, Jukkola-Vuorinen A, Tanner M, Kokko R, et al.
Outcome of patients with HER2-positive breast cancer treated with or without adjuvant trastuzumab in the Finland Capecitabine Trial (FinXX). Acta Oncol 2014;53:186-94.
Roca L, Diéras V, Roché H, Lappartient E, Kerbrat P, Cany L, et al.
Correlation of HER2, FCGR2A, and FCGR3A gene polymorphisms with trastuzumab related cardiac toxicity and efficacy in a subgroup of patients from UNICANCER-PACS 04 trial. Breast Cancer Res Treat 2013;139:789-800.
Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Hegg R, et al.
Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: A randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol 2013;24:2278-84.
Chow LW, Loo WT, Yip AY, Ng EL. Acceptable cardiac safety profile of neoadjuvant 5-fluorouracil, epirubicin, cyclophosphamide and celecoxib (FEC-C) for breast cancer: A subanalysis of biomarkers for cardiac injury. Int J Biol Markers 2013;28:E92-9.
Farolfi A, Melegari E, Aquilina M, Scarpi E, Ibrahim T, Maltoni R, et al.
Trastuzumab-induced cardiotoxicity in early breast cancer patients: A retrospective study of possible risk and protective factors. Heart 2013;99:634-9.
Heck SL, Gulati G, Ree AH, Schulz-Menger J, Gravdehaug B, Røsjø H, et al.
Rationale and design of the prevention of cardiac dysfunction during an Adjuvant Breast Cancer Therapy (PRADA) Trial. Cardiology 2012;123:240-7.
Sinnatamby M, Nagarajan V, Kanipakam Sathyanarayana R, Karunanidhi G, Singhavajala V. Study of the dosimetric differences between (192)Ir and (60)Co sources of high dose rate brachytherapy for breast interstitial implant. Rep Pract Oncol Radiother 2016;21:453-9.
De Santis MC, Nardone L, Diletto B, Canna R, Dispinzieri M, Marino L, et al.
Comparison of two radiation techniques for the breast boost in patients undergoing neoadjuvant treatment for breast cancer. Br J Radiol 2016;89:20160264.
Adams SC, Segal RJ, McKenzie DC, Vallerand JR, Morielli AR, Mackey JR, et al.
Impact of resistance and aerobic exercise on sarcopenia and dynapenia in breast cancer patients receiving adjuvant chemotherapy: A multicenter randomized controlled trial. Breast Cancer Res Treat 2016;158:497-507.
Di Franco R, Ravo V, Nieddu V, Crispo A, Falivene S, Giugliano FM, et al.
Detection of a numeric value predictive of increased dose to left anterior descending coronary artery (LAD) in radiotherapy of breast cancer. Springerplus 2016;5:841.
Lee J, Kim SW, Son SH. Dosimetric evaluation of incidental irradiation to the axilla during whole breast radiotherapy for patients with left-sided early breast cancer in the IMRT era. Medicine (Baltimore) 2016;95:e4036.
Wegorowski P, Stanislawek A, Domzal-Drzewicka R, Sysiak J, Rzaca M, Milanowska J, et al.
The effect of pre-emptive analgesia on the level of postoperative pain in women undergoing surgery for breast neoplasm. Contemp Oncol (Pozn) 2016;20:158-64.
Haciislamoglu E, Colak F, Canyilmaz E, Zengin AY, Yilmaz AH, Yoney A, et al.
The choice of multi-beam IMRT for whole breast radiotherapy in early-stage right breast cancer. Springerplus 2016;5:688.
Tiwari SR, Mishra P, Raska P, Calhoun B, Abraham J, Moore H, et al.
Retrospective study of the efficacy and safety of neoadjuvant docetaxel, carboplatin, trastuzumab/pertuzumab (TCH-P) in nonmetastatic HER2-positive breast cancer. Breast Cancer Res Treat 2016;158:189-93.
Chang JS, Chen J, Weinberg VK, Fowble B, Sethi RA. Evaluation of heart dose for left-sided breast cancer patients over an 11-year period spanning the transition from 2-dimensional to 3-dimensional planning. Clin Breast Cancer 2016;16:396-401.
Lu YF, Lin YC, Chen KH, Shueng PW, Yeh HP, Hsieh CH. Image-guided intensity-modulated radiotherapy for refractory bilateral breast cancer in a patient with extensive cutaneous metastasis in the chest and abdominal walls. Onco Targets Ther 2016;9:3025-30.
Chin-Yee NJ, Yan AT, Kumachev A, Ko D, Earle C, Tomlinson G, et al.
Association of hospital and physician case volumes with cardiac monitoring and cardiotoxicity during adjuvant trastuzumab treatment for breast cancer: A retrospective cohort study. CMAJ Open 2016;4:E66-72.
Obayomi-Davies O, Kole TP, Oppong B, Rudra S, Makariou EV, Campbell LD, et al.
Stereotactic accelerated partial breast irradiation for early-stage breast cancer: Rationale, feasibility, and early experience using the CyberKnife radiosurgery delivery platform. Front Oncol 2016;6:129.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]