Open Access

V5 and High Sensitivity Cardiac Troponin T for Early Detection of Cardiac Toxicity During Left Breast Cancer Irradiation


1Radiation Oncology, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy

2Radiation Oncology, INI s.p.a Divisione Città Bianca, Rome, Italy

3Radiation Oncology, Department of Biomedicine and Prevention, Università Tor Vergata di Roma, Rome, Italy

Cancer Diagnosis & Prognosis May-June; 3(3): 365-369 DOI: 10.21873/cdp.10225
Received 15 December 2022 | Revised 07 December 2023 | Accepted 01 March 2023
Corresponding author
Vera Cirnigliaro, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo, 21-00128 Rome, Italy. Tel: +39 3383419437, email:


Background/Aim: The high sensitivity cardiac troponin T (Hs-cTnT) is a myocardial damage biomarker that could have a predictive value in patients who undergo radiotherapy for left sided breast cancer. The aim of this study was to evaluate the early effect of left whole breast radiotherapy (WB-RT) on serum Hs-cTnT levels and its correlation with pre-existing factors. Patients and Methods: The study was conducted from December 2017 to May 2018. Forty-five patients with early stage left-sided breast cancer who received adjuvant breast hypofractionated RT without prior chemotherapy were included. Serum levels of Hs-cTnT were obtained before, weekly during RT, and within one week after the end of treatment. Considering the physiological variations of serum levels, an increase in Hs-cTnT (∆Hs-cTnT) of more than 30% from the baseline value was chosen as a threshold. The main cardiovascular risk factors were recorded. Dose volume histograms (DVHs) were used to provide a quantitative analysis for the whole heart, left ventricle, and left anterior descending artery (LAD). Results: Twelve of 45 patients (26.6%) showed a ∆Hs-cTnT ≥30%. The maximum Hs-cTnT level was recorded in the last week of treatment. ∆Hs-cTnT was strongly associated with heart V5 (p=0.05) and hypertension (p=0.05). Multivariate analysis confirmed the importance of the heart V5 and correlated with ∆Hs-cTnT. Conclusion: The increase in Hs-cTnT serum levels during adjuvant WB-RT suggested a correlation with the cardiac radiation dose in chemotherapy-naive breast cancer patients. A longer follow-up is needed to correlate Hs-cTnT values with cardiac events.
Keywords: High-sensitivity troponin T, cardiac toxicity, radiotherapy, breast cancer, V5

Adjuvant radiotherapy is a standard treatment for early stage breast cancer. Radiotherapy reduced the 10-year risk of any first recurrence from 35.0% to 19.3% and reduced the 15-year risk of breast cancer death from 25.2% to 21.4% (1), however there is potential for cardiac and pulmonary toxicity (2). Darby et al. recorded in 2013 that the rate of major coronary events increased linearly with the mean dose to the heart by 7.4% per gray in patients with left-sided breast cancer. Cardiovascular events could occur within the first 5 years after radiotherapy (RT) completion and continue up to 30 years after treatment (3). Damage to cardiac micro and macro-vasculature is the pathophysiological cause of radiation-related heart disease, with a predominance of ischaemic heart disease (4). This indicates that the coronary arteries, and the left anterior descending artery (LAD), may be a critical structure for the development of late radiation-induced heart morbidity. The risk of radiation-induced cardiotoxicity may be increased by baseline patient cardiac risk factors and systemic therapies (5,6), such as anthracyclines, trastuzumab, taxanes, tamoxifen (7,8). Furthermore, serum biomarkers may play an important role in the detection of heart damage after radiotherapy. Cardiac biomarkers have been applied for early identification, evaluation, and monitoring cardiotoxicity during chemotherapy (9).

High-sensitivity cardiac troponin T (Hs-cTnT) is a biomarker of myocardial damage and may have a predictive value in patients who underwent radiotherapy for left sided breast cancer (10,11). Cardiac troponins (cTn) are structural proteins that bind to the actin complexes in myofilaments and regulate muscle contraction by interacting with calcium ions and inhibiting the ATPase activity of actinomyosin. cTn represents a complex composed of three subunits: troponin T (cTnT), troponin I (cTnI), and troponin C (cTnC) (12). cTn have high specificities and high sensitivity for myocardial injury and are used in the diagnosis and risk stratification of acute coronary syndromes.

The aim of this study was to evaluate the early effect of left whole breast radiotherapy (WB-RT) on serum Hs-cTnT levels and to correlate them with radiation dose, to the whole heart, to its substructures and to patients’ clinical features.

Patients and Methods

Population. We conducted a prospective observational study between December 2017 and May 2018. A total of 45 consecutive patients with early stage left-sided breast cancer or ductal carcinoma in situ (DCIS) were analyzed. Exclusion criteria were: age over 75 years, previous chemotherapy treatment, pre-existing heart disease, severe lung disease, kidney failure, and autoimmune disease. Patients with pharmacologically treated hypertension were included. The main cardiovascular risk factors were recorded. All patients were treated with adjuvant conformal 3D RT after surgery in the supine position using “wing board” with arms above heads, computed tomography scan was performed with 2.5 mm thickness, without intravenous contrast. Conformal treatment plans were obtained using the Pinnacle treatment planning system (Phillips Medical Systems, Andover, MA, USA) and were delivered using an Elekta Precise linear accelerator. Treatment was given to a total dose of 42.5 Gy in 16 fractions over 3 weeks with eventually an additional boost to tumor bed.

High sensitivity cardiac troponin (Hs-cTnT) was analyzed in serum samples taken before RT (T0), weekly during the first, (T1), the second (T2) and the third week (T3) and one week after the end of the treatment (T4). Blood sampling was carried out in the timeslot between 8:00 and 9:00 am, since diurnal variation of troponin were observed with a decline in values of 0.8% per hour from 8:30 am to 2:30 pm (13).

Considering the physiological variations of serum levels, a significant increase in Hs-cTnT levels during RT was predefined to exceed 30% from baseline value in this protocol. Dose volume histograms (DVHs) were used to provide a quantitative analysis. The maximum dose and the mean dose and dose-volume parameters V5, V10, V15, V20, V25, and V30 were evaluated for the whole heart, left ventricle, and LAD. A comprehensive echocardiography study and 12-lead electrocardiogram (ECG) were performed at the baseline and at the end of RT. The study was approved by the local Ethics Committee and written consent was obtained for all patients.

Statistical analysis. Data are expressed as means±standard deviation (SD) for normally distribute continuous variables and as medians with inter-quartile range (IQR) for variables with non-normal distribution.

Statistical analyses were performed using MedCalc for Windows, version 17.9.6 (Medcalc Software, Ostend, Belgium). The χ2 test was performed for the correlation between ∆Hs-cTnT and clinical and dosimetric variables. Multivariate analysis was performed using binary logistic regression. Statistical significance was set at p<0.05.


Baseline characteristics of the patients are presented in Table I. Median Hs-cTnT for the whole study population was 3.1 ng/l before RT (IQR=3.0-5.7), 3.4 ng/l at 1 week (IQR=3-6), 4.8 ng/l at 2 weeks (IQR=3.0-6.0), 5.1 ng/l at 3 weeks (IQR=3.2-7.0) and 5.5 ng/l after RT (IQR=3.3-7.5). Hs-cTnT increased over 30% from the baseline value in 12/45 (26%) patients.

In these 12 patients, median Hs-cTnT was 3.1 ng/l before RT (IQR=3.0-5.3), 5.0 ng/l at 1week (IQR=3.3-6.8), 3.5 at 2 weeks (IQR=3.0-5.0), 7.4 at 3 weeks (IQR=4.1-10.2), 6.3 after RT (IQR=4.3-8.1) (Figure 1A). An increase in Hs-cTnt was not accompanied by early clinical changes in ECG or echocardiography. Finally, for the remaining 33 patients, median values at the same time points were: 4 ng/l (IQR=3.0-6.5), 3.8 ng/l (IQR=3.0-6.7), 4.2 ng/l (IQR=3.0-6.3), 3.6 ng/l (IQR=3.0-6.3), and 3.8 ng/l (IQR=3.0-6.7), respectively (Figure 1B).

Dose-volumes parameters are shown in Table II. The following maximum and average dose values [median (IQR)] were recorded for LAD: 33.7 Gy (IQR=14.4-42.1) and 6.4 Gy (IQR=3.3-11.7). For the maximum and average doses, the following values for the left ventricle were recorded [median (IQR)]: 40.2 Gy (IQR=17.5-42.3) and 2.2 Gy (IQR=1.4-3.5).

Univariate analysis (Table III) revealed that ∆Hs-cTnT is strongly associated with heart V5 (p=0.05) and pre-existing hypertension (p=0.05). Multivariate analysis confirmed the correlation between heart V5 and ∆Hs-cTnT (HR=3.75, 95%CI=0.9-14,8; p<0.005).


Several studies have shown the correlation between heart exposure to irradiation and an increased risk of heart disease (14). Although morbidity of radiation induced heart disease (RIHD) has been reduced by optimizing treatment plan and techniques, recent studies have shown that modern technology does not eliminate the risk of RIHD (15,16).

Specifically, patients with left side breast cancer clearly present higher risk for developing cardiac events in comparison with right –sided one’s (3). The early detection of radiation –induced cardiac toxicity may potentially indicate patients that will develop late toxicity among breast cancer survivors. The cardiac troponin has been extensively studied as early detector of cardiac toxicity resulting from anticancer therapies (17). Several studies have evaluated the increased levels of this biomarker after radiotherapy and suggested that the cardiac troponin could be a potential marker of early radiation-induced heart damage. Cramer et al. found a correlation between irradiation doses to cardiac tissue and Hs-cTnT (18). In patients with increased levels of this biomarker, the mean heart dose and mean LV were significantly higher (18). In our observational prospective study, we analyzed Hs-cTnT before, during, and after radiotherapy in chemotherapy–naive breast cancer patients.

The Hs-cTnT is a well-established biomarker of acute myocardial infarction (AMI) (19,20). In addition, elevated Hs-cTnT levels can be detected in chronic heart failure (21) and LV hypertrophy (22,23). The values of Hs-cTnT in healthy individuals show variations in the different published studies; the 99th percentile differs from 12 ng/l (24) to 20 ng/l (25) and it has been shown that these values are influenced by patient age, sex and comorbidities (26). Excluding patients with known heart diseases, it is estimated that the median Hs-cTnT in women aged 55 to 75 years is 3 ng /l (26). Based on these data and considering the physiological weekly and diurnal changes in Hs-cTnT, an increase more than 30% from baseline value was interpreted as significant (17). In our series, 12/45 (26%) patients recorded an increase in the levels of this biomarker, mainly during the last week of RT; however, during a median of 3 years follow-up, no cardiac event was recorded. To correlate the rise in troponin levels with the risk of long-term cardiovascular morbidity and mortality, a longer follow-up is needed, since the cardiotoxic effects of RT tend to increase even after long periods of irradiation (3).

Moreover, a correlation with hearth V5 was also observed. This suggests that V5 and its correlation with a serum biomarker could represent a potential tool to predict myocardial damage leading to an appropriate stratification of patients at greater risk for long-term cardiac toxicity. A prolonged follow-up seems mandatory to obtain long-term results.

Conflicts of Interest

The Authors declare that they have no competing interests in relation to this study.

Authors’ Contributions

All Authors participated in the study design and coordination and discussed the outcome during the study.


1 Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) Darby S McGale P Correa C Taylor C Arriagada R Clarke M Cutter D Davies C Ewertz M Godwin J Gray R Pierce L Whelan T Wang Y & Peto R Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet. 378(9804) 1707 - 1716 2011. PMID: 22019144. DOI: 10.1016/S0140-6736(11)61629-2
2 Patt DA Goodwin JS Kuo YF Freeman JL Zhang DD Buchholz TA Hortobagyi GN & Giordano SH Cardiac morbidity of adjuvant radiotherapy for breast cancer. J Clin Oncol. 23(30) 7475 - 7482 2005. PMID: 16157933. DOI: 10.1200/JCO.2005.13.755
3 Darby SC Ewertz M McGale P Bennet AM Blom-Goldman U Brønnum D Correa C Cutter D Gagliardi G Gigante B Jensen MB Nisbet A Peto R Rahimi K Taylor C & Hall P Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med. 368(11) 987 - 998 2013. PMID: 23484825. DOI: 10.1056/NEJMoa1209825
4 Senkus-Konefka E & Jassem J Cardiovascular effects of breast cancer radiotherapy. Cancer Treat Rev. 33(6) 578 - 593 2007. PMID: 17764850. DOI: 10.1016/j.ctrv.2007.07.011
5 Darby SC McGale P Taylor CW & Peto R Long-term mortality from heart disease and lung cancer after radiotherapy for early breast cancer: prospective cohort study of about 300,000 women in US SEER cancer registries. Lancet Oncol. 6(8) 557 - 565 2005. PMID: 16054566. DOI: 10.1016/S1470-2045(05)70251-5
6 Hooning MJ Botma A Aleman BM Baaijens MH Bartelink H Klijn JG Taylor CW & van Leeuwen FE Long-term risk of cardiovascular disease in 10-year survivors of breast cancer. J Natl Cancer Inst. 99(5) 365 - 375 2007. PMID: 17341728. DOI: 10.1093/jnci/djk064
7 Ng R Better N & Green MD Anticancer agents and cardiotoxicity. Semin Oncol. 33(1) 2 - 14 2006. PMID: 16473642. DOI: 10.1053/j.seminoncol.2005.11.001
8 Telli ML Hunt SA Carlson RW & Guardino AE Trastuzumab-related cardiotoxicity: calling into question the concept of reversibility. J Clin Oncol. 25(23) 3525 - 3533 2007. PMID: 17687157. DOI: 10.1200/JCO.2007.11.0106
9 Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC) Steg PG James SK Atar D Badano LP Blömstrom-Lundqvist C Borger MA Di Mario C Dickstein K Ducrocq G Fernandez-Aviles F Gershlick AH Giannuzzi P Halvorsen S Huber K Juni P Kastrati A Knuuti J Lenzen MJ Mahaffey KW Valgimigli M van ‘t Hof A Widimsky P & Zahger D ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J. 33(20) 2569 - 2619 2012. PMID: 22922416. DOI: 10.1093/eurheartj/ehs215
10 Erven K Florian A Slagmolen P Sweldens C Jurcut R Wildiers H Voigt JU & Weltens C Subclinical cardiotoxicity detected by strain rate imaging up to 14 months after breast radiation therapy. Int J Radiat Oncol Biol Phys. 85(5) 1172 - 1178 2013. PMID: 23149005. DOI: 10.1016/j.ijrobp.2012.09.022
11 Nellessen U Zingel M Hecker H Bahnsen J & Borschke D Effects of radiation therapy on myocardial cell integrity and pump function: which role for cardiac biomarkers. Chemotherapy. 56(2) 147 - 152 2010. PMID: 20407242. DOI: 10.1159/000313528
12 de Lemos JA Increasingly sensitive assays for cardiac troponins: a review. JAMA. 309(21) 2262 - 2269 2013. PMID: 23736735. DOI: 10.1001/jama.2013.5809
13 Aakre KM Røraas T Petersen PH Svarstad E Sellevoll H Skadberg Ø Sæle K & Sandberg S Weekly and 90-minute biological variations in cardiac troponin T and cardiac troponin I in hemodialysis patients and healthy controls. Clin Chem. 60(6) 838 - 847 2014. PMID: 24619542. DOI: 10.1373/clinchem.2013.216978
14 Lohr F El-Haddad M Dobler B Grau R Wertz HJ Kraus-Tiefenbacher U Steil V Madyan YA & Wenz F Potential effect of robust and simple IMRT approach for left-sided breast cancer on cardiac mortality. Int J Radiat Oncol Biol Phys. 74(1) 73 - 80 2009. PMID: 18973977. DOI: 10.1016/j.ijrobp.2008.07.018
15 Boero IJ Paravati AJ Triplett DP Hwang L Matsuno RK Gillespie EF Yashar CM Moiseenko V Einck JP Mell LK Parikh SA & Murphy JD Modern radiation therapy and cardiac outcomes in breast cancer. Int J Radiat Oncol Biol Phys. 94(4) 700 - 708 2016. PMID: 26972642. DOI: 10.1016/j.ijrobp.2015.12.018
16 Boekel NB Schaapveld M Gietema JA Russell NS Poortmans P Theuws JC Schinagl DA Rietveld DH Versteegh MI Visser O Rutgers EJ Aleman BM & van Leeuwen FE Cardiovascular disease risk in a large, population-based cohort of breast cancer survivors. Int J Radiat Oncol Biol Phys. 94(5) 1061 - 1072 2016. PMID: 27026313. DOI: 10.1016/j.ijrobp.2015.11.040
17 Cardinale D Sandri MT Colombo A Colombo N Boeri M Lamantia G Civelli M Peccatori F Martinelli G Fiorentini C & Cipolla CM Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy. Circulation. 109(22) 2749 - 2754 2004. PMID: 15148277. DOI: 10.1161/01.CIR.0000130926.51766.CC
18 Cramer G Bakker J Gommans F Brouwer M Kurvers M Fouraux M Verheugt F & Kofflard M Relation of highly sensitive cardiac troponin T in hypertrophic cardiomyopathy to left ventricular mass and cardiovascular risk. Am J Cardiol. 113(7) 1240 - 1245 2014. PMID: 24513467. DOI: 10.1016/j.amjcard.2013.12.033
19 Reichlin T Hochholzer W Bassetti S Steuer S Stelzig C Hartwiger S Biedert S Schaub N Buerge C Potocki M Noveanu M Breidthardt T Twerenbold R Winkler K Bingisser R & Mueller C Early diagnosis of myocardial infarction with sensitive cardiac troponin assays. N Engl J Med. 361(9) 858 - 867 2009. PMID: 19710484. DOI: 10.1056/NEJMoa0900428
20 Reichlin T Cullen L Parsonage WA Greenslade J Twerenbold R Moehring B Wildi K Mueller S Zellweger C Mosimann T Rubini Gimenez M Rentsch K Osswald S & Müller C Two-hour algorithm for triage toward rule-out and rule-in of acute myocardial infarction using high-sensitivity cardiac troponin T. Am J Med. 128(4) 369 - 79.e4 2015. PMID: 25446294. DOI: 10.1016/j.amjmed.2014.10.032
21 Jungbauer CG Riedlinger J Buchner S Birner C Resch M Lubnow M Debl K Buesing M Huedig H Riegger G & Luchner A High-sensitive troponin T in chronic heart failure correlates with severity of symptoms, left ventricular dysfunction and prognosis independently from N-terminal pro-b-type natriuretic peptide. Clin Chem Lab Med. 49(11) 1899 - 1906 2011. PMID: 21892905. DOI: 10.1515/CCLM.2011.251
22 Miao DM Zhang LP Yu HP Zhang JY Xiao WK & Ye P Serum levels of high-sensitivity troponin T: a novel marker for left ventricular remodeling and performance in hypertensive subjects. Genet Mol Res. 13(3) 5143 - 5153 2014. PMID: 25061739. DOI: 10.4238/2014.July.7.7
23 Cramer G Bakker J Gommans F Brouwer M Kurvers M Fouraux M Verheugt F & Kofflard M Relation of highly sensitive cardiac troponin T in hypertrophic cardiomyopathy to left ventricular mass and cardiovascular risk. Am J Cardiol. 113(7) 1240 - 1245 2014. PMID: 24513467. DOI: 10.1016/j.amjcard.2013.12.033
24 Latini R Masson S Anand IS Missov E Carlson M Vago T Angelici L Barlera S Parrinello G Maggioni AP Tognoni G Cohn JN & Val-HeFT Investigators Prognostic value of very low plasma concentrations of troponin T in patients with stable chronic heart failure. Circulation. 116(11) 1242 - 1249 2007. PMID: 17698733. DOI: 10.1161/CIRCULATIONAHA.106.655076
25 Apple FS Ler R & Murakami MM Determination of 19 cardiac troponin I and T assay 99th percentile values from a common presumably healthy population. Clin Chem. 58(11) 1574 - 1581 2012. PMID: 22983113. DOI: 10.1373/clinchem.2012.192716
26 Koerbin G Abhayaratna WP Potter JM Apple FS Jaffe AS Ravalico TH & Hickman PE Effect of population selection on 99th percentile values for a high sensitivity cardiac troponin I and T assays. Clin Biochem. 46(16-17) 1636 - 1643 2013. PMID: 23978509. DOI: 10.1016/j.clinbiochem.2013.08.004