biomarkers for the early detection of cancer treatment induced cardiotoxicity
In this thesis, the role of several imaging and nonimaging markers for the detection ofanthracycline-induced and trastuzumab-induced cardiotoxicity (respectively AIC and TIC)is evaluated. Especially, the pathophysiology of these processes and the interrelationship of the various markers are emphasised. Cardiotoxicity can be divided in acute, early-onset chronic and late-onset chronic cardiotoxicity. Acute cardiotoxicity is usually reversible and self-limiting, while the chronic variant persists after discontinuation of therapy and can potentially lead to congestive heart failure, arrhythmia and even death, up to twenty years after treatment. Since thesurvival of breast cancer patients keeps improving, the role of chronic cardiotoxicity a sa long-term side effect provides new challenges in the management of patients.
Ben Bulten is a PhD student in the research group Biomedical Photonic Imaging, directed by Wiendelt Steenbergen. Promotor is Lioe-Fee de Geus-Oei.
Furthermore, the increasing frequency of trastuzumab (and analogues like pertuzumab) as an adjuvant agent in human epidermal receptor 2 (HER2)-positive breast cancer could further increase the incidence of serious cardiac side effects. The current aim of cardio-oncologistsis therefore to identify patients at risk of developing these problems in a minimally invasive way. To date, cardiac function is assessed by conventional echocardiography or multigated radionuclide angiography (MUGA) and expressed as left ventricle ejection fraction (LVEF).
In the first part of this thesis, the findings of the TOXTAC study are presented. In this study,a cohort of anthracycline-treated breast cancer patients was assessed with different methods that probably are able to detect AIC. One of these, 2D strain imaging, is a new echocardiographic method to image the relative deformation of the cardiac wall. In 18%of our patients, global longitudinal strain (GLS) was decreased one year after treatment, while conventional echocardiographic parameters (including LVEF) remained normal. Furthermore, strain rate measurements, which depict the rate of wall deformation, showed a significant decrease compared to reference groups. Of the evaluated biomarkers, only N-terminal pro brain natriuretic peptide (NT-proBNP) showed promising results,returning an abnormal value in 18% of patients and significantly correlating with LVEF.Troponin I was not elevated, nor were other biomarkers like tumour necrosis factor α (TNF-α), soluble Fms-like tyrosine kinase 1 (sFlt-1), ST2 and galectin-3. The molecular imaging biomarker Iodine-123-meta-iodobenzylguanidine (123I-mIBG) was assessed, to depict the sympathetic response of the heart. Of the available parameters derived from this method, the delayed whole heart (WH) heart-to-mediastinum (H/M) ratio proved to be the most robust. Global radial strain was the only parameter of the other methods that predicted the delayed WH H/M ratio by multivariate analysis. Although trastuzumab in general induces reversible cardiotoxicity, it could become chronic, affecting the quality of life and aggravating AIC. The occurrence of TIC is therefore monitored by LVEF measurements through MUGA, indicating systolic dysfunction (SD).However, diastolic dysfunction (DD), which can also be evaluated by MUGA, might occur before SD, enabling detection of TIC before functional impairment takes place. In our study we could not find a significant difference in the time-to-occurrence of DD compared to SD. On the other hand, in 27% of patients a decrease in diastolic function without SD was seen, while only 16% of patients showed a decrease in systolic function without DD.In a small subgroup of patients with advanced (metastasised) breast cancer, 85% of patients developed DD, while 54% developed SD, but time-to-occurrence did not differ.The time-to-occurrence did differ in the subgroup of anthracycline-naive patients.
In conclusion, MUGA-derived DD seems unsuitable for the early detection of TIC. Many factors can affect the 123I-mIBG scintigraphic H/M ratio. Two of them, the presence of catecholamines in the circulation and the cardiac region of interest (ROI), were examinedin this thesis. We showed that circulating catecholamines, which are secreted by several hormonal active tumours, affect the calculation of the H/M ratio in such a way, that reliable assessment of the cardiac function by 123I-mIBG scintigraphy is not possible. This means that for children with neuroblastoma, often receiving high doses of anthracyclines, another method should be developed to assess their cardiotoxicity risk. The second factor, ROI placement, was also studied in this patient group. The ROI is the region of the heart (and the mediastinum) that is included in the H/M ratio calculation. The mediastinal ROI is generally drawn in the same way throughout literature, but for the heart ROI different approaches are used: the whole heart region, the left ventricular wall region and the small left ventricular wall region. For our patient group we concluded that the WH method should be used, since it provides the best interobserver agreement. However, in a patient group that contains patients with a dilated cardiomyopathy, this method could underestimate the H/M ratio since it includes a relatively large part of cardiac blood pool.
For these patients, the left ventricular wall ROI is probably more reliable. In the last chapter of this thesis we evaluated cardiac metabolism during anthracycline administration. In this preclinical study, mice were exposed to one, two, three or four cycles of doxorubicin, while cardiac molecular mechanisms were monitored by 99mTc-Annexin V, 99mTc-sestamibi, 99mTc-glucaric acid and 18F-FDG. Also, after each cycle mice were sacrificed to study the cardiac expression of several nonimaging markers including Bcl-2, Caspase 3 and 8, TUNEL, HIF-1α, p53 and JC-1. We observed a significant increase of cardiac uptake of all radiopharmaceuticals as compared to control mice.99mTc-Annexin V uptake increased at low cumulative anthracycline dose and correlated strongly to histological apoptosis markers, suggesting to allow apoptosis imaging early in the process of cardiotoxicity. 18F-FDG also increased at low cumulative dose and remained high during subsequent doses, implicating a fast glucose-mediated adaptive response, but also a high potential for reversibility, which could be used for patient risk stratification.
Starting-time: 12.30h in Building Waaier - Prof.dr. G. Berkhoff-zaal
