Graphical abstract
We thank Drs Xiang and Wu for their thoughtful considerations regarding our study.1
Indeed, in our study we discussed the possibility that circulating pretreatment vascular and inflammatory biomarkers may reflect aggressive tumor biology. Although we did not find a significant association between baseline circulating ANGPT2, MPO, or ENG level and tumor stage (Figure 1), it is possible that molecular features of the tumor may underlie circulating inflammatory and endothelial signatures. ANGPT2, MPO, and ENG may originate from the tumor itself. For example, ANGPT2 and ENG could reflect the proangiogenic microenvironment of the tumor and are known to facilitate breast tumor cell invasion and promote metastasis.2,3 Similarly, increased MPO may represent heightened neutrophil recruitment and tumor-associated inflammation, which are associated with poor cancer prognosis.4 Delineating the expression and functional impact of these factors within the tumor vs the cardiovascular system in preclinical models is warranted.
Figure 1.
ANGPT2, MPO, and ENG Levels in Plasma Do Not Correlate With Cancer Stage
Pretreatment circulating levels of ANGPT2, MPO, and ENG were measured using enzyme-linked immunosorbent assay in all patients from the EMBRACE-MRI (Evaluation of Myocardial Changes During BReast Adenocarcinoma Therapy to Detect Cardiotoxicity Earlier With MRI) cohort (n = 136). Spearman correlations are provided. There were no significant correlations with cancer stage.
We used cardiac magnetic resonance (CMR) imaging because it is considered the most accurate and reproducible imaging modality for measuring left ventricular ejection fraction. However, we also performed a sensitivity analysis to evaluate the use of echocardiography rather than CMR for cancer therapy–related cardiac dysfunction (CTRCD) detection and model performance. Using CMR measurements, there were 37 cases of CTRCD. With the ANGPT2+MPO+ENG-only model, the area under the receiver operating characteristic curve and specificity were 0.97 and 0.88, respectively. Using the same criteria and model, but with echocardiography, there were 32 cases of CTRCD, and the area under the curve and specificity were 0.83 and 0.53, respectively. These data are provided in Supplemental Figure VB in our paper.1 Although the model performed slightly less well with echocardiography, it was still strongly predictive. This suggests that the model should perform well in the real world, where echocardiography is more accessible, although this will need to be tested in external cohorts.
Finally, we agree that the ANGPT/Tie2 axis is an intriguing target for cardioprotection. In addition to its roles in tumor growth and metastasis, this axis may represent a cardioprotective target, as ANGPT1 protects the heart from ischemia-reperfusion injury.5 Whether this pathway can be exploited to improve cardiotoxicity outcomes remains to be explored.
Footnotes
Dr Mistry was funded by a Vanier Canada Graduate Doctoral Award from the Canadian Institutes of Health Research and an Ontario Graduate Scholarship. Dr Gustafson was funded by a Frederick Banting and Charles Best Canada Graduate Scholarship Doctoral Award, a Ted Rogers Centre for Heart Research Studentship, and an Ontario Graduate Scholarship. Research in the laboratory of Dr Fish was supported by project grants from the Canadian Institutes of Health Research (PJT148487, PJT175301, and PJT198168), a Canada Foundation for Innovation Grant, the John R. Evans Leaders Fund, and the Ontario Research Fund. Cardio-oncology research in the laboratory of Dr Thavendiranathan was supported by the Peter Munk Cardiac Centre Innovation Grant Program, a Ted Rogers Centre for Heart Research Grant, a Heart and Stroke Foundation Project Grant-in-Aid (G-20-0029537), and project grants from Canadian Institutes of Health Research (PJT175301 and PJT198168). Dr Thavendiranathan was supported by a Tier 2 Canada Research Chair in Cardio-Oncology (CRC-2019-00097/CRC-2023-00422) and the Canadian Cancer Society/Canadian Institutes of Health Research’s W. David Hargraft grant. Drs Gustafson, Thavendiranathan, and Fish are coinventors on a submitted patent related to these findings. Ms Mistry has reported that she has no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
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