Editor's Note: This is the Con article of a two-part Pro/Con Expert Analysis. Click here for the Pro article.

The history of the classification of Type I and Type II treatment-related cardiac dysfunction goes back nearly 2 decades. In 1998, trastuzumab had been shown to be highly effective in the treatment of human epidermal growth factor receptor 2-positive breast cancer, a form that had an unusually poor prognosis before the introduction of trastuzumab. Cardiotoxicity related to trastuzumab exposure had not been anticipated, and the early report by Slamon et al. drew attention to significant rates of cardiotoxicity and was of considerable concern. The incidence and extent of reported cardiac dysfunction exceeded what had been observed with the anthracyclines.¹ Cardiac dysfunction after anthracyclines was a well-recognized entity that had been extensively studied, both invasively with heart biopsies and with noninvasive testing.² After the observation of trastuzumab-related cardiotoxicity, the initial perception was that another agent had been found that caused the same clinical picture (i.e., decreased systolic function and the potential to cause clinically relevant, and sometimes severe, heart failure). This led to a summit held in July 1998 to explore how this new agent might be used safely.³ There was considerable concern and the expression of need for caution and that "prudent medical practice mandates that physicians learn more about the mechanisms of trastuzumab-induced cardiotoxicity and develop algorithms for assessing risk/benefit ratios before extending the use of this agent to patients with less invasive forms [i.e., use in the adjuvant setting] of breast cancer."⁴

To investigate the true extent of the problem, a number of adjuvant trials were initiated. They were designed conservatively so that patients who might have been cured of their disease through surgical intervention would not be exposed to excessive risk through the adjuvant use of trastuzumab. Years later, as the preliminary results of these adjuvant trials were being analyzed and as some anecdotal observations were made, including results from myocardial biopsies, the commentary by Ewer et al. in the Journal of Clinical Oncology "Type II chemotherapy-related cardiac dysfunction: time to recognize a new entity" was published.⁵ It established the fact that has now become obvious to most observers: the cardiac damage associated with trastuzumab was, and remains, inherently different from that seen with the anthracyclines: the damage seen on biopsy is hugely different, and the cumulative dose relationship that is well-established for the anthracyclines is not present with trastuzumab. Treatment-related cardiac injury could no longer be considered a single or fungible entity. The clinical manifestations of both forms of damage may show considerable overlap, and although they cannot be distinguished from each other even with modern ultrasound modalities, the cardiac effects of trastuzumab and the anthracyclines differ in a number of highly relevant ways that reflect the mechanistic differences that result in their respective injuries.

The concept that trastuzumab cardiotoxicity differed from what had been seen before was quickly embraced, and since the publication of the Ewer et al. commentary, the position that cardiotoxicity is a fungible entity is no longer seriously considered. Anthracyclines cause direct myocyte injury as a cumulative dose-related injury that is readily seen on cardiac ultrastructure and that eventually leads to cell death with ongoing exposure. Yet there is no evidence in humans that trastuzumab myocardial cellular effects are in this category; this includes reports where myocardial biopsy has been performed.^6-10 The fact that the Ewer et al. commentary is still being cited, and the fact that that total cites now exceed 400, speak to the ongoing interest in these variances.

Interestingly, the well-known adjuvant trials were set up, in part, to explore the extent of trastuzumab cardiotoxicity under the presumption that all cardiotoxicity was equal. Many women were excluded from the trastuzumab portions of the trial due to concerns of toxicity. The recognition that we were dealing with something different with trastuzumab occurred during these trials and was a driving factor in allowing the trials to be completed. The approval of trastuzumab for use in the adjuvant setting ensued as a result of these trials. It is, perhaps, unfortunate that the strict monitoring introduced in those trials, before the recognition of mechanistic variance, helped establish and dictate monitoring schedules that are still advocated by some. These schedules may be outdated, burdensome, and costly.

As might be expected from any report that differs from established thought, the publication of the Ewer et al. commentary garnished concern. It was recognized that although reversibility was reported, what was seen with trastuzumab was not always reversible.¹¹ Later, it became clear that trastuzumab treatment was, at least in some patients, associated with troponin release. There is no doubt that these instances exist, but we now have good evidence as to why.¹² What had not been known in 2005 was that trastuzumab could interfere with cell repair, and the biology pathways related to this inhibitory antibody's effects in the heart are certainly different from the anthracyclines.¹³

The explanation, which may not represent the final chapter of this story, is that the anthracycline injury leaves a pool of vulnerable cells, some of which would go on to recover, which may take weeks or months. In the presence of a substance that blocks cell repair, as has been reported to occur with trastuzumab, there is increased apoptosis; troponin is released, and additional cell loss may be sufficiently large to preclude full functional recovery.^14,15 These explanations have not been widely challenged; they are underscored by the fact that the incidence of cardiotoxicity is inversely related to the interval between the end of anthracycline administration and the start of trastuzumab. The incidence is highest if the drugs are used together, intermediate if there is a 3-week pause, and return almost to baseline when the interval was 89 days, as was the case in the HERA (Herceptin Adjuvant) trial.¹⁶ There are anecdotal reports of many patients who have been on trastuzumab for extended periods of greater than 5 years in the metastatic setting without serious cardiac sequelae.

As further expressions of acceptance for this way of classifying, or at least mentally organizing, what is clearly a mechanistic difference, a number of recent consensus statements make use of or reference this scheme. Three have received considerable recent attention. In "Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging," the panel incorporated and referenced the Type I and Type II characteristics.¹⁷ The European Society of Cardiology position paper on cancer treatment references the original commentary and calls attention to all of the characteristics. They note that "generally, trastuzumab-associated cardiotoxicity is not believed to be cumulative-dose related..." and that "trastuzumab-induced LV dysfunction and HF are usually reversible..."¹⁸ Lastly, the American Society of Clinical Oncology created a practice guideline document published in 2016.¹⁹ The document does not include a specific classification of cardiotoxicity; it does emphasize a distinction in that they note that "clinical trials that evaluated the efficacy of non-anthracycline-based regimens for breast cancer report a low incidence of cardiac dysfunction in women receiving trastuzumab-based therapy."²⁰

In summary, clearly, we must understand that not all cardiotoxicity is equal and that what anthracyclines can do and how they do it to the myocardium is different from what is seen with trastuzumab and other drugs. Therefore, there is room to classify these agents as Type II regarding their potential to foster or be a catalyst for contractile dysfunction. These distinctions remain indisputable. Newer data suggest that the mechanisms of cell injury or dysfunction are more complicated than was initially appreciated, but that fact does not detract from the legitimacy of the original observation or the significant role it has played, and continues to play, in our clinical perspective.

References

1. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344:783-92.
2. Ewer MS, Ali MK, Mackay B, et al., A comparison of cardiac biopsy grades and ejection fraction estimations in patients receiving Adriamycin. J Clin Oncol 1984;2:112-117.
3. Proceedings of the University of Texas M. D. Anderson Cancer Center Medical Oncologist Consensus Conference. Future Directions with Herceptin (Trastuzumab) for Breast Cancer. Maui, Hawaii, USA. July 16-18, 1998. Semin Oncol 1999;26(Suppl 12):1-123.
4. Feldman AM, Lorell BH, Reis SE. Trastuzumab in the treatment of metastatic breast cancer : anticancer therapy versus cardiotoxicity. Circulation 2000;102:272-4.
5. Ewer MS, Lippman SM. Type II chemotherapy-related cardiac dysfunction: time to recognize a new entity. J Clin Oncol 2005;23:2900-2.
6. Guarneri V, Lenihan DJ, Valero V, et al. Long-term cardiac tolerability of trastuzumab in metastatic breast cancer: the M.D. Anderson Cancer Center experience. J Clin Oncol 2006;24:4107-15.
7. Minichillo S, Gallelli I, Barbieri E, et al. Trastuzumab resumption after extremely severe cardiotoxicity in metastatic breast cancer patient: a case report. BMC Cancer 2017;17:722.
8. Billingham ME, Bristow MR, Glatstein E, Mason JW, Masek MA, Daniels JR. Adriamycin cardiotoxicity: endomyocardial biopsy evidence of enhancement by irradiation. Am J Surg Pathol 1977;1:17-23.
9. Suter TM, Cook-Bruns N, Barton C. Cardiotoxicity associated with trastuzumab (Herceptin) therapy in the treatment of metastatic breast cancer. Breast 2004;13:173-83.
10. de Azambuja E, Bedard PL, Suter T, Piccart-Gebhart M. Cardiac toxicity with anti-HER-2 therapies: what have we learned so far? Target Oncol 2009;4:77-88.
11. Telli ML, Hunt SA, Carlson RW, Guardino AE. Trastuzumab-related cardiotoxicity: calling into question the concept of reversibility. J Clin Oncol 2007;25:3535-33.
12. Boone JJ, Bhosle J, Tilby MJ, Hartley JA, Hochhauser D. Involvement of the HER2 pathway in repair of DNA damage produced by chemotherapeutic agents. Mol Cancer Ther 2009;8:3015-23.
13. Lemmens K, Doggen K, De Keulenaer GW. Role of neuregulin-1/ErbB signaling in cardiovascular physiology and disease: implications for therapy of heart failure. Circulation 2007:116:954-60.
14. de Korte MA, de Vries EG, Lub-de Hooge MN, et al. 111Indium-trastuzumab visualises myocardial human epidermal growth factor receptor 2 expression shortly after anthracycline treatment but not during heart failure: a clue to uncover the mechanisms of trastuzumab-related cardiotoxicity. Eur J Cancer 2007;43:2046-51.
15. Ewer MS, Ewer SM. Cardiotoxicity of anticancer treatments. Nat Rev Cardiol 2015;12: 547-58.
16. Suter TM, Procter M, van Veldhuisen DJ, et al. Trastuzumab-associated cardiac adverse effects in the herceptin adjuvant trial. J Clin Oncol 2007;25:3859-65.
17. Plana JC, Galderisi M, Barac A, et al. Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 2014;15:1063-93.
18. Zamorano JL, Lancellotti P, Rodriguez Muñoz D, et al. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur J Heart Fail 2017;19:9-42.
19. Armenian SH, Lacchetti C, Barac A, et al. Prevention and Monitoring of Cardiac Dysfunction in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2017;35:893-911.
20. Dang C, Guo H, Najita J, et al. Cardiac Outcomes of Patients Receiving Adjuvant Weekly Paclitaxel and Trastuzumab for Node-Negative, ERBB2-Positive Breast Cancer. JAMA Oncol 2016;2:29-36.

Keywords: Anthracyclines, Cardiotoxicity, Cardiotoxins, Troponin I, Consensus, Pharmaceutical Preparations, Heart Failure, Myocardium, Echocardiography, Biopsy, Medical Oncology, Algorithms

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