Know Your Denominator

Corresponding Author

Immune checkpoint inhibitors (ICIs) have fundamentally shifted the treatment landscape for many cancers, but this progress has arrived alongside the considerable challenge of immune-mediated toxicities. Chief among these is ICI-associated myocarditis. Initially, this was thought to be rare but carrying a high case-fatality rate, likely reflecting early reporting bias toward the most severe presentations.^1,2 A spectrum of severity is now increasingly recognized, yet the largest international case series confirm that this concern remains legitimate: a confirmed diagnosis carries an estimated 13% myocarditis-related mortality at 1 month.3, 4, 5

Cardiac troponin (cTn) is the most important biomarker in this context. Where symptoms are compatible, acute elevation from baseline triggers a cascade of ICI-therapy interruption, additional cardiac imaging, early immunosuppression, and intensified monitoring. When the diagnosis of ICI-associated myocarditis is clear-cut, these cTn changes are confirmatory, prognostic, and essential to guiding management, including treatment escalation and, in selected cases, ICI rechallenge.3, 4, 5, 6, 7 However, troponin elevation is common and often nonspecific in patients undergoing cancer therapy. Inappropriately labeling a patient with ICI-associated myocarditis carries its own risks: unnecessary treatment interruption and unwarranted immunosuppression both confer significant iatrogenic hazards in an already vulnerable population. The stakes in understanding cTn in this context could not be higher.

Clinical cardiology practice largely uses high-sensitivity (hs)–cTnI and hs-cTnT interchangeably, not least because hospital laboratories rarely offer routine access to more than one cTn assay. In the evaluation of patients presenting with potentially cardiac chest pain, both provide a very high negative predictive (rule-out) value for acute myocardial infarction (AMI), with similar diagnostic accuracy. At a population level, hs-cTnI is slightly more accurate for AMI diagnosis, and hs-cTnT carries greater prognostic utility for all-cause mortality. At the individual level, however, both assays provide comparable information to guide clinical decisions.8, 9, 10 In ICI-treated cancer patients, the interpretation becomes considerably more complex. At baseline, metabolically active advanced disease, demand ischemia, renal dysfunction, and other potentially cardiotoxic therapies are all prevalent. During treatment, other ICI-related toxicities—principally, ICI-associated skeletal myositis, which often overlaps with myasthenia gravis—may produce skeletal-muscle–derived hs-cTnT, further complicating the clinical picture.¹¹

In this issue of JACC: CardioOncology, Ismail et al¹² address the important issue of troponin T/I discordance in cancer patients receiving ICIs. Consecutive patients with cancer starting immunotherapy were prospectively enrolled (N = 693); 433 had paired baseline hs-cTnI and hs-cTnT measurements and comprised the primary analysis cohort. Commercially available hs-cTnT (Roche Elecsys; upper reference limit [URL], 14 ng/L) and hs-cTnI (Siemens Atellica; URL, 45.2 ng/L) were assessed at baseline, 1 month and, in a subset of patients, at 6 months. Based on both assays, patients were classified as normal, discordant (hs-cTnT+, hs-cTnI–), both elevated, or reverse discordant (hs-cTnT–, hs-cTnI+). Analyses focused on the level of hs-cTnT/hs-cTnI discordance, early temporal changes, clinical correlates, and associations with mortality. In keeping with this “real-world” analysis, patients with a wide range of primary cancer sites were represented. Patients were most commonly treated with the anti-PD-1 ICI class.

In 37.9% of patients, hs-cTnT was elevated at baseline, compared with just 1.8% of patients for hs-cTnI (P < 0.001). Discordance at baseline was therefore common (36.5%); both-elevated and reverse-discordant patterns were uncommon (1.4% and 0.5% of patients, respectively). Elevations of cTnT were low level, and the cTnT:cTnI ratio was similarly low. Importantly, in patients with elevated/discordant hs-cTn isoforms at baseline, the pattern remained consistent at 1 month. Had ICI therapy been inducing subclinical skeletal muscle injury, discordance would have been expected to increase, or hs-cTnT levels to have diverged from hs-cTnI, over the first month. Furthermore, creatine kinase was normal in the discordant patients in whom it was measured.^11,12

A major strength of the current analysis lies in its use of residual samples retained from clinically indicated routine blood draws. This is an elegant method for characterizing underlying biomarker trends, blinded to clinicians and without additional burden to patients. By excluding clinically suspected myocarditis cases, the authors capture trends across the majority of cancer patients unconfounded by ICI-associated myocarditis. In doing so, they perform an epidemiological service for practicing clinicians, providing much-needed context for interpreting different hs-cTn assays available in daily practice.

The study has limitations largely acknowledged by the authors, including its single-center population, restriction to a single hs-cTnI assay, and the relatively low number of patients with 6-month results (a “survivors' cohort” that should be interpreted with caution). By design, these data reflect ambulatory patterns in relatively “well” patients in the early stages of ICI therapy. As such, the study is a useful counterpoint to the learning derived from ICI-associated myocarditis case series. In this cohort, overall mortality was almost 50% at 30 months, and only 3.5% was attributable to a cardiovascular cause. This is a reminder of the bigger picture: the need to keep cardiovascular toxicities of ICI therapy in the perspective of other competing risks, not least the index malignancy.

What, then, is the optimum hs-cTn assay for surveillance of ICI-treated cancer patients? The study findings indicated that hs-cTnI was less frequently abnormal at baseline than hs-cTnT, which may reduce the likelihood of an incidental low-level elevation triggering unnecessary anxiety, cardiology referral, or delay to ICI initiation. In suspected ICI-associated myocarditis, hs-cTnI also tends to peak more quickly, track the cardiac process more directly, and return toward baseline more rapidly following treatment, making it clinically useful for charting recovery.^6,12, 13, 14 By contrast, hs-cTnT was commonly detectable at baseline in the current cohort. Indeed, it was abnormal in more than one-third of patients in the current study and was associated with comorbidity and all-cause mortality, analogous to observations in noncancer populations.¹⁰ During acute cardiac and skeletal muscle toxicity, hs-cTnT tends to peak higher relative to its URL than hs-cTnI, potentially better capturing the overall extent of immunotoxicity, though it may also remain chronically elevated well after the acute event has resolved. Finally, the magnitude of hs-cTnT elevation carries additional prognostic value for early (30-day) adverse outcomes directly related to immune-related cardiotoxicity (and associated myotoxicity).^3,11,12 There is therefore no simple correct answer in choosing between cTnI and cTnT, with each isoform assay providing complementary, but not always interchangeable, information.

The current study reinforces the critical importance of obtaining a baseline value for all patients commencing ICI.¹⁵ Its greatest value, however, lies in helping us know the denominator—the expected background rates of “abnormal” findings from the hs-cTn assay routinely available in our own practice, against which any individual result must be judged. For clinicians, this means understanding the subtleties that changes in each assay convey and recognizing the clinical scenarios in which obtaining both results may be diagnostically helpful. Examples include cases where ICI-associated myocarditis is strongly suspected but hs-cTnI is negative; where hs-cTnT remains elevated at a low level after immunosuppression but ICI rechallenge is being considered; or where analytical anomalies such as macro-troponin complexes are suspected, with hs-cTnI elevated but the clinical picture is otherwise inconsistent. Knowing your denominator, and the troponin assay that defines it, remains essential to the management of ICI-treated cancer patients.

Funding Support and Author Disclosures

Prof Austin is supported by a Consultant Research Award (FS/CRA/25/23080) from the British Heart Foundation (BHF). He has received research grants awarded to Newcastle University from Kancera and AstraZeneca. Professor Lang is supported by a BHF Special Initiative grant (SI/F/26/21170025) and has received research grants from Roche Diagnostics, AstraZeneca, and Boehringer Ingelheim as well as consultancy/speaker's fees from Roche Diagnostics, Myokardia, Pharmacosmos, Akero Therapeutics, CV6 Therapeutics, Pfizer, Jazz Pharma, and Novartis, all outside the submitted work.