JACC: CARDIOONCOLOGY VOL. 2, NO.

5, 2020

ª 2020 THE AUTHORS. PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN

COLLEGE OF CARDIOLOGY FOUNDATION. THIS IS AN OPEN ACCESS ARTICLE UNDER

THE CC BY-NC-ND LICENSE (http://creativecommons.org/licenses/by-nc-nd/4.0/).

HOW TO

Cardiac Biomarkers During

Cancer Therapy
Practical Applications for Cardio-Oncology

Jose A. Alvarez-Cardona, MD,a Kathleen W. Zhang, MD,a Joshua D. Mitchell, MD,a Vlad G. Zaha, MD, PHD,b
Michael J. Fisch, MD,c Daniel J. Lenihan, MDa

C ombined modality approaches to cancer

treatment have dramatically improved clin-
ical outcomes. At the same time, there has
been increased attention to acute, chronic, and late
peptides (N-terminal pro–B-type natriuretic peptide
[NT-proBNP] or B-type natriuretic peptide [BNP]) and
troponins, can help identify the development of a CV
adverse event during cancer therapy. In general, an
effects of treatment, including the management of elevated natriuretic peptide (NP) level represents he-
cardiac disease in patients with cancer (1). It is recog- modynamic congestion, whereas an abnormal
nized that there are limited sensitivity and specificity troponin is a marker of myocardial injury. Although the
of traditional cardiovascular (CV) testing, such as specific CV conditions a patient may experience with
electrocardiography (ECG) and transthoracic echocar- contemporary cancer therapy are broad (Figure 1),
diography (TTE), for early detection of myocardial cardiac biomarkers can indicate ongoing stress and
injury. Therefore, there is a compelling need to injury. The following cases illustrate how cardiac bio-
improve risk prediction and to detect subclinical dis- markers may be used to guide clinical decision-making
ease at a potentially reversible stage to allow imple- in cardio-oncology.
mentation of cardioprotective strategies and
improve outcomes (2). Cardiac blood-based bio- CASE 1: PREDICTION AND DETECTION
markers continue to be explored to improve the OF CARDIOTOXICITY
detection and long-term monitoring of subclinical
cardiotoxicity. A 73-year-old woman with stage IVB diffuse large
In order for a biomarker to be useful, it should be B-cell lymphoma was scheduled for 6 cycles of rit-
accurate, be easy to measure, and provide important uximab, cyclophosphamide, doxorubicin (anticipated
information relative to treatment outcome. A prog- cumulative dose 280 mg/m2), vincristine, prednisone,
nostic biomarker forecasts the likely course of a dis- and CC-122 (an experimental pleiotropic pathway
ease irrespective of treatment, whereas a predictive modifier that is an immune modulatory therapy), and
biomarker forecasts the likely response to a specific 4 cycles of intrathecal methotrexate. Pre-
treatment (3). It is important to understand the clinical chemotherapy evaluation showed a left ventricular
implications of an abnormal cardiac biomarker and (LV) ejection fraction (LVEF) of 53%, global longitu-
how this information can inform treatment decisions. dinal strain (GLS)
15.5% (normal <
18% to
22%),
Figure 1 shows 4 different profiles (I, II, III, and IV) and grade I diastolic dysfunction on TTE, NT-proBNP
in which traditional cardiac biomarkers, natriuretic elevation at 864 pg/ml (normal <300 pg/ml), and

From the aCardio-Oncology Center of Excellence, Cardiovascular Division, Washington University School of Medicine, St. Louis,
Missouri, USA; bDivision of Cardiology, Department of Internal Medicine, Harold C. Simmons Comprehensive Cancer Center and
Advanced Imaging Research Center, University of Texas Southwestern, Dallas, Texas, USA; and the cDepartment of General
Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA. Daniela Cardinale, MD, served as the Guest
Associate Editor for this paper. Anju Nohria, MD, served as Guest Editor-in-Chief for this paper.
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.

Manuscript received May 22, 2020; revised manuscript received August 19, 2020, accepted August 21, 2020.

ISSN 2666-0873 https://doi.org/10.1016/j.jaccao.2020.08.014

792 Alvarez-Cardona et al. JACC: CARDIOONCOLOGY, VOL. 2, NO. 5, 2020

Cardiac Biomarkers During Cancer Therapy DECEMBER 2020:791–4

ABBREVIATIONS undetectable troponin I (Figure 1) (profile II). biomarker elevation in this case, cardioprotective
AND ACRONYMS Her total cholesterol was 250 mg/dl and low- therapy and heightened surveillance for progressive
density lipoprotein was 133 mg/dl, and chest cardiac dysfunction are recommended (1).
BNP = B-type natriuretic
peptide
computed tomography revealed substantial LEARNING POINTS
coronary calcifications. Her age, hyperlipid-
cMRI = cardiac magnetic
emia, anticipated high-dose exposure to  Elevated pre-chemotherapy cardiac biomarkers
resonance imaging
anthracyclines (>250 mg/m ),2
coronary can detect underlying myocardial injury and stress,
CV = cardiovascular
calcification, and underlying heart failure and help with risk stratification and medical opti-
ECG = electrocardiography
(HF) with preserved ejection fraction mization before and during cancer therapy (5).
EMBx = endomyocardial biopsy
(HFpEF) placed her at high risk for car-  NPs and troponin may detect congestion and injury
GLS = global longitudinal
diotoxicity. Carvedilol, rosuvastatin, and during and after anthracycline-based cardiotoxic
strain
aspirin 81 mg were initiated before and cancer therapy, independent of detectable changes
HF = heart failure
continued through chemotherapy (1,4). in LVEF (6).
HFpEF = heart failure with
preserved ejection fraction Furosemide was prescribed for evidence of
LGE = late gadolinium volume overload and HF. At 3 months, LVEF CASE 2: DETECTION AND MONITORING
enhancement remained unchanged, but NT-proBNP OF IMMUNOTHERAPY-RELATED CARDIOTOXICITY
LV = left ventricular increased to 2,963 pg/ml, and troponin I had
LVEF = left ventricular ejection become minimally elevated at 0.05 ng/ml A 48-year-old African-American woman with stage IV
fraction (normal <0.03 ng/ml) indicating congestion lung adenocarcinoma was initially treated over a 4-
NP = natriuretic peptide and potential injury, prompting adjustment year period with right lower lobe wedge resection
NT-proBNP = N-terminal pro– of furosemide and carvedilol dosing. Upon followed by sequential carboplatin/pemetrexed and
B-type natriuretic peptide completion of 6 months of chemotherapy, the radiation therapy. She was ultimately switched to
TTE = transthoracic LVEF decreased to 45% (GLS not obtained), atezolizumab, a programmed cell death 1 receptor
echocardiography
NT-proBNP had improved to 795 pg/ml, but (PD-L1) inhibitor, due to suboptimal treatment
troponin I was persistently elevated (0.22 to 0.25 ng/ response. Cardiac testing was not obtained before
ml) on serial assessment (profile IV), with an un- initiation on immunotherapy. Approximately
changed ECG. Lisinopril was added to optimize CV 2 months later, she developed dyspnea and edema.
therapy. The differential diagnosis included myocar- TTE showed severe global hypokinesis with LVEF
dial ischemia, anthracycline-related cardiotoxicity, 28%, GLS
5%, normal right ventricular size and
and CC-122–related myocarditis, and a cardiac mag- function, and a small-to-moderate pericardial effu-
netic resonance imaging (cMRI) was performed sion without tamponade physiology. Biomarker
showing a mildly depressed LVEF (43%) with late testing included troponin I of 0.35 ng/ml, NT-proBNP
gadolinium enhancement (LGE) in the right coronary 3,863 pg/ml, and high-sensitivity C-reactive protein
artery territory suggestive of prior myocardial infarc- (hsCRP) 55.2 mg/dl (normal <3 mg/dl) (Figure 1)
tion. Subsequent left heart catheterization showed (profile IV). The ECG was unrevealing. A cMRI was not
mild, nonobstructive multivessel coronary artery dis- feasible, so an endomyocardial biopsy (EMBx) was
ease and elevated LV end-diastolic pressure at performed showing focal, mild cardiomyocyte dam-
18 mm Hg. The combination of a elevated troponin and age with mild lymphoplasmacytic inflammation
LGE on cMRI is consistent with myocardial injury, consistent with myocarditis (Figure 1). Atezolizumab
probably related to anthracycline chemotherapy was permanently discontinued, and she was treated
especially in the absence of significant coronary artery with methylprednisolone 1 g intravenously daily for 3
disease. It is currently unknown whether there are doses, followed by a slow taper of prednisone. In light
important CV effects of CC-122. Twelve months after of her depressed LVEF, she was started on carvedilol
initiating anthracycline-based chemotherapy and with and sacubitril-valsartan. One month later, troponin I
optimal cardioprotective therapy, her LVEF normal- was undetectable, and NT-proBNP and hsCRP both
ized (67%), but GLS did not (
11.9%). NT-proBNP decreased to 574 pg/ml and 17.7 mg/dl, respectively.
remained modestly elevated at 440 pg/ml and cMRI at this time showed a persistently reduced LVEF
troponin was undetectable (profile II). at 21% and no evidence of LGE. The patient continued
This case illustrates how cardiac biomarkers may on guideline-directed HF therapy including spi-
help with CV risk stratification before and during car- ronolactone as well as prednisone with resolution of
diotoxic cancer therapy (4). Although this patient’s her HF symptoms. On a 6-month follow-up TTE, LVEF
LVEF fully recovered at 1-year post-chemotherapy, had increased to 37% and GLS improved to
8.5%.
medical optimization is an essential priority to allow Immunotherapy-related adverse events, including
the most effective cancer therapy to occur. Given the myocarditis, are uncommon, but potentially serious.
JACC: CARDIOONCOLOGY, VOL. 2, NO. 5, 2020 Alvarez-Cardona et al. 793
DECEMBER 2020:791–4 Cardiac Biomarkers During Cancer Therapy

F I G U R E 1 Practical Strategy for Using Cardiac Biomarkers in Cardio-Oncology

Biomarker profiling can help identify patients with cardiotoxicity during cancer therapy (left). If abnormal, there is a broad differential diagnosis considered (right)
determined by the type of cancer therapy received. CV ¼ cardiovascular; ECG ¼ electrocardiogram; LV ¼ left ventricular; NP ¼ natriuretic peptide.

Although establishing the diagnosis of myocarditis  NT-proBNP response to HF therapy has been
frequently requires EMBx, cardiac biomarkers are shown to be prognostic of cardiac recovery.
usually elevated due to ongoing myocardial injury
and may be supportive of the diagnosis. Achieving CASE 3: PROGNOSIS IN THE TREATMENT
NT-proBNP <1,000 pg/ml on HF therapy has previ- OF CARDIOMYOPATHY
ously been associated with subsequent improve-
ments in LVEF and more substantial reductions in LV A 65-year-old man was diagnosed with HFpEF af-
volumes in patients with systolic HF (7). In the ter presenting with worsening lower extremity
absence of permanent myocardial damage or ongoing edema and dyspnea. His NT-proBNP (1,060 pg/ml)
exposure to cardiotoxic therapies, this patient’s and troponin I (0.22 ng/ml) levels were both
improved biomarker response to optimal HF treat- elevated, and his ECG demonstrated low QRS
ment correlated with improved symptoms and an voltages and a pseudoinfarct pattern (Figure 1)
improved LVEF. (profile IV). cMRI showed mild LVEF depression
(47%), diffuse biventricular wall thickening, bia-
LEARNING POINTS
trial enlargement, and extensive subendocardial
 Troponin and NPs have potential utility for the and transmural LGE. Serum lambda free light
diagnosis of immunotherapy-related adverse chain level was 8.0 mg/dl, kappa free light chain
events. 0.64 was mg/dl, and the kappa/lambda ratio was
794 Alvarez-Cardona et al. JACC: CARDIOONCOLOGY, VOL. 2, NO. 5, 2020

Cardiac Biomarkers During Cancer Therapy DECEMBER 2020:791–4

12.5. Bone marrow biopsy showed 20% lambda- additional myeloma treatment as well as consider-
restricted plasma cells, and an EMBx confirmed ation for advanced HF therapies, including trans-
the diagnosis of AL cardiac amyloidosis. He was plantation, in patients with progressive HF.
treated with 4 cycles of cyclophosphamide, borte- LEARNING POINTS
zomib, and dexamethasone. Upon completion of
therapy, NT-proBNP rose to 1,295 pg/ml and then  NT-proBNP and troponin T have diagnostic and
decreased to 656 pg/ml 1 year later, whereas prognostic utility in AL cardiac amyloidosis.
troponin T remained minimally elevated between  The prognostic significance of persistent cardiac
0.02 and 0.03 ng/ml (normal <0.01 ng/ml) (profile biomarker elevation in the setting of complete
IV). Serum kappa and lambda free light chain hematologic response to AL therapy requires
levels normalized after chemotherapy. He remains further investigation.
on spironolactone and torsemide with stable New
York Heart Association functional class II HF CONCLUSIONS
symptoms and relative hypotension since the
original diagnosis of cardiac amyloidosis. No In summary, the use of cardiac biomarkers as a tool
further chemotherapy is planned. for monitoring during cancer therapy has expanded
Cardiac biomarkers, specifically NT-proBNP and greatly in recent years; however, there continues to
troponin T, have been incorporated into the prog- be a need to establish the firm threshold for an
nostic staging system for AL amyloidosis since 2012 abnormal value and the requisite action that should
(8). Abnormal values in a patient with HFpEF and result from early detection of cardiac damage or
other suggestive clinical or cardiac imaging findings stress.
should prompt evaluation for cardiac amyloidosis AUTHOR DISCLOSURES
(Figure 1). Although a complete hematologic
response can be achieved with standard myeloma All authors have reported that they have no relationships relevant to
treatment, cardiac involvement may progress as the contents of this paper to disclose.

evidenced by persistent cardiac biomarker elevation

(9,10). In our experience, the decision to continue ADDRESS FOR CORRESPONDENCE: Dr. Daniel J
treatment for AL amyloidosis is based primarily on Lenihan, Cardio-Oncology Center of Excellence, Car-
hematologic response. In this situation, we recom- diovascular Division, Washington University in St.
mend periodic assessment of cardiac biomarkers, Louis, 660 South Euclid Avenue, Campus Box 8086, St.
careful assessment and management of volume Louis, Missouri 63110. E-mail: [email protected].
overload, and close collaboration with hematology/ Twitter: @ICOSociety, @kzhangmd, @joshmitchellmd,
oncology to discuss the benefit of pursuing @vgzmd, @fischmd.

REFERENCES

1. Curigliano G, Lenihan D, Fradley M, et al. Man- Clinical Oncology Clinical Practice Guideline. J Clin serum free light chain measurements. J Clin Oncol
agement of cardiac disease in cancer patients Oncol 2017;35:893–911. 2012;30:989–95.
throughout oncological treatment: ESMO
5. Cornell RF, Ky B, Weiss BM, et al. Prospective 9. Zhang KW, Mitchell J, Alvarez-Cardona J, et al.
consensus recommendations. Ann Oncol 2020;31:
study of cardiac events during proteasome inhib- Plasma hepatocyte growth factor for diagnosis
171–90.
itor therapy for relapsed multiple myeloma. J Clin and prognosis in light chain and transthyretin
2. Cardinale D, Colombo A, Sandri MT, et al. Pre- Oncol 2019;37:1946–55. cardiac amyloidosis. J Am Coll Cardiol CardioOnc
vention of high-dose chemotherapy-induced car- 2020;2:56–66.
6. Lenihan DJ, Stevens PL, Massey M, et al. The
diotoxicity in high-risk patients by angiotensin- utility of point-of-care biomarkers to detect car- 10. Palladini G, Dispenzieri A, Gertz MA, et al. New
converting enzyme inhibition. Circulation 2006; diotoxicity during anthracycline chemotherapy: a criteria for response to treatment in immunoglobulin
114:2474–81. feasibility study. J Cardiac Fail 2016;22:433–8. light chain amyloidosis based on free light chain
3. Buyse M, Sargent DJ, Grothey A, Matheson A, measurement and cardiac biomarkers: impact on
7. Daubert MA, Adams K, Yow E, et al. NT-proBNP
de Gramont A. Biomarkers and surrogate end survival outcomes. J Clin Oncol 2012;30:4541–9.
goal achievement is associated with significant
points–the challenge of statistical validation. Nat reverse remodeling and improved clinical outcomes
Rev Clin Oncol 2010;7:309–17. in HFrEF. J Am Coll Cardiol HF 2019;7:158–68.
4. Armenian SH, Lacchetti C, Barac A, et al. Pre- 8. Kumar S, Dispenzieri A, Lacy MQ, et al. Revised KEY WORDS amyloidosis, anthracyclines,
vention and monitoring of cardiac dysfunction in prognostic staging system for light chain biomarkers, cardiotoxicity, chemotherapy,
survivors of adult cancers: American Society of amyloidosis incorporating cardiac biomarkers and detection