HFA-ICOS cardio-oncology baseline risk assessment for HER2-targeted therapies

Clinical background

HER2-targeted treatment, trastuzumab in particular, is the cornerstone of adjuvant and palliative treatment of HER2-positive breast cancer and HER2-positive gastric cancer. The treatment is effective but carries a well-recognised risk of left ventricular dysfunction and heart failure, with an incidence of clinically relevant cardiotoxicity of about 5 to 17 per cent depending on the definition, the treatment regimen and the duration of follow-up [4]. The risk is markedly increased by concurrent or previous anthracycline exposure, radiotherapy to the left chest, and pre-existing cardiovascular risk factors.

The decision to start HER2-targeted treatment is rarely difficult from an oncological point of view, but the question of how intensively cardiac function should be monitored, and whether the patient should be referred to cardio-oncology before starting, requires a structured risk assessment. The HFA-ICOS baseline cardiovascular risk assessment for HER2-targeted treatment was developed to meet this need: to give oncologists and cardiologists a common, standardised tool for classifying the patient's cardiovascular risk before treatment begins, and thereby to guide the monitoring strategy [1].

Applying the HFA-ICOS baseline cardiovascular risk assessment

The instrument is a consensus-based risk stratification proforma produced by the Cardio-Oncology Study Group of the Heart Failure Association of the ESC in collaboration with the International Cardio-Oncology Society [1]. It was published in 2020 as a position statement and covers seven classes of cardiotoxic cancer therapy, of which HER2-targeted treatment is one. Unlike a statistically derived risk model, the scoring rests on expert consensus and a structured review of the existing evidence for each risk factor's contribution to cardiovascular toxicity.

The assessment is made at three levels:

Very high risk. The following criteria are binary and classify the patient as very high risk regardless of the other scoring:

• Existing heart failure or cardiomyopathy
• Previous trastuzumab-related cardiotoxicity
• Previous myocardial infarction or coronary artery bypass grafting
• Stable angina
• Severe valvular heart disease
• LVEF below 50 per cent at baseline
• Age 80 years or older

High risk. The following criteria are binary and classify the patient as high risk, provided that no very high risk criterion is present:

• Borderline LVEF 50 to 54 per cent
• Arrhythmia
• Raised troponin at baseline
• Raised BNP or NT-proBNP at baseline
• Age 65 to 79 years
• Previous (remote) anthracycline exposure
• Previous radiotherapy to the left chest or mediastinum

Medium-risk score. The following factors score 1 point each:

• Hypertension
• Diabetes mellitus
• Chronic kidney disease
• An anthracycline given shortly before the start of HER2-targeted treatment
• Current smoker or significant smoking history
• Obesity (BMI over 30 kg/m²)

The overall risk classification is calculated as:

$$\text{Risk} = \begin{cases} \text{Very high} & \text{if any very high risk criterion is present} \ \text{High} & \text{if any high risk criterion is present, or the medium-risk score is} \geq 5 \ \text{Moderate} & \text{if the medium-risk score is 2 to 4} \ \text{Low} & \text{if the medium-risk score is 0 or 1} \end{cases}$$

A single very high risk criterion overrides all other scoring. In the same way, a high risk criterion overrides the medium-risk classification. The medium-risk score becomes decisive only when no binary high or very high risk criteria are present.

Interpretation in practice

The risk category determines not whether HER2-targeted treatment should be given, but how the patient should be monitored and whether cardio-oncology referral is warranted. The 2022 ESC cardio-oncology guidelines give a class I recommendation for baseline assessment with HFA-ICOS before cardiotoxic cancer therapy [5].

A patient whose baseline LVEF is below 50 per cent automatically falls into the very high risk category. This does not mean that trastuzumab is contraindicated, but it does require a cardiologist to be involved before starting and a plan for possible heart failure treatment and intensified monitoring to be in place [1, 5].

Validation and performance

HFA-ICOS is a consensus-based instrument and has no derivation cohort in the traditional sense. Its validity therefore rests on external validation in independent cohorts.

The largest validation to date concerns anthracyclines, not HER2-targeted treatment. Rivero-Santana et al. validated the HFA-ICOS score in the CARDIOTOX registry of 1,066 patients treated with an anthracycline [2]. The primary endpoint was symptomatic or moderate to severe asymptomatic cancer therapy-related cardiac dysfunction (CTRCD). The AUC for predicting this outcome at 12 months was 0.78 (95 per cent CI 0.70 to 0.82), with Uno's C-statistic 0.78 (95 per cent CI 0.71 to 0.84). Calibration was good, with a Brier score of 0.04. Patients at very high risk had an HR of 28.74 (95 per cent CI 9.33 to 88.5) for CTRCD compared with low-risk patients.

For BCR-ABL inhibitors (nilotinib), Fernando et al. showed in a cohort of 229 patients that HFA-ICOS discriminated well between risk categories: cardiovascular events occurred in 11.2 per cent at low risk, 28.2 per cent at moderate risk and 32.4 per cent at high/very high risk [3]. The HR for high/very high versus low risk was 3.57 (95 per cent CI 1.77 to 7.20).

Specific validation of the HER2 proforma is more limited. A 2025 review notes that validation has been carried out for anthracyclines, HER2-targeted therapies and BCR-ABL inhibitors, but that published data specific to HER2 are sparse [6]. A Chinese retrospective cohort study of 600 patients with HER2-positive breast cancer treated with trastuzumab does, however, confirm the risk factors on which HFA-ICOS rests: age over 60 years, a raised baseline NT-proBNP, anthracycline treatment and chest radiotherapy were independent predictors of cardiotoxicity, with an incidence of 16.7 per cent over a median follow-up of 3.6 years [4].

In summary, the overall structure of the instrument is supported by external data, but the direct evidence for the predictive performance of the HER2 proforma (c-statistic, calibration) is weaker than for the anthracycline proforma.

Limitations

The instrument was designed for patients about to start HER2-targeted treatment and presupposes that a baseline assessment with echocardiography, ECG and biomarkers (troponin, BNP/NT-proBNP) has been performed. Without these data, several of the binary high risk criteria cannot be assessed and the score becomes meaningless.

The score is intended to guide the intensity of monitoring and referral pathways, not to justify withholding effective cancer treatment. A patient at high or very high risk should undergo multidisciplinary discussion, but the decision to modify or postpone cancer treatment rests with the treating oncologist in consultation with a cardiologist [1, 5].

The instrument does not capture dynamic risk. A patient classified as low risk at baseline may develop subclinical cardiac dysfunction early during treatment, and the baseline score does not replace ongoing monitoring with echocardiography and biomarkers. Global longitudinal strain (LVGLS) is not part of the scoring, but data show that a relative reduction in LVGLS of more than 15 per cent from baseline is a strong early marker of impending cardiotoxicity, superior to LVEF as a single measure [4].

Consensus-based instruments have an inherent weakness: the weights are not statistically derived. That age 65 to 79 years automatically confers high risk may over-stratify patients who are otherwise cardiovascularly healthy, particularly in populations where HER2-positive breast cancer affects younger women. Conversely, a patient with several medium-risk factors totalling 4 points is classified as moderate risk despite an overall risk profile that clinically might justify closer monitoring.

References

1. Lyon AR, Dent S, Stanway S, et al. Baseline cardiovascular risk assessment in cancer patients scheduled to receive cardiotoxic cancer therapies: a position statement and new risk assessment tools from the Cardio-Oncology Study Group of the Heart Failure Association of the ESC in collaboration with the International Cardio-Oncology Society. Eur J Heart Fail. 2020;22(11):1945-1960. PMID: 32463967
2. Rivero-Santana B, Saldaña-García J, Caro-Codón J, et al. Anthracycline-induced cardiovascular toxicity: validation of the Heart Failure Association and International Cardio-Oncology Society risk score. Eur Heart J. 2025;46(3):273-284. PMID: 39106857
3. Fernando F, Andres MS, Claudiani S, et al. Cardiovascular events in CML patients treated with Nilotinib: validation of the HFA-ICOS baseline risk score. Cardio-oncology. 2024;10:45. PMID: 39010172
4. Xia M, Ding S, Wang X, et al. Comprehensive risk profiling and long-term cardiovascular toxicity in HER2-positive breast cancer patients treated with trastuzumab. Front Oncol. 2025;15:480898. PMID: 41404068
5. Lyon AR, López-Fernández T, Couch LS, et al. 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS). Eur Heart J. 2022;43(41):4229-4361. PMID: 36017568
6. Tong J, Senechal I, Ramalingam S, et al. Risk Assessment Prior to Cardiotoxic Anticancer Therapies in 7 Steps. Br J Hosp Med. 2025;86(1):1-21. PMID: 39862029