HFA-ICOS cardio-oncology baseline risk assessment for combined RAF and MEK inhibitor therapy

Clinical background

Combined treatment with a RAF inhibitor (dabrafenib, vemurafenib) and a MEK inhibitor (trametinib, cobimetinib) is established in BRAF V600-mutated melanoma and in a growing number of other tumour types. The treatment carries a non-negligible risk of cardiovascular toxicity, above all a reduced LVEF, hypertension and arterial events. The probability of toxicity varies widely between patients, however, and depends on pre-existing cardiovascular risk factors, previous cardiotoxic exposure and age. Without a structured baseline assessment, high-risk patients risk receiving inadequate monitoring while low-risk patients may be over-investigated unnecessarily. The HFA-ICOS baseline cardiovascular risk assessment was developed by the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) in collaboration with the International Cardio-Oncology Society (ICOS) to provide a uniform and practically applicable risk stratification before starting cardiotoxic cancer treatment [1]. For RAF and MEK inhibitors it serves as a decision aid for the intensity of monitoring and for referral to cardio-oncology.

Applying the HFA-ICOS baseline cardiovascular risk assessment

The instrument has a three-part structure: categorical criteria for very high and for high risk, and a score for medium-risk factors.

Very high risk is present if any of the following applies: existing heart failure or cardiomyopathy, previous myocardial infarction or coronary artery bypass grafting, stable angina, severe valvular heart disease or previous anthracycline exposure. Any of these criteria overrides the score and immediately classifies the patient as very high risk.

High risk is present if any of the following applies: borderline LVEF 50–54%, raised troponin at baseline, raised BNP or NT-proBNP at baseline, hypertension or previous radiotherapy to the left chest or mediastinum. These criteria are weighted 2 points within the score.

The medium-risk score is the sum of six factors, each worth 1 point:

$$\text{Medium-risk score} = x_{\text{arrhythmia}} + x_{\text{age} \geq 65,\text{years}} + x_{\text{diabetes}} + x_{\text{chronic kidney disease}} + x_{\text{smoking}} + x_{\text{obesity}}$$

where each $x_i \in {0, 1}$ (0 = no, 1 = yes). The maximum medium-risk score is 6. The overall risk class is determined as:

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

The proforma is consensus-based, not derived from a patient cohort by statistical modelling. It was produced by an expert group within the HFA-ESC and ICOS on the basis of a systematic review of the available evidence on cardiovascular risk factors during cancer treatment and published as a position statement in 2020 [1]. The 2022 ESC cardio-oncology guidelines recommend structured baseline risk assessment with HFA-ICOS for patients due to be treated with cancer drugs of known cardiotoxicity [2].

Interpretation in practice

The risk class guides two decisions: the intensity of cardiac monitoring during treatment, and whether referral to cardio-oncology is warranted. The actual monitoring schedule should be adapted to the specific treatment and to local protocols.

A patient classified as very high risk because of existing heart failure should not automatically be denied effective cancer treatment. Decisions to modify or delay cancer therapy should be made in multidisciplinary consultation between oncologist and cardiologist, weighing the benefit of treatment against the cardiovascular risk [1].

Validation and performance

The HFA-ICOS proforma has been externally validated for some classes of cancer therapy, but not specifically for combined RAF and MEK inhibitor treatment.

In a single-centre study from Imperial College Healthcare NHS Trust, London, the HFA-ICOS baseline risk was calculated for 229 patients with chronic myeloid leukaemia treated with nilotinib (a BCR-ABL tyrosine kinase inhibitor) between 2006 and 2021 [3]. The median age at the start of treatment was 49 years and 49.7% were men. The median duration of treatment was 34.4 months and the median follow-up 62.9 months. The primary endpoint was any cardiovascular event during nilotinib treatment, which occurred in 20.9% of patients. The incidence rose in a dose-response manner with risk class: low 11.2%, moderate 28.2% (HR 2.51, 95% CI 1.17–5.66) and high/very high 32.4% (HR 3.57, 95% CI 1.77–7.20) compared with low risk [3]. For ischaemic events the corresponding incidences were 5.2%, 17.9% (HR 2.19) and 21.6% (HR 3.90). The study therefore confirmed that the instrument discriminates between risk levels, but it concerns a different drug class from RAF/MEK inhibitors.

A multicentre validation of HFA-ICOS in anthracycline-treated patients has been published and shows good predictive ability for cancer therapy-related cardiac dysfunction [4]. The results are not directly transferable to RAF/MEK inhibitors, however, since the mechanisms of toxicity and the relative weight of risk factors differ between drug classes. The 2022 ESC cardio-oncology guidelines give a class I recommendation for structured baseline risk assessment in cancer therapies of known cardiotoxicity and name the HFA-ICOS proforma as the instrument to be used [2].

Limitations

The most important limitation is that the HFA-ICOS baseline assessment for RAF and MEK inhibitors lacks specific external validation for this drug class. The validations published concern anthracyclines [4] and BCR-ABL inhibitors [3], where the toxicity profiles differ in part from the principal adverse effects of RAF/MEK inhibitors (hypertension and a reduced LVEF). It is unclear whether the point weights and thresholds are optimally calibrated for RAF/MEK exposure specifically.

The proforma is consensus-based and not derived from a patient cohort by regression modelling. The risk factors were chosen on the basis of expert judgement of their association with cardiovascular toxicity, not on statistically demonstrated independent predictive value in a RAF/MEK-treated population. The score threshold for moving from moderate to high risk (≥5 medium-risk points) is therefore approximate.

The instrument assesses risk at baseline and does not capture risk accumulating during treatment. A patient at low risk when starting may develop hypertension or a fall in LVEF during RAF/MEK treatment and should be followed clinically whatever the baseline class. Finally, the proforma does not include all risk factors that may be relevant to RAF/MEK-related toxicity, and it takes no account of the dose and duration of the planned cancer treatment.

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. López-Fernández T, Lyon AR, Herrmann J. 2022 ESC Guidelines on cardio-oncology: how can we improve the cardiovascular health of patients with cancer and cancer survivors? Eur Heart J Cardiovasc Pharmacother 2022;9(1):4–5. PMID: 36107817
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(1):45. PMID: 39010172
4. 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