Author:

Anna Lisa Bonfranceschi

Abstract

In 2018 ESCAT, a novel tool designed to enhance and standardize precision oncology, developed on the initiative of the ESMO Translational Research and Precision Medicine Working Group, has been presented. ESCAT employs data from massive sequencing (as next-generation sequencing analysis, NGS) to establish a hierarchy of genetic alterations in a tumor, thereby indicating those alterations that should be the primary focus of therapeutic action. The tool is divided into six main tiers, with the most evidence-based alterations and corresponding therapies located at the top and those with no evidence of applicability in the clinic at the other extreme. ESCAT is a tool that enables clinicians and researchers from diverse geographical and healthcare systems to communicate effectively, as it is primarily based on scientific evidence. This consequently promotes more equitable access to care, as it enables different clinicians to interpret complex genomic test results in a uniform manner, thereby harmonizing treatment decisions. In practice, ESCAT has been demonstrated to have clinical value for diverse cancer types, including breast cancer and cholangiocarcinoma. Clinical outcomes are enhanced when patients receive therapies situated at the upper end of the scale. In addition, ESCAT has facilitated the formulation of recommendations by the ESMO Precision Medicine Working Group on the conduct and reporting of NGS testing, delineating the categories of cancers in which patients could potentially derive greater benefit from comprehensive genomic analysis.

Introduction

The history of cancer as a genetic disease goes back a long way. It can be traced back at least to the insights of the German biologist Theodor Boveri, who understood that the disease was linked to something wrong with the chromosomes. But it was not until the 1970/80s, with the discovery of the first oncogenes and oncosuppressors, that the idea of cancer as a genetic disease became firmly established. While the discovery of the genetic basis of the disease initially helped to understand the biology and evolution of the disease and shed light on the mechanisms that allow a cell to replicate indefinitely and invade surrounding tissues, in the following years it would have its first practical implications. This would lead to the development of targeted therapies designed precisely to counter the effects of these alterations on cell function (Di Lonardo et al., 2015).

Precision oncology: matching the right drug to the right tumour

We now know that there are many mutations that can affect cancer cells, aided by the genetic instability that characterises them and predisposes them to accumulate new mutations. We do not know all of them, we know that some of them are common to tumours in different locations, and only some of them have been the subject of targeted therapies, but research is ongoing. The possibility of treating cancer on the basis of the mutations present in the diseased cell has led to a paradigm shift in the field of oncology over the years, with the idea of precision oncology becoming more and more established. According to this new vision of the discipline, cancer treatments are no longer administered - or rather not only - on the basis of tumour location but rather by taking into account its molecular characteristics. This is what experts in the field call the shift from oncology based on the histological model - which takes into account the organ and tissue in which the tumour developed - to oncology based on the mutational model, which instead takes into account the tumour alterations (Aiom, Esmo Oncology Pro, Danesi et al., 2021).

In this model, which sees cancer primarily as a disease of genes and seeks to target the mechanisms that drive uncontrolled cell replication, the ability to match the right drug to the right patient plays a very important role. This task is made possible by the ability to analyse and interpret in detail the genetic alterations in the tumour, which is most evident in the role of Molecular Tumour Boards (MTBs). However, this task is becoming increasingly challenging as new biomarkers are discovered, new clinical trials are launched and new target therapies enter the market (André et al. 2014, Danesi et al. 2021, Wolff et al. 2022, Kiesevetter 2022).

ESCAT, a common language for all oncologists

In this context, the work of the ESMO Translational Research and Precision Medicine Working Group came into play, in 2017. Discussions date back to then - in fairness, already started time before (André et al. 2014) - among experts in the field to find a way to clearly understand how much a genetic alteration could or could not be exploited as a therapeutic target. The discussions of this working group led the year later to the development of ESCAT (ESMO Scale for Clinical Actionability of molecular Targets, ESMO), defined by Joaquin Mateo et al. (2018 as a classification system that “provides a systematic framework to rank molecular targets based on clinical evidence of actionability”, with the aim of bringing genomics closer to the clinic.

The key concept around which the scale was developed is that of actionability, that is the real possibility of targeting a genomic alteration with a drug. In fact, some mutations affect tumour development more than others, some are targets of already approved drugs, some may be approved in some cancers but not in others, some are under investigation and others have not been thoroughly studied (Tamborero et al. 2022). ESCAT aims to bring order to this field by providing a method for prioritising these mutations (and in particular their association with potential therapies) based on clinical evidence.

The result is a pyramid divided into six different tiers, with the level of clinical evidence decreasing from top to bottom. This means that the higher a mutation-drug match is at the top of the pyramid, the more scientific evidence there is to support its use. Conversely, as you move down the pyramid, the level of clinical evidence decreases until you reach the lowest level of the pyramid, where genomic alterations are placed for which there is no evidence to support actionability. It is important to note, Mateo adds, that the same mutation may be found at different levels of the ESCAT system in relation to different treatments or in different cancers. This is because the scale is not about assigning a hierarchy to individual mutations, but about prioritising evidence-based clinical utility for matches between a mutation and a drug in a specific clinical setting, Mateo points out. “A mutation may have different ESCAT levels for different treatments, or even different ESCAT levels for different tumour types, because the level of evidence may be different for the same match in breast cancer versus colorectal cancer, for example”.

Figure 1: ESMO Scale for Clinical Actionability of Molecular Targets – ESCAT

Source: www.esmo.org

In this way, ESCAT provides a common language for all those involved in precision oncology, as it allows the results of next-generation genetic analyses to be interpreted in a single language, distinguishing those that can be considered for therapeutic purposes from those that cannot, or those that can but with greater uncertainty. This is a necessary effort that, even before facilitating communication between clinicians, the pharmaceutical industry and academia - as its creators also wished - responds to the need to ensure equitable and homogeneous access to treatment options for all patients regardless of the country they come from (Ciliberto et al. 2020; Wolff et al. 2022).

ESCAT: a classification system based on scientific evidence

ESCAT's classification system is based solely on scientific evidence and not on regional or national approval and reimbursement status, which varies in different parts of the world, as Mateo explains. “This is different from other classification systems where the approval status indicates the level, such as OncoKB, developed by the Memorial Sloan Kettering Cancer Center in New York, which is very useful but contingent on the approval status in the US, which may be different to other countries”.

However, this does not mean that ESCAT is a stand-alone project: experts who have been involved in the development of similar classification systems have also been invited to contribute to ESCAT. In addition, the same tool also takes into account scales that measure how effective new therapies are in clinical practice (ESCAT in fact includes assessments performed by the ESMO-Magnitude of Clinical Benefit Scale, ESMO-MCBS) (Wolff et al. 2022). “The primary criteria for classifying evidence in ESCAT is based on whether there are phase two or three clinical trials supporting an association, and then, whether there is a benefit for the intervention in terms of overall survival, progression-free survival or response rate”, adds Mateo.

Here is how ESCAT works in details. To position the different mutations along the scale, the researchers have established some criteria: for example, the highest tier is occupied by alteration-drug combinations for which there is evidence of clinical improvements in a survival end-point from randomized clinical trials for a given type of tumor (alteration-drug combinations means the possibility to match a drug to a biomarker in cancer cells). At this level are the drugs that should be used as standard of care, the experts explain. The tier just below will instead be occupied by those alteration-drug matches for which there is evidence of tumor-causing activity but it is not quantifiable, followed by those for which an activity is hypothesized and so on, downwards. For example, the first tier for advanced non-squamous non-small-cell lung cancer includes mutations affecting the EGFR gene that can be targeted by tyrosine kinase inhibitors.

“The criteria is relevant irrespectively of the country where you are practicing medicine or where the patient is located”, remarks Mateo. “What we tried to improve with ESCAT is that there was direct correlation between the recommended classification system and recommended clinical actions because we wanted ESCAT to be useful for the clinical community too and not just a theoretical document for discussion about drug evidence.”

The only factors that can influence the placement of an alteration-drug association is therefore the scientific evidence, which it is good to consider changeable. In fact, new data may appear over time: these are the reasons why, write Mateo et al. (2018), the positioning of an association may change over time and depending on the clinical setting.

ESCAT as a system for equitable access to treatment

Such an elaborate classification system makes it possible to ensure equitable access to treatments, as advocated by experts. “Part of equity comes from access to technologies and access to medicines, but part of equity also comes from harmonising the medical decision-making process”, Mateo continues. And that's how ESCAT could contribute.

Consider a hypothetical case. The results of large-scale next-generation sequencing (NGS) analyses of tumours or liquid biopsies are complex data to interpret because they contain a long list of tumour-associated mutations. “It is sometimes difficult for clinicians to identify which mutations are relevant for therapeutic decision-making. Therefore, different sequencing providers may have different criteria for classifying these mutations”, explains Mateo. Classifying the results according to ESCAT, on the other hand, ensures that any doctor, even a non-expert, faced with the results of a genomic report, can speak the same language: “If the doctor sees that this mutation in this report has ESCAT level one, he knows what it means. Different providers may give different reports, but if they all use the same classification system, when the doctor sees level one, level two or level three, he will always know what it means in terms of the treatment decision, but also for the patient”, explains Mateo.

To make the communication of genetic test results easier, the European Society for Medical Oncology (ESMO) Translational Research and Precision Medicine Working Group has also developed recommendations to standardise and facilitate the writing and interpretation of genomic reports (Van der Haar et al. 2024).

Figure 2: Example of what a genomic analysis report might look like (from Van der Haar et al 2024).

Although ESCAT was developed primarily as a clinical tool, the benefits of its implementation also impact on the doctor-patient relationship, helping to increase the patient's involvement in care planning in a more transparent way. “If we are giving a grade of evidence to the mutation, we are facilitating the conversation with the patient, and also the prioritisation. So, if there are different mutations, it will be easier to explain to the patient why we are basing our therapeutic decision on one or the other, because this will be ranked based on how much evidence there is that this is important for the therapeutic decision”.

Validate the ESCAT scale in clinical practice

If these are the benefits promised by the use of this new scale, how does ESCAT perform when it comes to moving from theory to practice? Since its development, a number of studies have attempted to apply and validate it. One of the most important of these was carried out by researchers at Institut Gustave Roussy in France on the use of ESCAT in certain metastatic breast cancers. The researchers showed that there were clinical benefits, in terms of disease-free progression, when therapies were combined with genomic alterations in the highest levels (level I/II) of ESCAT, rather than in the lowest levels (André et al. 2022).

Similar results have been reported in other tumours, such as advanced cholangiocarcinoma. Here, too, it was shown that targeted therapies based on combinations that fell within the highest levels of ESCAT were associated with longer survival than those that fell within the lowest levels of the scale. “Implementing an evidence-based scale such as ESCAT into treatment management paradigms complements the assessment of the clinical picture in advanced cholangiocarcinoma - the authors conclude - and may guide clinicians for prioritizing alterations and avoiding overestimating the potential benefits of tailored therapies, by adjusting expectations to the clinical reality” (Verdaguer et al. 2022).

ESCAT as a guide to genomic testing

ESCAT could not have existed without massive sequencing (NGS) analyses, which in recent years have allowed us to know the genetic makeup of tumors in ever greater detail at relatively low costs. At the same time, however, the results from this type of sequencing do not have the same value for all tumors. In some cases, the data that emerges from genetic analyses weighs more than in others, and this is because there are different markers that can be used as therapeutic targets, in other cases, however, not. “So, based on the ESCAT classification system, we scrutinize for which tumor types there are sufficient biomarkers as to vouch for multiplexed genomic testing” says Mateo.

In this way, the ESMO recommendations on when it would be most appropriate to proceed with access to NGS have been developed, with a first edition in 2020 and another just updated (Mosele et al. 2020, Mosele et al. 2024).

The experts' recommendations recognise that NGS should be incorporated into clinical practice for some advanced cancers: lung adenocarcinoma, prostate cancer, ovarian cancer, cholangiocarcinoma, but also advanced breast cancer, gastrointestinal stromal tumours, sarcoma, thyroid cancer and cancer of unknown primary, they added just a few months ago. This does not mean that NGS is useless in all other cases: it is important to continue using it in trials and in academia, as well as at the clinical level for those patients with metastatic cancer who may have mutations that can be targeted by agnostic drugs, Mosele et al. concluded.

Finally, in order to facilitate their use, also thanks to ESCAT, we mention the Molecular Tumour Board Portal initiative, a digital platform shared between several centres forming Cancer Core Europe that allows automating the interpretation of NGS, optimising resources and saving time (Tamborero et al. 2022).

Conclusions

ESCAT is a tool for optimising precision oncology by identifying the most promising treatments for a tumour based on its molecular alterations. To do this, it uses only the relevant scientific evidence, positioning itself as a universal tool. So far, it has proven to be a promising tool for clinical practice.

References

Aiom. I farmaci agnostici e il nuovo modello di oncologia di precisione - Retrieved from Aiom on January 2025

André F, Filleron T, Kamal M et al. 2022. Genomics to select treatment for patients with metastatic breast cancer, Nature 610, 343–348. doi: https://doi.org/10.1038/s41586-022-05068-3

André F, Mardis E, Salm M et al. 2014. Prioritizing targets for precision cancer medicine, Ann Oncol., 25(12), 2295-2303. doi: 10.1093/annonc/mdu478

Ciliberto G, Allegretti M, Babini G et al. 2020. Linee Guida per l’istituzione e la gestione dei Molecular Tumor Board negli Istituti di Alleanza Contro il Cancro - Alleanza Contro il Cancro

Danesi R, Fogli S, Indraccolo S et al. 2021. Druggable targets meet oncogenic drivers: opportunities and limitations of target-based classification of tumors and the role of Molecular Tumor Boards, Esmo Open 6 (2), 100040. doi: 10.1016/j.esmoop.2020.100040

Di Lonardo A, Nasi S, Pulciani S, 2015. Cancer: We Should Not Forget The Past. J Cancer 6(1), 29-39. doi:10.7150/jca.10336

ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) - Retrieved From https://www.esmo.org/scales-and-tools/esmo-scale-for-clinical-actionability-of-molecular-targets-escat on January 2025

New ESMO tumour DNA scale helps match patients with cancer to optimal targeted medicines - Retrieved from ESMO on January 2025

ESMO Oncology Pro. Molecular Tumor Boards and precision cancer medicine - Retrieved from ESMO Oncology Pro on January 2025

ESMO 2020. ESMO Issues First Recommendations on Using Next-Generation Sequencing for Advanced Cancers - Retrieved from https://www.esmo.org/newsroom/press-and-media-hub/esmo-media-releases/esmo-issues-first-recommendations-on-using-next-generation-sequencing-for-advanced-cancers on January 2025

Kiesewetter B 2022. Molecular profiling leading to personalized cancer treatment. memo, 15, 176–177. doi: https://doi.org/10.1007/s12254-022-00831-8

Mateo J, Chakravarty D, Dienstmann R et al. 2018. A framework to rank genomic alterations as targets for cancer precision medicine: the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT), Ann Oncol., 29 (9), 1895-1902. doi: 10.1093/annonc/mdy263

Mosele F, Remon J, Mateo J et al. 2020, Recommendations for the use of next-generation sequencing (NGS) for patients with metastatic cancers: a report from the ESMO Precision Medicine Working Group, Ann Oncol., 31 (11), 1491-1505. doi: 10.1016/j.annonc.2020.07.014

Mosele MF, Westphalen CB, Stenzinger A et al. 2024. Recommendations for the use of next-generation sequencing (NGS) for patients with advanced cancer in 2024: a report from the ESMO Precision Medicine Working Group, Ann Oncol., 35 (7), 588-606. doi: 10.1016/j.annonc.2024.04.005

Oncology Pro ESMO. The use of next-generation sequencing (NGS) for patients with metastatic cancers - Retrieved from https://oncologypro.esmo.org/oncology-in-practice/personalised-medicine/esmo-recommendations-in-precision-medicine/the-use-of-next-generation-sequencing-ngs-for-patients-with-metastatic-cancers#:~:text=ESMO%20recommends%20the%20use%20of,salivary%2C%20thyroid%20and%20vulvar%20cancers on January 2025

Tamborero D, Dienstmann R, Rachid MH et al. 2022. The Molecular Tumor Board Portal supports clinical decisions and automated reporting for precision oncology, Nat. Cancer 3, 251–261. doi: https://doi.org/10.1038/s43018-022-00332-x

Van der Haar J, Roepman P, André F et al. 2024. ESMO Recommendations on clinical reporting of genomic test results for solid cancers, Ann Oncol., 35 (11), 954-967. doi: 10.1016/j.annonc.2024.06.018

Verdaguer H, Saurí T, Acosta DA et al. 2022. ESMO Scale for Clinical Actionability of Molecular Targets Driving Targeted Treatment in Patients with Cholangiocarcinoma, Clin Cancer Res., 28 (8), 1662–1671. doi: https://doi.org/10.1158/1078-0432.CCR-21-2384

Wolff L, Kiesewetter B, 2022. Applicability of ESMO-MCBS and ESCAT for molecular tumor boards, memo, 15, 190-195. doi: https://doi.org/10.1007/s12254-022-00800-1