A framework to rank genomic alterations as targets for cancer precision medicine: the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT)

Mateo, Joaquín; Chakravarty, Debyani; Dienstmann, Rodrigo; Jezdic, S.; González-Pérez, Abel; López‐Bigas, Núria; Ng, Charlotte K.Y.; Bedard, Philippe L.; Tortora, Giampaolo; Jy, Douillard; Allen, Eliezer M. Van; Schultz, Nikolaus; Swanton, Charles; André, Fabrice; Pusztai, Lajos

doi:10.1093/annonc/mdy263

Cited by 500 publications

(444 citation statements)

References 46 publications

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“…Here, we considered only A and B level variants. This classification of actionable events roughly corresponds to the recently proposed ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) 73 as follows: ESCAT I-A+B (for A on-label) and I-C (for A off-label) and ESCAT II-A+B (for B on-label) and III-A (for B off-label). For each actionable mutation, it was also determined to be either on-label (ie.…”

Section: Somatic Driver Catalog Constructionmentioning

confidence: 61%

Pan-cancer whole genome analyses of metastatic solid tumors

Priestley

Baber

Lolkema

et al. 2018

Preprint

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Metastatic cancer is one of the major causes of death and is associated with poor treatment efficiency. A better understanding of the characteristics of late stage cancer is required to help tailor personalised treatment, reduce overtreatment and improve outcomes. Here we describe the largest pan-cancer study of metastatic solid tumor genomes, including 2,520 whole genome-sequenced tumor-normal pairs, analyzed at a median depth of 106x and 38x respectively, and surveying over 70 million somatic variants. Metastatic lesions were found to be very diverse, with mutation characteristics reflecting those of the primary tumor types, although with high rates of whole genome duplication events (56%). Metastatic lesions are relatively homogeneous with the vast majority (96%) of driver mutations being clonal and up to 80% of tumor suppressor genes bi-allelically inactivated through different mutational mechanisms. For 62% of all patients, genetic variants that may be associated with outcome of approved or experimental therapies were detected. These actionable events were distributed across various mutation types underlining the importance of comprehensive genomic tumor profiling for cancer precision medicine. Code availabilityAll bioinformatic analysis tools and scripts used are available at https://github.com/hartwigmedical/.

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Section: Somatic Driver Catalog Constructionmentioning

confidence: 61%

Pan-cancer whole genome analyses of metastatic solid tumors

Priestley

Baber

Lolkema

et al. 2018

Preprint

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“…They thus vary from trial to trial, although various organisations such as the European Society of Clinical oncology have launched initiatives to harmonise, for instance, the criteria defining levels of evidence for assessing the actionability of genomic alterations (Mateo et al . ). Efforts are also underway, for instance, by the Variant Interpretation Cancer Consortium to harmonise the content of knowledge bases (Wagner et al .…”

Section: Mtbs In Actionmentioning

confidence: 97%

“…Mateo et al . ) designed to obviate the lack of standards by helping MTB members assess the trustworthiness of drug‐biomarker matches. MTBs will also implement local tools such as algorithmic decision trees that, while open to revisions, are included in trial protocols.…”

Section: Mtbs In Actionmentioning

confidence: 99%

“…In addition to reports and visual inscriptions derived from the high-throughput analysis of patient material, they include generally available databases and, more specifically, 'knowledge bases' that provide access to highly curated functional information about variants, various kinds of software, but also convention-based tools such as levels of evidence tables (e.g. Mateo et al 2018) designed to obviate the lack of standards by helping MTB members assess the trustworthiness of drug-biomarker matches. MTBs will also implement local tools such as algorithmic decision trees that, while open to revisions, are included in trial protocols.…”

Section: Mtbs As Collective Bio-clinical Expertisementioning

confidence: 99%

“…These prioritisation rules, while referring to scientific evidence consigned in publications and knowledge bases, are also strongly derivative of the objectives of the trial, the drugs and panel of genes that are available as part of a specific trial, and other analytical parameters. They thus vary from trial to trial, although various organisations such as the European Society of Clinical oncology have launched initiatives to harmonise, for instance, the criteria defining levels of evidence for assessing the actionability of genomic alterations (Mateo et al 2018). Efforts are also underway, for instance, by the Variant Interpretation Cancer Consortium to harmonise the content of knowledge bases (Wagner et al 2018).…”

Section: Onco1: It's Clear-cut and Logicalmentioning

confidence: 99%

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Genomic expertise in action: molecular tumour boards and decision‐making in precision oncology

Bourret

Cambrosio

2019

Sociology Health & Illness

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The recent development of cancer precision medicine is associated with the emergence of ‘molecular tumour boards’ (MTBs). Attended by a heterogenous set of practitioners, MTBs link genomic platforms to clinical practices by establishing ‘actionable’ connections between drugs and molecular alterations. Their activities rely on a number of evidential resources – for example databases, clinical trial results, basic knowledge about mutations and pathways – that need to be associated with the clinical trajectory of individual patients. Experts from various domains are required to master and align diverse kinds of information. However, rather than examining MTBs as an institution interfacing different kinds of expertise embedded in individual experts, we argue that expertise is the emergent outcome of MTBs, which can be conceptualised as networks or ‘agencements’ of humans and devices. Based on the ethnographic analysis of the activities of four clinical trial MTBs (three in France and an international one) and of two French routine‐care MTBs, the paper analyses how MTBs produce therapeutic decisions, centring on the new kind of expertise they engender. The development and activities of MTBs signal a profound transformation of the evidentiary basis and processes upon which biomedical expertise and decision‐making in oncology are predicated and, in particular, the emergence of a clinic of variants.

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Concordance Between Recommendations From Multidisciplinary Molecular Tumor Boards and Central Consensus for Cancer Treatment in Japan

et al. 2022

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ImportanceQuality assurance of molecular tumor boards (MTBs) is crucial in cancer genome medicine.ObjectiveTo evaluate the concordance of recommendations by MTBs and centrally developed consensus treatment recommendations at all 12 leading institutions for cancer genomic medicine in Japan using 50 simulated cases.Design, Setting, and ParticipantsThis was a prospective quality improvement study of 50 simulated cancer cases. Molecular tumor boards from 12 core hospitals independently recommended treatment for 50 cases blinded to the centrally developed consensus treatment recommendations. The study’s central committee consisted of representatives from all 12 core hospitals in Japan who selected the 50 simulated cases from The Cancer Genome Atlas database, including frequently observed genomic alterations. The central committee recommended centrally developed consensus treatment. The concordance rate for genomically matched treatments between MTBs and centrally developed consensus treatment recommendations was evaluated. Data analysis was conducted from January 22 to March 3, 2021.ExposuresSimulated cases of cancer.Main Outcomes and MeasuresThe primary outcome was concordance, defined as the proportion of recommendations by MTBs concordant with centrally developed consensus treatment recommendations. A mixed-effects logistic regression model, adjusted for institutes as a random intercept, was applied. High evidence levels were defined as established biomarkers for which the treatment was ready for routine use in clinical practice, and low evidence levels were defined as biomarkers for genomically matched treatment that were under investigation.ResultsThe Clinical Practice Guidance for Next-Generation Sequencing in Cancer Diagnosis and Treatment (edition 2.1) was used for evidence-level definition. The mean concordance between MTBs and centrally developed consensus treatment recommendations was 62% (95% CI, 57%-65%). Each MTB concordance varied from 48% to 86%. The concordance rate was higher in the subset of patients with colorectal cancer (100%; 95% CI, 94.0%-100%), ROS1 fusion (100%; 95% CI, 85.5%-100%), and high evidence level A/R (A: 88%; 95% CI, 81.8%-93.0%; R:100%; 95% CI, 92.6%-100%). Conversely, the concordance rate was lower in cases of cervical cancer (11%; 95% CI, 3.1%-26.1%), TP53 mutation (16%; 95% CI, 12.5%-19.9%), and low evidence level C/D/E (C: 30%; 95% CI, 24.7%-35.9%; D: 25%; 95% CI, 5.5%-57.2%; and E: 18%; 95% CI, 13.8%-23.0%). Multivariate analysis showed that evidence level (high [A/R] vs low [C/D/E]: odds ratio, 4.4; 95% CI, 1.8-10.8) and TP53 alteration (yes vs no: odds ratio, 0.06; 95% CI, 0.03-0.10) were significantly associated with concordance.Conclusions and RelevanceThe findings of this study suggest that genomically matched treatment recommendations differ among MTBs, particularly in genomic alterations with low evidence levels wherein treatment is being investigated. Sharing information on matched therapy for low evidence levels may be needed to improve the quality of MTBs.

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A framework to rank genomic alterations as targets for cancer precision medicine: the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT)

Abstract: The ESCAT defines clinical evidence-based criteria to prioritise genomic alterations as markers to select patients for targeted therapies. This classification system aims to offer a common language for all the relevant stakeholders in cancer medicine and drug development.

Cited by 500 publications

References 46 publications

Pan-cancer whole genome analyses of metastatic solid tumors

Pan-cancer whole genome analyses of metastatic solid tumors

Genomic expertise in action: molecular tumour boards and decision‐making in precision oncology

Concordance Between Recommendations From Multidisciplinary Molecular Tumor Boards and Central Consensus for Cancer Treatment in Japan

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