EORTC-SPECTA Arcagen study, comprehensive genomic profiling and treatment adaptation of rare thoracic cancers

Our plain-English summary of EORTC-SPECTA Arcagen study, comprehensive genomic profiling and treatment adaptation of rare thoracic cancers, by M. Tagliamento, M. Morfouace, C. Loizides, et al (NPJ Precision Oncology, 2024).

The study

• Authors: M. Tagliamento, M. Morfouace, C. Loizides, J. Oliveira, L. Greillier, J. Raimbourg, A.C. Toffart, T. Chatellier, N. Cloarec, I. Sullivan, B. Brasiuniene, M. Duruisseaux, K. Oselin, M.S. Robert, C. Fernandes, A. Poncin, J.Y. Blay, B. Besse, N. Girard
• Journal: NPJ Precision Oncology
• Published: 2024;8(1):37
• Cited by: 13 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Arcagen (NCT02834884) is a European prospective study aiming at defining the molecular landscape of rare cancers for treatment guidance. We present data from the cohort of rare thoracic tumors. Patients with advanced pleural mesothelioma (PM) or thymic epithelial tumors (TET) underwent genomic profiling with large targeted assay [>300 genes, tumor mutational burden (TMB), microsatellite instability (MSI) status] on formalin-fixed paraffin-embedded (FFPE) or plasma samples. EORTC molecular tumor board (MTB) advised for biomarker-guided treatments. 102 patients recruited from 8 countries between July 2019 and May 2022 were evaluable: 56 with PM, 46 with TET (23 thymomas, 23 thymic carcinomas). Molecular profiling was performed on 70 FFPE samples (42 PM, 28 TET), and 32 cases on ctDNA (14 PM, 18 TET), within a median turnaround time of 8 days from sample reception. We detected relevant molecular alterations in 66 out of 102 patients (65%; 79% PM, 48% TET), 51 of 70 FFPE samples (73%; 90% PM, 46% TET), and 15 of 32 plasma samples (47%; 43% PM, 50% TET). The most frequently altered genes were CDKN2A/B, BAP1, MTAP in PM and TP53, CDKN2A/B, SETD2 in TET. The TMB was low (mean 3.2 Muts/MB), 2 PM had MSI-high status. MTB advised molecular-guided treatment options in 32 situations, for 17 PM and 15 TET patients (75% clinical trial option, 22% off-label drug or compassionate use, 3% early access program). Molecular testing and MTB discussion were feasible for patients with rare thoracic cancers and allowed the broadening of treatment options for 30% of the cases.

© 2024. The Author(s).

In plain English

This brief communication reported the thoracic-cancer group of Arcagen, a European prospective study. The study ran genetic tests on the tumors of patients with rare cancers, and an expert panel (a molecular tumor board) suggested treatments. Of 122 patients registered in 8 countries between July 2019 and May 2022, 102 could be analysed: 56 with advanced pleural mesothelioma and 46 with thymic epithelial tumors. Tumor tissue was tested where possible; otherwise a blood sample was used. Relevant genetic changes were found in 66 of 102 patients (65%), including 44 mesothelioma patients (79%). In mesothelioma the commonest changes involved the genes CDKN2A/B, BAP1, NF2, MTAP and TP53. Two mesothelioma patients had MSI-high status. Across both cancers, tissue found changes more often than blood (73% vs 47%). The panel suggested treatment options in 17 mesothelioma situations (30% of that group). It also advised germline (inherited) testing for 5 patients, mostly because of BAP1 changes. Patients' asbestos exposure was not reported. The authors concluded that systematic testing was feasible. They named short follow-up as a limitation.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Prospective multicentre genomic profiling study with molecular tumor board review (brief communication reporting the rare thoracic tumor cohort)
• Who was studied: 122 patients registered from 8 countries between July 2019 and May 2022. 102 (84%) were evaluable: 56 with pleural mesothelioma (PM) and 46 with thymic epithelial tumors (TET; 23 thymic carcinomas, 23 thymomas). Eligible patients were older than 12, with locally advanced or metastatic mesothelioma of pleura and pericardium, thymoma or thymic carcinoma.
• Exposure: Not an exposure study. Patients' asbestos exposure was not reported; asbestos is mentioned only as background in the introduction. The study tested tumor tissue (FoundationOne CDx, more than 300 genes) or blood (FoundationOne Liquid CDx). Tobacco exposure was reported for 58% of patients (61% PM, 54% TET).
• Main results:
  • Relevant molecular alterations were detected in 66 of 102 patients (65%), all cancers combined.
  • Pleural mesothelioma: 79% of cases (n = 44) had at least one molecular alteration.
  • Pleural mesothelioma: alterations were found in 38 of 42 tissue samples (90%) and 6 of 14 plasma samples (43%).
  • Pleural mesothelioma: the most frequent changes were deletions or rearrangements of CDKN2A/B, single nucleotide variants or deletions of BAP1 and NF2, deletions of MTAP and single nucleotide variants of TP53.
  • Pleural mesothelioma: tumor mutational burden was generally low (mean 4 mutations per megabase); 2 PM cases had MSI-high status.
  • Pleural mesothelioma: the molecular tumor board advised potential treatment options in 17 situations (30% of the PM cohort).
  • Pleural mesothelioma: germline testing and possible genetic counselling were recommended for 5 patients, mostly because of BAP1 pathogenic variants of suspected germline origin.
  • Thymic epithelial tumors: 48% of cases (n = 22) had at least one molecular alteration; the board advised options in 15 situations (33%).
  • PM and TET together: pathogenic or likely pathogenic alterations were detected more often in tissue (FFPE) samples than in liquid biopsy (73% vs 47%).
  • PM and TET together: the board advised treatment options in 32 situations (75% clinical trial option, 22% off-label drug or compassionate use, 3% early access program).
  • No ESCAT tier 1 or 2 molecular targets were detected.
  • For 11 patients there was no treatment adaptation because of early death from disease progression; in 19 cases the disease had not progressed at database lock.
  • Median turnaround time from sample receipt to molecular report was 8 days for both tissue and plasma analyses.
• The authors' conclusion: The authors concluded that the low failure rate (less than 20%) and successful operational set-up showed that systematic screening for rare thoracic cancers is feasible. They stated that genomic profiling could inform treatment strategies for 31% of patients.
• Limitations the authors state:
  • Short follow-up after enrollment limited data on whether board recommendations were implemented and on any clinical benefit.
  • Using circulating tumor DNA for genotyping has intrinsic limitations.
  • The detection rate may have been overestimated, especially in the liquid biopsy group, because some clonal hematopoiesis variants may have been misinterpreted.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Tumor Mutational Burden (TMB), Microsatellite Instability (MSI-H), Tumor Board, Biomarker, Carcinoma, Molecular Profiling, ctDNA.

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