Seeking the driver in tumours with apparent normal molecular profile on comparative genomic hybridization and targeted gene panel sequencing: what is the added value of whole exome sequencing?

Postel-Vinay, Sophie; Boursin, Yannick; Massard, Christophe; Hollebecque, Antoine; Ileana, Ecaterina; Chiron, Marielle; Jung, Joonil; Lee, J.S.; Balogh, Zsuzsanna; Adam, Julien; Vielh, Philippe; Angevin, Eric; Lacroix, Ludovic; Soria, Jean Charles

doi:10.1093/annonc/mdv570

Cited by 10 publications

(5 citation statements)

References 43 publications

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“…Our molecular analyses were limited to panels ranging from 23 to 80 tested genes. We potentially would have found more alterations with a whole exome sequencing 23 or with an RNA sequencing which detects viable fusion genes. NGS contributed to identify 90% of the nearly 10 000 gene fusions identified in cancer.…”

Section: Discussionmentioning

confidence: 99%

Relevance of a molecular tumour board (MTB) for patients’ enrolment in clinical trials: experience of the Institut Curie

et al. 2018

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BackgroundHigh throughput molecular screening techniques allow the identification of multiple molecular alterations, some of which are actionable and can be targeted by molecularly targeted agents (MTA). We aimed at evaluating the relevance of using this approach in the frame of Institut Curie Molecular Tumor Board (MTB) to guide patients with cancer to clinical trials with MTAs.Patients and methodsWe included all patients presented at Institut Curie MTB from 4 October 2014 to 31 October 2017. The following information was extracted from the chart: decision to perform tumour profiling, types of molecular analyses, samples used, molecular alterations identified and those which are actionable, and inclusion in a clinical trial with matched MTA.Results736 patients were presented at the MTB. Molecular analyses were performed in 442 patients (60%). Techniques used included next-generation sequencing, comparative genomic hybridisation array and/or other techniques including immunohistochemistry in 78%, 51% and 58% of patients, respectively. Analyses were performed on a fresh frozen biopsy in 91 patients (21%), on archival tissue (fixed or frozen) in 326 patients (74%) and on both archival and fresh frozen biopsy in 25 patients (6%). At least one molecular alteration was identified in 280 analysed patients (63%). An actionable molecular alteration was identified in 207 analysed patients (47%). Forty-five analysed patients (10%) were enrolled in a clinical trial with matched MTA and 29 additional patients were oriented and included in a clinical trial based on a molecular alteration identified prior to the MTB analysis. Median time between date of specimen reception and molecular results was 28 days (range: 5–168).ConclusionsThe implementation of an MTB at Institut Curie enabled the inclusion of 10% of patients into a clinical trial with matched therapy.

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Section: Discussionmentioning

confidence: 99%

Relevance of a molecular tumour board (MTB) for patients’ enrolment in clinical trials: experience of the Institut Curie

et al. 2018

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“…Tumor DNA, RNA, and germline DNA from whole-blood samples [used for whole-exome sequencing (WES)] were extracted using, respectively, AllPrep DNA/RNA Mini Kit and DNeasy Blood and Tissue Kit according to the manufacturer's instructions. The molecular analysis using targeted sequencing and aCGH was carried out as described previously (29,30). Briefly, targeted sequencing was performed using Personal Genome Machine (Ion Torrent PGM, ThermoFisher Scientific) with Ion AmpliSeq multiple genes panels, based on multiplex-PCR.…”

Section: Genomic Analysesmentioning

confidence: 99%

High-Throughput Genomics and Clinical Outcome in Hard-to-Treat Advanced Cancers: Results of the MOSCATO 01 Trial

et al. 2017

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High-throughput genomic analyses may improve outcomes in patients with advanced cancers. MOSCATO 01 is a prospective clinical trial evaluating the clinical benefit of this approach. Nucleic acids were extracted from fresh-frozen tumor biopsies and analyzed by array comparative genomic hybridization, next-generation sequencing, and RNA sequencing. The primary objective was to evaluate clinical benefit as measured by the percentage of patients presenting progression-free survival (PFS) on matched therapy (PFS2) 1.3-fold longer than the PFS on prior therapy (PFS1). A total of 1,035 adult patients were included, and a biopsy was performed in 948. An actionable molecular alteration was identified in 411 of 843 patients with a molecular portrait. A total of 199 patients were treated with a targeted therapy matched to a genomic alteration. The PFS2/PFS1 ratio was >1.3 in 33% of the patients (63/193). Objective responses were observed in 22 of 194 patients (11%; 95% CI, 7%-17%), and median overall survival was 11.9 months (95% CI, 9.5-14.3 months). This study suggests that high-throughput genomics could improve outcomes in a subset of patients with hard-to-treat cancers. Although these results are encouraging, only 7% of the successfully screened patients benefited from this approach. Randomized trials are needed to validate this hypothesis and to quantify the magnitude of benefit. Expanding drug access could increase the percentage of patients who benefit. .

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“…The variety of sequencing methods and the relatively limited size of targeted gene panels also possibly contributed. About half the cohort was analysed with targeted sequencing only, while whole-genome/exome sequencing enlarges the probability of finding druggable aberrations [54,55]. Although, in our data, the proportion of patients without recommendation was roughly the same for the WGS and targeted-sequencing patients.…”

Section: Clinical Outcomementioning

confidence: 54%

Impact of molecular tumour board discussion on targeted therapy allocation in advanced prostate cancer

Slootbeek

Kloots²,

Smits³

et al. 2021

Br J Cancer

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Background Molecular tumour boards (MTB) optimally match oncological therapies to patients with genetic aberrations. Prostate cancer (PCa) is underrepresented in these MTB discussions. This study describes the impact of routine genetic profiling and MTB referral on the outcome of PCa patients in a tertiary referral centre. Methods All PCa patients that received next-generation sequencing results and/or were discussed at an MTB between Jan 1, 2017 and Jan 1, 2020 were included. Genetically matched therapies (GMT) in clinical trials or compassionate use were linked to actionable alterations. Response to these agents was retrospectively evaluated. Results Out of the 277 genetically profiled PCa patients, 215 (78%) were discussed in at least one MTB meeting. A GMT was recommended to 102 patients (47%), of which 63 patients (62%) initiated the GMT. The most recommended therapies were PARP inhibitors (n = 74), programmed death-(ligand) 1 inhibitors (n = 21) and tyrosine kinase inhibitors (n = 19). Once started, 41.3% had a PFS of ≥6 months, 43.5% a PSA decline ≥50% and 38.5% an objective radiographic response. Conclusion Recommendation for a GMT is achieved in almost half of the patients with advanced prostate cancer, with GMT initiation leading to durable responses in over 40% of patients. These data justify routine referral of selected PCa patients to MTB’s.

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Seeking the driver in tumours with apparent normal molecular profile on comparative genomic hybridization and targeted gene panel sequencing: what is the added value of whole exome sequencing?

Cited by 10 publications

References 43 publications

Relevance of a molecular tumour board (MTB) for patients’ enrolment in clinical trials: experience of the Institut Curie

Relevance of a molecular tumour board (MTB) for patients’ enrolment in clinical trials: experience of the Institut Curie

High-Throughput Genomics and Clinical Outcome in Hard-to-Treat Advanced Cancers: Results of the MOSCATO 01 Trial

Impact of molecular tumour board discussion on targeted therapy allocation in advanced prostate cancer

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