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VHIO-300 and a thousand one nights, a tale of Precision Medicine

Date

28 Sep 2019

Session

Poster Display session 1

Presenters

Ginevra Caratù

Citation

Annals of Oncology (2019) 30 (suppl_5): v797-v815. 10.1093/annonc/mdz269

Authors

G. Caratù1, F.M. Mancuso1, M. Sansó1, J. Matito1, R. Fasani2, A. Oaknin3, M. Alsina Maqueda3, J. Capdevila3, E. Elez Fernández3, T. Macarulla Mercade3, J. Carles3, C. Saura3, J.A. Rodon3, R. Dienstmann3, P.G. Nuciforo2, E. Garralda3, E. Felip3, J. Tabernero3, A. Vivancos1

Author affiliations

  • 1 Cancer Genomics Group, Vall d'Hebron Institute of Oncology (VHIO)-Cellex Center, 08035 - Barcelona/ES
  • 2 Molecular Oncology Group, Vall d`Hebron Institute of Oncology (VHIO)-Cellex Center, 08035 - Barcelona/ES
  • 3 Department Of Medical Oncology, Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology (VHIO), 08035 - Barcelona/ES
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Abstract 5222

Background

Targeted hotspot cancer NGS panels are becoming an integral part of clinical practice for detection of clinically relevant mutations. Tumor mutation burden (TMB) has arisen as a biomarker in the immunotherapy field, challenging established hotspot panels. So far, testing has been steep, limited to whole exome sequencing (WES) or external commercial NGS assays, neither of which are feasible strategies for future local testing. Clinical routine implementation requires development and validation of new, comprehensive tests, able to deal with day-to-day reality in testing labs, such as input DNA quality and amount limitations or turnaround-time restraints.

Methods

We designed a custom NGS assay, VHIO-300, to detect mutations, copy number alterations (CNA), gene fusions, loss-of-heterozygosity and TMB scoring from tumor samples. VHIO-300 is a capture enrichment of over 430 cancer genes, covering enough sequence to allow TMB calculation (≈1.3 Mb), as well as 2 Mb of non-coding genomic regions. Here, we report the analytical and clinical validation procedures. Analytical sensitivity was conducted on positive control DNAs derived from 5 ATCC cell lines comprising 40 SNVs and indels. Clinical samples with WES data were used to determine specificity, sensitivity and robustness. VHIO-300 performance for TMB calling was tested using 50 FFPE-derived tumor specimens compared to scores provided from both WES and Foundation One test.

Results

Panel design was tuned to improve detection of capture-sensitive variants such as indels, that affect relevant genes in cancer like EGFR, BRCA1/2 or KIT, improving analytical sensitivity by two-fold. The VHIO-300 panel achieved 92.5% clinical sensitivity and 99.9% clinical specificity for SNVs and indel calling compared to WES data. CNA achieved 85% sensitivity and 99.6% specificity compared to array comparative genomic hybridization. Several in-silico TMB calculation algorithms were tested with WES data, the most accurate included both synonymous and non-synonymous calls (r2=0.94).

Conclusions

We provide a complete analytical validation of VHIO-300 panel that makes it a convenient choice for clinical laboratories where a comprehensive genome profiling of FFPE tumor samples is required.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Vall d’Hebron Institute of Oncology.

Funding

Bristol-Meyers Squibb.

Disclosure

A. Oaknin: Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Travel / Accommodation / Expenses: PharmaMar; Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: Inmunogen ; Advisory / Consultancy: Genmab ; Travel / Accommodation / Expenses: Roche. M. Alsina Maqueda: Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: MSD; Advisory / Consultancy: Servier; Research grant / Funding (institution): Merck. J. Capdevila: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Eisai; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Ipsen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Merk; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen. E. Elez Fernández: Research grant / Funding (institution): Novartis; Honoraria (self), Research grant / Funding (institution): Roche; Research grant / Funding (institution): Bayer; Honoraria (self), Research grant / Funding (self): Merck Sorono; Honoraria (self), Research grant / Funding (self): Sanofi. T. Macarulla Mercade: Advisory / Consultancy: Roche; Advisory / Consultancy: Bayer; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Servier. J. Carles: Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Johnson & Johnson ; Advisory / Consultancy: MSD Oncology; Advisory / Consultancy: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Astellas Pharma; Advisory / Consultancy: AstraZeneca. C. Saura: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Puma; Advisory / Consultancy: Sanofi. J.A. Rodon: Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Roche Pharmaceuticals ; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Orion Pharmaceuticals; Advisory / Consultancy: Servier Pharmaceuticals; Advisory / Consultancy: Peptomyc. R. Dienstmann: Advisory / Consultancy: Roche; Research grant / Funding (self): merck. P.G. Nuciforo: Advisory / Consultancy: Bayer; Advisory / Consultancy: Novartis; Advisory / Consultancy: MSD. E. Garralda: Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Leadership role: ESMO Women for Oncology; Non-remunerated activity/ies: ESMO. E. Felip: Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck KGaA; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck Sharp & Dohme; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche. J. Tabernero: Advisory / Consultancy: Foundation Medicine; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy: Genentech; Advisory / Consultancy: Chugai; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Novartis; Advisory / Consultancy: Hoffmann-La Roche Ltd; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Servier; Advisory / Consultancy: Symphogen; Advisory / Consultancy: Biocartis; Advisory / Consultancy: Roche Diagnostics; Advisory / Consultancy: Boehringer Ingelheim. A. Vivancos: Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Sysmex; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy: Roche; Advisory / Consultancy: Guardant Health; Research grant / Funding (institution): Debio; Research grant / Funding (institution): Cellestia Biotech. All other authors have declared no conflicts of interest.

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