Implementation and use of whole exome sequencing for metastatic solid cancer

Manon Réda, Corentin Richard, Aurelie Bertaut, Julie Niogret, Thomas Collot, Jean David Fumet, Julie Blanc, Caroline Truntzer, Isabelle Desmoulins, Sylvain Ladoire, Audrey Hennequin, Laure Favier, Leila Bengrine, Julie Vincent, Alice Hervieu, Jean-Florian Guion Dusserre, Come Lepage, Pascal Foucher, Christophe Borg, Juliette Albuisson, Laurent Arnould, Sophie Nambot, Laurence Faivre, Romain Boidot, Francois Ghiringhelli, Manon Réda, Corentin Richard, Aurelie Bertaut, Julie Niogret, Thomas Collot, Jean David Fumet, Julie Blanc, Caroline Truntzer, Isabelle Desmoulins, Sylvain Ladoire, Audrey Hennequin, Laure Favier, Leila Bengrine, Julie Vincent, Alice Hervieu, Jean-Florian Guion Dusserre, Come Lepage, Pascal Foucher, Christophe Borg, Juliette Albuisson, Laurent Arnould, Sophie Nambot, Laurence Faivre, Romain Boidot, Francois Ghiringhelli

Abstract

Background: Genomically-guided clinical trials are performed across different tumor types sharing genetic mutations, but trial organization remains complex. Here we address the feasibility and utility of routine somatic and constitutional exome analysis in metastatic cancer patients.

Methods: Exoma trial (NCT02840604) is a multicenter, prospective clinical trial. Eligible patients presented a metastatic cancer progressing after at least one line of systemic therapy. Constitutional genetics testing required geneticist consultation. Somatic and germline exome analysis was restricted to 317 genes. Variants were classified and molecular tumor board made therapeutic recommendations based on ESMO guidelines. Primary endpoint was the feasibility of the approach evaluated by the proportion of patient that received a therapeutic proposal.

Findings: Between May 2016 and October 2018, 506 patients were included. Median time required for tumor sample reception was 8 days. Median time from sample reception to results was 52 days. Somatic analysis was performed for 456 patients (90.1%). Both somatic and constitutional analyses were successfully performed for 386 patients (76.3%). In total, 342 patients (75%) received a therapeutic proposal. Genetic susceptibility to cancer was found in 35 (9%) patients. Only, 79 patients (23.1%) were treated with NGS matched therapy mainly PI3K/AKT/mTOR inhibitors 22 (27.8%), followed by PARP inhibitors 19 (24.1%), antiangiogenics 17 (21.5%), MEK inhibitors 7 (8.9%) and immunotherapy 5 (6.3%). Matched treatment was finally stopped because of disease progression 50 (63%), treatment toxicity 18 (23%), patients' death 4 (5%). PFS2/PFS1 ratio was > 1,3 for 23,5% of patients treated with the NGS matched therapy and 23,7% of patients treated with standard therapy.

Interpretation: Study shows that exome analysis is feasible in cancer routine care. This strategy improves detection of genetic predispositions and enhances access to target therapies. However, no differences were observed between PFS ratios of patients treated with matched therapy versus standard therapy.

Funding: This work was funding by the centre Georges Francois Leclerc.

Keywords: Molecular profiling of cancer; exome sequencing analysis; metastatic cancer precision Medicine; routine care; somatic and constitutional analysis.

Conflict of interest statement

Declaration of competing interest Other authors declare no relevant conflict of interests related to this publication.

Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.

Figures

Fig. 1
Fig. 1
a. Flow chart. b. Main tumor types in the trial.
Fig. 2
Fig. 2
Genomic characteristics. a. List of top mutated genes. b. top mutated genes in main cancers. c. Tumor mutational burden value across tumor type. d. relation between Tumor mutational burden and alterations in DNA repair pathways. e. List of constitutional alterations in actionable genes. (d,e: Lines represent median and interquartile ranges); for panel d * mean p value

References

    1. Zehir A., Benayed R., Shah R.H., Syed A., Middha S., Kim H.R. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 2017;23(6):703–713.
    1. Salvatore L., Aprile G., Arnoldi E., Aschele C., Carnaghi C., Cosimelli M. Management of metastatic colorectal cancer patients: guidelines of the Italian Medical Oncology Association (AIOM) ESMO Open. 2017;2(1)
    1. Kerr K.M., Bubendorf L., Edelman M.J., Marchetti A., Mok T., Novello S. Second ESMO consensus conference on lung cancer: pathology and molecular biomarkers for non-small-cell lung cancer. Ann Oncol. 2014;25(9):1681–1690.
    1. Dummer R., Hauschild A., Lindenblatt N., Pentheroudakis G., Keilholz U. Cutaneous melanoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26(suppl 5):v126–v132.
    1. Manolio T.A., Rowley R., Williams M.S., Roden D., Ginsburg G.S., Bult C. Opportunities, resources, and techniques for implementing genomics in clinical care. Lancet. 2019;394(10197):511–520.
    1. Berger M.F., Mardis E.R. The emerging clinical relevance of genomics in cancer medicine. Nat Rev Clin Oncol. 2018;15(6):353–365.
    1. Frampton G.M., Fichtenholtz A., Otto G.A., Wang K., Downing S.R., He J. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol. 2013;31(11):1023–1031.
    1. Mateo J., Chakravarty D., Dienstmann R., Jezdic S., Gonzalez-Perez A., Lopez-Bigas N. A framework to rank genomic alterations as targets for cancer precision medicine: the ESMO scale for clinical actionability of molecular targets (ESCAT) Ann Oncol. 2018;29(9):1895–1902.
    1. Von Hoff D.D., Stephenson J.J., Rosen P., Loesch D.M., Borad M.J., Anthony S. Pilot study using molecular profiling of patients’ tumors to find potential targets and select treatments for their refractory cancers. J Clin Oncol. 2010;28(33):4877–4883.
    1. Therasse P., Arbuck S.G., Eisenhauer E.A., Wanders J., Kaplan R.S., Rubinstein L. New guidelines to evaluate the response to treatment in solid tumors. JNCI J Natl Cancer Inst. 2000;92(3):205–216.
    1. Li M.M., Datto M., Duncavage E.J., Kulkarni S., Lindeman N.I., Roy S. Standards and guidelines for the interpretation and reporting of sequence variants in cancer. J Mol Diagn. 2017;19(1):4–23.
    1. Massard C., Michiels S., Ferté C., Le Deley M.-.C., Lacroix L., Hollebecque A. High-Throughput genomics and clinical outcome in hard-to-treat advanced cancers: results of the moscato 01 trial. Cancer Discov. 2017;7(6):586–595.
    1. Le Tourneau C., Delord J.-.P., Gonçalves A., Gavoille C., Dubot C., Isambert N. Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicentre, open-label, proof-of-concept, randomised, controlled phase 2 trial. Lancet Oncol. 2015;16(13):1324–1334.
    1. Beltran H., Eng K., Mosquera J.M., Sigaras A., Romanel A., Rennert H. Whole-Exome sequencing of metastatic cancer and biomarkers of treatment response. JAMA Oncol. 2015;1(4):466.
    1. Zhang P., Lehmann B.D., Shyr Y., Guo Y. The utilization of formalin fixed-paraffin-embedded specimens in high throughput genomic studies. Int J Genomics. 2017;2017:1–9.
    1. Sicklick J.K., Kato S., Okamura R., Schwaederle M., Hahn M.E., Williams C.B. Molecular profiling of cancer patients enables personalized combination therapy: the i-predict study. Nat Med. 2019;25(5):744–750.
    1. Rodon J., Soria J.-.C., Berger R., Miller W.H., Rubin E., Kugel A. Genomic and transcriptomic profiling expands precision cancer medicine: the winther trial. Nat Med. 2019;25(5):751–758.
    1. Bertucci F., Ng C.K.Y., Patsouris A., Droin N., Piscuoglio S., Carbuccia N. Genomic characterization of metastatic breast cancers. Nature. 2019;569(7757):560–564.

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