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Basic science

5353 - Landscape of DNA damage response (DDR) genes alterations in the prospective MOSCATO and MATCH R trials

Date

10 Sep 2017

Session

Basic science

Topics

Translational Research

Presenters

Yolla El Dakdouki

Citation

Annals of Oncology (2017) 28 (suppl_5): v595-v604. 10.1093/annonc/mdx391

Authors

Y. El Dakdouki1, L. Verlingue2, C. Massard3, R. Bahleda4, A. Hollebecque5, L. Mahjoubi2, E. Rouleau6, L. Lacroix7, N. Auger8, J. Scoazec9, E. Solary10, A. Marabelle11, F. André12, J. Soria13, S. Postel-Vinay14

Author affiliations

  • 1 Duertec, Institut Gustave Roussy, 94800 - Villejuif/FR
  • 2 Drug Development Department (ditep), Gustave Roussy, 94805 - Villejuif/FR
  • 3 Early Drug Development Department, Institut de Gustave Roussy, Villejuif/FR
  • 4 Early Drug Development Department, Gustave Roussy, 94805 - Villejuif/FR
  • 5 Drug Development Department (ditep), Gustave Roussy Cancer Campus, 94805 - Villejuif/FR
  • 6 Département De Biologie Et Pathologie Médicales, Gustave ROUSSY, 94805 - VILLEJUIF/FR
  • 7 Bmo, Institut Gustave Roussy, 94800 - Villejuif/FR
  • 8 Laboratoire De Recherche Translationnelle, Gustave Roussy, 94805 - Villejuif/FR
  • 9 Pathology, Gustave Roussy Institute, Villejuif/FR
  • 10 Umr 1170, Institut Gustave Roussy, 94800 - Villejuif/FR
  • 11 Département D’innovation Thérapeutique Et D’essais Précoces, Gustave Roussy, Université Paris-Saclay, Villejuif/FR
  • 12 Breast Cancer Unit, Department Of Medical Oncology, Gustave Roussy Institut de Cancérologie, 94805 - Villejuif/FR
  • 13 Department Of Drug Development, Gustave Roussy Cancer Campus, 94800 - Villejuif/FR
  • 14 Départemement D’innovation Thérapeutique Et Des Essais Précoces (ditep), Institut Gustave Roussy, 94800 - Villejuif/FR
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Resources

Abstract 5353

Background

DDR deficiency is a hallmark of cancer. We aimed at describing in 2 prospective trials run at Gustave Roussy Cancer Campus the molecular and clinical characteristics of patients (pts) harboring DDR gene alterations with special focus on mismatch repair (MMR).

Methods

Pts with metastatic solid tumors enrolled in MOSCATO (NCT01566019) and MATCHR (NCT02517892) trials had on-purpose tumor biopsy; molecular profiling was performed using Targeted Next Generation Sequencing (TGS) and Comparative Genomic Hybridization array (CGHa), or Whole Exome Sequencing (WES). Alterations in 46 genes involved in DNA repair were searched. After review by molecular geneticist, pathogenic variants (PV) were defined as variants causing protein truncation (frameshift indels, nonsense or splice site variants) or known to be deleterious missense variants according to databases such as LOVD, BRCAshare and OncoKB. Variants without deleterious prediction were excluded.

Results

Molecular data of 1092 pts of various histologies enrolled between Dec. 2011 and Oct. 2016 was used. Analysis of TGS (N = 1090), CGHa (N = 838) and WES (N = 304) data allowed identifying 156 alterations in 107 pts (9.8%) and 30 DDR genes: 60 PV, 86 variants of unknown pathogenicity (VUP) and 10 focal deletions (CGHa). Most frequent altered pathways were homologous recombination (47 PV, including 30 BRCA1/2 PV and 7 ATM PV in 13 primary sites) and MMR. The 27 pts with 35 MMR and POLE alterations (12 PV, 20 VUP and 3 deletions) had 11 different primary types including most frequently colorectal, genito-urinary and breast. Only one pt was previously known to have Lynch syndrome. Missense PV occurred most frequently in POLE, MLH1, MSH2, PMS1 (2 each), as well as, MSH3 and MLH3 (1 each); 14/27 pts received immunotherapy (IO). Median PFS was 6.5 months with IO and 6.2 months with conventional therapy. Correlation of MMR aberrations with immune infiltrates and outcome (response, PFS and OS) on IO will be presented at the congress time.

Conclusions

DDR genes alterations occur regularly in solid tumors. Systematic analysis of DDR alterations could allow customizing treatment of pts that specifically benefit from IO or DNA repair inhibitors through synthetic lethality.

Clinical trial identification

NCT01566019 and NCT02517892

Legal entity responsible for the study

Gustave Roussy Cancer Campus

Funding

Gustave Roussy Cancer Campus.

Disclosure

All authors have declared no conflicts of interest.

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