LBA6 - Serial next generation sequencing of cfDNA to monitor phase I targeted drug administration

Date 29 September 2014
Event ESMO 2014
Session Trials and tribulations in oncology: Future approaches
Topics Anti-Cancer Agents & Biologic Therapy
Translational Research
Presenter Jean-Sebastien Frenel
Citation Annals of Oncology (2014) 25 (5): 1-41. 10.1093/annonc/mdu438
Authors J. Frenel1, S. Carreira2, J. Goodall2, D. Roda-Perez3, A. Smith4, J. Mateo4, M. Ong5, D. Gasi-Tandefelt6, T. Yap3, G. Attard7, D. Nava-Rodrigues2, L.R. Molife3, S.B. Kaye8, U. Banerji9, J.S. De Bono10
  • 1Centre René Gauducheau, Institut de Cancérologie de l'Ouest, FR-44805 - St Herblain CEDEX/FR
  • 2Cancer Biomarkers Group, The Institute of Cancer Research, SM2 5PT - Sutton/GB
  • 3Cr-uk Cancer Therapeutics Unit, Drug Development Unit, The Institute of Cancer Research/Royal Marsden NHS Foundation Trust, SM2 5NG - Sutton/GB
  • 4Drug Development Unit, The Institute of Cancer Research & The Royal Marsden NHS Trust, SM2 5PT - Sutton/GB
  • 5Drug Development Unit, Royal Marsden Hospital, SM2 5PT - Sutton/GB
  • 6Cancer Biomarker, Institute for Cancer Research, sutton/GB
  • 7Prostate Targeted Therapy Group, The Royal Marsden NHS Foundation Trust and Institute of Cancer Research ICR, SM25PT - Sutton/GB
  • 8Drug Development Unit, Royal Marsden Hospital NHS Foundation Trust, SW3 6JJ - London/GB
  • 9Cr-uk Cancer Therapeutics Unit, Drug Development Unit, The Institute of Cancer Research/Royal Marsden NHS Foundation Trust, SM2 5PT - Sutton/GB
  • 10Drug Development Unit, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, SM2 5PT - Sutton/GB

Abstract

Aim

Plasma from patients with cancer contains cell free tumour DNA (cfDNA) that may be utilized for genotyping tumours in real time. We evaluated the use of cfDNA next generation sequencing (NGS) as a multipurpose response biomarker in advanced cancer patients receiving Phase I targeted drugs.

Methods

Between 12/2012 and 11/2013, 135 plasma samples from 24 patients with identified mutations in cfDNA and completing at least 2 courses of investigational targeted therapy were sequenced serially during treatment. Targeted NGS was performed on the Ion Torrent PGM platform with a 50-gene panel with a target coverage of at least 500X per amplicon.

Results

The mean sequencing coverage across the experiments was 1,685X. Overall, 24 patients with various tumour types receiving inhibitors of the PI3K-AKT-mTOR pathway (n = 18), MEK (n = 4), or in combination (n = 2) and others targets (n = 5) were included. Five patients received two consecutive Phase I trials. The mean number of mutations identified in cfDNA per patient was 2 (range 1-5) and the mean mutation allele frequency (AF) within the samples was 26% (Range 2-58%). TP53, PIK3CA and KRAS were the top 3 mutated genes identified, with respectively 19 (42%), 9 (20%) and 7 (16%) different mutations identified. The monitoring of mutation AF in consecutive plasma samples during treatment showed dynamic modifications related to treatment. In the 10 patients with multiple mutations in cfDNA, similar dynamic changes in serial plasma samples were generally observed but in some cases, evidence suggesting clonal heterogeneity was observed, whereby certain mutations dominated in the plasma during the course of the treatment. Patients having a fall in AF of cfDNA mutation after 2 cycles of treatment by >30% (n = 9) had a significantly better time to progression of 111 days compared to 53 days (n = 11) (p = 0.0169) for patients having an increasing AF of >20% compared to baseline.

Conclusions

Serial sequencing of cfDNA during targeted therapy allows monitoring of AF cfDNA mutations that can be associated with response and time to progression. This biomarker warrants further evaluation in the setting of developmental therapeutics.

Disclosure

All authors have declared no conflicts of interest.