Original ResearchHigh-depth sequencing of paired primary and metastatic tumours: Implications for personalised medicine

- We report the first large series comparing paired primary tumours and metastasis sequenced with a wide panel of genes.
- We found that up to 40% of paired primary tumour/metastases have discordant molecular profile.
- Genotyping the primary tumour may be inappropriate to guide systemic treatment in a significant proportion of cases.
- Discrepancies can be explained by heterogeneity and/or by therapeutic stress.

BackgroundNext-generation sequencing of large panel of genes had been associated with clinical benefit in a significant proportion of patients with advanced cancer. However, the molecular profile of the primary tumour from the initial surgical specimen might significantly differ from the molecular profile in a tumour sample obtained from a biopsy of a metastatic site.Patients and methodsWe compare the genetic profile of primary tumours and paired metastases by using a large panel of cancer genes. Training and validation set including a total of 152 primary and metastatic tumour pairs were sequenced (up to 429 genes) focussing on variants described in the Catalogue of Somatic Mutations in Cancer (COSMIC).ResultsTraining and validation set including a total of 152 primary and metastatic tumour pairs were sequenced focussing on variants described in COSMIC. Agreement rate between the couples of primary and metastasis on COSMIC variants was 65% (24/37) and 43% (49/115) in the training and validation cohort, respectively. That rose to 74% (20/27) and 58% (42/73) when focussing on targetable mutations. In five cases, the discordance was related to appearance of secondary resistance mutation, giving a targetable refined agreement rate of 67% (67/100).ConclusionUp to 40% of paired primary tumour/metastases have discordant molecular profile. Liquid biopsies may overcome, in the near future, the limits of tumour tissue genotyping.