Abstract 5045
Background
Systemic anti-cancer treatment is hampered by drug resistance (DR). However, little is known about the pharmacokinetic consequences of genetic changes in tumor cells. We hypothesize that somatic point mutations, small indels, copy number variations (sCNV) and/or structural variations in genes encoding drug transporters are drivers of DR mechanisms in tumor cells. We therefore performed an explorative analysis to quantify somatic aberrations that could reflect DR mechanisms and, in parallel, identify their stressors.
Methods
We interrogated whole-genome sequencing (WGS) data from a Dutch pan-cancer cohort of metastatic cancer patients (N = 3149 at ∼118x and matched peripheral blood at∼38x read depth), of which more than half had failed previous systemic treatment. Somatic aberrations (germline filtered) were analyzed in drug transporters (N = 51), present on the Drug Metabolizing Enzymes and Transporters (DMET™ plus) panel (v.32). Enrichment of somatic DR variants was estimated by assessing nonsynonymous/synonymous mutation ratio deviations (dN/dS) and sCNV were detected with GISTIC2.
Results
In total, 5137 somatic variants (2645 in treatment-naive and 2484 in pretreated patients) in drug transporter genes were observed in 1651 patients (52.4%) of whom 55.1% were systemically pretreated. Three genes (ABCB4, ABCC5, SLCO1B1) showed dN/dS enrichment (p = 0.0142 - 0.0364). sCNVs (N = 7656; 5849 deep gene-level gains and 1807 deletions) were observed in 1906 patients (60.5%). Interestingly, we identified 20 somatic DR-related variants in 12 patients (58.3% pretreated), not present in the matching germline samples, that were identical to SNP variants on DMET™ plus.
Conclusions
In the largest metastatic pan-cancer WGS cohort worldwide, we characterized the pharmacogenomic drug transporter landscape in tumor cells. Potentially, the incidence of somatic variants in pharmacogenes accounts for acquired DR in pretreated patients and/or intrinsic DR. We will extend our study with analyses of prior treatments and germline variations, in order to assess the clinical consequences of the variations and improve clinical decision-making.
Clinical trial identification
NCT01855477.
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
This publication and the underlying study have been made possible partly on the basis of the data that Hartwig Medical Foundation and the Center of Personalised Cancer Treatment (CPCT) have made available to the study.
Disclosure
C. van Herpen: Advisory/Consultancy: Bayer; Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Ipsen; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: Regeneron; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Sanofi. R.H.J. Mathijssen: Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas; Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Boehringer; Research grant / Funding (institution): Cristal Therapeutics; Honoraria (self), Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pamgene; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Sanofi; Honoraria (self): Servier. All other authors have declared no conflicts of interest.
Resources from the same session
5071 - Expression of estrogen receptor and programmed cell death-ligand 1 can be complementary prognostic factors in HPV-positive oropharyngeal squamous cell carcinoma
Presenter: Soohyeon Kwon
Session: Poster Display session 3
Resources:
Abstract
5306 - Real-world data of clinicopathologic characteristics of young oropharyngeal cancer patients.
Presenter: Maria Nieva
Session: Poster Display session 3
Resources:
Abstract
3407 - The clinical significance and biological mechanisms of miR-499a in high-tobacco exposed head and neck squamous cell carcinoma
Presenter: Shiqi Gong
Session: Poster Display session 3
Resources:
Abstract
3310 - Liquid biopsy for mutational profiling of locoregional recurrent and/or metastatic squamous cell carcinoma of the head and neck
Presenter: Rachel Galot
Session: Poster Display session 3
Resources:
Abstract
2362 - Blood-based testing of mutations in patients with Head and neck squamous cell carcinoma (HNSCC) using highly sensitive SafeSEQ technology
Presenter: Florentia Fostira
Session: Poster Display session 3
Resources:
Abstract
4533 - The head and neck Lung Immune Prognostic Index (HN-LIPI): a prognostic Score for Immune Checkpoint Inhibitors (ICI) in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (R/M SCCHN) patients.
Presenter: Ruth Gabriela Herrera Gomez
Session: Poster Display session 3
Resources:
Abstract
5262 - Immune-related adverse events (irAEs) and outcome in recurrent/metastatic (R/M) Head and Neck Squamous Cell Carcinoma (HNSCC) patients (pts) treated by immune-checkpoints inhibitors (ICI)
Presenter: Neus Baste Rotllan
Session: Poster Display session 3
Resources:
Abstract
3725 - Intratumoral and peripheral exploratory biomarker analysis in patients with locoregional, recurrent head and neck squamous cell carcinoma (rHNSCC) treated with RM-1929 photoimmunotherapy
Presenter: Jack Bui
Session: Poster Display session 3
Resources:
Abstract
2533 - A nomogram based prognostic score to predict overall survival (OS) in recurrent-metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients (pts) treated with immune checkpoint inhibitors (ICI).
Presenter: Luay Mousa
Session: Poster Display session 3
Resources:
Abstract
2929 - Changes of the Commensal Microbiome during Treatment are Associated with Clinical Response in the Nasopharyngeal Carcinoma Patients
Presenter: Tingting Huang
Session: Poster Display session 3
Resources:
Abstract