Abstract 3799
Background
Colorectal carcinoma 5-year survival ranges from 90% in patients with localized disease to 15% for those with distant metastasis. Recent research has suggested that hypermutation may predict response to immunotherapy in these tumors, but routine tests for microsatellite (MS) instability miss tumours which acquire hypermutation through other mechanisms. Tumour mutational burden (TMB) measured by next-generation sequencing has been proposed to overcome this limitation.
Methods
A commercially available next-generation sequencing panel targeting 409 cancer-relevant genes was validated for TMB measurement using 12 MS stable and 14 MS instable metastatic colorectal carcinomas, defined by routine testing of MS loci. The same panel was applied to 53 untested colorectal carcinomas with matched synchronous metastases, collected across 10 years to determine both their TMB and presence of KRAS/BRAF mutations.
Results
All samples could be sequenced at a mean coverage depth of 766x and uniformity of 97%. Mean TMB (mutations/megabase) was 8.84 for MS stable vs. 33.36 for MS instable cases in the assay validation cohort. A cut-off value of 15.56 reached 100% sensitivity (95% CI 77-100%) and 100% specificity (95% CI 73-100%). Analysis of the 10 years cohort showed KRAS mutation in 25 cases and BRAF mutation in 4; automated TMB analysis was feasible for samples collected within 7 years (n = 16), while in older specimens DNA deamination caused artefactual calls. 14 cases showed a low TMB in both primary and metastasis, one MS instable case showed high TMB in both primary and metastasis, and one MS stable case showed low TMB (11.61) in the primary and a higher TMB (21.37) in the metastasis. The mutational signature of the metastatic sample showed C>A transversions (11%), missing in the primary tumour, suggesting an additional mutational mechanism.
Conclusions
Gene panel-based TMB analysis can be performed on routine histology samples to detect both hypermutation and cancer relevant somatic mutations. Analysis of older samples may lead to deamination artifacts, which can however be revealed by mutational signature analysis.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Aldo Scarpa (ARC-NET Cancer Research Centre).
Funding
Associazione Italiana Ricerca Cancro [AIRC grant n. 12182].
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
5105 - Fresh blood Immune cell monitoring in patients treated with nivolumab in the GETUG-AFU26 NIVOREN study: association with toxicity and treatment outcome
Presenter: Aude DESNOYER
Session: Poster Display session 3
Resources:
Abstract
1877 - Advanced clear-cell renal cell carcinoma (accRCC): association of microRNAs (miRNAs) with molecular subtypes, mRNA targets and outcome.
Presenter: Annelies Verbiest
Session: Poster Display session 3
Resources:
Abstract
5543 - Prior tyrosine kinase inhibitors (TKI) and antibiotics (ATB) use are associated with distinct gut microbiota ‘guilds’ in renal cell carcinoma (RCC) patients
Presenter: Valerio Iebba
Session: Poster Display session 3
Resources:
Abstract
2689 - mTOR mutations are not associated with shorter PFS and OS in patients treated with mTOR inhibitors
Presenter: Cristina Suarez Rodriguez
Session: Poster Display session 3
Resources:
Abstract
3069 - Efficacy of immune checkpoint inhibitors (ICI) and genomic alterations by body mass index (BMI) in Advanced Renal Cell Carcinoma (RCC)
Presenter: Aly-Khan Lalani
Session: Poster Display session 3
Resources:
Abstract
5089 - Finding the Right Biomarker for Renal Cell Carcinoma (RCC): Nivolumab treatment induces the expression of specific peripheral lymphocyte microRNAs in patients with durable and complete response.
Presenter: Lorena Incorvaia
Session: Poster Display session 3
Resources:
Abstract
2594 - Algorithms derived from quantitative pathology can be a gatekeeper in patient selection for clinical trials in localised clear cell renal cell carcinoma (ccRCC)
Presenter: In Hwa Um
Session: Poster Display session 3
Resources:
Abstract
2566 - High baseline blood volume is an independent favorable prognostic factor for overall and progression-free survival in patients with metastatic renal cell carcinoma
Presenter: Aska Drljevic-nielsen
Session: Poster Display session 3
Resources:
Abstract
2675 - Impact of estimand selection on adjuvant treatment outcomes in renal cell carcinoma (RCC)
Presenter: Daniel George
Session: Poster Display session 3
Resources:
Abstract
1541 - TERT gene fusions characterize a subset of metastatic Leydig cell tumors
Presenter: Bozo Kruslin
Session: Poster Display session 3
Resources:
Abstract