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
5056 - Phase 2 study of 2 dosing regimens of cemiplimab, a human monoclonal anti–PD-1, in metastatic cutaneous squamous cell carcinoma (mCSCC)
Presenter: Danny Rischin
Session: Poster Display session 3
Resources:
Abstract
5710 - Avelumab for advanced Merkel cell carcinoma in the Netherlands; a nationwide survey
Presenter: Sonja Levy
Session: Poster Display session 3
Resources:
Abstract
3152 - Health-related quality of life in patients with metastatic Merkel cell carcinoma receiving second-line or later avelumab treatment: 36-month follow-up data
Presenter: Sandra D'Angelo
Session: Poster Display session 3
Resources:
Abstract
5715 - A Phase 2, Randomized Study of Nivolumab (NIVO) and Ipilimumab (IPI) versus NIVO, IPI and Stereotactic Body Radiation Therapy (SBRT) for Metastatic Merkel Cell Carcinoma (MCC, NCT03071406) – a preliminary report.
Presenter: Sungjune Kim
Session: Poster Display session 3
Resources:
Abstract
2854 - Real-world impact of immune checkpoint inhibitors in metastatic uveal melanoma
Presenter: Kalijn Bol
Session: Poster Display session 3
Resources:
Abstract
2928 - Immune checkpoint inhibitors in a cohort of 206 metastatic uveal melanomas patients
Presenter: Mathilde Saint-Ghislain
Session: Poster Display session 3
Resources:
Abstract
1235 - Incidence and survival of Uveal Melanoma occurring as single cancer versus its occurrence as a first or second primary neoplasm
Presenter: Ahmad Alfaar
Session: Poster Display session 3
Resources:
Abstract
3615 - Validation of a Clinicopathological and Gene Expression Profile (CP-GEP) Model for Sentinel Lymph Node Metastasis in Primary Cutaneous Melanoma
Presenter: Evalyn Mulder
Session: Poster Display session 3
Resources:
Abstract
1793 - External validation of the 8th Edition Melanoma Staging System of the American Joint Committee on Cancer (AJCC) using the Surveillance, Epidemiology and End Results (SEER) Program
Presenter: Angelina Tjokrowidjaja
Session: Poster Display session 3
Resources:
Abstract
4278 - Clinical factors and overall survival (OS) associated with patterns of metastases (mets) in melanoma patients (pts).
Presenter: Ines Pires da Silva
Session: Poster Display session 3
Resources:
Abstract