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
3047 - Health-related quality of life in Greek haematogical malignancies patients undergoing chemotherapy
Presenter: Maria Lavdaniti
Session: Poster Display session 3
Resources:
Abstract
1121 - Experiences of endocrine therapy after breast cancer surgery
Presenter: Susanne Ahlstedt Karlsson
Session: Poster Display session 3
Resources:
Abstract
2305 - The effects of progressive muscle relaxation and mindfulness meditation on fatigue, coping styles, and quality of life in breast cancer patients receiving adjuvant paclitaxel regimen: An-assessor blinded, three-arm randomized controlled trial
Presenter: Zehra Gok Metin
Session: Poster Display session 3
Resources:
Abstract
4561 - Agreement between breast cancer patients and oncologists on the severity of patients’ symptoms and functions during a one-year follow-up after treatment.
Presenter: Randi Reidunsdatter
Session: Poster Display session 3
Resources:
Abstract
1768 - Taste Changes and Associated Factors in Patients Receiving Chemotherapy
Presenter: Gulcan Bagcivan
Session: Poster Display session 3
Resources:
Abstract
1830 - CART-19: a comparative between literature versus experience
Presenter: Cassandra Andersson Vila
Session: Poster Display session 3
Resources:
Abstract
4027 - Unplanned emergency department use by people receiving ambulatory anti-cancer agents with potential febrile neutropenia
Presenter: Meritxell Casanovas-Blanco
Session: Poster Display session 3
Resources:
Abstract
4754 - Examining the benefits of medical exercise during radiotherapy in patients after mastectomy
Presenter: Nikolina Dodlek
Session: Poster Display session 3
Resources:
Abstract
2510 - Assessment Quality of Life with Hand-Foot Syndrome Induced by Apatinib Combined with Anti-PD-1 Therapy in NSCLC
Presenter: Qi Jiang
Session: Poster Display session 3
Resources:
Abstract
2989 - Adverse effects of chemotherapy influence the patients’ quality of life : Analysis of implicated factors
Presenter: Maria Lavdaniti
Session: Poster Display session 3
Resources:
Abstract