Abstract 3748
Background
Tumor mutation burden (TMB) has been shown as a new predictive biomarker for immune checkpoint inhibitor in various cancer types. It is typically measured by processing tumor tissue with substantial input which limits its clinical utility in patients with metastatic or unresectable disease. Meanwhile, there is increasing interest in circulating tumor DNA (ctDNA) that act as a noninvasive real-time biomarker for cancer patients. Therefore, here we develop a new next generation sequencing assay that can identify patients with sufficient tumor fraction in plasma and accurately measures the TMB from blood (bTMB).
Methods
Cell free DNA (cfDNA) was extracted from plasma across four original tissue types by different tumor stages. CfDNA Assay was performed with unique molecular identifier (UMI) , sequenced on the Illumina® platforms and analyzed using an internal pipeline for variants down to 0.4%. By integrating the fragment size distribution and the clonal mutation frequency, we were able to estimate the tumor fraction per plasma sample. A bTMB score was also derived using all the coding variants on a 1.3M panel across 500+ genes. The matched TMB score is derived by the same assay using FFPE tissue.
Results
Our assay has generated sufficient results from 1-4ml plasma for variant detection down to 0.4%. Across four tissue types by various cancer stages, our assay and pipeline yield a variant concordance of 70% between cfDNA and FFPE. Majority of mutations only found in plasma may be associated with clonal hematopoiesis in genes such as TET2, DMBT3A and etc. By combining fragment size distribution and driver mutation frequency, we were able to estimate tumor fraction in plasma. Tumor fraction in plasma is significantly associated with tumor stage that >50% of metastatic cancers and > 25% early stage lung cancers contain high tumor fraction. In patients with at least 1% tumor content, there is high correlation between bTMB measured by plasma and TMB measured by FFPE (R2=0.92).
Conclusions
We have developed a ctDNA assay to detect somatic variants and determine bTMB with high accuracy and precision with input as low as 10 ng of cfDNA. Our assay yield accurate measurement of TMB compared to tissue biopsy.
Clinical trial identification
Legal entity responsible for the study
Illumina, Inc.
Funding
Has not received any funding.
Editorial Acknowledgement
Disclosure
T. Jiang, S. Zhang, A. Jager, S. Katz, J. Lococo, P. Le, B. Andrian, C. Zhao, D. Baker, T. Pawlowski, S. Bilke: Employee and shareholder: Illumina, Inc.
Resources from the same session
5877 - TCR beta chain convergence defines the tumor infiltrating T cell repertoire of melanoma and non-small cell lung carcinoma.
Presenter: Timothy Looney
Session: Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research
Resources:
Abstract
3212 - PI3K inhibition and modulation of immune and tumor microenvironment markers by copanlisib in patients with non-Hodgkin's lymphoma or advanced solid tumors
Presenter: Ahmad Awada
Session: Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research
Resources:
Abstract
3574 - Pan-squamous genomic profiling stratified by anatomic tumor site and viral association
Presenter: Meagan Montesion
Session: Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research
Resources:
Abstract
4113 - Toward the Standardization of Bioinformatics Methods for the Accurate Assessment of Tumor Mutational Burden (TMB)
Presenter: Han Chang
Session: Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research
Resources:
Abstract
4468 - Prediction of primary resistance to anti-PD1 therapy (APD1) in 2nd line NSCLC
Presenter: Egbert Smit
Session: Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research
Resources:
Abstract
4570 - Immunomodulatory germline variation impacts the development of multiple primary melanoma (MPM).
Presenter: Robert Ferguson
Session: Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research
Resources:
Abstract
1169 - Leukocyte telomere length and recurrence risk after EGFR-TKIs therapy in patients with advanced lung adenocarcinoma
Presenter: Ming Yang
Session: Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research
Resources:
Abstract
1707 - Gene embedding: a novel machine learning approach to identify gene candidates related to immunotherapy responsiveness
Presenter: Chi Tung Choy
Session: Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research
Resources:
Abstract
2123 - Common and rare DPYD variants are predictive for 5FU/capecitabine (5FU) toxicity: The MRC COIN and COIN-B trials
Presenter: Ayman Madi
Session: Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research
Resources:
Abstract
5671 - The landscape of NTRK fusions in Chinese solid tumor patients
Presenter: Qi Ling
Session: Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research
Resources:
Abstract