Abstract 5654
Background
Tumor heterogeneity is difficult to characterize with tissue biopsies in late stage cancers, in which primary and metastatic tumors may have diverged in their mutational profiles. Assessing the diversity of mutations detected by sequencing circulating tumor DNA (ctDNA) from liquid biopsies can quantify the genetic complexity of tumors shedding DNA into the blood.
Methods
In a prospective, observational study, we obtained pre-treatment plasma samples from 56 subjects with Stage IV small cell lung cancer (SCLC) treated with first-line chemo or chemoradiation therapies. Plasma samples were analyzed with the AVENIO ctDNA Surveillance Kit, a targeted next-generation sequencing panel of 198 kilobases. We applied the Shannon and Simpson diversity indices by considering each somatic variant as a species and the number of detected duplex molecules with that mutation as the abundance of that species. Samples were ranked as low tumor heterogeneity if their plasma variant diversity score was below the first tertile of the cohort.
Results
Stage IV SCLC subjects with low tumor heterogeneity evaluated by the Shannon diversity had shorter overall survival (hazard ratio = 1.8; 95% CI 1-3.3; log-rank p = 0.034; median survival difference = 4.5 months). Furthermore, subjects with low tumor heterogeneity evaluated by the Gini-Simpson or inverse Simpson diversity index had shorter overall survival (hazard ratio = 1.8; 95% CI 1-3.3; log-rank p = 0.033; median survival difference = 4.5 months).
Conclusions
The molecular barcoding scheme in the AVENIO kit allows for each strand of the original double-stranded ctDNA molecule to be tracked. From this reconstructed profile of circulating duplex molecules harboring tumor variants, we derived a tumor heterogeneity measure based on the Shannon and Simpson diversity indices commonly used in ecology. We found that late stage SCLC subjects with low tumor heterogeneity had shorter overall survival, suggesting that highly heterogeneous SCLC tumors may respond better to chemotherapy or radiation. Studies to further validate these findings are ongoing.
Clinical trial identification
Legal entity responsible for the study
Roche Sequencing Solutions, Inc.
Funding
Roche Sequencing Solutions, Inc.
Editorial Acknowledgement
Disclosure
S. Yaung, L. Xi, C. Woestmann, S. McNamara, B. Hinzmann, S. Froehler, C. Ju, A. Balasubramanyam, H-P. Adams, B. Wehnl, X.M. Ma: Employment: Roche. N. Tikoo: Employment: Roche; Stock ownership: BeiGene, Celgene, Denali Therapeutics, Exelixis, Gilead Sciences. F. Lasitschka: Consulting role: Roche; Research funding: Boehringer Ingelheim International GmbH. M. Meister, M. Schneider: Research funding: Roche. F.J.F. Herth: Stock ownership: Roche, Lilly, Novartis; Consulting role: Novartis. T. Muley: Royalty sharing agreement: Roche; Research funding: Roche. J. Palma: Employment: Roche; Stock ownership: Exact Sciences, Clovis Oncology, Johnson & Johnson, Roche. All other authors have declared no conflicts of interest.
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