1910P - Evaluation of a genome-wide methylome enrichment platform for circulating tumor DNA quantification and prognostic performance in renal cell carcinoma (RCC)

Background

Circulating tumor DNA (ctDNA) can be utilized to identify the presence of cancer as well as minimal residual disease. Quantification of ctDNA using plasma-based tests can be a useful cancer management tool to assess prognosis; however, some methodologies also require tumor tissue for analysis or are limited to tumor types that tend to have higher amounts of associated ctDNA. Here we demonstrate the feasibility of using a tumor-uninformed genome-wide methylome enrichment platform to quantify ctDNA in plasma and predict prognosis in RCC.

Methods

Biobanked pre-treatment samples from individuals with newly diagnosed stage I-IV RCC (University Health Network, Ontario Tumor Biobank) were analyzed with a bisulfite-free, non-degradative genome-wide DNA methylation enrichment platform using 5-10 ng of cell-free DNA isolated from plasma. ctDNA was quantified from average normalized counts across informative regions. Events were defined as cancer recurrence or progression. A ctDNA quantity threshold was set such that 95% of samples without an event fell below the threshold (i.e., 95% specificity). Time to event was compared for samples with ctDNA quantities above the threshold to those below the threshold.

Results

The cohort included 151 samples [64 stage I, 2 stage II, 23 stage III, 15 stage IV, 47 with unknown or incomplete stage information]. There was a median follow-up of 15.4 months and a total of 21 events. Samples with ctDNA quantities above the threshold were significantly more likely to recur or progress than those below the threshold [hazard ratio 13.28 (95% CI 5.47, 32.26), log-rank P<0.001].

Conclusions

This analysis demonstrates the feasibility of using a blood-based, tumor-uninformed genome-wide methylome enrichment platform for ctDNA quantification and prognostic prediction in renal cancer. This is a promising demonstration of prognostic performance in a cancer type that is typically difficult to detect due to low amounts of ctDNA. Additional evaluation in post-treatment and longitudinal samples will further test the performance of this platform.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Adela, Inc.

Funding

Adela, Inc.

Disclosure

B.I. Rini: Financial Interests, Personal, Advisory Board: Merck, BMS, AVEO, Alkermes, Pfizer, Eisai, Corvus, EUSA, Debiopharm, Athenex, Surface Oncology, Genentech/Roche, Aravive; Financial Interests, Personal, Stocks/Shares: PTC Therapeutics; Financial Interests, Institutional, Coordinating PI: Merck, Pionyr, Surface Oncology, Daiichi Sankyo, Adela; Financial Interests, Institutional, Other, Research funding to institution: BMS, Arrowhead, Aravive; Financial Interests, Institutional, Steering Committee Member: Pfizer; Financial Interests, Institutional, Local PI: AstraZeneca; Financial Interests, Institutional, Funding: AVeo; Financial Interests, Institutional, Other, Study funding: Janssen. J. Zhang: Financial Interests, Personal, Full or part-time Employment: Adela, GRAIL; Financial Interests, Personal, Stocks/Shares, Stock Options: Adela. O. Hall: Financial Interests, Personal, Full or part-time Employment: Adela, RAND Corporation, Standard of Proof; Financial Interests, Personal, Stocks/Shares, Stock options: Adela; Financial Interests, Personal, Stocks/Shares: GSK, Haleon PLC ADR, Merck, Organon and Co, Williams Company. J. Bergener, S.Y. Shen: Financial Interests, Personal, Full or part-time Employment: Adela; Financial Interests, Personal, Stocks/Shares, Stock Options: Adela; Non-Financial Interests, Institutional, Other, Patents associated with cfMeDIP-seq technology: Adela. Y. Wang: Financial Interests, Personal, Full or part-time Employment: Adela; Financial Interests, Personal, Stocks/Shares, Stock Options: Adela. B. Brown: Financial Interests, Personal, Other, Consultant: Pattern Biosciences, NAMSA; Financial Interests, Personal, Full or part-time Employment: Adela Bio, Natera, Talis Biomedical; Financial Interests, Personal, Stocks/Shares: Adela Bio. J. Min: Financial Interests, Personal, Full or part-time Employment: Adela, Guardant Health; Financial Interests, Personal, Stocks/Shares, Stock Options: Adela; Financial Interests, Personal, Stocks/Shares: Guardant Health. N. Fleshner: Financial Interests, Personal and Institutional, Advisory Role: Janssen, Sanofi, Astellas, Bayer; Financial Interests, Institutional, Funding: Nucleix, Progenix; Financial Interests, Personal, Advisory Role: AbbVie, Ferring; Financial Interests, Personal, Member of Board of Directors: Verity, Point. A. Polio: Financial Interests, Personal, Full or part-time Employment: Adela; Financial Interests, Personal, Stocks/Shares, Stock Options: Adela; Financial Interests, Personal, Stocks/Shares: Oyster Point Pharma. E. Sosa: Financial Interests, Personal, Full or part-time Employment: Adela, Grail; Financial Interests, Personal, Stocks/Shares, Stock Options: Adela; Financial Interests, Personal, Stocks/Shares: Illumina. S. Bratman: Financial Interests, Personal, Royalties: Roche; Non-Financial Interests, Personal, Officer: Adela; Non-Financial Interests, Personal, Member of Board of Directors: Adela; Financial Interests, Personal, Ownership Interest: Adela; Financial Interests, Personal, Full or part-time Employment: Adela. B. Allen: Financial Interests, Personal, Full or part-time Employment: Adela, Grail; Financial Interests, Personal, Stocks/Shares: Adela, Illumina. K. Brown: Financial Interests, Personal, Full or part-time Employment: Adela, Inc., Myriad Genetics; Financial Interests, Personal, Stocks/Shares: Myriad Genetics; Financial Interests, Personal, Other, Stock Options: Adela, Inc.. A. Licon: Financial Interests, Personal, Full or part-time Employment: Adela, Invitae; Financial Interests, Personal, Stocks/Shares: Adela, Invitae. A. Hartman: Financial Interests, Personal, Full or part-time Employment: Adela; Non-Financial Interests, Personal, Officer: Adela; Financial Interests, Personal, Ownership Interest: Adela; Financial Interests, Personal, Stocks/Shares: Delfi, Mirvie. D.D. De Carvalho: Financial Interests, Personal, Full or part-time Employment: Adela; Non-Financial Interests, Personal, Officer: Adela; Financial Interests, Personal, Ownership Interest: Adela; Non-Financial Interests, Personal, Other, Patents associated with cfMeDIP-seq technology: Adela. B. Ho Park: Financial Interests, Personal, Royalties: Horizon Discovery LTD; Financial Interests, Personal, Advisory Board: Janssen, Guardant Health, Jackson Laboratories, Hologics, Caris; Financial Interests, Personal, Ownership Interest: Celcuity; Non-Financial Interests, Personal and Institutional, Advisory Board: Tempus; Financial Interests, Institutional, Sponsor/Funding: GE Healthcare, Lilly, Pfizer. G. Liu: Financial Interests, Personal, Advisory Board: AstraZeneca, Takeda, Novartis, Lilly, Pfizer, Merck, EMD Serono, Jazz, BMS; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim, Takeda, AstraZeneca, EMD Serono.