474P - ctDNA-based copy number dynamics during anti-PD1 treatment in patients with metastatic triple-negative breast cancer

Background

Circulating tumor DNA (ctDNA) is an emerging technology to predict outcome in cancer patients and monitor treatment response including immune checkpoint blockade (ICB). So far, data on ctDNA dynamics during ICB in breast cancer are lacking. Moreover, in the context of ICB, most of the ctDNA assays focus on detection of mutations, while many cancer types including breast cancer are mainly driven by copy number alterations (CNA). Here we present ctDNA-based CNA dynamics in patients with metastatic triple-negative breast cancer (mTNBC) treated with anti-PD1 in the TONIC-trial.

Methods

Low-coverage (0.5x) whole genome sequencing was performed on plasma samples taken at baseline and after 8 weeks of treatment for a subset (n=30) of patients with mTNBC treated with nivolumab in the TONIC trial (Voorwerk et al., Nat Med 2019). 16 patients had progressive disease; 14 patients (‘responders’) responded to nivolumab or had stable disease for at least 24 weeks. CNA profiles were generated with QDNASeq, NoWaves and CGHcall, followed by calculating copy number profile abnormality (CPA) scores.

Results

ctDNA CNA profiles were significantly correlated with tumor CNA profiles with an average correlation of 0.5 (range 0.21 - 0.86). Baseline ctDNA levels and ctDNA-based CPA scores were not associated with response to anti-PD1. While in non-responders ctDNA levels increased during ICB (p = 0.008), in responders CPA scores decreased (p = 0.0004). Higher on-treatment CPA scores were negatively correlated with overall survival (OS) and progression-free survival (PFS) (p = 0.000005, p = 0.0008, respectively).

Conclusions

ctDNA-based copy number alterations dynamics in patients with mTNBC was highly correlated with anti-PD1 response. This pilot study is the first report on the potential utility of low coverage ctDNA-based surveillance during ICB treatment and warrants further validation in TNBC and other tumor types.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Netherlands Cancer Institute.

Funding

Bristol Myers Squibb, NWO (VIDI).

Disclosure

H. Horlings: Financial Interests, Institutional, Speaker, Consultant, Advisor: Roche. J. Martens: Financial Interests, Personal, Funding: Novartis, Roche; Financial Interests, Institutional, Funding: Pfizer, GSK, MLDS, Oncode, Eurostar. L. Wessels: Financial Interests, Institutional, Funding: BMS. D. Van Den Broek: Financial Interests, Institutional, Advisory Board: Roche, NWO; Financial Interests, Institutional, Expert Testimony: Roche; Financial Interests, Institutional, Invited Speaker: Roche; Financial Interests, Institutional, Funding: DELFI diagnostics. M. Kok: Financial Interests, Institutional, Funding: BMS, Roche, AstraZeneca, Daiichi Sankyo; Non-Financial Interests, Institutional, Advisory Role: Alderaan Biotechnology, Domain Therapeutics, Daiichi Sankyo, BMS, MSD, Roche; Financial Interests, Institutional, Invited Speaker: Roche, BMS, Gilead. All other authors have declared no conflicts of interest.