2272P - Minimal DNA-methylation (DNAm) signatures for non-invasive tumor-agnostic estimation of tumor content (TC) and molecular subtype in patients (pts) with metastatic breast cancer (mBC)

Background

Non-invasive detection and quantification of circulating tumor DNA by DNAm signatures is emerging as powerful tool for monitoring disease status in pts with metastatic cancer. We recently developed MIMESIS, a computational workflow to design tumor agnostic DNAm signatures of few dozen sites for TC and molecular subtype estimation in liquid biopsy. Here we applied a MIMESIS informed assay to a retrospective cohort of mBC pts (MIMESIS-BC).

Methods

72 mBC pts (42 ER+/HER2-, 2 ER+/HER2 N/A, 8 ER+/HER2+, 6 ER-/HER2+, 14 ER-/HER2-, up to 6 previous lines of treatment) and 11 healthy individuals (ctrl) were included. Plasma from mBC pts was collected before starting treatment (T0, n=58) and after the first cycle (T1, n=52) (n=38 pts T0 and T1). MIMESIS-BC for TC, PAM50 molecular subtypes and ER status (n=139 sites) was applied to circulating free DNA as described in the MIMESIS study. Samples were defined as TC+ when TC>0. TC values as continuous variable and TC classes (+/-) were associated with OS and PFS. Concordance of subtype and ER status by MIMESIS-BC with IHC-based from primary tumor was estimated by chi-square and percent agreement.

Results

TC was not detected in ctrl. A significantly higher median TC was observed at T0 compared to T1 (5.6% (range 0-73%) vs 0% (range 0-47%); p=0.02). 39 TC+ samples at T0 showed 61% agreement for molecular subtype (p=0.002) and 86% for ER status (p<0.001). In the entire population, PFS and OS were significantly associated with TC values both at T0 and T1 (max p=0.002). TC+ pts had significantly worse OS compared to TC- at T0 (HR=2.1 CI=1.1-3.9 p=0.02) and T1 (HR=2.0 CI=1.1-3.6 p=0.03) and worse PFS at T1 (HR=2.9 CI=1.5-5.4 p<0.001). In ER+ pts, TC+ at T0 and T1 associated with worse PFS (HR=2.6 CI=1.2-5.3 p=0.008, and HR=3.8 CI=1.7-8.2 p<0.001) and OS (HR=3.5 CI=1.6-7.6 p=0.001, HR=3.0 CI=1.4-6.1 p=0.002), while in ER- pts TC classes showed no association with outcome.

Conclusions

In a small and heterogenous retrospective cohort of mBC pts, MIMESIS-BC showed promising capabilities for prognostic stratification and subtype estimation from liquid biopsy. Validation in an extended prospective cohort is ongoing.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Italian Minister of Health (GR-2018-12365195 to Benelli).

Disclosure

M. Benelli: Financial Interests, Personal, Advisory Role: Novartis. E. Risi: Financial Interests, Personal, Invited Speaker: Eisai, Lilly; Other, Personal, Other: Gilead, Eisai, Roche, Pfizer. L. Malorni: Financial Interests, Personal, Advisory Role: Novartis, Seagen, Pfizer; Financial Interests, Personal and Institutional, Research Grant: Pfizer, Novartis; Other, Personal, Other: Roche, Celgene. L. Biganzoli: Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo, Eisai, Novartis, Pfizer, Pierre Fabre, Gilead, Sanofi, Seattle Genetics, Exact Sciences; Financial Interests, Personal, Invited Speaker: Lilly, Roche; Financial Interests, Institutional, Research Grant: Celgene, Genomic Health, Novartis; Non-Financial Interests, Member of Board of Directors: SIOG. All other authors have declared no conflicts of interest.