57P Intrinsic and acquired blood-based tumor mutational burden in metastatic ER+/HER2- breast cancer treated with endocrine therapy and a CDK4/6-inhibitor

Endocrine therapy (ET) in combination with CDK4/6-inhibitors (-i) are the first-line treatment for HR+/HER2- metastatic breast cancer (mBC). The post-CDK4/6i genomic landscape is heterogenous; several therapeutic vulnerabilities are recognized. The PACE trial suggests a potential role for immune checkpoint inhibitors (ICI) in the second-line; ICI activity in unselected HR+/HER2- mBC is low. Blood-based tumor mutational burden-high (bTMB-H) is associated with ICI response. Longitudinal bTMB is not well characterized in HR+/HER2- mBC pre and post CDK4/6i. Patients (pts) with HR+/HER2- mBC receiving ET and CDK4/6i were enrolled in a prospective cohort study. Plasma samples were collected at baseline (BL) and regularly on-treatment. Samples were analyzed using Guardant Infinity, a tumor-agnostic genomic and epigenomic platform. bTMB-High (-H; ≥20 muts/Mb, corrected for ctDNA shed) and methylation tumor fraction (mTF) were evaluated at each timepoint. Clinical information, time to treatment discontinuation (TTD), and overall survival (OS) was collected. 57 pts with 350 timepoints were evaluated. Median follow up was 28.2m (range: 1.6-66.0m). 32/57 (56.1%) pts had progressed on CDK4/6i with 22/32 patients having matched samples collected at baseline and at disease progression. Median baseline bTMB was 7.6 (range: 0-43.9); 2/22 pts were bTMB-H at baseline which was associated with a worse TTD (6.5 vs. 17.2m; p=0.0434). 5/22 (22.7%) were classified as bTMB-H at progression (med: 28.4, range: 24.6-36.9) with bTMB increase on treatment in 3/5 patients. There was no difference between mTF in baseline/progression samples amongst patients classified as bTMB-H post-CDK4/6i (p=0.14). Acquired bTMB-H status was associated with a numerically shorter post-CDK4/6i OS (8.4 vs. 16.0m; p=0.0742). No patients received ICI in subsequent lines of therapy. Longitudinal assessment of bTMB in HR+/HER2- mBC identified patients where biomarker-directed evaluation of ICI could be considered. Further evaluation of outcome and genomic correlates will be presented.