Evaluating metrics of circulating tumor DNA response and progression using a high sensitivity tumor-agnostic assay in metastatic HR+/HER2- breast cancer receiving endocrine therapy and a CDK4/6-inhibitor.
Authors: Mitchell Elliott, Jesus Fuentes Antras, Sasha Main, Aaron Dou, Nancy Gregorio, Elizabeth Shah, Emily Van de Laar, Geethika Yalamanchili, Leylah Drusbosky, Caroline M. Weipert, Eitan Amir, Michelle B. Nadler, Celeste Yu, Hal K. Berman, Lillian L. Siu, Philippe L. Bedard, David W. Cescon
Journal: Journal of Clinical Oncology (2024)

1043 Background: CDK4/6-inhibitors (-i) and endocrine therapy (ET) are first-line treatment for HR+/HER2- metastatic breast cancer (mBC). Clinical evaluation and cross-sectional imaging are used for treatment response assessment. The relationship between clinical/radiographic response and ctDNA dynamics using a high sensitivity tumor-agnostic assay is unknown in HR+/HER2- mBC. ctDNA monitoring in mBC may support clinical decision-making, enable new strategies for response assessment in clinical trials, and facilitate enrolment of patients lacking measurable disease (bone-only). Methods: 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. ctDNA-response (-R) was defined as a ≥50% decrease (dec) in methylation tumor fraction (mTF) from BL. ctDNA-progression (-P) was defined as a &lt;50% dec in mTF from BL or any subsequent increase in mTF above an absolute mTF of 0.001% (cohort specific definition). Imaging outcomes and dates of treatment discontinuation (TD) were collected. Results: 57 pts with 350 clinical timepoints were evaluated. Median follow up was 28.2m (range: 1.6-66.0m). 42/57 (74%) pts received palbociclib and 40/57 (70%) received an aromatase inhibitor. ctDNA-R/-P was evaluable in 49/57 patients. ctDNA-P identified within the first 90d on CDK4/6i was not prognostic of TD (p=0.7972); when assessed between 90-180d it was prognostic of early TD (med: 6.3m vs. not reached; HR: 5.17, 95%CI: 1.04-25.7; p=0.0003). 156 matched radiographic and ctDNA assessments (blood collected within 30d of CT) were evaluable for ctDNA-R/-P and imaging concordance. Excluding those with clinician-identified sclerotic bone changes suggestive of treatment effect (n=5 events), adjudicated radiographic progression did not occur in the setting of ctDNA-R (NPV: 100%, sensitivity: 100%); no pts had clinical progression in the presence of ctDNA-R. ctDNA rise in the absence of radiographic progression occurred in 13 pts; 7/13 had TD (med: 10.1m, range: 3.0-21.9m) in the follow up period reflecting a molecular lead time. Blood first monitoring, using these metrics, could have avoided 104/150 (69%) staging CT scans in this cohort. Conclusions: ctDNA dynamics are associated with clinical outcomes in HR+/HER2- mBC. The use of a high sensitivity assay permits assessment of response in nearly all patients and suggests the possibility that radiographic surveillance could be reduced in patients with ctDNA-R. Prospective validation of these findings are required. Additional ctDNA-R/-P definitions and relationship with RECIST 1.1 criteria will be presented at the meeting.