Characterization of molecular response and progression in patients with metastatic HR+/HER2- breast cancer receiving endocrine therapy and CDK4/6 inhibitors using a high-sensitivity tumor-informed assay.
Authors: Antras Jesus Fuentes , Elliott Mitchell , Main Sasha , Echelard Philippe , Dou Aaron , Bedard Philippe L. , Amir Eitan , Nadler Michelle B. , Gregorio Nancy , Shah Elizabeth , Van de Laar Emily , Yu Celeste , Gates Lisa , Murray Clodagh , Smith Christopher Gareth , Chevalier Amber , Bratman Scott Victor , Siu Lillian L. , Berman Hal K. , Cescon David W. 
Published: June 2024

3052 Background: Tumor-informed circulating tumor DNA (ctDNA) assays, designed to track patient (pt) specific variants identified by tumor sequencing, offer enhanced sensitivity compared to traditional assays focused on driver genes. This approach enables precise ctDNA quantification, facilitating early detection of molecular progression and innovative strategies in metastatic breast cancer (mBC). Methods: HR+/HER2- mBC pts receiving standard endocrine therapy + CDK4/6 inhibitors (CDKi) were enrolled in a prospective observational cohort (2018–2023). Plasma samples were collected at baseline (BL), within 30 days (d) and ~q3 months with restaging scans. Archival tumor WES was used to design personalized panels for ctDNA monitoring. The primary endpoint was time to treatment failure (TTF). Results: Of 51 pts analyzed (median age 60 years [range 38-88], 1/2L [75/20%], visceral disease 63%, palbo-/ribo-/abemaciclib 76/22/2%), tumor-informed panels were successfully designed for 43 (1 failed WES, 7 failed QC), detecting BL ctDNA in 39 (91%). The median BL estimated variant allele fraction (eVAF) was 0.5% (0.006–17.9) and was associated with liver metastases but no other covariates (e.g. bone-only disease, history of 1ry endocrine resistance [ER]). Higher BL eVAF predicted shorter TTF (HR 1.14 CI 95% 1.05–1.23, p<0.01). Most pts had eVAF decreases below BL in the first 30 d (78%) and before the first scan (89%; median 90 d, 23–158). Early increases above BL did not significantly predict TTF, with 3/8 cases showing prolonged responses. ctDNA clearance was observed in 11/39 (28%) pts at a median of 172 d (14–410) and predicted longer TTF (HR 0.06, CI 95% 0.01–0.45, p<0.01; median TTF not reached vs 14.5 mo for pts with and without clearance), with treatment failure (TF) rates of 0% vs 40%, and 8% vs 80%, at the 1- and 2-year landmarks, respectively. Clearance was not associated with any clinical covariate (i.e. disease sites, therapy line, CDKi, history of 1ry ER). For any sample irrespective of the trajectory, higher eVAF ratios to BL predicted shorter lead times to TF, though with poor correlation (r2 0.08, p=0.01). eVAF ratios to BL >1, >0.5 and <0.5 at any timepoint had median lead times to TF of 76 d (Q1–Q3 25–135), 133 d (41–360), and 326 d (174–471). A complete analysis of ctDNA dynamics and operating parameters will be presented along with RECIST 1.1 evaluation and WES-based genomic subgroups. Conclusions: ctDNA levels and changes on therapy are prognostic and high sensitivity tumor-informed assays expand the proportion of pts who can be monitored. ctDNA clearance identified pts with better outcome and might inform pt follow up and interventional strategies. Reappraisal of existing early response cutoffs, with limited precision for individual decision making, may be necessary with more sensitive assays.