70. Assessment of circulating tumor DNA tumor mutational burden to define resistance in HR+ HER2- metastatic breast cancer

Andrew A. Davis

Andrew Davis received his medical degree and completed his internal medicine and hematology/oncology fellowship training at Northwestern University in Chicago. During his final year of training, he served as a Chief Fellow. In September 2020, he became as Assistant Professor of Medicine at Washington University in St. Louis. His clinical focus is breast cancer. His research interests include utilizing liquid biopsies including circulating tumor DNA (ctDNA) as tools to identify micrometastasis, define disease resistance, and incorporate biomarker-based stratification and novel endpoints into clinical trial design. Additionally, he is actively involved in early-phase clinical trials of investigational agents.

Abstract

Andrew A. Davis^a, Jingqin Luo^a, Tiantian Zheng^b, Xiaoxi Dong^b, Lu Tan^b, Amy Wang^b, Rama Suresh^a, Foluso Ademuyiwa^a, Caron Rigden^a, Timothy Rearden^a, Katherine Clifton^a, Katherine Weilbaecher^a, Ashley Frith^a, Pavan K. Tandra^c, Tracy Summa^a, Britney Haas^a, Shana Thomas^a, Leonel Hernandez-Aya^a, Lindsay Peterson^a, Chao Dai^b, Bonnie L. King^b, Pan Du^b, Shidong Jia^b, Jairam Krishnamurthy^c, Cynthia X. Ma^a

^aWashington University School of Medicine, St. Louis, MO, USA; ^bPredicine, Inc., Hayward, CA, USA; ^cUniversity of Nebraska Medical Center, Omaha, NE, USA

Identifying subsets of patients with baseline resistance to endocrine therapy (ET) combined with CDK4/6 inhibition (CDK4/6i) is challenging. Our study examined circulating tumor DNA (ctDNA) using whole-exome sequencing to derive blood tumor mutational burden (bTMB) and mutational signatures to assess patients with early progression on ET + CDK4/6i.

Patients and Methods: ctDNA was isolated from 285 serial plasma samples of patients with metastatic HR+ breast cancer treated on a phase II trial with alternative dose palbociclib and ET. bTMB was determined using whole-exome sequencing of plasma at baseline (N=50) and at the time of clinical progression. bTMB was associated with clinical benefit and progression-free survival (PFS). Dominant APOBEC signatures were identified using the COSMIC database.

Results: High bTMB, defined by above the median, top quartile, or 10 mutations/megabase, was associated with lack of clinical benefit and significantly shorter PFS compared to patients with low TMB. Baseline clinical variables and sites of metastasis on imaging did not predict bTMB or PFS. A dominant APOBEC signature was only present in patients with high bTMB (5/13, 38%) and not in patients with low bTMB (0/37, 0%). bTMB did not significantly increase at progression.

Conclusions: Baseline genomic complexity, as defined by high bTMB, was associated with lack of response and poor outcome for patients treated with ET and CDK4/6i. Non-invasive monitoring in blood identified resistance alterations at baseline and progression. Identification of novel treatment strategies, including immunotherapy-based combinations, are needed to improve outcomes in patients with baseline resistance to ET and CDK4/6i.