Genomic Landscape of Circulating Tumor DNA in Patients With Hormone Receptor–Positive/Human Epidermal Growth Factor Receptor-2–Negative Metastatic Breast Cancer Treated With Abemaciclib: Data From the SCRUM-Japan Cancer Genome Screening Project

PURPOSE To understand the mutational landscape of circulating tumor DNA (ctDNA) and tumor tissue of patients with hormone receptor–positive (HR+), human epidermal growth factor receptor-2–negative (HER2–) metastatic breast cancer (MBC) treated with abemaciclib + endocrine therapy (ET). METHODS Blood samples for ctDNA and/or tissue samples were collected from abemaciclib-treated patients with HR+/HER2– MBC enrolled in the SCRUM-Japan MONSTAR-SCREEN project. Blood samples were collected before abemaciclib initiation (baseline) and at disease progression/abemaciclib discontinuation (post abemaciclib treatment). Clinical and genomic characteristics including neoplastic burden (measured by shedding rate and maximum variant allele frequency VAF) were assessed at baseline. Genomic alterations in ctDNA were compared in paired baseline and post abemaciclib treatment samples. RESULTS All patients (N = 97) were female (median age, 57 years IQR, 50-67). In baseline ctDNA (n = 77), PIK3CA (37%), TP53 (28%), ESR1 (16%), and GATA3 (11%) were the most frequently mutated genes. Baseline tissue samples (n = 79) showed similar alteration frequencies. Among patients with baseline ctDNA data, 30% had received previous ET. ESR1 alteration frequency (35% v 8%; P < .01), median shedding rate (3 v 2), and maximum somatic VAF (4 v 0.8; both P < .05) were significantly higher in ctDNA from patients with previous ET than those without previous ET. In paired ctDNA samples (n = 33), PIK3CA and ESR1 alteration frequencies were higher after abemaciclib treatment than at baseline, though not statistically significant. Among the post-treatment alterations, those newly acquired were detected most frequently in FGF3/4/19 (18%); PIK3CA, TP53, CCND1, and RB1 (all 15%); and ESR1 (12%). CONCLUSION We summarized the ctDNA and cancer tissue mutational landscape, including overall neoplastic burden and PIK3CA and ESR1 hotspot mutations in abemaciclib-treated patients with HR+/HER2– MBC. The data provide insights that could help optimize treatment strategies in this population.