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.

Abstract

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). 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. All patients (N = 97) were female (median age, 57 years [IQR, 50-67]). In baseline ctDNA (n = 77), <i>PIK3CA</i> (37%), <i>TP53</i> (28%), <i>ESR1</i> (16%), and <i>GATA3</i> (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. <i>ESR1</i> alteration frequency (35% <i>v</i> 8%; <i>P</i> < .01), median shedding rate (3 <i>v</i> 2), and maximum somatic VAF (4 <i>v</i> 0.8; both <i>P</i> < .05) were significantly higher in ctDNA from patients with previous ET than those without previous ET. In paired ctDNA samples (n = 33), <i>PIK3CA</i> and <i>ESR1</i> 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 <i>FGF3/4/19</i> (18%); <i>PIK3CA</i>, <i>TP53</i>, <i>CCND1</i>, and <i>RB1</i> (all 15%); and <i>ESR1</i> (12%). We summarized the ctDNA and cancer tissue mutational landscape, including overall neoplastic burden and <i>PIK3CA</i> and <i>ESR1</i> hotspot mutations in abemaciclib-treated patients with HR+/HER2- MBC. The data provide insights that could help optimize treatment strategies in this population.