Circulating Tumor DNA Genotyping of Intrinsic and Acquired Gene Alterations in Patients With Advanced Breast Cancer Receiving Palbociclib: Biomarker Results From POLARIS Study.

Abstract

To identify gene alterations in circulating tumor DNA (ctDNA) from palbociclib-treated patients with advanced or metastatic breast cancer (ABC) in POLARIS to identify potential mutagenic drivers of resistance. POLARIS was a prospective, real-world study of palbociclib in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) ABC in the United States and Canada. Patients who received ≥1 palbociclib dose and had ≥1 ctDNA measurement were included in the biomarker analysis. ctDNA samples were analyzed using the Guardant360 platform (73 genes) at baseline, cycle 2 day 1 (C2D1), and end of treatment (EOT). Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% CIs. A total of 344 patients were included in the biomarker analysis. Gene alterations were detected in 85% (286 of 336) of baseline samples, 72% (201 of 278) of C2D1 samples, and 85% (88 of 104) of EOT samples. The most frequently mutated genes were <i>ESR1</i>, <i>PIK3CA</i>, and <i>TP53</i>. <i>CCND1</i>, <i>FGFR1</i>, and <i>EGFR</i> were most frequently amplified. Real-world progression-free survival (rwPFS) was better in patients without baseline mutations in <i>ESR1</i> (HR, 0.42) or <i>PIK3CA</i> (HR, 0.60) and amplifications in <i>CCND1</i> (HR, 0.52) or <i>FGFR1</i> (HR, 0.62) versus altered genes. Patients with undetectable versus detectable mutations at C2D1 also had better rwPFS (HR, 0.57). Patients without altered <i>ESR1</i>, <i>PIK3CA</i>, <i>CCND1</i>, or <i>FGFR1</i> at baseline had better rwPFS than patients with altered genes. Genotyping analysis of ctDNA over time highlights the emergence of mutations in estrogen receptor and cell cycle pathways under selective therapeutic pressure and could guide monitoring and therapeutic sequencing for patients with HR+/HER2- ABC.