| Summary: | Previously undescribed molecular mechanisms of resistance will emerge with the increased use of cyclin-dependent kinase 4/6 inhibitors in clinical settings. To identify genomic aberrations in circulating tumor DNA associated with treatment resistance in palbociclib-treated metastatic breast cancer (MBC) patients, we collected 35 pre- and post-treatment blood samples from 16 patients with estrogen receptor-positive (ER<sup>+</sup>) MBC, including 9 with inflammatory breast cancer (IBC). Circulating cell-free DNAs (cfDNAs) were isolated for sequencing using a targeted panel of 91 genes. Our data showed that <i>FBXW7</i> and <i>CDK6</i> were more frequently altered in IBC than in non-IBC, whereas conversely, <i>PIK3CA</i> was more frequently altered in non-IBC than in IBC. The cfDNA samples collected at follow-up harbored more mutations than baseline samples. By analyzing paired samples, we observed a higher percentage of patients with mutations in <i>RB1</i>, <i>CCNE1</i>, <i>FBXW7</i>, <i>EZH2</i>, and <i>ARID1A</i>, but a lower proportion of patients with mutated <i>TSC2</i> at the post-treatment stage when they developed progression. Moreover, acquisition of <i>CCNE1</i> mutations or loss of <i>TSC2</i> mutations after treatment initiation conferred an unfavorable prognosis. These data provide insights into the relevance of novel genomic alterations in cfDNA to palbociclib resistance in MBC patients. Future large-scale prospective studies are warranted to confirm our findings.
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