Genomic Aberrations in Circulating Tumor DNAs from Palbociclib-Treated Metastatic Breast Cancer Patients Reveal a Novel Resistance Mechanism

SIMPLE SUMMARY: The combination of CDK4/6 inhibitors and endocrine therapy is now considered the standard of care for patients with estrogen receptor-positive (ER(+)) breast cancer. The emerging tide of CDK4/6 inhibitor resistance urges more research to explore underlying resistance mechanisms. This study profiled circulating cell-free DNA obtained before and after palbociclib treatment in ER(+) metastatic breast cancer patients using 91-gene panel sequencing. The results revealed that the acquisition of CCNE1 mutations and the loss of TSC2 mutations confer an unfavorable prognosis, suggesting that these mutations may potentially serve as novel genomic biomarkers for treatment resistance. Future large-scale population studies and mechanism-focused research are needed to confirm the findings of this study and elucidate the underlying molecular mechanisms. Ultimately, such efforts may lead to the development of improved methods to predict treatment efficacy and clinical outcomes, as well as more effective targeted treatment approaches for the benefit of breast cancer patients. ABSTRACT: 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(+)) 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 FBXW7 and CDK6 were more frequently altered in IBC than in non-IBC, whereas conversely, PIK3CA 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 RB1, CCNE1, FBXW7, EZH2, and ARID1A, but a lower proportion of patients with mutated TSC2 at the post-treatment stage when they developed progression. Moreover, acquisition of CCNE1 mutations or loss of TSC2 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.