Abstract 335P
Background
Despite therapeutic improvements, all patients (pts) sooner or later acquire resistance to CDK4/6 inhibitors. Mutations in KRAS have been thought to be the main cause of resistance in several cancers, but have not been analysed extensively in breast cancer in the era of Palbociclib+Fulvestrant (P+F). In our study, using liquid biopsy, we correlated the emerging KRAS-mutated ctDNA and overexpression of CDK9 with resistance to P+F as first line metastatic treatment in HR+/HER2-Metastatic Breast Cancer (MBC).
Methods
A total of 948 blood samples were collected from 106 pts with HR+/HER2-MBC treated with P+F as first-line metastatic therapy (Dec17-Mar20). KRAS ctDNA levels in plasma were determined with Bio-Rad QX200 ddPCR system; we used exoRNeasy kit to analyze CDK4/9 expression.
Results
KRAS mutations were detected in ctDNA of 54% (57pts) of pts before starting P+F treatment: detection of KRAS ctDNA was significantly associated with resistance, recurrence and prognosis (p<0.001). At 18-month follow up [1-NA], pts with KRAS-mutated ctDNAand overexpression of CDK9 had a median PFS of 3 months [1-6months,95%CI 0.8-3.6] contrary to ones with no detection of KRAS ctDNA whose PFS had not yet been reached (p<0.001). We demonstrated the association between circulating number of copies/ml of KRAS-mutated ctDNA and tumoral burden: hgher number of metastatic sites correlated with higher mutant ctDNA copy number (p<0.0001). Moreover, lower LMr (<5.0) was associated with progression disease within 12months (p<0.001).
Conclusions
Despite the study’s limitations, our findings suggest detection of KRAS ctDNA levels, which correlates with overexpression of CDK9, enables to predict the onset of resistance to P+F treatment. Monitoring KRAS status with liquid biopsy, we could predict who will take advantage from P+F, offering highly individualized treatment plans. With a careful treatment selection, we could decrease wastes of resources ensuring the best pts’ quality of life.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
ASL Latina - University of Rome \"Sapienza\".
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.