Abstract P4-10-27: Genomic aberrations in circulating tumor DNAs associated with progression in palbociclib-treated metastatic breast cancer patients

Background: Palbociclib is the first-in-class cyclin dependent kinase (CDK) 4/6 inhibitor approved for the treatment of patients (pts) with hormone receptor (HR) positive/human epidermal growth factor receptor 2 (HER2) negative metastatic breast cancer (MBC). Despite an initial response, pts eventually develop resistance to therapy; however, the underlying molecular mechanisms remain elusive. This study aimed to identify genomic aberrations in circulating tumor DNA (ctDNA) associated with treatment resistance and disease progression in MBC pts receiving palbociclib. Methods: Blood samples were collected from pts with HR+/HER2− MBC who were treated with palbociclib plus endocrine therapies (letrozole or fulvestrant). Circulating cell-free DNAs were isolated from plasma and assayed by targeted-capture next-generation sequencing using an in-house developed panel that covers the exons in 92 breast cancer-related genes. Unique molecular index (UMI)-based sequencing was performed using the Illumina HiSeq 4000 system. Progression free survival (PFS) differences between pts with different mutation status were compared using the log-rank test. The Cox proportional hazards model with time-dependent covariates was used to evaluate associations between mutations and PFS. Results: The study included 16 pts with a median age of 54.7 years (range: 32.6-74.8 years). A total of 42 blood samples were collected, including 16 baseline samples before the initiation of palbociclib +/- endocrine therapies (within 1.5 months prior to initiation), 10 samples during treatment (1.0-3.9 months after initiation), and 16 after treatment completion (within 1.2 months after completion). During a median follow-up of 23.7 weeks (range: 6.0-99.6 weeks), 8 pts had disease progression at initial blood collection after treatment initiation, and 11 had disease progression at final blood collection during follow-up. Among the 3 pts without progression, 2 were lost to follow-up and 1 had a change in regimen due to adverse events. Mutations were detected in 77 out of 92 genes. Mutations were identified for PIK3CA, ALK, ERBB2, NOTCH1, IDH1 in the baseline samples of 7, 3, 7, 6, and 12 patients, respectively. A shorter time to progression was observed in the pts with PIK3CA, ALK, ERBB2, or NOTCH1 mutations (log-rank P = 0.011, 0.016, 0.057, and 0.059, respectively), whereas those pts with IDH1 mutations had a prolonged PFS (log-rank P = 0.005). Similar results were obtained when the events and survival time at the final blood collection were used for analyses (log-rank P = 0.007, 0.004, 0.046, 0.023, and 0.001 for PIK3CA, ALK, ERBB2, NOTCH1, and IDH1 mutations, respectively). To analyze the association between a given mutation and disease progression, we separated pts into four risk groups according to the status change of the mutation prior to and after treatment: Group 1, persistent absence of the mutation; Group2, loss of the mutation after treatment; Group 3, acquisition of the mutation after treatment; Group 4, persistent presence of the mutation. Longitudinal analyses showed that PIK3CA E542K, ERBB2 P1035H, and NOTCH1 K1069Q mutations were associated with unfavorable survival. For PIK3CA E542K mutation, pts in Group 2 had an increased risk for progression, as compared with those in Group 1 (hazard ratio [HR] =9.90, P = 0.110). For ERBB2 P1035H and NOTCH1 K1069Q mutations, when compared with pts in Group 1, those in Group 4 had the highest risk of progression (HR = 17.24, P = 0.049; HR = 19.17, P = 0.043, respectively), whereas pts in Group 2 had a non-significant slightly increased risk. Conclusions: Results of this study show that genomic aberrations in ctDNA were associated with progression in MBC pts receiving palbociclib-containing regimens. Further research is needed to validate these findings in larger independent studies. Citation Format: Maysa M Abu-Khalaf, Chun Wang, Zhong Ye, Zhenchao Zhang, Daniel Silver, Frederick Fellin, Saveri Bhattacharya, Rebecca Jaslow, Terrence Cescon, AnaMaria Lopez, Ronald Myers, Qiang Wei, Bingshan Li, Hushan Yang. Genomic aberrations in circulating tumor DNAs associated with progression in palbociclib-treated metastatic breast cancer patients [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-10-27.