Circulating cell-free DNA in the blood of castration-resistant prostate cancer patients harbors tumor-specific genomic information. Here, we investigated common genomic variants and whether these data correlate with treatment response.

Minimum 20ng of cfDNA were extracted from plasma of CRPC patients. Hybrid-capture based genomic profiling (Axen Cancer Panel 1, Macrogen) was performed to sequence 88 genes in each samples. The data was presented with mutated gene, DNA change, allele frequency(AF). The final reports provided each variants’ clinical effect based on Clinvar reference. We considered ‘pathologic’, ‘likely pathologic’, and ‘unknown significance’ as meaningful variants.

Total 22 CRPC patients who were receiving chemotherapy and/or androgen receptor antagonists participated in our study. Patients’ median age was 73.5 years old, and almost all the patients had bone metastasis (21/22, 95.5%). Follow up samples were available in 17 patients at the time of response evaluation. Thus, 39 samples were analyzed with NGS platform. Median 6 mutations were detected per each analysis, and 3 of them were clinically pathogenic or had unknown significance. Most common meaningful variant was TP53 (21/39, 53.8%), followed by ALK (16/39, 41.0%) and PTEN (15/39, 38.5%). In TP53 gene, c.734G>A, c.659A>G, and c.844C>T missense variants were detected. We also compared number of mutations in 17 pairing samples according to patients’ clinical response based on Recist Criteria v1.1. 6 out of 8 patients in PR group had pathogenic TP53 mutation initially; 3 of them disappeared, and 3 of them showed decreased AF in f/u data. In PD group of another 8 patients, 1 out of 3 initially mutated TP53 showed increased AF and 2 new TP53 mutations appeared in f/u analysis. Median delta between the number of meaningful mutated gene was -1 in PR groups (range -4 ~ +6), and +0.5 in PD groups (range -2 ~ +4). Each group had one outstanding value against the tendency, which showed +6 in PR and -2 in PD. Without these outliers, median delta was -2 in PR and +1 in PD. The outlier in PR group with a significant increase (Δ+6) in the number of mutation showed favorable results in PSA and bone scan. However, soon after that, his next follow up imaging study was presented with highly aggravated bone metastasis. With this case, we suspected that cfDNA could function as an early surrogate marker of upcoming treatment failure.

We examined the common variants in cfDNA of CRPC patients and consequences of treatment responses. Pathologic TP53 mutation was detected more than half of the analysis, and its AF tended to change as treatment went on. The total amount of variants was also correlated with clinical response. If cfDNA sequencing data and clinical aspect are conflicting, the increasing number of mutation could be a sign of treatment failure. We will present more data from 30 patients at the time of conference.

Citation Format: Ju Won Kim, Hye Sun Lee, Yeul Hong Kim, Yoon Ji Choi, Won Jin Jang, Jeong Yoon Choi, Kyong Hwa Park. Allele frequencies of TP53 in liquid biopsy of castration-resistant prostate cancer patients were correlated with clinical response : A pilot study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3979.