Ashley Wittmer

Introduction: The most common malignancy in men is prostate cancer and it is the second highest cause of cancer-related deaths among males.^1,2 Metastatic prostate cancer patients are primarily treated with androgen deprivation therapy (also called castration), but 10-20% of them develop castration-resistant prostate cancer (CRPC) within 5 years.³ From the time castration resistance has developed in a patient, the average survival is calculated at about 16-18 months, or 18-36 months in some cases.^1,4 During the progression to CRPC, cellular adaptive pathways develop and allow for survival in environments where androgens are depleted.¹ In nearly all cases where CRPC initially responds well to treatment, resistance eventually occurs within months to years.⁵ TP53 and RB1 are tumor suppressors frequently mutated in CRPC patients.² Loss of function mutations of these two genes are more prevalent among patients with metastatic CRPC compared to those with nonmetastatic disease.⁶ To optimize treatment and prevent advancement to CRPC, it is necessary to identify genomic aberrations early on in diagnoses.⁶ However, it is challenging to collect a specimen from a metastatic CRPC patient for such genomic tests. Liquid biopsy is a minimally invasive way to collect specimens through blood draws, and sequencing circulating tumor DNA (ctDNA) in blood could be used to direct clinical treatment for prostate cancer.⁷ Methods. One study profiled 470 treatment-naïve prostate cancer diagnostic biopsies using targeted and low-pass whole-genome sequencing.⁶ Another study enrolled 168 patients with metastatic CRPC and collected tumor biopsies before treatment with AR signaling inhibitors.⁸ In the 3rd study, genomic profiling with a hybridization capture based next-generation sequencing assay was used to evaluate ctDNA from liquid biopsies of 396 prostate cancer patients.⁷ Results. Mutations in RB1 were associated with significantly shorter survival. Mutations of both TP53 and RB1 were associated with shorter time to CRPC.⁹ Mutations in TP53 alone outperformed any androgen receptor perturbation in terms of being able to infer prognosis.⁸ Conclusions. Loss of function of TP53 and RB1 are associated with aggressive prostate cancer.⁹ Compared with tumor biopsy, liquid biopsies showed similar capacity to evaluate the genomic profile of the tumor through ctDNA sequencing, are minimally invasive, and easier to perform. More studies are underway to determine the next steps for implementing this approach into clinical practice.⁷

1. Mansinho, A., Macedo, D., Fernandes, I., & Costa, L. (2018). Castration-Resistant Prostate Cancer: Mechanisms, Targets and Treatment. Advances in experimental medicine and biology, 1096, 117–133. https://doi-org.srv-proxy2.library.tamu.edu/10.1007/978-3-319-99286-0_7
2. Komura, K., Sweeney, C. J., Inamoto, T., Ibuki, N., Azuma, H., & Kantoff, P. W. (2018). Current treatment strategies for advanced prostate cancer. International journal of urology : official journal of the Japanese Urological Association, 25(3), 220–231. https://doi-org.srv-proxy2.library.tamu.edu/10.1111/iju.13512
3. Kirby M, Hirst C, Crawford ED. Characterizing the castration-resistant prostate cancer population: a systematic review. Int J Clin Pract. 2011;65(11):1180-1192. doi:10.1111/j.1742-1241.2011.02799.x
4. Davies, A., Conteduca, V., Zoubeidi, A., & Beltran, H. (2019). Biological Evolution of Castration-resistant Prostate Cancer. European urology focus, 5(2), 147–154. https://doi-org.srv-proxy2.library.tamu.edu/10.1016/j.euf.2019.01.016
5. Malihi PD, Graf RP, Rodriguez A, et al. Single-cell circulating tumor cell analysis reveals genomic instability as a distinctive feature of aggressive prostate cancer. Clinical Cancer Research. 2020;26(15):4143-4153. doi:10.1158/1078-0432.ccr-19-4100
6. Mateo, J., Seed, G., Bertan, C., Rescigno, P., Dolling, D., Figueiredo, I., Miranda, S., Nava Rodrigues, D., Gurel, B., Clarke, M., Atkin, M., Chandler, R., Messina, C., Sumanasuriya, S., Bianchini, D., Barrero, M., Petermolo, A., Zafeiriou, Z., Fontes, M., Perez-Lopez, R., … de Bono, J. S. (2020). Genomics of lethal prostate cancer at diagnosis and castration resistance. The Journal of clinical investigation, 130(4), 1743–1751. https://doi-org.srv-proxy2.library.tamu.edu/10.1172/JCI132031
7. Fan L, Fei X, Zhu Y, et al. Comparative analysis of genomic alterations across castration sensitive and castration resistant prostate cancer via circulating tumor DNA sequencing. Journal of Urology. 2021;205(2):461-469. doi:10.1097/ju.0000000000001363
8. De Laere B, Oeyen S, Mayrhofer M, et al. TP53 outperforms other androgen receptor biomarkers to predict abiraterone or enzalutamide outcome in metastatic castration-resistant prostate cancer. Clinical Cancer Research. 2018;25(6):1766-1773. doi:10.1158/1078-0432.ccr-18-1943
9. Soerohardjo I, Widodo I, Heriyanto DS, Zulfiqqar A, Anwar SL. Down-regulation of RB1 and TP53 as potential predicting biomarkers for castration-resistant prostate cancer (CRPC): Indonesian retrospective cohort study. Annals of Medicine and Surgery. 2020;60:549-554. doi:10.1016/j.amsu.2020.11.017