Belle Skaggs

Background:  Prostate cancer is the second most common cancer and second leading cause of cancer related mortality in American men¹. One therapy commonly used to treat prostate cancer is androgen deprivation therapy (ADT), which creates a state of androgen deprivation in cancer cells that induces apoptosis¹. Unfortunately, after a mean time of 2-3 years the cancer cells become resistant to ADT and are then referred to as being castration resistant. Castration resistant prostate cancer is an advanced form of prostate cancer that is terminal. The androgen receptor (AR) gene is one of the most common genes involved in CRPC. The AR gene is located in the Xq11-q13 region and makes the androgen receptor protein¹. While there are several androgen receptor related mechanisms thought to be behind the development of CRPC, androgen receptor amplification is one of the most common and is present in 20-31% of individuals with CRPC¹.

Liquid biopsies offer a minimally invasive method for detecting biomarkers in bodily fluids, revolutionizing cancer diagnosis and monitoring. While traditional tumor biopsies are invasive and pose possible adverse risks, liquid biopsies are minimally invasive as they can be retrieved from blood, urine, and cerebrospinal fluid². Liquid biopsies contain cell free DNA (cfDNA), which is released into the bloodstream most commonly through apoptosis. Circulating tumor DNA (ctDNA) is a subset of cfDNA which specifically originates from tumors².

Objective: With liquid biopsies, androgen receptor aberrations present in CRPC can be non-invasively analyzed.

Methods: PubMed was used to identify the current research being done on this topic. Search terms including “liquid biopsies and CRPC” as well as “liquid biopsies and androgen receptor amplification” were used to find pertinent research articles published between 2018-2024.

Results: In one study published in 2020, ctDNA was collected from 892 advanced prostate cancer patients, many of whom had CRPC³. Upon sequencing, it was found that 49% of the patients had only AR amplifications while 18% had both AR amplifications and mutations. Interestingly, AR aberrations were found to be significantly associated with mutations in the tumor suppressor genes APC and MYC³. In another study from 2019, cfDNA was used to evaluate AR aberrations in 102 patients with CRPC⁴. From this cohort, 14 patients began treatment with abiraterone and 25 began treatment with enzalutamide. It was seen that the presence of AR amplifications predicted poorer response to abiraterone but had no predictive value when evaluating responses to enzalutamide⁴. This study shows that liquid biopsies are a useful tool for evaluating individualized treatments of CRPC. In the same study, cfDNA was collected from 41 patients multiple times to track AR status⁴. While 19 patients already had AR amplifications at baseline, 8 more patients developed amplifications upon becoming resistant to treatment. This suggests that AR amplifications arise as an adaptive response to treatment⁴. Lastly, a study from 2022 analyzed cfDNA from 21 patients undergoing treatment for CRPC with AR signaling inhibitors⁵. Whole genome analysis of the samples concluded the only highly recurrent amplification or mutations occurred at the AR locus⁵.

Conclusion: Ultimately, the research discussed above reveals that liquid biopsies are a useful tool for investigating AR amplifications and mutations in patients with CRPC. Given that the AR gene is one of the main drivers in the development of CRPC, it is promising to see that liquid biopsies represent an emerging non-invasive method for analyzing mutations in this gene. Further research needs to be conducted to confirm that liquid biopsies are as reliable as traditional tumor biopsies.

Works Cited:

1. Crowley F, Sterpi M, Buckley C, Margetich L, Handa S, Dovey Z. A Review of the Pathophysiological Mechanisms Underlying Castration-resistant Prostate Cancer. Res Rep Urol. 2021;13:457-472. Published 2021 Jun 30. doi:10.2147/RRU.S264722
2. Dao J, Conway PJ, Subramani B, Meyyappan D, Russell S, Mahadevan D. Using cfDNA and ctDNA as Oncologic Markers: A Path to Clinical Validation. Int J Mol Sci. 2023;24(17):13219. Published 2023 Aug 25. doi:10.3390/ijms241713219
3. Ledet EM, Lilly MB, Sonpavde G, et al. Comprehensive Analysis of AR Alterations in Circulating Tumor DNA from Patients with Advanced Prostate Cancer. Oncologist. 2020;25(4):327-333. doi:10.1634/theoncologist.2019-0115
4. Sumiyoshi T, Mizuno K, Yamasaki T, et al. Clinical utility of androgen receptor gene aberrations in circulating cell-free DNA as a biomarker for treatment of castration-resistant prostate cancer. Sci Rep. 2019;9(1):4030. Published 2019 Mar 11. doi:10.1038/s41598-019-40719-y
5. Herberts C, Annala M, Sipola J, et al. Deep whole-genome ctDNA chronology of treatment-resistant prostate cancer. Nature. 2022;608(7921):199-208. doi:10.1038/s41586-022-04975-9