clinical topic updates

Noninvasive Profiling of Advanced Prostate Cancer

by Tanya B. Dorff, MD

Overview

Our featured expert discusses emerging noninvasive tools for advanced prostate cancer. These include circulating tumor DNA (ctDNA) assays and prostate-specific membrane antigen (PSMA)–based imaging, the latter of which is now approved by the US Food and Drug Administration to select patients for PSMA-targeted radioligand therapy.

Expert Commentary

Tanya B. Dorff, MD

Associate Professor, Department of Medical Oncology & Therapeutics Research
Section Chief, Genitourinary Disease Program
City of Hope
Duarte, CA

“With the advent of ctDNA, which has been very exciting, we have an opportunity to obtain an early indication of how well a patient is responding to treatment. Additionally, ctDNA has the potential to provide more information about the biology of the cancer, including which clones are becoming dominant.”

Tanya B. Dorff, MD

Alternatives to tissue biopsy have long been sought for patients with advanced metastatic disease. The need for liquid biopsy stems, in part, from logistical challenges associated with traditional tissue biopsies. For example, we may not want to sequence tissue from prostatectomies that were performed years ago. In other cases, we may want to test a specimen but do not have access to it. With bone-only metastases, biopsy is invasive and may be technically challenging, and it does not always result in a good sample. 

Multiple studies have shown that circulating tumor cells carry strong, independent, prognostic information; however, this approach was never incorporated into clinical practice because no prospective study was done in which results from a circulating tumor cell assay were used to make treatment decisions. 

With the advent of ctDNA, which has been very exciting, we have an opportunity to obtain an early indication of how well a patient is responding to treatment. Additionally, ctDNA has the potential to provide more information about the biology of the cancer, including which clones are becoming dominant. It becomes a bit more complex when profiling noninvasively using ctDNA to select patients for treatment with poly (ADP-ribose) polymerase inhibitors. Liquid biopsies are certainly desirable in metastatic castration-resistant prostate cancer, but there are gaps in our understanding of the most appropriate diagnostic testing method to identify those who would quality for and benefit from treatment with poly (ADP-ribose) polymerase inhibitors. Most of the clinical trials have actually required tissue-based DNA sequencing, or germline testing, so whether ctDNA liquid biopsy is the right tool is a bit of a gray area. There have been studies examining concordance between tissue and liquid biopsy, and they are usually fairly concordant, but, again, this is still an evolving area. It is also likely that additional education and experience are needed in using ctDNA (eg, with allele fractions and the pathogenicity of identified alterations) to select patients for therapy.

Next-generation imaging with PSMA positron emission tomography (PET) is another noninvasive means of prostate cancer profiling. For the selection of patients with metastatic castration-resistant prostate cancer for lutetium Lu 177 vipivotide tetraxetan, which was recently approved, the studies all use PSMA PET scans to identify those who qualify and may benefit. It is a very unique and relatively specific imaging biomarker. At the 2022 Genitourinary Cancers Symposium, there was a presentation by Buteau et al showing that the avidity of tumors on the PET scan actually may impact the likelihood of response. So, I think that PSMA PET is going to be a very helpful tool for selecting patients who will benefit the most from this targeted radioligand therapy.

References

Buteau JP, Martin AJ, Emmett L, et al. PSMA PET and FDG PET as predictors of response and prognosis in a randomized phase 2 trial of 177Lu-PSMA-617 (LuPSMA) versus cabazitaxel in metastatic, castration-resistant prostate cancer (mCRPC) progressing after docetaxel (TheraP ANZUP 1603) [abstract 10]. Abstract presented at: 2022 Genitourinary Cancers Symposium; February 17-19, 2022.

Casanova-Salas I, Athie A, Boutros PC, et al. Quantitative and qualitative analysis of blood-based liquid biopsies to inform clinical decision-making in prostate cancer. Eur Urol. 2021;79(6):762-771. doi:10.1016/j.eururo.2020.12.037

Dong B, Fan L, Yang B, et al. Use of circulating tumor DNA for the clinical management of metastatic castration-resistant prostate cancer: a multicenter, real-world study. J Natl Compr Canc Netw. 2021;19(8):905-914. doi:10.6004/jnccn.2020.7663

Galletti G, Portella L, Tagawa ST, Kirby BJ, Giannakakou P, Nanus DM. Circulating tumor cells in prostate cancer diagnosis and monitoring: an appraisal of clinical potential. Mol Diagn Ther. 2014;18(4):389-402. doi:10.1007/s40291-014-0101-8

Hodara E, Morrison G, Cunha A, et al. Multiparametric liquid biopsy analysis in metastatic prostate cancer. JCI Insight. 2019;4(5):e125529. doi:10.1172/jci.insight.125529

Liu Z, Wang L, Zhou Y, et al. Application of metastatic biopsy based on "When, Who, Why, Where, How (4W1H)" principle in diagnosis and treatment of metastatic castration-resistance prostate cancer. Transl Androl Urol. 2021;10(4):1723-1733. doi:10.21037/tau-21-23

Sartor O, de Bono J, Chi KN, et al; VISION Investigators. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. 2021;385(12):1091-1103. doi:10.1056/NEJMoa2107322

Tukachinsky H, Madison RW, Chung JH, et al. Genomic analysis of circulating tumor DNA in 3,334 patients with advanced prostate cancer identifies targetable BRCA alterations and AR resistance mechanisms. Clin Cancer Res. 2021;27(11):3094-3105. doi:10.1158/1078-0432.CCR-20-4805

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