Targeted Next-Generation Sequencing in Men with Metastatic Prostate Cancer: a Pilot Study
Tumor profiling by targeted next-generation sequencing (tNGS) and personalized treatment based on these results is becoming increasingly common in patients with metastatic solid tumors, but it remains unclear whether this strategy results in benefit to patients with metastatic prostate cancer (mPCa).
To assess the clinical utility of tNGS in treatment decision-making for patients with mPCa.
Patients and Methods
Patients with available genomic profiling using tumor tissue (FoundationOne, F1) or cell-free DNA (FoundationACT, Guardant360) were included. Targetable genomic alterations (tGA) included a change in the copy number or mutations in DNA repair genes, mismatch repair genes, PTEN, cyclin-dependent kinases, ERBB2, BRAF, TSC, and the PIK3/mTOR pathway.
The study included 66 patients, 86% of which had metastatic castration-resistant prostate cancer (mCRPC), and who had received a median of 3 (range 0–7) treatments prior to tNGS. The most frequent alterations were found in TP53 (42%), PTEN (35%), androgen receptor (AR) (30%), DNA repair (30%), PIK3CA signaling pathway (21%), cyclin-dependent kinases (15%), BRAF (9%), and MMR/MSI (6%) genes. Among the 45 (68%) tGA+ patients, tNGS influenced treatment in 13 (29%) [PARP inhibitor (n = 7), mTOR inhibitor (n = 4), anti-PD-1 (n = 2), anti-HER2 (n = 1)]. The median progression-free survival (PFS) was 4.1 months [95% confidence interval (CI), 2.8–5.4]. Among tGA+ patients who did not receive tNGS-based therapy, systemic treatment (n = 17) included chemotherapy (71%), new generation anti-androgen therapy (24%), and cabozantinib (6%); the median PFS was 4.3 months (95% CI, 2.6–6.0; p = 0.7 for tGA+ with personalized therapy vs. tGA+ without personalized therapy).
In this cohort, the use of tNGS was feasible, detected frequent genomic alterations, and was used late in the disease course. Further studies and larger portfolios of targeted therapy trials are needed to maximize the benefit of tNGS in this population.
Compliance with Ethical Standards
No external funding was used in the preparation of this manuscript.
Conflict of Interest
Brandie Heald has disclosed to be on an advisory board for Invitae and the speakers’ bureau for Myriad Genetics Laboratory. Dr. Petros Grivas has disclosed to be a consultant or advisor for Foundation Medicine, Genentech, Dendreon, Bayer, Driver Inc., Exelixis, Merck & Co., Bristol-Myers Squibb, AstraZeneca, Biocept, Clovis Oncology, EMD Serono, and Seattle Genetics; has received research funding from Mirati Therapeutics, Genentech/Roche, Merck, Oncogenex, Bayer, Pfizer, and AstraZeneca. Dr. Davendra Sohal has disclosed to be a consultant or advisor for Perthera and Foundation Medicine, and received research funding from Novartis, Celgene, OncoMed, Bayer, and Genentech/Roche. Dr. Jorge Garcia has disclosed to be a consultant or advisor for Sanofi, Pfizer, Bayer, Eisai, Exelexis, Medivation/Astellas, and Genentech/Roche; has received research funding from Pfizer, Astellas Pharma, Orion Pharma GmbH, Bayer, Janssen Oncology, Genentech/Roche, and Lilly. Pedro C. Barata, Prateek Mendiratta, and Stefan Klek declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.
- 2.Huggins C, Stevens RE Jr, Hodges CV. Studies on prostatic cancer: II. The effects of castration on advanced carcinoma of the prostate gland. Arch Surg. 1941;43(2):209–23. https://doi.org/10.1001/archsurg.1941.01210140043004.CrossRefGoogle Scholar
- 10.Lanman RB, Mortimer SA, Zill OA, Sebisanovic D, Lopez R, Blau S, et al. Analytical and clinical validation of a digital sequencing panel for quantitative, highly accurate evaluation of cell-free circulating tumor DNA. PLoS One. 2015;10(10):e0140712. https://doi.org/10.1371/journal.pone.0140712.CrossRefPubMedPubMedCentralGoogle Scholar
- 11.Chung JH, Pavlick D, Hartmaier R, Schrock AB, Young L, Forcier B, et al. Hybrid capture-based genomic profiling of circulating tumor DNA from patients with estrogen receptor-positive metastatic breast cancer. Ann Oncol. 2017;28(11):2866–73. https://doi.org/10.1093/annonc/mdx490.CrossRefPubMedGoogle Scholar
- 14.Von Hoff DD, Stephenson JJ Jr, Rosen P, Loesch DM, Borad MJ, Anthony S, et al. Pilot study using molecular profiling of patients’ tumors to find potential targets and select treatments for their refractory cancers. J Clin Oncol. 2010;28(33):4877–83. https://doi.org/10.1200/jco.2009.26.5983.CrossRefGoogle Scholar
- 16.Ritch E, Wyatt AW. Predicting therapy response and resistance in metastatic prostate cancer with circulating tumor DNA. Urol Oncol. 2017. https://doi.org/10.1016/j.urolonc.2017.11.017.
- 17.Barata PC, Koshkin VS, Funchain P, Sohal D, Pritchard A, Klek S, et al. Next-generation sequencing (NGS) of cell-free circulating tumor DNA and tumor tissue in patients with advanced urothelial cancer: a pilot assessment of concordance. Ann Oncol. 2017;28(10):2458–63. https://doi.org/10.1093/annonc/mdx405.CrossRefPubMedGoogle Scholar