Clinical implications of AR alterations in advanced prostate cancer: a multi-institutional collaboration.
Journal
Prostate cancer and prostatic diseases
ISSN: 1476-5608
Titre abrégé: Prostate Cancer Prostatic Dis
Pays: England
ID NLM: 9815755
Informations de publication
Date de publication:
22 Feb 2024
22 Feb 2024
Historique:
received:
24
07
2023
accepted:
06
02
2024
revised:
09
01
2024
medline:
22
2
2024
pubmed:
22
2
2024
entrez:
22
2
2024
Statut:
aheadofprint
Résumé
AR gene alterations can develop in response to pressure of testosterone suppression and androgen receptor targeting agents (ARTA). Despite this, the relevance of these gene alterations in the context of ARTA treatment and clinical outcomes remains unclear. Patients with castration-resistant prostate cancer (CRPC) who had undergone genomic testing and received ARTA treatment were identified in the Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort (PROMISE) database. Patients were stratified according to the timing of genomic testing relative to the first ARTA treatment (pre-/post-ARTA). Clinical outcomes such as time to progression, PSA response, and overall survival were compared based on alteration types. In total, 540 CRPC patients who received ARTA and had tissue-based (n = 321) and/or blood-based (n = 244) genomic sequencing were identified. Median age was 62 years (range 39-90) at the time of the diagnosis. Majority were White (72.2%) and had metastatic disease (92.6%) at the time of the first ARTA treatment. Pre-ARTA genomic testing was available in 24.8% of the patients, and AR mutations and amplifications were observed in 8.2% and 13.1% of the patients, respectively. Further, time to progression was longer in patients with AR amplifications (25.7 months) compared to those without an AR alteration (9.6 months; p = 0.03). In the post-ARTA group (n = 406), AR mutations and AR amplifications were observed in 18.5% and 35.7% of the patients, respectively. The most common mutation in post-ARTA group was L702H (9.9%). In this real-world clinicogenomics database-driven study we explored the development of AR alterations and their association with ARTA treatment outcomes. Our study showed that AR amplifications are associated with longer time to progression on first ARTA treatment. Further prospective studies are needed to optimize therapeutic strategies for patients with AR alterations.
Sections du résumé
BACKGROUND
BACKGROUND
AR gene alterations can develop in response to pressure of testosterone suppression and androgen receptor targeting agents (ARTA). Despite this, the relevance of these gene alterations in the context of ARTA treatment and clinical outcomes remains unclear.
METHODS
METHODS
Patients with castration-resistant prostate cancer (CRPC) who had undergone genomic testing and received ARTA treatment were identified in the Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort (PROMISE) database. Patients were stratified according to the timing of genomic testing relative to the first ARTA treatment (pre-/post-ARTA). Clinical outcomes such as time to progression, PSA response, and overall survival were compared based on alteration types.
RESULTS
RESULTS
In total, 540 CRPC patients who received ARTA and had tissue-based (n = 321) and/or blood-based (n = 244) genomic sequencing were identified. Median age was 62 years (range 39-90) at the time of the diagnosis. Majority were White (72.2%) and had metastatic disease (92.6%) at the time of the first ARTA treatment. Pre-ARTA genomic testing was available in 24.8% of the patients, and AR mutations and amplifications were observed in 8.2% and 13.1% of the patients, respectively. Further, time to progression was longer in patients with AR amplifications (25.7 months) compared to those without an AR alteration (9.6 months; p = 0.03). In the post-ARTA group (n = 406), AR mutations and AR amplifications were observed in 18.5% and 35.7% of the patients, respectively. The most common mutation in post-ARTA group was L702H (9.9%).
CONCLUSION
CONCLUSIONS
In this real-world clinicogenomics database-driven study we explored the development of AR alterations and their association with ARTA treatment outcomes. Our study showed that AR amplifications are associated with longer time to progression on first ARTA treatment. Further prospective studies are needed to optimize therapeutic strategies for patients with AR alterations.
Identifiants
pubmed: 38383885
doi: 10.1038/s41391-024-00805-3
pii: 10.1038/s41391-024-00805-3
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024. The Author(s).
Références
Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA: A Cancer J Clin. 2022;72:7–33.
Huggins C, Hodges CV. Studies on prostatic cancer. I. The effect of castration, of estrogen and androgen injection on serum phosphatases in metastatic carcinoma of the prostate. CA Cancer J Clin 1972;22:232–40.
doi: 10.3322/canjclin.22.4.232
pubmed: 4625049
National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology. Prostate Cancer (Version 3.2022) [Internet]. [cited 2022 Apr 8]. Available from: https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf .
Heinlein CA, Chang C. Androgen receptor in prostate cancer. Endocr Rev. 2004;25:276–308.
doi: 10.1210/er.2002-0032
pubmed: 15082523
Research C for DE and. FDA approves olaparib for HRR gene-mutated metastatic castration-resistant prostate cancer. FDA [Internet]. 2021 Jun 11 [cited 2022 Oct 30]; Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-olaparib-hrr-gene-mutated-metastatic-castration-resistant-prostate-cancer .
Tukachinsky H, Madison RW, Chung JH, Gjoerup OV, Severson EA, Dennis L, et al. Genomic analysis of circulating tumor DNA in 3334 patients with advanced prostate cancer identifies targetable BRCA alterations and AR resistance mechanisms. Clin Cancer Res. 2021;27:3094–105.
doi: 10.1158/1078-0432.CCR-20-4805
pubmed: 33558422
pmcid: 9295199
Abida W, Cyrta J, Heller G, Prandi D, Armenia J, Coleman I, et al. Genomic correlates of clinical outcome in advanced prostate cancer. Proc Natl Acad Sci. 2019;116:11428–36.
doi: 10.1073/pnas.1902651116
pubmed: 31061129
pmcid: 6561293
Abeshouse A, Ahn J, Akbani R, Ally A, Amin S, Andry CD, et al. The molecular taxonomy of primary prostate. Cancer Cell 2015;163:1011–25.
van Dessel LF, van Riet J, Smits M, Zhu Y, Hamberg P, van der Heijden MS, et al. The genomic landscape of metastatic castration-resistant prostate cancers reveals multiple distinct genotypes with potential clinical impact. Nat Commun. 2019;10:5251.
doi: 10.1038/s41467-019-13084-7
pubmed: 31748536
pmcid: 6868175
Chmelar R, Buchanan G, Need EF, Tilley W, Greenberg NM. Androgen receptor coregulators and their involvement in the development and progression of prostate cancer. Int J Cancer. 2007;120:719–33.
doi: 10.1002/ijc.22365
pubmed: 17163421
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;43:209–23.
doi: 10.1001/archsurg.1941.01210140043004
Jernberg E, Bergh A, Wikström P. Clinical relevance of androgen receptor alterations in prostate cancer. Endocr Connect. 2017;6:R146–61.
doi: 10.1530/EC-17-0118
pubmed: 29030409
pmcid: 5640574
Quigley DA, Dang HX, Zhao SG, Lloyd P, Aggarwal R, Alumkal JJ, et al. Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer. Cell. 2018;174:758–69.e9.
doi: 10.1016/j.cell.2018.06.039
pubmed: 30033370
pmcid: 6425931
Herberts C, Annala M, Sipola J, Ng SWS, Chen XE, Nurminen A, et al. Deep whole-genome ctDNA chronology of treatment-resistant prostate cancer. Nature. 2022;608:199–208.
doi: 10.1038/s41586-022-04975-9
pubmed: 35859180
Azad AA, Volik SV, Wyatt AW, Haegert A, Le Bihan S, Bell RH, et al. Androgen receptor gene aberrations in circulating cell-free DNA: biomarkers of therapeutic resistance in castration-resistant prostate cancer. Clin Cancer Res. 2015;21:2315–24.
doi: 10.1158/1078-0432.CCR-14-2666
pubmed: 25712683
Wyatt AW, Azad AA, Volik SV, Annala M, Beja K, McConeghy B, et al. Genomic alterations in cell-Free DNA and enzalutamide resistance in castration-resistant prostate cancer. JAMA Oncol. 2016;2:1598–606.
doi: 10.1001/jamaoncol.2016.0494
pubmed: 27148695
pmcid: 5097690
Romanel A, Gasi Tandefelt D, Conteduca V, Jayaram A, Casiraghi N, Wetterskog D, et al. Plasma AR and abiraterone-resistant prostate cancer. Sci Transl Med. 2015;7:312re10.
doi: 10.1126/scitranslmed.aac9511
pubmed: 26537258
pmcid: 6112410
Salvi S, Casadio V, Conteduca V, Burgio SL, Menna C, Bianchi E, et al. Circulating cell-free AR and CYP17A1 copy number variations may associate with outcome of metastatic castration-resistant prostate cancer patients treated with abiraterone. Br J Cancer. 2015;112:1717–24.
doi: 10.1038/bjc.2015.128
pubmed: 25897673
pmcid: 4430717
Smith MR, Thomas S, Chowdhury S, Olmos D, Li J, Mainwaring PN, et al. Abstract 2605: Androgen receptor (AR) anomalies and efficacy of apalutamide (APA) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC) from the phase 3 SPARTAN study. Cancer Res. 2018;78:2605.
doi: 10.1158/1538-7445.AM2018-2605
Koshkin VS, Patel VG, Ali A, Bilen MA, Ravindranathan D, Park JJ, et al. PROMISE: a real-world clinical-genomic database to address knowledge gaps in prostate cancer. Prostate Cancer Prostatic Dis. 2022;25:388–96.
Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ, Mosquera JM, et al. Integrative clinical genomics of advanced prostate cancer. Cell 2015;161:1215–28.
doi: 10.1016/j.cell.2015.05.001
pubmed: 26000489
pmcid: 4484602
Ledet EM, Lilly MB, Sonpavde G, Lin E, Nussenzveig RH, Barata PC, et al. Comprehensive analysis of AR alterations in circulating tumor DNA from patients with advanced prostate cancer. Oncologist. 2020;25:327–33.
doi: 10.1634/theoncologist.2019-0115
pubmed: 32297439
Annala M, Vandekerkhove G, Khalaf D, Taavitsainen S, Beja K, Warner EW, et al. Circulating tumor DNA genomics correlate with resistance to abiraterone and enzalutamide in prostate cancer. Cancer Discov. 2018;8:444–57.
doi: 10.1158/2159-8290.CD-17-0937
pubmed: 29367197
McKay RR, Kwak L, Crowdis JP, Sperger JM, Zhao SG, Xie W, et al. Phase II multicenter study of enzalutamide in metastatic castration-resistant prostate cancer to identify mechanisms driving resistance. Clin Cancer Res. 2021;27:3610–9.
doi: 10.1158/1078-0432.CCR-20-4616
pubmed: 33849963
pmcid: 8254786
Salvi S, Casadio V, Conteduca V, Lolli C, Gurioli G, Martignano F, et al. Circulating AR copy number and outcome to enzalutamide in docetaxel-treated metastatic castration-resistant prostate cancer. Oncotarget. 2016;7:37839–45.
doi: 10.18632/oncotarget.9341
pubmed: 27191887
pmcid: 5122353
Tolmeijer SH, Boerrigter E, Schalken JA, Geerlings MJ, van Oort IM, van Erp NP, et al. A systematic review and meta-analysis on the predictive value of cell-free DNA-based androgen receptor copy number gain in patients with castration-resistant prostate cancer. JCO Precis Oncol. 2020;4:714–29.
Jayaram A, Wingate A, Wetterskog D, Conteduca V, Khalaf D, Sharabiani MTA, et al. Plasma androgen receptor copy number status at emergence of metastatic castration-resistant prostate cancer: a pooled multicohort analysis. JCO Precis Oncol. 2019;3:PO.19.00123.
Beltran H, Yelensky R, Frampton GM, Park K, Downing SR, MacDonald TY, et al. Targeted next-generation sequencing of advanced prostate cancer identifies potential therapeutic targets and disease heterogeneity. Eur Urol. 2013;63:920–6.
doi: 10.1016/j.eururo.2012.08.053
pubmed: 22981675
Carreira S, Romanel A, Goodall J, Grist E, Ferraldeschi R, Miranda S, et al. Tumor clone dynamics in lethal prostate cancer. Sci Transl Med. 2014;6:254ra125.
doi: 10.1126/scitranslmed.3009448
pubmed: 25232177
pmcid: 4422178
Shiota M, Akamatsu S, Tsukahara S, Nagakawa S, Matsumoto T, Eto M. Androgen receptor mutations for precision medicine in prostate cancer. Endocr Relat Cancer. 2022;29:R143–55.
doi: 10.1530/ERC-22-0140
pubmed: 35900853
Phase 1/2 study of ARV-110, an androgen receptor (AR) PROTAC degrader, in metastatic castration-resistant prostate cancer (mCRPC). | Journal of Clinical Oncology [Internet]. [cited 2022 Oct 30]. Available from: https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.6_suppl.017 .