Programmed cell death ligand-1 (PD-L1)/programmed cell death-1 (PD-1) blockade has been unsuccessful in prostate cancer, with poor immunogenicity and subsequent low PD-L1 expression in prostate ...cancer being proposed as an explanation. However, recent studies indicate that a subset of prostate cancer may express significant levels of PD-L1. Furthermore, the androgen antagonist enzalutamide has been shown to upregulate PD-L1 expression in prostate cancer preclinical models. In this study, we evaluated the effect of neoadjuvant androgen deprivation therapy with abiraterone acetate plus prednisone and leuprolide (Neo-AAPL) on PD-L1 expression in prostate cancer.
Radical prostatectomy (RP) tissues were collected from 44 patients with intermediate- to high-risk prostate cancer who underwent RP after Neo-AAPL treatment. Untreated prostate cancer tissues were collected from 130 patients, including 44 matched controls for the Neo-AAPL cases. Tumor PD-L1 expression was detected by IHC using validated anti-PD-L1 antibodies. Tumor-infiltrating CD8
cells were analyzed in trial cases and matched controls. Expression of DNA mismatch repair genes was examined in PD-L1-positive tumors.
Neo-AAPL-treated tumors showed a trend toward decreased PD-L1 positivity compared with matched controls (7% vs. 21% having ≥1% positive tumor cells;
= 0.062). Treated tumors also harbored significantly fewer tumor-infiltrating CD8
cells (
= 0.029). In 130 untreated prostate cancers, African American ethnicity, elevated serum PSA, and small prostate independently predicted tumor PD-L1 positivity. Loss of MSH2 expression was observed in 1 of 21 PD-L1-positive tumors.
A subset of prostate cancer expresses PD-L1, which is not increased by Neo-AAPL treatment, indicating that combining Neo-AAPL treatment with PD-L1/PD-1 blockade may not be synergistic.
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The CYP17A1 inhibitor abiraterone markedly reduces androgen precursors and is thereby effective in castration-resistant prostate cancer (CRPC). However, abiraterone increases progesterone, which can ...activate certain mutant androgen receptors (AR) identified previously in flutamide-resistant tumors. Therefore, we sought to determine if CYP17A1 inhibitor treatment selects for progesterone-activated mutant ARs.
AR was examined by targeted sequencing in metastatic tumor biopsies from 18 patients with CRPC who were progressing on a CYP17A1 inhibitor (17 on abiraterone, 1 on ketoconazole), alone or in combination with dutasteride, and by whole-exome sequencing in residual tumor in one patient treated with neoadjuvant leuprolide plus abiraterone.
The progesterone-activated T878A-mutant AR was present at high allele frequency in 3 of the 18 CRPC cases. It was also present in one focus of resistant tumor in the neoadjuvant-treated patient, but not in a second clonally related resistant focus that instead had lost one copy of PTEN and both copies of CHD1. The T878A mutation appeared to be less common in the subset of patients with CRPC treated with abiraterone plus dutasteride, and transfection studies showed that dutasteride was a more potent direct antagonist of the T878A versus the wild-type AR.
These findings indicate that selection for tumor cells expressing progesterone-activated mutant ARs is a mechanism of resistance to CYP17A1 inhibition.
Androgen receptor (AR) plays a central role in prostate cancer, and most patients respond to androgen deprivation therapies, but they invariably relapse with a more aggressive prostate cancer that ...has been termed hormone refractory or androgen independent. To identify proteins that mediate this tumor progression, gene expression in 33 androgen-independent prostate cancer bone marrow metastases versus 22 laser capture-microdissected primary prostate cancers was compared using Affymetrix oligonucleotide microarrays. Multiple genes associated with aggressive behavior were increased in the androgen-independent metastatic tumors (MMP9, CKS2, LRRC15, WNT5A, EZH2, E2F3, SDC1, SKP2, and BIRC5), whereas a candidate tumor suppressor gene (KLF6) was decreased. Consistent with castrate androgen levels, androgen-regulated genes were reduced 2- to 3-fold in the androgen-independent tumors. Nonetheless, they were still major transcripts in these tumors, indicating that there was partial reactivation of AR transcriptional activity. This was associated with increased expression of AR (5.8-fold) and multiple genes mediating androgen metabolism (HSD3B2, AKR1C3, SRD5A1, AKR1C2, AKR1C1, and UGT2B15). The increase in aldo-keto reductase family 1, member C3 (AKR1C3), the prostatic enzyme that reduces adrenal androstenedione to testosterone, was confirmed by real-time reverse transcription-PCR and immunohistochemistry. These results indicate that enhanced intracellular conversion of adrenal androgens to testosterone and dihydrotestosterone is a mechanism by which prostate cancer cells adapt to androgen deprivation and suggest new therapeutic targets.
To update eligibility and outcome measures in trials that evaluate systemic treatment for patients with progressive prostate cancer and castrate levels of testosterone.
A committee of investigators ...experienced in conducting trials for prostate cancer defined new consensus criteria by reviewing previous criteria, Response Evaluation Criteria in Solid Tumors (RECIST), and emerging trial data.
The Prostate Cancer Clinical Trials Working Group (PCWG2) recommends a two-objective paradigm: (1) controlling, relieving, or eliminating disease manifestations that are present when treatment is initiated and (2) preventing or delaying disease manifestations expected to occur. Prostate cancers progressing despite castrate levels of testosterone are considered castration resistant and not hormone refractory. Eligibility is defined using standard disease assessments to authenticate disease progression, prior treatment, distinct clinical subtypes, and predictive models. Outcomes are reported independently for prostate-specific antigen (PSA), imaging, and clinical measures, avoiding grouped categorizations such as complete or partial response. In most trials, early changes in PSA and/or pain are not acted on without other evidence of disease progression, and treatment should be continued for at least 12 weeks to ensure adequate drug exposure. Bone scans are reported as "new lesions" or "no new lesions," changes in soft-tissue disease assessed by RECIST, and pain using validated scales. Defining eligibility for prevent/delay end points requires attention to estimated event frequency and/or random assignment to a control group.
PCWG2 recommends increasing emphasis on time-to-event end points (ie, failure to progress) as decision aids in proceeding from phase II to phase III trials. Recommendations will evolve as data are generated on the utility of intermediate end points to predict clinical benefit.
Persistence of ligand-mediated androgen receptor signaling has been documented in castration-resistant prostate cancers (CRPCs). Abiraterone acetate (AA) is a potent and selective inhibitor of CYP17, ...which is required for androgen biosynthesis in the testes, adrenal glands, and prostate tissue. This trial evaluated the efficacy and safety of AA in combination with prednisone to reduce the symptoms of secondary hyperaldosteronism that can occur with AA monotherapy.
Fifty-eight men with progressive metastatic CRPC who experienced treatment failure with docetaxel-based chemotherapy received AA (1,000 mg daily) with prednisone (5 mg twice daily). Twenty-seven (47%) patients had received prior ketoconazole. The primary outcome was > or = 50% prostate-specific antigen (PSA) decline, with objective response by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and changes in Eastern Cooperative Oncology Group (ECOG) performance status (PS) and circulating tumor cell (CTC) numbers. Safety was also evaluated.
A > or = 50% decline in PSA was confirmed in 22 (36%) patients, including 14 (45%) of 31 ketoconazole-naïve and seven (26%) of 27 ketoconazole-pretreated patients. Partial responses were seen in four (18%) of 22 patients with RECIST-evaluable target lesions. Improved ECOG PS was seen in 28% of patients. Median time to PSA progression was 169 days (95% CI, 82 to 200 days). CTC conversions with treatment from > or = 5 to < 5 were noted in 10 (34%) of 29 patients. The majority of AA-related adverse events were grade 1 to 2, and no AA-related grade 4 events were seen.
AA plus prednisone was well tolerated, with encouraging antitumor activity in heavily pretreated CRPC patients. The incidence of mineralocorticoid-related toxicities (hypertension or hypokalemia) was reduced by adding low-dose prednisone. The combination of AA plus prednisone is recommended for phase III investigations.
Biology of prostate-specific antigen Balk, Steven P; Ko, Yoo-Joung; Bubley, Glenn J
Journal of clinical oncology,
01/2003, Letnik:
21, Številka:
2
Journal Article
Recenzirano
Prostate-specific antigen (PSA) is an androgen-regulated serine protease produced by both prostate epithelial cells and prostate cancer (PCa) and is the most commonly used serum marker for cancer. It ...is a member of the tissue kallikrein family, some of the members of which are also prostate specific. PSA is a major protein in semen, where its function is to cleave semenogelins in the seminal coagulum. PSA is secreted into prostatic ducts as an inactive 244-amino acid proenzyme (proPSA) that is activated by cleavage of seven N-terminal amino acids. PSA that enters the circulation intact is rapidly bound by protease inhibitors, primarily alpha1-antichymotrypsin, although a fraction is inactivated in the lumen by proteolysis and circulates as free PSA. This proteolytic inactivation, as well as the cleavage of proPSA to PSA, is less efficient in PCa. Serum total PSA levels are increased in PCa, and PSA screening has dramatically altered PCa presentation and management. Unfortunately, although high PSA levels are predictive of advanced PCa, a large fraction of organ-confined cancers present with much lower total PSA values that overlap those levels found in men without PCa. Measurement of free versus total PSA can increase specificity for PCa, and tests under development to measure forms of proPSA may further enhance the ability to detect early-stage PCa. PSA is also widely used to monitor responses to therapy and is under investigation as a therapeutic target. Finally, recent data indicate that there may be additional roles for PSA in the pathogenesis of PCa.
Men with metastatic prostate cancer who are treated with androgen deprivation therapies (ADT) usually relapse within 2 to 3 years with disease that is termed castration-resistant prostate cancer ...(CRPC). To identify the mechanism that drives these advanced tumors, paired-end RNA-sequencing (RNA-seq) was performed on a panel of CRPC bone marrow biopsy specimens. From this genome-wide approach, mutations were found in a series of genes with prostate cancer relevance, including AR, NCOR1, KDM3A, KDM4A, CHD1, SETD5, SETD7, INPP4B, RASGRP3, RASA1, TP53BP1, and CDH1, and a novel SND1:BRAF gene fusion. Among the most highly expressed transcripts were 10 noncoding RNAs (ncRNAs), including MALAT1 and PABPC1, which are involved in RNA processing. Notably, a high percentage of sequence reads mapped to introns, which were determined to be the result of incomplete splicing at canonical splice junctions. Using quantitative PCR (qPCR), a series of genes (AR, KLK2, KLK3, STEAP2, CPSF6, and CDK19) were confirmed to have a greater proportion of unspliced RNA in CRPC specimens than in normal prostate epithelium, untreated primary prostate cancer, and cultured prostate cancer cells. This inefficient coupling of transcription and mRNA splicing suggests an overall increase in transcription or defect in splicing.
Inefficient splicing in advanced prostate cancer provides a selective advantage through effects on microRNA networks but may render tumors vulnerable to agents that suppress rate-limiting steps in splicing.
Low-grade prostate cancers (Gleason pattern 3, G3) detected on needle biopsies are generally viewed as indolent and suitable for conservative management with only interval repeat biopsies to monitor ...by watchful waiting. Higher grade tumors eventually emerge in 20% to 30% of these cases, but this process may only reflect incomplete sampling on the initial biopsy, such that it remains unknown whether G3 tumors generally progress to higher grades. In this study, we examined a series of adjacent G3 and Gleason pattern 4 (G4) tumors in radical prostatectomy specimens and found that all were concordant for the TMPRSS2:ERG gene fusion. Using hybrid-capture and deep sequencing in four fusion-positive cases, we found that adjacent laser-capture microdissected G3 and G4 tumors had identical TMPRSS2:ERG fusion breakpoints, confirming their clonal origin. Two of these G3 tumors had deletion of a single PTEN gene that was also deleted in the adjacent G4, while the G4 tumors in two cases had additional PTEN losses. These findings establish that a subset of G3 tumors progress to G4 or emerge from a common precursor. Further, they show that G3 tumors that progress to G4 may have molecular features distinguishing them from G3 tumors that do not progress. Thus, determining the spectrum of these genetic or epigenetic features may allow for the identification of G3 tumors on needle biopsies that are truly indolent versus those that have the potential to progress or that may already be associated with a G4 tumor that was not sampled at the initial biopsy, therefore, requiring more aggressive surveillance or intervention.
Prostate cancer is dependent on androgen receptor (AR) activation. Optimal AR antagonism may effectively cytoreduce local disease and suppress or eliminate micrometastases. We evaluated neoadjuvant ...therapy prior to prostatectomy with the potent AR antagonist enzalutamide (enza) either alone or in combination with dutasteride (dut) and leuprolide (enza/dut/luteinizing hormone-releasing hormone analogues LHRHa).
Forty-eight of 52 men with intermediate or high-risk localized prostate cancer proceeded to prostatectomy after neoadjuvant enzalutamide or enza/dut/LHRHa for 6 months. We assessed pathologic complete response (pCR), minimal residual disease (MRD; ≤3 mm maximum diameter of residual disease), residual cancer burden (RCB), and expression of PSA and serum and tissue androgen concentrations. We compared the proportion of patients with pCR in each treatment arm with a historical control rate of 5%, based on previous reports of flutamide with LHRHa.
In the enzalutamide arm, none of the 25 patients achieved pCR or MRD. In the enza/dut/LHRHa arm, one of 23 patients (4.3%) achieved pCR and 3 of 23 (13.0%) achieved MRD. Median RCB was higher in the enzalutamide arm than in the enza/dut/LHRHa arm (0.41 cm
vs. 0.06 cm
, respectively). Tissue testosterone and dihydrotestosterone levels correlated with RCB. No adverse events leading to study drug discontinuation were reported.
Combination therapy with enza/dut/LHRHa resulted in pCR and MRD rates comparable with historical controls. Evidence of continued AR activity in residual tumor suggests that AR signaling may contribute to survival. Strategies to more effectively ablate AR activity are warranted to determine whether more substantial antitumor effects are observed.
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