The androgen-receptor isoform encoded by splice variant 7 lacks the ligand-binding domain, which is the target of enzalutamide and abiraterone, but remains constitutively active as a transcription ...factor. We hypothesized that detection of androgen-receptor splice variant 7 messenger RNA (AR-V7) in circulating tumor cells from men with advanced prostate cancer would be associated with resistance to enzalutamide and abiraterone.
We used a quantitative reverse-transcriptase-polymerase-chain-reaction assay to evaluate AR-V7 in circulating tumor cells from prospectively enrolled patients with metastatic castration-resistant prostate cancer who were initiating treatment with either enzalutamide or abiraterone. We examined associations between AR-V7 status (positive vs. negative) and prostate-specific antigen (PSA) response rates (the primary end point), freedom from PSA progression (PSA progression-free survival), clinical or radiographic progression-free survival, and overall survival.
A total of 31 enzalutamide-treated patients and 31 abiraterone-treated patients were enrolled, of whom 39% and 19%, respectively, had detectable AR-V7 in circulating tumor cells. Among men receiving enzalutamide, AR-V7-positive patients had lower PSA response rates than AR-V7-negative patients (0% vs. 53%, P=0.004) and shorter PSA progression-free survival (median, 1.4 months vs. 6.0 months; P<0.001), clinical or radiographic progression-free survival (median, 2.1 months vs. 6.1 months; P<0.001), and overall survival (median, 5.5 months vs. not reached; P=0.002). Similarly, among men receiving abiraterone, AR-V7-positive patients had lower PSA response rates than AR-V7-negative patients (0% vs. 68%, P=0.004) and shorter PSA progression-free survival (median, 1.3 months vs. not reached; P<0.001), clinical or radiographic progression-free survival (median, 2.3 months vs. not reached; P<0.001), and overall survival (median, 10.6 months vs. not reached, P=0.006). The association between AR-V7 detection and therapeutic resistance was maintained after adjustment for expression of full-length androgen receptor messenger RNA.
Detection of AR-V7 in circulating tumor cells from patients with castration-resistant prostate cancer may be associated with resistance to enzalutamide and abiraterone. These findings require large-scale prospective validation. (Funded by the Prostate Cancer Foundation and others.).
Chronic inflammation promotes the development of several types of solid cancers and might contribute to prostate carcinogenesis. This hypothesis partly originates in the frequent observation of ...inflammatory cells in the prostate microenvironment of adult men. Inflammation is associated with putative prostate cancer precursor lesions, termed proliferative inflammatory atrophy. Inflammation might drive prostate carcinogenesis via oxidative stress and generation of reactive oxygen species that induce mutagenesis. Additionally, inflammatory stress might cause epigenetic alterations that promote neoplastic transformation. Proliferative inflammatory atrophy is enriched for proliferative luminal epithelial cells of intermediate phenotype that might be prone to genomic alterations leading to prostatic intraepithelial neoplasia and prostate cancer. Studies in animals suggest that inflammatory changes in the prostate microenvironment contribute to reprogramming of prostate epithelial cells, a possible step in tumour initiation. Prostatic infection, concurrent with epithelial barrier disruption, might be a key driver of an inflammatory microenvironment; the discovery of a urinary microbiome indicates a potential source of frequent exposure of the prostate to a diverse number of microorganisms. Hence, current evidence suggests that inflammation and atrophy are involved in prostate carcinogenesis and suggests a role for the microbiome in establishing an inflammatory prostate microenvironment that might promote prostate cancer development and progression.
For cancer screening to be successful, it should primarily detect cancers with lethal potential or their precursors early, leading to therapy that reduces mortality and morbidity. Screening ...programmes have been successful for colon and cervical cancers, where subsequent surgical removal of precursor lesions has resulted in a reduction in cancer incidence and mortality. However, many types of cancer exhibit a range of heterogeneous behaviours and variable likelihoods of progression and death. Consequently, screening for some cancers may have minimal impact on mortality and may do more harm than good. Since the implementation of screening tests for certain cancers (for example, breast and prostate cancers), a spike in incidence of in situ and early-stage cancers has been observed, but a link to reduction in cancer-specific mortality has not been as clear. It is difficult to determine how many of these mortality reductions are due to screening and how many are due to improved treatments of tumours. In cancers with lower incidence but high mortality (for example, pancreatic cancer), screening has focused on high-risk populations, but challenges similar to those for general population screening remain, particularly with regard to finding lesions with difficult-to-characterize malignant potential (for example, intraductal papillary mucinous neoplasms). More sensitive screening methods are detecting smaller and smaller lesions, but this has not been accompanied by a comparable reduction in the incidence of invasive cancers. In this Opinion article, we focus on the contribution of screening in general and high-risk populations to overdiagnosis, the effects of overdiagnosis on patients and emerging strategies to reduce overdiagnosis of indolent cancers through an understanding of tumour heterogeneity, the biology of how cancers evolve and progress, the molecular and cellular features of early neoplasia and the dynamics of the interactions of early lesions with their surrounding tissue microenvironment.
Sfanos K S & De Marzo A M (2012) Histopathology 60, 199–215 Prostate cancer and inflammation: the evidence
Chronic inflammation is now known to contribute to several forms of human cancer, with an ...estimated 20% of adult cancers attributable to chronic inflammatory conditions caused by infectious agents, chronic non‐infectious inflammatory diseases and/or other environmental factors. Indeed, chronic inflammation is now regarded as an ‘enabling characteristic’ of human cancer. The aim of this review is to summarize the current literature on the evidence for a role for chronic inflammation in prostate cancer aetiology, with a specific focus on recent advances regarding the following: (i) potential stimuli for prostatic inflammation; (ii) prostate cancer immunobiology; (iii) inflammatory pathways and cytokines in prostate cancer risk and development; (iv) proliferative inflammatory atrophy (PIA) as a risk factor lesion to prostate cancer development; and (v) the role of nutritional or other anti‐inflammatory compounds in reducing prostate cancer risk.
From a clinical, morphological and molecular perspective, prostate cancer is a heterogeneous disease. Primary prostate cancers are often multifocal, having topographically and morphologically ...distinct tumour foci. Sequencing studies have revealed that individual tumour foci can arise as clonally distinct lesions with no shared driver gene alterations. This finding demonstrates that multiple genomically and phenotypically distinct primary prostate cancers can be present in an individual patient. Lethal metastatic prostate cancer seems to arise from a single clone in the primary tumour but can exhibit subclonal heterogeneity at the genomic, epigenetic and phenotypic levels. Collectively, this complex heterogeneous constellation of molecular alterations poses obstacles for the diagnosis and treatment of prostate cancer. However, advances in our understanding of intra-tumoural heterogeneity and the development of novel technologies will allow us to navigate these challenges, refine approaches for translational research and ultimately improve patient care.
Genomic aberrations of the PTEN tumour suppressor gene are among the most common in prostate cancer. Inactivation of PTEN by deletion or mutation is identified in ∼20% of primary prostate tumour ...samples at radical prostatectomy and in as many as 50% of castration-resistant tumours. Loss of phosphatase and tensin homologue (PTEN) function leads to activation of the PI3K-AKT (phosphoinositide 3-kinase-RAC-alpha serine/threonine-protein kinase) pathway and is strongly associated with adverse oncological outcomes, making PTEN a potentially useful genomic marker to distinguish indolent from aggressive disease in patients with clinically localized tumours. At the other end of the disease spectrum, therapeutic compounds targeting nodes in the PI3K-AKT-mTOR (mechanistic target of rapamycin) signalling pathway are being tested in clinical trials for patients with metastatic castration-resistant prostate cancer. Knowledge of PTEN status might be helpful to identify patients who are more likely to benefit from these therapies. To enable the use of PTEN status as a prognostic and predictive biomarker, analytically validated assays have been developed for reliable and reproducible detection of PTEN loss in tumour tissue and in blood liquid biopsies. The use of clinical-grade assays in tumour tissue has shown a robust correlation between loss of PTEN and its protein as well as a strong association between PTEN loss and adverse pathological features and oncological outcomes. In advanced disease, assessing PTEN status in liquid biopsies shows promise in predicting response to targeted therapy. Finally, studies have shown that PTEN might have additional functions that are independent of the PI3K-AKT pathway, including those affecting tumour growth through modulation of the immune response and tumour microenvironment.
Prostate cancer is a major cause of cancer morbidity and mortality. Intra-prostatic inflammation is a risk factor for prostate carcinogenesis, with diet, chemical injury and an altered microbiome ...being causally implicated. Intra-prostatic inflammatory cell recruitment and expansion can ultimately promote DNA double-strand breaks and androgen receptor activation in prostate epithelial cells. The activation of the senescence-associated secretory phenotype fuels further 'inflammatory storms', with free radicals leading to further DNA damage. This drives the overexpression of DNA repair and tumour suppressor genes, rendering these genes susceptible to mutagenic insults, with carcinogenesis accelerated by germline DNA repair gene defects. We provide updates on recent advances in elucidating prostate carcinogenesis and explore novel therapeutic and prevention strategies harnessing these discoveries.
MSH2 Loss in Primary Prostate Cancer Guedes, Liana B; Antonarakis, Emmanuel S; Schweizer, Michael T ...
Clinical cancer research,
11/2017, Letnik:
23, Številka:
22
Journal Article
Recenzirano
Odprti dostop
Inactivation of mismatch repair (MMR) genes may predict sensitivity to immunotherapy in metastatic prostate cancers. We studied primary prostate tumors with MMR defects.
A total of 1,133 primary ...prostatic adenocarcinomas and 43 prostatic small cell carcinomas (NEPC) were screened by MSH2 immunohistochemistry with confirmation by next-generation sequencing (NGS). Microsatellite instability (MSI) was assessed by PCR and NGS (mSINGS).
Of primary adenocarcinomas and NEPC, 1.2% (14/1,176) had MSH2 loss. Overall, 8% (7/91) of adenocarcinomas with primary Gleason pattern 5 (Gleason score 9-10) had MSH2 loss compared with 0.4% (5/1,042) of tumors with any other scores (
< 0.05). Five percent (2/43) of NEPC had MSH2 loss. MSH2 was generally homogenously lost, suggesting it was an early/clonal event. NGS confirmed
loss-of-function alterations in all (12/12) samples, with biallelic inactivation in 83% (10/12) and hypermutation in 83% (10/12). Overall, 61% (8/13) and 58% (7/12) of patients had definite MSI by PCR and mSINGS, respectively. Three patients (25%) had germline mutations in
Tumors with MSH2 loss had a higher density of infiltrating CD8
lymphocytes compared with grade-matched controls without MSH2 loss (390 vs. 76 cells/mm
;
= 0.008), and CD8
density was correlated with mutation burden among cases with MSH2 loss (
= 0.72,
= 0.005). T-cell receptor sequencing on a subset revealed a trend toward higher clonality in cases versus controls.
Loss of MSH2 protein is correlated with
inactivation, hypermutation, and higher tumor-infiltrating lymphocyte density, and appears most common among very high-grade primary tumors, for which routine screening may be warranted if validated in additional cohorts.
.
We leveraged two trials to test the hypothesis of an inflammation-prostate cancer link prospectively in men without indication for biopsy.
Prostate Cancer Prevention Trial (PCPT) participants who had ...an end-of-study biopsy performed per protocol that was negative for cancer and who subsequently enrolled in the Selenium and Vitamin E Cancer Prevention Trial (SELECT) were eligible. We selected all 100 cases and sampled 200 frequency-matched controls and used PCPT end-of-study biopsies as "baseline." Five men with PSA > 4 ng/mL at end-of-study biopsy were excluded. Tissue was located for 92 cases and 193 controls. We visually assessed inflammation in benign tissue. We estimated ORs and 95% confidence intervals (CI) using logistic regression adjusting for age and race.
Mean time between biopsy and diagnosis was 5.9 years. In men previously in the PCPT placebo arm, 78.1% of cases (
= 41) and 68.2% of controls (
= 85) had at least one baseline biopsy core (∼5 evaluated per man) with inflammation. The odds of prostate cancer (
= 41 cases) appeared to increase with increasing mean percentage of tissue area with inflammation, a trend that was statistically significant for Gleason sum <4+3 disease (
= 31 cases; vs. 0%, >0-<1.8% OR = 1.70, 1.8-<5.0% OR = 2.39, ≥5% OR = 3.31,
= 0.047). In men previously in the finasteride arm, prevalence of inflammation did not differ between cases (76.5%;
= 51) and controls (75.0%;
= 108).
Benign tissue inflammation was positively associated with prostate cancer.
This first prospective study of men without biopsy indication supports the hypothesis that inflammation influences prostate cancer development.
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