Ligand-mediated activation of the androgen receptor (AR) is critical for prostate cancer (PCa) survival and proliferation. The failure to completely ablate tissue androgens may limit suppression of ...PCa growth. We evaluated combinations of CYP17A and 5-α-reductase inhibitors for reducing prostate androgen levels, AR signaling, and PCa volumes.
Thirty-five men with intermediate/high-risk clinically localized PCa were randomly assigned to goserelin combined with dutasteride (ZD), bicalutamide and dutasteride (ZBD), or bicalutamide, dutasteride, and ketoconazole (ZBDK) for 3 months before prostatectomy. Controls included patients receiving combined androgen blockade with luteinizing hormone-releasing hormone agonist and bicalutamide. The primary outcome measure was tissue dihydrotestosterone (DHT) concentration.
Prostate DHT levels were substantially lower in all experimental arms (0.02 to 0.04 ng/g v 0.92 ng/g in controls; P < .001). The ZBDK group demonstrated the greatest percentage decline in serum testosterone, androsterone, and dehydroepiandrosterone sulfate (P < .05 for all). Staining for AR and the androgen-regulated genes prostate-specific antigen and TMPRSS2 was strongly suppressed in benign glands and moderately in malignant glands (P < .05 for all). Two patients had pathologic complete response, and nine had ≤ 0.2 cm(3) of residual tumor (defined as a near-complete response), with the largest numbers of complete and near-complete responses in the ZBDK group.
Addition of androgen synthesis inhibitors lowers prostate androgens below that achieved with standard therapy, but significant AR signaling remains. Tissue-based analysis of steroids and AR signaling is critical to informing the search for optimal local and systemic control of high-risk prostate cancer.
A significant proportion of patients with metastatic castration-resistant prostate cancer (mCRPC) harbor mutations in homologous recombination (HR) repair genes, with some of these mutations ...associating with increased tumor susceptibility to poly(ADP-ribose) polymerase (PARP) inhibitors and platinum-based chemotherapy. While mutations in some HR repair genes (e.g., BRCA1/2) have been associated with a more aggressive clinical course, prior studies correlating HR mutational status with treatment response to androgen receptor (AR) signaling inhibitors (ARSIs) or taxane-based chemotherapy have yielded conflicting results.
We conducted a single-center retrospective analysis to assess clinical outcomes to conventional, regulatory-approved therapies in mCRPC patients with somatic (monoallelic and biallelic) and/or germline HR repair mutations compared to patients without alterations as determined by clinical-grade next-generation sequencing assays. The primary endpoint was PSA30/PSA50 response, defined as ≥30%/≥50% prostate-specific antigen (PSA) reduction from baseline. Secondary endpoints of PSA progression-free survival (pPFS) and clinical/radiographic progression-free survival (crPFS) were estimated using Kaplan-Meier methods.
A total of 90 consecutively selected patients were included in this analysis, of which 33 (37%) were identified to have HR repair gene mutations. Age, race, Gleason score, prior surgery, and receipt of prior radiation therapy were comparable between carriers and non-carriers. There was no evidence that PSA30/PSA50 differed by HR gene mutational status. Median pPFS and crPFS ranged 3-14 months across treatment modalities, but there was no evidence either differed by HR gene mutational status (all p>0.05). There was also no difference in outcomes between those with BRCA2 or PALB2 mutations (n = 17) compared to those without HR repair mutations.
HR gene mutational status was associated with comparable clinical outcomes following treatment with ARSIs or taxane-based chemotherapy. Additional prospective studies are needed to confirm these findings.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cancer dormancy refers to the prolonged clinical disease-free time between removal of the primary tumor and recurrence, which is common in prostate cancer (PCa), breast cancer, esophageal cancer, and ...other cancers. PCa disseminated tumor cells (DTC) are detected in both patients with no evidence of disease (NED) and advanced disease (ADV). However, the molecular and cellular nature of DTC is unknown. We performed a first-in-field study of single DTC transcriptomic analyses in cancer patients to identify a molecular signature associated with cancer dormancy. We profiled eighty-five individual EpCAM⁺/CD45⁻ cells from the bone marrow of PCa patients with NED or ADV. We analyzed 44 DTC with high prostate-epithelial signatures, and eliminated 41 cells with high erythroid signatures and low prostate epithelial signatures. DTC were clustered into 3 groups: NED, ADV_1, and ADV_2, in which the ADV_1 group presented a distinct gene expression pattern associated with the p38 stress activated kinase pathway. Additionally, DTC from the NED group were enriched for a tumor dormancy signature associated with head and neck squamous carcinoma and breast cancer. This study provides the first clinical evidence of the p38 pathway as a potential biomarker for early recurrence and an attractive target for therapeutic intervention.
Cabozantinib is an inhibitor of multiple receptor tyrosine kinases, including MET and VEGFR2. In a phase II clinical trial in advanced prostate cancer (PCa), cabozantinib treatment improved bone ...scans in 68% of evaluable patients. Our studies aimed to determine the expression of cabozantinib targets during PCa progression and to evaluate its efficacy in hormone-sensitive and castration-resistant PCa in preclinical models while delineating its effects on tumor and bone. Using immunohistochemistry and tissue microarrays containing normal prostate, primary PCa, and soft tissue and bone metastases, our data show that levels of MET, P-MET, and VEGFR2 are increasing during PCa progression. Our data also show that the expression of cabozantinib targets are particularly pronounced in bone metastases. To evaluate cabozantinib efficacy on PCa growth in the bone environment and in soft tissues we used androgen-sensitive LuCaP 23.1 and castration-resistant C4-2B PCa tumors. In vivo, cabozantinib inhibited the growth of PCa in bone as well as growth of subcutaneous tumors. Furthermore, cabozantinib treatment attenuated the bone response to the tumor and resulted in increased normal bone volume. In summary, the expression pattern of cabozantinib targets in primary and castration-resistant metastatic PCa, and its efficacy in two different models of PCa suggest that this agent has a strong potential for the effective treatment of PCa at different stages of the disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To identify the molecular signature associated with abiraterone acetate (AA) response and mechanisms underlying AA resistance in castration-resistant prostate cancer patient-derived xenografts ...(PDXs).
SCID mice bearing LuCaP 136CR, 77CR, 96CR, and 35CR PDXs were treated with AA. Tumor volume and prostate-specific antigen were monitored, and tumors were harvested 7 days after treatment or at end of study for gene expression and immunohistochemical studies.
Three phenotypic groups were observed based on AA response. An ultraresponsive phenotype was identified in LuCaP 136CR with significant inhibition of tumor progression and increased survival, intermediate responders LuCaP 77CR and LuCaP 96CR with a modest tumor inhibition and survival benefit, and LuCaP 35CR with minimal tumor inhibition and no survival benefit upon AA treatment. We identified a molecular signature of secreted proteins associated with the AA ultraresponsive phenotype. Upon resistance, AA ultraresponder LuCaP 136CR displayed reduced androgen receptor (AR) signaling and sustainably low nuclear glucocorticoid receptor (nGR) localization, accompanied by steroid metabolism alteration and epithelial-mesenchymal transition phenotype enrichment with increased expression of NF-κB-regulated genes; intermediate and minimal responders maintained sustained AR signaling and increased tumoral nGR localization.
We identified a molecular signature of secreted proteins associated with AA ultraresponsiveness and sustained AR/GR signaling upon AA resistance in intermediate or minimal responders. These data will inform development of noninvasive biomarkers predicting AA response and suggest that further inhibition along the AR/GR signaling axis may be effective only in AA-resistant patients who are intermediate or minimal responders. These findings require verification in prospective clinical trials.
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Abstract Objective To project long-term estimates of the number needed to screen (NNS) and the additional number needed to treat (NNT) to prevent one prostate cancer death with prostate-specific ...antigen (PSA) screening in Europe and in the United States. Study Design and Setting A mathematical model of disease-specific deaths in screened and unscreened men given information on overdiagnosis, disease-specific survival in the absence of screening, screening efficacy, and other-cause mortality is presented. A simulation framework is used to incorporate competing causes of death. Results Assuming overdiagnosis and screening efficacy consistent with European Randomized study of Screening for Prostate Cancer (ERSPC) results, we project that, after 25 years, 262 men need to be screened and nine additional men need to be screen detected to prevent one prostate cancer death. Corresponding estimates of the NNS and the additional NNT under a range of overdiagnosis rates that are consistent with U.S. incidence are 186–220 and 2–5. Conclusions Long-term estimates of the NNS and the additional NNT are an order of magnitude lower than the short-term estimates published with the results of the ERSPC trial and may be consistent with cost-effective PSA screening in the general U.S. population.
Study Type – Harm (case series)
Level of Evidence 4
What's known on the subject? and What does the study add?
We know that radiation therapy is associated with an increased risk of second ...malignancies in patients with testicular cancer. However, we know that radiation is being used very commonly in patients with clinical stage I seminoma, despite evidence that it is not required. Moreover, we have now identified which specific second malignancies occur in these patients after radiotherapy.
OBJECTIVES
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To determine the use of adjuvant external beam radiotherapy (EBRT) for patients with clinical stage I testicular seminoma in the USA.
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To quantify the risk of specific second primary malignancies (SPMs) associated with radiation exposure in these patients.
PATIENTS AND METHODS
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We used the Surveillance, Epidemiology and End Results database to identify patients diagnosed with clinical stage I testicular seminoma between 1973 and 2000.
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We evaluated the use of EBRT in these patients.
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We calculated standardized incidence ratios of specific SPMs in these patients.
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We stratified the incidence of SPMs based on age at seminoma diagnosis and time to SPM from initial seminoma diagnosis.
RESULTS
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Adjuvant EBRT use declined from the first decade of the study period to the last decade of the study period (80.6% vs 70.2%).
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Overall, there was a 19% increase in SPMs in patients exposed to EBRT (observed/expected, O/E, 1.51; 95% CI, 1.08–1.31) compared to the general population.
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Specifically, significantly increased risks were observed for thyroid cancer (O/E, 2.32; 95% CI, 1.16–4.16), pancreatic cancer (O/E, 2.38; 95% CI, 1.43–3.72), non‐bladder urothelial malignancies (O/E, 4.27; 95% CI, 1.57–9.29), bladder cancer (O/E, 1.47; 95% CI, 1.01–2.28), all haematological malignancies (O/E, 1.44; 95% CI, 1.08–1.89) and non‐Hodgkin's lymphoma (O/E, 1.77; 95% CI, 1.22–2.48).
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Patients had a persistently elevated risk of SPMs 15 years from the time of initial clinical stage I testicular seminoma diagnosis (O/E, 1.29; 95% CI, 1.10–1.49).
CONCLUSIONS
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We confirmed the increased risk of SPMs after EBRT for seminoma, and we identified the specific types of SPMs that develop.
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The risk of EBRT‐associated SPM persists for years after the initial seminoma diagnosis, and patients should be informed about these long‐term risks.
This was an exploratory analysis of a trial of intermittent androgen deprivation (IAD) in men with biochemical relapse (BR) to establish first cycle characteristics prognostic for progression to ...castration-resistant prostate cancer (CRPC) and death.
Men with BR of prostate cancer after radical prostatectomy (RP) or radiation (RT) were treated with androgen deprivation therapy (ADT) comprised of leuprolide and flutamide. After 9 months on treatment, ADT was stopped, and monthly prostate-specific antigen (PSA) levels were observed during the off-treatment interval. When the PSA reached a threshold value (1 ng/mL for RP, 4 ng/mL for RT), ADT was resumed in a new cycle. Patients were treated intermittently in this manner until CRPC, which was defined as > or = two consecutive increasing PSA values while on ADT with castrate testosterone levels.
Seventy-two of 100 patients enrolled onto the study met criteria for this analysis. The duration of the first off-treatment interval (< or = v > 40 weeks) was associated with shorter time to CRPC (hazard ratio = 2.9; 95% CI, 1.1 to 7.7; P = .03) and death (hazard ratio = 3.8; 95% CI, 1.1 to 13.6; P = .04) after adjusting for age, stage, grade, and PSA at diagnosis.
In patients who completed the first cycle of IAD, a duration of the first off-treatment interval of < or = 40 weeks defines a subset of patients at higher risk of CRPC and death. Conversely, patients with an off-treatment interval of more than 40 weeks have a significantly better long-term prognosis.
Disease-specific mortality is a consensus endpoint in cancer screening trials. New liquid biopsy-based screening tests, including multi-cancer early detection (MCED) tests, are creating a need to ...reduce the typically lengthy screening trial process. Endpoints based on the reduction in late-stage disease (stage shift) have been proposed but it is unclear how well they predict the impact of screening on disease-specific mortality across a variety of cancers potentially detectable by MCED tests.
We develop a mathematical formulation relating the reduction in late-stage cancer to the expected reduction in disease-specific mortality if cases diagnosed early via screening receive a corresponding shift in mortality. We investigate the similarity between the expected mortality reduction and the observed mortality reduction in published trials of screening for breast, lung, ovarian, and prostate cancer.
The expected mortality reduction for a given stage shift varies significantly depending on cancer- and stage-specific survival distributions, with some cancer types showing little possibility for mortality improvement even under substantial stage shift. The expected mortality reduction fails to consistently match the mortality outcomes of published trials.
In MCED, any mortality benefit is likely to vary substantially across target cancers. Stage shift does not appear to be a reliable basis for inference about mortality reduction across cancers potentially detectable by MCED tests.
Stage shift may be an appealing endpoint for evaluation of cancer screening tests but it appears to be an unreliable predictor of mortality benefit; furthermore, the same stage shift can mean different things for different cancers.
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