Changing presentation of prostate cancer in a UK population – 10 year trends in prostate cancer risk profiles in the East of England

Background:

Prostate cancer incidence is rising in the United Kingdom but there is little data on whether the disease profile is changing. To address this, we interrogated a regional cancer registry for temporal changes in presenting disease characteristics.

Methods:

Prostate cancers diagnosed from 2000 to 2010 in the Anglian Cancer Network (n=21 044) were analysed. Risk groups (localised disease) were assigned based on NICE criteria. Age standardised incidence rates (IRs) were compared between 2000–2005 and 2006–2010 and plotted for yearly trends.

Results:

Over the decade, overall IR increased significantly (P<0.00001), whereas metastasis rates fell (P<0.0007). For localised disease, IR across all risk groups also increased but at different rates (P<0.00001). The most striking change was a three-fold increase in intermediate-risk cancers. Increased IR was evident across all PSA and stage ranges but with no upward PSA or stage shift. In contrast, IR of histological diagnosis of low-grade cancers fell over the decade, whereas intermediate and high-grade diagnosis increased significantly (P<0.00001).

Conclusion:

This study suggests evidence of a significant upward migration in intermediate and high-grade histological diagnosis over the decade. This is most likely to be due to a change in histological reporting of diagnostic prostate biopsies. On the basis of this data, increasing proportions of newly diagnosed cancers will be considered eligible for radical treatment, which will have an impact on health resource planning and provision.     

XMRV: a new virus in prostate cancer?

Several recent articles have reported the presence of a gammaretrovirus, termed "XMRV" (xenotropic murine leukemia virus-related virus) in prostate cancers (PCa). If confirmed, this could have enormous implications for the detection, prevention, and treatment of PCa. However, other articles report failure to detect XMRV in PCa. We tested nearly 800 PCa samples, using a combination of real-time PCR and immunohistochemistry (IHC). The PCR reactions were simultaneously monitored for amplification of a single-copy human gene, to confirm the quality of the sample DNA and its suitability for PCR. Controls showed that the PCR assay could detect the XMRV in a single infected cell, even in the presence of a 10,000-fold excess of uninfected human cells. The IHC used 2 rabbit polyclonal antisera, each prepared against a purified murine leukemia virus (MLV) protein. Both antisera always stained XMRV-infected or -transfected cells, but never stained control cells. No evidence for XMRV in PCa was obtained in these experiments. We discuss possible explanations for the discrepancies in the results from different laboratories. It is possible that XMRV is not actually circulating in the human population; even if it is, the data do not seem to support a causal role for this virus in PCa.     

Is there a role for chemotherapy in prostate cancer?

There is evidence from randomised-controlled trials that patients with symptomatic hormone-refractory prostate cancer may experience palliative benefit from chemotherapy with mitoxantrone and prednisone. This treatment is well tolerated, even by elderly patients, although the cumulative dose of mitoxantrone is limited by cardiotoxicity. Treatment with docetaxel or paclitaxel, with or without estramustine, appears to convey higher rates of prostate-specific antigen response in phase II trials, but is more toxic. Large phase III trials comparing docetaxel with mitoxantrone have completed accrual. There is no role for chemotherapy in earlier stages of disease except in the context of a well-designed clinical trial.     

Stromal TGF-β signaling induces AR activation in prostate cancer

AR signaling is essential for the growth and survival of prostate cancer (PCa), including most of the lethal castration-resistant PCa (CRPC). We previously reported that TGF-β signaling in prostate stroma promotes prostate tumor angiogenesis and growth. By using a PCa/stroma co-culture model, here we show that stromal TGF-β signaling induces comprehensive morphology changes of PCa LNCaP cells. Furthermore, it induces AR activation in LNCaP cells in the absence of significant levels of androgen, as evidenced by induction of several AR target genes including PSA, TMPRSS2, and KLK4. SD-208, a TGF-β receptor 1 specific inhibitor, blocks this TGF-β induced biology. Importantly, stromal TGF-β signaling together with DHT induce robust activation of AR. MDV3100 effectively blocks DHT-induced, but not stromal TGF-β signaling induced AR activation in LNCaP cells, indicating that stromal TGF-β signaling induces both ligand-dependent and ligand-independent AR activation in PCa. TGF-β induces the expression of several growth factors and cytokines in prostate stromal cells, including IL-6, and BMP-6. Interestingly, BMP-6 and IL-6 together induces robust AR activation in these co-cultures, and neutralizing antibodies against BMP-6 and IL-6 attenuate this action. Altogether, our study strongly suggests tumor stromal microenvironment induced AR activation as a direct mechanism of CRPC.     

What's new in the treatment of advanced prostate cancer?

Increased insight into the biology of prostate cancer and the emergence of new therapeutic strategies and chemotherapeutic agents has changed approaches in treating patients with advanced prostate cancer. After secondary hormonal manipulations, new approaches include: second-line hormonal therapy, chemotherapy, immunotherapy with granulocyte macrophage-colony stimulating factor (GM-CSF) therapy, dendritic cell therapy, gene vaccination therapy, inhibition and/or blockade of growth factor receptors or growth factor receptor pathways, inhibition of neo-angiogenesis and inhibition of invasion and metastases.     

Pitfalls or promise in prostate cancer immunotherapy-which is winning?

PURPOSE: Immunotherapy with vaccines, cytokines, and monoclonal antibodies against checkpoint molecules has been introduced into the clinical arena. Although all have demonstrated safety in clinical trials in patients with castrate metastatic prostate cancer, no one approach has been able to provide improved overall survival. This article is a review of the current issues and potential resolutions as to how we might go forward in developing and interpreting immunologic trials. DESIGN: Phase I, II, and III trials showed that immunologic tolerance can be abrogated against specific tumor-associated antigens, but the immunologic readouts are suboptimal in determining whether a trial can go forward in its development. RESULTS: Combinatorial approaches appear to be necessary for inducing immunogenicity and antitumor effects. Strategies include irradiated tumor cells lines, costimulatory molecules, or immune checkpoint inhibitors, which are in trials and are under intense scrutiny as to their impact on clinical end points such as time to disease progression and survival. DISCUSSION: Strategies to enhance immunogenicity of vaccines and reassess how to effectively establish interpretable immunologic end points are under development and appear to be successful in affecting how these trials go forward.     

Immunohistochemical labelling for prostate–specific antigen in breast carcinomas

Immunohistochemical detection of prostate–specific antigen (PSA) is an aid in determining the prostatic origin of metastatic cells. However, small amounts of PSA have also been found in non–prostatic tissues and tumors, for example in some breast carcinomas, by highly sensitive immunofluorometric methods, but also by immunohistochemistry. Our aim was to evaluate the prevalence and prognostic value of histologically confirmed PSA immunoreactivity in breast carcinoma.Sections of formalin–fixed, paraffin–embedded samples from 171 breast carcinomas were immunostained for PSA. The staining results were compared with the mitotic activity, tumor size, histological grade, steroid receptors and follow–up data. For analysis the material was divided into subgroups according to the patients' age (pre- and postmenopausal). PSA was found by immunohistochemistry in 54 (32) breast carcinomas. In survival analysis of the whole patient material PSA positivity did not show prognostic value. Among premenopausal patients concomitant estrogen receptor and PSA–negativity proved to be associated with high risk of breast cancer death (RR 6.2), also after adjustment for tumor size, histological grade, and axillary lymph node status. Among postmenopausal patients PSA positivity was associated with progesterone receptor positivity and high differentiation but not with age, nodal status, or mitotic activity. PSA can be detected by immunohistochemistry in a considerable number of breast carcinomas. PSA immunoreactivity alone does not seem to have any value as general prognosticator of breast carcinoma patients. However, concomitant absence of PSA and estrogen receptors was an indicator of unfavourable prognosis among premenopausal patients.     

Advantage of biological over physical optimization in prostate cancer?

The biological effects of an applied dose can be accounted for by using biological objective functions with IMRT. A commonly used concept is the generalized equivalent uniform dose (gEUD), developed by Niemierko. Unlike the equivalent uniform dose (EUD) which is defined for tumor only, the gEUD can be used for both target volume and organs-at-risk (OAR). In this study, the gEUD has been integrated in our in-house inverse treatment planning system DMCO. DMCO is based on an inverse kernel concept and maintains full Monte-Carlo precision. The system applies direct aperture optimization by means of simulated annealing. Thereby DMCO is per se predestined for the optimization of non-quadratic biological objective functions. In this work, the feasibility of gEUD-based optimization with DMCO is investigated and compared to modified physical optimization. A 'pseudo' Pareto study is performed in order to derive the gEUD-parameters 'a' for the volumes-of-interest of a prostate case. The best biological plan is compared to a physically optimized plan, based on dose-volume objectives (DVO). Furthermore, a hybrid objective function (OF) was developed. It consists of both a biological OF for the OARs and a physical OF for the PTV. The plans are compared to another physically optimized plan, which includes additional zero-DVOs in order to further improve OAR-sparing. As a result of the comparisons it turns out, that the biological OF may improve plan quality with regard to the OARs, but at the price of a degradation of the PTV. This disadvantage can be overcome by a hybrid OF, by which the advantages of both biological and physical OF can be combined. With the application of the physical OF with properly set zero-DVOs, a similar or even superior plan quality may be achieved. The physical OFs do not need the time consuming stochastic optimization, which is mandatory in biological optimization and which is included in DMCO. Furthermore, biological evaluation leaves plan quality rather similar compared to physical optimization, but it cares automatically for the target and the OARs.