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UROLOGY Key advances ■ Abiraterone acetate can now be considered standard of care for patients with CRPC who progress on docetaxel 1 ■ Dual blockade of the PI3K–AKT pathway and the androgen receptor has emerged as an important potential strategy for reversing castration resistance 5 ■ Preclinical validation of targeting of PARP in ETS-positive cancers introduces a potential new biologically rational approach for treating advanced prostate cancer 7 ■ Denosumab is superior to zoledronic acid in delaying skeletal-related events in men with bone metastasis 9 ■ Radium 223 chloride improves survival in patients with advanced CRPC and symptomatic bone metastases 10 owing to ETS gene rearrangements has been directly implicated in tumor invasion and metastasis in prostate cancer cell lines; therefore, the downregulation of these proteins could help explain the antitumor activity of therapeutics that disrupt AR signaling in nonselected patients. Accordingly, it has been suggested that direct targeting of ETS proteins could avoid the toxicity and AR-related drug resistance of hormone therapies. In a study published this year, Brenner et al. 7 screened for proteins that interact with ERG. They found that trans cription regulated by both ERG and ETV1 was mediated by a protein complex comprising PARP1 (poly ADP-ribose polymerase 1) and DNAPKcs (DNA-dependent protein kinase, catalytic subunit), and that disruption of this complex using PARP1 inhibitors suppressed growth of ETS-driven cancers. Moreover, it has also been hypothesized that some sporadic prostate cancers (possibly those involving loss of PTEN) contain DNA repair defects, so PARP1 inhibition could function as an effective therapy either directly via synthetic lethality or indirectly through inhibition of the PARP1–ETS complex. 8 Studies of PARP inhibitors, both alone and in combination with AR-targeting drugs, are now planned. Targeting of bone metastases has long been a priority in CRPC, because of both its frequent occurrence and associated morbidity. The phase III double-blind study of denosumab, a humanized monoclonal antibody against receptor activator of nuclear factor κB ligand (RANKL; a stimulator of osteoclastic bone resorption) versus zoledronic acid was published earlier this year. 9 Although denosumab treatment resulted in a 3.6-month advantage in the composite end point of time to a skeletal-related event (SRE), there was no alteration in overall survival or disease progression. The clinically important adverse event of jaw osteonecrosis was rare, occurring in 22 patients in the denosumab group and 12 men who received zoledronate. These results suggest that denosumab is more effective at delaying SREs than the current standard. Denosumab also offers advantages in terms of its subcutaneous administration and a lesser requirement for renal monitoring; however, cost may limit its widespread use. The potential survival benefit of effective bone targeting was proven in the recently presented phase III ALSYMPCA trial, testing the intravenously delivered alphaemitter radium 223 chloride, which incorporates in place of calcium in replicating bone causing double-strand DNA damage in adjacent cells. ALSYMPCA compared radium 223 chloride with best supportive care in men with symptomatic bone-only meta stases. 10 The trial was unblinded after the preplanned interim analysis met efficacy criteria, demonstrating a 2.8-month improvement in the primary survival end point in the radium 223 chloride group (HR 0.695; P = 0.00185). Secondary efficacy end points of time to SRE, time to PSA progression, and extent and duration of alkaline phosphatase response also favored the experimental arm. The rate of hemato logical toxicity was low, but there was an increased rate of grade 1–2 diarrhea observed in patients who received active treatment. Radium 223 chloride could therefore prove to be a highly effective treatment with low morbid ity for men with bone metastases. In summary, significant milestones in prostate cancer research in 2011 included announcement of the results of two positive phase III trials (ALSYMPCA and AFFIRM); granting of marketing approval for abiraterone acetate by the FDA and the EMA; and approval of cabazitaxel, already approved by the FDA in 2010, by the EMA. Furthermore, increased use of the autologous vaccine therapy sipuleucel-T for the treatment of predominantly chemotherapy-naive patients was reported in the USA. Over the next 12 months physicians could therefore have at their disposal five new agents (abiraterone acetate, MDV3100, cabazitaxel, sipuleucel-T and radium 223 chloride) in addition to docetaxel that prolong the life of patients with CRPC, and a second bone-modulating agent in addition to bisphosphonates (denosumab). Additionally, an unprecedented number of clinical trials are currently accruing patients with prostate cancer to test promising novel therapies. The therapeutic landscape of CRPC has certainly been redefined over the past 2 years. It is now anticipated that significant further advances will require biologically rational targeting of mol ecularly defined subgroups. Section of Medicine, The Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, UK (C. Pezaro, G. Attard). Correspondence to: G. Attard gerhardt.attard@icr.ac.uk Competing interests G. Attard declares associations with the following companies/organizations: AstraZeneca, The Institute of Cancer Research, Ipsen, Janssen-Cilag and Sanofi-Aventis. See the article online for full details of the relationships. C. Pezaro declares no competing interests. 1. de Bono, J. S. et al. Abiraterone and increased survival in metastatic prostate cancer. N. Engl. J. Med. 364, 1995–2005 (2011). 2. Attard, G. & de Bono, J. S. Translating scientific advancement into clinical benefit for castrationresistant prostate cancer patients. Clin. Cancer Res. 17, 3867–3675 (2011). 3. Scher, H. I. et al. Evaluation of circulating tumor cell enumeration as an efficacy response biomarker of overall survival in metastatic castration-resistant prostate cancer (mCRPC): Planned final analysis of COU-AA-301, a randomized, double-blind, placebo-controlled, phase III study of abiraterone acetate plus lowdose prednisone post docetaxel [abstract]. J. Clin. Oncol. 29, LBA4517 (2011). 4. Mulholland, D. J. et al. Cell autonomous role of PTEN in regulating castration-resistant prostate cancer growth. Cancer Cell 19, 792–804 (2011). 5. Carver, B. S. et al. Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell 19, 575–586 (2011). 6. Wang, Y. et al. Differential regulation of PTEN expression by androgen receptor in prostate and breast cancers. Oncogene 30, 4327–4338 (2011). 7. Brenner, J. C. et al. Mechanistic rationale for inhibition of poly(ADP-ribose) polymerase in ETS gene fusion-positive prostate cancer. Cancer Cell 19, 664–678 (2011). 8. de Bono, J., Sandhu, S. & Attard, G. Beyond hormone therapy for prostate cancer with PARP inhibitors. Cancer Cell 19, 573–574 (2011). 9. Fizazi, K. et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 377, 813–822 (2011). 10. Parker, C. et al. Overall survival benefit of radium-223 chloride (Alpharadan) in the treatment of patients with symptomatic bone metastasis in castration-resistant prostate cancer: a phase III randomised trial (ALSYMPCA) [abstract LBA1]. Presented at the 16 th ECCO–36 th ESMO Annual Congress. S78 | JANUARY 2012 www.nature.com/reviews
BLADDER CANCER IN 2011 The dawn of personalized medicine Thomas W. Flaig and Dan Theodorescu Long awaited data from the clinical investigation of bladder cancer in both the neoadjuvant and adjuvant settings were released in 2011, setting the stage for the next generation of work in this area. The findings of a number of studies provide the first steps towards a personalized approach to this disease. Flaig, T. W. & Theodorescu, D. Nat. Rev. Urol. 9, 65–66 (2012); published online 20 December 2011; doi:10.1038/nrurol.2011.220 2011 was a year of progress in the field of bladder cancer. Efforts to set the context for more definitive, practice-changing studies of targeted agents in bladder cancer were reported. Updated analysis of a large European phase III trial of neoadjuvant chemo therapy confirmed a significant survival advantage, and mutations that define potential drivers of disease, as well as a gene signature that predicts lymph node involvement before cystectomy, are now available. Taken together, these advances make signifi cant strides in our understanding of bladder cancer and begin to pour the founda tion for a more personalized approach to the assessment and treatment of affected patients. Currently, no targeted therapies are utilized in the routine clinical care of advanced bladder cancer, and this is largely due to lack of study rather than negative results. Two notable studies published in 2011 addressed this dearth of evidence. The importance of angiogenesis in oncogenesis is widely accepted and several antiangiogenic agents have been approved for cancer treatment in recent years. Preclinical evidence indicates that the vascular end othelial growth factor (VEGF) axis is important in urothelial carcinoma, but there has been little clinical investigation of vascular inhibition in patients with urothelial cancer. This year, the Hoosier Oncology Group published a single-arm, phase II study of a 21-day cisplatin– gemcitabine regimen for advanced urothelial carcinoma with addition of the VEGF-directed antibody bevacizumab, in 43 patients. 1 The overall radiographic response rate was 72% (19% were complete responses), with a median overall survival of 19.1 months. Both of these outcomes are encouraging and suggest improvement over historical series, in which overall survival has ranged from 14 to 18 months. Pulmonary embolism or deep vein thrombosis was observed in 21% of the study cohort, prompting a dose reduction of gemcitabine midway through the trial. The Cancer and Leukemia Group B is sponsoring a randomized, phase III study of this regimen in patients with advanced uro thelial carcinoma (Clinical trials.gov identifier: NCT00942331). Adding to our insight of targeted therapy, a new understanding of the mechanism of pulmonary metastasis in bladder cancer was described in 2011. Endothelin-1 (ET-1) is a vasoconstrictor, expression levels of which correlate positively with muscle invasion and negatively with bladder cancer- specific survival. In new preclinical findings, ET-1 and its receptor were determined to be neces sary for lung metastasis in bladder cancer, and this process was shown to be dependent on macrophage activity in the lung. 2 Importantly, pharmacologic inhibition of the ET-1 axis, using orally bioavailable ET-1 receptor inhibitors, prevented the development of lung metastases, but had little effect on established primary or metastatic tumors. Attempting to translate these findings into a clinical context suggests that the use of ET-1 receptor inhibitors will be most efficacious in the adjuvant setting, not in the metastatic setting. This information may guide the future development of ET-1 inhibitors for bladder cancer, given their availability and tolerability for chronic use. An important update to the large European phase III neoadjuvant chemotherapy trial was reported in 2011. 3 This trial included patients with T2 grade 3, T3 or T4a bladder cancer (N0 M0) planning to undergo radical cystectomy or definitive radiation therapy. A total of 976 patients were randomized to either three cycles of a 21-day cisplatin, methotrexate and vinblastine (CMV) chemotherapy regimen or no chemotherapy before undergoing cyst ectomy or radiation therapy. The initial reports of this study in 1999 revealed a trend toward chemotherapy benefit that did not reach significance. In the © Orlando Florin Rosu | Dreamstime.com UROLOGY updated report, there was a 16% reduction in the risk of death and an absolute increase in the 10-year survival (from 30% to 36%) with CMV chemotherapy. Of note, the reduction in the risk of death was 26% in patients treated with cyst ectomy, which is compar able to that reported in the neo adjuvant findings with metho trexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy reported by SWOG. 4 Importantly, there is now evidence of a survival advantage with the use of neoadjuvant chemotherapy in two randomized, phase III studies, so a discussion of neo adjuvant chemotherapy should take place in all fit patients with muscle- invasive disease preparing for definitive local bladder cancer therapy. Despite these positive findings, which are based on pathological risk stratification, it is clear that the majority of patients treated with neoadjuvant chemotherapy do not benefit. A robust prognostic test is needed that would facilitate the use of chemotherapy in those at highest risk of recurrence, with a predictive test to select the therapy most likely to elicit a response in each patient. We did see some progress in the search for better prognostic markers for bladder cancer in 2011. In one new study, gene expression was assessed in three separate cystectomy cohorts and evaluated in the context of pathologic lymph node status at the time of surgery. 5 Two cohorts (including 90 and 66 patients) were used as training sets and a 20-gene signature was developed, which was validated in a larger group (n = 185). Patients in the valida tion cohort were prospectively collected in an earlier clinical trial and analyzed retrospectively. The 20-gene expression model yielded an RR for the discovery of lymph node metastases of 1.74 in the desig nated ‘high-risk’ group compared to an RR of 0.70 in ‘low-risk’ patients, and was independent of stage and lymphovascular KEY ADVANCES IN MEDICINE JANUARY 2012 | S79
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Cover image: Hippocrates of Cos ref
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CARDIOLOGY ACUTE CORONARY SYNDROMES
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5. Alexander, J. H. et al. Apixaban
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HYPERTENSION IN 2011 New insights
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malignancy and, until recently, doc
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in CLL. Four cases were analyzed an
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of patients. 1,2 The phase III BRIM
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metastasis has provided a new speci
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ENDOCRINOLOGY THYROID DISEASE IN PR
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gene that encodes steroid 11β-hydr
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using the Rotterdam cri teria (two
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