Validation of metastasis-free survival as a surrogate endpoint for overall survival in localized prostate cancer in the era of docetaxel for castration-resistant prostate cancer.

BACKGROUND: Prior work from the Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) consortium (ICECaP-1) demonstrated that metastasis-free survival (MFS) is a valid surrogate for overall survival (OS) in localized prostate cancer (PCa). This was based on data from patients treated predominantly before 2004, prior to docetaxel being available for the treatment of metastatic castrate-resistant prostate cancer (mCRPC). We sought to validate surrogacy in a more contemporary era (ICECaP-2) with greater availability of docetaxel and other systemic therapies for mCRPC. PATIENTS AND METHODS: Eligible trials for ICECaP-2 were those providing individual patient data (IPD) after publication of ICECaP-1 and evaluating adjuvant/salvage therapy for localized PCa, and which collected MFS and OS data. MFS was defined as distant metastases or death from any cause, and OS was defined as death from any cause. Surrogacy was evaluated using a meta-analytic two-stage validation model, with an R2 ≥ 0.7 defined a priori as clinically relevant. RESULTS: A total of 15 164 IPD from 14 trials were included in ICECaP-2, with 70% of patients treated after 2004. The median follow-up was 8.3 years and the median postmetastasis survival was 3.1 years in ICECaP-2, compared with 1.9 years in ICECaP-1. For surrogacy condition 1, Kendall's tau was 0.92 for MFS with OS at the patient level, and R2 from weighted linear regression (WLR) of 8-year OS on 5-year MFS was 0.73 (95% confidence interval 0.53-0.82) at the trial level. For condition 2, R2 was 0.83 (95% confidence interval 0.64-0.89) from WLR of log[hazard ratio (HR)]-OS on log(HR)-MFS. The surrogate threshold effect on OS was an HR(MFS) of 0.81. CONCLUSIONS: MFS remained a valid surrogate for OS in a more contemporary era, where patients had greater access to docetaxel and other systemic therapies for mCRPC. This supports the use of MFS as the primary outcome measure for ongoing adjuvant trials in localized PCa.

Next generation radiotheranostics promoting precision medicine.

Radiotheranostics is a field of rapid growth with some approved treatments including 131I for thyroid cancer, 223Ra for osseous metastases, 177Lu-DOTATATE for neuroendocrine tumors, and 177Lu-PSMA (prostate-specific membrane antigen) for prostate cancer, and several more under investigation. In this review, we will cover the fundamentals of radiotheranostics, the key clinical studies that have led to current success, future developments with new targets, radionuclides and platforms, challenges with logistics and reimbursement and, lastly, forthcoming considerations regarding dosimetry, identifying the right line of therapy, artificial intelligence and more.

Transcriptional profiling of primary prostate tumor in metastatic hormone-sensitive prostate cancer and association with clinical outcomes: correlative analysis of the E3805 CHAARTED trial.

BACKGROUND: The phase III CHAARTED trial established upfront androgen-deprivation therapy (ADT) plus docetaxel (D) as a standard for metastatic hormone-sensitive prostate cancer (mHSPC) based on meaningful improvement in overall survival (OS). Biological prognostic markers of outcomes and predictors of chemotherapy benefit are undefined. PATIENTS AND METHODS: Whole transcriptomic profiling was performed on primary PC tissue obtained from patients enrolled in CHAARTED prior to systemic therapy. We adopted an a priori analytical plan to test defined RNA signatures and their associations with HSPC clinical phenotypes and outcomes. Multivariable analyses (MVAs) were adjusted for age, Eastern Cooperative Oncology Group status, de novo metastasis presentation, volume of disease, and treatment arm. The primary endpoint was OS; the secondary endpoint was time to castration-resistant PC. RESULTS: The analytic cohort of 160 patients demonstrated marked differences in transcriptional profile compared with localized PC, with a predominance of luminal B (50%) and basal (48%) subtypes, lower androgen receptor activity (AR-A), and high Decipher risk disease. Luminal B subtype was associated with poorer prognosis on ADT alone but benefited significantly from ADT + D [OS: hazard ratio (HR) 0.45; P = 0.007], in contrast to basal subtype which showed no OS benefit (HR 0.85; P = 0.58), even in those with high-volume disease. Higher Decipher risk and lower AR-A were significantly associated with poorer OS in MVA. In addition, higher Decipher risk showed greater improvements in OS with ADT + D (HR 0.41; P = 0.015). CONCLUSION: This study demonstrates the utility of transcriptomic subtyping to guide prognostication in mHSPC and potential selection of patients for chemohormonal therapy, and provides proof of concept for the possibility of biomarker-guided selection of established combination therapies in mHSPC.

Targeted therapy for advanced salivary gland carcinoma based on molecular profiling: results from MyPathway, a phase IIa multiple basket study.

BACKGROUND: Systemic therapy options for salivary cancers are limited. MyPathway (NCT02091141), a phase IIa study, evaluates targeted therapies in non-indicated tumor types with actionable molecular alterations. Here, we present the efficacy and safety results for a subgroup of MyPathway patients with advanced salivary gland cancer (SGC) matched to targeted therapies based on tumor molecular characteristics. PATIENTS AND METHODS: MyPathway is an ongoing, multiple basket, open-label, non-randomized, multi-center study. Patients with advanced SGC received pertuzumab + trastuzumab (HER2 alteration), vismodegib (PTCH-1/SMO mutation), vemurafenib (BRAF V600 mutation), or atezolizumab [high tumor mutational burden (TMB)]. The primary endpoint is the objective response rate (ORR). RESULTS: As of January 15, 2018, 19 patients with SGC were enrolled and treated in MyPathway (15 with HER2 amplification and/or overexpression and one each with a HER2 mutation without amplification or overexpression, PTCH-1 mutation, BRAF mutation, and high TMB). In the 15 patients with HER2 amplification/overexpression (with or without mutations) who were treated with pertuzumab + trastuzumab, 9 had an objective response (1 complete response, 8 partial responses) for an ORR of 60% (9.2 months median response duration). The clinical benefit rate (defined by patients with objective responses or stable disease >4 months) was 67% (10/15), median progression-free survival (PFS) was 8.6 months, and median overall survival was 20.4 months. Stable disease was observed in the patient with a HER2 mutation (pertuzumab + trastuzumab, n = 1/1, PFS 11.0 months), and partial responses in patients with the PTCH-1 mutation (vismodegib, n = 1/1, PFS 14.3 months), BRAF mutation (vemurafenib, n = 1/1, PFS 18.5 months), and high TMB (atezolizumab, n = 1/1, PFS 5.5+ months). No unexpected toxicity occurred. CONCLUSIONS: Overall, 12 of 19 patients (63%) with advanced SGC, treated with chemotherapy-free regimens matched to specific molecular alterations, experienced an objective response. Data from MyPathway suggest that matched targeted therapy for SGC has promising efficacy, supporting molecular profiling in treatment determination.

What is the optimal systemic treatment of men with metastatic, hormone-naive prostate cancer? A STOPCAP systematic review and network meta-analysis.

Background: Our prior Systemic Treatment Options for Cancer of the Prostate systematic reviews showed improved survival for men with metastatic hormone-naive prostate cancer when abiraterone acetate plus prednisolone/prednisone (AAP) or docetaxel (Doc), but not zoledronic acid (ZA), were added to androgen-deprivation therapy (ADT). Trial evidence also suggests a benefit of combining celecoxib (Cel) with ZA and ADT. To establish the optimal treatments, a network meta-analysis (NMA) was carried out based on aggregate data (AD) from all available studies. Methods: Overall survival (OS) and failure-free survival data from completed Systemic Treatment Options for Cancer of the Prostate reviews of Doc, ZA and AAP and from recent trials of ZA and Cel contributed to this comprehensive AD-NMA. The primary outcome was OS. Correlations between treatment comparisons within one multi-arm, multi-stage trial were estimated from control-arm event counts. Network consistency and a common heterogeneity variance were assumed. Results: We identified 10 completed trials which had closed to recruitment, and one trial in which recruitment was ongoing, as eligible for inclusion. Results are based on six trials including 6204 men (97% of men randomised in all completed trials). Network estimates of effects on OS were consistent with reported comparisons with ADT alone for AAP [hazard ration (HR) = 0.61, 95% confidence interval (CI) 0.53-0.71], Doc (HR = 0.77, 95% CI 0.68-0.87), ZA + Cel (HR = 0.78, 95% CI 0.62-0.97), ZA + Doc (HR = 0.79, 95% CI 0.66-0.94), Cel (HR = 0.94 95% CI 0.75-1.17) and ZA (HR = 0.90 95% CI 0.79-1.03). The effect of ZA + Cel is consistent with the additive effects of the individual treatments. Results suggest that AAP has the highest probability of being the most effective treatment both for OS (94% probability) and failure-free survival (100% probability). Doc was the second-best treatment of OS (35% probability). Conclusions: Uniquely, we have included all available results and appropriately accounted for inclusion of multi-arm, multi-stage trials in this AD-NMA. Our results support the use of AAP or Doc with ADT in men with metastatic hormone-naive prostate cancer. AAP appears to be the most effective treatment, but it is not clear to what extent and whether this is due to a true increased benefit with AAP or the variable features of the individual trials. To fully account for patient variability across trials, changes in prognosis or treatment effects over time and the potential impact of treatment on progression, a network meta-analysis based on individual participant data is in development.

Racial disparities in prostate cancer outcome among prostate-specific antigen screening eligible populations in the United States.

Background: In 2012, the United States Preventive Services Task Force (USPSTF) recommended against prostate-specific antigen (PSA) screening, despite evidence that Black men are at a higher risk of prostate cancer-specific mortality (PCSM). We evaluated whether Black men of potentially screening-eligible age (55-69 years) are at a disproportionally high risk of poor outcomes. Patients and methods: The SEER database was used to study 390 259 men diagnosed with prostate cancer in the United States between 2004 and 2011. Multivariable logistic regression modeled the association between Black race and stage of presentation, while Fine-Gray competing risks regression modeled the association between Black race and PCSM, both as a function of screening eligibility (age 55-69 years versus not). Results: Black men were more likely to present with metastatic disease (adjusted odds ratio [AOR] 1.65; 1.58-1.72; P < 0.001) and were at a higher risk of PCSM (adjusted hazard ratio [AHR] 1.36; 1.27-1.46; P < 0.001) compared to non-Black men. There were significant interactions between race and PSA-screening eligibility such that Black patients experienced more disproportionate rates of metastatic disease (AOR 1.76; 1.65-1.87 versus 1.55; 1.47-1.65; Pinteraction < 0.001) and PCSM (AHR 1.53; 1.37-1.70 versus 1.25; 1.14-1.37; Pinteraction = 0.01) in the potentially PSA-screening eligible group than in the group not eligible for screening. Conclusions: Racial disparities in prostate cancer outcome among Black men are significantly worse in PSA-screening eligible populations. These results raise the possibility that Black men could be disproportionately impacted by recommendations to end PSA screening in the United States and suggest that Black race should be included in the updated USPSTF PSA screening guidelines.

Phase I study of every 2- or 3-week dosing of ramucirumab, a human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2 in patients with advanced solid tumors.

BACKGROUND: Ramucirumab is a fully human immunoglobulin G1 monoclonal antibody receptor antagonist designed to block the ligand-binding site of vascular endothelial growth factor receptor-2 (VEGFR-2). An initial phase I study evaluated ramucirumab administered weekly in advanced cancer patients. This phase I study of ramucirumab [administered every 2 or 3 weeks (Q2W or Q3W)] examined safety, maximum tolerated dose, pharmacokinetics, immunogenicity, antitumor activity, and pharmacodynamics. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of ramucirumab i.v. over 1 h. Blood was sampled for pharmacokinetics studies throughout treatment; levels of circulating vascular endothelial growth factor-A (VEGF-A) and soluble VEGF receptors (R)-1 and -2 were assessed. RESULTS: Twenty-five patients were treated with ramucirumab: 13 with 6, 8, or 10 mg/kg Q2W, and 12 with 15 or 20 mg/kg Q3W. The median treatment duration was 12 weeks (range 2-81). No dose-limiting toxicities were observed. The most frequently reported adverse events (AEs) included proteinuria and hypertension (n = 6 each), and diarrhea, fatigue and headache (n = 4 each). Treatment-related grade 3/4 AEs were: two grade 3 hypertension (10 and 20 mg/kg), one each grade 3 vomiting, fatigue (20 mg/kg), atrial flutter (15 mg/kg), and one each grade 4 duodenal ulcer hemorrhage (6 mg/kg) and grade 4 pneumothorax (20 mg/kg). Pharmacokinetic analysis revealed low clearance and half-life of ∼110-160 h. Analysis of serum biomarkers indicated considerable patient-to-patient variability, but trends toward elevated VEGF-A and a transient decline in soluble VEGFR-2. Fifteen patients (60%) had best response of stable disease, with a median duration of 13 months (range 2-18 months) in tumor types including colorectal, renal, liver, and neuroendocrine cancers. CONCLUSION: Ramucirumab was well tolerated. Study results led to recommended phase II doses of 8 mg/kg Q2W and 10 mg/kg Q3W. Prolonged stable disease was observed, suggesting ramucirumab efficacy in various solid tumors. CLINICALTRIALSGOV: NCT00786383.

A refined risk stratification scheme for clinical stage 1 NSGCT based on evaluation of both embryonal predominance and lymphovascular invasion.

BACKGROUND: Active surveillance is an increasingly accepted approach for managing patients with germ-cell tumors (GCTs) after an orchiectomy. Here we investigate a time-to-relapse stratification scheme for clinical stage 1 (CS1) nonseminoma GCT (NSGCT) patients according to factors associated with relapse and identify a group of patients with a lower frequency and longer time-to-relapse who may require an alternative surveillance strategy. PATIENTS AND METHODS: We analyzed 266 CS1 GCT patients from the IRB-approved DFCI GCT database that exclusively underwent surveillance following orchiectomy from 1997 to 2013. We stratified NSGCT patients according to predominance of embryonal carcinoma (EmbP) and lymphovascular invasion (LVI), using a 0, 1, and 2 scoring system. Cox regression and conditional risk analysis were used to compare each NSGCT group to patients in the seminomatous germ-cell tumor (SGCT) category. Median time-to-relapse values were then calculated among those patients who underwent relapse. Relapse-free survival curves were generated using the Kaplan-Meier method. RESULTS: Fifty (37%) NSGCT and 20 (15%) SGCT patients relapsed. The median time-to-relapse was 11.5 versus 6.3 months for the SGCT and NSGCT groups, respectively. For NSGCT patients, relapse rates were higher and median time-to-relapse faster with increasing number of risk factors (RFs). Relapse rates (%) and median time-to-relapse (months) were 25%/8.5 months, 41%/6.8 months and 78%/3.8 months for RF0, RF1 and RF2, respectively. We found a statistically significant difference between SGCT and patients with one or two RFs (P < 0.001) but not between SGCT and NSGCT RF0 (P = 0.108). CONCLUSION: NSGCT patients grouped by a risk score system based on EmbP and LVI yielded three groups with distinct relapse patterns -and patients with neither EmbP nor LVI appear to behave similar to SGCT.

Management of patients with advanced prostate cancer: recommendations of the St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) 2015.

The first St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) Expert Panel identified and reviewed the available evidence for the ten most important areas of controversy in advanced prostate cancer (APC) management. The successful registration of several drugs for castration-resistant prostate cancer and the recent studies of chemo-hormonal therapy in men with castration-naïve prostate cancer have led to considerable uncertainty as to the best treatment choices, sequence of treatment options and appropriate patient selection. Management recommendations based on expert opinion, and not based on a critical review of the available evidence, are presented. The various recommendations carried differing degrees of support, as reflected in the wording of the article text and in the detailed voting results recorded in supplementary Material, available at Annals of Oncology online. Detailed decisions on treatment as always will involve consideration of disease extent and location, prior treatments, host factors, patient preferences as well as logistical and economic constraints. Inclusion of men with APC in clinical trials should be encouraged.

A meta-analysis of patient outcomes with subcentimeter disease after chemotherapy for metastatic non-seminomatous germ cell tumor.

BACKGROUND: Approximately a quarter of men with metastatic non-seminomatous germ cell tumor (NSGCT) have a residual mass, typically in the retroperitoneum, after chemotherapy. The management of small residual masses (≤1 cm) is controversial, with good outcomes seen with either post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND) or surveillance. We sought to review our experience of surveillance and synthesize the cumulative findings with the current literature in the form of a meta-analysis. PATIENTS AND METHODS: We searched PubMed, EMBASE and abstracts from ASCO and AUA to identify relevant, English-language studies for the meta-analysis. The DFCI (Dana Farber Cancer Institute) database was constructed from a database of men undergoing cisplatin-based chemotherapy for metastatic NSGCT. The outcomes of interest were the proportion with necrosis, teratoma or active cancer on histology at PC-RPLND (literature) and the total number of relapses, RP-only relapses and overall survival in men undergoing surveillance (literature and DFCI cohort). RESULTS: Three of 47 men undergoing post-chemotherapy surveillance at our institution relapsed over a median follow-up of 5.4 years. All three were alive at a median of 4.2 years after relapse. On meta-analysis, the pooled estimates of necrosis, teratoma and active cancer in the 588 men who underwent PC-RPLND were 71, 24 and 4%, respectively. Of the combined 455 men who underwent surveillance, the pooled estimate of the relapse rate was 5%, with an RP-only relapse rate of 3%. Of the 15 men who suffered an RP-only relapse on surveillance, two died of disease. CONCLUSION: Surveillance is a reasonable strategy for men with minimal residual RP disease after chemotherapy and avoids an RPLND in ∼97% of men who are cured with chemotherapy alone.

Presence of the metabolic syndrome is associated with shorter time to castration-resistant prostate cancer.

BACKGROUND: Metabolic syndrome (MS) is a set of risk factors that includes obesity and insulin resistance and has been implicated in the development of prostate cancer. Its impact on androgen deprivation therapy (ADT) efficacy has not been studied. PATIENTS AND METHODS: Retrospective study of prostate cancer patients seen from 1998 to 2005 in a medical oncology clinic. MS, as defined by modified Adult Treatment Panel III criteria, was assessed at the time of initiation of ADT. The study end points were time to prostate-specific antigen (PSA) progression and overall survival (OS) from time of starting ADT. RESULTS: Eighty-two patients treated with ADT and data to assess for presence of MS were identified. Median age in men with and without MS was 70 years and 49% of the patients evaluated met criteria for MS. Median time to PSA progression for patients with MS was 16 versus 36 months without MS (P=0.003). The median OS for patients with MS was 36.5 months after commencing ADT compared with 46.7 months for those patients without MS (P=0.061). CONCLUSIONS: This preliminary data suggest that MS is a risk factor for earlier development of castration-resistant prostate cancer and support the need for a prospective evaluation of this finding.

A phase I study to determine the safety, pharmacokinetics and pharmacodynamics of a dual VEGFR and FGFR inhibitor, brivanib, in patients with advanced or metastatic solid tumors.

BACKGROUND: This study was designed to determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of brivanib in patients with advanced/metastatic solid tumors. PATIENTS AND METHODS: Ninety patients enrolled in this two-part, phase I open-label study of oral brivanib alaninate. The primary objectives of this study were (in part A) dose-limiting toxicity, maximum tolerated dose (MTD) and the lowest biologically active dose level and (in part B) the optimal dose/dose range. The secondary objectives of this study were preliminary evidence of antitumor activity, PK and PD. RESULTS: Across part A (open-label dose escalation and MTD) and part B (open-label dose optimization), 68 patients received brivanib alaninate. Brivanib demonstrated a manageable toxicity profile at doses of 180-800 mg. Most toxic effects were mild. Systemic exposure of the active moiety brivanib increased linearly ≤1000 mg/day. The MTD was 800 mg/day. Forty-four patients were treated at the MTD: 20 with 800 mg continuously, 11 with 800 mg intermittently and 13 with 400 mg b.i.d. doses. Partial responses were confirmed in two patients receiving brivanib ≥600 mg. Dynamic contrast-enhanced magnetic resonance imaging demonstrated statistically significant decreases in parameters reflecting tumor vascularity and permeability after multiple doses in the 800-mg continuous q.d. and 400-mg b.i.d. dose cohorts. CONCLUSION: In patients with advanced/metastatic cancer, brivanib demonstrates promising antiangiogenic and antitumor activity and manageable toxicity at doses ≤800 mg orally q.d., the recommended phase II study dose.

A phase II study of pemetrexed as second-line chemotherapy for the treatment of metastatic castrate-resistant prostate cancer (CRPC); Hoosier Oncology Group GU03-67.

BACKGROUND: No standard therapy exists for post-docetaxel castrate-resistant prostate cancer (CRPC) patients. This trial aimed to determine the safety and efficacy of pemetrexed in post-docetaxel CRPC patients. MATERIALS AND METHODS: CRPC patients with progression after docetaxel (Taxotere) therapy received pemetrexed (500 mg/m2) i.v. every 3 weeks. The primary end point was prostate-specific antigen (PSA) response. A pharmacogenetic analysis of the reduced folate carrier-1 gene (RFC1) G80A polymorphism was also carried out. RESULTS: Forty-nine patients were enrolled: median age 68 years, median baseline PSA 72 ng/ml, and median Karnofsky performance status of 90. Grade 3 or 4 toxicity occurred in 20 (43%) and four patients (8%), respectively. Confirmed >50% PSA decline occurred in four patients (8%), stable PSA lasting at least 12 weeks in 10 patients (20%). A significant relationship was observed between time from prior docetaxel therapy and overall survival. Pharmacogenetic analyses of RFC1 G80A genotype frequencies showed no relationship between genotypes and clinical efficacy. CONCLUSIONS: Pemetrexed treatment of CRPC patients after docetaxel therapy was associated with only modest clinical activity. Further investigation of pemetrexed as a single agent in a nonenriched CRPC population is unlikely to add significant clinical benefit over that seen with traditional second-line chemotherapy agents such as mitoxantrone.

The antiangiogenic property of docetaxel is synergistic with a recombinant humanized monoclonal antibody against vascular endothelial growth factor or 2-methoxyestradiol but antagonized by endothelial growth factors.

Numerous chemotherapeutic agents have been shown to have an inhibitory effect on endothelial cell proliferation and migration, and tubule formation. In this study, we examined the antiangiogenic activity of docetaxel. Docetaxel inhibited endothelial cell proliferation and tubule formation in vitro in a dose-dependent fashion. Docetaxel treatment also inhibited angiogenesis in an in vivo Matrigel plug assay. The endothelial stimulating factors, vascular endothelial cell growth factor (VEGF) and basic fibroblast growth factor are able to protect endothelial cells from the antiangiogenic properties of docetaxel. This protective effect can be overcome by a recombinant humanized monoclonal antibody directed against VEGF in both in vitro and in vivo models. Similarly, combination of docetaxel with the antiangiogenic agent 2-methoxyestradiol also overcomes the protective effect of VEGF in both in vitro and in vivo models. These data suggest that microenvironmental factors (e.g., local release of VEGF and basic fibroblast growth factor) could play a role in decreasing the antiangiogenic effects of docetaxel, whereas agents such as 2- methoxyestradiol and recombinant humanized monoclonal antibody directed against VEGF may reverse this protective effect.

Chemotherapy for metastatic castrate-sensitive prostate cancer.

BACKGROUND: The role of docetaxel chemotherapy in combination with androgen deprivation therapy for metastatic castrate-sensitive prostate cancer is emerging. METHODS: We reviewed the results from the pivotal randomized phase III trials in this area: GETUG15, CHAARTED and STAMPEDE. RESULTS: All three studies demonstrated a benefit in progression-free survival with the use of docetaxel. However, two of the studies demonstrated a clinically meaningful overall survival benefit (CHAARTED and STAMPEDE), whereas the GETUG15 study did not demonstrate a major benefit. CONCLUSIONS: Docetaxel is an important option to consider for men who are fit for chemotherapy with newly diagnosed metastatic prostate cancer commencing androgen deprivation therapy.

Secretory leukocyte protease inhibitor is a survival and proliferation factor for castration-resistant prostate cancer.

Androgen receptor (AR)-mediated gene expression continues to have a critical role in promoting castration-resistant prostate cancer (CRPC) survival and growth even after androgen deprivation therapy. AR cistrome analyses in CRPC cells have identified a large number of AR target genes involved in proliferative and cell cycle-related functions, and hold promise for development of novel therapeutic approaches for CRPC. However, there is little understanding of how these genes function in vivo and what the clinical implications are. We previously reported that secretory leukocyte peptidase inhibitor (SLPI) is regulated by the AR in a ligand-independent manner in CRPC cells and required for CRPC cell proliferation under androgen-deprived conditions. SLPI is a secreted serine protease inhibitor, which is overexpressed in a number of cancers, including lung, breast and ovarian cancer, and involved in tumor progression. However, the oncogenic potential of SLPI in prostate cancer remains unknown. Here we provide the first evidence that SLPI is upregulated in a subset of CRPC cell lines and CRPC patient tumors. In addition, serum SLPI levels are significantly elevated in metastatic CRPC patients compared with hormone naive patients, raising the possibility that this could serve as a biomarker. We demonstrated that SLPI expression has functional significance, as it promotes CRPC cell survival and growth after androgen withdrawal in vivo and in vitro. Last, we demonstrated that the oncogenic effect of SLPI may be due to protection of growth factor progranulin from enzymatic cleavage or suppression of CRPC cell apoptosis independent of anti-protease activity of SLPI. These findings implicate SLPI as a potential biomarker of resistance to AR inhibition and therapeutic target for CRPC treatment.

Redefining the target: chemotherapeutics as antiangiogenics.

Angiogenesis, or new blood vessel formation, is now known to play an important role in both growth and metastasis of many cancers. The central importance of angiogenesis and the understanding of how new blood vessels are formed, has led to novel therapies designed to interrupt this process. Though specific antiangiogenic compounds have only recently entered the clinic, they herald a new era, one in which biology is the basis for therapy. The intense interest in angiogenesis has also lead to a re-examination of the activity of many established cytotoxic agents. Claims of antiangiogenic activity abound, unfortunately, with no common criteria and often little evidence of clinical relevance. What are we to think? Have oncologists unknowingly been administering antiangiogenic therapy all these years? If chemotherapeutics are really antiangiogenics in disguise, why have they failed to cure most solid tumors? Might the hard-learned lessons of chemotherapy resistance pertain to the novel antiangiogenics as well? Though we can offer no certain answers to these important questions, we do offer a framework on which to order the rapidly burgeoning literature. We suggest criteria by which a cytotoxic agent might reasonably be considered to have meaningful antiangiogenic activity. Finally, we describe potential mechanisms of resistance to antiangiogenic chemotherapies-some of which may apply to the pure antiangiogenics currently in development.

Results and outcome of retroperitoneal lymph node dissection for clinical stage I embryonal carcinoma--predominant testis cancer.

PURPOSE: To determine the incidence of metastatic disease and usage of chemotherapy (adjuvant or metastatic) after primary retroperitoneal lymph node dissection (RPLND) in patients with clinical stage (CS) I embryonal carcinoma (EC)-predominant testicular cancer. EC predominance was defined as the presence of EC at a level greater than that of any other histologic diagnosis. PATIENTS AND METHODS: All CS I patients with nonseminomatous germ cell tumors who underwent RPLND at Indiana University from 1990 to 1995 were reviewed retrospectively. RESULTS: Two-year follow-up was available for 292 of 320 patients. EC-predominant disease was found in 125 (42.8%) of 292. Eighty-five (68.0%) of 125 patients with EC-predominant disease had pathologic stage (PS) I, and 18 (21.2%) of this group of 85 relapsed. A significantly lower PS I relapse rate of 3% was found for patients who had non-EC-predominant disease (P <.0001). PS II disease was more frequent in patients with EC predominance, as 40 (32.0%) of 125 had retroperitoneal metastases, compared with 26 (15.6%) of 167 patients with a non-EC-predominant histologic diagnosis (P =.0024). Chemotherapy was administered to 48 (38.4%) of the 125 patients with CS I EC-predominant disease after RPLND. This included 25 CS I patients with PS II disease who received adjuvant chemotherapy in addition to 23 patients who subsequently required chemotherapy for relapse after RPLND. Ten (66. 6%) of 15 PS II EC-predominant patients were cured by surgery alone. Currently, all 125 EC-predominant patients are disease-free. CONCLUSION: Patients with CS I EC-predominant disease are at a relatively high risk for metastatic disease.