Testing a multigene signature of prostate cancer death in the Swedish Watchful Waiting Cohort.

Although prostate cancer is a leading cause of cancer death, most men die with and not from their disease, underscoring the urgency to distinguish potentially lethal from indolent prostate cancer. We tested the prognostic value of a previously identified multigene signature of prostate cancer progression to predict cancer-specific death. The Orebro Watchful Waiting Cohort included 172 men with localized prostate cancer of whom 40 died of prostate cancer. We quantified protein expression of the markers in tumor tissue by immunohistochemistry and stratified the cohort by quintiles according to risk classification. We accounted for clinical variables (age, Gleason, nuclear grade, and tumor volume) using Cox regression and calculated receiver operator curves to compare discriminatory ability. The hazard ratio of prostate cancer death increased with increasing risk classification by the multigene model, with a 16-fold greater risk comparing highest-risk versus lowest-risk strata, and predicted outcome independent of clinical factors (P = 0.002). The best discrimination came from combining information from the multigene markers and clinical data, which perfectly classified the lowest-risk stratum where no one developed lethal disease; using the two lowest-risk groups as reference, the hazard ratio (95% confidence interval) was 11.3 (4.0-32.8) for the highest-risk group and difference in mortality at 15 years was 60% (50-70%). The combined model provided greater discriminatory ability (area under the curve = 0.78) than the clinical model alone (area under the curve = 0.71; P = 0.04). Molecular tumor markers can add to clinical variables to help distinguish lethal and indolent prostate cancer and hold promise to guide treatment decisions.     

Nine-gene molecular signature is not associated with prostate cancer death in a watchful waiting cohort

Tumor molecular markers hold promise to distinguish potentially lethal from indolent prostate cancer and to guide treatment choices. A previous study identified a nine-gene molecular signature in tumors associated with prostate-specific antigen relapse after prostatectomy. We examined this molecular model in relation to prostate cancer death among 172 men with initially localized disease. We quantified protein expression of the nine genes in tumors to classify progression risk. Accounting for clinical prognostic factors, the nine-gene model did not provide discrimination to predict lethal and indolent prostate cancer.     

CT and pathologic predictive features of residual mass histologic findings after chemotherapy for nonseminomatous germ cell tumors: can residual malignancy or teratoma be excluded?

Forty-eight patients with disseminated nonseminomatous germ cell tumors were studied retrospectively to determine whether initial pathologic features and pre- and post-chemotherapy computed tomographic (CT) features could be used to exclude malignancy or teratoma in residual masses that were excised after chemotherapy. Neither CT findings (residual mass size, attenuation, and degree of shrinkage during chemotherapy) nor type of primary testicular tumor cell was significantly correlated with malignancy or teratoma versus necrosis in residual masses. No significant correlation was demonstrated between the combined features of (a) the absence of teratoma in a histologic specimen of the primary testicular tumor and (b) greater than 90% shrinkage of masses during chemotherapy and the absence of malignancy or teratoma in residual masses as suggested in the literature. Of nine patients with both of these findings, two had malignancy and two had teratoma. Radiographic and pathologic features cannot be used to reliably exclude malignancy or teratoma in residual abdominal masses after chemotherapy for nonseminomatous testicular cancer.     

Chemotherapy for muscle-infiltrating bladder cancer.

Successful integration of chemotherapy into the management of patients with invasive bladder tumors is critical to improve survival. With currently available treatment programs, only a modest improvement in survival can be anticipated. Thus, the routine use of chemotherapy for all patients with invasive bladder cancers cannot be recommended outside of the protocol setting. Research must focus on improving the proportion of patients who achieve complete remissions to therapy, because only complete responders have the opportunity to enjoy long-term survival. Effective salvage regimens need to be developed, along with a better understanding of the mechanisms of resistance to treatment. Equally important will be the ability to define which cases are destined to metastasize, for whom chemotherapy will be essential, as well as those who are not destined to develop metastatic disease, for whom chemotherapy is unnecessary. The choice of a neoadjuvant versus an adjuvant approach remains controversial. The ability to determine response in vivo, as well as the potential for bladder preservation, remains the primary benefit of neoadjuvant therapy. However, chemotherapy alone cannot replace definitive therapy for most patients, because the complete response proportions to chemotherapy alone remain under 30%. In other cases, postoperative adjuvant therapy may represent a better strategy, with the need for treatment based on pathologic as opposed to clinical grounds. Patients with nodal involvement at the time of surgery would be an appropriate group for whom therapy should be routinely recommended. It must be emphasized, however, that neither the neoadjuvant nor adjuvant approaches have been shown to definitively improve survival. This can only be demonstrated through randomized trials.     

Chemotherapy for metastatic bladder cancer.

Over the past decade, a large amount of information has been acquired regarding the use of chemotherapy for metastatic bladder cancer. Combination regimens including M-VAC and CMV have been developed that generate high response rates; however, the impact of chemotherapy on survival has been modest. The available data would strongly suggest that therapy needs to be improved, and therefore current regimens should not be considered the standards of care as much as the standards of comparison for improved future treatments.     

CML28 is a broadly immunogenic antigen,which is overexpressed in tumor cells

Donor lymphocyte infusion (DLI) reliably induces durable remission in 75-80% of patients with relapsed chronic myelogenous leukemia (CML) after allogeneic hematopoietic stem cell transplantation. To identify immunological targets of the graft-versus-leukemia response (GVL) after DLI, we used CML post-DLI responder sera to screen a CML cDNA expression library. One of the antigens identified in this screen is a M(r) 28,000 protein, termed CML28. CML28 is identical to hRrp46p, a component of the human exosome, a multiprotein complex involved in the 3' processing of RNA. Components of the human exosome include known autoantigens, such as PMScl-100, an autoantibody target in patients with polymyositis, scleroderma, or polymyositis-scleroderma overlap syndrome. Recombinant CML28-GST fusion protein was purified, and used in Western blot and ELISA to demonstrate the development of a high-titer CML28-specific IgG antibody response in a patient with relapsed CML who responded to DLI. Northern blotting demonstrated that CML28 is highly expressed in a variety of hematopoietic and epithelial tumor cell lines, but not in normal hematopoietic tissues or other normal tissue, with the exception of testis. Purified recombinant CML28 was used to generate a CML28-specific murine monoclonal antibody. Western blotting with CML28 monoclonal antibody against whole-cell lysates derived from blood and marrow of normal donors and patients with leukemia revealed high expression of this antigen in tumor but not in normal samples. Because CML28 was highly expressed in epithelial tumor cell lines, anti-CML28 responses were also examined in patients with solid tumors. By ELISA, we found specific serological responses in 10-33% of patients with lung cancer, melanoma, and prostate cancer. Our studies suggest that immunogenicity of CML28 is likely because of overexpression of this antigen in tumor cells. Moreover, given its expression and immunogenicity in a wide variety of malignancies, CML28 merits additional evaluation as a target for antigen-specific immunotherapy.     

Initial decline in hemoglobin during neoadjuvant hormonal therapy predicts for early prostate specific antigen failure following radiation and hormonal therapy for patients with intermediate and high-risk prostate cancer

BACKGROUND: Declines in serum hemoglobin (Hgb) levels occur from the use of androgen suppression therapy (AST) in the treatment of prostate cancer patients. We studied whether time to prostate specific antigen (PSA) failure following external beam radiation therapy (RT) and AST could be predicted by the rate of decline in the Hgb level following the administration of neoadjuvant AST or by the Hgb level at presentation or at the start of RT. METHODS: The study cohort comprised 110 intermediate or high-risk prostate cancer patients who were managed using three-dimensional conformal RT (70 Gy) and 6 months of AST (2 months neoadjuvant, concurrent, and adjuvant). A Cox regression multivariable analysis was performed to evaluate the ability of the rate of decline of the Hgb from baseline to the start of RT, baseline PSA level, Gleason score, percent positive biopsies, and T-category to predict time to PSA failure. RESULTS: A decline in the Hgb level of 1 g/dL or more during the first month of AST was the only significant predictor of time to PSA failure (P = 0.02) on multivariable analysis. The relative risk of PSA failure (95% confidence interval) for patients with a decline in Hgb level during the first month (> or = 1 g/dL vs. < 1 g/dL) was 6.3 (2.4, 8.3) and the 3-year estimate of PSA outcome was 66% versus 82% (P = 0.04), respectively. There were no imbalances in the pretreatment prognostic factors or length of follow-up in each of these groups. CONCLUSION: A decline of 1 g/dL or more in Hgb level during the first month of neoadjuvant AST was a predictor of early PSA failure following RT and AST in intermediate and high-risk prostate cancer patients.     

Rapid rise of serum prostate specific antigen levels after discontinuation of the herbal therapy PC-SPES in patients with advanced prostate carcinoma: report of four cases

BACKGROUND: PC-SPES is an herbal supplement whose mechanisms of action are poorly understood, but may be estrogenic. The objective of the current report is to describe the effects of discontinuing PC-SPES treatment in four patients with androgen-independent prostate carcinoma. METHODS: Patient charts were retrospectively reviewed. A MEDLINE search was performed to investigate whether these effects of PC-SPES had been previously reported. RESULTS: Four men whose metastatic prostate carcinoma progressed despite androgen ablation and subsequent PC-SPES treatment are described. All four patients developed a rapid increase in serum prostate specific antigen (PSA) within one month of stopping PC-SPES, ranging from 345% to 880%. Two patients increased their PSA levels to 1300% and 1400% after 7 weeks. Compared to the rate of rise of PSA levels prior to and during PC-SPES therapy, the rise after stopping this treatment was much higher than expected. Clinical symptoms remained relatively stable despite the serologic changes. CONCLUSIONS: Discontinuing PC-SPES therapy can be associated with a rapid rise in PSA. To the authors' knowledge, this effect has not been reported previously. This effect should be considered in the design of clinical trials as well as in the standard management of androgen-independent prostate carcinoma patients.     

Phase II trial of RAD001 and bicalutamide for castration‐resistant prostate cancer

Study Type – Therapy (cohort) Level of Evidence 2a What's known on the subject? and What does the study add? Despite expanding treatment options for castration‐resistant prostate cancer (CRPC), therapies with long response duration remain intangible due to prostate cancer cells’ natural ability to develop iterative resistance. Androgen receptor (AR) signaling has been shown to play a critical role in CRPC and its expression is regulated by the PI3K‐Akt pathway. Thus inhibition of AR signalling and PI3K‐Akt‐mTOR (a downstream mediator of the PI3K‐Akt pathway) pathway is a logical combination in CRPC and we report a phase II trial of RAD001 and bicalutamide. Our study is the first clinical trial report of an AR inhibitor of PI3K‐Akt‐mTOR. The AR pathway and the PI3K‐Akt‐mTOR pathway are two of the most relevant growth pathway for CRPC. Despite low efficacy results from our trial there will be significant interest in the field for these data (dose, schedule, response, toxicity, trial design) as newer generations of both AR inhibitors and PI3K‐Akt‐mTOR inhibitors are in development and likely will be tested in combination in CRPC.

OBJECTIVES

• ? To determine best overall response and duration of response of RAD001, a selective inhibitor of mammalian target of rapamycin, in combination with bicalutamide in castration‐resistant prostate cancer (CRPC).
• ? To characterize the toxicity profile of RAD001 in combination with bicalutamide in patients with CRPC.

PATIENTS AND METHODS

• ? A phase II study was conducted to explore the efficacy and tolerability of RAD001 (10 mg daily) in combination with bicalutamide (50 mg daily) in men with progressive CRPC.
• ? The primary endpoint was a composite of prostate‐specific antigen (PSA) level and measurable disease response by standard criteria.
• ? This single‐stage trial with a sample size of 38 eligible patients provided 90% power to differentiate a response rate of ≥40% from a response rate of ≤20%, as expected for bicalutamide alone (α= 0.10, power = 0.90).

RESULTS

• ? In total, 36 men were enrolled, with a median (range) age of 68 (60–72) years and median (range) baseline PSA level of 22.2 (8.4–121.3) ng/mL, and 89% had metastatic disease.
• ? There were 31 (86%) patients had previously used bicalutamide for a median duration of 7.4 months.
• ? There were two patients with a confirmed PSA level decline ≥50%.
• ? The median (interquartile range) time to progression was 8.7 (7.9–15.9) weeks.
• ? The most common toxicity was grade 1/2 mucositis, which was observed in 20 (56%) patients.

CONCLUSION

• ? The combination of RAD001 and bicalutamide in men with CRPC was well tolerated but had low activity and failed to achieve the primary endpoint of improved response compared to the results previously achieved for bicalutamide alone in this population.