Serum 25-OH vitamin D levels and risk of developing prostate cancer in older men.

OBJECTIVE: Multiple studies have shown clear evidence of vitamin D's anti-tumor effects on prostate cancer cells in laboratory experiments, but the evidence has not been consistent in humans. We sought to examine the association between vitamin D and prostate cancer risk in a cohort of older men. METHODS: We conducted a prospective case-cohort study nested within the multicenter Osteoporotic Fractures in Men (MrOS) study. Baseline serum 25-OH vitamin D was measured in a randomly selected sub-cohort of 1,433 men > or = 65 years old without a history of prostate cancer and from all participants with an incident diagnosis of prostate cancer (n = 297). Cox proportional hazards models were used to evaluate the associations between quartiles of total 25-OH vitamin D and incident prostate cancer, as well as Gleason score. RESULTS: In comparison with the lowest quartile of 25-OH vitamin D, the hazard ratio for the highest quartile of 25-OH vitamin D was 1.22 (CI 0.50-1.72, p = 0.25), no trend across quartiles (p = 0.94) or association with Gleason score was observed. Adjustment for covariates did not alter the results. CONCLUSIONS: In this prospective cohort of older men, we found no association between serum 25-OH vitamin D levels and subsequent risk of prostate cancer.

Genetic profiling to determine risk of relapse-free survival in high-risk localized prostate cancer.

PURPOSE: The characterization of actionable mutations in human tumors is a prerequisite for the development of individualized, targeted therapy. We examined the prevalence of potentially therapeutically actionable mutations in patients with high-risk clinically localized prostate cancer. EXPERIMENTAL DESIGN: Forty-eight samples of formalin-fixed paraffin-embedded prostatectomy tissue from a neoadjuvant chemotherapy trial were analyzed. DNA extracted from microdissected tumor was analyzed for 643 common solid tumor mutations in 53 genes using mass spectroscopy-based sequencing. In addition, PTEN loss and erythroblast transformation-specific-related gene (ERC) translocations were examined using immunohistochemistry (IHC) in associated tissue microarrays. Association with relapse during 5 years of follow-up was examined in exploratory analyses of the potential clinical relevance of the genetic alterations. RESULTS: Of the 40 tumors evaluable for mutations, 10% had point mutations in potentially actionable cancer genes. Of the 47 tumors evaluable for IHC, 36% had PTEN loss and 40% had ERG rearrangement. Individual mutations were not frequent enough to determine associations with relapse. Using Kaplan-Meier analysis with a log-rank test, the 16 patients who had PTEN loss had a significantly shorter median relapse-free survival, 19 versus 106 months (P = 0.01). CONCLUSIONS: This study confirms that point mutations in the most common cancer regulatory genes in prostate cancer are rare. However, the PIK3CA/AKT pathway was mutated in 10% of our samples. Although point mutations alone did not have a statistically significant association with relapse, PTEN loss was associated with an increased relapse in high-risk prostate cancer treated with chemotherapy followed by surgery.

Gastrointestinal stromal tumors: molecular markers and genetic subtypes.

Mutation-activated signaling from the KIT and PDGFRA kinases has been successfully targeted in gastrointestinal stromal tumors (GISTs), with subtle differences between the mutations serving to refine prognosis and more precisely tailor therapy. There is a growing understanding of the molecular drivers of GISTs lacking mutations in KIT or PDGFRA, so called wild-type GISTs, further aiding in management decisions. This article provides an overview of all the known molecular subtypes of GIST and provides information about clinical correlates, treatment, and prognosis depending on the subtype.

Management of tyrosine kinase inhibitor-resistant gastrointestinal stromal tumors.

The treatment of gastrointestinal stromal tumors (GISTs) has been a model for targeted cancer therapy. The discovery of driver somatic mutations in the KIT and PDGFRA receptor tyrosine kinases led to a shift of therapy from conventional cytotoxic chemotherapy to inhibitors of these receptors. Targeted molecular therapy of GIST has markedly increased the overall survival of patients with advanced disease. However, the ability of kinase therapy to control metastatic disease is ultimately limited by the ability of these agents to overcome intrinsic or acquired resistance mechanisms. Ongoing basic and clinical research is focusing on identifying new agents to inhibit KIT/PDGFRA kinase activity and/or other novel molecular targets in GIST.

Prostate cancer and vitamin D: what does the evidence really suggest?

The optimal approach to vitamin D supplementation for the average healthy person is debatable. In patients with cancer, the role of vitamin D supplementation, possibly in treatment, is even less clear. Vitamin D is shown to play a role in prostate cancer biology; however, the clinical data have not consistently demonstrated a link. Additional studies are needed to determine if higher doses of vitamin D supplements could benefit selected populations (ie, the elderly or patients with cancer) even if they may not be beneficial for the general population.

Gastrointestinal stromal tumours: origin and molecular oncology.

Gastrointestinal stromal tumours (GISTs) are a paradigm for the development of personalized treatment for cancer patients. The nearly simultaneous discovery of a biomarker that is reflective of their origin and the presence of gain-of-function kinase mutations in these tumours set the stage for more accurate diagnosis and the development of kinase inhibitor therapy. Subsequent studies of genotype and phenotype have led to a molecular classification of GIST and to treatment optimization on the basis of molecular subtype. The study of drug-resistant tumours has advanced our understanding of kinase biology, enabling the development of novel kinase inhibitors. Further improvements in GIST treatment may require targeting GIST stem cell populations and/or additional genomic events.

Prolonged response to early docetaxel in a patient with biochemical relapse after primary therapy for prostate cancer and incomplete response to androgen suppression therapy.

Sensitivity to androgen suppression therapy (AST) is a key determinant of survival in patients with non-localized prostate cancer. While an incomplete response to AST is associated with poor survival, additional therapy is typically withheld until obvious cancer progression. It is not known if the application of additional therapy earlier can have a favorable impact on long-term outcomes. We present the case of a patient with biochemically relapsed prostate cancer treated with early docetaxel after initial incomplete response to AST who now has a prolonged response to therapy.