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High-risk prostate cancer-classification and therapy.

ABSTRACT: Approximately 15% of patients with prostate cancer are diagnosed with high-risk disease. However, the current definitions of high-risk prostate cancer include a heterogeneous group of patients with a range of prognoses. Some have the potential to progress to a lethal phenotype that can be fatal, while others can be cured with treatment of the primary tumour alone. The optimal management of this patient subgroup is evolving. A refined classification scheme is needed to enable the early and accurate identification of high-risk disease so that more-effective treatment paradigms can be developed. We discuss several principles established from clinical trials, and highlight other questions that remain unanswered. This Review critically evaluates the existing literature focused on defining the high-risk population, the management of patients with high-risk prostate cancer, and future directions to optimize care.

SUBMITTER: Chang AJ

PROVIDER: S-EPMC4508854 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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High-risk prostate cancer-classification and therapy.

Chang Albert J AJ Autio Karen A KA Roach Mack M Scher Howard I HI

Nature reviews. Clinical oncology 20140520 6

Approximately 15% of patients with prostate cancer are diagnosed with high-risk disease. However, the current definitions of high-risk prostate cancer include a heterogeneous group of patients with a range of prognoses. Some have the potential to progress to a lethal phenotype that can be fatal, while others can be cured with treatment of the primary tumour alone. The optimal management of this patient subgroup is evolving. A refined classification scheme is needed to enable the early and accura ...[more]

PMID: 24840073

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Project description:Purpose To assess acute gastrointestinal (GI) and genitourinary (GU) toxicities of intensity-modulated proton therapy (IMPT) targeting the prostate/seminal vesicles and pelvic lymph nodes for prostate cancer. Materials and Methods A prospective study (ClinicalTrials.gov: NCT02874014), evaluating moderately hypofractionated IMPT for high-risk or unfavorable intermediate-risk prostate cancer, accrued a target sample size of 56 patients. The prostate/seminal vesicles and pelvic lymph nodes were treated simultaneously with 6750 and 4500 centigray radiobiologic equivalent (cGyRBE), respectively, in 25 daily fractions. All received androgen-deprivation therapy. Acute GI and GU toxicities were prospectively assessed from 7 GI and 9 GU categories of the Common Terminology Criteria for Adverse Events (version 4), at baseline, weekly during radiotherapy, and 3-month after radiotherapy. Fisher exact tests were used for comparisons of categorical data. Results Median age was 75 years. Median follow-up was 25 months. Fifty-five patients were available for acute toxicity assessment. Sixty-two percent and 2%, respectively, experienced acute grade 1 and 2 GI toxicity. Grade 2 GI toxicity was proctitis. Sixty-five percent and 35%, respectively, had acute grade 1 and 2 GU toxicity. The 3 most frequent grade 2 GU toxicities were urinary frequency, urgency, and obstructive symptoms. None had acute grade ≥ 3 GI or GU toxicity. The presence of baseline GI and GU symptoms was associated with a greater likelihood of experiencing acute GI and GU toxicity, respectively. Of 45 patients with baseline GU symptoms, 44% experienced acute grade 2 GU toxicity, compared with only 10% among 10 with no baseline GU symptoms (P = 0.07). Although acute grade 1 and 2 GI and GU toxicities were common during radiotherapy, most resolved at 3 months after radiotherapy. Conclusion A moderately hypofractionated IMPT targeting the prostate/seminal vesicles and regional pelvic lymph nodes was well tolerated with no acute grade ≥ 3 GI or GU toxicity. Patients with baseline GU symptoms had a higher rate of acute grade 2 GU toxicity.

Project description:There remains a large discrepancy between the known genetic contributions to cancer and that which can be explained by genomic variants, both inherited and somatic. Recently, understudied repetitive DNA regions called microsatellites have been identified as genetic risk markers for a number of diseases including various cancers (breast, ovarian and brain). In this study, we demonstrate an integrated process for identifying and further evaluating microsatellite-based risk markers for lung cancer using data from the cancer genome atlas and the 1000 genomes project. Comparing whole-exome germline sequencing data from 488 TCGA lung cancer samples to germline exome data from 390 control samples from the 1000 genomes project, we identified 119 potentially informative microsatellite loci. These loci were found to be able to distinguish between cancer and control samples with sensitivity and specificity ratios over 0.8. Then these loci, supplemented with additional loci from other cancers and controls, were evaluated using a target enrichment kit and sample-multiplexed nextgen sequencing. Thirteen of the 119 risk markers were found to be informative in a well powered study (>0.99 for a 0.95 confidence interval) using high-depth (579x±315) nextgen sequencing of 30 lung cancer and 89 control samples, resulting in sensitivity and specificity ratios of 0.90 and 0.94, respectively. When 8 loci harvested from the bioinformatic analysis of other cancers are added to the classifier, then the sensitivity and specificity rise to 0.93 and 0.97, respectively. Analysis of the genes harboring these loci revealed two genes (ARID1B and REL) and two significantly enriched pathways (chromatin organization and cellular stress response) suggesting that the process of lung carcinogenesis is linked to chromatin remodeling, inflammation, and tumor microenvironment restructuring. We illustrate that high-depth sequencing enables a high-precision microsatellite-based risk classifier analysis approach. This microsatellite-based platform confirms the potential to create clinically actionable diagnostics for lung cancer.

Dataset Information

High-risk prostate cancer-classification and therapy.

Publications

High-risk prostate cancer-classification and therapy.

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