Validation of a prostate cancer polygenic risk score.

BACKGROUND: Genome-wide association studies have identified over 100 single-nucleotide polymorphisms (SNPs) associated with prostate cancer (PrCa), and polygenic risk scores (PRS) based on their combined genotypes have been developed for risk stratification. We aimed to assess the contribution of PRS to PrCa risk in a large multisite study. METHODS: The sample included 1972 PrCa cases and 1919 unaffected controls. Next-generation sequencing was used to assess pathogenic variants in 14 PrCa-susceptibility genes and 72 validated PrCa-associated SNPs. We constructed a population-standardized PRS and tested its association with PrCa using logistic regression adjusted for age and family history of PrCa. RESULTS: The mean age of PrCa cases at diagnosis and age of controls at testing/last clinic visit was 59.5 ± 7.2 and 57.2 ± 13.0 years, respectively. Among 1740 cases with pathology data, 57.4% had Gleason score ≤ 6, while 42.6% had Gleason score ≥ 8. In addition, 39.6% cases and 20.1% controls had a family history of PrCa. The PRS was significantly higher in cases than controls (mean ± SD: 1.42 ± 1.11 vs 1.02 ± 0.76; P < .0001). Compared with men in the 1st quartile of age-adjusted PRS, those in the 2nd, 3rd, and 4th quartile were 1.58 (95% confidence interval [CI]: 1.31-1.90), 2.36 (95% CI: 1.96-2.84), and 3.98 (95% CI: 3.29-4.82) times as likely to have PrCa (all P < .0001). Adjustment for family history yielded similar results. PRS predictive performance was consistent with prior literature (area under the receiver operating curve = 0.64; 95% CI: 0.62-0.66). CONCLUSIONS: These data suggest that a 72-SNP PRS is predictive of PrCa, supporting its potential use in clinical risk assessment.

Skin Toxicity: Clinical Summary of the ONS Guidelines™ for Cancer Treatment-Related Skin Toxicity.

Cancer treatment-related skin toxicities are a frequent and distressing side effect of antineoplastic therapies, especially chemotherapy and targeted therapies. Skin toxicities associated with these therapies can include rashes, hand-foot skin reaction, hand-foot syndrome, and hair loss. These symptoms cause not only physical pain and discomfort but also psychological distress, and they can become a stigma of the patient's cancer diagnosis. Skin toxicities can cause treatment delays and even discontinuation, which affects clinical outcome. The prevention of toxicities and effective, early management can reduce the risk for distress and treatment delays.

STAT: Spinal Cord Compression.

Spinal cord compression involves tumor invasion or extension into the epidural space or pathologically collapsed vertebral bone fragments impinging on the spinal cord.

ONS Guidelines™ for Cancer Treatment-Related Skin Toxicity.

BACKGROUND: Management of cancer treatment-related skin toxicities can minimize treatment disruptions and improve patient well-being. OBJECTIVES: This guideline aims to support patients and clinicians in decisions regarding management of cancer treatment-related skin toxicities. METHODS: A panel developed a guideline for management of cancer treatment-related skin toxicities using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) for certainty of evidence and the National Academies of Sciences, Engineering, and Medicine criteria for trustworthy guidelines. The Cochrane risk-of-bias tool assessed risk of bias. A quantitative or narrative synthesis of the evidence was completed. RESULTS: The panel issued seven conditional recommendations for epidermal growth factor receptor inhibitor rash, hand-foot skin reaction, hand-foot syndrome, and chemotherapy-induced alopecia. The panel suggested strategies for prevention and treatment for all toxicities except hand-foot syndrome, which only has a prevention recommendation. IMPLICATIONS FOR NURSING: Cancer treatment-related skin toxicities can significantly affect quality of life. Incorporation of these interventions into clinical care can improve patient outcomes. SUPPLEMENTARY MATERIAL CAN BE FOUND AT&NBSP;HTTPS: //onf.ons.org/supplementary-material-ons-guidelines-cancer-treatment-related-skin-toxicity.

Rare Germline Pathogenic Mutations of DNA Repair Genes Are Most Strongly Associated with Grade Group 5 Prostate Cancer.

BACKGROUND: Rare germline mutations in several genes, primarily DNA repair genes, have been proposed to predict worse prognosis of prostate cancer (PCa). OBJECTIVE: To compare the frequency of germline pathogenic mutations in commonly assayed PCa genes between high- and low-grade PCa in patients initially presenting with clinically localized disease. DESIGN, SETTING, AND PARTICIPANTS: A retrospective case-case study of 1694 PCa patients who underwent radical prostatectomy at Johns Hopkins Hospital, including 706 patients with high-grade (grade group [GG] 4 and GG5) and 988 patients with low-grade (GG1) disease. Germline DNA was sequenced for 13 candidate PCa genes using a targeted next-generation sequencing assay by Ambry Genetics. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Carrier rates of pathogenic mutations were compared between high- and low-grade PCa patients using the Fisher's exact test. RESULTS AND LIMITATIONS: Overall, the carrier rate of germline pathogenic mutations in the 13 genes was significantly higher in high-grade patients (8.64%) than in low-grade patients (3.54%, p = 9.98 × 10-6). Individually, significantly higher carrier rates for patients with high- versus low-grade PCa were found for three genes: ATM (2.12% and 0.20%, respectively, p = 9.35 × 10-5), BRCA2 (2.55% and 0.20%, respectively, p = 8.99 × 10-6), and MSH2 (0.57% and 0%, respectively, p = 0.03). The mutation carrier rate was significantly higher in patients with GG5 than in patients with GG1 disease for the 13 genes overall (13.07% and 3.54%, respectively, p = 1.27 × 10-9); for the three genes ATM, BRCA2, and MSH2 (7.73% and 0.40%, respectively, p = 3.20 × 10-13); and for the remaining nine DNA repair genes (5.07% and 2.43%, respectively, p = 0.02). CONCLUSIONS: In men undergoing treatment for clinically localized disease, pathogenic mutations in 13 commonly assayed genes, especially ATM, BRCA2, and MSH2, are most strongly associated with GG5 PCa. These findings emphasize the importance of genetic testing in men with high-grade PCa, particularly GG5 disease, to inform both treatment decisions and familial risk assessment. PATIENT SUMMARY: Prostate cancer in men with inherited mutations in 13 commonly assayed susceptibility genes is more likely to be high-grade, high-risk disease.

Germline Mutations in ATM and BRCA1/2 Are Associated with Grade Reclassification in Men on Active Surveillance for Prostate Cancer.

BACKGROUND: Mutations in DNA repair genes are associated with aggressive prostate cancer (PCa). OBJECTIVE: To assess whether germline mutations are associated with grade reclassification (GR) in patients undergoing active surveillance (AS). DESIGN, SETTING, AND PARTICIPANTS: Two independent cohorts of PCa patients undergoing AS; 882 and 329 patients from Johns Hopkins and North Shore, respectively. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Germline DNA was sequenced for DNA repair genes, including BRCA1/2 and ATM (three-gene panel). Pathogenicity of mutations was defined according to the American College of Medical Genetics guidelines. Association of mutation carrier status and GR was evaluated by a competing risk analysis. RESULTS AND LIMITATIONS: Of 1211, 289 patients experienced GR; 11 of 26 with mutations in a three-gene panel and 278 of 1185 noncarriers; adjusted hazard ratio (HR)=1.96 (95% confidence interval [CI]=1.004-3.84, p=0.04). Reclassification occurred in six of 11 carriers of BRCA2 mutations and 283 of 1200 noncarriers; adjusted HR=2.74 (95% CI=1.26-5.96, p=0.01). The carrier rates of pathogenic mutations in the three-gene panel, and BRCA2 alone, were significantly higher in those reclassified (3.8% and 2.1%, respectively) than in those not reclassified (1.6% and 0.5%, respectively; p=0.04 and 0.03, respectively). Carrier rates for BRCA2 were greater for those reclassified from Gleason score (GS) 3+3 at diagnosis to GS ≥4+3 (4.1% vs 0.7%, p=0.01) versus GS 3+4 (2.1% vs 0.6%; p=0.03). Results are limited by the small number of mutation carriers and an intermediate end point. CONCLUSIONS: Mutation status of BRCA1/2 and ATM is associated with GR among men undergoing AS. PATIENT SUMMARY: Men on active surveillance with inherited mutations in BRCA1/2 and ATM are more likely to harbor aggressive prostate cancer.

Germline mutations in PPFIBP2 are associated with lethal prostate cancer.

BACKGROUND: Few genes have germline mutations which predispose men to more aggressive prostate cancer (PCa). This study evaluated the contribution of germline loss of function (LOF) variants in PPFIBP2 to risk of lethal PCa. METHODS: A case-case study of 1414 PCa patients with lethal PCa and low-risk localized PCa was performed. Germline DNA samples from these patients were sequenced for PPFIBP2. Mutation carrier rates and association with lethal PCa were analyzed using the Fisher exact test, logistic regression, and Kaplan-Meier survival analysis. RESULTS: In the entire study population, eight patients, all of European ancestry, were identified as carrying PPFIBP2 pathogenic or likely pathogenic mutations. Seven (1.52%) of 462 lethal PCa patients were carriers compared with only one (0.12%) carrier in 810 low-risk PCa patients, P = 0.0029. The estimated Odds Ratio (OR) of carrying PPFIBP2 mutation for lethal PCa was 13.8 in European American population. The PPFIBP2 loss-of-function mutation carrier rate in lethal PCa cases was also higher than in 33 370 non-Finnish European individuals from the Exome Aggregation Consortium (ExAC) (carrier rate of 0.17%, P = 1.92 × 10-5 ) and in 498 men with localized PCa from The Cancer Genome Atlas cohort (TCGA) cohort (carrier rate of 0%, P = 0.0058). Survival analysis in European American lethal cases revealed PPFIBP2 mutation status as an independent predictor of shorter survival after adjusting for age at diagnosis, PSA at diagnosis, and genetic background (hazard ratio = 2.62, P = 0.034). CONCLUSIONS: While larger studies are needed, germline mutations in a novel gene, PPFIBP2, differentiated risk for lethal PCa from low-risk cases and were associated with shorter survival times after diagnosis.

A comprehensive evaluation of CHEK2 germline mutations in men with prostate cancer.

BACKGROUND: Germline mutations in CHEK2 have been associated with prostate cancer (PCa) risk. Our objective is to examine whether germline pathogenic CHEK2 mutations can differentiate risk of lethal from indolent PCa. METHODS: A case-case study of 703 lethal PCa patients and 1455 patients with low-risk localized PCa of European, African, and Chinese origin was performed. Germline DNA samples from these patients were sequenced for CHEK2. Mutation carrier rates and their association with lethal PCa were analyzed using the Fisher exact test and Kaplan-Meier survival analysis. RESULTS: In the entire study population, 40 (1.85%) patients were identified as carrying one of 15 different germline CHEK2 pathogenic or likely pathogenic mutations. CHEK2 mutations were detected in 16 (2.28%) of 703 lethal PCa patients compared with 24 (1.65%) of 1455 low-risk PCa patients (P = 0.31). No association was found between CHEK2 mutation status and early-diagnosis or PCa-specific survival time. However, the most common mutation in CHEK2, c.1100delC (p.T367 fs), had a significantly higher carrier rate (1.28%) in lethal PCa patients than low-risk PCa patients of European American origin (0.16%), P = 0.0038. The estimated Odds Ratio of this mutation for lethal PCa was 7.86. The carrier rate in lethal PCa was also significantly higher than that (0.46%) in 32 461 non-Finnish European subjects from the Exome Aggregation Consortium (ExAC) (P = 0.01). CONCLUSIONS: While overall CHEK2 mutations were not significantly more common in men with lethal compared to low-risk PCa, the specific CHEK2 mutation, c.1100delC, appears to contribute to an increased risk of lethal PCa in European American men.

Genetic factors influencing prostate cancer risk in Norwegian men.

Norway has one of the highest rates of death due to prostate cancer (PCa) in the world. To assess the contribution of both common and rare single nucleotide variants (SNPs) to the prostate cancer burden in Norway, we assessed the frequency of the established prostate cancer susceptibility allele, HOXB13 G84E, as well as a series of validated, common PCa risk SNPs in a Norwegian PCa population of 779 patients. The G84E allele was observed in 2.3% of patients compared to 0.7% of control individuals, OR = 3.8, P = 1 × 10-4. While there was a trend toward an earlier age at diagnosis, overall the clinicopathologic features of PCa were not significantly different in G84E carriers and non-carriers. Evaluation of 32 established common risk alleles revealed significant associations of risk alleles at 13 loci, including SNPs at 8q24, and near TET2, SLC22A3, NKX3-1, CASC8, MYC, DAP2IP, MSMB, HNF1B, PPP1R14A, and KLK2/3. When the data for each SNP are combined into a genetic risk score (GRS), Norwegian men within the top decile of GRS have over 5-fold greater risk to be diagnosed with PCa than men with GRS in the lowest decile. These results indicate that risk alleles of HOXB13 and common variant SNPs are important components of inherited PCa risk in the Norwegian population, although these factors appear to contribute little to the malignancy's aggressiveness.

Immunotherapy Administration: Oncology Nursing Society Recommendations
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As the use of immunotherapeutic agents increases in single-agent and multimodality treatment regimens, oncology nurses face the challenge of administering and caring for patients receiving new and unique agents. Oncology Nursing Society clinical staff and clinical nurses collaborated to produce a set of recommendations to educate nurses involved with the monitoring of patients receiving immunotherapy on administration procedures and safe handling of these agents to ensure patient and staff safety and to reduce risk of error. The recommendations are meant to provide clinical nurses with a framework on which to build policies and procedures for administering new treatment modalities.
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Germline Mutations in ATM and BRCA1/2 Distinguish Risk for Lethal and Indolent Prostate Cancer and are Associated with Early Age at Death.

BACKGROUND: Germline mutations in BRCA1/2 and ATM have been associated with prostate cancer (PCa) risk. OBJECTIVE: To directly assess whether germline mutations in these three genes distinguish lethal from indolent PCa and whether they confer any effect on age at death. DESIGN, SETTING, AND PARTICIPANTS: A retrospective case-case study of 313 patients who died of PCa and 486 patients with low-risk localized PCa of European, African, and Chinese descent. Germline DNA of each of the 799 patients was sequenced for these three genes. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Mutation carrier rates and their effect on lethal PCa were analyzed using the Fisher's exact test and Cox regression analysis, respectively. RESULTS AND LIMITATIONS: The combined BRCA1/2 and ATM mutation carrier rate was significantly higher in lethal PCa patients (6.07%) than localized PCa patients (1.44%), p=0.0007. The rate also differed significantly among lethal PCa patients as a function of age at death (10.00%, 9.08%, 8.33%, 4.94%, and 2.97% in patients who died ≤ 60 yr, 61-65 yr, 66-70 yr, 71-75 yr, and over 75 yr, respectively, p=0.046) and time to death after diagnosis (12.26%, 4.76%, and 0.98% in patients who died ≤ 5 yr, 6-10 yr, and>10 yr after a PCa diagnosis, respectively, p=0.0006). Survival analysis in the entire cohort revealed mutation carriers remained an independent predictor of lethal PCa after adjusting for race and age, prostate-specific antigen, and Gleason score at the time of diagnosis (hazard ratio=2.13, 95% confidence interval: 1.24-3.66, p=0.004). A limitation of this study is that other DNA repair genes were not analyzed. CONCLUSIONS: Mutation status of BRCA1/2 and ATM distinguishes risk for lethal and indolent PCa and is associated with earlier age at death and shorter survival time. PATIENT SUMMARY: Prostate cancer patients with inherited mutations in BRCA1/2 and ATM are more likely to die of prostate cancer and do so at an earlier age.

Genome-wide association of familial prostate cancer cases identifies evidence for a rare segregating haplotype at 8q24.21.

Previous genome-wide association studies (GWAS) of prostate cancer risk focused on cases unselected for family history and have reported over 100 significant associations. The International Consortium for Prostate Cancer Genetics (ICPCG) has now performed a GWAS of 2511 (unrelated) familial prostate cancer cases and 1382 unaffected controls from 12 member sites. All samples were genotyped on the Illumina 5M+exome single nucleotide polymorphism (SNP) platform. The GWAS identified a significant evidence for association for SNPs in six regions previously associated with prostate cancer in population-based cohorts, including 3q26.2, 6q25.3, 8q24.21, 10q11.23, 11q13.3, and 17q12. Of note, SNP rs138042437 (p = 1.7e(-8)) at 8q24.21 achieved a large estimated effect size in this cohort (odds ratio = 13.3). 116 previously sampled affected relatives of 62 risk-allele carriers from the GWAS cohort were genotyped for this SNP, identifying 78 additional affected carriers in 62 pedigrees. A test for an excess number of affected carriers among relatives exhibited strong evidence for co-segregation of the variant with disease (p = 8.5e(-11)). The majority (92 %) of risk-allele carriers at rs138042437 had a consistent estimated haplotype spanning approximately 100 kb of 8q24.21 that contained the minor alleles of three rare SNPs (dosage minor allele frequencies <1.7 %), rs183373024 (PRNCR1), previously associated SNP rs188140481, and rs138042437 (CASC19). Strong evidence for co-segregation of a SNP on the haplotype further characterizes the haplotype as a prostate cancer predisposition locus.

How Oncology Nurses Can Address the Challenges of CLASBI Prevention.

Oncology nurses must be vigilant in adhering to evidence-based interventions in central line-associated bloodstream infection (CLABSI) prevention.

Association analysis of 9,560 prostate cancer cases from the International Consortium of Prostate Cancer Genetics confirms the role of reported prostate cancer associated SNPs for familial disease.

Previous GWAS studies have reported significant associations between various common SNPs and prostate cancer risk using cases unselected for family history. How these variants influence risk in familial prostate cancer is not well studied. Here, we analyzed 25 previously reported SNPs across 14 loci from prior prostate cancer GWAS. The International Consortium for Prostate Cancer Genetics (ICPCG) previously validated some of these using a family-based association method (FBAT). However, this approach suffered reduced power due to the conditional statistics implemented in FBAT. Here, we use a case-control design with an empirical analysis strategy to analyze the ICPCG resource for association between these 25 SNPs and familial prostate cancer risk. Fourteen sites contributed 12,506 samples (9,560 prostate cancer cases, 3,368 with aggressive disease, and 2,946 controls from 2,283 pedigrees). We performed association analysis with Genie software which accounts for relationships. We analyzed all familial prostate cancer cases and the subset of aggressive cases. For the familial prostate cancer phenotype, 20 of the 25 SNPs were at least nominally associated with prostate cancer and 16 remained significant after multiple testing correction (p ≤ 1E (-3)) occurring on chromosomal bands 6q25, 7p15, 8q24, 10q11, 11q13, 17q12, 17q24, and Xp11. For aggressive disease, 16 of the SNPs had at least nominal evidence and 8 were statistically significant including 2p15. The results indicate that the majority of common, low-risk alleles identified in GWAS studies for all prostate cancer also contribute risk for familial prostate cancer, and that some may contribute risk to aggressive disease.

The oncology phone: an innovative program for the management of the oncology population in an academic medical center.

The Oncology Nursing Leadership Team at the Hospital of the University of Pennsylvania designed and implemented a phone consultation and intervention service to address increasing needs for specialty oncology nursing consultation and care for patients located on nononcology units. This article describes the planning, implementation, and evaluation of this service, which the team named the oncology phone. The service is available 24 hours per day, seven days per week by members of the Oncology Nursing Leadership Team and designated senior members of the clinical nursing staff. Consultation is initiated by any clinical nurse throughout the hospital who determines the need for oncology nursing expertise. Those needs include support for chemotherapy administration, symptom management, and care coordination. Data are collected from each call as well as subsequent face-to-face consultations and interventions. Evaluation of the data reveals important areas for education. A similar program may be valuable to other inpatient settings in addressing the needs of patients and staff.

HOXB13 is a susceptibility gene for prostate cancer: results from the International Consortium for Prostate Cancer Genetics (ICPCG).

Prostate cancer has a strong familial component but uncovering the molecular basis for inherited susceptibility for this disease has been challenging. Recently, a rare, recurrent mutation (G84E) in HOXB13 was reported to be associated with prostate cancer risk. Confirmation and characterization of this finding is necessary to potentially translate this information to the clinic. To examine this finding in a large international sample of prostate cancer families, we genotyped this mutation and 14 other SNPs in or flanking HOXB13 in 2,443 prostate cancer families recruited by the International Consortium for Prostate Cancer Genetics (ICPCG). At least one mutation carrier was found in 112 prostate cancer families (4.6 %), all of European descent. Within carrier families, the G84E mutation was more common in men with a diagnosis of prostate cancer (194 of 382, 51 %) than those without (42 of 137, 30 %), P = 9.9 × 10(-8) [odds ratio 4.42 (95 % confidence interval 2.56-7.64)]. A family-based association test found G84E to be significantly over-transmitted from parents to affected offspring (P = 6.5 × 10(-6)). Analysis of markers flanking the G84E mutation indicates that it resides in the same haplotype in 95 % of carriers, consistent with a founder effect. Clinical characteristics of cancers in mutation carriers included features of high-risk disease. These findings demonstrate that the HOXB13 G84E mutation is present in ~5 % of prostate cancer families, predominantly of European descent, and confirm its association with prostate cancer risk. While future studies are needed to more fully define the clinical utility of this observation, this allele and others like it could form the basis for early, targeted screening of men at elevated risk for this common, clinically heterogeneous cancer.