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The Pharmacogene Variation Consortium (PharmVar) provides nomenclature for the highly polymorphic human CYP2D6 gene locus. CYP2D6 genetic variation impacts the metabolism of numerous drugs and, thus, can impact drug efficacy and safety. This GeneFocus provides a comprehensive overview and summary of CYP2D6 genetic variation and describes how the information provided by PharmVar is utilized by the Pharmacogenomics Knowledgebase (PharmGKB) and the Clinical Pharmacogenetics Implementation Consortium (CPIC).

Background and purpose Thromboembolic events are recognized complications of aneurysm coiling. Objective To identify any protective effects of antiplatelet therapy use before coiling of unruptured aneurysms. Methods We conducted a meta-analysis of clinical studies published up to February 2019. We included studies reporting symptomatic thromboembolic events (defined as clinical stroke or transient ischemic attacks) in patients who received antiplatelet therapy before coiling of unruptured aneurysms using unassisted coiling, balloon assistance, or multiple microcatheters. We excluded ruptured aneurysms and those treated with stent coiling or flow diverters. Results We identified 14 studies (2486 patients). All were single-center studies and four were prospective. In three studies with a control (no treatment) arm, the pooled risk ratio for symptomatic thromboembolic events with versus without antiplatelet therapy was 0.33 (95% CI 0.17 to 0.92, p= 0.035). The cumulative risk of symptomatic thromboembolic events with single antiplatelet agents was 5.0% ‘56/1122’ (95% CI 1.6% to 8.4%, I283.63%), and with dual or multiple agents 2.7% ‘33/1237’ (95% CI 1.0% to 3.0%, I239.9%). The incidence of diffusion lesions was reported in seven studies. It was 50.5% ‘96/190’ (95% CI 7.3% to 93.9%, I294.4%) with single agents compared with 43.9% ‘196/446’ (95% CI 25.9% to 61.9%, I273.4%) with dual or multiple agents. Conclusion Periprocedural antiplatelet therapy was associated with a low symptomatic thromboembolic event after coiling-only for unruptured aneurysms. However, available evidence is of limited quality with significant heterogeneity, requiring evidence from randomized controlled trials.

Abstract Objectives Salivary duct carcinoma is a rare high-grade salivary gland tumor, sharing common features with invasive ductal carcinoma of the breast—particularly apocrine type. Increased density of tumor-infiltrating lymphocytes (TILs) is a favorable prognostic factor in many solid tumors and has been correlated with elevated expression of programmed death-ligand 1 (PD-L1), a targetable molecule. We investigated the prognostic role of TILs and PD-L1 expression in salivary duct carcinoma. Methods Clinical records and archived surgical pathology material were evaluated from 28 patients with a diagnosis of salivary duct carcinoma at Mayo Clinic Rochester (between 1961 and 2007). TILs were evaluated on hematoxylin and eosin–stained slides and reported as continuous variables. Immunohistochemistry for PD-L1 (clone 22C3) was performed on unstained slides and evaluated using the Combined Positive Score (CPS). Fisher’s exact test was used to assess frequency distribution differences. Log-rank test and Cox proportional hazards model were used to assess the impact of the variables on survival. Results Twenty-eight patients had salivary duct carcinoma (age range 35-87, mean 61), and follow-up averaged 60 months (range 6-252 months). At the end of the follow-up period, 22 patients (79%) had died of salivary duct carcinoma, while remaining patients were alive (4.14%) or had died of other causes (2.7%). For the entire follow-up period, levels of TILs of 40% or more were associated with favorable overall survival (log-rank test, P = .01) and were predictors of better survival in univariate analysis (hazard ratio: 0.18, P = .02). PD-L1 expression was not significantly different between the high and low TIL groups (Fisher’s exact test, P = .67). Survival analysis regarding PD-L1 expression did not yield statistically significant results (log-rank test, P = .74; hazard ratio: 0.87, P = .74). Conclusion High TIL levels, but not PD-L1 expression as determined using the CPS, predict better survival in patients with salivary duct carcinoma.

Abstract BACKGROUND The impact of treatment on both the quality and the quantity of life, i.e. the ‘net clinical benefit’, should be considered to inform glioma patients and facilitate shared decision making. We applied two methods (i.e. Quality Adjusted Effect Sizes (QASES) and Joint Modelling (JM)) that combine survival and health-related quality of life (HRQoL) data into one outcome, to gain insight in the net clinical benefit of a treatment strategy. In addition, we assessed if both methods result in similar interpretations. MATERIAL AND METHODS We calculated the net clinical benefit in one randomized controlled trial, EORTC 26951 comparing radiotherapy (RT) + PCV chemotherapy versus RT alone, as a proof of concept for other trials. With the QASES method, effect sizes for differences in survival and HRQoL between treatment arms were calculated. Next, the combined effect size can be determined by weighing the emphasis put on survival or HRQoL (e.g. survival more important). JM allows simultaneous modeling of a longitudinal outcome (HRQoL), and a time-to event outcome (survival). HRQoL scales/items that were selected for primary analysis in the main study were also selected for this analysis: fatigue, global health, social functioning, communication deficit, seizures, physical functioning, and nausea/vomiting. RESULTS 288/386 patients completed baseline HRQoL forms and were included in the analysis. Overall survival (OS) was significantly longer with combined treatment (difference of 10.8 months). In contrast, the percentage of patients who experienced a clinically relevant deterioration (≥10 points) in nausea/vomiting, fatigue, social functioning and global health up to one year after treatment compared to baseline was larger in the RT+PCV arm. The QASES corresponded to a reduction in the median OS difference from 10.8 months to 6.8 months when adjusted for the HRQoL scales/items, when given equal weights to OS and HRQoL. JM analyses resulted in a theoretical loss of treatment effect in OS of 2–6% when adjusting for HRQoL. CONCLUSION Both methods showed that adjusting for the impact of treatment on a relevant HRQoL parameter reduced the survival benefit in the experimental treatment arm compared to standard treatment arm. Applying these methods may facilitate communicating the impact of treatment to patients in clinical practice.

PURPOSE To update the ASCO guideline on pharmacologic interventions for breast cancer risk reduction and provide guidance on clinical issues that arise when deciding to use endocrine therapy for breast cancer risk reduction. METHODS An Expert Panel conducted targeted systematic literature reviews to identify new studies. RESULTS A randomized clinical trial that evaluated the use of anastrozole for reduction of estrogen receptor–positive breast cancers in postmenopausal women at increased risk of developing breast cancer provided the predominant basis for the update. UPDATED RECOMMENDATIONS In postmenopausal women at increased risk, the choice of endocrine therapy now includes anastrozole (1 mg/day) in addition to exemestane (25 mg/day), raloxifene (60 mg/day), or tamoxifen (20 mg/day). The decision regarding choice of endocrine therapy should take into consideration age, baseline comorbidities, and adverse effect profiles. Clinicians should not prescribe anastrozole, exemestane, or raloxifene for breast cancer risk reduction to premenopausal women. Tamoxifen 20 mg/day for 5 years is still considered standard of care for risk reduction in premenopausal women who are at least 35 years old and have completed childbearing. Data on low-dose tamoxifen as an alternative to the standard dose for both pre- and postmenopausal women with intraepithelial neoplasia are discussed in the Clinical Considerations section of this article. Additional information is available at www.asco.org/breast-cancer-guidelines .