Combinatorial pharmacogenomic algorithm is predictive of sertraline metabolism in patients with major depressive disorder.

Pharmacogenomic testing can be used to guide medication selection in patients with major depressive disorder (MDD). Currently, there is no consensus on which gene or genes to consider in medication management. Here, we assessed the clinical validity of the combinatorial pharmacogenomic algorithm to predict sertraline blood levels in a subset of patients enrolled in the Genomics Used to Improve DEpression Decisions (GUIDED) trial.

Age of ovarian cancer diagnosis among BRIP1, RAD51C, and RAD51D mutation carriers identified through multi-gene panel testing.

Background: Professional society guidelines recommend risk-reducing salpingo-oophorectomy (RRSO) for women with pathogenic variants (PVs) in ovarian cancer-risk genes. Personalization of that intervention is based on gene-specific phenotypes; however, the age of ovarian cancer diagnosis in women with PVs in moderate penetrance ovarian cancer-risk genes is not well characterized. Women who had hereditary cancer panel testing from September 2013-May 2019 were included (N = 631,950).

Multigene assessment of genetic risk for women for two or more breast cancers.

Purpose: The prevalence, penetrance, and spectrum of pathogenic variants that predispose women to two or more breast cancers is largely unknown.

Methods: We queried clinical and genetic data from women with one or more breast cancer diagnosis who received multigene panel testing between 2013 and 2018. Clinical data were obtained from provider-completed test request forms.

Interpretation of BRCA2 Splicing Variants: A Case Series of Challenging Variant Interpretations and the Importance of Functional RNA Analysis.

A substantial proportion of pathogenic variants associated with an increased risk of hereditary cancer are sequence variants affecting RNA splicing. The classification of these variants can be complex when both non-functional and functional transcripts are produced from the variant allele. We present four BRCA2 splice site variants with complex variant interpretations (BRCA2 c.

Psychosocial outcomes following germline multigene panel testing in an ethnically and economically diverse cohort of patients.

Background: Little is known about the psychological outcomes of germline multigene panel testing, particularly among diverse patients and those with moderate-risk pathogenic variants (PVs).

Methods: Study participants (N = 1264) were counseled and tested with a 25- or 28-gene panel and completed a 3-month postresult survey including the Multidimensional Impact of Cancer Risk Assessment (MICRA).

Results: The mean age was 52 years, 80% were female, and 70% had cancer; 45% were non-Hispanic White, 37% were Hispanic, 10% were Asian, 3% were Black, and 5% had another race/ethnicity.

Impact of a Cancer Gene Variant Reclassification Program Over a 20-Year Period.

Purpose: Hereditary cancer genetic testing can inform personalized medical management for individuals at increased cancer risk. However, many variants in cancer predisposition genes are individually rare, and traditional tools may be insufficient to evaluate pathogenicity. This analysis presents data on variant classification and reclassification over a 20-year period.

Predicting Expected Absolute Chemotherapy Treatment Benefit in Women With Early-Stage Breast Cancer Using EndoPredict, an Integrated 12-Gene Clinicomolecular Assay.

Purpose: Previous studies have shown EndoPredict (EPclin), a test that integrates 12-gene expression data with nodal status and tumor size, to be predictive for risk of distant recurrence in women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative early-stage breast cancer. Here, we modeled expected absolute chemotherapy benefit on the basis of EPclin test results.

Methods: The effect of chemotherapy was modeled using previously validated 10-year risk of distant recurrence as a function of EPclin score for patients treated without chemotherapy.

Combinatorial Pharmacogenomic Algorithm is Predictive of Citalopram and Escitalopram Metabolism in Patients with Major Depressive Disorder.

Pharmacogenomic tests used to guide clinical treatment for major depressive disorder (MDD) must be thoroughly validated. One important assessment of validity is the ability to predict medication blood levels, which reflect altered metabolism. Historically, the metabolic impact of individual genes has been evaluated; however, we now know that multiple genes are often involved in medication metabolism.

The clinical utility of combinatorial pharmacogenomic testing for patients with depression: a meta-analysis.

To perform a meta-analysis of prospective, two-arm studies examining the clinical utility of using the combinatorial pharmacogenomic test, GeneSight Psychotropic, to inform treatment decisions for patients with major depressive disorder (MDD). The pooled mean effect of symptom improvement and pooled relative risk ratio (RR) of response and remission were calculated using a random effect model. Overall, 1556 patients were included from four studies, with outcomes evaluated at week 8 or week 10.

Impact of Pharmacogenomics on Clinical Outcomes for Patients Taking Medications With Gene-Drug Interactions in a Randomized Controlled Trial.

Objective: The objective of the Genomics Used to Improve DEpression Decisions (GUIDED) trial was to evaluate the utility of pharmacogenomic testing to improve outcomes among patients with major depressive disorder (MDD) who had not responded to at least 1 prior medication trial. The objective of the present analysis was to assess outcomes for the subset of patients expected to benefit from combinatorial pharmacogenomic testing because they were taking medications with predicted gene-drug interactions.

Methods: Participants (enrolled from April 14, 2014, to February 10, 2017) had an inadequate response to at least 1 psychotropic medication in the current episode of MDD.

Detection of large rearrangements in a hereditary pan-cancer panel using next-generation sequencing.

Background: Healthcare providers increasingly use information about pathogenic variants in cancer predisposition genes, including sequence variants and large rearrangements (LRs), in medical management decisions. While sequence variant detection is typically robust, LRs can be difficult to detect and characterize and may be underreported as a cause for hereditary cancer risk. This report describes the outcomes of hereditary cancer genetic testing using a comprehensive strategy that employs next-generation sequencing (NGS) for LR detection, coupled with LR confirmation using repeat hybrid capture NGS, microarray comparative genomic hybridization (microarray-CGH), and/or multiplex ligation-dependent probe amplification (MLPA).

Prediction of Distant Recurrence Using EndoPredict Among Women with ER, HER2 Node-Positive and Node-Negative Breast Cancer Treated with Endocrine Therapy Only.

Purpose: Prognostic molecular assays may aid in treatment decisions for women with estrogen receptor (ER)-positive, HER2-negative breast cancer. The prognostic value of a 12-gene expression assay (EndoPredict) was reevaluated in the combined ABCSG-6/8 cohorts with longer clinical follow-up.

Experimental Design: EndoPredict (EP; molecular score, EPclin score) was evaluated in women with ER-positive, HER2-negative node-positive and node-negative breast cancer who received 5 years of endocrine therapy only (median follow-up, 9.

Multicenter Prospective Cohort Study of the Diagnostic Yield and Patient Experience of Multiplex Gene Panel Testing For Hereditary Cancer Risk.

Purpose: Multiplex gene panel testing (MGPT) allows for the simultaneous analysis of germline cancer susceptibility genes. This study describes the diagnostic yield and patient experiences of MGPT in diverse populations.

Patients And Methods: This multicenter, prospective cohort study enrolled participants from three cancer genetics clinics-University of Southern California Norris Comprehensive Cancer Center, Los Angeles County and University of Southern California Medical Center, and Stanford Cancer Institute-who met testing guidelines or had a 2.

Impact of pharmacogenomics on clinical outcomes in major depressive disorder in the GUIDED trial: A large, patient- and rater-blinded, randomized, controlled study.

Current prescribing practices for major depressive disorder (MDD) produce limited treatment success. Although pharmacogenomics may improve outcomes by identifying genetically inappropriate medications, studies to date were limited in scope. Outpatients (N = 1167) diagnosed with MDD and with a patient- or clinician-reported inadequate response to at least one antidepressant were enrolled in the Genomics Used to Improve DEpression Decisions (GUIDED) trial - a rater- and patient-blind randomized controlled trial.

Correlation of melanoma gene expression score with clinical outcomes on a series of melanocytic lesions.

A 23-gene expression signature was recently developed as an adjunct to histopathology to differentiate melanocytic nevi from melanoma. The current study correlated the gene expression signature scores to actual clinical outcomes in cases from the first validation study. RNA was extracted from 127 archival formalin-fixed paraffin-embedded tissue sections of melanocytic lesions.

Prevalence of Variant Reclassification Following Hereditary Cancer Genetic Testing.

Importance: Variant reclassification is an important component of hereditary cancer genetic testing; however, there are few published data quantifying the prevalence of reclassification.

Objective: Retrospective cohort study of individuals who had genetic testing from 2006 through 2016 at a single commercial laboratory.

Design, Setting, And Participants: A retrospective cohort of individuals who had genetic testing between 2006 and 2016 at a single commercial laboratory was assessed.

Biomarker Assessment of HR Deficiency, Tumor Mutations, and Copy Number in Ovarian Cancer: Associations with Clinical Outcome Following Platinum Monotherapy.

The current study evaluated three biomarkers [homologous recombination deficiency (HRD), tumor BRCA1/2 (tBRCA) mutations, and CCNE1 copy-number variation (CNV)] in ovarian tumors from patients enrolled on the SCOTROC4 clinical trial for associations with outcome following carboplatin monotherapy. Ovarian tumors ( = 250), with high-grade serous (HGSOC) subgroup analysis ( = 179) were classified as HRD positive (HRD score ≥42 or tBRCA mutation) and as CCNE1 amplification positive (CCNE1 CNV score >2.4).

Identification of men with low-risk biopsy-confirmed prostate cancer as candidates for active surveillance.

Background: A combined clinical cell-cycle risk (CCR) score that incorporates prognostic molecular and clinical information has been recently developed and validated to improve prostate cancer mortality (PCM) risk stratification over clinical features alone. As clinical features are currently used to select men for active surveillance (AS), we developed and validated a CCR score threshold to improve the identification of men with low-risk disease who are appropriate for AS.

Methods: The score threshold was selected based on the 90th percentile of CCR scores among men who might typically be considered for AS based on NCCN low/favorable-intermediate risk criteria (CCR = 0.

Impact of a genetic counseling requirement prior to genetic testing.

Background: Genetic counseling by a Genetic Counselor (GC) is a requirement prior to genetic testing for cancer susceptibility genes (GC-mandate policy) for some insurers. This study evaluated the impact of this policy from the patient perspective.

Methods: Surveys were sent to individuals for whom their insurer ordered genetic testing for the cancer susceptibility genes BCRA1 and BRCA2 over a 1 year time period that spanned the introduction of a GC-mandate policy.

Clinical testing with a panel of 25 genes associated with increased cancer risk results in a significant increase in clinically significant findings across a broad range of cancer histories.

Genetic testing for inherited cancer risk is now widely used to target individuals for screening and prevention. However, there is limited evidence available to evaluate the clinical utility of various testing strategies, such as single-syndrome, single-cancer, or pan-cancer gene panels. Here we report on the outcomes of testing with a 25-gene pan-cancer panel in a consecutive series of 252,223 individuals between September 2013 and July 2016.

Identification of pathogenic retrotransposon insertions in cancer predisposition genes.

Cancer risks have been previously reported for some retrotransposon element (RE) insertions; however, detection of these insertions is technically challenging and very few oncogenic RE insertions have been reported. Here we evaluate RE insertions identified during hereditary cancer genetic testing using a comprehensive testing strategy. Individuals who had single-syndrome or pan-cancer hereditary cancer genetic testing from February 2004 to March 2017 were included.