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The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic/likely pathogenic (P/LP) variants associated with increased risk of breast, ovarian, pancreatic, and prostate cancer, including BRCA1, BRCA2, CDH1, PALB2, PTEN, and TP53, and recommended approaches to genetic counseling/testing and care strategies in individuals with these P/LP variants. These NCCN Guidelines Insights summarize important updates regarding: (1) a new section for transgender, nonbinary and gender diverse people who have a hereditary predisposition to cancer focused on risk reduction strategies for ovarian cancer, uterine cancer, prostate cancer, and breast cancer; and (2) testing criteria and management associated with TP53 P/LP variants and Li-Fraumeni syndrome.

Triple-negative breast cancers (TNBCs) are a heterogeneous set of tumors defined by an absence of actionable therapeutic targets (ER, PR, and HER-2). Microdissected normal ductal epithelium from healthy volunteers represents a novel comparator to reveal insights into TNBC heterogeneity and to inform drug development. Using RNA-sequencing data from our institution and The Cancer Genome Atlas (TCGA) we compared the transcriptomes of 94 TNBCs, 20 microdissected normal breast tissues from healthy volunteers from the Susan G. Komen for the Cure Tissue Bank, and 10 histologically normal tissues adjacent to tumor. Pathway analysis comparing TNBCs to optimized normal controls of microdissected normal epithelium versus classic controls composed of adjacent normal tissue revealed distinct molecular signatures. Differential gene expression of TNBC compared with normal comparators demonstrated important findings for TNBC-specific clinical trials testing targeted agents; lack of over-expression for negative studies and over-expression in studies with drug activity. Next, by comparing each individual TNBC to the set of microdissected normals, we demonstrate that TNBC heterogeneity is attributable to transcriptional chaos, is associated with non-silent DNA mutational load, and explains transcriptional heterogeneity in addition to known molecular subtypes. Finally, chaos analysis identified 146 core genes dysregulated in >90 % of TNBCs revealing an over-expressed central network. In conclusion, use of microdissected normal ductal epithelium from healthy volunteers enables an optimized approach for studying TNBC and uncovers biological heterogeneity mediated by transcriptional chaos.

Purpose: To ascertain whether single nucleotide polymorphisms (SNPs) in the Vascular Endothelial Growth factor (VEGFA), Complement Factor H (CFH), and LOC387715 genes could predict outcome to anti-VEGF therapy for patients with age related macular degeneration (AMD). Methods: Patients with "wet" AMD were identified by chart review. Baseline optical coherence tomography (OCT) and visual acuity (VA) data, and at least 6 months of clinical follow up after 3 initial monthly injections of bevacizumab or ranibizumab were required for inclusion. Based on OCT and VA, patients were categorized into two possible clinical outcomes: (a) responders and (b) non-responders. DNA was extracted from saliva and genotyped for candidate SNPs in the VEGFA, LOC387715, and CFH genes. Clinical outcomes were statistically compared to patient genotypes. Results: 101 patients were recruited, and one eye from each patient was included in the analysis. 97% of samples were successfully genotyped for all SNPs. We found a statistically significant association between the LOC387715 A69S TT genotype and outcome based on OCT. Conclusion: Genetic variation may be associated with outcome in patients receiving anti-VEGF therapy. [ABSTRACT FROM AUTHOR]

Purpose: This retrospective analysis aimed to determine the relationship between body mass index (BMI) and circulating tumor DNA (ctDNA) in triple-negative breast cancer (TNBC), and to evaluate the impact of BMI on disease recurrence and survival in the homogeneous, high-risk population of patients with residual TNBC after neoadjuvant chemotherapy., Experimental Design: BRE12-158 was a phase II trial of genomically directed therapy versus physician's choice in residual TNBC after chemotherapy. ctDNA was isolated from plasma samples, and categorized as positive or negative. BMI (kg/m 2 ) after surgery was analyzed as both a continuous and categorical variable: normal weight, <25; overweight, 25-30; and obese, ≥30. We compared ctDNA category and BMI, and estimated probability of disease-free survival (DFS), distant DFS (DDFS), and overall survival (OS) by BMI., Results: Of 177 patients in BRE12-158, 172 had BMI and 140 had ctDNA data. There was no difference in mean BMI between those with ctDNA positivity versus negativity ( P = 0.48). There was no relationship between BMI category and presence of ctDNA ( P = 0.31). In multivariate analysis, continuous BMI was not prognostic of DDFS ( P = 0.996), DFS ( P = 0.41), or OS ( P = 0.98). There was no association between BMI categories and survival ( P = 0.92, 0.74, and 0.97 for DDFS, DFS, and OS, respectively)., Conclusions: In patients with residual TNBC after neoadjuvant chemotherapy, BMI was not prognostic of DDFS, DFS, or OS. There was no signal of a relationship between BMI and presence of ctDNA. This suggests inherent aggressive tumor biology, in which host phenotype may have less influence and impact of weight loss interventions may be diminished., (©2020 American Association for Cancer Research.)