The prevalence and clinical significance of HER2 overexpression in prostate adenocarcinoma.

212 Background: The HER2 oncogene serves as a prognostic marker in breast cancer and is a therapeutic target in breast, lung, and GI malignancies, including cancers with low Her2 overexpression. A prior study by Minner et al ( Clin Cancer Res, 2010) evaluating Her2 overexpression in prostate cancer (PCa) showed a prevalence ~20%. The goal of this study is to evaluate the prevalence and clinical significance of Her2 overexpression in PCa in a predominantly African American (AA) cohort. Methods: 124 PCa patients managed at the Washington DC VA Medical Center between 2000-2021 were randomly selected: 35 indolent (AJCC stage I), 46 locally advanced (AJCC stages II&amp;III), 19 locally advanced at diagnosis but progressed to metastatic (AJCC stage IV), and 24 de novo metastatic (AJCC stage IV). Immunohistochemistry (IHC) for Her2 was performed on one representative tissue section from core biopsies or a radical prostatectomy for each case. IHC intensity was scored independently by two experienced pathologists as negative (0, no staining), low positive (1+, faint membranous staining), moderate positive (2+, weak to moderate complete, basolateral or lateral membranous staining) or strong positive (3+, strong complete, basolateral or lateral membranous staining). Fisher’s exact test was used to test the association between Her2 expression and categorical variables. Results: 108 patients (87%) self-identified as AA. The mean age at diagnosis was 62.9 years. The prevalence of positive Her2 expression (1+, 2+,3+) was 48% (59/124) in the entire cohort, 29% (10/35) in the indolent group, 48% (22/46) in the locally advanced group, 68% (13/19) in the locally advanced group that progressed to metastatic disease, and 58% (14/24) in the de novo metastatic group ( p=0.0014). Prevalence of Her2 positive expression was 28% (10/36) in patients with a Gleason Score (GS) of 6, whereas in patients with a GS of 9 it was 78% (9/11) ( p&lt;0.0001). Mean (non-zero) Her2 expression was highest in the de novo metastatic group (Her2 2.0, SD 0.78), followed by the locally advanced group that progressed to metastatic disease (Her2 1.54, SD 0.66), the locally advanced group without metastatic disease (Her2 1.36, SD 0.58), and lowest in the indolent group (Her2 1.0, SD 0.0) ( p=0.0016). Next generation sequencing data was available for 20 metastatic patients (12 positive for Her2 expression) and did not show the presence of HER2 mutations or amplifications. Conclusions: In this predominantly AA cohort, expression of Her2 was identified in almost 50% of patients with PCa. Her2 scores ≥2 were associated with higher GS and advanced disease. Moreover, a Her2 score of 3 was seen in 6 patients in our cohort. Historic studies on targeting Her2 in advanced PCa have failed to demonstrate clinical benefit. However, in the era of targeted therapy, Her2 inhibition addressing low-levels of Her2 overexpression should be considered in future trials. </jats:p

Why African Americans Say “No”: A Study of Pharmacogenomic Research Participation

Objective: To identify reasons for nonpar­ticipation by African Americans in cardio­vascular pharmacogenomic research.Design: Prospective, open-ended, qualita­tive survey.Setting: Research staff approached patients eligible for the Discovery Project of The African American Cardiovascular pharma­cogenomics CONsorTium in the inpatient or outpatient setting at four different institu­tions during September and October 2018.Participants: Potential Discovery Proj­ect participants self-identified as African American, aged &gt;18 years, were on one of five cardiovascular drugs of interest, and de­clined enrollment in the Discovery Project.Methods: After declining participation in the Discovery Project, patients were asked, “What are your reasons for not participat­ing?” We analyzed their responses using a directed content analytic approach. Ultimately, responses were coded into one of nine categories and analyzed using descriptive statistics.Main Outcome Measures: Reasons for nonparticipation.Results: Of the 194 people approached for the Discovery Project during an eight-week period, 82 declined participation and provided information for this study. The most common reason for refusal was concern about the amount of blood drawn (19.5%). The next most common reasons for refusal to participate included concerns about genetic testing (14.6%) and mistrust of research (12.2%). Across study sites, significantly more patients enrolled in the inpatient than outpatient setting (P&lt;.001). Significantly more women and younger individuals declined participation due to concerns about genetic testing and too little compensation (P&lt;.05).Conclusions: Collection of blood samples and concerns about genetic testing are ob­stacles for the recruitment of African Ameri­cans to pharmacogenomics studies. Efforts to overcome these barriers to participation are needed to improve representation of minorities in pharmacogenomic research. Enrolling participants from inpatient populations may be a solution to bolster recruitment efforts.Ethn Dis. 2020;30(Suppl 1):159-166; doi:10.18865/ed.30.S1.159</jats:p

Mapping the human genetic architecture of COVID-19

AbstractThe genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3–7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.</jats:p