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

Abstract

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 2.5% or greater probability of a pathogenic variant (N = 2,000). All patients underwent 25- or 28-gene MGPT and results were compared with differential genetic diagnoses generated by pretest expert clinical assessment. Post-test surveys on distress, uncertainty, and positive experiences were administered at 3 months (69% response rate) and 1 year (57% response rate). Results Of 2,000 participants, 81% were female, 41% were Hispanic, 26% were Spanish speaking only, and 30% completed high school or less education. A total of 242 participants (12%) carried one or more pathogenic variant (positive), 689 (34%) carried one or more variant of uncertain significance (VUS), and 1,069 (53%) carried no pathogenic variants or VUS (negative). More than one third of pathogenic variants (34%) were not included in the differential diagnosis. After testing, few patients (4%) had prophylactic surgery, most (92%) never regretted testing, and most (80%) wanted to know all results, even those of uncertain significance. Positive patients were twice as likely as negative/VUS patients (83% v 41%; P < .001) to encourage their relatives to be tested. Conclusion In a racially/ethnically and socioeconomically diverse cohort, MGPT increased diagnostic yield. More than one third of identified pathogenic variants were not clinically anticipated. Patient regret and prophylactic surgery use were low, and patients appropriately encouraged relatives to be tested for clinically relevant results.

“I wish that there was more info”: characterizing the uncertainty experienced by carriers of pathogenic ATM and/or CHEK2 variants

“…Multigene panel testing allows for an efficient approach to determine a potential genetic cause for inherited cancer susceptibility [1]. However, the clinical utility of such testing remains in question as many genes included on panels are moderate-risk genes with less established data on cancer risk estimates and risk management [2,3].…”

“…Quantitative studies investigating patient outcomes after undergoing multigene panel testing for cancer susceptibility demonstrated increased levels of anxiety and uncertainty in those who test positive for a pathogenic variant [1,8,9]. Other studies have found that uncertainty and anxiety are not predominant feelings among individuals who pursue genetic testing for cancer susceptibility, and that in fact, learning about cancer risk provides individuals with an opportunistic sense to be more proactive about their healthcare [10][11][12].…”

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

“…16,17,19 We conducted a multicenter, prospective study of a hereditary cancer panel in a diverse cohort of 1264 participants responding to a survey 3 months after disclosure of the results. 21 We hypothesized that panel testing would be received favorably overall but that high-risk PV carriers would have higher levels of distress than other participants, whereas moderate-risk PV carriers would have higher levels of uncertainty than other participants. The results of our study will inform cancer genetic counseling and testing strategies.…”

A Retrospective 5-Year Single Center Study Highlighting the Risk of Cancer Predisposition in Adolescents and Young Adults

“…Of 149 patients with high-penetrance PGVs, 42 (28.2%) had clinically actionable management and treatment changes including targeted therapy ( n = 21), enrollment in clinical trials ( n = 2), and surgery ( n = 18). In the study reported by Idos et al, 12% of 2000 patients harbored PGVs [ 47 ]. Sixteen of those tested positive underwent prophylactic surgery.…”