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].…”

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.…”

Risk assessment and genetic counseling for hereditary breast and ovarian cancer syndromes—Practice resource of the National Society of Genetic Counselors

“…While P/LPVs in BRCA1 and BRCA2 are responsible for most hereditary breast and ovarian cancer, other genes can influence risk for those cancers (Tung et al, 2016). Several publications have demonstrated that multigene panel testing yields findings likely to change clinical management for substantially more patients than does BRCA1 and BRCA2 testing alone (Desmond et al., 2015; Frey et al, 2017; Idos, et al., 2019; Pederson et al., 2018; Ricker et al., 2016; Rosenthal et al., 2017). Multigene testing has been shown to alter near‐term cancer risk assessment and management recommendations for individuals found to carry P/LPVs across a broad spectrum of cancer predisposition genes (Desmond et al., 2015).…”

“…Multigene panel testing can result in a higher probability of finding a variant of uncertain significance (VUS) or a P/LPV in any of the genes suspected based on personal and/or family history (Idos et al., 2019; Yurgelun et al., 2015). It also increases the likelihood that a VUS or an unexpected P/LPV may be found in other genes included in the panel.…”