Decoding Ambiguity: Evaluating the Psychological Harms and Utility of Returning Cancer Variants of Uncertain Significance
Clinical Genetics and Therapeutics
-
Primary Categories:
-
Secondary Categories:
Introduction:
Variants of uncertain significance (VUS) account for up to 40% of classified variants in cancer predisposition genes, posing diagnostic and decision-making challenges. These challenges are compounded when communicating the implications of VUSs in pre- and post-test counseling. Previous studies have highlighted the psychosocial harms and overestimation of clinical significance of returning VUSs. This study aims to evaluate whether receiving VUSs related to a patient's personal or family history of cancer (primary VUS) has greater psychosocial harms and utility compared to receiving a negative result or unrelated cancer-related VUSs (secondary VUS).
Methods:
Participants with a personal or family history of cancer were recruited from familial cancer clinics in Toronto between Sept 2018 and Jan 2021. All participants underwent exome sequencing (ES) and received cancer-related results. The primary outcome was genetic test-related concerns, measured by the Multidimensional Impact of Cancer Risk Assessment (MICRA; range 0–125, higher scores indicate more negative perception) at 12 months post-results, analyzed by linear regression. Secondary outcomes were perceived utility and medical actions, measured by the Perceived Utility Scale and Behavioral Risk Factor Surveillance System, with changes in perceived utility assessed using analysis of covariance.
Results:
Seventy-two participants received negative or VUS results (negative results, n=16; primary VUS, n=22; secondary VUS, n = 34): mean age = 59 years, diverse (42% non-white/European ethnicity), and majority female (81.9%). At 12 months post return of results, mean MICRA scores for those with negative results was 20.3 (SD = 1.6), while those with primary VUSs and secondary VUSs were 17.2 (SD = 7.8) and 20.2 (SD = 7.7), respectively. MICRA scores of those who received negative results were similar to those with a primary VUS (coefficient = -2.63, 95% CI -7.12, 1.89) and secondary VUS (coefficient = 0.05, 95% CI -4.07, 4.18) (p=0.23). In terms of perceived utility, there was no strong evidence of differences in baseline adjusted scores among result types at 12 months (p = 0.62). Regarding medical actions, one participant with a negative result, two with a primary VUS, and two with a secondary VUS consulted a healthcare provider about their ES results.
Conclusion:
We did not find evidence that receiving a primary or secondary VUS leads to greater psychological harms or perceived utility of ES compared to negative ES results. Medical actions were also consistent with clinical guidelines on communicating the implications and medical management of VUSs.
Variants of uncertain significance (VUS) account for up to 40% of classified variants in cancer predisposition genes, posing diagnostic and decision-making challenges. These challenges are compounded when communicating the implications of VUSs in pre- and post-test counseling. Previous studies have highlighted the psychosocial harms and overestimation of clinical significance of returning VUSs. This study aims to evaluate whether receiving VUSs related to a patient's personal or family history of cancer (primary VUS) has greater psychosocial harms and utility compared to receiving a negative result or unrelated cancer-related VUSs (secondary VUS).
Methods:
Participants with a personal or family history of cancer were recruited from familial cancer clinics in Toronto between Sept 2018 and Jan 2021. All participants underwent exome sequencing (ES) and received cancer-related results. The primary outcome was genetic test-related concerns, measured by the Multidimensional Impact of Cancer Risk Assessment (MICRA; range 0–125, higher scores indicate more negative perception) at 12 months post-results, analyzed by linear regression. Secondary outcomes were perceived utility and medical actions, measured by the Perceived Utility Scale and Behavioral Risk Factor Surveillance System, with changes in perceived utility assessed using analysis of covariance.
Results:
Seventy-two participants received negative or VUS results (negative results, n=16; primary VUS, n=22; secondary VUS, n = 34): mean age = 59 years, diverse (42% non-white/European ethnicity), and majority female (81.9%). At 12 months post return of results, mean MICRA scores for those with negative results was 20.3 (SD = 1.6), while those with primary VUSs and secondary VUSs were 17.2 (SD = 7.8) and 20.2 (SD = 7.7), respectively. MICRA scores of those who received negative results were similar to those with a primary VUS (coefficient = -2.63, 95% CI -7.12, 1.89) and secondary VUS (coefficient = 0.05, 95% CI -4.07, 4.18) (p=0.23). In terms of perceived utility, there was no strong evidence of differences in baseline adjusted scores among result types at 12 months (p = 0.62). Regarding medical actions, one participant with a negative result, two with a primary VUS, and two with a secondary VUS consulted a healthcare provider about their ES results.
Conclusion:
We did not find evidence that receiving a primary or secondary VUS leads to greater psychological harms or perceived utility of ES compared to negative ES results. Medical actions were also consistent with clinical guidelines on communicating the implications and medical management of VUSs.