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. 2024 Jul 23;34(2):e1940. doi: 10.1002/jgc4.1940

Psychological distress following multi‐gene panel testing for hereditary breast and ovarian cancer risk

Lindsay Carlsson 1,2,✉, Philippe L Bedard 1,3,4, Raymond H Kim 3,4,5,6,7, Kelly Metcalfe 2,8
PMCID: PMC11907178  PMID: 39044246

Abstract

Advances in our understanding of the genetic landscape of hereditary breast and ovarian cancer (HBOC) have led to the clinical adoption of multi‐gene panel testing. Panel testing introduces new sources of genetic uncertainty secondary to the inclusion of moderate‐ and low‐penetrance genes, as well as the increased likelihood of identifying a variant of uncertain significance (VUS). This cross‐sectional study explored the post‐test psychological functioning of women who underwent multi‐gene panel testing for HBOC susceptibility genes. Two hundred and ninety‐five women who underwent panel testing within the previous 2 years completed a study questionnaire to measure levels of cancer‐related and genetic testing‐related distress using the Impact of Events Scale (IES) and the Multidimensional Impact of Cancer Risk Assessment (MICRA), respectively. Multiple regression analyses were conducted to evaluate the relationship between genetic test results and levels of psychological distress captured by the IES and MICRA. In this cohort, a pathogenic variant (PV) was identified in 41 (14%) of participants, and 77 (26%) participants were found to have a VUS. In the multi‐variate model, higher mean levels of genetic testing‐related distress were observed in individuals with a PV (p < 0.001) or a VUS (p = 0.007) compared to those with a negative result. Furthermore, participants with a PV in a moderate‐penetrance gene were found to have higher levels of genetic testing‐related distress compared to those with a PV in a high‐risk gene (p = 0.03). Overall, participants were highly satisfied with their genetic testing experience, with 92% of individuals reporting they would recommend testing to others. Our findings highlight differences in psychological outcomes based on both variant pathogenicity and gene penetrance, which contribute to our understanding of the impact of panel testing and sources of both cancer‐related and genetic testing‐related distress secondary to testing.

Keywords: breast cancer, genetic testing, hereditary cancer, multi‐gene panels, ovarian cancer, psychological distress

What is known about this topic

Multi‐gene panel testing for hereditary breast and ovarian cancer susceptibility genes is associated with new sources of clinical uncertainty secondary to the evolving data supporting cancer risk estimates with certain moderate‐ and low‐penetrance genes; the increased likelihood of identifying variants of uncertain significance (VUS); and the inclusion of genes where the clinical implications extend beyond HBOC risk. Existing literature exploring psychological outcomes secondary to panel testing suggests that individuals found to have a PV experience higher levels of psychological distress compared to those individuals with a VUS or negative result.

What this paper adds to the topic

The findings of this research emphasize the importance of examining psychological outcomes following multi‐gene panel testing based on both variant pathogenicity and gene penetrance and suggest that heightened levels of psychological distress (both cancer related and genetic testing related) can be observed with longer follow‐up.

1. INTRODUCTION

Multi‐gene panels are now widely used in clinical care to screen for hereditary cancer risk. The shift from single‐gene testing (e.g. BRCA1 and BRCA2) towards screening with multi‐gene panels was prompted by advances in genetic sequencing technologies and our evolving understanding of the number of genes implicated in hereditary breast and ovarian cancer (HBOC). Panels offered to individuals with high‐risk features of HBOC, based on personal or family cancer history, are typically composed of genes involved in known cancer syndromes (e.g. Lynch syndrome), moderate‐to‐highly penetrant breast and ovarian cancer susceptibility genes, as well as those identified as interacting with BRCA1 or BRCA2 (BRCA1/2) along critical molecular pathways.

Multi‐gene panel testing identifies individuals with hereditary cancer syndromes, who otherwise would go undetected by targeted single‐gene testing, thus improving access for high‐risk individuals to cancer screening and prevention strategies (Crawford et al., 2017; Greve et al., 2021). The studies informing the lifetime cancer risk estimates associated with certain genes included on these panels, specifically moderate‐penetrance and lower‐risk genes, are continually evolving to reflect the most current data (Bergstrom et al., 2021; Hamilton & Robson, 2019; Liu et al., 2022; Slavin et al., 2017; Suszynska et al., 2020; Tung et al., 2016; Tung & Desai, 2021; Yang et al., 2020). In addition, the data informing risk estimates associated with specific genetic variants is found to vary depending upon the clinical population being studied (Hu et al., 2021). This can introduce uncertainty for patients and practitioners who are making decisions regarding cancer screening and prevention, as the clinical recommendations associated with certain genetic variants can be limited due to insufficient evidence (Hamilton & Robson, 2019; Tung & Desai, 2021). There are also concerns regarding the implications of panel testing for genetic counseling services, given the high likelihood of identifying variants of unknown significance (VUS) (range between 16% and 42%) and variants with clinical implications extending beyond the indication for testing (Hu et al., 2021). The introduction of panel testing increases the complexity and time required at both pre‐ and post‐test counseling sessions to ensure that patients are able to make informed decisions (Hooker et al., 2017; Marcus et al., 2015). Additionally, long‐term clinical follow‐up is required, such that changes in variant pathogenicity are followed and communicated to patients and family members (Marcus et al., 2015).

There is growing recognition that research needs to be directed toward exploring the impact of multi‐gene panels on patient psychological functioning. There is a wealth of literature examining the psychological outcomes associated with BRCA1/2 testing, which demonstrates that BRCA1/2 genetic testing does not lead to long‐term negative psychological outcomes. Following BRCA1/2 testing, levels of psychological distress have been found to decrease or return to baseline with time, with certain studies suggesting a transient increase in distress among BRCA1/2 carriers (Lapointe et al., 2013; Pieterse et al., 2011). However, a subset of tested individuals experience persistent negative psychological outcomes, including heightened psychological distress and uncertainty (Eijzenga et al., 2014; Lapointe et al., 2013; O'Neill et al., 2009; Smith et al., 2008). This has led investigators to focus on the identification of variables that are associated with heightened psychological distress. Risk factors associated with short‐ and long‐term psychological distress include cancer risk perceptions, familial cancer history, individual factors (e.g. younger age) and social support (Eijzenga et al., 2014; Farrelly et al., 2013; Lombardi et al., 2019; van Oostrom et al., 2006). There is also evidence that the type of genetic test result will impact psychological outcomes (Farrelly et al., 2013; Hamilton et al., 2009). Importantly, uncertain genetic risk associated with uninformative results and VUS following BRCA1/2 testing has been shown to be associated with heightened levels of psychological distress and an overestimation of one's cancer risk (Graves et al., 2012; Vadaparampil et al., 2006; van Dijk et al., 2006, 2008; Vos et al., 2012). Similarly, receipt of a VUS following panel testing can be challenging for individuals to understand in terms of their cancer risks and can be perceived as a health threat (Medendorp et al., 2020; Mighton et al., 2021). Further research is needed as there are conflicting findings in the literature (Makhnoon et al., 2019). Regardless, this highlights that genetic uncertainty can impact the psychological outcomes of tested individuals.

Panel testing introduces new sources of scientific complexity and clinical uncertainty, compared to single‐gene testing, which may impact the psychological response of tested individuals. Initial studies evaluating psychological outcomes secondary to panel testing suggest higher levels of distress and uncertainty experienced by individuals with a positive test result compared to those with a VUS or negative result (Esteban et al., 2018; Idos et al., 2019). Findings across studies are variable due to both different psychological outcomes measured and timing of assessments. One study has demonstrated higher levels of distress and uncertainty associated with a pathogenic variant (PV) in moderate‐penetrance genes 12‐month post‐disclosure (Esteban et al., 2018). These early findings highlight the need for additional studies to compare differences in psychological outcomes based on both variant pathogenicity (positive, VUS, and negative result) and gene penetrance, as well as to measure psychological outcomes with longer follow‐up. In the current study, we report on post‐test psychological functioning of women who have undergone genetic testing for breast and ovarian cancer susceptibility genes within the previous 2 years. Building on existing literature, this study aims to explore differences in psychological distress levels between genetic test result subgroups, based on both variant pathogenicity (PV, VUS, and negative result) and gene penetrance (PV in moderate‐ and high‐penetrance genes). In addition, this study aims to identify different personal and clinical variables associated with psychological distress following panel testing, as well as patient satisfaction with the testing process.

2. METHODS

2.1. Participants

Study participants were recruited from the cancer genetics clinics at Women's College Hospital and the Princess Margaret Cancer Centre in Toronto, Ontario, between October 2018 and April 2021. Genetic testing at both study centers involved pre‐ and post‐test genetic counseling by registered Genetic Counselors. All cases were reviewed by a Medical Geneticist. The genetic test results, including relevant cancer risk estimates and clinical management recommendations, were documented as summary letters in the patient chart. At both centers, individuals were offered multi‐gene panel testing if they met the regional hereditary cancer testing eligibility criteria.

Eligible participants met the following criteria: (i) individuals of the female sex between 18 and 69 years of age; (ii) able to read and write in English; and (iii) received genetic test results from a multi‐gene panel for hereditary breast and ovarian cancer susceptibility genes within previous 24 months. Eligible participants needed to be consented to the study within 24 months of result disclosure (either in person or via telephone). Individuals unaffected and affected by cancer were eligible, as well as those who underwent prior BRCA1/2 genetic testing. Affected individuals must have had an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1. This study was reviewed and approved by the REB at both clinical institutions and at the University of Toronto. As such, this study adhered to the ethical guidelines set forth by these institutions.

2.2. Measurements

Study participants completed a one‐time questionnaire online. The study questionnaire was composed of psychometrically validated tools and study‐specific questions adapted from the BRCA1/2 literature. This questionnaire was drafted in consultation with practitioners in the clinical area and feedback from the initial 8–10 study participants. The study questionnaire captured demographic, clinical variables (personal cancer history and prior genetic testing), knowledge of HBOC, and satisfaction with genetic testing. Knowledge of HBOC was evaluated by a 9‐item, true‐false questionnaire measuring understanding of different concepts including gene penetrance and transmission (Claes et al., 2003; Pieterse et al., 2011). Satisfaction levels with different components of genetic testing, including informational support, time to disclosure, and decision to undergo testing, were measured using five questions (5‐point Likert scale from very satisfied to very dissatisfied) (Wevers et al., 2011).

In addition, participants were asked to complete the Impact of Event Scale (IES) (Horowitz et al., 1979; Thewes et al., 2001) to evaluate cancer‐related distress. The event was being at high risk of developing cancer. This 15‐item self‐report questionnaire can be divided into two subscales, which measure intrusive (7‐items) and avoidant (8‐items) thoughts, with each item measured on a 4‐point scale from ‘not at all’ to ‘often’ (Horowitz et al., 1979). The total score ranges from 0 to 75 and offers clinically significant thresholds, including sub‐clinical distress (0–8); mild distress (9–25); moderate distress (26–44); and severe distress (>44). The psychometric properties of the IES have been studied across different oncology populations, including high‐risk individuals undergoing genetic testing (Thewes et al., 2001). This tool demonstrates strong reliability, with a Cronbach alpha of 0.88 and 0.84 for the intrusion and avoidant subscales, respectively (Thewes et al., 2001). Participants were also asked to complete the Multidimensional Impact of Cancer Risk Assessment (MICRA) questionnaire to capture genetic testing‐related distress (Cella et al., 2002). Within this study, the researchers used the total MICRA score to measure levels of genetic‐testing‐related distress and also examined the distress and uncertainty subscales as a means to understand the sources of distress. The MICRA tool is composed of a total of 25 questions, with each question answered on a 4‐point scale from ‘not at all’ to ‘often’. Factor analysis revealed that the MICRA tool is composed of three subscales: (i) distress scale (6 items – a = 0.86); (ii) uncertainty scale (9 items – a = 0.77); and (iii) positive experiences (4 items – a = 0.75) (Cella et al., 2002). Higher scores on the MICRA tool (and subscales) demonstrate higher levels of genetic testing‐related distress; however, there are no associated clinical thresholds or categories as with the IES tool. The psychometric properties have been evaluated in a cohort of high‐risk women offered BRCA1/2 testing (Cella et al., 2002), and were found to effectively distinguish between BRCA1/2 carriers and those with a negative test result (both uninformative and true negatives). The IES and MICRA tools were selected as they measure different psychological concerns and sources of distress, which enables a more robust understanding of the psychological impact of panel testing.

A medical chart review was completed, and data were abstracted on family cancer history (three‐generation pedigree), personal cancer history (affected or unaffected), and genetic testing‐related variables. Details of the genetic test result, including variant pathogenicity, gene penetrance, relevant cancer risk estimates, and clinical recommendations, were based on available evidence and clinical guidelines at the time of result disclosure, which was documented in the participants' chart by the responsible Genetic Counselor and Medical Geneticist. All genetic testing results were confirmed by reviewing the source laboratory report. Test results were classified as follows based on variant pathogenicity: (i) pathogenic variants (including both pathogenic and likely pathogenic variants); (ii) variant of uncertain significance; and (iii) negative (or benign) results. Participants who were found to have both a PV and VUS were categorized as having a PV, as this was most relevant to their clinical management. During medical chart review, any concerns regarding the classification of genetic test results, in terms of variant pathogenicity or gene penetrance, were flagged to the respective Genetic Counselor and/or Medical Geneticist for confirmation.

2.3. Study procedures

Participants were sent an introductory letter and consent form via email or mail, depending upon the ‘preferred method’ of future communication documented in their medical charts. Within 1–2 weeks of distributing the introductory letter and consent form, participants received a telephone call from the study coordinator to explain the purpose of this study and respond to any questions and/or concerns. The introductory letter provided a web address to access the online questionnaire, as well as the individualized participant identification code. Study questionnaires were completed on the SurveyMonkey online platform. Participants who did not complete the online questionnaire within 3 weeks of the introductory letter distribution date received two follow‐up reminder telephone calls from the study coordinator (3 and 5 weeks following initial contact).

2.4. Statistical analyses

Each variable will be summarized using descriptive statistics. Independent t tests and chi‐square tests will be performed to assess relationships between key demographic and clinical variables and the psychological outcomes. One‐way ANOVA tests will be conducted to compare mean IES and MICRA scores across genetic test result categories. Necessary assumptions will be evaluated and met prior to advancing with the analysis. Providing the F ratio is found to be significant (p < 0.05) (Field, 2013).

Multiple regression analyses will be performed to test the relationship between the genetic test results and the psychological distress outcomes, while controlling for potential confounding variables and testing the moderating effect of age (at the time of questionnaire completion), having children (yes or no), knowledge levels, and time since disclosure (months). Hierarchical data entry will be conducted using variables selected a priori based on the literature. The first block in the model will include the group effect (panel test result – three categories) and potential confounding variables, including personal cancer history (affected or unaffected), family history and prior BRCA1/2 testing (yes or no). A positive family history corresponds to at least one first‐degree or second‐degree relative with breast and/or ovarian cancer. The second block will add the main effects of the hypothesized moderators outlined above. Finally, the third block includes the interaction effects. The “global” test described by Kleinbaum (2014) will be used to test for interactions. Prior to modeling the data, preliminary work will be undertaken including testing for assumptions, such as linearity, homoscedasticity, and normally distributed errors. The R 2 statistic will be used to assess overall model fit and the amount of variance explained. Furthermore, the beta‐value (b), standardized beta‐value (β), and corresponding t‐statistic and level of significance (p value) will be evaluated to determine the role and significance of each variable (Field, 2013).

3. RESULTS

3.1. Study population

A total of 856 patients from the Familial Breast Cancer Research Unit at Women's College Hospital and the Familial Cancer Clinic at Princess Margaret Cancer Centre were screened for this study. A final sample of 580 patients were deemed eligible, with patients excluded due to poor performance status (n = 46); no current contact details (n = 120); greater than 2 years since result disclosure (n = 97); or non‐English speaking (n = 13). Five individuals consented but did not complete the study questionnaire. Of the 580 eligible patients, a total of 295 individuals consented and completed the study questionnaire (51% response rate).

Of the 295 participants, the mean age at the time of questionnaire completion was 52 years (range 23–70 years), 74% self‐identified as White, 86% were university or college educated, and 70% were married (Table 1). In total, 226 (77%) participants reported a personal history of breast and/or ovarian cancer, and 119 (40%) reported more than one first‐ or second‐degree relative with breast or ovarian cancer. All participants underwent multi‐gene panel testing, and 65 (22%) reported prior negative BRCA1/2 testing. The panel tests ranged between testing 4 and 36 genes, with 56% of participants (n = 165) offered a 20‐gene panel. The mean time since disclosure of the panel test result was 17.3 months (range 6.2–29.3 months).

TABLE 1.

Patient characteristics.

Baseline characteristics n = 295 (%)
Age a
Mean (SD) 52 (SD = 10.7)
Range 23–70
Ethnicity
White 219 (74%)
Middle Eastern 14 (5%)
Latin American 8 (3%)
Other 54 (18%)
Education level
University or College Education 254 (86%)
High School Diploma 21 (7%)
Other 20 (7%)
Marital status
Single 33 (11%)
Married or common‐law 206 (70%)
Separated or divorced 37 (13%)
Other 22 (7%)
Have children 191 (65%)
No children 104 (35%)
Family history of breast cancer
1 FDR 40 (14%)
1 SDR 42 (14%)
>1 FDR or SDR 110 (37%)
Family history of ovarian cancer
1 FDR 29 (10%)
1 SDR 18 (6%)
>1 FDR or SDR 9 (3%)
Cancer status
Breast cancer 186 (63%)
Ovarian cancer 40 (14%)
Prior BRCA1/2 testing 65 (22%)
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Abbreviations: FDR, first‐degree relative; SDR, second‐degree relative.

a

Age at the time of questionnaire completion.

3.2. Panel test results

Overall, a pathogenic variant (PV) was identified in 41 (14%) individuals, with 18 in a high‐penetrance gene (BRCA1 (8), BRCA2 (8), MLH1 (1), and MSH2 (1)) and 18 in a moderate‐penetrance gene (CHEK2 (7), BRIP1 (3), ATM (4), RAD51C (1), and RAD51D (3)). An additional five PV were identified in low‐risk genes (FANCC (4) and FANCM (1)). A total of 77 (26%) individuals were found to have a VUS. Demographic and clinical variables were not found to significantly differ based upon the genetic test result (PV, VUS, and negative result) (Table 2).

TABLE 2.

Demographic and clinical variables based on genetic test results.

Negative (n = 177) VUS (n = 77) Pathogenic (n = 41) p Value Total sample (n = 295)
Personal cancer history 135 (76%) 60 (78%) 31 (76%) 0.90 226 (77%)
Family history of breast and/or ovarian cancer 137 (77%) 62 (81%) 27 (65%) 0.17 226 (77%)
Prior BRCA testing 39 (22%) 19 (25%) 7 (17%) 0.86 65 (22%)
Age 52 (SD = 10.8) 53 (SD = 10.3) 52 (SD = 10.9) 0.79 52 (SD = 10.7)
Knowledge level 7.4 (SD = 1.7) 7.3 (SD = 1.6) 7.6 (SD = 1.5) 0.61 7.4 (SD = 1.6)
Have children 115 (65%) 53 (69%) 23 (56%) 0.45 191 (65%)
Time since disclosure (days) 518 (SD = 165) 543 (SD = 171) 534 (SD = 166) 0.56 527 (SD = 166)
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3.3. Psychological outcomes

3.3.1. Cancer‐related distress

The mean total scores for the Impact of Event Scale (IES) did not significantly differ based on genetic test results among PV, VUS, and negative result subgroups (p = 0.85). The mean total IES score was 23.81 for PV, 23.31 for VUS, and 25.24 for negative (Table 3). Among individuals with a PV, the mean total IES score was 29.31 for women with a moderate‐penetrance variant compared to 19.19 for women with a variant in a high‐risk gene (p = 0.095). Mean scores on the IES intrusion subscale were higher in women with a PV in a moderate‐penetrance gene compared to a PV in a high‐risk gene (p = 0.011). This difference was not observed in the IES avoidance subscale (Data S1).

TABLE 3.

Mean scores for cancer‐related and genetic testing‐related distress.

Total sample (n = 295), mean (SD) Pathogenic (n = 41), mean (SD) VUS (n = 77), mean (SD) Negative (n = 177), mean (SD) ANOVA (p‐value)
IES
Total 24.5 (SD = 17.1) 23.81 (SD = 16.7) 23.31 (SD = 17.1) 25.24 (SD = 17.3) 0.85
Intrusion 10.87 (SD = 8.8) 10.32 (SD = 8.9) 10.50 (SD = 8.6) 11.16 (SD = 8.8) 0.81
Avoidance 14.79 (SD = 10.8) 14.76 (SD = 11.8) 14.15 (SD = 9.6) 15.06 (SD = 11.0) 0.71
MICRA
Total 20.49 (SD = 12.9) 31.18 (SD = 17.3) 21.93 (SD = 10.8) 17.26 (SD = 10.8) <0.001
Distress 3.67 (SD = 5.4) 8.11 (SD = 8.2) 3.10 (SD = 4.6) 2.79 (SD = 4.3) 0.001
Uncertainty 9.55 (SD = 8.4) 13.16 (SD = 10.4) 9.93 (SD = 7.9) 8.50 (SD = 7.8) 0.03
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Bold values indicates p‐values were deemed statistically significant if < 0.05.

Overall, 45.6% of participants had moderate or severe cancer‐related distress (IES total score > 26). There were no significant differences based on genetic test results (p = 0.95). Thirty‐one percent of individuals with a PV in a high‐risk gene had moderate or severe cancer‐related distress, compared to 63% of women with a PV in a moderate‐risk gene (p = 0.062).

In the multivariate model, when controlling for demographic and clinical factors increasing age (p = 0.004) and higher knowledge levels (p < 0.001) were associated with lower levels of cancer‐related distress. Having children was associated with higher levels of cancer‐related distress (p = 0.004) (Table 4).

TABLE 4.

Multivariate model for cancer‐related distress (IES).

Beta SE p Value
Genetic test result
Pathogenic −0.51 3.05 0.87
VUS −2.49 2.38 0.30
Negative Reference
Confounders
Positive personal cancer history 4.88 2.51 0.054
Positive family history −1.77 2.45 0.47
Prior BRCA testing 1.36 2.45 0.58
Moderators
Age −0.30 0.10 0.004
Knowledge level −2.65 0.63 <0.001
Presence of children 6.27 2.18 0.004
Time since disclosure (days) 0.0001 0.006 0.95
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Bold values indicates p‐values were deemed statistically significant if < 0.05.

3.3.2. Genetic testing‐related distress

The mean total scores on the Multidimensional Impact of Cancer Risk Assessment (MICRA) scale were significantly different among PV, VUS, and negative result subgroups (p < 0.001) (Table 3). The mean total MICRA score was 31.18 for PV, 21.93 for VUS, and 17.26 for a negative result. Participants with a PV had significantly higher mean MICRA total scores compared to participants with a VUS or negative result (p < 0.001). On the MICRA distress (p = 0.001) and uncertainty (p = 0.03) subscales, individuals with a PV had significantly higher mean scores compared to individuals with a VUS or negative result (Table 3). Individuals with a PV in moderate‐penetrance gene had significantly higher mean scores for the MICRA total (p = 0.03), as well as distress (p = 0.027) and uncertainty (p = 0.014) subscales, compared to individuals with a PV in a high‐risk gene (Data S1).

In the multivariate model, after controlling for clinical and demographic variables, participants with a PV or VUS genetic test result had significantly higher mean total MICRA scores compared to participants with a negative test result (Table 5). On the MICRA distress and uncertainty subscales, individuals with a PV had significantly higher mean scores compared to those with a negative result (Table 5). Overall, higher knowledge scores were associated with lower levels of uncertainty (p = 0.03) and distress levels (p = 0.001). Older age was associated with lower levels of uncertainty (p = 0.04) (Table 5).

TABLE 5.

Multivariate model for genetic testing‐related distress (MICRA).

Total MICRA score Distress subscale Uncertainty subscale
Beta SE p Value Beta SE p Value Beta SE p Value
Genetic test result
Pathogenic 13.63 2.25 <0.001 5.23 0.95 <0.001 4.35 1.54 0.005
VUS 4.98 1.81 0.007 0.47 0.77 0.55 1.57 1.24 0.21
Negative Reference Reference Reference
Confounders
Positive personal cancer history −1.48 1.86 0.43 −0.51 0.79 0.52 0.19 1.28 0.88
Positive family history −0.50 1.86 0.79 −0.74 0.79 0.35 −0.50 1.27 0.70
Prior BRCA testing 1.86 1.88 0.32 1.40 0.80 0.08 1.72 1.29 0.18
Moderators
Age −0.13 0.08 0.08 −0.031 0.03 0.33 −0.11 0.052 0.04
Knowledge level −0.55 0.50 0.28 −0.69 0.21 0.001 −0.77 0.34 0.03
Presence of children 2.72 1.64 0.10 0.38 0.70 0.59 2.16 1.13 0.06
Time since disclosure (days) −0.006 0.005 0.20 −0.002 0.002 0.23 −0.002 0.003 0.54
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Bold values indicates p‐values were deemed statistically significant if < 0.05.

3.4. Satisfaction levels with genetic testing

Overall, participants were satisfied with their genetic testing experience. Ninety‐three percent of individuals reporting being either ‘satisfied’ or ‘highly satisfied’ with their decision to have panel genetic testing and 88% of individuals were either satisfied or highly satisfied with the information and support provided during the testing process. The wait time to receive their genetic test results was the item on the satisfaction questionnaire with the lowest proportion of individuals being either ‘satisfied’ or ‘highly satisfied’ (82%). Ninety‐two percent of individuals reported being ‘likely’ or ‘highly likely’ to recommend multi‐gene panel testing to others.

4. DISCUSSION

This cross‐sectional study was designed to explore the post‐test psychological functioning of women who have undergone multi‐gene panel testing for HBOC risk. We found that after an average of 17 months following result disclosure, cancer‐related distress did not differ based upon the type of genetic test result received (PV, VUS, or negative result) and mean levels of distress across all test result subgroups were below the IES clinically significant threshold (<26). Conversely, genetic testing‐related distress was higher in participants with PV and VUS compared to those with a negative test result. In addition, we found that participants with a PV in a moderate‐penetrance gene experienced higher levels of genetic testing‐related distress compared to those with a PV in high‐risk gene.

Concerns have been raised regarding the psychological impact of panel testing related to the limited data informing age‐specific cancer risk estimates and clinical recommendations associated with certain moderate‐penetrance and low‐risk genes (Couch et al., 2017; Hamilton & Robson, 2019). Our findings demonstrate the importance of exploring differences in psychological distress based not only on variant pathogenicity (PV, VUS, and negative result) but also gene penetrance (high‐risk and moderate‐penetrance variants). When comparing outcomes based upon variant pathogenicity, we found statistical differences in levels of genetic testing‐related distress (MICRA tool), where individuals with a PV and VUS reported higher levels of distress compared to those with a negative result. In addition, we found that individuals with a PV in a moderate‐penetrance gene experienced higher levels of genetic testing‐related distress (MICRA total score and subscales), as well as higher scores on the intrusion subscale of the IES tool, compared to individuals with a PV in high‐risk gene. Currently, much of the existing literature evaluating psychological outcomes following panel testing is focused on exploring differences based on variant pathogenicity (PV, VUS, and negative result) (Bradbury et al., 2020; Idos et al., 2019; Lumish et al., 2017). These studies suggest carriers of a PV experience higher levels of genetic testing‐related distress, although these initial findings are inconsistent, which likely reflects the variable timing of assessments and tools used to measure psychological outcomes (Bradbury et al., 2016; Esteban et al., 2018).

Similar to our findings, Esteban et al. (2018) also observed higher levels of cancer‐related distress and genetic testing‐related concerns among individuals with a PV in a moderate‐penetrance gene compared to a high‐risk gene. Our findings support that genetic testing‐related distress persists with longer follow‐up, which suggests that this subgroup of individuals may benefit from additional support. Current research, both prospective and cross‐sectional studies, have focused on examining psychological outcomes 12–13 months post‐disclosure of panel test results (Esteban et al., 2018; Lumish et al., 2017), whereas on average, individuals in this study received their results within 17 months. Currently, it is unclear why women with a PV in a moderate‐penetrance gene experience higher levels of distress. Literature examining the impact of uncertainty secondary to uninformative genetic results and VUS highlights that patients struggle to interpret the clinical significance of these test results (Makhnoon et al., 2019, 2021). This can negatively impact their cancer risk perceptions, communication of their results to family members, and decisions surrounding cancer screening and prevention (Graves et al., 2012; Makhnoon et al., 2019, 2021; Scherr et al., 2021; van Dijk et al., 2006, 2008; Vos et al., 2012). Future studies should explore this idea of uncertainty as it relates to variants in moderate‐penetrance genes, and how this influences the psychological response of tested individuals.

Although our findings identify subgroups of tested individuals who experience higher levels of psychological distress, overall, most individuals in our study do not experience moderate or severe cancer‐related distress following panel testing. This aligns with the BRCA1/2 literature, where transient elevations in distress can be observed after result disclosure, but then return to baseline levels or below over time (Lapointe et al., 2013; Lombardi et al., 2019). However, 10%–25% of individuals undergoing BRCA1/2 testing experience long‐term negative psychological outcomes. In our study, the mean scores on the IES were below the validated clinically significant distress threshold, however, 45.6% of respondents reported moderate or severe distress (IES > 26). Of note, 43.2% of women with PV also reported moderate or severe distress. This is substantially higher than previously reported levels in studies evaluating long‐term psychological distress among BRCA1/2 carriers (Farrelly et al., 2013; Metcalfe et al., 2020). For example, Farrelly et al. (2013) measured cancer‐related distress among BRCA1/2 carriers on average 1.7 years following disclosure and found that 34% of participants reported moderate or severe cancer‐related distress. These authors demonstrated that higher levels of unmet informational and supportive needs were associated with heightened levels of distress (Farrelly et al., 2013).

Interestingly, in our sample, a higher proportion of women with a PV in a moderate‐penetrance gene (62.5%) reported moderate or severe cancer‐related distress compared to those with a PV in a high‐risk gene (31.3%). Currently, there is limited reporting on the proportion of individuals who report clinically significant distress following multi‐gene panel testing. Esteban et al. (2018) found individuals with a PV in moderate‐penetrance gene 12 months post‐disclosure reported a mean score of 30.67 on the revised version of the IES. This mean value falls within the range where symptoms of distress are expected, suggesting clinical significance. Further research is needed to evaluate the proportion of individuals reporting long‐term, clinically significant psychological distress in the context of multi‐gene panel testing. Moving forward, it is important to evaluate clinical and personal factors that contribute to clinically significant levels of distress, such that at‐risk individuals can be identified through screening and offered additional education and support.

Our findings suggest that both higher knowledge scores and older age were associated with lower levels of both cancer‐related and genetic testing‐related distress, whereas having children was the only factor associated with increased cancer‐related distress. Age and family characteristics were previously shown to influence individual psychological response to BRCA1/2 testing (Farrelly et al., 2013; Lombardi et al., 2019). The literature suggests that individuals undergoing BRCA1/2 testing worry about the implications of their genetic test results for their family members, especially their children (Farrelly et al., 2013; Lombardi et al., 2019). The impact of age on cancer‐related distress has also been observed in individuals who have undergone panel testing, where older age was associated with lower levels of reported distress (Bradbury et al., 2020). In addition, there is evidence from the BRCA1/2 literature that having access to counseling and education prior to genetic testing acts as a protective factor in terms of one's distress response (Lombardi et al., 2019). This aligns with the findings of Lumish et al. (2017), who demonstrated that higher levels of genetics knowledge were associated with lower scores on the IES avoidance subscale in high‐risk cohorts who underwent multi‐gene panel testing for HBOC risk. Multi‐gene panel testing introduces new sources of clinical uncertainty and complexity that can be challenging for patients to understand. It is recognized that patients offered panel testing will have specific informational and supportive needs to ensure they are making informed decisions (Domchek et al., 2013; Hamilton & Robson, 2019). New approaches to genetic counseling are being implemented given the strain placed on existing services due to the mainstreaming of germline testing (Stoll et al., 2018). In addition to such research efforts, future studies also need to explore the specific informational needs of patients and families offered more comprehensive forms of genetic screening, as well as the development of screening tools that can effectively triage patients who may need additional counseling and educational support.

4.1. Limitations

There are several limitations to this current study. A convenience study sample was used in this study, which potentially introduces sampling bias. Participants were recruited from urban academic cancer centers, and the majority of participants were White and had post‐secondary education, which potentially limits the generalizability of our findings. However, the clinical and demographic composition of our study sample is similar to both the BRCA1/2 and multi‐gene panel testing literature. The cross‐sectional study design does not allow us to capture changes over time or account for key baseline levels that may influence the psychological outcomes of interest in this study. In addition, given the average time between questionnaire completion and disclosure of genetic test results was approximately 17 months, there is potential for recall bias. Our study was designed to meaningfully capture both cancer‐related and genetic testing‐related distress in an attempt to better understand the psychological response to multi‐gene panel testing. However, only 14% of our study sample was reported to have a PV test result, which limited our ability to evaluate differences based on gene penetrance. Finally, given differences in the size of gene panels used within this study, this may have influenced the patient experience and psychological distress levels in response to panel testing.

4.2. Practice implications

Genetic counseling services are increasingly stretched secondary to the widespread availability of next‐generation sequencing and decreasing costs associated with testing (Greve et al., 2021; Stoll et al., 2018). In response to the current burden on genetic counseling services, alternate models of genetic counseling are being evaluated, including group and telephone‐based counseling services, as well as online tools (Greve et al., 2021; Stoll et al., 2018). An understanding of the specific demographic and clinical variables that are associated with heightened levels of psychological distress, such as younger age and having children as demonstrated in our findings, may support the stratification of patients at the time of pre‐test counseling. Identifying patients at risk of higher levels of psychological distress following testing will support appropriate access to additional support and education. In addition, an examination of the tools used to measure levels of psychological distress can support our understanding of the specific concerns of tested individuals. Within our study, a PV was associated with higher levels of genetic testing‐related distress compared to those with a negative result, which suggests that individuals with a PV experience an emotional response to their test results, as well as have concerns surrounding the implications of the result for themselves and their children. Thus, careful examination of the tools used to measure psychological outcomes based on both variant pathogenicity and gene penetrance may provide key insights into the sources of psychological distress, which can then support the tailoring of genetic counseling.

5. CONCLUSIONS

We conclude that although the majority of women in this cohort do not report clinically significant cancer‐related distress following multi‐gene panel testing, a substantial proportion of tested individuals (45.6%) do fall within clinically significant levels. In addition, subgroups of women based on their genetic test results do report long‐term genetic‐testing‐related distress. Collectively, this warrants further investigation, with particular attention directed toward evaluating differences based on gene penetrance in the subset of women with a PV. Furthermore, prospective research is needed to identify predictors of heightened distress, such that women at risk of experiencing long‐term distress are offered additional educational and psychosocial support.

AUTHOR CONTRIBUTIONS

All authors provided substantial contributions to this manuscript. Conceptualization of study design: L.C., P.L.B., R.H.K., and K.M.; data collection and analysis: L.C. and K.M.; and data analysis and manuscript development: L.C., P.L.B., R.H.K., and K.M.

CONFLICT OF INTEREST STATEMENT

Not applicable.

ETHICS STATEMENT

Institutional REB approval was received for the research conducted in this manuscript.

Supporting information

Data S1:

JGC4-34-0-s001.docx (152KB, docx)

ACKNOWLEDGMENTS

The authors would like to acknowledge the study staff at Women's College Hospital and the Princess Margaret Cancer Centre who supported this research project. In addition, we would like to acknowledge the study participants for their time and willingness to participate in this study. This research was completed as part of a PhD dissertation for the primary author (L.C.).

Carlsson, L. , Bedard, P. L. , Kim, R. H. , & Metcalfe, K. (2025). Psychological distress following multi‐gene panel testing for hereditary breast and ovarian cancer risk. Journal of Genetic Counseling, 34, e1940. 10.1002/jgc4.1940

DATA AVAILABILITY STATEMENT

Raw study data will not be made available due to the restrictions placed by the local REB.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Data S1:

JGC4-34-0-s001.docx (152KB, docx)

Data Availability Statement

Raw study data will not be made available due to the restrictions placed by the local REB.

Articles from Journal of Genetic Counseling are provided here courtesy of Wiley

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