Open access Original research Psychosocial problems in women attending French, German and Spanish genetics clinics before and after targeted or multigene testing results: an observational prospective study Anne Brédart,‍ ‍ 1,2 Jean-Luc Kop,3 Julia Dick,4 Alejandra Cano,5 Antoine De Pauw,6 Amélie Anota,7 Joan Brunet,8 Peter Devilee,9 Dominique Stoppa-Lyonnet,6 Rita Schmutzler,4 Sylvie Dolbeault10,11 To cite: Brédart A, Kop J-L, Abstract Dick J, et al. Psychosocial Strengths and limitations of this study Objectives and setting Advances in multigene problems in women attending panel testing for cancer susceptibility has increased French, German and Spanish ►► The Psychosocial Aspects of Hereditary Cancer the complexity of counselling, requiring particular genetics clinics before and questionnaire proved useful for monitoring further attention to counselees’ psychosocial needs. Changes in after targeted or multigene counselling needs after multigene or targeted he- testing results: an observational psychosocial problems before and after genetic testing reditary breast or ovarian cancer testing. prospective study. BMJ Open were prospectively compared between genetic test results ►► The study was performed in cancer genetics prac- 2019;9:e029926. doi:10.1136/ in women tested for breast or ovarian cancer genetic tices from three European countries. bmjopen-2019-029926 susceptibility in French, German and Spanish clinics. ►► The study findings are valid to women opting for Participants and measures Among 752 counselees ►► Prepublication history and genetic testing and test disclosure,who were mainly consecutively approached, 646 (86%) were assessed after additional material for this affected with breast cancer and could not be com- paper are available online. To the initial genetic consultation (T1), including 510 (68%) pared with an appropriate control group. view these files, please visit affected with breast cancer, of which 460 (61%) were ►► Only one genetics clinic per country precludes the journal online (http://​dx.​doi.​ assessed again after receiving the test result (T2), using comparisons of psychosocial difficulties between org/​10.​1136/​bmjopen-​2019-​ questionnaires addressing genetic-specific psychosocial countries. 029926). problems (Psychosocial Aspects of Hereditary Cancer ►► Further research should address the variability be- (PAHC)-six scales). Sociodemographic and clinical data tween clinicians in communication style. Received 19 February 2019 were also collected. Revised 20 August 2019 Results Seventy-nine (17.2%), 19 (4.1%), 259 (56.3%), Accepted 23 August 2019 44 (9.6%) and 59 (12.8%) women received a BRCA1/2, another high/moderate-risk pathogenic variant (PV), Introduction negative uninformative, true negative (TN) or variant A hereditary predisposition explains approx- of uncertain significance result (VUS), respectively. On imately 10% of all breast cancers (BC).1 With multiple regression analyses, compared with women next-generation DNA sequencing and the receiving another result, those with a VUS decreased more in psychosocial problems related to hereditary discovery of new cancer susceptibility genes, predisposition (eg, coping with the test result) (ß=−0.11, the simultaneous analysis of multiple genes, p<0.05) and familial/social issues (eg, risk communication) so-called multigene panel testing, is imple- (ß=−0.13, p<0.05), almost independently from their mented in clinical practice.2 In addition to problems before testing. Women with a PV presented no the highly penetrant hereditary breast or change in hereditary predisposition problems and, so as ovarian cancer (HBOC) predisposition genes women with a TN result, a non-significant increase in © Author(s) (or their such as BRCA1, BRCA2 and PALB2, multi- familial/social issues. Other PAHC scales (ie, emotions, employer(s)) 2019. Re-use familial cancer, personal cancer and children-related gene panels also involve BC (eg, ATM and permitted under CC BY-NC. No CHEK2),3 ovarian cancer (OC) (eg, BRIP1, commercial re-use. See rights issues) were not affected by genetic testing. and permissions. Published by Conclusions In women tested for breast or ovarian RAD51C or RAD51D) 4 moderate-risk genes BMJ. cancer genetic risk in European genetics clinics, and other hereditary syndrome high-pen- For numbered affiliations see psychosocial problems were mostly unaffected by genetic etrant BC susceptibility genes (eg, TP53, end of article. testing. Apart from women receiving a VUS result, those PTEN, CDH1 or STK11). Multigene testing is with another test result presented unchanged needs in generally primarily proposed to a woman in Correspondence to counselling in particular about hereditary predisposition Dr Anne Brédart; the family who developed BC or OC (index and familial/social issues. ​anne.​bredart@​curie.​fr case). If a pathogenic variant is found, blood Brédart A, et al. BMJ Open 2019;9:e029926. doi:10.1136/bmjopen-2019-029926 1 Open access relatives are currently proposed for targeted genetic test result. We also estimated the effect of psychosocial testing. problems before testing on the relationship between the Individuals undergoing genetic testing for cancer risk genetic result and psychosocial problems after testing ask help to appraise and manage their risk of developing to further clarify remaining counselling needs, as initial cancer, inform their family about cancer genetic predis- worries often predict subsequent difficulties.6 19 28 30 position, clarify their children’s risk and, when affected by cancer, gain information about why they developed the disease.5 6 They experience counselling needs for specific Methods problems related to the hereditary predisposition, familial Patient and public involvement and personal cancer, familial and social issues and chil- Counselees were involved in the study by providing feed- dren-related issues within the cancer genetic context,7 back on the content, format and burden of the survey. which may elicit request for psychological help.8 Questionnaires were revised according to counselees’ Different national guidelines in Europe recommend feedback. They will be involved in plans for dissemination genetic counselling before and after genetic testing for of the study. The study results will be publicly available breast or ovarian cancer risk.9–12 This healthcare disci- through the website of ‘Breast Cancer Risk after Diag- pline is defined as ‘the process of helping people under- nostic Gene Sequencing’ research programme (https://​ stand and adapt to the medical, psychological, and familial bridges-​research.​eu). implications of genetic contributions to disease’,13 and so it aims at responding to counselees’ specific psychosocial Study design and setting problems.14 An observational prospective study37 was undertaken Genetic counselling provides a large quantity of infor- within the clinical translation work package of ‘Breast mation involving genetic and statistic concepts, which Cancer Risk after Diagnostic Gene Sequencing’ research may be ambiguous and imprecise.15 16 With multigene programme (https://​bridges-​research.​eu). The study panel testing, this complexity is increased especially design is showed in figure 1. Accrual took place from because of the addition of moderate-risk genes and the November 2016 to April 2018 in the genetics clinics of identification of an increased number of variants of Institute Curie (France), University Hospital of Cologne uncertain significance (VUS).17 Both have unclear clin- (Germany) or Catalan Institute of Oncology (Spain). ical recommendations.16 18 Prolonged clinical distress is uncommon after single-gene testing for HBOC suscep- BC gene testing and counselling tibility.19 However, an inconclusive result such as a VUS BC gene testing and counselling were specific by setting may elicit misunderstanding,20 21 uncertainty21 22 and and based on specific guidelines in each country (Groupe decisional conflicts about clinical management,23 poten- Génétique et Cancer in France12 38; German Consortium tially leading to increased distress,24 miscommunication for Hereditary Breast and Ovarian Cancer-German Gynae- between family members25 and inadequate cancer risk cological Oncology Group in Germany10; and ‘Oncoguia’ management decisions.21 26 27 On receiving a pathogenic guidelines in Spain.11 moderate-penetrance gene variant, counselees may expe- Genetic counselling was considered important, before rience higher distress and uncertainty compared with a and after testing,9 10 38 and to be performed according to negative, VUS and even a pathogenic high-penetrance principles of patient-centred communication.10 variant.28 Across guidelines, gene panel testing was mainly Few studies have addressed psychosocial outcomes after performed in women affected with BC (index cases). A multigene testing for cancer risk.28–30 This observational 12-gene, 34-gene and 9-gene panel was tested in France prospective study assessed the effect of HBOC testing (Paris), Germany (Cologne) and Spain (Barcelona), on specific psychosocial problems in women attending respectively. Targeted testing was proposed to relatives of different European genetics clinics (ie, in France, pathogenic variant carriers. Germany and Spain). Specifically estimating the effect Genetic counselling was provided in face-to-face consul- of genetic testing, we assessed changes in these problems tations: in the French setting, pretest consultation was before and after test disclosure. The outcome measure provided by one of five genetic counsellors with a biology consists in a recently validated questionnaire purported to background and the result disclosure by one of five monitor a comprehensive range of psychosocial problem medical geneticists; in the German setting, pretest and specifically relevant to the cancer genetics context.31 post-test consultations were provided by one of ten physi- Indeed, counselees may experience a wide range of cians, including a medical geneticist and nine gynaecol- psychosocial problems, which unaddressed may exacer- ogists and in the Spanish setting, by one of four genetic bate their distress32 and so pointing to these problems counsellors with a background in biology for one of them according to the test result might target specific counsel- or nursing for the three others. ling needs.33 We hypothesised a lower decrease before and The pretest consultation lasted up to 1 hour. Women after testing in psychosocial problems of women receiving were informed about hereditary cancer risks and the a high/moderate-risk pathogenic variant28 30 34 35 or VUS genetic testing process. Information most systematically result21 36 compared with women receiving a negative provided at that time comprised the probability that the 2 Brédart A, et al. BMJ Open 2019;9:e029926. doi:10.1136/bmjopen-2019-029926 Open access Figure 1 Design of the prospective cohort study. BC, breast cancer; HBOC, hereditary breast or ovarian cancer; IC, Institute Curie; ICO, Barcelona Institute of Oncology; UHC, University Hospital Cologne. woman be carrier of a pathogenic mutation and cancer consecutively approached, including 258, 324 and 170 in risks (breast or ovarian) according to the test result. the French, German and Spanish genetics clinics, respec- The duration of the post-test consultation ranged from tively. Women with a BC recurrence, a personal history 15 min in case of a negative result to 1 hour for a patho- of OC or a major psychiatric disorder were not included. genic variant. Information on cancer risks and medical In each setting, women accepting to participate in the management was validated in multidisciplinary team study received a set of questionnaires to fill in at home meetings. Women were systematically informed about and return within 1 month after the initial (pre-test) their cancer risk in words and, depending on the test consultation (T1) and then 2 months after the genetic result and the country setting, also in percentage (ie, test result disclosure (post-test) consultation (T2). systematically in women receiving a pathogenic variant in the German setting, most frequently in these women Study variables and sources of measurement in the French and Spanish settings, never in percentage Sociodemographic characteristics were collected from in case of negative uninformative in the Spanish setting), counselees after the initial consultation. Women were using ‘Breast and Ovarian Analysis of Disease Incidence also asked whether they had lost family member(s) due to and Carrier Estimation Algorithm’ (BOADICEA) esti- breast or ovarian cancer and if they had received psycho- mates39 in the French and German settings. logical help after the receipt of the test result. Women receiving an uninformative test result were Clinical data were collected from medical records. BC generally told that no pathogenic variant was found, risk estimates were computed at T1 and just before the test which does not preclude a possible yet unknown genetic result disclosure using the BOADICEA web application predisposition explaining the family history of cancer. (BWA v3, University of Cambridge, Cambridge, UK)39 When a VUS was identified, women were told that this (data only available for IC, Paris and UHC, Cologne). result does not allow for concluding that a causal variant Possible gene panel testing results included: (1) a was found; however, clinicians would keep the woman pathogenic variant on BRCA1/2 or (2) other high/moder- informed if this variant was reclassified as pathogenic in ate-risk gene, or (3) a non-informative result (no patho- the future. Women receiving a true negative result were genic variant in index person) or (4) a VUS. Possible informed that their risk of breast or ovarian cancer was targeted gene testing included either a high/moder- the same as the general population. ate-risk pathogenic variant or true negative result (no A psychological consultation was systematically pathogenic variant in predictive tested healthy woman). proposed at the pretest and post-test consultations but Outcomes consist in the genetic-specific psychoso- only available on-site in the French and German settings. cial problems that were assessed at T1 and T2 using the Further details on genetic counselling40 in the three 26-item ‘Psychosocial Aspects of Hereditary Cancer’ settings are provided in online supplementary material (PAHC) questionnaire31 translated according to standard S1. guidelines41 and comprehensively assessed for psycho- metric performance (Brédart et al, The ‘Psychosocial Study participants Aspects in Hereditary Cancer’ questionnaire in women Seven hundred and fifty-two women aged above 18 years, attending BC genetic clinics: reliability, validity, respon- eligible for BC risk testing according to national criteria, siveness and interpretability across French, German and unaffected or affected with a non-metastatic BC were Spanish versions. Under review). A six-factor PAHC model Brédart A, et al. BMJ Open 2019;9:e029926. doi:10.1136/bmjopen-2019-029926 3 Open access Table 1 Sociodemographic and clinical characteristics of study participants by country setting French participants German participants Spanish participants (n=213) (n=300) (n=133) Age (years) Mean (SD) 48.0 (11.9) 47.4 (10.7) 47.9 (12.0) Median (range) 48.0 (21–78) 48.2 (18–77) 48.0 (19–80) Education level, n (%)**** Compulsory education or below 6 (2.8) 37 (12.4) 45 (34.1) Secondary or technical/vocational education 60 (28.4) 167 (56.0) 44 (33.3) Higher education or above 145 (68.7) 94 (31.5) 43 (32.6) Marital status, n (%) Married/partnered 149 (70.3) 212 (71.4) 102 (77.3) Others (widowed, separated/ divorced, single/never 63 (29.7) 85 (28.6) 30 (22.7) married) Having children, n (%) (yes) 170 (79.8) 213 (71.0) 103 (77.4) Personal breast cancer, n (%) (yes) Overall women**** 171 (80.3) 254 (84.7) 85 (63.9) Women with gene panel test† 168 (93.9) 242 (98.8) 82 (97.6) Women with targeted test† 3 (8.8) 12 (22.2) 3 (6.1) Time since breast cancer diagnostic (months)* Mean (SD) 39.1 (62.3) 27.7 (65.4) 41.4 (70.3) Median (range) 13.3 (0.36–342.3) 4.0 (-0.99–490.5) 7.8 (0.69–390.8) Having lost a family member due to breast/ovarian 86 (42.8) 128 (44.4) 60 (46.9) cancer, n (%)(yes) BOADICEA breast cancer first or contralateral risk estimates Mean (SD) 19.6 (11.9) 18.1 (9.2) / Median (range) 17.7 (0.8–82.9) 16.6 (0.7–81.1) / BOADICEA, Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm. French participants German participants Spanish participants Participants at T2 (n=172) (n=220) (n=68) Psychological help since test result receipt, n (%) 20 (11.6) 32 (15.3) 7 (10.3) (yes)*‡ Psychological help since test result receipt among 11 (61.1) 19 (65.5) 3 (42.9) counselees’ referred by genetics clinician, n (%)§ one BOADICEA BC risk estimates missing in French sample as not computed for bilateral breast cancer; other missing data (≤12) due to women self-report omissions. Significant difference between country setting: *p<0.05, ****p<0.0001. †Total n for gene panel and targeted testing are 179 and 34, 245 and 54, 84 and 49, in France, Germany and Spain, respectively. ‡Missing data: n=11 and 1 in German and Spanish participants. §Missing data: n=2 and 3 for French and German participants. yielded acceptable confirmatory factor analysis good- (eg, worry about chance of getting cancer (again)) and chil- ness-of-fit indexes (χ2/df=3.64, root mean square error of dren-related issues (CRI) (eg, guilt about passing the genetic approximation (RMSEA)=0.061 (90% CI 0.057 to 0.066), alteration). These PAHC scales demonstrated expected Comparative Fit Index (CFI)=0.91, Tucker Lewis Index conceptual differences with distress and satisfaction with (TLI)=0.90), providing scales about concerns about counselling. Different interindividual levels of psychoso- hereditary predisposition (HP) (eg, coping about the DNA cial difficulties were evidenced (p values <0.05). We also test result), family and social issues (FSI) (eg, contacting assessed the PAHC ability to respond to change (ie, intra- family members about genetic testing), emotions (E) (eg, inse- individual improvement or deterioration) in perceived cure about the future), familial cancer (FC) (eg, worry that difficulties and computed a minimal clinically important a family member would have cancer), personal cancer (PC) difference threshold in PAHC scores comparing these 4 Brédart A, et al. BMJ Open 2019;9:e029926. doi:10.1136/bmjopen-2019-029926 Open access scores with self-reported needs for additional counsel- BC (new) risk perception, distress and genetic-specific ling (ie, resolution or development of further counsel- problems at T1. Paired Student t-test was used to compare ling needs before and after testing), which yielded a 10% PAHC mean scale scores over assessment times and by change threshold on the PAHC score 1–100 score range. countries, with Bonferroni correction. Internal consistencies for these scales administered at T1 Multiple regression analyses were performed on PAHC and T2 were adequate with Cronbach’s alphas of 0.84 and scale scores at T2 as the dependent variables, and in order 0.84 for HP, 0.72 and 0.81 for FSI, 0.87 and 0.89 for E, to estimate the effect of the test result (ie, the change 0.79 and 0.83 for FC, 0.71 and 0.65 for PC, and 0.73 and before and after testing may reflect the effect of genetic 0.74 for CRI. testing), we controlled for PAHC scores at T1. In addi- Psychosocial covariates included generic distress (ie, tion, for each regression model, we also controlled for anxiety and depression) measured at T2 by the Hospital possible risk or protective factors of psychosocial prob- Anxiety and Depression Scale (HADS), available in lems,47 48 including country, sociodemographic (age, French,42 German43 and Spanish44 versions. Scores range education level, marital and parental status) and clin- from 0 to 42; a cut-off of 12 versus 13 has been proposed ical factors (BC diagnostic status, reported loss of family to identify possible cases of distress.42 45 Additionally, member(s) due to BC or OC), the type of genetic test counselee’s perceived lifetime risks of developing (new (targeted or panel), BC risk perception and distress after or recurrence) BC was measured at T2 in words and in the test result disclosure, the length of time between the figures. As responses to these items were highly correlated pretest and post-test consultations and psychological help (r=0.86), a single variable was created. Taking the ‘Don’t receipt after test disclosure. We also tested the interaction know’ response apart, other response categories of both between PAHC scale scores at T1 and the test result on items were coded from 0 (‘not concerned’) to 6 (‘major PAHC scale scores at T2. risk’ or ‘over 80%’), and an average score was derived. Multiple regression analyses were performed49 in The later variable was then recoded as 0 (‘don’t know’; which, in all models, covariates were introduced in a first ‘not concerned’), 1 (‘low risk’ below 2.5), 2 (‘moderate block, the test result in a second block and the interaction risk’ between score 2.5 and 3.5) and 3 (‘high risk’ above terms in a third block. As the effect of the type of genetic 3.5). test was confounded with the comparison of true nega- To address potential questionnaire non-responses, tive (only identified in counselees’ undergoing targeted when necessary, a reminder call was made 2 weeks after testing) and negative uninformative, these results were the date of expected questionnaire receptions. Question- lumped together. Similarly, as the effect of a patho- naires not received within 1 month after the initial visit genic variants on another high/moderate-risk gene was and within 3 months after the post-test genetic visit were confounded with country (among 19 of these, 18 were considered missing. A sample size of 500 counselees was identified in the German sample), all pathogenic gene targeted in order to compare groups of at least 50 coun- variant results were grouped. The reference category was selees by main genetic test results (ie, positive, negative the negative results (true and uninformative) to which or VUS) and allow for multivariate analyses. Question- we compared either pathogenic variants or VUS results. naire completion online was possible through CleanWeb There was no concern about multicollinearity given that technology. all variables displayed a VIF (variance inflation factor) inferior to an acceptable value of 4.4.50 Statistical analyses Statistical analyses were performed with R software.46 Sociodemographic and clinical characteristics were Results described using mean (SD) or median (range) for contin- Description of the samples uous variables and the number (percentage) for cate- Among 752 counselees consecutively approached, 213 gorical variables. Respondents were defined as having and 172 (82.6% and 66.7%) in France, 300 and 220 provided one response at least to the sociodemographic (92.6% and 67.9%) in Germany and 133 and 68 (78.2% and PAHC questionnaires. For each multi-item scale, and 40.0%) in Spain, respectively, completed the ques- missing data were replaced by the mean value of the scale tionnaires after pretest (T1) and post-test (T2). when at least half of the items on that scale had been Table 1 displays sociodemographic and clinical char- completed. acteristics of the French, German and Spanish respon- We used the F-test (analysis of variance) for contin- dents. Less than 12 missing data were observed in women uous data and the χ2 test for categorical data to compare self-reported information. Their mean ages (SD) were of respondents and non-respondents at T1 (for age, parental 48.0 (11.9), 47.4 (10.7) and 47.9 (12.0) years, and 171 and disease status), respondents by country settings and (80.3%), 254 (84.7) and 85 (63.9) of them were affected differences in PAHC mean scale scores by test result with BC, respectively. Based on the BOADICEA BC risk and country. Respondents and non-respondents at T2 estimation model,39 the mean (SD) per cent of BC life- were compared using logistic regression, accounting for time risk estimates by age 80 years before testing was 19.6 country, age, education, marital and parental status, loss (11.9) and 18.1 (9.2) in France and Germany, respectively of a relative due to BC or OC, BC status, genetic test type, (data not available in Spain). Brédart A, et al. BMJ Open 2019;9:e029926. doi:10.1136/bmjopen-2019-029926 5 Open access Country samples differed significantly in terms of and ‘children-related issues’ (p<0.001). This decrease level of education (p<0.0001) and BC diagnosis status was also statistically significant for ‘hereditary predisposi- (p<0.0001). At T1, there was no significant difference tion’ in France (p<0.01) and Germany (p<0.001) and for between respondents and non-respondents on age, ‘children-related issues’ only in Germany (p<0.001). No having children, BC diagnosis and, for the French and statistically significant decrease appeared in psychosocial German samples, on BOADICEA estimates. At T2, problems related to ‘familial and social issues’, ‘emotion’ respondents and non-respondents differed on BC diag- and ‘familial cancer’. nosis and country samples such that women affected with Among scales displaying a statistical difference over BC and from the German relative to the Spanish setting time, this decrease was clinically significant (according were more frequently respondents (p<0.05). to the validated 10% change threshold in PAHC scale Seventy-nine (17.2%), 19 (4.1%), 259 (56.3%), 44 scores) only in concerns about ‘hereditary predisposi- (9.6%) and 59 (12.8%) women received a pathogenic tion’ (10.7) and ‘children-related issues’ (11.8) in the BRCA1/2 or high/moderate-risk variant other than German sample. BRCA1/2, uninformative, true negative or VUS result. The median length of time between the initial and test Mean change in genetic-specific psychosocial problems by disclosure consultations was shorter in Germany (56 genetic test results and country days) compared with France (183 days) and Spain (98 Bivariate analyses were performed comparing test results days) (online supplementary material S2). on mean changes in levels of psychosocial problems After testing, 20 (11.6), 32, (15.3) and 7 (10.3) coun- before and after testing (table 3). A statistically signifi- selees had received psychological help, respectively cant difference between test results appeared on change (p<0.05 for comparison between countries), and among in hereditary predisposition and familial/social issues them 11 (61.1%), 19 (65.5%) and 3 (42.9%) had been (p<0.01). referred by a genetics clinician, in the French, German Only women receiving a true negative (TN) or a VUS and Spanish setting, respectively. result presented a clinically significant decrease in hered- itary predisposition concerns; although increasing in Change in genetic-specific psychosocial problems over women receiving a pathogenic variant (PV) or TN result, assessment time changes in familial/social difficulties did not reach clin- On the PAHC questionnaire, the level of missing data per ical significance. item was below 5% in all three countries. At both assess- A statistically significant difference between countries ment times, mean scores of psychosocial problems were was also observed on familial/social issues’ (p<0.05). lowest in the ‘Familial/Social Issues’ domain across coun- PAHC scores at T2 only by test result and country are tries, ranging from 11.9 in Spain to 16.6 in Germany. After provided in online supplementary material S3, and testing, psychosocial problem mean scores were highest details of table 3 are provided in online supplementary in the ‘familial cancer’ domain in France (65.8) and material S4. Spain (79.0) and in ‘personal cancer’ (55.0) in Germany (table 2). Multiple regression analyses Over assessment times, an overall statistically significant In multiple regression analysis (table 4), across models decrease was observed in the following concerns: ‘heredi- including covariates, the genetic test result and the inter- tary predisposition’ (p<0.001), ‘personal cancer’ (p<0.05) action between the test result and PAHC scale scores at Table 2 Bivariate analyses of genetic-specific psychosocial difficulties mean (SD) score over assessment times, overall and for each country French participants German participants Spanish participants Psychosocial difficulties (PAHC scales) T1 T2 T1 T2 T1 T2 Mean (SD) n=213 n=172 n=300 n=220 n=133 n=68 Hereditary predisposition*** 29.1 (20.2) 22.4 (20.4) ** 33.7 (24.1) 23.0 (24.9) *** 45.4 (26.6) 35.7 (27.5) Familial and social issues 15.9 (17.3) 15.8 (16.7) 16.6 (16.7) 14.6 (20.4) 11.9 (16.0) 15.1 (20.3) Emotions 30.0 (23.1) 30.6 (24.1) 33.8 (24.3) 30.4 (22.8) 29.3 (23.3) 27.1 (24.0) Familial cancer 67.7 (25.0) 65.8 (27.5) 51.9 (24.3) 50.3 (25.9) 80.0 (18.8) 79.0 (21.4) Personal cancer* 57.7 (27.0) 54.6 (28.5) 58.5 (28.6) 55.0 (27.2) 53.6 (31.8) 48.8 (29.8) Children-related issues*** 47.6 (26.7) 41.7 (27.7) 43.2 (26.9) 31.4 (25.4) *** 60.3 (25.3) 54.8 (25.5) T1=assessment after the initial genetic consultation; T2=assessment 2 months after the receipt of genetic test result. PAHC score range: (0–100). Statistically significant difference between assessment times (with Bonferroni correction): *p<0.05; **p<0.01; ***p<0.001 and in bold clinically significant differences (over 10% change threshold in PAHC scale scores), overall and for each country setting. PAHC, Psychosocial Aspects of Hereditary Cancer. 6 Brédart A, et al. BMJ Open 2019;9:e029926. doi:10.1136/bmjopen-2019-029926 Open access T1, the percentage of explained variance (adjusted R2) in domains of psychosocial problems at T2 ranged from Children-related 28% (hereditary predisposition) to 60% (emotion) (all p<0.001). Notes: T1=assessment after initial genetic consultation; T2=assessment 2 months after receipt of genetic test result. PAHC: score range=0–100, a difference of~10 of the scale range is −2.7 (19.0) −3.7 (21.7) −7.2 (23.0) −11.7 (24.3) −11.9 (23.6) −4.8 (23.0) −10.0 (22.6) −5.5 (21.0) Only adding the test result to covariates in these models PAHC 6 issues improved the prediction of psychosocial problems in clinically significant. Overall statistically significant difference between test results on respondents at T1 and at T2: HP and FSI=**p<0.01 and between countries: FSI=**p<0.05. ‘hereditary predisposition’ (p<0.01) and ‘familial and social issues’ (p<0.05). Compared with a negative test result (true negative and uninformative), receiving a VUS was associated to lower problems in ‘hereditary predispo- −8.8 (20.3) −3.3 (25.0) −11.6 (29.7) −5.5 (21.3) −2.7 (27.3) −4.4 (20.6) −5.2 (29.5) 0.9 (22.2) sition’ (ß=−0.11, p<0.05). Addition of the combined effect Personal PAHC 5 cancer of the test result and PAHC scale scores at T1 tended to Bivariate analyses of mean (SD) differences between T2 and T1 in genetic-specific psychosocial difficulties between test results be significant for scores in ‘hereditary predisposition’ (F (2,381)=2.9, p<0.06) and was significant for ‘familial and social issues’ (F (2,365)=3.7, p<0.05). The effect of scores at T1 on scores at T2 was weaker for a VUS than other −0.1 (19.6) −6.1 (25.3) −2.5 (19.8) −3.0 (21.9) −3.2 (21.9) −1.4 (19.7) −0.6 (18.9) 1.4 (20.5) genetic test results (figures showing the interactions in Familial PAHC 4 cancer online supplementary material S5). Among covariates, compared with Germany, counselees in Spain presented higher levels of problems in ‘heredi- tary predisposition’ (ß=0.14, p<0.01), ‘familial cancer’ −0.1 (18.1) −3.2 (20.2) −1.9 (20.8) −4.0 (15.4) −0.7 (25.8) −2.8 (21.5) 0.5 (18.8) (ß=0.11, p<0.05) and ‘children-related issues’ (ß=0.21, Emotions −34 (21.1) PAHC 3 p<0.001). Distress and PAHC scores at T1 significantly predicted all problems (ß ranging from 0.13, p<0.01, for distress and ‘children-related issues’ to 0.61, p<0.001, for T1 PAHC scores and ‘familial cancer’). Being affected social issues Familial and with BC was associated to higher problems in ‘personal −0.2 (17.1) −6.5 (20.7) −1.5 (18.9) 4.9 (17.7) 6.0 (28.3) 4.3 (17.2) 1.7 (17.8) 4.5 (18.4) cancer’ (ß=0.18, p<0.05). Compared with women PAHC 2 who reported not knowing their risk of BC, those who presented a low risk perception presented lower ‘familial cancer’ and ‘personal cancer’ scores (ß=−0.10, p<0.05). PAHC, Psychosocial Aspects of Hereditary Cancer; VUS, variants of uncertain significance. The receipt of psychological help after testing was asso- ciated to higher problems in the ‘emotions’ domain predisposition (ß=0.09, p<0.01). −3.5 (23.1) −2.5 (22.7) −7.3 (23.2) −12.9 (24.6) −18.3 (29.8) −5.7 (19.7) −10.3 (26.6) −9.5 (28.0) Hereditary Other covariates did not significantly predict psychoso- PAHC 1 cial problems. Discussion In this study, we assessed changes in a comprehensive range of specific psychosocial problems before and after Other high/moderate-risk pathogenic variant (n=19) genetic testing, in women undergoing gene panel or targeted testing for HBOC syndrome in three European country genetics clinics and compared these changes according to the test result received and the problem levels before testing. Information on the extent to which BRCA1/2 pathogenic variant (n=79) genetic testing presents gaps in responding to counselees’ Negative (uninformative) (n=259) psychosocial needs14 and focus for improved counselling could thus be provided. Psychosocial problems only decreased in the domains of hereditary predisposition, personal cancer and children-re- Negative (true) (n=44) Genetic test result lated issues but this decrease was clinically significant only in Germany (n=220) German participants and for hereditary predisposition and France (n=172) children-related domains. Problems remained high, espe- Spain (n=68) VUS (n=59) cially in the domains of personal and familial cancer and Country Table 3 children-related issues (mean level above 33 corresponding to Eijzenga et al31 cut-off score converted on a 0–100 scale indicating need of clinical attention). These problems Brédart A, et al. BMJ Open 2019;9:e029926. doi:10.1136/bmjopen-2019-029926 7 8 Table 4 Multivariable analyses: effect of the genetic test result on scores of genetic-specific psychosocial difficulties at T2 controlled for scores at T1 PAHC 1 PAHC 2 PAHC 6 Hereditary Familial and social PAHC 3 PAHC 4 PAHC 5 Children-related predisposition issues Emotions Familial cancer Personal cancer issues ß ß ß ß ß ß Country Open access Spain versus Germany 0.14** 0.08 0.01 0.11* 0.03 0.21*** France versus Germany 0.04 0.05 0.02 0.01 −0.00 0.15 (0.063) Age (years) −0.01 −0.02 0.01 0.03 −0.06 0.06 Education level Secondary education versus compulsory or −0.06 −0.08 −0.01 −0.01 −0.02 0.03 below Superior education versus compulsory or below −0.09 −0.07 0.07 −0.02 −0.00 −0.04 Marital status (married/partnered vs others) 0.00 −0.06 0.04 0.01 −0.03 −0.03 Having children (yes) −0.03 −0.02 0.02 0.01 −0.00 −0.07 Having lost a family member due to breast/ 0.03 0.02 0.01 0.05 −0.05 0.00 ovarian cancer (yes) Personal breast cancer (yes) −0.06 −0.10 −0.07 −0.06 0.18* 0.04 Type of genetic test (gene panel vs targeted 0.06 0.11 0.06 −0.05 0.04 0.01 test) Breast cancer risk perception at T2 Don’t know vs Low −0.01 −0.05 −0.07 −0.10* −0.10* −0.10 (0.092) Moderate 0.00 −0.06 −0.02 0.00 −0.03 0.00 High 0.02 0.06 0.06 −0.01 0.05 0.01 Generic distress (HADS) at T2 0.28*** 0.21*** 0.54*** 0.23*** 0.29*** 0.13** Psychological help at T2 −0.05 0.03 0.09** 0.01 0.06 0.03 Length of time between initial and genetic test −0.02 −0.00 −0.05 0.07 −0.00 0.00 disclosure consultations PAHC score at T1 0.39*** 0.45*** 0.30*** 0.61*** 0.41*** 0.57*** Block 1 (control variables): F(df); R2; adjusted 9.2 (17,385); 0.29; 9.5 (17,369); 0.30; 36.1 (17,379); 0.62; 32.0 (17,386); 0.59; 26.1 (17,383); 0.54; 15.1 (17,282); 0.48; R2 0.26 0.27 0.60 0.57 0.52 0.44 Genetic test result High/moderate-risk pathogenic variant 0.07 0.06 −0.01 −0.03 −0.01 0.06 VUS −0.11* −0.08 0.02 −0.03 −0.04 −0.04 Block 2 (+genetic test result): F(df); R2; 9.1 (19,383); .031; 9.0 (19,367); 0.32; 32.2 (19,377); 0.62; 28.7 (19,384); 0.59; 23.3 (19,381); 0.54; 13.7 (19,280); 0.48; adjusted R2 0.28 0.28 0.60 0.57 0.51 0.46 Difference between block 1 and block 2: F(df); 5.7 (2,383); 0.004 3.7 (2,367); 0.026 0.30 (2,377); 0.74 0.64 (2,384); 0.53 0.37 (2,381); 0.69 1.20 (2,280); 0.29 p Continued Brédart A, et al. BMJ Open 2019;9:e029926. doi:10.1136/bmjopen-2019-029926 Open access concern pain about the (possible) loss of family members, fear of developing (new or recurrence) cancer or increased 12.4 (21,278); 0.48; 0.46 (2,278); 0.63 Children-related cancer risk in children, which were also highly prevalent in women from HBOC syndrome in other country settings.32 51 In multivariate analyses, the genetic test result was asso- PAHC 6 issues ciated to psychosocial problems only in domains of hered- −0.02 −0.05 0.44 ß itary predisposition and familial and social issues. These study findings and the high level of problems underline the overall impact of undergoing HBOC genetic testing, what- 21.1 (21,379); 0.54; 0.66 (2,379); 0.52 Personal cancer ever the actual test result communicated.52 Two months after the test result disclosure, women carrying a patho- genic variant or an uninformative test result revealed little PAHC 5 change in problems related to ‘hereditary predisposition’ 0.05 0.00 0.51 and so remaining needs in aspects such as clinical decision ß making. We acknowledge the following limitations in this study. 29.4 (21,378); 62; 0.60 26.2 (21,382); 0.59; 1.71 (2,382); 0.18 Samples comprised women opting for genetic testing and Familial cancer test result disclosure and who were mainly affected with −0.07 (0.082) BC, reflecting current population of counselees in the PAHC 4 participating centres (respondents did not differ on key 0.01 HADS, Hospital Anxiety and Depression Scale; PAHC, Psychosocial Aspects of Hereditary Cance; VUS, variant uncertain significance. 0.57 available characteristics). Recruiting counselees from only ß one genetics clinic per country did not allow differentiating between the potential effect of the country and genetics 1.6 (2,375); 0.20 clinic. We could not systematically record which clinician met which counselee and so the variability between clini- −0.06 (0.076) T1=assessment after the initial genetic consultation; T2=assessment 2 months after the receipt of genetic test result. cians was not controlled. The communication content was Emotions PAHC 3 validated during multidisciplinary team meetings in the −0.02 different settings; however, variability may have occurred in ß subtle aspects such as clinicians’ communication style.53 As the rates of pathogenic variants on moderate-risk genes was Familial and social 8.6 (21,365); 0.33; 3.7 (2,365); 0.027 small and almost only present in German participants, we could not adequately contrast this type of test result with others. Finally, as the outcome measure was specifically PAHC 2 designed for individuals undergoing genetic counselling in issues −0.13* 0.01 0.29 order to highlight further counselling needs after testing, ß we could not compare levels of difficulties in our samples with an appropriate control group. 2.9 (2,381); 0.055 8.6 (21,381);0.32; Unexpectedly,36 women receiving a VUS result predisposition decreased in problems related to hereditary predispo- sition, almost independently from their levels of prob- Hereditary PAHC 1 lems before testing. The effect of the test result may −0.11* 0.02 0.28 partly reflect the information provided during counsel- ß ling. Lower problems in women receiving a VUS result Difference between block 2 and block 3: F(df); compared with non-carriers suggests a particular atten- Block 3 (+genetic test result and PAHC scale High/moderate-risk pathogenic variant × PAHC tion to the content of counselling in the case of this partic- ular genetic test result. A VUS result raises uncertainty about clinical management.22 In these study settings, interaction): F(df); R2; adjusted R2 the message conveyed by the communication of a VUS seemed more reassuring than that of an uninformative *p<0.05, **p<0.01, ***p<0.001. negative test result. Recommendations for managing VUS have recently been issued, advising that counselees VUS × PAHC score at T1 Continued may be recontacted if a VUS is reclassified into ‘clinically actionable’ or ‘definitively non-pathogenic’.18 Adherence to these guidelines may avoid detrimental between-clini- cians discordant messages.54 This information imparted Interaction score at T1 Table 4 to counselees may have led them to put their concerns and expectations on hold while non-carriers, mostly individuals receiving an uninformative result in these p Brédart A, et al. BMJ Open 2019;9:e029926. doi:10.1136/bmjopen-2019-029926 9 Open access samples, remained uncertain about their cancer risk psychosocial problems were mostly unaffected by genetic status (eg, how to explain one’s BC diagnostic) and its testing. Apart from women who received a VUS, those medical consequences. with another test results presented unchanged needs in Problems in familial and social issues were relatively low counselling in particular about hereditary predisposition and significantly different across test results: in women and familial/social issues. carriers of a PV and those receiving a TN result, these problems increased (non-significantly), which may be Author affiliations 1 Department of Supportive Care, Psycho-Oncology Unit, Institut Curie, Paris, France explained by the need to inform relatives after learning 2 Psychopathology and Health Process Laboratory, University Paris Descartes, one’s test result. This may be challenging, especially Boulogne-Billancourt, Paris, France to those tested positively55 or elicit feelings of guilt in 3 Département de Psychologie, Université de Lorraine, 2LPN (CEMA), Nancy, France non-carriers towards family members who might receive a 4 Familial Breast and Ovarian Cancer Centre and Faculty of Medicine, Cologne pathogenic result,7 therefore causing need for additional University Hospital, Cologne, Germany 5 Clinical and Health Psychology Department, University Autónoma of Barcelona, counselling for familial or social support and communi- Barcelona, Spain cation.56 57 6 Cancer Genetic Clinic, Institut Curie, Paris, France Distress was strongly related to all domains of psycho- 7 French National Quality of Life in Oncology Platform, and Methodology; Quality of social problems 2 months after the receipt of the test Life in Oncology Unit, University Hospital of Besançon, Besançon, France 8 result,32 48 highlighting the many facets underlying 9 Medical Oncology Department, Catalan Institute of Oncology, Barcelona, Spain Division of Pathology; Department of Human Genetics, Leiden University Medical distress that may be targeted for counselling. The role of Center, Leiden, The Netherlands genetic clinicians, psychologists or psychosocial workers 10 Department of Supportive Care, Psycho-Oncology Unit, Institut Curie, Paris, France with regard to psychosocial problems specific to the 11 CESP, University Paris-Sud, UVSQ, INSERM, University Paris-Saclay, Villejuif, France genetic context is not clearly delineated.58 The effect of genetic testing on psychosocial problems related to Acknowledgements We are grateful to clinical geneticists and counsellors from hereditary predisposition concerns suggests that genetic the Curie Institute, the University Hospital of Cologne and the Catalan Oncology Institute of Barcelona for inviting counselees to participate in the study, and clinicians played a main role in that domain. A recent we would like to thank all participants who provided their time to complete the study observed that genetic counsellors define their role questionnaires. regarding psychosocial problems as short term, refer- Contributors AB, J-LK, PD, DS-L, RS and SD designed the project. AB, JD, AC, ADP, ring counselees to mental health services when they JB, DS-L, RS and SD collected data. AB, J-LK, JD, DS-L, AA, RS and SD analysed, perceive limited social support or significant anxiety interpret data and draft the work. All authors revised and provided final approval of related to a high-risk status or recent cancer diagnosis.58 the version to be published. Psychological care after the test result receipt was associ- Funding This project has received funding from the European Union Horizon 2020 research and innovation programme under grant agreement No 634935 (BRIDGES). ated to higher negative emotions, suggesting that more In France, this work has been partly financed through the SiRIC label, which has distressed counselees received psychological care or designated the Institut Curie, an integrated cancer research site, and a grant from that this was ineffective in reducing negative emotions Ile-de-France Cancer Pole N° 2015-1-EMERG-14-ICH-1. 2 months after the receipt of test result. Less than 15% Competing interests PD reports grants from EU Horizon2020 programme during of counselees received psychological care after testing, the conduct of the study. and among these, about 40%–60% of them had been Patient consent for publication Not required. referred by genetics clinicians depending on the country Ethics approval This study protocol was approved in France by the Comité setting. This study suggests the need to improve access consultatif sur le traitement de l’information en matière de recherche dans le and uptake of psychosocial counselling in women under- domaine de la santé (CCTIRS: Consultative committee for information management in health research – N°16.314), in Germany by the Ethics Committee of the going genetic testing for cancer susceptibility.8 59 University Hospital of Cologne (N°16-098) and, in Spain by the Ethics Committee of As expected due to possible dissimilarities in cultural the Instituto Catalán de Oncología of Barcelona (N° - PR111/16). values and expectations60 and genetic counselling modal- Provenance and peer review Not commissioned; externally peer reviewed. ities,61 significant differences in some genetic-specific Data availability statement Data are available on reasonable request. problems were observed between countries. Concerning Open access This is an open access article distributed in accordance with the genetic counselling, variations between study settings Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which in terms of clinicians’ background, risk communica- permits others to distribute, remix, adapt, build upon this work non-commercially, tion precision (eg, in figures in addition to words) and and license their derivative works on different terms, provided the original work is psychological care availability may partly explain these properly cited, appropriate credit is given, any changes made indicated, and the use differences. Aspects of the genetic counselling consul- is non-commercial. See: http://​creativecommons.​org/​licenses/​by-​nc/​4.​0/. tation such as the content of risk communication and approach to facilitate coping and decision making in relation to resolution of psychosocial problems require References further research.62 1. Fountzilas C, Kaklamani VG. 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