Mainstream genetic testing pathway

We previously described the development and workflow of our mainstream genetic testing pathway [9]. We implemented this pathway in the four hospitals in our region where patients are diagnosed and treated for EOC. In April and August 2018, we started in the two hospitals with the highest numbers of newly diagnosed patients with EOC. In March and July 2019, we implemented our pathway in the other two hospitals. After completion of a training module, non-genetic HCPs could perform pre-test genetic counseling and order genetic testing for all patients eligible for genetic testing according to national guidelines (i.e., EOC, including fallopian tube and extra ovarian carcinomas), including patients who were diagnosed in the past and had not yet received genetic testing [1]. These non-genetic HCPs included gynecologic oncologists, gynecologists with a subspecialty training in oncology, and nurse specialists. If indicated by the patient or non-genetic HCP, patients could still be referred for pre-test counseling by a genetic HCP (e.g., when the patient had questions that the non-genetic HCP could not answer). Our gene panel first consisted of the genes: BRCA1 and BRCA2 [1]. During our study, this panel was complemented by the genes BRIP1, RAD51C, and RAD51D.

During pre-test counseling, non-genetic HCPs informed patients of the implications of genetic testing and handed out an information sheet with general information about genetic testing. For patients who accepted genetic testing, written informed consent was obtained and the DNA test ordered. In addition, non-genetic HCPs filled out a checklist to identify patients with a relevant personal or family history indicative for referral to a genetics department (e.g., meeting eligibility criteria for Lynch syndrome testing and/or preventive measures for family members).

The genetics department sent the test results to patients in a letter, which also included a general information sheet explaining this result. This letter was also sent to the HCP who had ordered the DNA test and to the general practitioner. An invitation for post-test counseling at the genetics department was added to this letter for all patients carrying a pathogenic variant or variant of unknown significance within five working days, or patients with a relevant personal or family history within 6–8 weeks.

Standard genetic testing pathway

For patients referred to the genetics department, a clinical geneticist or genetic counselor performed pre-test counseling and acquired information regarding the family history, obtained written informed consent and ordered the DNA test. During our study period, patients could either be referred to the genetics department by non-genetic HCPs who were not trained in the mainstream genetic testing pathway (e.g., general practitioners or medical oncologists) or by trained non-genetic HCPs when there was an indication for such a referral. Test results were discussed with the patient in person, via telephone or videoconference. Subsequently, the test result and possible implications of this result for patient and family members were summarized in a letter to the patient. This letter was also sent to the general practitioner and the non-genetic HCP who referred the patient.

Study design and participants

All patients who received pre-test genetic counseling and testing in the mainstream genetic testing pathway were invited prospectively to participate in our questionnaire study between April 2018 and April 2020 (see Fig. 1). All patients who received pre-test counseling were eligible to participate in our intervention group, even if they declined genetic testing. They received information about the study, including a response sheet, directly after discussing the DNA test with their HCP (T0). We sent a reminder letter after two weeks to all patients for whom a DNA test was requested by a non-genetic HCP. The first questionnaire was sent to patients who accepted the invitation to participate in our study. Patients only received a second questionnaire if a DNA test was performed. This second questionnaire was sent to patients approximately four weeks after receiving their test result (T1).

Fig. 1

Study design and participation in questionnaire study. aTwo questionnaires were returned without being completed and with a comment that the patient had died. bPatients in the control group received pre-test genetic counseling both before and during our study period (from January 2017 until April 2020). Patients who received genetic counseling during our study period received the questionnaire approximately four weeks after the test result was made available. Patients who received genetic counseling before our study period received the questionnaire between four weeks and one year after receiving the test result. cTwo patients were excluded after receiving the questionnaire, one because of a language barrier and one because the patient received counseling for breast cancer and the EOC was diagnosed after preventive surgery

For our control group, we retrospectively invited patients who had received pre-test genetic counseling and testing in the standard genetic testing pathway to participate in our questionnaire study at least four weeks after receiving the test result. We identified all patients with EOC who had received pre-test counseling at the genetics department between January 2017 and April 2020. We only invited patients to participate in our study when we could confirm vital status and current address. In addition, we excluded patients who previously declined to participate in research, had not completed their genetic counseling, or when a pathogenic variant in one of the ovarian cancer genes was already identified in a family member. We sent out a reminder letter after two weeks to non-responders.

We obtained data from medical records of patients who participated in our questionnaire study regarding: diagnosis, age at diagnosis, interval between receiving test result and completing the questionnaire, turnaround times, genes tested, and test results. The consent forms for diagnostic germline genetic testing and checklists evaluating patients’ personal and family history were only evaluated for patients in the intervention group. For the evaluation of these consent forms, checklists and, in addition, turnaround times, our intervention group consisted of all patients who received mainstream genetic testing, and not only the patients who participated in our questionnaire study.

Questionnaires

The questionnaires consisted of nine elements: (1) sociodemographics, (2) treatment history, (3) distress, (4) anxiety and depression, (5) knowledge, (6) discussed topics during pre-test counseling, (7) satisfaction with pre-test counseling, (8) satisfaction with receiving the test result, and (9) satisfaction with the decision to accept or decline genetic testing. Table 1 shows which elements were present in the different questionnaires for the intervention and control group.

Table 1 Overview of topics in questionnairesOutcome measuresPsychosocial outcomes

Psychosocial outcomes consisted of (1) anxiety and depression, (2) distress, (3) decisional conflict, and (4) decision regret.

Anxiety and depression were measured using the Hospital Anxiety and Depression Scale (HADS) [22, 23]. The HADS is a validated questionnaire consisting of 14 items with a four-point Likert scale: seven questions for anxiety (HADS-A) and seven questions for depression (HADS-D). Scores for both subscales range between zero and 21. Scores on a subscale ≥ 11 indicate clinically significant levels of anxiety or depression [24].

Distress was measured using the one-item Distress Thermometer (DT) [25]. The DT has a scale from 0 to 10, with 0 indicating ‘no distress’ and 10 indicating ‘extreme distress’. A score of ≥ 4 indicates moderate to severe distress [25].

Decisional conflict was measured with the decisional conflict scale [26, 27]. This questionnaire consists of 16 items with a five-point Likert scale for each question. A total score and five subscores can be determined, all ranging from 0 to 100, with 0 indicating no decisional conflict and 100 indicating maximal decisional conflict. The question: ‘I expect to stick with my decision’ was left out of the T1 questionnaire for the intervention group and questionnaire for the control group because these questionnaires were sent after the DNA test had already been performed and therefore this question did not apply at that time.

The level of decision regret was measured with the decision regret scale [28]. This questionnaire consists of five items with a 5-point Likert scale. Scores range between 0 and 100, with 0 indicating no regret and 100 indicating maximal regret.

Knowledge and discussed topics

Knowledge was measured with five statements adapted from Claes et al. that can be answered with ‘true’, ‘false’ or ‘don’t know’ [29].

Discussed topics consisted of (1) consequences for patients’ treatment, (2) possible implications for family members, and (3) the associated higher risk of developing breast cancer if a pathogenic variant in a BRCA gene is found. Patients were able to select one or more of these three options and were asked to select the topic that was most important to them.

Satisfaction

The patients’ satisfaction with pre-test counseling and how they received the test result were measured using self-developed questions, derived from the questionnaires used in the Mainstreaming Cancer Genetics (MCG) program and developed for the TIME trial, which evaluated breast cancer patients’ experiences with rapid genetic testing and counseling [6, 30].

Turnaround times

For both groups, we evaluated the time between diagnosis, pre-test counseling, and communicating the test result to the patient. For patients in the control group, we also included the time of referral. For patients in the intervention group, we also included the time of additional post-test counseling at the genetics department, if applicable.

We used the date of the histology report as the time of diagnosis. If a histology report was lacking, the date of the cytology report was used. For patients in the intervention group, we used the date that the letter with the test result was sent to the patient as the time that the test result was communicated to the patient. For patients in the control group, we used the date that the test result was first communicated to the patient, which was foremost the date of a telephone consultation.

If the month and/or day of the date were missing, June and/or the 15th were added in order to be able to calculate the turnaround times.

Adherence to the mainstream genetic testing protocol

We assessed whether written informed consent was obtained for diagnostic germline genetic testing based on the presence of a consent form in the patient file. In addition, we assessed whether non-genetic HCPs evaluated whether the patient required additional post-test counseling at the genetics department based on patient or family history. We determined this based on the presence of the checklist in the patient file. We also assessed whether or not patients were actually referred to the genetics department if indicated by this checklist.

Statistical analyses

We calculated mean and standard deviation or median and range for continuous variables and frequencies and percentages for categorical variables. Groups were compared using univariate analysis with logistic regression or a chi-square test for categorical variables and linear regression for continuous variables. We performed multivariate analyses on the decisional conflict scale, the decision regret scale, the HADS and DT. We adjusted for the possible confounders, based on literature and expert opinion: having a pathogenic variant or variant of unknown significance, having one or more children, educational level, having a personal history of another type of cancer in addition to the EOC diagnosis, the interval between receiving the DNA test result and completing the questionnaire, and being offered genetic testing ≤ 6 months after diagnosis. We imputed (five times) the missing data (< 6%) of these outcomes and possible confounders. For the calculation of the turnaround times, we excluded the extreme outliers. We defined extreme outliers as values that were either 3 times the interquartile range above the 3rd quartile value or 3 times below the 1st quartile. IBM SPSS statistics 26.0.0.1 was used to perform the statistical analyses.