Facilitated referral pathway for genetic testing at the time of ovarian cancer diagnosis: uptake of genetic counseling and testing and impact on patient-reported stress, anxiety and depression

YGYNO-977798; No. of pages: 7; 4C: Gynecologic Oncology xxx (xxxx) xxx

Contents lists available at ScienceDirect

Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno

Facilitated referral pathway for genetic testing at the time of ovarian cancer diagnosis: uptake of genetic counseling and testing and impact on patient-reported stress, anxiety and depression Melissa K. Frey a,⁎, Sarah S Lee b, Deanna Gerber b, Zachary P. Schwartz b, Jessica Martineau b, Kathleen Lutz b, Erin Reese b, Emily Dalton c, Annie Olsen b, Julia Girdler b, Bhavana Pothuri b, Leslie Boyd b, John P. Curtin b, Douglas A. Levine b, Stephanie V. Blank d a

Weill Cornell Medicine, United States of America New York University Langone Medical Center, United States of America c Ambry Genetics, United States of America d Blavatnik Family Women's Health Research Institute, Icahn School of Medicine at Mount Sinai, United States of America b

H I G H L I G H T S • • • •

Facilitated referral to genetic counselors resulted in high uptake of genetic counseling and testing. Genetics referral at time of ovarian cancer diagnosis did not demonstrate a long term psychologic toll. Despite leveling of financial barriers, patients at the public hospital were less likely to present for genetic counseling. Ashkenazi Jewish patients reported higher levels of stress, anxiety and depression at time of genetic counseling.

a r t i c l e

i n f o

Article history: Received 25 September 2019 Received in revised form 3 December 2019 Accepted 2 January 2020 Available online xxxx Keywords: Genetic testing Genetic counseling BRCA1 BRCA2 Ovarian cancer

a b s t r a c t Background. Timely genetic testing at ovarian cancer diagnosis is essential as results impact front line treatment decisions. Our objective was to determine rates of genetic counseling and testing with an expedited genetics referral pathway wherein women with newly-diagnosed ovarian cancer are contacted by a genetics navigator to facilitate genetic counseling. Methods. Patients were referred for genetic counseling by their gynecologic oncologist, contacted by a genetics navigator and offered appointments for genetic counseling. Patients completed quality of life (QoL) surveys immediately pre- and post-genetic assessment and 6 months later. The primary outcome was feasibility of this pathway defined by presentation for genetic counseling. Results. From 2015 to 2018, 100 patients were enrolled. Seventy-eight had genetic counseling and 73 testing. Median time from diagnosis to genetic counseling was 34 days (range 10–189). Among patients who underwent testing, 12 (16%) had pathogenic germline mutations (BRCA1-7, BRCA2-4, MSH2-1). Sixty-five patients completed QoL assessments demonstrating stress and anxiety at time of testing, however, scores improved at 6 months. Despite the pathway leveling financial and logistical barriers, patients receiving care at a public hospital were less likely to present for genetic counseling compared to private hospital patients (56% versus 84%, P = 0.021). Conclusions. Facilitated referral to genetic counselors at time of ovarian cancer diagnosis is effective, resulting in high uptake of genetic counseling and testing, and does not demonstrate a long term psychologic toll. Concern about causing additional emotional distress should not deter clinicians from early genetics referral as genetic testing can yield important prognostic and therapeutic information. © 2020 Published by Elsevier Inc.

1. Introduction

⁎ Corresponding author at: Division of Gynecologic Oncology, United States of America. E-mail address: [email protected] (M.K. Frey).

The landscape of ovarian cancer genetics is rapidly evolving. Approximately 25% of ovarian cancers are associated with germline mutations, with BRCA1/2 genes accounting for 15–18% of cases [1]. The Society of

https://doi.org/10.1016/j.ygyno.2020.01.007 0090-8258/© 2020 Published by Elsevier Inc.

Please cite this article as: M.K. Frey, S.S. Lee, D. Gerber, et al., Facilitated referral pathway for genetic testing at the time of ovarian cancer diagnosis: uptake of ..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2020.01.007

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Gynecologic Oncology (SGO), National Comprehensive Cancer Network (NCCN), American College of Obstetricians and Gynecologists (ACOG) and American Society of Clinical Oncology (ASCO) all recommend universal genetic counseling and genetic testing for women with new diagnoses of epithelial ovarian cancer [2–5]. For a patient with ovarian cancer, the identification of an underlying mutation can elucidate the etiology of disease, inform risk of other malignancies for the patient and her at-risk relatives and impact treatment decisions. Targeted therapy in the form of poly (ADP-ribose) polymerase (PARP) inhibitors are United States Food and Drug Administration (FDA) approved for use in multiple clinical settings for women with BRCA1/2-associated ovarian cancer. Most recently, the PARP inhibitor olaparib received approval as maintenance therapy following front-line treatment for women with ovarian cancer and germline or somatic BRCA mutations, demonstrating a remarkable 70% reduction of risk of disease progression compared with placebo [6]. The benefits of targeted therapeutics and cascade genetic testing rely on access to genetic counseling and successful uptake of testing. For patients potentially eligible for frontline maintenance therapy, this testing is time sensitive, as standard systemic chemotherapy for primary ovarian cancer is typically completed in under six months from diagnosis. However, genetic counseling referral rates remain low. Prior to 2018, rates of referral to genetic counseling ranged from 12 to 23% and rates of completion of genetic testing ranged from 5 to 17% [7–13]. More recent studies demonstrate some improvement, with almost 50% of patients being referred to genetic counseling and about 30% completing genetic testing [14–16]. Improved uptake has largely been attributed to bundled interventions that include provider and patient education, referral templates, genetic risk checklists, enhanced electronic family history documentation and improved patient appointment scheduling strategies. While the trends are encouraging, N50% of women with ovarian cancer still are not referred for genetic counseling, demonstrating a missed opportunity with perilous implications for the health of the patient and her family members. Among women who are underinsured, these statistics are even less encouraging [17]. For women with ovarian cancer, the rate of referral to genetic counseling should be 100%. Our objective was to determine whether a facilitated genetics referral pathway whereby all women with newlydiagnosed ovarian cancer are referred to genetic counseling by their gynecologic oncologist and proactively contacted by a genetics navigator to schedule genetic counseling increases rates of genetic counseling and genetic testing uptake without increased patient-reported stress, anxiety or depression.

genetic counseling by their treating oncologist. The personnel scheduling genetic counseling sessions were trained in order to serve as the genetics navigators. This training involved education about the importance of timely genetic evaluation for all women with a diagnosis of ovarian cancer, the specifics and purpose of trial design as well as standardized language. All patients enrolled in the study were contacted by the genetics navigator within one week of enrollment and offered an appointment for genetic counseling and genetic testing within six weeks of contact. The genetics navigator contacted the patient in their designated language for communication using telephone interpreters as needed. Three telephone attempts were made for each patient; if these attempts were not successful the patient was deemed to be uncontacted. The system for genetic navigation was the same for patients at the public and private hospital. Patients underwent thorough in-person genetic counseling by a certified genetic counselor and were offered genetic testing. For those interested in genetic testing, the genetic panel was selected at the discretion of the genetic counselor based on the personal history, family history and patient preferences. Patients completed the standard consent for genetic testing and submitted a blood sample. Patients returned for in-person disclosure of results and post-test genetic counseling. Genetic testing was billed to the patient's insurance per standard protocol however if there was an additional charge it was covered as part of protocol participation and patients were informed that there would be no additional cost for genetic testing. In order to assess whether the facilitated genetics referral pathway affected patient-reported stress, anxiety and depression, three quality of life (QoL) instruments were incorporated into the study design. The validated QoL surveys were chosen based on prior literature addressing QoL implications for oncologic genetic testing and included the Impact of Events Scale [18], State-Trait Anxiety Inventory [19] and Hospital Anxiety and Depression Scale [20]. English-speaking patients completed QoL instruments immediately prior to genetic counseling, immediately following genetic counseling and 6 months following genetic assessment. QoL instruments were distributed in-person on the day of genetic counseling and by mail for 6 month follow-up. Non-English speaking patients were eligible for the study and underwent genetic counseling with certified translators via telephone. As the instruments used to assess stress, anxiety and depression were not validated in non-English speakers, such patients did not participate in this component of the study.

2. Materials and methods

The primary outcome was feasibility of this facilitated genetics referral pathway defined by patients receiving genetic counseling. Secondary outcomes included rate of genetic testing, patient-reported stress, anxiety and depression, outcomes of genetic testing and associations of patient demographics with uptake of genetic services, genetic testing results and QoL scores.

2.1. Patients Patients were eligible for the facilitated referral pathway if they were 18 years of age or older and had a newly diagnosed, histologically confirmed epithelial ovarian, primary peritoneal, fallopian tube or extra-uterine mullerian cancer. Patients were treated at either New York University Langone Hospital/Perlmutter Cancer Center, a private hospital, or Bellevue Hospital Center, a public hospital. The private and public hospitals are affiliated with the same academic institution. The same team of gynecologic oncologists (attending physicians, fellows, residents) and genetic counselors provided care at both hospital settings. Newly diagnosed cancer was defined as histologic diagnosis within the preceding eight weeks. 2.2. Trial design and interventions This prospective study was approved by the Institutional Review Board. All patients with newly diagnosed ovarian cancer were offered study participation by their treating oncologist and prior to enrollment provided informed consent. Patients were recommended referral to

2.3. Endpoints

2.4. Statistical analysis The distribution of continuous variables was tested for normality via the Kolmogorov–Smirnov test. Univariate tests were applied based on whether the variable of interest was distributed normally (e.g. t-test, analysis of variance) or not normally (e.g. Mann–Whitney U test). Associations between categorical variables were evaluated by chi-square tests or Fisher's exact tests as appropriate for category size. For assessment of QoL, survey scores were compared across the three time points using the Wilcoxon signed rank test. The acceptable α error level was set at P = 0.05 using 2-tailed tests. Data were analyzed using SPSS Statistical software (version 21, SPSS, INC, 2012). We determined that enrollment of 30 patients would provide the trial with 90% power at a two-sided significance level of 0.05, to show a significant difference in rate of uptake of genetic counseling with the

Please cite this article as: M.K. Frey, S.S. Lee, D. Gerber, et al., Facilitated referral pathway for genetic testing at the time of ovarian cancer diagnosis: uptake of ..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2020.01.007

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facilitated genetics referral pathway corresponding to an improvement from 20% (the rate reported in the literature at time of trial initiation and consistent with the institutional experience) to a goal of 50% (confidence interval 47–53%). We elected to accrue a total of 100 patients in order to obtain results for our secondary outcomes. 3. Results From October 2015 to October 2018, a total of 100 patients were offered participation in the facilitated genetics referral pathway. All 100 patients agreed to participate and signed informed consent. The median patient age at time of screening was 64 years (range 23–90 years). Selfreported race and ethnicity included sixty-five White patients, 16 Hispanic, 10 Asian, 6 Black and 3 mixed ethnicity. Among the 100 patients, 10 were non-English speaking (primary language was Spanish-4, Mandarin-2, Cantonese-2, Japanese-1, Albanian-1). Twenty-seven patients were of Ashkenazi Jewish ancestry. See Table 1 for a complete description of patient demographics. Among these patients, 18 received care at the public hospital and 82 at the private hospital. There were no differences in patient age, tumor site, disease stage, primary treatment modality or time from cancer diagnosis to study enrollment between the two hospital settings. Patient race and ethnicity was significantly different between the two hospitals. At the private hospital 76% of patients were White, 11% Hispanic, 7% Asian, 5% Black and 1% mixed ethnicity versus at the public hospital 17% of patients were White, 39% Hispanic, 22% Asian, 11% Black and 11% mixed ethnicity (P b 0.001). All patients (100%) were referred to genetic counseling by their oncologist and successfully contacted by a genetics navigator by telephone. Seventy-eight patients presented for genetic counseling. Twenty-one patients declined genetic counseling for the following reasons: not

Table 1 Patient demographics (N = 100). N/% Age (median, range) Ethnicity White Asian Black Hispanic Mixed Tumor site Ovary Fallopian tube Primary peritoneal Unknown Tumor histology Serous Mucinous Endometrioid Clear cell Mixed Other Tumor stage Stage I Stage II Stage III Stage IV Stage X Tumor grade 1 2 3 Not available Primary oncologic treatment Surgical debulking Neoadjuvant chemotherapy Unknown Hospital setting Private Public

64.5 years (23–90) 65 10 6 16 3 66 18 1 15 61 8 11 7 8 5 24 10 36 9 21 15 8 73 4 70 29 1 82 18

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interested (7), scheduled an appointment but did not present and declined attempt a re-scheduling (6), transferred care to an outside hospital (2), concern about test result confidentiality (1), not feeling well enough for the appointment (1), feeling too nervous (1), feeling too stressed (1), feeling overwhelmed due to recent hospitalization (1) and death prior to testing (1). One patient was excluded due to enrollment at more than eight weeks following cancer diagnosis. Five patients underwent genetic counseling but declined genetic testing for the following reasons: not interested (2), already had genetic testing (1), preference to undergo genetic testing outside of the study protocol (1) and one patient requested a separate appointment for blood draw but did not return for the scheduled laboratory appointment (Fig. 1). The median time from enrollment to genetic counseling was 14 days (range 0–163 days). The median time from diagnosis to genetic counseling was 34 days (range 10–189 days). Patients treated at the public hospital were less likely to accept genetic counseling as compared to patients at the private hospital (56% versus 84%, P = 0.021). There was a trend towards Hispanic patients being less likely to accept genetic counseling compared to nonHispanic White patients (62.5% versus 75.4%, P = 0.09). There were no other identified patient variables associated with presentation for genetic counseling. None of the evaluated patient variables were associated with acceptance of genetic testing following genetic counseling. Among the 73 patients who had genetic testing, 12 (16%) had pathogenic mutations (BRCA1-7; BRCA2-4; MSH2-1). Twenty-five patients (34%) had variants of uncertain significance (VUS). One of the patients listed above with a BRCA1 mutation was also found to have a VUS in SMARCA4. There was a non-significant trend towards increased rate of pathogenic mutations among patients treated at the public versus the private hospital (22%, 4/18, versus 11%, 9/81, P = 0.28). Among the 89 English-speaking patients, 65 (73%) completed the pre-genetic counseling surveys, 56 (63%) the post-genetic counseling surveys and 39 (44%) the 6 month follow-up surveys. Based on the Impact of Events Scale, patients reported moderate stress and this was consistent at each survey collection time point. The State-Trait Anxiety Inventory provides a state score, measuring the current level of anxiety and a trait score, measuring the general/overall level of anxiety. Immediately prior to and following genetic counseling patients reported clinically significant state scores for anxiety. At 6 month follow-up patients reported significantly improved state and trait anxiety scores. The Hospital Anxiety and Depression Scale also detected a reduction in depression scores at 6 month follow-up (Table 2). None of the patient clinicodemographic variables influenced QoL scores except for Ashkenazi Jewish ancestry. Ashkenazi Jewish patients reported significantly higher levels of stress, depression and anxiety immediately prior to and following genetic counseling. At 6 month follow-up surveys there was no difference in patient reported stress, depression or anxiety between Ashkenazi Jewish and other study patients (Table 3). 4. Discussion For more than a decade, consensus guidelines have recommended genetic testing for all women with epithelial ovarian cancer however N50% of women are still not referred to genetic counseling [21,22]. Our proposed facilitated genetics referral pathway resulted in the referral of 100% of patients to genetic counseling with 78% completing counseling, exceeding our primary endpoint goal of 50%. Among the 78 patients who completed genetic counseling, 73 (94%) completed genetic testing. Of note, this study was initiated prior to the FDA approval of PARP inhibitors as frontline ovarian cancer maintenance therapy and therefore counseling for many of the patients did not include a discussion of eligibility for maintenance treatment. It is possible that uptake of counseling and testing would be even greater due to current potential access to maintenance therapy. A core component of this pathway was the designation of a genetics navigator who acted as the contact member of the patient's care team to proactively assume responsibility for scheduling

Please cite this article as: M.K. Frey, S.S. Lee, D. Gerber, et al., Facilitated referral pathway for genetic testing at the time of ovarian cancer diagnosis: uptake of ..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2020.01.007

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Fig. 1. CONSORT flow diagram.

the genetic counseling appointment in a timely fashion. The protocol mandated that patients be enrolled and recommended referral to genetic counseling within eight weeks of diagnosis and this resulted in a median time from diagnosis to genetic assessment of just 34 days. The expedited course from diagnosis to genetic testing allowed ample time for discussion of results and, following the 2018 FDA approval of olaparib maintenance therapy, for identification of patients who were candidates for this promising targeted agent. Given that discussion of

maintenance therapy often needs to start during chemotherapy, having the testing results prior to completion is critical. Despite the facilitated protocol with universal referral to genetic counseling, removal of financial barriers and a genetics navigator, patients receiving oncologic care at the public hospital were less likely to undergo genetic counseling. Among those patients who did present for genetic counseling, testing uptake and testing results were similar between the two hospital settings. Recent literature

Table 2 Patient-reported stress, anxiety and depression immediately prior to genetic counseling, immediately following genetic counseling and 6 months following genetic counseling. Pre-genetic counseling

Impact of Events Scale Stress score State-Trait Anxiety Inventory State score Trait score Hospital Anxiety and Depression Scale Depression score Anxiety score

Post-genetic counseling

6 month follow-up

Pre-counseling vs. post-counseling

Pre-counseling vs. 6 month follow-up

Post-counseling vs. 6 months follow-up

Median (range)

N

Median (range)

N

Median (range)

N

Wilcox signed rank - P value (Z)

26.5 (3–53)

62

26 (1–51)

55

26 (1–47)

36

0.096 (−1.663)

0.365 (−0.906)

0.977 (−0.029)

39 (7–65) 36 (0–61)

65 65

41 (19–68) 37 (22–63)

55 56

30 (19–66) 30 (20–60)

39 39

0.845 (−0.196) 0.276 (−1.090)

0.027 (−2.205) 0.068 (−1.827)

0.004 (−2.872) 0.052 (−1.964)

4 (0−21) 7 (1–38)

65 65

5 (0–18) 7 (0−13)

56 55

2 (0–8) 5 (0–17)

39 39

0.088 (−1.708) 0.001 (−3.280)

b0.001 (−3.896) 0.014 (−2.448)

b0.001 (−3.658) 0.366 (−0.903)

Interpretation of results: Impact of Events Scale: Subclinical stress – 0-8; Mild stress – 9-25; Moderate stress – 26-43; Severe stress – 44+. State-Trait Anxiety Questionnaire: Clinically significant anxiety - N39-40. Hospital Anxiety and Depression Scale: Normal anxiety - 0-7; Borderline anxiety - 8-10; Abnormal anxiety - 11-21; Normal depression - 0-7; Borderline depression - 8-10; Abnormal depression - 11-21. Patients were encouraged to complete all survey instruments however occasionally elected to complete only some of the instruments.

Please cite this article as: M.K. Frey, S.S. Lee, D. Gerber, et al., Facilitated referral pathway for genetic testing at the time of ovarian cancer diagnosis: uptake of ..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2020.01.007

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Table 3 Patient-reported stress, anxiety and depression for Ashkenazi Jewish and non-Ashkenazi Jewish patients.

Impact of Events Scale Stress score State-Trait Anxiety Inventory State score Trait score Hospital Anxiety and Depression Scale Depression score Anxiety score

Pre-genetic counseling

Post-genetic counseling

6 month follow-up

Mann Non-Ashkenazi Ashkenazi Jewish (median, Jewish (median, Whitney P value range) range)

Mann Non-Ashkenazi Ashkenazi Jewish (median, Jewish (median, Whitney P value range) range)

Mann Non-Ashkenazi Ashkenazi Jewish (median, Jewish (median, Whitney P value range) range)

22 (3–53)

35 (4–49)

0.005

21 (1–45)

34.5 (8–51)

0.001

21 (1–47)

30 (2–42)

0.349

37 (7–62) 34 (0–61)

48 (26–65) 41 (15–60)

0.001 0.027

39 (20–68) 34 (22–63)

46 (19–67) 46 (23–61)

0.027 0.002

29 (21–50) 30 (21–56)

32.5 (19–66) 31 (20–60)

0.309 0.652

3.5 (0–21) 7 (1–38)

7 (1−13) 7 (1–15)

0.021 0.114

3 (0–13) 5 (0−12)

7 (1–18) 8 (0–13)

0.009 0.044

2 (0–6) 4 (0−10)

2 (0–8) 6.5 (0–17)

0.652 0.113

demonstrates significant disparities in medically underserved and minority populations with regards to awareness of, access to and use of genetic services [17]. Meyer et al. evaluated the use of genetic services among patients with epithelial ovarian cancer and found that African American and Hispanic patients were significantly less likely to be referred for genetic counseling compared to White patients [11]. Manrriques et al. similarly found that rates of referral to genetic counseling differed by patient race, insurance type and primary spoken language [16]. Our study differs from prior literature in that a uniform process of facilitated genetics referrals was applied for all patients regardless of hospital setting, race, ethnicity, language spoken or insurance status. However, even with this facilitated pathway we still identified disparities in uptake of genetic counseling. This is important as currently much of the effort to reduce healthcare disparities in genetic testing has focused on improving access to genetic counseling through alternative service delivery models and reduction of financial barriers through expansion of health insurance payer policies, inclusion of genetic testing in the Affordable Care Act and other financial assistance programs [23]. Our data suggest that there may be additional barriers preventing the uptake of genetic counseling and these barriers must be further investigated in order to successfully reduce this important healthcare disparity. We utilized patient navigators to assist patients with scheduling appointments however future studies may expand the role of patient navigators, especially in populations where patients are historically less likely to utilize genetics services. A meta-analysis found that for patients with chronic diseases and difficulty coordinating care, navigator programs, especially when tailored to individual patient needs, could overcome barriers to care for marginalized populations and improve adherence to treatment recommendations and follow-up [24]. Navigation services have also been studied in the setting of oncologic genetic testing and, not surprisingly, patient navigators can improve uptake and reduce time to oncologic genetic counseling [25]. Patient navigators can also assist in organizing cascade testing for relatives at risk of carrying the same pathogenic germline mutation and recent data suggest that strategies facilitated by the medical teams can significantly improve uptake of testing among at-risk relatives [26]. Concern about provoking psychological distress with genetic testing is a topic that has been debated since the onset of such testing. While the research to date in understanding the immediate- and long-term psychological consequences of genetic testing for cancer patients has been encouraging, a clear consensus regarding the psychosocial impact has not yet been reached. Most studies evaluating cancer-affected patients with a new diagnosis of a pathogenic mutation demonstrate no relevant negative impact on psychosocial well-being [27–29]. However, there have been other studies suggesting that disclosure of positive genetic testing results to cancer-affected patients can lead to additional anxiety, isolation, distress and depression [30–32]. We found moderate stress and clinically significant anxiety among all patients immediately prior to and following genetic counseling. At 6 month follow-up,

patients reported significantly improved anxiety and depression. We found no difference in patient-reported stress, anxiety or depression when comparing patients with negative results to those with positive results or VUS at any of the survey time points. It is not surprising that we found elevated levels of stress and anxiety at the time of genetic counseling as all of these patients had experienced a recent diagnosis of ovarian cancer. Furthermore, it is reassuring that both anxiety and depression scores improved 6 months following genetic counseling, although these changes may also represent recovery from surgery and acclimation to an ovarian cancer diagnosis. We evaluated QoL scores in the context of all measured clinical variables to determine if any subpopulations are more vulnerable to negative psychosocial consequences of genetic counseling and genetic testing. Interestingly, the only patient variable significantly associated with QoL outcomes was Ashkenazi Jewish ancestry. Ashkenazi Jewish patients reported significantly higher levels of stress, anxiety and depression immediately prior to genetic counseling and immediately following genetic counseling. At 6 month follow-up there was no difference in stress, anxiety or depression when comparing Ashkenazi Jewish to other study patients. While in our cohort we found no difference in the prevalence of germline mutations among Ashkenazi Jewish and non-Ashkenazi Jewish women with ovarian cancer, larger studies suggest that in Ashkenazi Jewish women with a diagnosis of ovarian cancer, the prevalence of a BRCA1/2 founder mutation is estimated to be as high as 41% [33,34]. Furthermore, approximately 2.5% of Ashkenazi Jewish people in the general population carry one of the three BRCA1/2 founder mutations [35,36]. While we cannot know for sure why the Ashkenazi Jewish patients reported higher levels of stress, anxiety and depression at the time of genetic testing, an explanation may be that they have a higher perceived risk of harboring a pathogenic mutation. However, it was reassuring that differences in patient-reported outcomes did not persist at long-term follow-up. Our findings suggest that this group of patients may require more psychosocial support at the time of referral to genetic counseling and genetic testing. This study has many limitations. Patients at this institution had access to trained oncologic genetic counselors that were easily accessible. This setting allows patients to be seen quickly and receive thorough preand post-test counseling however is certainly not the standard for most oncology practices. With the growing need for genetic testing and limited number of genetic counselors, alternatives to pre-test counseling by in-person genetic counselors are necessary. Telephone-based genetic counseling has been evaluated and demonstrated both patient and provider satisfaction with lower cost and similar clinical outcomes including knowledge, decision conflict and QoL [37,38]. Other proposed strategies to address under-referral to genetic counseling include group counseling and clinic support tools including video education, computer-assisted family history collection and patient navigation, however, knowledge of the effectiveness, quality of life implications, risks and benefits remain limited [17,39,40]. Some have proposed using universal point-of-service germline genetic testing at time of

Please cite this article as: M.K. Frey, S.S. Lee, D. Gerber, et al., Facilitated referral pathway for genetic testing at the time of ovarian cancer diagnosis: uptake of ..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2020.01.007

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diagnosis with genetic counseling only for patients with positive genetic testing results or universal tumor genetic sequencing to identify mutations that can then triage patients to germline genetic testing, however, data on the success and QoL implications for these approaches are scarce [43]. The ongoing Making Genetic Testing Accessible (MAGENTA) study aims to reduce barriers to genetic screening by providing “genetic testing from your living room.” Women without ovarian cancer eligible for genetic testing enrolled on MAGENTA are randomized to online genetic education alone or in combination with telephone counseling [41]. The international ENGAGE study evaluated a model whereby oncologists ordered genetic testing without genetic counselors and found the pathway feasible with high levels of patient and physician satisfaction [42]. With a limited genetic counseling workforce and increasing need for genetic counseling, approaches such as those used in the MAGENTA and ENGAGE studies may be the future of genetic counseling [44]. Our pathway had several components that likely improved uptake of genetic counseling and testing and therefore it is not possible to determine the individual contributions to the pathway's overall success. First, genetic counseling was recommended to all patients by their oncologist as part of the study protocol which is something we know does not happen for all women with ovarian cancer. Second, scheduling the genetic counseling appointment was facilitated by a telephone genetics navigator who reached out directly to the patient. Finally, as part of study protocol, patients did not experience the financial burden of genetic testing. However, based on the current consensus guidelines published by multiple medical societies supporting routine genetic counseling and testing for all women with ovarian cancer, this testing often comes without additional cost to the patient [2–5]. Finally, our quality of life data was limited by loss of follow-up with only 44% of eligible patients completing surveys at 6 month-follow-up. Our facilitated genetics referral pathway resulted in universal referral to genetic counseling and high uptake of both genetic counseling and genetic testing compared to rates currently documented in the literature without negatively impacting long-term patient-reported stress, anxiety or depression. Our results suggest that creating standard pathways for patients with newly diagnosed ovarian cancer that include referral to genetic counseling with an embedded genetics navigator can significantly improve utilization of genetics services. Further studies are required to determine if we can maintain high rates of uptake of genetic services when using a similar pathway but replacing in-person counseling with alternative delivery models like telegenetics. Finally, our finding of decreased uptake of genetic counseling for patients receiving care at a public versus a private hospital even in the setting of universal referral to genetic counselors is concerning and highlights the importance of identifying other strategies to tackle disparities in gynecologic cancer genetics. Prior presentations This study has been presented as a poster at the Society of Gynecologic Oncology Annual Meeting, National Harbor, MD, 2017 and the American Society of Clinical Oncology Annual Meeting, Chicago, IL, 2018.

Funding source Ambry Genetics provided support for this project in the form of coverage of genetic testing that was not covered by the patient's insurance. Ambry genetics was not involved in study design, execution or analysis. Author contribution Melissa K Frey: Conceptualization, data curation, formal analysis, investigation, methodology, project administration, resources, supervision, writing - original draft, writing - review and editing.

Sarah Lee: Data curation, formal analysis, investigation, methodology, project administration, writing - original draft, writing - review and editing. Deanna Gerber: Data curation, formal analysis, investigation, methodology, project administration, writing - original draft, writing - review and editing. Zachary Schwartz MD: Data curation, writing - review and editing. Jessica Martineau: Data curation, investigation, methodology, project administration, writing - review and editing. Kathleen Lutz: Data curation, investigation, writing - review and editing. Erin Reese: Data curation, investigation, writing - review and editing. Emily Dalton: Conceptualization, resources, writing - review and editing. Annie Olsen: Data curation, investigation, writing - review and editing. Julia Girdler: Data curation, investigation, writing - review and editing. Bhavana Pothuri: Conceptualization, investigation, methodology, writing - original draft, writing - review and editing. Leslie Boyd: Conceptualization, investigation, methodology, writing - review and editing. John P. Curtin: Conceptualization, investigation, methodology, writing - review and editing. Douglas Levine: Data curation, investigation, project administration, resources, supervision, writing - review and editing. Stephanie V. Blank: Conceptualization, data curation, formal analysis, investigation, methodology, project administration, resources, supervision, writing - original draft, writing - review and editing. Declaration of competing interest Emily Dalton, a co-author, is employed by Ambry Genetics. Bhavana Pothuri - Tesaro, Merck, AstraZeneca, Clovis, Esai - advisory board consultant. The remaining authors have nothing to disclose. References [1] T. Walsh, S. Casadei, M.K. Lee, C.C. Pennil, A.S. Nord, A.M. Thornton, et al., Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing, Proc. Natl. Acad. Sci. U. S. A. 108 (2011) 18032–18037. [2] L.M. Randall, B. Pothuri, E.M. Swisher, J.P. Diaz, A. Buchanan, C.T. Witkop, et al., Multi-disciplinary summit on genetics services for women with gynecologic cancers: a Society of Gynecologic Oncology white paper, Gynecol. Oncol. 146 (2017) 217–224. [3] K.H. Lu, M.E. Wood, M. Daniels, C. Burke, J. Ford, N.D. Kauff, et al., American Society of Clinical Oncology expert statement: collection and use of a cancer family history for oncology providers, J. Clin. Oncol. 32 (2014) 833–840. [4] Committee on Practice Bulletins–Gynecology CoG, Society of Gynecologic Oncology. Practice bulletin no 182: hereditary breast and ovarian cancer syndrome, Obstet. Gynecol. 130 (2017)(e110-e26). [5] NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Genetic/Familial High-risk Assessment: Breast and Ovarian Version 2.20192018. [6] K. Moore, N. Colombo, G. Scambia, B.G. Kim, A. Oaknin, M. Friedlander, et al., Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer, N. Engl. J. Med. 379 (2018) 2495–2505. [7] T. Febbraro, K. Robison, J.S. Wilbur, J. Laprise, A. Bregar, V. Lopes, et al., Adherence patterns to National Comprehensive Cancer Network (NCCN) guidelines for referral to cancer genetic professionals, Gynecol. Oncol. 138 (2015) 109–114. [8] C.B. Powell, R. Littell, E. Hoodfar, F. Sinclair, A. Pressman, Does the diagnosis of breast or ovarian cancer trigger referral to genetic counseling? Int. J. Gynecol. Cancer 23 (2013) 431–436. [9] S.V. Petzel, R.I. Vogel, T. Bensend, A. Leininger, P.A. Argenta, M.A. Geller, Genetic risk assessment for women with epithelial ovarian cancer: referral patterns and outcomes in a university gynecologic oncology clinic, J. Genet. Couns. 22 (2013) 662–673. [10] R. Demsky, J. McCuaig, M. Maganti, K.J. Murphy, B. Rosen, S.R. Armel, Keeping it simple: genetics referrals for all invasive serous ovarian cancers, Gynecol. Oncol. 130 (2013) 329–333. [11] L.A. Meyer, M.E. Anderson, R.A. Lacour, A. Suri, M.S. Daniels, D.L. Urbauer, et al., Evaluating women with ovarian cancer for BRCA1 and BRCA2 mutations: missed opportunities, Obstet. Gynecol. 115 (2010) 945–952.

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Please cite this article as: M.K. Frey, S.S. Lee, D. Gerber, et al., Facilitated referral pathway for genetic testing at the time of ovarian cancer diagnosis: uptake of ..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2020.01.007