Original Paper Public Health Genomics 2015;18:225–232 DOI: 10.1159/000431352
Received: October 9, 2014 Accepted: May 13, 2015 Published online: June 24, 2015
Referral of Ovarian Cancer Patients for Genetic Counselling by Oncologists: Need for Improvement Maria Teresa Ricci a Stefania Sciallero b Serafina Mammoliti b Viviana Gismondi a Marzena Franiuk a Paolo Bruzzi c Liliana Varesco a a
Unit of Hereditary Cancer, b Medical Oncology Unit 1, and c Unit of Clinical Epidemiology, IRCCS AOU San Martino-IST, Genoa, Italy
Abstract Background/Aims: Nearly 15% of all ovarian cancer patients carry a germline BRCA mutation. A pilot project was started at IRCCS AOU San Martino – IST, Genoa, to assess the feasibility and consequences of offering genetic counselling to all ovarian cancer patients during routine oncology appointments. We present early results of this project. Methods: Patients who attended an oncology visit at the Medical Oncology Unit 1 between November 2012 and December 2013 were identified. Medical records were reviewed for clinical data, genetic counselling and testing outcomes. Results: Out of 104 women diagnosed with ovarian cancer undergoing an oncology visit, 94 had not had genetic counselling in the past. Twenty-nine patients (29/94, 31%) were referred to the Unit of Hereditary Cancer; of these, 14/26 (54%) were referred at the first visit and 15/68 (22%) at the follow-up visit (p = 0.003). Most referred women attended genetic counsel-
© 2015 S. Karger AG, Basel 1662–4246/15/0184–0225$39.50/0 E-Mail [email protected] www.karger.com/phg
ling (22/29, 76%) and had BRCA genetic testing (21/22, 95%). Four BRCA1 mutations were detected (4/21, 19%). Conclusions: Oncologists discuss genetic counselling with a minority of ovarian cancer patients. Mainstreaming such practice is important to optimize the management of these patients and their families. Efforts are needed to identify new models for introducing ovarian cancer genetic risk assessment in oncology practice. © 2015 S. Karger AG, Basel
Introduction
Ovarian cancer is a significant cause of cancer morbidity and mortality in Western women, accounting for approximately 3% of all incident cancers and 5–6% of all cancer deaths [1]. It has been shown that approximately in 1 out of 4 unselected ovarian cancer patients, germline mutations in tumor suppressor genes are found, potentially causing an inherited cancer predisposition [2], and two thirds of these mutations are in the BRCA1 and BRCA2 genes. In Liliana Varesco Unit of Hereditary Cancer IRCCS AOU San Martino – IST Largo Rosanna Benzi, 10, IT–16132 Genoa (Italy) E-Mail liliana.varesco @ hsanmartino.it
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Key Words BRCA testing · Capacity building · Feasibility · Genetic counselling · Ovarian cancer
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Ovarian Cancer outpatients Genetic counselling proposed Oncologist
Genetic Nurse
Contacts of interested patients left on UHC answering machine
Telephone contact and personal/family medical history reconstruction Appointment arranged
Medical Geneticist
Genetic counselling Genetic testing proposed
Fig. 1. Study protocol. The oncologists propose genetic counselling to all women with a recent or past diagnosis of invasive epithelial ovarian cancer during routine visits and, for patients who confirm to be interested in genetic risk assessment, directly arrange a contact with the UHC.
At present, in Italy, there are no specific national guidelines regarding the referral of ovarian cancer patients to genetic counselling and testing. In particular, until the year 2013, BRCA testing was offered only to ovarian cancer patients with an additional family history of breast or ovarian cancer [21]. In 2012, a pilot project was started by the Unit of Hereditary Cancer (UHC) and the Medical Oncology Unit 1 (MOU-1) of the Istituto di Ricovero e Cura a Carattere Scientifico – Azienda Ospedaliera Universitaria San Martino – Istituto Nazionale per la Ricerca sul Cancro (IRCCS AOU San Martino – IST) of Genoa, aimed at assessing the feasibility and consequences of offering genetic counselling to all women diagnosed with an invasive ovarian cancer, regardless of age at diagnosis or the presence of a family history of breast or ovarian cancer. One year after the introduction of this pilot project, we present its early results in terms of oncologists’ adherence to the protocol, patients’ compliance with genetic counselling and testing, and the prevalence of BRCA mutations.
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fact, 13–18% of unselected ovarian cancer patients carry a deleterious mutation in one of these two genes [2–4]. Among these patients, the likelihood of carrying a mutation varies with age at diagnosis, histology, family history and ethnicity [5], but if the patients were selected on the basis of these factors, a significant number of mutation carriers would be missed [2–4]. Indeed, genetic testing is recommended to all patients with invasive ovarian cancer by many clinical practice guidelines because of the high prevalence of BRCA mutations in series of unselected women with ovarian cancer [6–8], and it is already the practice in Australia, Scotland and Ontario. BRCA genetic testing is provided for several reasons. Family members found to be at an increased risk of breast and ovarian cancer have the opportunity to undertake appropriate prevention strategies, including, for breast cancer, intensive surveillance or risk reduction surgery, and for ovarian cancer, salpingo-oophorectomy. In two recent studies [9, 10], among women with a BRCA mutation who had undergone salpingo-oophorectomy, a significant reduction was reported in ovarian cancer risk [HR 0.28 (95% CI 0.12–0.69); HR 0.20 (95% CI 0.13– 0.30)], in breast cancer risk [HR 0.63 (95% CI 0.41–0.96)], in BRCA1 carriers [HR 0.36 (95% CI 0.16–0.82)], in BRCA2 carriers and in all-cause mortality [HR 0.40 (95% CI 0.26–0.61) and HR 0.23 (95% CI 0.13–0.39), respectively]. For the patients themselves, the increased risk of primary breast cancer warrants appropriate surveillance, while the relatively low yearly breast cancer incidence and the significant ovarian cancer-related mortality argue against an aggressive surgical management of breast cancer risk in these patients, in particular in the first 5 years after the diagnosis [11]. In addition, BRCA mutation status may influence ovarian cancer treatment in the near future; BRCA-related ovarian cancer seems to be characterized by an increased responsiveness to platinum chemotherapy [12] and to poly ADP-ribose polymerase inhibitors [13]. A poly ADP-ribose polymerase inhibitor was recently approved by the European Medicines Agency (EMA) for the maintenance treatment of patients with platinum-sensitive, relapsed, BRCA-mutated (germline and/or somatic), high-grade, serous, epithelial ovarian, fallopian tube, or primary peritoneal cancer who respond (complete response or partial response) to platinumbased chemotherapy [14]. Despite the growing awareness of the high prevalence of BRCA mutations in ovarian cancer patients, health providers continue to refer only some of them to genetic services [15–20].
Table 1. Clinical characteristics of ovarian
cancer patients included in the study Number of patients Mean age at diagnosis (range), years Presence of symptoms, n (%) Yes No Indication of chemotherapy, n (%) Yes No
The study protocol was developed in November 2012 by the UHC of the IRCCS AOU San Martino – IST of Genoa and the MOU-1 that is in charge of the care for most ovarian cancer patients at the same institute. According to the protocol (fig. 1), the oncologists are expected to propose a genetic risk assessment during routine visits to all women diagnosed with an invasive epithelial ovarian cancer. Two types of visits are considered: (a) first visits, usually of 1 h duration, that include the compilation of a family history box in the clinical chart, and (b) follow-up visits, usually of 30 min duration and not including the compilation of a family history box in the specific clinical chart (to view/update the family history, the clinician must go back to the first visit chart). Then, the oncologist leaves the contacts of each patient interested in genetic counselling on the UHC answering machine. No other change in their current practice was introduced. The subsequent steps of the genetic risk assessment process are not different from usual care; in particular, genetic counselling is performed without the direct involvement of oncologists in preand post-test genetic consultations. The UHC genetic nurses contact the patient by phone and arrange an appointment with the medical geneticist after a preliminary reconstruction of the personal and familial medical history. The genetic testing is proposed during genetic counselling following a detailed pedigree construction and a discussion about its advantages and limits. BRCA genetic testing is proposed to all patients with invasive epithelial ovarian cancer, while testing of other genes is offered only if a personal and/or familial history pattern suggestive of a known hereditary cancer syndrome is present (e.g. Lynch syndrome). For women who give their consent, BRCA1 and BRCA2 genetic testing is performed on DNA isolated from peripheral blood lymphocytes, using direct sequencing and multiplex ligation-dependent probe amplification. Genetic counselling and testing are free for the patients as the costs are covered by the Italian national healthcare system. One year after the introduction of the pilot protocol, we evaluated (a) the proportion of ovarian cancer patients referred to genetic counselling by oncologists out of the total number of ovarian cancer patients attending their clinics who never had genetic counselling before; (b) the proportion of ovarian cancer patients who accepted to be referred to genetic counselling out of the total number of ovarian cancer patients to whom genetic counselling was offered by oncologists; (c) the proportion of women attending
BRCA1 and BRCA2 Genetic Testing in Oncology Practice
Follow-up Overall oncology visit
26 59.8 (43 – 83)
68 58.2 (29 – 80)
94 58.7 (29 – 83)
8 (31) 18 (69)
19 (28) 49 (72)
27 (29) 67 (71)
24 (92) 2 (8)
9 (13) 59 (87)
33 (35) 61 (65)
the genetic counselling session out of the total number of referred women; (d) the detection rate, that is the proportion of pathogenic BRCA variants out of the total number of performed tests, and (e) the occurrence of cascade testing (number of predictive tests on other family members after the identification of a pathogenic variant). The list of all unrelated patients with ovarian cancer cared for in the MOU-1 between the start of its activity in 2002 and December 2013 was identified. Women diagnosed with ovarian cancer who attended at least one oncology visit in the MOU-1 between November 2012 and December 2013 were selected. Women who had undergone genetic testing in the past were excluded. Information on the age at the visit (and at ovarian cancer diagnosis when different), the presence of symptoms and the indication of chemotherapy (ongoing/programmed) was derived from medical records for all women who should have been referred to genetic counselling during the considered period. Family history data were not collected from medical records because the quality of this information was judged to be generally poor by the oncologists if compared with the suggested standard [22]. Ovarian cancer patients referred to the UHC were identified from the list of women for whom a contact with the unit was registered during the study period. Information on the following steps of the genetic risk assessment process was derived from clinical genetics notes of each referred woman: (1) telephone interview with a genetic nurse (done/not possible); (2) genetic consultation with a medical geneticist (done/not done); (3) BRCA genetic testing (done/not done); (4) results of the BRCA testing (uninformative, variant of uncertain significance, pathogenic variant), and (5) number of relatives who underwent predictive genetic testing after a pathogenic BRCA variant was identified in the index case. The study was conducted following the rules of the local ethical committee. Statistical Analysis The aims of all statistical analyses were merely descriptive. The data were presented as means with range, proportions and 95% confidence limits, as appropriate. The distributions of continuous variables were compared and assessed for statistical significance using the Mann-Whitney test, while the χ2 test was used for comparing proportions.
Public Health Genomics 2015;18:225–232 DOI: 10.1159/000431352
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Patients and Methods
First oncology visit
Color version available online
Fig. 2. Results of the study according to the
oncology setting (first and follow-up visits). No GC = Genetic counselling not performed.
Referral to genetic counselling Yes 29 (31%) No 65 (69%) Mean age at ovarian cancer diagnosis (range), years Referred 56.7 (43 – 73) Not referred 59.5 (29 – 83)a Consented to be contacted by the UHC Yes 29 (100%) No 0 Contact with the UHC successful Yes 27 (93%) No 2 (7%) Genetic counselling Yes 22 (81.5%) No 5 (18.5%) BRCA genetic testing Yes 21 (95%) No 1 (5%) BRCA mutation Yes 4 (19%) VUS 2 (9.5%) No 15 (71.5%) VUS = Variant of unknown significance. a p = 0.261.
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Results
A total of 345 unrelated women diagnosed with invasive epithelial ovarian cancer were cared for in the MOU1 between 2002 and 2013. Most of these patients (n = 241) were no longer followed in November 2012 because they had died or at some point received oncology care elsewhere. A total of 104 patients (78 follow-up patients and 26 new patients) attended at least one oncology visit between November 2012 and December 2013. Since 10 patients had already undergone genetic testing in the past, 94 ovarian cancer patients were eligible for the present study. The clinical characteristics of the patients included in the study are shown in table 1. The mean age at ovarian cancer diagnosis was 58.7 years (range 29–83). No difference in the mean age at diagnosis was observed among women seen at first and follow-up visits (59.8 vs. 58.2 years, respectively; p = 0.559). The majority of follow-up patients were asymptomatic (49/68; 72%, 95% CI 60–81) and did not undergo chemotherapy, nor was it programmed at the moment of the visit (59/68; 87%, 95% CI 77–93). The results of the study are summarized in table 2 and figure 2. Oncologists offered genetic counselling to 29 of 94 patients (31%, 95% CI 22–41); all of them said they Ricci/Sciallero/Mammoliti/Gismondi/ Franiuk/Bruzzi/Varesco
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Table 2. Referral to genetic counselling, uptake and the results of BRCA genetic testing
Table 3. Referral to genetic counselling and BRCA genetic testing uptake at the first and follow-up oncology visits
First oncology visit Referral to genetic counselling Yes 14 (54%) No 12 (46%) BRCA genetic testing uptake Yes 8 (57%) Noa 6 (43%)
Follow-up oncology visit
p
15 (22%) 53 (78%)
0.003
13 (87%) 2 (13%)
0.109
a
Genetic counselling not performed (n = 7) or refusal of undergoing testing (n = 1).
Here, we report the preliminary results of a pilot multidisciplinary protocol conducted at an Italian institution aiming at facilitating the referral of all patients diagnosed with ovarian cancer for genetic counselling and testing. During the first year of its introduction, 31% of the women diagnosed with ovarian cancer were referred by oncologists to the UHC, and approximately three quarters of these accepted to undergo genetic testing. The observed prevalence of BRCA1/2 mutations among women who had undergone testing (19%) was close to the expected value (13–18% [2–4]), and cascade testing allowed the identification of 4 at-risk family members. The 31% referral rate is consistent with the rates previously reported in Ontario, Canada, where, as at our institution, BRCA genetic testing is freely available to all wom-
en with invasive ovarian cancer [15, 19]. This lack of referral may be in part due to practical barriers that can be reduced by the introduction of specific tools; for example, Petzel et al. [20] reported that the introduction of a systematically generated electronic referral form increased the referral of ovarian cancer patients from 17 to 30%. Other reported barriers to clinicians’ referral for cancer genetic risk evaluation include the limited knowledge on hereditary cancer and the lack of specific training [23, 24]. Indeed, a recent survey indicates that the knowledge of and attitudes about BRCA genetic testing of Italian physicians are heterogeneous [25], suggesting that targeted educational and training programs in this field are needed in our country. Of note, we observed that referral was substantially higher at first visits (54%) than in women attending follow-up visits (22%). This difference could be related to some practical aspects of the visits, such as their duration (allowing or not allowing time for the introduction of additional information related to genetic issues) and the type of checklist used (including or not including the family history). Besides practical barriers, as an alternative explanation for this unexpected finding, one might also speculate that during the initial oncology visit, broad questions on disease development (i.e. cancer etiology) and family history are discussed and, therefore, it is easier for the oncologist to introduce the issue of a possible inherited cancer susceptibility. On the contrary, during follow-up visits, both the oncologist and the patient may be more focused on the present clinical situation. In addition, we observed that patients’ uptake of testing varied by the point in care at which referral was made,
BRCA1 and BRCA2 Genetic Testing in Oncology Practice
Public Health Genomics 2015;18:225–232 DOI: 10.1159/000431352
Discussion
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were interested, and their contacts were left on the UHC answering machine. The mean age at ovarian cancer diagnosis of women referred to the UHC was similar (56.7 years, range 43–73) to that of women who were not referred (59.5 years, range 29–83; p = 0.261). Referral was higher for women attending the first oncology visit (14/26; 54%, 95% CI 35–71) than for follow-up patients (15/68; 22%, 95% CI 14–33; p = 0.003; table 3). In the group of the 29 ovarian cancer patients referred to the UHC for genetic counselling, 2 were not contactable by phone, and 5 did not show up on the day of the scheduled genetic counselling. Therefore, 22 of 29 referred women (76%, 95% CI 58–88) attended genetic counselling, and 95% (95% CI 78–99) of these (21/22) consented to BRCA genetic testing; no patient attending genetic counselling was eligible for testing other hereditary ovarian cancer genes. In total, the uptake of BRCA genetic testing was 87% (95% CI 62–96; 13/15) in women referred for genetic counselling during follow-up visits and 57% (95% CI 33–79; 8/14) in women referred during the first visits (p = 0.109; table 3). A total of four pathogenic BRCA1 mutations were detected (4/21; 19%, 95% CI 6–42). In addition, 2 patients carried one variant of unknown significance in BRCA1 and in BRCA2, respectively. Among healthy close relatives, 8 women belonging to three BRCA mutation carriers’ families decided to undergo genetic counselling and testing. At least one BRCA1 mutation carrier was identified in each of the three families and, in total, 4 at-risk women were mutation positive.
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patients in the frame of the Mainstreaming Cancer Genetics (MCG) program, a cross-disciplinary initiative that aims to develop infrastructures, processes and education that will allow the implementation of gene testing into the routine clinical care of cancer patients and their relatives [28]. According to this model, oncologists discuss BRCA genetic testing with ovarian cancer patients during routine appointments, directly obtain consent for the genetic analysis and send blood samples to the molecular genetics laboratory. After reviewing and interpreting the results, the genetic team sends the test results to the patients and offers a genetic appointment only to women found to carry a BRCA mutation; referral to genetic counselling is possible at every stage of the process if requested. The forthcoming therapeutic use of BRCA germline/somatic testing will change profoundly the ethical, procedural and organizational aspects of genetic counselling for ovarian cancer patients and their families. Hence, the development of new service delivery models in Italy (and other countries) should consider the implications of this new scenario (e.g. who will be responsible for helping the patient to resolve dilemmas related to BRCA germline testing? Who will be responsible for interpreting BRCA germline/somatic testing?). In addition, the results of this study suggest that the majority of ovarian cancer patients are pursuing genetic risk assessment when told of this possibility. Assuming a 50% referral rate of new ovarian cancer cases to genetic counselling at a national level, a 75% BRCA genetic testing acceptance rate and a 15–20% mutation detection rate among referred cases, this would imply that every year in Italy, where almost 5,000 new cases of ovarian cancer are diagnosed each year, between 280 and 380 new BRCA families would be detected during the initial years of the program. This may appear as a significant financial and organizational burden for the regional healthcare systems. However, the Italian 2014– 2018 national prevention plan prompts for the first time Italian regional healthcare services to define and implement regional programs for the identification and management of healthy women carrying BRCA mutations in the context of breast cancer prevention [29]. We believe that the figures reported above strongly indicate that the development of BRCA mutation carrierstargeted prevention programs in Italy should take into account the significant contribution of testing all ovarian cancer patients to the identification and management of BRCA families. On the other hand, programs involving ovarian cancer patients must consider the fact Ricci/Sciallero/Mammoliti/Gismondi/ Franiuk/Bruzzi/Varesco
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being lower in women referred during first visits than in follow-up visits (57 vs. 87%, respectively). A possible explanation for this observation is that genetic testing could heighten psychological distress, particularly in women coping with a new ovarian cancer diagnosis who may prefer to postpone genetic counselling. Since patients’ preferences for the optimal timing of genetic counselling and testing are personal and cannot be known without informing them about this possibility, discussing referral early and tailoring the timing of the genetic visit to each patient could be the best way to promote an informed choice on genetic testing [26]. Several limits exist in this study, and its results should be interpreted with caution. The first is the limited number of observations; in particular, the number of referred women is too low to draw any conclusion about the possibility that the referral during first visits may be associated with a significantly lower rate of attendance to genetic counselling/testing in our population. The second is that the reasons for the lack of referral were not investigated. This study was not designed to distinguish the oncologist’s willingness to postpone the genetic discussion to the next visit from its omission during a busy clinical practice. In addition, the study was not designed to analyze some plausible factors (e.g. number and age of close female relatives or psychosocial distress measures) that may have influenced the decision to refer ovarian cancer patients for genetic risk assessment. An additional limit of the study is that we did not analyze other genes involved in ovarian cancer hereditary predisposition; therefore, we probably underestimated the consequences of systematic referral of ovarian cancer patients to genetic counselling in light of the upcoming multi-gene testing [2]. Despite these limitations, our findings suggest that oncologists do not discuss genetic counselling with the majority of ovarian cancer patients. According to the present literature, this seems to be a general attitude, and the barriers to the referral of ovarian cancer patients to genetic counselling during oncology routine appointments remain largely unknown [15–20]. Besides the traditional face-to-face pre- and post-test genetic counselling provided by a genetic professional, alternative genetic testing delivery models have been developed [27]. In some of these models, nongeneticists carry out one or more of the classical genetic counselling steps, and only selected cases (e.g. mutation carriers, complex cases) are managed by the genetic professionals. In the United Kingdom, a model for BRCA testing has recently been developed for ovarian cancer
that this disease is part of the spectrum of other hereditary cancer syndromes associated with a high risk of preventable cancers (e.g. colorectal cancer in Lynch syndrome). In conclusion, given the current and future therapeutic implications, it is essential to develop new efficient and patient-centered approaches and procedures for delivering genetic counselling and testing to all ovarian cancer patients who may benefit from it.
Acknowledgments This study was supported by ‘Fondi 5 per mille’ to IRCCS AOU San Martino – IST, Genoa (L.V., Unit of Hereditary Cancer), and by the Italian Association for Research on Cancer (AIRC, Project IG 5706 2008; P.B.).
Disclosure Statement The authors declare that there are no conflicts of interest to disclose.
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Received: October 9, 2014 Accepted: May 13, 2015 Published online: June 24, 2015
Referral of Ovarian Cancer Patients for Genetic Counselling by Oncologists: Need for Improvement Maria Teresa Ricci a Stefania Sciallero b Serafina Mammoliti b Viviana Gismondi a Marzena Franiuk a Paolo Bruzzi c Liliana Varesco a a
Unit of Hereditary Cancer, b Medical Oncology Unit 1, and c Unit of Clinical Epidemiology, IRCCS AOU San Martino-IST, Genoa, Italy
Abstract Background/Aims: Nearly 15% of all ovarian cancer patients carry a germline BRCA mutation. A pilot project was started at IRCCS AOU San Martino – IST, Genoa, to assess the feasibility and consequences of offering genetic counselling to all ovarian cancer patients during routine oncology appointments. We present early results of this project. Methods: Patients who attended an oncology visit at the Medical Oncology Unit 1 between November 2012 and December 2013 were identified. Medical records were reviewed for clinical data, genetic counselling and testing outcomes. Results: Out of 104 women diagnosed with ovarian cancer undergoing an oncology visit, 94 had not had genetic counselling in the past. Twenty-nine patients (29/94, 31%) were referred to the Unit of Hereditary Cancer; of these, 14/26 (54%) were referred at the first visit and 15/68 (22%) at the follow-up visit (p = 0.003). Most referred women attended genetic counsel-
© 2015 S. Karger AG, Basel 1662–4246/15/0184–0225$39.50/0 E-Mail [email protected] www.karger.com/phg
ling (22/29, 76%) and had BRCA genetic testing (21/22, 95%). Four BRCA1 mutations were detected (4/21, 19%). Conclusions: Oncologists discuss genetic counselling with a minority of ovarian cancer patients. Mainstreaming such practice is important to optimize the management of these patients and their families. Efforts are needed to identify new models for introducing ovarian cancer genetic risk assessment in oncology practice. © 2015 S. Karger AG, Basel
Introduction
Ovarian cancer is a significant cause of cancer morbidity and mortality in Western women, accounting for approximately 3% of all incident cancers and 5–6% of all cancer deaths [1]. It has been shown that approximately in 1 out of 4 unselected ovarian cancer patients, germline mutations in tumor suppressor genes are found, potentially causing an inherited cancer predisposition [2], and two thirds of these mutations are in the BRCA1 and BRCA2 genes. In Liliana Varesco Unit of Hereditary Cancer IRCCS AOU San Martino – IST Largo Rosanna Benzi, 10, IT–16132 Genoa (Italy) E-Mail liliana.varesco @ hsanmartino.it
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Key Words BRCA testing · Capacity building · Feasibility · Genetic counselling · Ovarian cancer
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Ovarian Cancer outpatients Genetic counselling proposed Oncologist
Genetic Nurse
Contacts of interested patients left on UHC answering machine
Telephone contact and personal/family medical history reconstruction Appointment arranged
Medical Geneticist
Genetic counselling Genetic testing proposed
Fig. 1. Study protocol. The oncologists propose genetic counselling to all women with a recent or past diagnosis of invasive epithelial ovarian cancer during routine visits and, for patients who confirm to be interested in genetic risk assessment, directly arrange a contact with the UHC.
At present, in Italy, there are no specific national guidelines regarding the referral of ovarian cancer patients to genetic counselling and testing. In particular, until the year 2013, BRCA testing was offered only to ovarian cancer patients with an additional family history of breast or ovarian cancer [21]. In 2012, a pilot project was started by the Unit of Hereditary Cancer (UHC) and the Medical Oncology Unit 1 (MOU-1) of the Istituto di Ricovero e Cura a Carattere Scientifico – Azienda Ospedaliera Universitaria San Martino – Istituto Nazionale per la Ricerca sul Cancro (IRCCS AOU San Martino – IST) of Genoa, aimed at assessing the feasibility and consequences of offering genetic counselling to all women diagnosed with an invasive ovarian cancer, regardless of age at diagnosis or the presence of a family history of breast or ovarian cancer. One year after the introduction of this pilot project, we present its early results in terms of oncologists’ adherence to the protocol, patients’ compliance with genetic counselling and testing, and the prevalence of BRCA mutations.
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fact, 13–18% of unselected ovarian cancer patients carry a deleterious mutation in one of these two genes [2–4]. Among these patients, the likelihood of carrying a mutation varies with age at diagnosis, histology, family history and ethnicity [5], but if the patients were selected on the basis of these factors, a significant number of mutation carriers would be missed [2–4]. Indeed, genetic testing is recommended to all patients with invasive ovarian cancer by many clinical practice guidelines because of the high prevalence of BRCA mutations in series of unselected women with ovarian cancer [6–8], and it is already the practice in Australia, Scotland and Ontario. BRCA genetic testing is provided for several reasons. Family members found to be at an increased risk of breast and ovarian cancer have the opportunity to undertake appropriate prevention strategies, including, for breast cancer, intensive surveillance or risk reduction surgery, and for ovarian cancer, salpingo-oophorectomy. In two recent studies [9, 10], among women with a BRCA mutation who had undergone salpingo-oophorectomy, a significant reduction was reported in ovarian cancer risk [HR 0.28 (95% CI 0.12–0.69); HR 0.20 (95% CI 0.13– 0.30)], in breast cancer risk [HR 0.63 (95% CI 0.41–0.96)], in BRCA1 carriers [HR 0.36 (95% CI 0.16–0.82)], in BRCA2 carriers and in all-cause mortality [HR 0.40 (95% CI 0.26–0.61) and HR 0.23 (95% CI 0.13–0.39), respectively]. For the patients themselves, the increased risk of primary breast cancer warrants appropriate surveillance, while the relatively low yearly breast cancer incidence and the significant ovarian cancer-related mortality argue against an aggressive surgical management of breast cancer risk in these patients, in particular in the first 5 years after the diagnosis [11]. In addition, BRCA mutation status may influence ovarian cancer treatment in the near future; BRCA-related ovarian cancer seems to be characterized by an increased responsiveness to platinum chemotherapy [12] and to poly ADP-ribose polymerase inhibitors [13]. A poly ADP-ribose polymerase inhibitor was recently approved by the European Medicines Agency (EMA) for the maintenance treatment of patients with platinum-sensitive, relapsed, BRCA-mutated (germline and/or somatic), high-grade, serous, epithelial ovarian, fallopian tube, or primary peritoneal cancer who respond (complete response or partial response) to platinumbased chemotherapy [14]. Despite the growing awareness of the high prevalence of BRCA mutations in ovarian cancer patients, health providers continue to refer only some of them to genetic services [15–20].
Table 1. Clinical characteristics of ovarian
cancer patients included in the study Number of patients Mean age at diagnosis (range), years Presence of symptoms, n (%) Yes No Indication of chemotherapy, n (%) Yes No
The study protocol was developed in November 2012 by the UHC of the IRCCS AOU San Martino – IST of Genoa and the MOU-1 that is in charge of the care for most ovarian cancer patients at the same institute. According to the protocol (fig. 1), the oncologists are expected to propose a genetic risk assessment during routine visits to all women diagnosed with an invasive epithelial ovarian cancer. Two types of visits are considered: (a) first visits, usually of 1 h duration, that include the compilation of a family history box in the clinical chart, and (b) follow-up visits, usually of 30 min duration and not including the compilation of a family history box in the specific clinical chart (to view/update the family history, the clinician must go back to the first visit chart). Then, the oncologist leaves the contacts of each patient interested in genetic counselling on the UHC answering machine. No other change in their current practice was introduced. The subsequent steps of the genetic risk assessment process are not different from usual care; in particular, genetic counselling is performed without the direct involvement of oncologists in preand post-test genetic consultations. The UHC genetic nurses contact the patient by phone and arrange an appointment with the medical geneticist after a preliminary reconstruction of the personal and familial medical history. The genetic testing is proposed during genetic counselling following a detailed pedigree construction and a discussion about its advantages and limits. BRCA genetic testing is proposed to all patients with invasive epithelial ovarian cancer, while testing of other genes is offered only if a personal and/or familial history pattern suggestive of a known hereditary cancer syndrome is present (e.g. Lynch syndrome). For women who give their consent, BRCA1 and BRCA2 genetic testing is performed on DNA isolated from peripheral blood lymphocytes, using direct sequencing and multiplex ligation-dependent probe amplification. Genetic counselling and testing are free for the patients as the costs are covered by the Italian national healthcare system. One year after the introduction of the pilot protocol, we evaluated (a) the proportion of ovarian cancer patients referred to genetic counselling by oncologists out of the total number of ovarian cancer patients attending their clinics who never had genetic counselling before; (b) the proportion of ovarian cancer patients who accepted to be referred to genetic counselling out of the total number of ovarian cancer patients to whom genetic counselling was offered by oncologists; (c) the proportion of women attending
BRCA1 and BRCA2 Genetic Testing in Oncology Practice
Follow-up Overall oncology visit
26 59.8 (43 – 83)
68 58.2 (29 – 80)
94 58.7 (29 – 83)
8 (31) 18 (69)
19 (28) 49 (72)
27 (29) 67 (71)
24 (92) 2 (8)
9 (13) 59 (87)
33 (35) 61 (65)
the genetic counselling session out of the total number of referred women; (d) the detection rate, that is the proportion of pathogenic BRCA variants out of the total number of performed tests, and (e) the occurrence of cascade testing (number of predictive tests on other family members after the identification of a pathogenic variant). The list of all unrelated patients with ovarian cancer cared for in the MOU-1 between the start of its activity in 2002 and December 2013 was identified. Women diagnosed with ovarian cancer who attended at least one oncology visit in the MOU-1 between November 2012 and December 2013 were selected. Women who had undergone genetic testing in the past were excluded. Information on the age at the visit (and at ovarian cancer diagnosis when different), the presence of symptoms and the indication of chemotherapy (ongoing/programmed) was derived from medical records for all women who should have been referred to genetic counselling during the considered period. Family history data were not collected from medical records because the quality of this information was judged to be generally poor by the oncologists if compared with the suggested standard [22]. Ovarian cancer patients referred to the UHC were identified from the list of women for whom a contact with the unit was registered during the study period. Information on the following steps of the genetic risk assessment process was derived from clinical genetics notes of each referred woman: (1) telephone interview with a genetic nurse (done/not possible); (2) genetic consultation with a medical geneticist (done/not done); (3) BRCA genetic testing (done/not done); (4) results of the BRCA testing (uninformative, variant of uncertain significance, pathogenic variant), and (5) number of relatives who underwent predictive genetic testing after a pathogenic BRCA variant was identified in the index case. The study was conducted following the rules of the local ethical committee. Statistical Analysis The aims of all statistical analyses were merely descriptive. The data were presented as means with range, proportions and 95% confidence limits, as appropriate. The distributions of continuous variables were compared and assessed for statistical significance using the Mann-Whitney test, while the χ2 test was used for comparing proportions.
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Patients and Methods
First oncology visit
Color version available online
Fig. 2. Results of the study according to the
oncology setting (first and follow-up visits). No GC = Genetic counselling not performed.
Referral to genetic counselling Yes 29 (31%) No 65 (69%) Mean age at ovarian cancer diagnosis (range), years Referred 56.7 (43 – 73) Not referred 59.5 (29 – 83)a Consented to be contacted by the UHC Yes 29 (100%) No 0 Contact with the UHC successful Yes 27 (93%) No 2 (7%) Genetic counselling Yes 22 (81.5%) No 5 (18.5%) BRCA genetic testing Yes 21 (95%) No 1 (5%) BRCA mutation Yes 4 (19%) VUS 2 (9.5%) No 15 (71.5%) VUS = Variant of unknown significance. a p = 0.261.
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Results
A total of 345 unrelated women diagnosed with invasive epithelial ovarian cancer were cared for in the MOU1 between 2002 and 2013. Most of these patients (n = 241) were no longer followed in November 2012 because they had died or at some point received oncology care elsewhere. A total of 104 patients (78 follow-up patients and 26 new patients) attended at least one oncology visit between November 2012 and December 2013. Since 10 patients had already undergone genetic testing in the past, 94 ovarian cancer patients were eligible for the present study. The clinical characteristics of the patients included in the study are shown in table 1. The mean age at ovarian cancer diagnosis was 58.7 years (range 29–83). No difference in the mean age at diagnosis was observed among women seen at first and follow-up visits (59.8 vs. 58.2 years, respectively; p = 0.559). The majority of follow-up patients were asymptomatic (49/68; 72%, 95% CI 60–81) and did not undergo chemotherapy, nor was it programmed at the moment of the visit (59/68; 87%, 95% CI 77–93). The results of the study are summarized in table 2 and figure 2. Oncologists offered genetic counselling to 29 of 94 patients (31%, 95% CI 22–41); all of them said they Ricci/Sciallero/Mammoliti/Gismondi/ Franiuk/Bruzzi/Varesco
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Table 2. Referral to genetic counselling, uptake and the results of BRCA genetic testing
Table 3. Referral to genetic counselling and BRCA genetic testing uptake at the first and follow-up oncology visits
First oncology visit Referral to genetic counselling Yes 14 (54%) No 12 (46%) BRCA genetic testing uptake Yes 8 (57%) Noa 6 (43%)
Follow-up oncology visit
p
15 (22%) 53 (78%)
0.003
13 (87%) 2 (13%)
0.109
a
Genetic counselling not performed (n = 7) or refusal of undergoing testing (n = 1).
Here, we report the preliminary results of a pilot multidisciplinary protocol conducted at an Italian institution aiming at facilitating the referral of all patients diagnosed with ovarian cancer for genetic counselling and testing. During the first year of its introduction, 31% of the women diagnosed with ovarian cancer were referred by oncologists to the UHC, and approximately three quarters of these accepted to undergo genetic testing. The observed prevalence of BRCA1/2 mutations among women who had undergone testing (19%) was close to the expected value (13–18% [2–4]), and cascade testing allowed the identification of 4 at-risk family members. The 31% referral rate is consistent with the rates previously reported in Ontario, Canada, where, as at our institution, BRCA genetic testing is freely available to all wom-
en with invasive ovarian cancer [15, 19]. This lack of referral may be in part due to practical barriers that can be reduced by the introduction of specific tools; for example, Petzel et al. [20] reported that the introduction of a systematically generated electronic referral form increased the referral of ovarian cancer patients from 17 to 30%. Other reported barriers to clinicians’ referral for cancer genetic risk evaluation include the limited knowledge on hereditary cancer and the lack of specific training [23, 24]. Indeed, a recent survey indicates that the knowledge of and attitudes about BRCA genetic testing of Italian physicians are heterogeneous [25], suggesting that targeted educational and training programs in this field are needed in our country. Of note, we observed that referral was substantially higher at first visits (54%) than in women attending follow-up visits (22%). This difference could be related to some practical aspects of the visits, such as their duration (allowing or not allowing time for the introduction of additional information related to genetic issues) and the type of checklist used (including or not including the family history). Besides practical barriers, as an alternative explanation for this unexpected finding, one might also speculate that during the initial oncology visit, broad questions on disease development (i.e. cancer etiology) and family history are discussed and, therefore, it is easier for the oncologist to introduce the issue of a possible inherited cancer susceptibility. On the contrary, during follow-up visits, both the oncologist and the patient may be more focused on the present clinical situation. In addition, we observed that patients’ uptake of testing varied by the point in care at which referral was made,
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Discussion
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were interested, and their contacts were left on the UHC answering machine. The mean age at ovarian cancer diagnosis of women referred to the UHC was similar (56.7 years, range 43–73) to that of women who were not referred (59.5 years, range 29–83; p = 0.261). Referral was higher for women attending the first oncology visit (14/26; 54%, 95% CI 35–71) than for follow-up patients (15/68; 22%, 95% CI 14–33; p = 0.003; table 3). In the group of the 29 ovarian cancer patients referred to the UHC for genetic counselling, 2 were not contactable by phone, and 5 did not show up on the day of the scheduled genetic counselling. Therefore, 22 of 29 referred women (76%, 95% CI 58–88) attended genetic counselling, and 95% (95% CI 78–99) of these (21/22) consented to BRCA genetic testing; no patient attending genetic counselling was eligible for testing other hereditary ovarian cancer genes. In total, the uptake of BRCA genetic testing was 87% (95% CI 62–96; 13/15) in women referred for genetic counselling during follow-up visits and 57% (95% CI 33–79; 8/14) in women referred during the first visits (p = 0.109; table 3). A total of four pathogenic BRCA1 mutations were detected (4/21; 19%, 95% CI 6–42). In addition, 2 patients carried one variant of unknown significance in BRCA1 and in BRCA2, respectively. Among healthy close relatives, 8 women belonging to three BRCA mutation carriers’ families decided to undergo genetic counselling and testing. At least one BRCA1 mutation carrier was identified in each of the three families and, in total, 4 at-risk women were mutation positive.
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patients in the frame of the Mainstreaming Cancer Genetics (MCG) program, a cross-disciplinary initiative that aims to develop infrastructures, processes and education that will allow the implementation of gene testing into the routine clinical care of cancer patients and their relatives [28]. According to this model, oncologists discuss BRCA genetic testing with ovarian cancer patients during routine appointments, directly obtain consent for the genetic analysis and send blood samples to the molecular genetics laboratory. After reviewing and interpreting the results, the genetic team sends the test results to the patients and offers a genetic appointment only to women found to carry a BRCA mutation; referral to genetic counselling is possible at every stage of the process if requested. The forthcoming therapeutic use of BRCA germline/somatic testing will change profoundly the ethical, procedural and organizational aspects of genetic counselling for ovarian cancer patients and their families. Hence, the development of new service delivery models in Italy (and other countries) should consider the implications of this new scenario (e.g. who will be responsible for helping the patient to resolve dilemmas related to BRCA germline testing? Who will be responsible for interpreting BRCA germline/somatic testing?). In addition, the results of this study suggest that the majority of ovarian cancer patients are pursuing genetic risk assessment when told of this possibility. Assuming a 50% referral rate of new ovarian cancer cases to genetic counselling at a national level, a 75% BRCA genetic testing acceptance rate and a 15–20% mutation detection rate among referred cases, this would imply that every year in Italy, where almost 5,000 new cases of ovarian cancer are diagnosed each year, between 280 and 380 new BRCA families would be detected during the initial years of the program. This may appear as a significant financial and organizational burden for the regional healthcare systems. However, the Italian 2014– 2018 national prevention plan prompts for the first time Italian regional healthcare services to define and implement regional programs for the identification and management of healthy women carrying BRCA mutations in the context of breast cancer prevention [29]. We believe that the figures reported above strongly indicate that the development of BRCA mutation carrierstargeted prevention programs in Italy should take into account the significant contribution of testing all ovarian cancer patients to the identification and management of BRCA families. On the other hand, programs involving ovarian cancer patients must consider the fact Ricci/Sciallero/Mammoliti/Gismondi/ Franiuk/Bruzzi/Varesco
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being lower in women referred during first visits than in follow-up visits (57 vs. 87%, respectively). A possible explanation for this observation is that genetic testing could heighten psychological distress, particularly in women coping with a new ovarian cancer diagnosis who may prefer to postpone genetic counselling. Since patients’ preferences for the optimal timing of genetic counselling and testing are personal and cannot be known without informing them about this possibility, discussing referral early and tailoring the timing of the genetic visit to each patient could be the best way to promote an informed choice on genetic testing [26]. Several limits exist in this study, and its results should be interpreted with caution. The first is the limited number of observations; in particular, the number of referred women is too low to draw any conclusion about the possibility that the referral during first visits may be associated with a significantly lower rate of attendance to genetic counselling/testing in our population. The second is that the reasons for the lack of referral were not investigated. This study was not designed to distinguish the oncologist’s willingness to postpone the genetic discussion to the next visit from its omission during a busy clinical practice. In addition, the study was not designed to analyze some plausible factors (e.g. number and age of close female relatives or psychosocial distress measures) that may have influenced the decision to refer ovarian cancer patients for genetic risk assessment. An additional limit of the study is that we did not analyze other genes involved in ovarian cancer hereditary predisposition; therefore, we probably underestimated the consequences of systematic referral of ovarian cancer patients to genetic counselling in light of the upcoming multi-gene testing [2]. Despite these limitations, our findings suggest that oncologists do not discuss genetic counselling with the majority of ovarian cancer patients. According to the present literature, this seems to be a general attitude, and the barriers to the referral of ovarian cancer patients to genetic counselling during oncology routine appointments remain largely unknown [15–20]. Besides the traditional face-to-face pre- and post-test genetic counselling provided by a genetic professional, alternative genetic testing delivery models have been developed [27]. In some of these models, nongeneticists carry out one or more of the classical genetic counselling steps, and only selected cases (e.g. mutation carriers, complex cases) are managed by the genetic professionals. In the United Kingdom, a model for BRCA testing has recently been developed for ovarian cancer
that this disease is part of the spectrum of other hereditary cancer syndromes associated with a high risk of preventable cancers (e.g. colorectal cancer in Lynch syndrome). In conclusion, given the current and future therapeutic implications, it is essential to develop new efficient and patient-centered approaches and procedures for delivering genetic counselling and testing to all ovarian cancer patients who may benefit from it.
Acknowledgments This study was supported by ‘Fondi 5 per mille’ to IRCCS AOU San Martino – IST, Genoa (L.V., Unit of Hereditary Cancer), and by the Italian Association for Research on Cancer (AIRC, Project IG 5706 2008; P.B.).
Disclosure Statement The authors declare that there are no conflicts of interest to disclose.
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22 Lu KH, Wood ME, Daniels M, Burke C, Ford J, Kauff ND, Kohlmann W, Lindor NM, Mulvey TM, Robinson L, Rubinstein WS, Stoffel EM, Snyder C, Syngal S, Merrill JK, Wollins DS, Hughes KS; American Society of Clinical Oncology: American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. J Clin Oncol 2014;32:833–840. 23 Brandt R, Ali Z, Sabel A, McHugh T, Gilman P: Cancer genetics evaluation: barriers to and improvements for referral. Genet Test 2008; 12:9–12.
