The clinical role of BRCA1 and BRCA2 mutation testing for younger women with breast cancer is in rapid transition because of advances in gene sequencing technologies and accumulating evidence for the contribution of BRCA mutation status to acute management of early breast cancer. Women diagnosed with breast cancer are offered genetic counseling and testing for germline mutations in BRCA1 and BRCA2 if they have a strong family history of the disease and/or they meet other criteria which point to a mutation detection rate that exceeds a predefined threshold for her local service. Genetic risk assessment has usually been offered on completion of surgery and adjuvant therapy for a new breast cancer, and routine genetic test results in Australia has to date taken between one and six months from blood draw. In contrast, genetic counseling and testing offered around the time of breast cancer diagnosis aims to provide the patient with genetic information that will assist in the choice of breast cancer treatment, primarily the choice between breast-conserving therapy (BCT) and mastectomy. The secondary effects of directing risk-reducing ovarian surgery and informing family members of their own cancer risks are not time dependent but useful outcomes of a genetic test at any time.
Women newly diagnosed with breast cancer with a BRCA
mutation must choose whether to undergo BCT, unilateral mastectomy, or prophylactic bilateral mastectomies to prevent future breast cancers [1
]. The incidence of another tumor developing in the treated breast increases in BRCA
mutation carriers with longer follow-up [1
] and it also varies with the type of local therapy [2
]. Pierce et al. found that there was a significantly increased risk of local tumor recurrence in BRCA1
mutation carriers treated with BCT compared to carriers treated with mastectomy at 10
years (10.5% versus 3.5%) and at 20
years (30.2% versus 5.5%) [2
]. Compared with noncarriers, BRCA1
mutation carriers have a substantially increased lifetime risk of contralateral breast cancer that is age dependent and can be up to 68%, if the age of the first cancer is <40 [3
]. While there is no evidence that prophylactic mastectomy improves breast cancer survival for BRCA
mutation carriers [5
], the risk of and potential emotional impact of a subsequent breast cancer and the need for further treatment are important issues to consider [1
]. Contralateral prophylactic mastectomy can decrease the risk of subsequent breast cancer by up to 95% [6
]. The BRCA
mutations also confer a 13-46% lifetime risk of ovarian cancer [9
]. The secondary breast cancer prevention role of premenopausal risk-reducing bilateral salpingo-oophorectomy (RRSO) is less well established. Although there is an important breast cancer risk reduction of between 39% (BRCA1
) and 72% (BRCA2
] among mutation carriers who have RRSO before the age of 50
years, Domchek et al. 2010 did not find a similar reduction in women who had had prior breast cancer [8
mutation testing can now be made available rapidly, within 5 working days if required. Soon, further advances in sequencing will substantially reduce the cost of genetic analysis [11
] and will open the opportunity for genetic testing to even more women who might benefit from this information. This means that a woman’s BRCA
mutation status can feasibly be used now to inform her surgical decisions regarding BCT or mastectomy (unilateral or bilateral). In the future, timely BRCA
mutation testing will extend to selection of specific adjuvant systemic chemotherapy once the optimal systemic therapy for BRCA
mutation carriers is established, including the role of poly (ADP-ribose) polymerase (PARP) inhibitors [12
] and platinum-based chemotherapy. Hereafter, genetic counseling and testing offered shortly after a women’s diagnosis of breast cancer will be referred to as ‘treatment-focused genetic testing’ (TFGT). The potential for ever increasing scope for the use of TFGT in acute breast cancer management in the very near future means that new models for genetic counseling will be needed in order to manage the increased demand for and delivery of genetic information. In particular, there is a pressing need to develop cost effective clinical pathways which utilize the multidisciplinary cancer and genetics team, in order to offer TFGT in a streamlined way which is acceptable to patients and health care providers.
A concern shared by both patients and health professionals is that TFGT may create undue psychological burden among women diagnosed with breast cancer at a very vulnerable time in their life [14
]. There is limited empirical data available on the psychosocial implications of TFGT. Two studies have described the behavioral and psychological impact of TFGT in the US [15
] and The Netherlands [18
]. In the US study, 194 patients newly diagnosed with breast cancer were offered genetic testing before definitive treatment and the impact on surgical decision-making was evaluated. Definitive treatment was defined as mastectomy (unilateral or bilateral) or BCT, including commencement of radiation treatment [15
]. Forty-eight percent of women who were found to carry a BRCA1
mutation opted for bilateral mastectomy (BM), compared to 4% of women who declined genetic testing. Compared to women who chose BCT or unilateral mastectomy, those who chose BM did not report diminished quality of life or increased distress [17
]. The Dutch prospective study assessed the psychological impact of TFGT in women diagnosed with breast cancer who were about to commence adjuvant radiotherapy. Patients’ distress levels did not increase after genetic counseling and testing [18
]. Another randomized controlled trial is currently in progress in The Netherlands, which is assessing the impact of rapid genetic testing and counseling on women newly diagnosed with breast cancer on surgical decision making and psychosocial outcomes [19
A limitation of these studies is that they have selected or are selecting women based primarily on a significant family history of breast and/or ovarian cancer [16
] or have retrospectively selected women based upon their BRCA
mutation status [14
]. In addition, these previous studies have not included a health economic analysis assessing the cost effectiveness of delivering TFGT to women diagnosed with breast cancer. The concept of a strong family history as the optimum criterion for selection for genetic testing is being challenged with evidence for several personal and disease characteristics that are suggestive of BRCA
mutations. For example, between 30-50% of women with a BRCA1/2
mutation have no significant or known family history of breast or ovarian cancer [20
] and up to 8% of women with Ashkenazi Jewish ancestry and breast cancer diagnosed under 50
years have no relevant family history [22
]. Up to 27% of women under the age of 50 and 36% of women diagnosed at or under age 40, unselected for family history with triple negative breast cancer are BRCA1
mutation carriers [23
]. Of over 12,000 new breast cancer diagnoses in Australia annually, 24% are in women under 50 [24
]. In relation to genetic testing, the predictive value of having a BRCA
mutation in these younger age-of-onset cases increases especially when combined with triple negative disease [25
]. Yet little is known about the acceptability of TFGT among younger women without a relevant cancer family history but with disease, tumor or ethnic features suggestive of a high risk of actually having a BRCA
mutation. Meiser and colleagues conducted in-depth semi-structured interviews with 26 younger women (aged 50
years or less) diagnosed with breast cancer (14 had undergone TFGT and 12 had not), which explored their actual and hypothetical attitudes toward, and experiences (if any) of TFGT [26
], and their information preferences regarding TFGT [27
]. Women with and without a relevant family history of breast and/or ovarian cancer were included. All of the participants viewed TFGT as highly acceptable and wanted to receive information about it early, either at diagnosis or shortly thereafter, to inform their treatment options and to assist family members. Women preferred to receive the offer of TFGT verbally in a face-to-face consultation with a health professional. However, they also highlighted the importance of provision of supportive brief written information about TFGT that they could take away and consider at home [27
In this paper, we report the design of a study that compares two different models of delivering information about TFGT to younger women newly diagnosed with breast cancer. We also report several key issues encountered in the implementation of the study, which will have important implications for the integration of TFGT into acute breast cancer management in the near future.
Study objectives and hypotheses
The aim of this study is to compare the behavioral and psychosocial impact, efficiency and safety of offering information about TFGT to younger women newly diagnosed with breast cancer (a) using a brief educational pamphlet about TFGT (educational materials, ‘EM’ intervention) or (b) using pre-test genetic counseling at a family cancer service (standard care, ‘SC’ control). The efficiency of offering information about TFGT will be operationalised in a health economic analysis and through an assessment of health professionals’ views on the effectiveness of the TFGT process. The safety of the intervention will be determined by assessing its impact on psychological distress. This is a non-inferiority trial, in which our primary hypothesis is that patient decisional conflict regarding TFGT will be no worse in the intervention compared to that of the control group. A summary of the research questions that are addressed in the study are presented in Figure .
Research questions addressed in the study.
Our secondary hypotheses are: (i) that other decision-related and psychological outcomes (including decision regret regarding TFGT and surgery; anxiety; depression; cancer-specific distress; test-related experiences and distress; knowledge of TFGT; and uptake of genetic testing) will not be inferior in the intervention group compared to the control group, and (ii) that women who opt for TFGT will have a higher uptake of BM compared to data from the Royal Australasian College of Surgeons National Breast Cancer Audit on over 12,000 women with early breast cancer diagnosed annually [28
This is a multicenter randomized controlled trial which is being conducted at nine hospital sites located in three states in Australia (New South Wales, Victoria and Queensland) in two stages. The study protocol adheres to CONSORT guidelines [29
]. The study design is presented in Figure . In Stage I, 140 eligible patients are being randomized to receive either EM or SC. Randomization is in a 1:1 ratio and is achieved through a computerized random sequence, which is generated by an independent person. Each number in the sequence is printed and placed in an unmarked envelope such that allocation is concealed from the study coordinator until randomization occurs. It is not possible to blind participants to their allocation because they become aware of it once the genetics staff arrange patients’ genetic counseling appointments. The primary outcome measurement is level of decisional conflict regarding TFGT. The secondary behavioral and psychological outcome measures include: (i) uptake of TFGT; (ii) uptake of BM; (iii) cancer-specific distress; (iv) general anxiety and depression; (v) distress associated with decision to have genetic testing; (vi) level of decision regret regarding TFGT and surgical decisions, and (vii) family involvement in decision-making. Over the course of the study, four questionnaires will be administered: at baseline (prior to randomization); one week after receiving education about TFGT; 3
weeks after receipt of genetic testing result (or at the equivalent time point for those who do not have genetic testing or who choose not to receive their test result); and 12
months after study enrolment.
Study design and recruitment flow.
A health economic analysis is also included with the objective of ascertaining the cost effectiveness of the intervention compared to standard care, and the potential benefit of the intervention in terms of number of life years saved. The health economic analysis is modeled on similar evaluations conducted in a cancer/medical setting [30
]. The costs associated with each mode of information delivery are collected from each site by the study coordinator, including printing costs, blood collection fees, and courier fees. Surgeons’ and genetic counselors’ time (minutes) associated with discussing TFGT with each patient is recorded by each practitioner on a record sheet, which is faxed to the study coordinator after the relevant appointment. In Stage II, a retrospective health professionals’ survey will be conducted to determine health care providers’ attitudes toward and experiences of the TFGT process. The survey is targeted to breast surgeons, medical oncologists, radiation oncologists, and breast care nurses involved in the delivery of TFGT. Ethics approval has been received from the institutional review board for each site.