The Breast Cancer Susceptibility Gene 1 (BRCA1) and the Breast Cancer Susceptibility Gene 2 (BRCA 2) are tumor suppressor genes that encode proteins involved in the repair of DNA double-strand breaks by way of the homologous recombination repair pathway [1
]. Inherited mutations confer a heightened lifetime risk of breast cancer and/or ovarian cancer [2
]. The detection of these mutations is important in the prevention and surveillance of the disease and since their discovery over 20 years ago there has been increased availability of genetic testing.
Once given a positive BRCA mutation result, individuals can begin surveillance that combines mammography and magnetic resonance imaging (MRI), clinician breast examination and breast self-examination commencing at age 25 to 35 years [4
]. While heightened surveillance cannot prevent the development of breast cancer, it increases the likelihood of early detection. However, the sensitivity of mammographic surveillance is lower amongst younger women, which is problematic for BRCA mutation carriers in whom the risk for early onset (<40 years) breast cancer is increased up to 20-fold [6
]. It has been estimated by Meijers-Heijboer et al. that 25% of young, high-risk women that undergo close surveillance will develop breast cancer and eventually die from the disease [7
]. Even with a combination of MRI and mammography, the largest prospective single-center study to date has demonstrated a ten-year breast cancer-free survival of 74% for BRCA mutation carriers choosing surveillance [8
]. Moreover, there are concerns that women may not comply with the schedule of regular examinations or that the radiation incurred by mammography may increase the risk of breast cancer in BRCA mutation carriers, who by the nature of the mutations have defective DNA repair mechanisms [9
]. Given these factors, it is not surprising that many patients will decide to proceed with a risk-reducing prophylactic mastectomy with or without immediate breast reconstruction (PM/IBR) [10
The process leading to a prophylactic mastectomy is complex. Patients require access to health services required to make an informed decision, consultation with specialized health care professionals, time to consider the physical and emotional consequences of this type of surgery and balancing this intervention with life events such as child-bearing. Therefore, once a woman receives a positive mutation result, the time to risk-reducing surgery is affected by a multitude of factors [11
]. We examined the patient journey in those electing to proceed with risk-reducing surgery in order to determine the incidence of breast cancer prior to surgery and to compare this with patients choosing surveillance. We identified key milestones and modifiable decision points that might shorten the time to surgery and decrease the risk of development of cancer prior to prophylactic intervention.
2. Experimental Section
2.1. British Columbia (BC) Cancer Hereditary Cancer Program (HCP)
The HCP offers risk assessment, counseling and genetic testing. Those who test positive for BRCA1/2 are advised of options including surveillance, chemoprevention and prophylactic surgery. Patients can choose to be followed at the High Risk Clinic (HRC) where breast imaging and surgical referrals are arranged. The HRC maintains a database that includes demographics, genetic test results, a history of cancer diagnoses and a history of hereditary cancer-related surgery.
2.2. Patient Selection
A historical cohort study design was employed. The HRC database was interrogated to identify individuals with a positive BRCA1/2 mutation between 1 January 2000 and 31 December 2012. Patient charts were reviewed until 2018. Men, women younger than 25 years and patients who had any cancer diagnosis prior to genetic testing were excluded. Patients were divided into three groups based on a decision at the time of counseling: surveillance (S), prophylactic mastectomy with immediate breast reconstruction (PM/IBR) and prophylactic mastectomy only (PM).
2.3. Frequency of Surveillance and Surgical Techniques
Evidence based recommendations during the study period included a yearly breast MRI from age 25 to 65 and a yearly mammography from age 30, alternating every six months. The risk-reduction measures included a bilateral PM, a bilateral salpingo-oophorectomy (BSO) by age 40 and the use of risk-reducing medications [12
]. Prophylactic mastectomies were either total, skin sparing or nipple-sparing. Patients that chose PM/IBR continued regular surveillance while awaiting surgery.
2.4. Definition of Time Periods
Time periods were defined as T1: BRCA mutation disclosure to decision for surgery; T2: decision to surgical consultation; T3: consultation to surgery.
Approval was obtained from the University of British Columbia Clinical Research Ethics Board (CREB) and the Hereditary Cancer Program (HCP) within the British Columbia Cancer Agency (BCCA). The CREB waived the requirement for informed consent.
2.6. Statistical Analysis
The baseline patient characteristics for each patient group were described. Discrete variables were summarized by frequencies and percentages. Continuous variables were summarized by mean (SD) and median with percentiles (10th, 90th). Wait times were summarized with median with percentiles (10th, 90th). For the PM/IBR group time to surgery was summarized with a cumulative frequency curve. The cumulative incidence of breast cancer over time was calculated for each group; death was treated as a competing risk in all groups. A competing risks regression model was used to examine the differences in the development of cancer between the groups (Fine and Gray, JASA 1999) with group (S vs. PM/IBR), BRCA1 vs. BRCA2, years of hormone exposure and age included as covariates. A two-sided P value of less than 0.05 was considered to indicate statistical significance. All analyses were performed with the use of SAS 9.4 (SAS Institute Inc., Cary, NC, USA) and R version 3.4.1.
2.7. Funding Support
This study was supported by a grant from the Canadian Breast Cancer Research Alliance. This sponsor was not involved in the study design, data collection, analysis, interpretation of data or writing of the manuscript.
The goal of this study was to determine the incidence of BRCA mutation positive patients developing breast cancer prior to prophylactic surgery as well as modifiable patient and/or system factors that may decrease this incidence. We found a 31-month patient journey between BRCA mutation diagnosis disclosure and surgery with 6% of patients developing breast cancer during this time. This can be compared with the 14% incidence of breast cancer in patients choosing no intervention (surveillance), which is comparable with that found in other studies [13
]. The mean time to cancer detection in the surveillance group was 59.3 months. The shorter time to diagnosis in the PM/IBR group may be due to the fact that a subset of the cancers was detected at the time of surgical intervention; these cancers may have gone undetected for longer in the surveillance group. We hypothesized that patients would face delays to consultation with specialized health care professionals and delays to surgery due to the long wait times for non-urgent medical consultations and surgery in Canada. However, we found that the majority of the time between mutation disclosure and surgery in the PM/IBR group was attributable to time to make the decision to proceed with surgery. This held true for the subset of patients that developed cancer prior to surgery.
The protective effect of a prophylactic mastectomy against the subsequent development of cancer in BRCA mutation carriers is well documented with the majority of studies showing zero incidence of cancer in patients after they have proceeded with a prophylactic mastectomy [13
]. The development of cancer in patients after they have decided to proceed but prior to a prophylactic mastectomy is less studied and even fewer papers comment on the time to a prophylactic mastectomy. Ingham et al. reported five cases of occult cancer (3.9%) in 126 patients undergoing prophylactic surgery [15
]. Kaas et al. reported one case of an occult IDC (5 mm in size) and six cases of an occult DCIS (4.7%) in 147 similar cases [16
]. Heemskerk-Gerretsen et al. reported two cases of an occult DCIS and four cases of an occult IDC in 212 asymptomatic carriers at the time of a prophylactic mastectomy (2.8%) [18
]. Skytte et al. reported one case of an IDC in 96 women undergoing a prophylactic mastectomy (1%) [14
]. Yao et al. found a 2.7% incidental risk of an IDC at the time of a mastectomy in 150 BRCA mutation patients undergoing a prophylactic nipple-sparing mastectomy [21
]. Of these studies only Skytte et al. in Denmark reported the time between BRCA mutation disclosure and a prophylactic mastectomy (11.5 months). Two additional studies comment on this time; Beattie et al. at the University of San Francisco reported a four month median time between BRCA mutation disclosure and risk-reducing surgery [22
] and Flippo-Morton et al. in North Carolina reported a seven and a half month time [23
]. Our study revealed a 6% incidence of breast cancer diagnosed prior to surgery or at the time of a prophylactic mastectomy. This is slightly higher than the cited studies and associated with a longer time period between BRCA disclosure and surgery (31 months).
The time to the decision to proceed with risk-reducing surgery (T1) is a key modifiable factor. This time period is complex as decision-making in the BRCA1/2 patient may be impaired due to psychological distress after the disclosure of the genetic mutation and the time required to make such an important decision [24
]. Additionally, many patients may defer surgery for reasons such as a desire for child-bearing or may opt to start with surveillance and then subsequently decide to proceed with surgery, as was seen in our cohort. The genetic counselor is the first point of contact and it is incumbent upon this specialist to provide the time and information necessary for the patient to make an informed decision. Metcalfe et al. found that 28% of BRCA1/2 patients felt that they were not given sufficient information pertaining to prophylactic surgery at the time of the disclosure of their genetic mutation [25
]. These authors went on to create a decision aid (DA) to help reduce decisional conflict. In a randomized controlled trial, BRCA1/2 patients were randomized to DA + standard care or standard care. The DA was a 15-page self-administered booklet summarizing information regarding the risk of breast cancer, preventive options, studies evaluating preventive strategies, guidelines for evaluating the evidence, risks and benefits associated with each option and definitions [26
]. For a prophylactic mastectomy, the proportion of women undecided decreased by 11.5% in the intervention group and by 5.3% in the control group. Additionally, among women who were undecided about surgery, the mean cancer-related distress scores were significantly lower at 12 months for those in the intervention group than for those in the control group. Other studies have confirmed that decision aids are effective in reducing decisional conflict, the reduction of which would likely reduce T1 [27
T2 and T3 are system-related and reflect the prioritization of more “urgent” patients within the health care system. BRCA mutation patients fall into a category somewhere between elective and urgent but are typically wait listed as elective while patients with active cancer are prioritized. Access to specialist consultation and the supply of elective surgery depends upon system capacity and the productivity with which that capacity is used [28
]. Many studies have shown that productivity is affected by physician compensation with fee-for-service payment schedules increasing productivity. Other factors such as health expenditure per capita, hospital personnel and the number of surgical beds have an impact on wait times but the exact nature of these relationships is unclear and varied. In the case of the BRCA mutation patient at risk of developing cancer prior to prophylactic surgery, two main approaches can be considered. First, these patients need to be clearly prioritized on a surgeon wait list for consultation and surgery with a guaranteed maximum wait program for the delivery of service. Second, a dedicated block of operative time should be allocated to BRCA mutation patients in order to provide a rapid access model of care. This would ideally include two concurrently running operative rooms with surgical oncology and plastic surgery moving between rooms to perform the maximum number of surgical cases each operative day.
Despite the strengths of our study including a large sample size from a single institution and a sufficiently long follow-up period for breast cancer risk estimates, a prospective design would more accurately capture the exact reasons for the length of time between BRCA mutation diagnosis and prophylactic surgery. This would also allow the allocation of each cancer diagnosis into a specific time period (T1–T3) to further establish where to target resources. However, we have shown that at the 31-month time point from a BRCA mutation disclosure, 6% of BRCA patients awaiting prophylactic surgery (and still under surveillance) developed cancer. The majority of the patients that chose to proceed with PM/IBR and still developed cancer had a long T1 period, which may be attributed to a difficulty making the decision to proceed with risk-reducing surgery. This can be extrapolated to all healthcare systems that use similar hereditary cancer programs and be used to inform patients of the risk of developing cancer even after deciding to proceed with risk-reducing surgery. This may in turn focus centers on methods to optimize the decision-making process (T1) and, once a patient has decided to proceed, to ensure surgery is expedited in this high-risk group.