Background: The majority of breast cancers are thought to occur sporadically, with approximately 5% thought to be due to inherited susceptibility to cancer. The most commonly mutated genes predisposing women to breast cancer are BRCA1 and BRCA2. The Hereditary High-Risk Clinic at BC Cancer organizes breast screening and provides assessment and management recommendations for women with hereditary breast cancer risk. A study was done to ascertain the effectiveness of the clinic and identify areas of need.
Methods: A retrospective chart review was conducted using BC Cancer data for all patients seen at the High-Risk Clinic from 1997 to 31 July 2015. Study subjects included women with confirmed gene mutations that predispose them to increased risk for breast cancer and women who were untested but had a first-degree relative with a confirmed mutation. Patient data were anonymized prior to analysis.
Results: The study population included 654 women first seen in the clinic at a mean age of 42 years. Of these, 151 patients had previous diagnoses for cancer, including 142 breast cancers. During management of these women at the clinic, a total of 80 new breast tumors were identified and 77 of these were found to be malignant. Diagnosis occurred at a mean age of 48 years. The majority of new cancers were identified by either MRI or mammographic screening. During the study period, 38% of patients underwent prophylactic mastectomy and over 80% of patients older than 40 completed bilateral salpingo-oophorectomy. The mean age of patients undergoing bilateral mastectomy was 45 (22 to 79) years, while the mean age of patients undergoing bilateral salpingo-oophorectomy was 47 (26 to 77) years.
Discussion: Women with genetic risk for breast cancer require enhanced screening that includes annual MRI and mammography. The High-Risk Clinic is providing hereditary high risk women in BC with diagnostic and prophylactic services, and achieving rates of risk-reducing surgery comparable to those in the literature. However, 53% of women attending the clinic were older than 40 at their first visit and so may have missed the full benefit of risk reduction that might be achieved with earlier referral. In future, the centralization of care in the High-Risk Clinic and ongoing data collection should provide an opportunity to evaluate new imaging modalities, long-term outcomes of risk-reducing surgery, and new risk-reducing strategies.
Evidence-based management of women at increased risk for breast cancer has resulted in early diagnosis of tumors and preventive surgery rates comparable to those in the literature.
Women in the general population have a 1 in 9 lifetime risk of developing breast cancer—the number one cancer diagnosed in women in BC. The majority of breast cancers are thought to occur sporadically, with approximately 5% thought to be due to inherited susceptibility to cancer.
The most commonly mutated genes predisposing women to breast cancer are BRCA1 and BRCA2. The lifetime breast cancer risk for a BRCA1 mutation carrier is 47% to 66% and for a BRCA2 mutation carrier is 40% to 57%. The ovarian cancer risk is also greatly increased in BRCA mutation carriers: 35% to 46% for BRCA1 carriers and 13% to 23% for BRCA2 carriers, compared with a 1% to 2% lifetime risk for ovarian cancer in the general population.
The Hereditary Cancer Program (HCP) at BC Cancer accepts physician or self-referrals for hereditary breast and ovarian cancer assessment. Referral criteria for the HCP are shown in the accompanying (Figure).
Through the Hereditary Cancer Program, women receive a genetic risk assessment for cancer with extended counseling and options for genetic testing. These services have been shown to improve understanding of breast cancer risk, increase knowledge of breast cancer and genetics, and help reduce patient stress.
Women who have an increased risk of breast cancer due to inheritance of a mutation in a breast cancer susceptibility gene or who have a first-degree relative with a confirmed mutation are eligible for referral to the High-Risk Clinic at the BC Cancer Vancouver Centre. The clinic is run by a nurse practitioner and a medical director who arrange regular breast screening and provide consistent and up-to-date recommendations on risk-reducing measures.
Evidence-based recommendations for this population include yearly breast magnetic resonance imaging from age 25 to 65 and yearly mammography from age 30. Risk-reduction measures include bilateral mastectomy, bilateral salpingo-oophorectomy (BSO) by age 40, and the use of risk-reducing medications.
A review was done to evaluate the outcomes for women seen in consultation and followed at the High-Risk Clinic to ascertain the effectiveness of the clinic and identify areas of need.
Data were obtained from BC Cancer charts of patients first seen at the High-Risk Clinic from its opening in 1997 to 31 July 2015. The study population included patients with confirmed gene mutations that predispose them to increased risk for breast cancer and patients who were untested but had a first-degree relative with a confirmed mutation. Upon referral to the clinic these patients were not under the care of an oncologist, had not completed bilateral mastectomy, and were able to attend appointments in Vancouver. Data from incomplete charts were included in the study. Patient data were anonymized prior to analysis and the study was approved by the UBC BC Cancer Research Ethics Board.
The study population consisted of 654 women who were first seen in the clinic at a mean age of 42 years (range 18 to 83 years). Almost half (47%) of the women were younger than age 40 at their first visit. Personal BRCA mutations or BRCA mutation in a first-degree relative accounted for 98% of the study population, with the remaining 2% having a personal risk or familial presence of other gene mutations (TP53, ATM, CDH1) that increase risk for breast cancer, as presented in (Table 1). To date, 358 women (55%) have been discharged from the clinic. Of the women discharged, 175 (49%) were discharged due to the completion of risk-reducing surgeries, 86 (24%) due to a new cancer diagnoses and transfer to oncologic care, and 16 (4%) due to negative genetic testing results for a familial mutation. The remainder were discharged from the clinic for other reasons (e.g., patient older than 65 years, patient lost to follow-up, patient provided with prophylactic surgical plans, patient moved out of province).
Previous cancer diagnoses
The number and pathology of previous cancers in BRCA patients are presented in (Table 2). Of the 627 confirmed BRCA mutation carriers, 156 (24%) had a previous cancer diagnosis. Of these, 129 patients had previously been diagnosed with a single cancer, 18 with two cancers (including 16 women with bilateral breast cancer), and 4 with three cancers. Previous breast cancers occurred at a mean age of 45 (27 to 71) years.
In addition to the cancers in BRCA patients, five previous cancers were identified in carriers of other gene mutations (TP53, ATM, and CDH1). These included diagnoses of gastric cancer, sarcoma, and non-Hodgkin lymphoma.
New cancer diagnoses
While the 654 patients in the study were being followed by the High-Risk Clinic, 116 new tumors were identified in 106 patients (16%). A total of 80 new breast tumors (77 of them malignant) were identified, with the majority being detected by MRI or mammography. Breast cancers accounted for 68% of new cancers and ovarian or fallopian cancers for 16%. The remaining 16% of new cancers included two peritoneal cancers (after prophylactic BSO), three pancreatic cancers, and ten other cancers. The mean age of patients diagnosed with new breast tumors was 48 (25 to 74) years. The distribution of new breast tumors by mutation type is presented in (Table 3). A previous history of cancer was present in 30% of these patients, and of these 78% had a previous diagnosis of breast cancer.
The methods used to detect new tumors and the time since the last normal screening results (obtained by MRI, mammography, or clinical examination) are presented in (Table 4). The method of tumor detection was defined as the means by which an abnormality was reported before further investigations led to a cancer diagnosis.
Bilateral mastectomies have been completed for 246 of 654 patients attending the High-Risk Clinic (38%). Of these, 157 bilateral mastectomies (64%) and 78 contralateral mastectomies (32%) were done for prophylactic purposes. The indications for these mastectomies are presented in (Table 5).
The mean age of patients undergoing bilateral mastectomy was 45 (22 to 79) years.
More than 80% of patients older than 40 with BRCA mutations have had bilateral salpingo-oophorectomy at a mean age of 47 (26 to 77) years. Surgery was completed for prophylactic indications in 93% of cases and for treatment purposes in 7% of patients. Of 100 patients who were younger than 40 when first seen in the High-Risk Clinic, 50 (50%) had prophylactic BSO by age 40. At the time of this review, 204 active clinic patients are younger than 40, and 31 of these (15%) have already had prophylactic BSO.
Bilateral salpingectomy alone has been completed in 13 of 643 patients (2%) with a personal or familial BRCA1 or BRCA2 mutation, with a plan for completion of oophorectomy at a later date. The mean age for bilateral salpingectomy is 35 (29 to 42) years.
Women with genetic risk for breast cancer require enhanced screening that includes annual MRI and mammography. Multiple international studies have investigated the additional cancer detection yield when screening MRI and mammography are combined for women with an elevated breast cancer risk.[7-11] The sensitivity of MRI (77% to 93%) was found to be much higher than the sensitivity of mammography (33% to 50%), although with a slightly lower specificity (81% to 99% for MRI vs 93% to100% for mammography). At the High-Risk Clinic, annual MRI is available from age 25 with the addition of mammography at age 30. Compared with strategies that initiate imaging at other ages, this screening strategy has been shown by computer modeling to increase life expectancy and decrease breast cancer mortality. Traditionally, the majority of women in the High-Risk Clinic were followed with alternating MRI and mammogram every 6 months because while the initial studies of breast MRI involved concurrent procedures, the more frequent imaging assessment was thought to reassure patients. However, no scientific evidence has been found to support a diagnostic benefit for this schedule, and more recently the clinic has adopted concurrent annual imaging with MRI and mammogram, since mammograms are often required for investigation of abnormalities identified on MRI and because concurrent imaging simplifies scheduling for out-of-town patients.[9,13]
We cannot directly compare the performance of MRI and mammography as the screens were not performed concurrently during the entire study period. Of the tumors found during regular screening with imaging, 28% were either interval cancers or incidental findings on prophylactic mastectomy, usually within 1 year of the last normal screen. This speaks to the rapid growth of breast cancers in these high-risk patients and the need to investigate any new palpable abnormalities, regardless of normal findings on recent imaging. As well, high-risk patients need to be counseled that new cancers can develop quickly.
Considering both the 142 breast cancers diagnosed in BRCA1 or BRCA2 carriers prior to beginning surveillance at the High-Risk Clinic and the 80 breast tumors diagnosed in the clinic, a total of 222 breast tumors were diagnosed in 181 women followed at the clinic during the study period. The mean age of breast cancer diagnosis in women with a hereditary risk is lower than in women without such risk.
The mean age of these patients at diagnosis was 46 years and the majority (62%) were women age 30 to 49. By contrast, in the general population the majority of breast cancers (51%) occur in women age 50 to 69 and only 18% occur in women younger than 50. Early referral of women at risk based on their personal or family history is essential in order to provide them with appropriate care in a timely fashion. More than half of the women at the High-Risk Clinic (53%) were older than 40 at their first visit and may have missed the full potential benefit of early risk-reducing surgery. This suggests that further research is needed to identify barriers to early identification of patients at risk.
Bilateral prophylactic mastectomy reduces the risk of breast cancer in women with a BRCA gene mutation by 90% to 95%.[14-16] Despite the risk reduction possible with prophylactic mastectomy, many women opt instead for radiologic surveillance. Women choosing surveillance rather than prophylactic mastectomy are influenced by many psychological, medical, and demographic factors. In our study, 24% of patients opted for bilateral mastectomies for purely prophylactic purposes. This is comparable to findings by Friebel and colleagues, who report a 22% rate of risk-reducing mastectomy, although not as high as the findings of Chai and colleagues, who report a 46% rate of risk-reducing mastectomy by age 70.
The risk of developing a contralateral breast cancer is significantly increased for mutation carriers with a history of breast cancer. This information has been shown to influence a woman’s surgical decision regarding breast cancer treatment, with increased rates of bilateral mastectomy at the time of initial surgical treatment. Given the high risk in this patient population, such treatment is appropriate. In our study, one-third of the bilateral mastectomies involved removal of one breast for cancer treatment and the other for prophylactic purposes.
Bilateral salpingo-oophorectomy is recommended for BRCA mutation carriers primarily for reducing ovarian cancer risk. The reported rate of risk reduction for ovarian, fallopian, and peritoneal cancers achieved by prophylactic BSO is 80% to 96%.[22-24] The effect of prophylactic BSO on reducing breast cancer risk when the procedure is performed before natural menopause is still being investigated, but it may reduce the risk of breast cancer by up to 50%. In the literature, the reported rate of uptake for risk-reducing BSO in BRCA carriers is higher than that for bilateral mastectomy, with rates of approximately 45% in women younger than age 40 and up to 86% for women older than 40.[18,19] In our clinic population, 50% of patients who were seen before age 40 had prophylactic BSO by age 40, with more than 80% older than 40 having had BSO.
The fallopian tube epithelium is believed to be the site of origin for most ovarian cancers. Data from studies of patients who had undergone tubal ligations for fertility control have shown a subsequent risk reduction in ovarian cancer occurrence for both members of the general population and BRCA mutation carriers.
For these reasons, consultation with young premenopausal patients in the High-Risk Clinic includes discussion of bilateral salpingectomy and oophorectomy for ovarian cancer risk reduction, with delayed oophorectomy as an option for those not yet prepared to proceed to oophorectomy. There is no evidence that this procedure impacts breast cancer risk, and the efficacy of salpingectomy alone as a risk-reduction measure for ovarian cancer is still to be defined. Bilateral salpingo-oopherectomy remains our primary risk-reduction recommendation for ovarian cancer.
Our data indicate that we are achieving risk-reduction surgery rates for both prophylactic mastectomy and prophylactic BSO that are comparable to those in the literature. Given the complexity of factors influencing a woman’s decision regarding prophylactic surgery, further research is needed to determine whether it is possible to increase the uptake of preventive breast surgery. As well, a more in-depth exploration of patient understanding of the risks and benefits of breast surveillance versus surgery is needed and research in this area is planned.
To our knowledge this is the third published report on a screening program for high-risk women and the second to report on a clinic designed to meet the needs of women at high risk for breast cancer. In 2012, Chiarelli and colleagues reported on the results from the first year of the Ontario high-risk breast screening program, which provides annual MRI with digital mammography in 28 centres around the province. Before this, a preliminary report was published by Chart and colleagues in 1997 on outcomes from the Familial Breast Cancer Clinic at Sunnybrook Regional Cancer Centre in Toronto.
This study is based on medical information from BC Cancer charts and only considers data for patients seen at the High-Risk Clinic. There are patients in the Hereditary Cancer Program who have chosen not to be followed by the clinic, and we do not have data on their outcomes. The location of the clinic at the BC Cancer Vancouver Centre is a limiting factor for assessment for some patients, and in the past year we have been developing an expanded model with teleconsultation options. Access to breast MRI throughout the province continues to pose a challenge for a distributed model of care.
In future, the centralization of care in the High-Risk Clinic and ongoing data collection should provide an opportunity to evaluate imaging outcomes and new imaging modalities, long-term outcomes of risk-reducing surgery, and new risk-reducing strategies.
The Hereditary Cancer Program and the High-Risk Clinic at BC Cancer provide important services for women with an inherited predisposition for and increased lifetime risk of breast cancer. This study shows that British Columbian women with an increased risk of breast cancer are able to receive evidence-based screening and management through the High-Risk Clinic. The clinic is achieving risk-reduction surgery rates for both prophylactic mastectomy and prophylactic bilateral salpingo-oophorectomy that are comparable to those in the literature. The clinic also provides opportunities for future research that may enhance the uptake of risk-reducing surgery and identify barriers to early identification of patients at risk. More than 50% of women are older than 40 when first seen at the clinic and may not be receiving the full risk-reducing benefit of early referral and intervention.
This article has been peer reviewed.
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Dr Blood is a resident in the Department of Medical Genetics at UBC. Ms McCullum is a nurse educator in the Hereditary Cancer Program at BC Cancer. Dr Wilson is the director of breast imaging at BC Cancer and is a clinical associate professor in the Department of Radiology at UBC. Dr Cheifetz is the medical lead of the Hereditary High-Risk Clinic at BC Cancer and an associate professor in the Department of Surgery at UBC.
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