Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation.

BACKGROUND: Women with a BRCA1 or BRCA2 mutation have a high risk of breast cancer and may choose to undergo prophylactic bilateral total mastectomy. We investigated the efficacy of this procedure in such women. METHODS: We conducted a prospective study of 139 women with a pathogenic BRCA1 or BRCA2 mutation who were enrolled in a breast-cancer surveillance program at the Rotterdam Family Cancer Clinic. At the time of enrollment, none of the women had a history of breast cancer. Seventy-six of these women eventually underwent prophylactic mastectomy, and the other 63 remained under regular surveillance. The effect of mastectomy on the incidence of breast cancer was analyzed by the Cox proportional-hazards method in which mastectomy was modeled as a time-dependent covariate. RESULTS: No cases of breast cancer were observed after prophylactic mastectomy after a mean (+/-SE) follow-up of 2.9+/-1.4 years, whereas eight breast cancers developed in women under regular surveillance after a mean follow-up of 3.0+/-1.5 years (P=0.003; hazard ratio, 0; 95 percent confidence interval, 0 to 0.36). The actuarial mean five-year incidence of breast cancer among all women in the surveillance group was 17+/-7 percent. On the basis of an exponential model, the yearly incidence of breast cancer in this group was 2.5 percent. The observed number of breast cancers in the surveillance group was consistent with the expected number (ratio of observed to expected cases, 1.2; 95 percent confidence interval, 0.4 to 3.7; P=0.80). CONCLUSIONS: In women with a BRCA1 or BRCA2 mutation, prophylactic bilateral total mastectomy reduces the incidence of breast cancer at three years of follow-up.     

Development and testing of a decision aid for breast cancer prevention for women with a BRCA1 or BRCA2 mutation

For women who carry a mutation in BRCA1 or BRCA2, the risk of breast cancer is up to 87% by the age of 70. There are options available to reduce the risk of breast cancer; however, each option has both risks and benefits, which makes decision making difficult. The objective is to develop and pilot test a decision aid for breast cancer prevention for women with a BRCA1 or BRCA2 mutation. The decision aid was developed and evaluated in three stages. In the first stage, the decision aid was developed and reviewed by cancer genetics experts. The second stage was a review of the decision aid by women with a BRCA1 or BRCA2 mutation for acceptability and feasibility. The final stage was a pre-test--post-test evaluation of the decision aid. Twenty-one women completed the pre-test questionnaire and 20 completed the post-test questionnaire. After using the decision aid, there was a significant decline in mean decisional conflict scores (p = 0.001), a significant improvement in knowledge scores (p = 0.004), and fewer women uncertain about prophylactic mastectomy (p = 0.003) and prophylactic oophorectomy (p = 0.009). Use of the decision aid decreased decisional conflict to levels suggestive of implementation of a decision. In addition, knowledge levels increased and choice predisposition changed with fewer women being uncertain about each option. This has significant clinical implications as it implies that with greater uptake of cancer prevention options by women with a BRCA1 or BRCA2 mutation, fewer women will develop and/or die of hereditary breast cancer.     

Risk-reducing surgery, screening and chemoprevention practices of BRCA1 and BRCA2 mutation carriers: a prospective cohort study

This study prospectively evaluated the utilization of cancer risk management strategies in a multi-institutional cohort of BRCA1 and BRCA2 mutation carriers using a self-report questionnaire. Of 142 unaffected female mutation carriers, 70 (49%) had elected to receive their mutation result. Of those who knew their mutation result, 11% underwent bilateral mastectomy (BM), 29% had bilateral oophorectomy (BO), 78% performed regular breast self-examination (BSE), and 80%, 89%, 67%, and 0% had at least annual clinical breast examination (CBE), mammography, transvaginal ultrasound (TVU), and CA125, respectively. A further 20%, 7%, 0%, 21%, and 75%, respectively, reported never having had these tests. For women who elected not to receive their mutation result, 0% underwent BM, 6% underwent BO, and 77%, 42%, 56%, 7%, and 0% had regular BSE, CBE, mammography, TVU, and CA125, respectively. Only one woman used chemoprevention outside a clinical trial. Uptake of prophylactic surgery and screening was associated with knowing one's mutation status (for all behaviors except BSE), age (for BO and CBE) and residence (for mammography). In this cohort, the minority of mutation carriers utilized risk-reducing surgery or chemoprevention and a substantial minority were not undergoing regular cancer-screening tests.     

BRCA1 and BRCA2 mutation testing in Cyprus; a population based study

This paper presents the largest study in Cyprus evaluating the frequency and distribution of BRCA1/2 mutations in a high risk patient cohort. Deleterious mutations in the BRCA1/2 genes were identified in 68 of the 527 patients tested (13%). It is of interest that a quarter of those tested positive, did not have an extensive family history of breast/ovarian cancer but were diagnosed with early onset breast cancer, ovarian cancer under the age of 60 or triple negative breast cancer. The spectrum of mutations identified in our patient cohort is different compared to other Mediterranean countries. Furthermore, several of the mutations detected are novel and have not been identified in other ethnic populations. This highlights the importance of operating a national reference center for cancer genetic diagnosis which offers services tailored to the needs of the Cypriot population.     

Genetic testing for BRCA1 and BRCA2 in the Province of Ontario

In 2001, genetic testing for BRCA1 and BRCA2 was introduced in Ontario, for women at high‐risk of breast or ovarian cancer. To date over 30,000 individuals have been tested throughout Ontario. Testing was offered to all Ontario residents who were eligible under any of 13 criteria. We report the results of tests conducted at Mount Sinai Hospital from 2007 to 2014. A total of 4726 individuals were tested, 764 (16.2%) were found to carry a pathogenic variant (mutation). Among 3684 women and men who underwent testing without a known familial BRCA mutation, 331 (9.0%) were found to carry a mutation. Among 1042 women and men tested for a known family mutation, 433 (41.6%) were positive. There were 603 female mutation carriers, of these, 303 were affected with breast or ovarian cancer (50%) and 16 with another cancer (2.3%). Of 284 unaffected female carriers, 242 (85%) were tested for a known family mutation and 42 (15%) were the first person in the family to be tested. By placing greater emphasis on recruiting unaffected female relatives of known mutation carriers for testing, greater than one‐half of newly identified carriers will be unaffected.     

Cascade screening in BRCA1/2 mutation carriers

Genetic counselling for families with BRCA1 & 2 has been available in Ireland since 1998. We describe the follow-on cascade from the initial 29 index cases that tested positive for either gene. 28 of the index cases were female and 1 was male. Their combined sibship and offspring totalled 125 and 129 respectively. Of the 125 siblings, 21/72 (29%) females and 10/53 (19%) males came forward for counselling and all were tested. Of the 129 at risk offspring, 56 (43%) [25 females and 31 males] were over 18 years and therefore were eligible for testing. 20/25 (80%) females and 6/31 (19%) males came for counselling and all bar one female was tested. In summary, 31/125 (25%) at risk siblings were tested and 25/56 (45%) offspring were tested. Only one person, a daughter of an affected individual who attended clinic, declined testing. The remaining 197 (77%) individuals have not come forward for counselling. Our results suggest that a) there is a low-moderate testing rate in Ireland when compared to other European centres; and that b) daughters of BRCA1/2 carriers are more likely to come forward for testing than female siblings. Specific factors which appeared to influence attendance included poor dissemination of information among families about the test; and lower levels of communication among siblings than within the nuclear family.     

Uptake and timing of bilateral prophylactic salpingo-oophorectomy among BRCA1 and BRCA2 mutation carriers

PurposeTo evaluate prophylactic salpingo-oophorectomy uptake and timing among BRCA1/2 mutation carriers in a cancer risk assessment program.MethodsClinical records of female BRCA1/2 mutation carriers who received cancer genetic counseling between 1996 and 2003 were reviewed to determine the completion and the timing of prophylactic salpingo-oophorectomy. Logistic regression models evaluated associations between subject characteristics and surgery. Survival analysis methods were used to estimate the distribution of time to surgery.ResultsAmong 88 women, 70% underwent prophylactic salpingo-oophorectomy. Prophylactic salpingo-oophorectomy was associated with older age, white race, having children, and a family history of ovarian cancer. Many women waited more than 12 months to undergo surgery and some delayed by several years. Younger age and not having children were associated with delays to surgery.ConclusionProphylactic salpingo-ooporectomy is an acceptable risk reduction measure for many BRCA1/2 mutation carriers. Some women make this decision many years after genetic testing. Continued discussion of the risks and benefits of risk reduction options may facilitate the uptake of recommended risk reduction interventions among BRCA mutation carriers.     

Attitudes and distress levels in women at risk to carry a BRCA1/BRCA2 gene mutation who decline genetic testing

Genetic testing enables women at risk for hereditary breast and/or ovarian cancer to find out whether they have inherited the gene mutation, and if so, to opt for undergoing frequent surveillance and/or prophylactic surgery. However, the option to know about one's genetic status is not always seen as a benefit by women at risk. Motives for declining genetic testing were explored in 13 women at 25% or 50% risk to be a BRCA1/BRCA2 mutation carrier, who participated in a surveillance program for breast/ovarian cancer (the non-tested group). We hypothesized that high anxiety might be an important motive to decline testing. In addition, we investigated whether the non-tested group differed from a reference group of women who did undergo the test (tested group; n = 85) with regard to biographical factors, experience with cancer in relatives, and personality traits. Most non-tested women (10/13) were satisfied with participating in the surveillance program. Four reported to feel emotionally unprepared to cope with the consequences of testing. Compared with the tested group, the non-tested women had similar mean distress levels (which were not high), but a higher education level, they were more often childless, showed more reluctance towards prophylactic surgery, were younger when first confronted with a relative affected with breast/ovarian cancer, and were longer aware of the genetic nature of the disease. This study showed that women were more likely to have thoroughly reflected on their decision not to undergo genetic testing, than to deny the whole issue due to high anxiety. Being confronted at a relatively young age with breast/ovarian cancer in a relative, and being aware of the genetic risk for a many years, may have resulted in the risk for cancer becoming an integrated part of their lives. However, generalization of these results to women who neither underwent the test nor participated in a surveillance program should be considered with caution.     

A DGGE system for comprehensive mutation screening of BRCA1 and BRCA2: application in a Dutch cancer clinic setting

Rapid and reliable identification of deleterious changes in the breast cancer genes BRCA1 and BRCA2 has become one of the major issues in most DNA services laboratories. To rapidly detect all possible changes within the coding and splice site determining sequences of the breast cancer genes, we established a semiautomated denaturing gradient gel electrophoresis (DGGE) mutation scanning system. All exons of both genes are covered by the DGGE scan, comprising 120 amplicons. We use a semiautomated approach, amplifying all individual amplicons with the same PCR program, after which the amplicons are pooled. DGGE is performed using three slightly different gel conditions. Validation was performed using DNA samples with known sequence variants in 107 of the 120 amplicons; all variants were detected. This DGGE mutation scanning, in combination with a PCR test for two Dutch founder deletions in BRCA1 was then applied in 431 families in which 52 deleterious changes and 70 unclassified variants were found. Fifteen unclassified variants were not reported before. The system was easily adopted by five other laboratories, where in another 3,593 families both exons 11 were analyzed by the protein truncation test (PTT) and the remaining exons by DGGE. In total, a deleterious change (nonsense, frameshift, splice-site mutation, or large deletion) was found in 661 families (16.4%), 462 in BRCA1 (11.5%), 197 in BRCA2 (4.9%), and in two index cases a deleterious change in both BRCA1 and BRCA2 was identified. Eleven deleterious changes in BRCA1 and 36 in BRCA2 had not been reported before. In conclusion, this DGGE mutation screening method for BRCA1 and BRCA2 is proven to be highly sensitive and is easy to adopt, which makes screening of large numbers of patients feasible. The results of screening of BRCA1 and BRCA2 in more than 4,000 families present a valuable overview of mutations in the Dutch population.     

Hierarchical mutation screening protocol for the BRCA1 gene

The identification of mutations in the BRCA1 gene poses difficulties in achieving a screening outcome that satisfies the twin needs of speed and accuracy. These needs must also take into account the patient's family history and the statistical evaluation of the probability of detecting a mutation. Given the above, we present here a hierarchical mutation screening strategy that comprises two tiers: first, multiplex heteroduplex and exon 13 duplication analysis; second, exon amplification and direct sequencing using a 96-well tray format. The advantages of this strategy are two-fold: first, the division of analytical tools in order to achieve low and high-resolution mutation screening, respectively; second, a streamlined sequencing approach that leads to a sensitive and rapid assay that reduces labor costs and handling errors. The success of this approach is shown by the identification of a novel deletion mutation in exon 14 of the BRCA1 gene, which was not detected by the more conventional protein truncation assay due to the small size of the predicted truncated protein.     

Timing of BRCA1/BRCA2 genetic testing in women with ovarian cancer

PurposeTo determine when, in reference to the course of their treatment, women with ovarian cancer are seen for genetic counseling, as well as to determine what factors influence this timing.MethodsSingle institution retrospective chart review of patients with ovarian cancer who underwent BRCA1/BRCA2 genetic testing.ResultsThirty-three percent of our sample (n = 100) were seen for genetic counseling after ovarian cancer recurrence. In four cases, genetic test results were disclosed to next of kin. Thirty percent of women seen for genetic counseling after recurrence received their initial treatment elsewhere. Women with a history of breast cancer were significantly more likely to be seen for genetic counseling at an earlier phase of their treatment than women with no history of breast cancer.ConclusionWe found that one third of patients with ovarian cancer who underwent genetic testing were seen for initial genetic counseling after disease recurrence. In some cases, genetic counseling took place during the end of life care, with genetic test results disclosed to next of kin. Given the poor prognosis of women with recurrent ovarian cancer, we advocate providing genetic counseling at the time of initial ovarian cancer treatment both in comprehensive cancer centers and in community oncology settings.     

Parental origin of mutation and the risk of breast cancer in a prospective study of women with a BRCA1 or BRCA2 mutation

The objective is to estimate the risk of breast cancer in women who carry a deleterious BRCA1 or BRCA2 mutation, according to parental origin of mutation. We conducted a cohort study of women with a BRCA1 mutation (n = 1523) or BRCA2 mutation (n = 369) who had not been diagnosed with breast or ovarian cancer. For each woman, the pedigree was reviewed and the origin of the mutation was assigned as probable paternal or maternal. The hazard ratio (HR) for developing breast cancer in the follow‐up period was estimated for women with a paternal mutation compared to a maternal mutation. The risk of breast cancer was modestly higher in women with a paternal BRCA1 mutation compared to women with a maternal BRCA1 mutation (HR = 1.46; 95% CI = 0.99–2.16) but the difference was not significant (p = 0.06). The parental mutation origin did not affect the risk in women with a BRCA2 mutation. Our results are consistent with the hypothesis that there is an increased risk of breast cancer among women with a paternally inherited BRCA1 mutation compared to a maternally inherited mutation. However, the data are not sufficiently compelling to justify different screening recommendations for the two subgroups.     

Quality of life and health status after prophylactic salpingo-oophorectomy in women who carry a BRCA mutation: A review

Prophylactic salpingo-oophorectomy is recommended to women who carry a BRCA1 or BRCA2 mutation at age 35 or after childbearing is complete. This procedure is the mainstay of ovarian and fallopian tube cancer prevention in these women. Therefore an understanding of the short and long-term impact of the surgery is essential. Salpingo-oophorectomy, particularly when done prior to natural menopause, may impact on several aspects of quality of life and health. The health benefits of this surgery (cancer prevention) should outweigh the costs of the procedure in terms of quality of life and long term health. In this review, the impact of this surgery on quality of life and health in women who carry a BRCA mutation is discussed. Preliminary studies have focused on short-term effects, such as quality of life. In the short term, overall quality of life appears to be similar before and after surgery, however vasomotor symptoms related to surgical menopause and changes in sexual functioning are common. HRT appears to mitigate some but not all of these symptoms. Women report high levels of satisfaction with their decision to have the surgery despite the impact of prophylactic salpingo-oophorectomy. Studies of the long term health and quality of life after salpingo-oophorectomy in women who carry a BRCA mutation have not yet been published.     

Testing for inherited susceptibility to breast cancer: A survey of informed consent forms for BRCA1 and BRCA2 mutation testing

The identification of genetic mutations linked to breast cancer has made it possible to test for the genetic predisposition to this disease. However, though this test may provide certain benefits, there are also potential risks involved with the testing process, including social and economic considerations. In light of these potential risks, we sought to determine what information individuals are receiving in the informed decision making process. To learn the minimal amount of information the actual testees receive, we obtained 10 informed consent forms from seven different testing facilities. These testing centers include the major sources of BRCA1 and BRCA2 mutation testing in the United States at this time. We analyzed the content of these forms by developing content categories and scoring them appropriately. We found all ten forms discussed in varying ways and to varying degrees the purpose of genetic testing, limitations of the test, implications of both positive and negative results, and confidentiality procedures; most, but not all, addressed various psychological and insurance risks. Overall, the forms demonstrated substantial variation in content and organization, underlining the need for more discussion and research on the purpose, nature, and effectiveness of informed consent forms for this type of genetic test. Am. J. Med. Genet. 75:82–87, 1998. © 1998 Wiley-Liss, Inc.     

Phenocopies in BRCA1 and BRCA2 families: evidence for modifier genes and implications for screening

Background

The identification of BRCA1 and BRCA2 mutations in familial breast cancer kindreds allows genetic testing of at‐risk relatives. Those who test negative are usually reassured and additional breast cancer surveillance is discontinued. However, we postulated that in high‐risk families, such as those seen in clinical genetics centres, the risk of breast cancer might be influenced not only by the BRCA1/BRCA2 mutation but also by modifier genes. One manifestation of this would be the presence of phenocopies in BRCA1/BRCA2 kindreds.

Methods

277 families with pathogenic BRCA1/BRCA2 mutations were reviewed and 28 breast cancer phenocopies identified. The relative risk of breast cancer in those testing negative was assessed using incidence rates from our cancer registry based on local population.

Results

Phenocopies constituted up to 24% of tests on women with breast cancer after the identification of the mutation in the proband. The standardised incidence ratio for women who tested negative for the BRCA1/BRCA2 family mutation was 5.3 for all relatives, 5.0 for all first‐degree relatives (FDRs) and 3.2 (95% confidence interval 2.0 to 4.9) for FDRs in whose family all other cases of breast and ovarian cancer could be explained by the identified mutation. 13 of 107 (12.1%) FDRs with breast cancer and no unexplained family history tested negative.

Conclusion

In high‐risk families, women who test negative for the familial BRCA1/BRCA2 mutation have an increased risk of breast cancer consistent with genetic modifiers. In light of this, such women should still be considered for continued surveillance.Epidemiological studies suggest that approximately 5% of breast cancer in Western countries is caused by high‐risk dominantly inherited susceptibility genes.^1,2 However, twin studies suggested a genetic component in 27% of breast cancer cases.³ High‐risk dominantly inherited breast cancer susceptibility was first described in 1866 by Broca,⁴ but proof of dominant inheritance was obtained 120 years later with the localisation and identification of BRCA1 and BRCA2.^5,6,7,8 Mutations in these genes account for most high‐risk families with ⩾4 breast cancers in members aged <60 years.⁹ Studies to find other genes associated with breast cancer continue; the elusive BRCA3 gene has not yet been identified.¹⁰ In the mean time, many high‐risk familial breast cancer kindreds are offered BRCA1/BRCA2 mutation analysis. If this is successful, predictive genetic testing is offered to at‐risk relatives. In some centres, relatives who test negative are reassured that their breast cancer risk is at population levels, as recommended by the recently published UK National Institute for Clinical Excellence (NICE) guidelines.¹¹ This policy assumes that, with few exceptions, the risk of a second high‐risk familial mutation is minimal. However, breast cancer risks in high‐risk kindreds with BRCA1/BRCA2 mutations are substantially higher than risks derived from population‐based studies.^9,12,13,14 In high‐risk clusters in the Breast Cancer Linkage Consortium, BRCA1 and BRCA2 mutations were estimated to cause cumulative lifetime risks of breast cancer of 85–87% and 77–84% by 70 years, respectively.^9,15,16 However, estimates of breast cancer risks by 70 years from population‐based studies are much lower (28–60%)^12,13,14 for BRCA1 and still lower for BRCA2. It has been suggested that even these studies may overestimate the effect of BRCA1/BRCA2 alone.¹⁷ It is therefore feasible that a substantial proportion of the risk in familial clusters with a BRCA1/BRCA2 mutation (the group of families that are usually seen by a Cancer Genetics Service) might be due to modifier genes.^18,19 Such a hypothesis would predict that some members of high‐risk families might be at increased risk of breast cancer even if they tested negative for the pathogenic BRCA1/BRCA2 mutation.²⁰ Phenocopies may be due to chance or environmental effects, another high‐risk mutation in a family, ascertainment bias or the presence of modifier genes. We have identified a large number of phenocopies from 277 families with a pathogenic BRCA1/BRCA2 mutation and have assessed breast cancer risks for people testing negative for a familial pathogenic mutation.