Breast cancer in women at high risk: The role of rapid genetic testing for BRCA1 and -2 mutations and the consequences for treatment strategies

Specific clinical questions rise when patients, who are diagnosed with breast cancer, are at risk of carrying a mutation in BRCA1 and -2 gene due to a strong family history or young age at diagnosis. These questions concern topics such as 1. Timing of genetic counseling and testing, 2. Choices to be made for BRCA1 or -2 mutation carriers in local treatment, contralateral treatment, (neo)adjuvant systemic therapy, and 3. The psychological effects of rapid testing. The knowledge of the genetic status might have several advantages for the patient in treatment planning, such as the choice whether or not to undergo mastectomy and/or prophylactic contralateral mastectomy. The increased risk of developing a second breast cancer in the ipsilateral breast in mutation carriers, is only slightly higher after primary cancer treatment, than in the general population. Prophylactic contralateral mastectomy provides a substantial reduction of contralateral breast cancer, although only a small breast cancer specific survival benefit. Patients should be enrolled in clinical trials to investigate (neo)-adjuvant drug regimens, that based on preclinical and early clinical evidence might be targeting the homologous recombination defect, such as platinum compounds and PARP inhibitors. If rapid testing is performed, the patient can make a well-balanced decision. Although rapid genetic counseling and testing might cause some distress, most women reported this approach to be worthwhile. In this review the literature regarding these topics is evaluated. Answers and suggestions, useful in clinical practice are discussed.     

Aspectos psicológicos en las mastectomías reductoras de riesgo en mujeres portadoras de mutación patogénica BRCA1/2

Risk-reducing surgeries decrease the risk of developing breast cancer by 95%. But this type of surgery can be life-changing. This systematic review analyzed anxiety/depressive symptomatology, body image and quality of life on BRCA1/2 mutation carriers with or without a previous oncological history who have undergone risk-reducing mastectomy. PRISMA method was used to conduct this review. The initial search identified 234 studies. However, only 7 achieved the inclusion criteria. No statistically significant differences were found in terms of anxious symptomatology. One study found that depressive symptomatology had increased significantly in women without previous oncological history at the long-term follow-up measure. Women who underwent bilateral risk-reducing mastectomy and implant-based breast reconstruction tended to be satisfied with their body image/cosmetic outcome. No differences were reported at long-term follow-ups, independently of the surgery performed.     

Breast Reconstruction after Bilateral Prophylactic Mastectomy in Women at High Risk for Breast Cancer

Abstract:  Several studies have shown the effectiveness of bilateral prophylactic mastectomies (BPM) at reducing the risk of developing breast cancer in women by more than 90%. A growing number of women at high risk for breast cancer are electing to undergo prophylactic mastectomy as part of a risk reduction strategy. This unique group of women frequently chooses to undergo reconstructive surgery as a part of their immediate treatment plan. Breast reconstruction after BPM has profound physiological and emotional impact on body image, sexuality, and quality of life. These factors should be taken into consideration and addressed when consulting the patient prior to BPM and reconstructive surgery. The timing of reconstructive surgery, the type of mastectomy performed, the reconstructive modalities available, and the possibility to preserve the nipple–areola complex, should all be discussed with the patient prior to surgery. In this article, we review our experience and the current existing literature on breast reconstruction for high-risk women after BPM.     

Role of Breast Surgery in BRCA Mutation Carriers

BRCA mutation carriers have a life-long breast cancer risk between 55 and 85% and a high risk of developing breast cancer at a very young age, depending on the type of mutation. The risk of developing contralateral breast cancer after a first breast cancer is elevated up to 65%, especially in case of BRCA1 mutation and young age at the first breast cancer. Since bilateral prophylactic mastectomy is associated with a risk reduction of 90–95% of developing primary or contralateral breast cancer, this option is a key point within the counseling process for patient information and shared decision-making of mutation carriers. Although the local control after breast-conserving therapy in mutation carriers seems to be comparable to that of sporadic breast cancer patients, individual patient information and counseling should include all alternative procedures of oncologically adequate mastectomy techniques and immediate reconstruction. Excellent cosmetic results, high levels of life quality, and good patient acceptance can be achieved with the recent developments in reconstructive surgery of the breast.     

Increasing trend of contralateral prophylactic mastectomy: What are the factors behind this phenomenon?

IntroductionNumerous studies have shown a trend towards increasing rates of contralateral prophylactic mastectomy (CPM) in the US. In this review, we will explore the trend, possible causative factors and outcomes from CPM.MethodsWe performed a literature review of all relevant retrospective reviews, clinical trials and review articles regarding contralateral prophylactic mastectomy.ResultsSeveral studies have noted a four to fivefold increase in CPM in recent years; an increase most notable in younger patients. When surveyed, patients report that the most important factors affecting their choice of CPM include fear of cancer recurrence, genetic counseling/testing, family history or additional high risk factors, stress surrounding close follow up, the availability of reconstructive surgery and information provided about contralateral breast cancer (CBC) risk and risk for local recurrence. Women who have undergone CPM do report high satisfaction with the procedure and some studies suggest risk reduction.ConclusionCPM rates have increased across the US and numerous factors have been reported to increase the likelihood of choosing CPM. Despite that bilateral mastectomy is associated with an increased risk of wound and overall postoperative complications for certain populations, this surgery appears to have psychological, cosmetic and possibly oncologic benefit.     

Prophylactic Mastectomy

Abstract: Prophylactic mastectomy may be an appropriate treatment for several groups of women. These groups include women with a strong family history of breast cancer, especially those with known BRCA mutations, women with high risk pathologic changes found on previous breast biopsies, women with an immobilizing fear of developing breast cancer, and women with contralateral breast cancer. The effectiveness of prophylactic mastectomy is controversial although recent data suggests a possible gain in life expectancy for high risk women undergoing bilateral prophylactic mastectomy. Each woman should have a thorough discussion with her treatment team, which should include a oncologic surgeon, plastic surgeon, psychologist, and genetic counselor, to realistically assess her risk due to family history, genetic mutations, or high risk pathologic findings, as well as the expectations and limitations of prophylactic mastectomy.     

Bilateral nipple-sparing mastectomy and breast reconstruction in BRCA1 mutation-positive simultaneous bilateral breast cancer: A case study

BackgroundMutation-positive patients who develop unilateral breast cancer require different treatments, such as prophylactic mastectomy of the contralateral breast, from those used for other breast cancer patients. If a mutation is found before surgery, it is necessary to consider a surgical procedure that includes reconstruction. For BRCA mutation-positive patients, a suitable treatment must be selected. In Japan, a test for BRCA mutation has been covered by health insurance since 2020, making it possible to preoperatively test patients who are suspected of being positive. We report a case of simultaneous bilateral breast cancer that was found to be BRCA mutation-positive preoperatively and underwent bilateral subcutaneous mastectomy and breast reconstruction.Case presentationA 57-year-old woman was admitted to our hospital after a breast cancer screening revealed a mass in the left breast. She had a family history of breast cancer, including her sister, aunt, and cousin. She was suspected of being malignant with a mass on both sides of her breast on imaging. She underwent needle biopsy and was diagnosed as having bilateral invasive ductal carcinoma, for which she was placed on preoperative chemotherapy. Due to the strong family history of bilateral breast cancer, the patient was recommended to undergo a BRCA gene-mutation test and she consented. The result was positive for BRCA1 mutation. Although it was judged that bilateral breast-conserving surgery was sufficiently possible, bilateral subcutaneous mastectomy and breast reconstruction were performed based on BRCA mutation-positive status.DiscussionPerforming a preoperative BRCA test may change the surgical procedure.BRCA tests are beneficial to patients, but the timing of the tests is important. Care must be taken not to force the patient.ConclusionsKnowing whether the patient is BRCA mutation-positive is extremely important for selecting surgical procedures and treatment methods. BRCA testing should be recommended for patients who are strongly suspected of being positive, but the decision should be the patient’s. It is therefore necessary to provide accurate information and engage in a dialogue with the patient, but the medical staff should not pressure the patient to have the test.     

Practical aspects of genetic counseling in breast cancer: Lights and shadows

In unselected populations, less than 10% of breast cancers are associated with germline mutations in predisposing genes. Breast cancer type 1 and 2 (BRCA1 and BRCA2) susceptibility genes are the most common involved genes and confer a 10–30 times higher risk of developing the disease compared to the general population. A personal or family history suggestive of inherited breast cancer syndrome may be further evaluated to assess the risk of genetic predisposition and the presence of a genetic mutation. Breast cancer genetic counseling should include a careful risk assessment with associated psychosocial evaluation and support, possible molecular testing, personalized discussion of results. Knowledge of BRCA status can influence individualized cancer risk-reduction strategies. i.e. active surveillance, prophylactic surgery and/or pharmacoprevention.     

Issues of Regret in Women With Contralateral Prophylactic Mastectomies

Background: Patients with a history of carcinoma of one breast have an estimated risk of 0.5% to 0.75% per year of developing a contralateral breast cancer. This risk prompts many women to consider contralateral prophylactic mastectomy (CPM) as a preventive measure. Virtually nothing is known about patient acceptance following CPM. We have developed a National Prophylactic Mastectomy Registry comprised of a volunteer population of 817 women from 43 states who have undergone prophylactic (unilateral or bilateral) mastectomy.Methods: Of the 346 women with CPM who responded to national notices, 296 women returned detailed questionnaires. The information obtained included patient demographics, family history, reproductive history, ipsilateral breast cancer staging and treatment, as well as issues involving the CPM.Results: At median follow-up of 4.9 years, the respondents were primarily married (79%), white (97%) women who had some level of college education or above (81%). These women cited the following reasons for choosing CPM: (1) physician advice regarding the high risk of developing contralateral breast cancer (30%); (2) fear of developing more breast cancer (14%); (3) desire for cosmetic symmetry (10%); (4) family history (7%); (5) fibrocystic breast disease (4%); (6) a combination of all of these reasons (32%); (7) other (2%); and (8) unknown (1%). Eighteen of the 296 women (6%) expressed regrets regarding their decision to undergo CPM. Unlike women with bilateral prophylactic mastectomies, regrets tended to be less common in the women with whom the discussion of CPM had been initiated by their physician (5%) than in the women who had initiated the discussion themselves (8%) (P = ns). Family history and stage of index lesion had no impact on regret status. The reasons for regret included: (1) poor cosmetic result, either of the CPM or of the reconstruction (39%); (2) diminished sense of sexuality (22%); (3) lack of education regarding alternative surveillance methods or CPM efficacy (22%); and (4) other reasons (17%).Conclusions: To minimize the risk of regrets in women contemplating CPM, it is imperative that these women be counseled regarding an estimation of contralateral breast cancer risk, the alternatives to CPM, and the efficacy of CPM. In addition, these women should have realistic expectations of the cosmetic outcomes of surgery and understand the potential impact on their body image.     

Newly diagnosed breast cancer patients choose bilateral mastectomy over breast-conserving surgery when testing positive for a BRCA1/2 mutation

In women diagnosed with breast cancer and testing positive for a BRCA1/2 mutation, decisions as to whether to undergo prophylactic risk-reduction surgery may differ from those women who test positive in a presymptomatic phase. Eighty-four women were identified who had undergone genetic testing at the time of breast cancer diagnosis. The study group consisted of 46 of these women who had initially undergone breast-conserving surgery. Eight patients (17.4%) tested positive for a mutation. Seven of the eight underwent bilateral prophylactic mastectomy prior to receiving radiation therapy. The only patient not undergoing bilateral mastectomy was awaiting liver transplant. Women who are candidates for breast-conserving surgery and who test positive for a breast cancer gene mutation choose mastectomy over surveillance.     

Risk-reducing mastectomy

Breast cancer is a malignant proliferation of epithelial cells lining the ducts or lobules of the breast. Excluding skin cancer, breast cancer is the most common cancer in women. Only lung cancer accounts for more cancer deaths in women. Breast cancer may exist for a long period either as an invasive or noninvasive disease, but not as a nonmetastatic disease. Consequently, timely diagnosis and appropriate management are lifesaving. Approximately 10% of human breast cancers are linked to germline mutations, such BRCA1 and BRCA2. Correct staging of breast cancer patients is critical. It permits an accurate diagnosis, as well as in many cases, therapeutic decisions based largely on the TNM classification. Staging provides the most important prognostic variable. Second opinions of the staging of breast cancer by pathologic examination of the tissue is recommended. There are some variables in which the association with disease-free survival and overall survival seem clear and include estrogen and progesterone receptor cells, S-phase analysis using flow cytometry, histologic classification, molecular changes in the tumor as well as neovasculature semi-quantitative scoring systems. There are four objectives to risk-reducing mastectomy. First, risk-reducing mastectomy should reduce the incidence of breast cancer in high-risk women, for example, BRCA1 or BRCA2 carriers. It should reduce mortality from breast cancer in high-risk women. Moreover, it should have psychological benefits in relieving anxiety about developing breast cancer. Finally, there must be a balance in the reduction in risk against cosmetic outcome, with subsequent quality of life issues. Women should be offered risk reduction mastectomy only on the basis of a strict selection and management plan, like that used in Manchester protocol. This protocol involves a minimum of two sessions with a geneticist/oncologist, a session with a psychiatrist and two sessions with a plastic and reconstructive surgeon with the support of a breast care nurse. The surgical technique should aim at removing substantially all at-risk breast tissue. However, there is an obvious balance between reduction of cancer risk and cosmetic outcome. The surgical technique involves several operations to include the risk-reducing mastectomy as well as breast reconstructive procedures. Skin-sparing mastectomy represents a new surgical approach that allows a mastectomy, whereas preserving the natural skin envelope of the breast. Breast reconstruction will involve several operations, especially if the nipple areola complex is resected and is subsequently reconstructed. The contraindications to risk-reducing mastectomy include the following. The status of the family history or Munchausen's syndrome has not been confirmed. The risk-reducing mastectomy is not the women's own choice. The patient has a current psychiatric disorder including clinical depression, cancer phobia or body dysmorphic syndrome. If the co-morbidity outweighs the clinical benefits, surgery should not be undertaken. Finally, the patient must not have unrealistic expectations of the benefits of surgery. She must understand the subsequent risk-reducing mastectomy may significantly reduce, but not eliminate the risk of subsequent breast cancer.     

The Development of New, Primary, Noninvasive Carcinoma of the Breast 29 Years after Bilateral Radical Mastectomy

Abstract: We present the case of a patient with a new, primary noninvasive breast carcinoma arising in residual breast tissue 29 years after radical mastectomy. The patient, a 75-year-old black woman with no family history of breast or ovarian cancer, had undergone left radical mastectomy in 1956 (age 35) and right radical mastectomy in 1965 (age 44). Examination revealed a 3-mm nodule in the right anterior axillary line. On excision, the lesion was a 1.5-mm intracystic papillary ductal carcinoma in situ arising in a background of atypical ductal hyperplasia (representing residual breast tissue). The patient has not agreed to testing for BRCA1 or BRCA2 mutations. The theoretical risk of new primary breast cancers arising in residual breast tissue has been suggested as a reason why prophylactic mastectomy may not be completely effective. This case suggests that even after what appeared to be aggressive radical mastectomy, enough breast tissue remained so that the patient was at risk for recurrent breast cancer.     

Current National Health Insurance Coverage Policies for Breast and Ovarian Cancer Prophylactic Surgery

Background: The efficacy of prophylactic mastectomy and oophorectomy in reducing breast and ovarian carcinoma has recently been reported in high-risk women. Because cost has become central to medical decision-making, this study was designed to evaluate currently existing coverage policies for these procedures.Methods: A confidential detailed cross-sectional nationwide survey of 481 edical directors from the American Association of Health Plans, Medicare, and Medicaid was conducted.Results: Of the 150 respondents, 65% (n 5 97) had 100,000 or more enrolled members and 35% (n 5 53) had fewer than 100,000 enrolled members. Only 44% of private plans have specific policies for coverage of prophylactic mastectomy for a strong family history of breast cancer and 38% of plans for a BRCA mutation. Only 20% of total responding plans had a policy for coverage of prophylactic oophorectomy under any clinical circumstance. Governmental carriers were significantly less likely to have any policy for prophylactic surgery (range, 2%–12%) compared with nongovernmental plans (range, 24%–44%; P,.001). No significant regional differences for coverage policies were identified (P.05).Conclusions: Significant variations currently exist for health insurance coverage of prophylactic mastectomy and oophorectomy. As genetic testing becomes widespread, more uniform policies should be established to enable appropriate high-risk candidates equal access and coverage for these procedures.     

Women’s Regrets After Bilateral Prophylactic Mastectomy

Background: Primary prevention strategies such as chemopreventive agents (e.g., tamoxifen) and bilateral prophylactic mastectomy (PM) have received increasingly more attention as management options for women at high risk of developing breast cancer.Methods: A total of 370 women, who had registered in the Memorial Sloan-Kettering Cancer Center National Prophylactic Mastectomy Registry, reported having undergone a bilateral PM. Twenty-one of these women expressed regrets about their decision to have a PM. A psychiatrist and psychologist interviewed 19 of the women about their experiences with the PM.Results: A physician-initiated rather than patient-initiated discussion about the PM represented the most common factor in these women. Psychological distress and the unavailability of psychological and rehabilitative support throughout the process were the most commonly reported regrets. Additional regrets about the PM related to cosmesis, perceived difficulty of detecting breast cancer in the remaining breast tissue, surgical complications, residual pain, lack of education about the procedure, concerns about consequent body image, and sexual dysfunction.Conclusions: Although a PM statistically reduces the chances of a woman developing breast cancer, the possibility of significant physical and psychological sequelae remains. Careful evaluation, education, and support both before and after the procedure will potentially reduce the level of distress and dissatisfaction in these women. We discuss recommendations for the appropriate surgical and psychiatric evaluation of women who are considering a PM as risk-reducing surgery.     

Cáncer de mama contralateral y recurrencia en portadoras BRCA1/2 y no portadoras con alto riesgo de cáncer de mama hereditario tras mastectomía bilateral

IntroductionContralateral prophylactic mastectomy (CPM) has been reported to reduce risk of contralateral breast cancer (CBC) by at least 90%.In addition, BRCA carriers presents higher risk of ipsilateral recurrence and a second primary tumor.The aim is to evaluate risk of CBC and recurrence and to analyze predictive factors in BRCA1/2 mutation carriers and non-carriers at high-risk of hereditary breast cancer patients.MethodsRetrospective observational study. 46 patients underwent bilateral mastectomy during 2004-2018.ResultsCohort comprised 9 patients BRCA1,12 BRCA2 and 25 at high-risk without mutation. Median follow-up 79 months. 16 patients recently diagnosed and 30 previously treated by breast cancer whom underwent CPM at second time (because of later detection of BRCA mutation in 10 cases). The external lateral incision was most frequent surgical technique. In all patients immediate reconstruction was performed.In CPM pieces, 4 in situ carcinoma, 3 invasive and 1 atypical hyperplasia were found. The incidence of occult contralateral cancer was 15.2%. Recurrence was observed in 5 patients a media of 21.2 months after surgery. FSD was 83.74 months and OS 84.33 months. Regression models identified BRCA1/2 mutation and high risk without mutation as significant occult tumor predictive factors while tumor size ≥ 2 cm was predictive of recurrence.ConclusionsIn our series we found a10.8% recurrence despite CPM and 7 patients (15.2%) would have developed a CBC in subsequent years.     

Initial experience with surgical treatment planning in the newly diagnosed breast cancer patient at high risk for BRCA-1 or BRCA-2 mutation

Despite an abundance of information available for dealing with patients with BRCA-1 and BRCA-2 mutations, little guidance is available to assist the surgeon in dealing with the genetically high-risk patient recently diagnosed with breast cancer. A retrospective review was undertaken of 170 patients who underwent genetic counseling and testing over a 3-year period from March 2000 to March 2003. Forty-three of the 170 patients tested were diagnosed with breast cancer prior to genetic testing. Nine patients (20.9%) tested positive for a deleterious mutation. Fifty-eight percent underwent genetic counseling prior to definitive cancer surgery. Five of the 25 patients who underwent lumpectomy tested positive for a deleterious mutation. Testing results became available during systemic therapy or radiation was delayed until results were known. After counseling, all five patients testing positive went on to bilateral prophylactic mastectomy and reconstruction. None had radiation therapy. Because of a strong family history, eight patients elected to undergo prophylactic mastectomy and reconstruction prior to obtaining genetic test results; and despite compelling histories, all eight tested negative for a mutation. Treatment algorithms are developed to manage patients that are first discovered to be at high risk for a BRCA-1 or BRCA-2 mutation at the time they are diagnosed with breast cancer. Patients diagnosed with breast cancer who are discovered to be at high risk for a genetic mutation should undergo counseling prior to definitive surgery. This maximizes the time that patients have to consider options for prophylaxis and monitoring should their test be positive. It also prevents women who would otherwise be candidates for breast preservation from undergoing unnecessary radiation therapy should they chose prophylactic mastectomy in the face of a positive test.     

BRCA mutation genetic testing implications in the United States

BRCA mutation carriers have a very high risk of breast and ovarian cancer by age 70, in the ranges 47%–66% and 40%–57%, respectively. Additionally, women with BRCA mutation-associated breast cancer also have an elevated risk of other or secondary malignancies. Fortunately, the breast and ovarian cancer outcome for BRCA1/2 mutation carriers is at least as good as for non-carriers with chemoprevention, prophylactic surgeries and appropriate use of therapies. Therefore, identification of those who might have a mutation is important so that genetic counseling, testing, screening and prevention strategies can be applied in a timely manner. This article reviews the impact of genetic testing in general, timing of genetic testing after diagnosis and prior knowledge of mutation status in BRCA carriers with newly diagnosed breast cancer. Additionally, risk-reducing surgeries including the prophylactic contralateral mastectomy, and bilateral salpingo-oophorectomy and the sensitivity of BRCA-defective breast cancer cell lines to differential chemotherapeutic agents will be discussed.     

Reasons for risk-reducing mastectomy versus MRI-screening in a cohort of women at high hereditary risk of breast cancer

Objective

To determine the reasons that motivate women in a cohort of women under intensive surveillance for breast cancer to undergo risk-reducing mastectomy (RRM).

Patients and methods

Women with a BRCA1 or BRCA2 mutation who were enrolled in an MRI-based breast screening study were eligible to participate in this survey. A self-administered questionnaire was given to women who did, and who did not terminate annual MRI-based surveillance in order to undergo RRM. The questionnaire included information on family history, risk perception and satisfaction with screening. In addition, women were asked to provide the principal reason for their choice of having preventive surgery or not, and were asked about their satisfaction with this choice.

Results

246 women without breast cancer participated in the study. Of these, 39 women (16%) elected to have RRM at some point after initiating screening. Although women who had a mother or sister with breast cancer were more likely to opt for RRM than were women with no affected first-degree relative (21% versus 10%) this did not reach statistical significance. Women who perceived their breast cancer risk to be greater than 50% were more likely to opt for RRM than were women who estimated their risk to be less than 50% (19% versus 6%). Fear of cancer was the most common reason cited for choosing to have RRM (38% of respondents) followed by having had a previous cancer, (25%), then concern over their children (16%).

Conclusion

Among women with a BRCA mutation who are enrolled in an MRI-based screening program, a high perception of personal breast cancer risk and a history of breast cancer in a first-degree relative are predictors of the decision to have RRM.     

Brustrekonstruktion nach prophylaktischer Mastektomie

Reconstruction of the breast after prophylactic mastectomy is generally performed in the context of immediate breast reconstruction (IBR). This ablative, intentionally risk-reducing surgery presents a challenge in terms of patient counselling, surgical indication and technical performance for the interdisciplinary breast center. It is also demanding in terms of the patient’s ability to provide informed consent: body image, sexuality, partnerships, aspects of risk assessment in the case of hereditary and sporadic breast cancer, as well as willingness to take the risk of possible follow-up surgery and morbidity are all issues involved in the decision-making process. After focussing on the possible indications for and the risk reduction to be achieved by prophylactic mastectomy, a further developed technique of prophylactic skin-sparing mastectomy with immediate implant reconstruction is discussed.     

Review of risk factors for the development of contralateral breast cancer

Background

Women treated for breast cancer have an increased risk for developing metachronous contralateral breast cancer (CBC). Patient perception of this risk is often overestimated and has been found to contribute to the decision to undergo contralateral prophylactic mastectomy. An individual's risk is dependent on both patient and tumor characteristics. This review examines and summarizes the current literature on the factors that affect CBC risk.

Data Sources

English-language publications with the keyword “contralateral breast cancer” were identified through a MEDLINE literature search.

Conclusions

The global incidence of CBC is decreasing, a trend that is attributed to more effective adjuvant therapies. Patients with BRCA germ-line mutations demonstrate the highest risk for CBC. In the absence of known genetic mutations, patients with strong family histories who are diagnosed at young ages (<35 years) with estrogen receptor–negative index tumors appear to have a higher incidence of CBC.