Nonsurgical Prevention Strategies in BRCA1 and BRCA2 Mutation Carriers

BackgroundFemale carriers of a BRCA1 or 2 germline mutation face a high lifetime risk to develop breast and ovarian cancer. Risk-reducing surgery, such as prophylactic bilateral mastectomy and prophylactic bilateral salpingo-oophorectomy, are proven strategies to prevent breast and ovarian cancer. These procedures are, however, associated with considerable side effects, and the uptake of these highly effective interventions is therefore low in many countries. This highlights the need for alternative and noninvasive strategies for risk reduction in mutation carriers.SummaryWhile endocrine treatments with tamoxifen and aromatase inhibitors (AI) have been shown to be effective in secondary prevention, their benefit in primary prevention has never been prospectively evaluated. Moreover, their side effect profile makes them inappropriate candidates for chemoprevention in healthy premenopausal women. Recently, denosumab, a well-tolerated osteoprotective drug, has been shown to have an antitumoral effect on RANK+, BRCA1-deficient luminal progenitor cells in vitro, and has been demonstrated to abrogate tumors in BRCA1-deficient mouse models.Key MessageThe prospectively randomized, double-blind BRCA-P trial is currently investigating the preventative effect of denosumab in healthy BRCA1 germline mutation carriers.     

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.     

Screening and Clinical Implications for BRCA1 and BRCA2 Mutation Carriers

In this article, we review the history oftesting for mutations in breast cancer susceptibilitygenes and discuss the current state of testing formutations in BRCA1 and BRCA2 in different clinicalsettings including at-risk individuals and cancerpatients. The risk of breast cancer, other associatedmalignancies and prognosis in carriers of thesemutations are reviewed. A final section includesdiscussion of current recommendations for surveillance andthe need for further research to identify environmentaland genetic factors which modify the risk of developingcancer in mutation carriers.     

BRCA1和BRCA2在胶东半岛地区女性散发性乳腺癌中的表达研究

Objective To study the expression and clinical significance of BRCA1 and BRCA2 in sporadic breast cancer in women of Jiaodong peninsula. Methods Immunohistochemistry and tissue array were used to detect the expression of BRCA1 and BRCA2 in 100 cases of sporadic breast cancer and 30 cases of benign breast tumor in women of Jiaodong peninsula. Results ① The expression rate of BRCA1 and BRCA2 was 49% (49/100) and 50% (50/100) in breast cancer, 80% (24/30) and 83.33% (25/30) in benign breast lesions respectively. The expression rate of BRCA1 and BRCA2 in breast cancer was lower than that in benign breast lesions (P<0.05). ② The expression of BRCA1 and BRCA2 was uncorrelated with factors such as tumor size, lymphatic metastases, age and menopause or not(P>0.05). ③ There was no dependency between the expression of BRCA1 and BRCA2 (P> 0. 05). Conclusions The expression rate of BRCA1 and BRCA2 in breast carcinoma in women of Jiaodong peninsula was lower than that in benign breast lesions, suggesting that the expression of BRCA1 and BRCA2 was related to the occurrence of sporadic breast carcinoma in women of Jiaodong peninsula. However, the role of BRCA1 and BRCA2 in the genesis and development of the breast carcinoma is independent.     

Efficacy of anthracycline/taxane‐based neo‐adjuvant chemotherapy on triple‐negative breast cancer in BRCA1/BRCA2 mutation carriers

This study aims to estimate the pathologic complete response (pCR) rate after neo‐adjuvant chemotherapy and to compare disease‐free survival (DFS) and overall survival (OS) between pCR and non‐pCR groups of patients with triple‐negative breast cancer (TNBC) and deleterious BRCA1 or BRCA2 mutation. We carried out a retrospective analysis of 53 patients including 46 BRCA1, 6 BRCA2, and 1 combined BRCA1 and BRCA2 mutation. All patients had been diagnosed with triple‐negative breast cancer (TNBC) between 1997 and 2014. Neo‐adjuvant therapy consisted of regimens that were based on anthracycline or an anthracycline‐taxane doublet. DFS included any relapse or second cancer. The Kaplan‐Meier method and the log‐rank test were used to compare pCR and non‐pCR groups. A pCR was observed in 23 (42.6% [95% CI, 29.2%‐56.8%]) of the TNBC included. The pCR rate was 38.3% [95% CI, 26%‐55%] among BRCA1 mutation carriers, and 66% among the 6 BRCA2 mutation carriers. Median follow‐up was 4.4 years (range 0.62‐16.2 years) and did not differ between the groups (P = .25). Fifteen relapses and six second cancers were recorded during the follow‐up period. Eleven deaths occurred, all of which were in the non‐pCR group. DFS (P < .01) and OS (P < .01) were significantly better in the pCR group than the non‐pCR group. This study shows a high pCR rate after neo‐adjuvant therapy in BRCA‐mutated triple‐negative breast cancer, and the survival results confirm the prognostic value of pCR in this group. These outcomes should be considered as a basis of comparison to be used by future studies about new therapies in this domain.     

BRCA mutation characteristics in a series of index cases of breast cancer selected independent of family history

Certain genetic predisposition factors, such as BRCA1 and BRCA2 mutations play a pivotal role in familial breast cancer development in both males and females. Due to this, the importance and necessity of genetic screening to identify mutations affecting the population is paramount. Undergoing genetic screenings allows for a more knowledgeable risk assessment for the patients and their care providers. The aim of this study was to evaluate the prevalence of BRCA1/BRCA2 mutated genes in the Turkish population among unselected patients. To identify the molecular markers, we utilized a gene panel analysis consisting of BRCA1 and BRCA2 genes, with a next generation sequencing platform (MiSeq System, Illumina). Sequencing was performed using leukocyte DNA from breast cancer patients. In‐silico analysis for novel mutations was carried out using SIFT, PolyPhen2 and MutationTaster. BRCA1 and BRCA2 pathogenic variants were identified in 18 of 129 (14%) patients among the study population; of those 18 patients, seven (39%) were found in the BRCA1 gene and 11 (61%) in the BRCA2 gene. Ten of the eleven BRCA2 variants (90%) were novel mutations. Four of ten (40%) of the novel mutations were determined to be deleterious and six out of ten (60%) were identified as single nucleotide variations. Clinically significant mutations of the BRCA1/BRCA2 genes are related to an increased susceptibility for breast cancer. There is however, little known about BRCA mutations amongst the general population. Thus, it is important that patients are able to undergo genetic screenings and counseling. This also allows for greater care from health care providers and can only facilitate disease prevention which in turn can lead to a decreased cancer morbidity rate.     

Family Information Service Participation Increases the Rates of Mutation Testing Among Members of Families with BRCA1/2 Mutations

Abstract:  Some members of hereditary breast-ovarian cancer (HBOC) families may not participate in BRCA testing to determine their mutation status in part because they are unaware of their cancer risk and the availability of BRCA testing. Participation in a family information service (FIS), of which we have provided more than 100 sessions during the past 30 years, has been seen to effectively allow family members to be educated regarding their cancer genetic risk and potential benefits from cancer control measures such as mutation testing. However, the effect of the FIS on the rate of mutation testing has not been studied. One thousand five hundred seventy-four eligible (>18-year old, at a 25% or higher pedigree risk) members from 60 extended HBOC families with BRCA1/2 mutations were invited to attend a FIS to learn about their risk and undergo genetic testing. The rates of mutation testing were compared between those who had attended an FIS, and those who had not with chi-squared test and logistic regression analysis. Seventy five percent (334/444) of FIS attendees had undergone mutation testing following or during an FIS which was significantly higher than the 33.8% (382/1130) rate among nonattendees (p   <   0.0001). Logistic regression analysis showed that FIS attendance, breast-ovarian cancer history, gender, and age were significant variables for undertaking a mutation test. FIS attendance significantly increased the rate of mutation testing among high-risk family members.     

BRCA status,molecular markers,and clinical variables in early,conservatively managed breast cancer

Conservatively treated premenopausal breast cancer has a higher rate of local relapse as well as an increased genetic predisposition to cancer. The current study's purpose was to evaluate the interactions between BRCA-1/2 status and molecular biologic markers in a cohort of conservatively managed breast cancer patients. Seventy-six premenopausal women treated with breast-conserving surgery and radiation therapy were this study's focus. All patients were treated with wide local excision with or without axillary dissection, followed by radiation to the intact breast. Systemic therapy was administered as clinically indicated. All patients in this study had an available paraffin block from the primary tumor and agreed to undergo complete sequencing of the BRCA-1 and BRCA-2 genes. The primary breast tumor tissue from each patient was immunohistochemically stained for estrogen receptor (ER), progesterone receptor (PR), p53, HER-2/neu, and Proliferating Cell Nuclear Antigen (PCNA). Of the 76 patients tested for BRCA, 50 patients had wild-type BRCA-1 and BRCA-2, 15 had variants of unclear significance, 6 had deleterious mutations in BRCA-1, and 5 had deleterious mutations in BRCA-2. p53 positivity correlated with deleterious mutations in BRCA-1 (p = 0.023), but not in BRCA-2. Though not significant, there was a trend for ER and PR negativity to correlate with BRCA-1 mutation (p = 0.087 and 0.054, respectively); there were no correlations between ER, PR, and BRCA-2. Though not significant, all 11 tumors with BRCA mutations were HER-2/neu negative. Patients with BRCA mutations have a unique molecular profile. These data can be helpful in understanding differences in the biologic behavior of patients with familial breast cancers.     

Post-mastectomy surveillance of BRCA1/BRCA2 mutation carriers: Outcomes from a specialized clinic for high-risk breast cancer patients

Female BRCA1/BRCA2 mutation carriers may elect bilateral risk-reducing mastectomy. There is a paucity of data on yield of imaging surveillance after risk-reducing mastectomy. This retrospective study focused on female BRCA1/BRCA2 mutation carriers who underwent bilateral mastectomy either as primary preventative, or as secondary preventative, after breast cancer diagnosis. All participants underwent breast imaging at 6- to 12-month intervals after mastectomy. Data on subsequent breast cancer diagnosis and timing were collected and compared between the groups. Overall, 184 female mutation carriers (134 BRCA1, 45 BRCA2, 5 both BRCA genes) underwent bilateral mastectomy after initial breast cancer diagnosis, between April 1, 2009 and August 31, 2018. During a mean follow-up of 6.2 ± 4.2 years, 13 (7.06%) were diagnosed with breast cancer; 12 ipsilateral (range: 0.4–28.8 years) and 1 contralateral breast cancer, 15.9 years after surgery. On the contrary, among asymptomatic BRCA1 (n = 40) and BRCA2 (n = 13) mutation carriers who underwent primary risk-reducing mastectomy (mean age at surgery 39.5 ± 8.4 years); none has developed breast cancer after a mean follow-up of 5.4 ± 3.4 years. BRCA1/BRCA2 mutation carriers with prior disease who underwent risk-reducing mastectomy after breast cancer diagnosis are still prone for developing ipsi or contralateral breast cancer, and therefore may benefit from continues clinical and imaging surveillance, unlike BRCA1/BRCA2 mutation carriers who undergo primary preventative bilateral mastectomy.     

Awareness and Availability of Routine Germline BRCA1/2 Mutation Testing in Patients with Advanced Breast Cancer in Germany

IntroductionDiagnostic testing of germline mutations in breast cancer susceptibility genes 1 or 2 (gBRCA1/2) in patients with human epidermal growth factor receptor 2 negative (HER2–) advanced breast cancer (ABC; locally advanced or metastatic breast cancer) is necessary to assess eligibility for poly(ADP-ribose) polymerase inhibitors (PARPi). We investigated awareness, clinical practice, and the availability of gBRCA1/2 mutation testing in the German outpatient oncology setting.MethodsOffice-based oncologists completed a 23-item online survey. Responses were evaluated collectively and by center type.ResultsOf 50 oncologists, 33 and 17 were medical and gynecological oncologists, respectively. Oncologists treated a median of 65 (range 14–350) patients with ABC per year. The strongest decision factors to initiate gBRCA1/2 mutation testing were: patient''s known family history of gBRCA1/2 mutation-related cancer(s), guideline recommendations, and triple-negative breast cancer (TNBC). In routine practice, 86% of oncologists tested for gBRCA1/2 mutations. Most oncologists (76–98%) reported testing patients with a known family history of gBRCA1/2 mutation-related cancer(s) irrespective of receptor status. For unknown family history, 92% of oncologists reported testing patients with advanced TNBC versus 30% for HR+/HER2− ABC. Oncologists (66%) rated the awareness of therapeutic relevance of gBRCA1/2 mutation testing for targeted treatment selection as good to satisfactory; 22% rated awareness as poor to in­sufficient.ConclusionDiagnostic gBRCA1/2 mutation testing in patients with HER2− ABC is available and routinely performed in Germany''s outpatient oncology setting. However, specific patient subgroups were not routinely tested despite therapeutic indications. Given PARPi availability, opportunities exist to improve testing rates especially for patients with HR+/HER2− ABC without a known family history of gBRCA1/2 mutation-related cancer(s).     

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.     

Prophylactic Mastectomy in BRCA1/2 Mutation Carriers and Women at Risk of Hereditary Breast Cancer: Long-Term Experiences at the Rotterdam Family Cancer Clinic

Background BRCA1/2 mutation carriers and women from a hereditary breast(/ovarian) cancer family have a highly increased risk of developing breast cancer (BC). Prophylactic mastectomy (PM) results in the greatest BC risk reduction. Long-term data on the efficacy and sequels of PM are scarce. Methods From 358 high-risk women (including 236 BRCA1/2 carriers) undergoing PM between 1994 and 2004, relevant data on the occurrence of BC in relation to PM, complications in relation to breast reconstruction (BR), mutation status, age at PM and preoperative imaging examination results were extracted from the medical records, and analyzed separately for women without (unaffected, n = 177) and with a BC history (affected, n = 181). Results No primary BCs occurred after PM (median follow-up 4.5 years). In one previously unaffected woman, metastatic BC was detected almost 4 years after PM (primary BC not found). Median age at PM was younger in unaffected women (P < .001), affected women more frequently were 50% risk carriers (P < .001). Unexpected (pre)malignant changes at PM were found in 3% of the patients (in 5 affected, and 5 unaffected women, respectively). In 49.6% of the women opting for BR one or more complications were registered, totaling 215 complications, leading to 153 surgical interventions (71%). Complications were mainly related to cosmetic outcome (36%) and capsular formation (24%). Conclusions The risk of developing a primary BC after PM remains low after longer follow-up. Preoperative imaging and careful histological examination is warranted because of potential unexpected (pre)malignant findings. The high complication rate after breast reconstruction mainly concerns cosmetic issues.     

Awareness and attitudes concerning BRCA gene testing

Background: The availability of a commercial test for the breast cancer susceptibility genes, BRCA1 and BRCA2, has generated interest in both the medical community and the general public. Methods: Patients and family members were approached in the waiting room and asked to fill out an anonymous questionnaire about their awareness of breast cancer genes and breast cancer gene testing, and their desire to be tested. ² analysis was used to analyze frequencies between groups. Results: A total of 354 women completed a questionnaire concerning the breast cancer genes BRCA1 and BRCA2. The very young, the very old, and African-Americans were the least informed in terms of awareness of the genes and the availability of testing for the breast cancer susceptibility genes. Jewish people, people with a college education or beyond, people earning more than $30,000 a year, and Caucasians were more aware of the genes and of testing for these genes. Interest in being tested was similar in all groups, except for participants over 60 and those who had only an elementary-school education. Conclusions: Information concerning the breast cancer susceptibility genes has not reached the general public uniformly. A concerted effort is needed if this information is to be passed on to those people at risk.Poster presented at the 50th Annual Cancer Symposium of The Society of Surgical Oncology, Chicago, Illinois, March 17–21, 1997.     

Influence of Race/Ethnicity on Genetic Counseling and Testing for Hereditary Breast and Ovarian Cancer

Abstract:  Risk assessment coupled with genetic counseling and testing for the cancer predisposition genes BRCA1 and BRCA2 ( BRCA1/2 ) has become an integral element of comprehensive patient evaluation and cancer risk management in the United States for individuals meeting high-risk criteria for hereditary breast and ovarian cancer (HBOC). For mutation carriers, several options for risk modification have achieved substantial reductions in future cancer risk. However, several recent studies have shown lower rates of BRCA1/2 counseling and testing among minority populations. Here, we explore the role of race/ethnicity in cancer risk assessment, genetic counseling and genetic testing for HBOC and the BRCA1/2 cancer predisposition genes. Barriers to genetic services related to race/ethnicity and underserved populations, including socioeconomic barriers (e.g., time, access, geographic, language/cultural, awareness, cost) and psychosocial barriers (e.g., medical mistrust, perceived disadvantages to genetic services), as well as additional barriers to care once mutation carriers are identified, will be reviewed.