The management of familial breast cancer

Epidemiological studies over the past several decades have consistently supported the concept that a proportion of breast cancers develop as the result of an inherited familial predisposition. However, until recently our understanding and knowledge of the underlying genetic processes involved have been limited. Current advances in molecular biology have shown that hereditary breast cancer may arise as the result of mutations of several specific gene loci including BRCA1, BRCA2, ATM gene, PTEN and p53. Several other less frequently occurring predisposition genes such as the androgen receptor gene (AR), the HNPCC genes and the oestrogen receptor gene may also be involved, but to a lesser extent. It is estimated that approximately 5-10% of all breast cancers involve one of these inherited predisposition genes, with BRCA1 and BRCA2 accounting for up to 90% of this group. Mutation analysis is complex in nature and is presently in a developmental and evolving phase, for which reason genetic testing should be offered on a selective basis and through genetic counselling clinics. This report reviews the current knowledge and roles of the various predisposition genes and discusses the management implications for both affected and nonaffected members of breast cancer families. Comprehensive and informative counselling is critical for women with an inherited predisposition to breast cancer and this has led to the evolution of familial cancer clinics involving a multi-disciplinary specialist team approach. Familial cancer clinics can provide individuals with information about their risk of developing breast cancer and offer advice regarding the various management options presently available.     

Can Unknown Predisposition in Familial Breast Cancer be Family‐Specific?

Genetic predisposition plays a key role in the development of familial breast cancer. In spite of strong familial clustering of the disease and extensive efforts made during the past decade; however, progress has been slow in identifying genetic predisposition for the majority of familial breast cancer families. The question arises therefore as to whether current approaches are adequate in identifying the unknown genetic predisposition. We analyzed eight members of a BRCA1‐, BRCA2‐, p53‐, and PTEN‐negative breast cancer family, of which five had breast cancer, one is an obligate gene carrier, and two were unaffected. We sequenced the entire coding region of the genome for each member using exome sequencing to identify nonsynonymous variants. We identified 55 nonsynonymous germline variants affecting 49 genes in multiple members of the family, of which 22 are predicted to have damaging effects. We validated 20 of the 22 selected variants in the family by Sanger sequencing. Two variants in KAT6B, an acetal transferase gene, were identified in six family members of which five were affected with breast cancer and one is the unaffected obligate carrier. We further examined the presence of the identified variants in a cohort of 40 additional breast cancer cases from 22 familial breast cancer families, but none of the 22 variants was detected in these cases. Sequencing the entire coding exons in KAT6B detects no variants in these cases. Our results show that genetic predisposition for familial breast cancer can be rich in an affected family, but the predisposition can be family‐specific. As such, it will be difficult to detect them by applying population‐based approach. Our study supports the concept that focusing on each affected family will be required to determine the genetic predisposition for many familial breast cancer families whose genetic dispositions remain unknown.     

Recommendation and Acceptance of Counselling for Familial Cancer Risk in Newly Diagnosed Breast Cancer Cases

BackgroundIn clinical routine, not every patient who is offered genetic counselling and diagnostics in order to investigate a familial cancer risk predisposition opts for it. Little is known about acceptance of counselling and testing in newly diagnosed breast cancer cases in Germany.MethodsAll primary breast cancer cases and patients with DCIS (ductal carcinoma in situ) treated at the University Hospital of Dresden between 2016 and 2019 were included. The number of tumor board recommendations for genetic counselling on the basis of the GC-HBOC risk criteria was recorded. Acceptance was analyzed by number of cases with counselling in the GC-HBOC-Center Dresden.ResultsOf 996 primary breast cancer and DCIS cases, 262 (26.3%) were eligible for genetic counselling. Recommendation for genetic counselling was accepted by 64.1% (168/262). Of these 90.5% (152/168) opted for molecular genetic analysis. The acceptance rate for counselling increased between 2016 and 2019 from 58.3 to 72.6%. Altogether, 20.4% (31/152) patients were found to carry a pathogenic variant in the breast cancer genes BRCA1 or BRCA2.ConclusionAcceptance of recommendation is increasing as clinical consequences augment. Optimization in providing information about hereditary cancer risk and in accessibility of counselling and testing is required to further improve acceptance of recommendation.     

Cancer risks for Australian women with a BRCA1 or a BRCA2 mutation

One of the primary purposes of genetic testing for mutations in the BRCA1 and BRCA2 genes in patients with familial breast/ovarian cancer has been to provide accurate advice to at-risk relatives. The provision of such advice has been hampered by a lack of appropriate data regarding the cancer risks. Chen and colleagues recently provided precise estimates of the relative risks of breast and ovarian cancer in almost 2000 kindreds with such mutations ascertained through familial cancer clinics across USA. The baseline incidence of breast cancer is lower in Australia than in North America. The relative risks derived from the study have been combined with Australian baseline incidence data to estimate the absolute short-term and long-term risks of breast and ovarian cancers for Australian carriers of different ages. The results are presented as a series of graphs that may be useful in counselling an unaffected carrier of a specified age. It is of note that the incidence of breast cancer in carriers is high in premenopausal women, but approaches the population incidence in postmenopausal women. Conversely, the incidence of ovarian cancer continues to increase from the age of 40 years. Among carriers of BRCA1 or BRCA2 mutations, the cumulative lifetime risk of developing breast cancer is 50-60% and the equivalent risk of ovarian cancer is 20-40%. An unaffected carrier aged 60 years is at greater risk of developing ovarian cancer than breast cancer. These observations have important implications for genetic counselling and decisions regarding prophylactic surgery.     

Genetic predisposition to breast cancer: a surgical perspective

BACKGROUND: Molecular alterations in proto-oncogenes, tumour suppressor genes, and genes that function in DNA damage recognition and repair are considered to be hallmarks of a carcinogenic process, including breast carcinogenesis. METHODS: A computer-assisted search of the English literature (Medline database, 1990-1999) was performed, followed by a manual search of the reference list of pertinent articles retrieved. RESULTS: Hereditary breast cancer accounts for 5-10 per cent of all breast cancer cases. About 90 per cent of hereditary breast cancers involve mutation of the BRCA1 and/or BRCA2 genes. Other cancer-related genes (including myc, c-erbB2, Tsg101 and Mdgi) are involved in breast carcinogenesis, but they do not give rise to familial breast cancer syndromes. Risk estimation is the most important clinical implication. Management options for the high-risk mutation carriers include cancer surveillance and preventive strategies (prophylactic surgery or chemoprevention). CONCLUSION: Despite inadequate knowledge about the genetic predisposition to breast cancer and its clinical implications, the demand for genetic testing is likely to expand rapidly. In addition to risk estimation, cancer surveillance and preventive strategies, gene therapy offers a new and theoretically attractive approach to breast cancer management.     

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.     

Preventive mastectomy in patients at breast cancer risk due to genetic alterations in the<Emphasis Type="Italic"> BRCA1</Emphasis> and<Emphasis Type="Italic"> BRCA2</Emphasis> gene

BACKGROUND: The availability of genetic testing for inherited mutations in the BRCA1 and BRCA2 gene provides potentially valuable information to women at high risk of breast and ovarian cancer. METHODS AND FOCUS: We review the literature on the value of prophylactic surgical strategies in patients with hereditary predisposition to develop breast cancer and discuss the surgical options available in high-risk cancer patients, decision analyses, and possible complications. RESULTS: Preventive surgical interventions to reduce cancer risk in high-risk patients are often strongly recommended. A patient's life-time risk to develop breast cancer in the presence of BRCA1 and BRCA2 mutations is 50-90%. Despite the reduction in the risk of developing breast cancer, prophylactic mastectomy often leads to significant physical and psychological sequelae.     

Assessing the Knowledge and Attitudes Regarding Genetic Testing for Breast Cancer Risk in our Region of Southeastern Georgia

Abstract: Genetic testing for the breast cancer susceptibility genes, BRCA1 and BRCA2, has been available for over a decade. Positive test results carry significant medical, psychological, and social implications. Knowledge of the public’s awareness concerning BRCA testing, and perceived benefits and barriers to testing can help refine educational programs and identify subgroups needing additional support. Patients and their acquaintances with a breast complaint attending a surgical clinic or private office were asked to complete a questionnaire about their knowledge of breast cancer genes and their desire to be tested. Demographic information collected included ethnicity, education background, age, income, and personal and family history of breast cancer, knowledge of BRCA genes and testing, and their willingness to participate in genetic counseling. A total of 222 people completed the questionnaire that showed the majority of subjects in southeast Georgia believe breast cancer is inherited 26–50% of the time. Caucasians and those with advanced degrees are the most informed regarding awareness of BRCA genes (p < 0.05); the least informed groups include African Americans and those with no more than a college education. Participants with a family history of breast cancer were significantly more likely to know that genes had been identified that indicate an increased risk of breast cancer (p < 0.05). A history of breast cancer did not impact the degree of awareness (p > 0.05). Subjects aware of genetic testing are more willing to utilize counseling (p < 0.05). Perceptions of breast cancer inheritance, awareness of susceptibility genes, and availability of testing and counseling are not uniform among all population subgroups. In southeast Georgia, educational efforts should focus on the less educated and minority groups.     

Setting up a breast cancer family history clinic

Breast cancer causes around 21,000 deaths per year in the UK, the vast majority of these occurring in women aged over 50 years with no genetic predisposition to the disease. Screening and symptomatic services for these women, although by no means perfect or homogeneous, have gradually improved over the last 10 years and, perhaps as a result of this, together with increased use of adjuvant systemic therapy, mortality in this group has fallen. Despite this reassuring state of affairs, media interest in the disease and patients' perception of their risk of developing breast cancer have risen. Part of this is undoubtedly due to the new scientific developments in cancer genetics and, in particular, identification of the BRCA1 gene in 1994 and BRCA2 gene shortly afterwards. These genes are dominantly inherited with up to 80% penetrance; thus, women (and occasionally men) inherit these genes and have a high lifetime risk of developing breast cancer, usually at a younger age than average and possibly of a more aggressive phenotype. Unaffected family members can now be screened and, if they prove carriers, screening for early detection and prevention strategies such as bilateral prophylactic mastectomy can be offered. Because of the high risk of ovarian cancer in BRCA1 carriers, screening or prophylactic ovariectomy may also be considered.     

Surgical management of an Irish cohort of BRCA-mutation carriers

Little information is available regarding the management of BRCA-related breast cancer in Ireland. A cancer genetics programme was initiated in 1992 at our institution to provide counselling and expert management for those with cancers resulting from inherited predisposition. We examined a cohort of BRCA mutation-carriers treated at a single institution over 16 years. A total of 107 women from 57 families were found to be carriers of mutations in BRCA1/2. Bilateral salpingo-oophorectomy was the most common prophylactic surgery performed. Overall survival between BRCA-related and sporadic breast cancer was equivalent.This is the first publication on surgical management of BRCA-mutation carriers in Ireland. It is imperative that those considered likely to harbour a mutation are referred early to a dedicated clinic so that appropriate counselling, testing and subsequent management to reduce the risk of dying from cancer can be undertaken.     

Educational Review: Role of the Surgeon in Hereditary Breast Cancer

Up to 10% of the breast cancers detected in the United States are related to an inherited germline mutation, usually in the BRCA1 or BRCA2 genes, and the majority of these patients will at some point require surgical evaluation and/or treatment. Women who harbor a genetic predisposition for breast cancer face an increased risk for early onset disease, bilateral tumors, and other non-breast malignancies, such as ovarian cancer. These issues raise questions regarding the appropriate surveillance regimen, and the potential efficacy of risk reduction strategies that should be considered. Once a breast cancer diagnosis has been established, the prognosis appears to be similar to stage-controlled sporadic breast cancer, despite an increased prevalence of adverse primary tumor features. However, the role of breast conservation therapy for these patients and the optimal means of addressing the substantially increased risk for contralateral tumors is not yet defined. The reported literature in this area, including a discussion of the value of genetic counseling and genetic testing, is reviewed.     

BRCA1 and BRCA2 in Breast Cancer Predisposition and Recombination Control

Hereditary predisposition to breast and ovarian cancer is determined in large part by loss-of-function mutations in one of two genes, BRCA1 and BRCA2 . Early discoveries that the two genes function in the control of homologous recombination and the prevention of genomic instability have been strongly supported by subsequent work. Our aim here is to highlight new advances in the study of BRCA1 and BRCA2 , and to place these advances in the context of existing knowledge.     

The contribution of inherited factors to the clinicopathological features and behavior of breast cancer

This review is focused on genetic factors that may influence the development and/or appearance of breast cancer metastases. Over the last decade there have been significant advances in the understanding of genetic predisposition to breast cancer. The first breast cancer predisposing gene to be identified was TP53, and this was followed over the next 5 years by two more genes, BRCA1 and BRCA2, which from a population perspective are much more important than TP53. Other rarer genes have subsequently been identified, but the role of more common, less penetrant genes in breast cancer susceptibility remains unknown. Recent work has shown that breast cancers occurring in women carrying germ-line BRCA1 mutations tend to have clinicopathological features that are usually associated with a poor prognosis, such as high grade, estrogen receptor negative status and somatic TP53 mutations. On the other hand, they are usually ERBB2 negative. Whether or not such tumors are more or less likely to metastasize, and hence be associated with a poor outcome, is currently uncertain and has been the subject of much debate. Here, we outline some of the clinicopathological features of hereditary breast cancer, discuss the prognostic studies that have been performed, and introduce some possible new research directions.     

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.     

Moderate penetrance genes complicate genetic testing for breast cancer diagnosis: ATM,CHEK2, BARD1 and RAD51D

Breast cancer risk associated with germline likely pathogenic/pathogenic variants (PV) varies by gene, often by penetrance (high >50% or moderate 20–50%), and specific locus.Germline PVs in BRCA1 and BRCA2 play important roles in the development of breast and ovarian cancer in particular, as well as in other cancers such as pancreatic and prostate cancers and melanoma. Recent studies suggest that other cancer susceptibility genes, including ATM, CHEK2, PALB2, RAD51C and RAD51D confer differential risks of breast and other specific cancers.In the era of multigene panel testing, advances in next-generation sequencing technologies have notably reduced costs in the United States (US) and enabled sequencing of BRCA1/2 concomitantly with additional genes. The use of multigene-panel testing is beginning to expand in Europe as well.Further research into the clinical implications of variants in moderate penetrance genes, particularly in unaffected carriers, is needed for appropriate counselling and risk management with data-driven plans for surveillance and/or risk reduction. For individuals at high risk without any pathogenic or likely pathogenic variant in cancer susceptibility genes or some carriers of pathogenic variants in moderate-risk genes such as ATM and CHEK2, polygenic risk scores offer promise to help stratify breast cancer risk and guide appropriate risk management options.Cancer patients whose tumours are driven by the loss of function of both copies of a predisposition gene may benefit from therapies targeting the biological alterations induced by the dysfunctional gene e.g. poly ADP ribose polymerase (PARP) inhibitors and other novel pathway agents in cancers with DNA repair deficiencies. A better understanding of mechanisms by which germline variants drive various malignancies may lead to improvements in both therapeutic and preventive management options.     

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.     

Breast cancer and ovarian cancer genetics

Breast and ovarian cancers are the second and fifth leading causes of cancer death, respectively, among women in the United States. Individuals with breast cancer have a 20--30% chance of having at least one relative with the disease. However, only 5--10% of the cases are a direct result of germline mutations in highly penetrable genes, such as BRCA1 and BRCA2 (BRCA1/2) as well as genes TP53 and PTEN. Since 1996, genetic testing for these mutations has been clinically available. A strategy for the management of women at increased familial risk of breast and ovarian cancers is described, which includes genetic assessment, chemoprevention, radiologic screening, and clinical and self-examination. Genetic testing should occur within a cancer genetic clinic after genetic counseling. A blood sample allows determination of the presence of the BRCA1 and BRCA2 genes, the TP53 gene, the PTEN gene, and the ATM gene. Tumor examination has identified a growth factor receptor gene, human epidermal growth factor receptor (HER-2).With regard to diet and lifestyle, women at increased risk of breast cancer could be advised to reduce dietary fat, avoid obesity, decrease alcohol consumption, and take regular exercise. Although chemoprotection is a valuable consideration, it is important to emphasize that the use of Tamoxifen in BRCA1 and BRCA2 mutation carriers is not established, nor is the optimum duration of benefit. An overview of the main outcomes of the current published studies confirms a 38% decrease in breast cancer incidence with Tamoxifen but recommends its use be restricted to women at high risk of breast cancer and low risk for potential side effects. The role of bilateral risk-reducing mastectomy or prophylactic mastectomy has been controversial for several reasons, including the psychosocial significance of the breast in Western cultures, the wide acceptance of breast conservation in surgery for early breast cancer, and the previous lack of data on its efficacy. The surgical procedure should aim to remove substantially all at-risk breast tissue. However, there is a balance between reduction of cancer risk and cosmetic outcome. Bilateral prophylactic oophorectomy can significantly decrease ovarian cancer risk in women who carry BCRA1 mutations. Oophorectomy lowers the risk of breast cancer, even in women who have previously used hormone replacement therapy. There are no published randomized controlled trials examining the effectiveness of mammographic screening in women under 50 years of age with a family history of breast cancer. However, the published studies do suggest that mammographic screening of a high-risk group of women under 50 years of age may detect cancer at a rate equivalent to that seen in women 10 years older with normal risk. Other initial studies also support MRI as having a greater sensitivity than mammography in high-risk women. Breast clinical and self-examination is often advocated, but its effectiveness is unproved, and only one randomized study has been undertaken in women at risk. On the basis of this study as well as one nonrandomized study, it can be concluded that clinical examination as well as mammography are essential in detecting breast cancer. under 50 years of age with a family history of breast cancer. However, the published studies do suggest that mammographic screening of a high-risk group of women under 50 years of age may detect cancer at a rate equivalent to that seen in women 10 years older with normal risk. Other initial studies also support MRI as having a greater sensitivity than mammography in high-risk women. Breast clinical and self-examination is often advocated, but its effectiveness is unproved, and only one randomized study has been undertaken in women at risk. On the basis of this study as well as one nonrandomized study, it can be concluded that clinical examination as well as mammography are essential in detecting breast cancer.     

Testing for hereditary breast and ovarian cancer in the southeastern United States

OBJECTIVES: To detail characterization of mutations and uncharacterized variants in the breast cancer susceptibility genes BRCA1 and BRCA2, as observed in a population of breast cancer patients from the southeastern United States, and to examine baseline characteristics of women referred for counseling and testing and provide a preliminary look at how counseling and testing affected intentions toward prophylactic surgery. BACKGROUND: Mutations in the BRCA1 and BRCA2 genes give rise to a dramatically increased risk of developing breast or ovarian cancer or both. There are many reports about special populations in which deleterious mutations are present at a high frequency. It is useful to study these genes in more heterogeneous populations, reflecting different geographic regions. Interest in preventive surgery for gene carriers is high in women and their surgeons. METHODS: Women were recruited through a prospective clinical trial of counseling and free genetic testing. BRCA1 and BRCA2 were screened for mutations using standard techniques, and results were given to participants. Baseline questionnaires determined interest in preventive surgery at the beginning of the study. Follow-up questionnaires for those who completed testing surveyed interest in prophylactic surgery after counseling and receiving test results. RESULTS: Of 213 women who completed counseling and testing, 44 (20.6%) had 29 separate mutations; there were 11 Jewish women carrying three founder mutations. Twenty-eight women (13.1%) had uncharacterized variants in BRCA1 or BRCA2; nine were not previously reported. Women overestimated their chances of possessing a deleterious gene mutation compared to a statistical estimate of carrier risk. A number of women changed their intentions toward preventive surgery after genetic counseling and testing. CONCLUSIONS: Hereditary breast cancer due to mutations in BRCA1 and BRCA2 was a heterogeneous syndrome in the southeastern United States. Most mutations were seen just once, and uncharacterized variants were common and of uncertain clinical significance. In general, positive test results tended to reinforce intentions toward prophylactic surgery. In contrast, women not interested in surgery at the time of entry tended to remain reluctant after testing and counseling.