Familial Breast Cancer Syndromes Research Articles

Black and Minority Ethnic women's decision-making for risk reduction strategies after BRCA testing: Use of context and knowledge

Within the field of breast cancer care, women concerned about their family history are offered genetic testing and subsequent treatment options based on several factors which include but are not limited to personal and family cancer disease histories and clinical guidelines. Discussions around decision-making in genetics in Black and Minority Ethnic (BME) groups are rarely documented in literature, and information regarding interactions with genetics services is usually discussed and linked to lack of scientific knowledge. As such, counselling sessions based only on scientific and medical information miss out the many reasons participants consider in making health decisions, information which can be used to encourage BME women to engage in cancer genetics services. 10 BME women with a mixed personal and family history of breast and ovarian cancer backgrounds, were interviewed in a study exploring issues of knowledge about familial breast cancer syndromes, to understand how they created and used familial knowledge for health decisions, with a particular focus on attitudes towards risk reducing strategies.Study results show that our participants are not unique in the ways they make decisions towards the use of cancer genetics and risk reduction strategies and as such, there are no specific ethnically defined pathways for decision-making. Our participants demonstrated mixed biomedical, social and individual cultural reasons for their decision-making towards risk reduction surgeries and treatment options which are similar to women from different ethnicities and are individual rather than group-specific. Narratives about suspicion of scientific utility of genetic knowledge, the perceived predictive value of mutations for future cancers or the origin of mutations and family disease patterns feature heavily in how participants evaluated genetic information and treatment decisions. The diversity of results shows that our participants are interested in engaging with genetic information but use multiple sources for evaluating the extent of involvement in genetic services and the place of genetic information and treatment options for themselves and their families. Genetic information is considered within various bio-social scenarios before decision-making for risk reduction is undertaken. BME women are shown to undertake evaluative processes which clinicians are encouraged to explore for better patient support. Continuing to focus on links between superficial and un-representative meanings of ethnicity, ethnic identity and attitudes and behaviours by only searching for differences between ethnic groups, are unhelpful in further understanding how women from those diverse backgrounds make decisions towards risk reduction interventions. Future research must find ways of investigating and understanding populations in ways that are not focussed solely on ethnic differences but on how meaning is created out of social circumstances and experiences.

Abstract 989: Organoid cultures from normal and cancer-prone human breast tissues preserve complex epithelial lineages and can form chimeric mammary glands in vivo

Abstract Use of cell culture models to investigate the development of cancer associated with familial breast cancer syndromes is challenging because many culture methodologies do not maintain all of the lineages that are present in vivo, particularly the progenitor cells that may be the specific cancer cell-of-origin. We evaluated the ability of organoid culture technology to preserve stem/progenitor and differentiated cell types via long-term propagation of normal human mammary tissues. Tissue samples were obtained from elective reduction mammoplasties or from prophylactic mastectomies for cancer prevention, and were histologically normal. These were grown using conditions similar to organoid cultures for other epithelial cell types, as has been recently described (Sachs et al., Cell 2018). We found that basal stem and luminal progenitor cells could be cultured long-term, and differentiated in culture to generate mature basal and luminal cell types. Analysis of matched organoid cultures and native tissues by mass cytometry (CyTOF) for 38 markers at single-cell resolution confirmed the presence of multiple mammary epithelial cell types in the organoids, and demonstrated that protein expression patterns of the tissue of origin were largely preserved in culture. In addition, we generated a panel of over 40 mammary organoids derived from patients harboring inherited mutations in the cancer predisposition gene BRCA1 and from unaffected controls. Despite interindividual variability, an expansion in luminal progenitor populations associated with BRCA1 mutation could be detected in cultured organoids. Human mammary organoids heterozygous for BRCA1 could be engrafted into the murine mammary gland, resulting in mixed ductal and acinar structures. These studies indicate that this new model system is well suited for studies of aberrant phenotypes associated with BRCA1 mutation and approaches to prevent cancer development in these genetically predisposed tissues. Citation Format: Jennifer M. Rosenbluth, Ronald Schackmann, Carman Li, Norman Sachs, Deborah Dillon, Andrea Richardson, Jane Brock, Judy Garber, Gary Kenneth Gray, Jason Zoeller, Mackenzie Boedicker, Hendrick Johannes Kuiken, Hans Clevers, Joan Brugge. Organoid cultures from normal and cancer-prone human breast tissues preserve complex epithelial lineages and can form chimeric mammary glands in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 989.

Proteomic profile in familial breast cancer patients

ObjectivesBreast cancer is the most common form of cancer affecting women, and the strongest risk factor remains family history. Although screening in asymptomatic women seems able to reduce breast-cancer related mortality, it is of limited usefulness in young women and patients with familial breast cancer syndrome. New diagnostic tools useful for breast cancer management are urgently needed. The aim of the present paper is to look for new candidate tumor markers useful for diagnosis in these patients. Design and methodsIn this prospective study 292 serum samples (100 from healthy people, 100 from sporadic breast cancer patients and 92 from familial breast cancer patients) were analyzed by SELDI-TOF–MS. All samples both from cancer patients and healthy subjects were run in duplicate and randomly spotted on CM10 and IMAC30 protein chip array. Data were analyzed using the expression differential mapping (EDM) tool, decisional tree and multivariate analysis. A further in silico investigation was performed in order to hypothesize the identity of evidenced peptides. ResultsEDM highlighted thirteen and sixteen significant differentially expressed peaks by CM10 and IMAC30 protein chip respectively. Subsequent analysis showed that two peaks at m/z 11730 and 5066 were differentially expressed in sporadic and familial breast cancer patients respectively, while a peak at m/z 8127 was overexpressed only in familial breast cancer patients. The diagnostic power of protein peaks was tested by decisional tree; sensitivity and specificity ranged from 17% to 91.67%. ConclusionsWe show that the serum profile of familial breast cancer patients was different when compared with that of sporadic breast cancer patients. We hypothesized the identity of the most significant peaks, and further studies are now planned in order to definitively establish the identity.

TGFBR1 Signaling and Breast Cancer

Over the past decade mutations discovered in genes such as BRCA1, BRCA2, TP53 and PTEN, have emerged as high-penetrance susceptibility genes and are clinically relevant for determination of breast cancer risk. Genetic counseling and subsequent screening for mutations and gene rearrangement has improved patient outcome through early detection and prophylactic interventions in patients with familial breast cancer syndromes. However, these high-penetrance genes only account for a small fraction of the hereditary linked breast cancers. It is currently believed that low-penetrance susceptibility alleles and/or environmental factors may play an important role in the remaining cases. TGFBR1*6A (*6A) is a common hypomorphic variant of the type I TGF-β receptor gene (TGFBR1) that has been associated with risk for several forms of cancer, in particular breast cancer. Several epidemiological studies have suggested that patients who carry the *6A allele have an increased risk of breast cancer. Furthermore, functional analysis suggests that this mutation alters TGF-β signaling and promotes tumorigenesis. Although a decade of research has provided basic information in regards to the prevalence of this mutation in several cancer types and populations the molecular underpinning of its functional effects are poorly understood. A better understanding of the molecular mechanism of TGFBR1 signaling in breast cancer may have an impact on breast cancer risk assessment and breast cancer prevention.

Early Detection of Pancreatic Cancer: Why, who, and how to Screen

Pancreatic cancer represents the fourth-leading cause of cancer death in the United States, with a dismal 5-year survival rate of less than 5%. Despite advancements in screening and early detection of other cancers such as breast and colon cancer, no reliable screening test exists for pancreatic cancer. Subsequently, the majority of patients present with advanced-stage disease leading to a poor prognosis. Because of the relatively low incidence, current efforts are focused on early detection and screening only in patients at high risk for the development of the disease. We discuss the practical considerations encountered when determining if an individual should be screened for pancreatic cancer. The current literature was reviewed regarding risk factors, genetic syndromes, screening modalities, and screening studies of pancreatic cancer. The current high-risk pancreatic screening program at our institute is also summarized. Current efforts to detect pancreatic cancer at a curative phase are focused on screening individuals at high risk for the development of this disease. They include kindreds with two or more first-degree relatives affected with this disease and those with known hereditary pancreatic cancer syndromes. Hereditary pancreatic cancer syndromes include Peutz-Jeghers syndrome, familial breast cancer syndrome, and familial atypical multiple mole melanoma syndrome. Of all the screening modalities available, endoscopic ultrasound is the most sensitive and specific screening tool to evaluate the pancreas and has been proven to detect early precancerous and cancerous changes in clinical studies. Early detection and screening for pancreatic cancer in the current state should be limited to high-risk patients, although hereditary/familial factors account for only 10% of patients with pancreatic cancer. Continued efforts are needed to discover effective test to identify patients with nonhereditary risk factors who will benefit from screening and also to develop less invasive and more cost-effective screening modalities aimed at controlling pancreatic cancer.

A hypothesis-generating search for new genetic breast cancer syndromes – a national study in 803 Swedish families

Among Swedish families with an inherited predisposition for breast cancer, less than one third segregate mutations in genes known to be associated with an increased risk of breast cancer in combination with other types of tumours. In a search for new putative familial breast cancer syndromes we studied Swedish families undergoing genetic counselling during 1992-2000.Four thousand families from counselling clinics in Sweden were eligible for study. Families with breast cancer only were excluded, as were families with mutations in genes already known to be associated with malignant diseases. We identified 803 families with two or more cases of breast cancer and at least one other type of cancer. The observed proportion of different types of non-breast cancer was compared with the percentage distribution of non-breast cancer tumours in Sweden in 1958 and 1999.We found tumours in the colon, ovary, endometrium, pancreas and liver, as well as leukaemia in a significantly larger proportion of the study population than in the general population in both years. These tumours were also seen among families where several members had one additional tumour, suggesting that malignancies at these sites, in combination with breast tumours, could constitute genetic syndromes. Endometrial carcinoma has not previously been described in the context of breast cancer syndromes and the excess of malignancies at this site could not be explained by secondary tumours. Thus, we suggest that endometrial carcinoma and breast cancer constitute a new breast cancer syndrome. Further investigation is warranted to categorize phenotypes of both breast and endometrial tumours in this subgroup.

American Society of Clinical Oncology 2006 Update of the Breast Cancer Follow-Up and Management Guidelines in the Adjuvant Setting

To update the 1999 American Society of Clinical Oncology (ASCO) guideline on breast cancer follow-up and management in the adjuvant setting. An ASCO Expert Panel reviewed pertinent information from the literature through March 2006. More weight was given to studies that tested a hypothesis directly relating testing to one of the primary outcomes in a randomized design. The evidence supports regular history, physical examination, and mammography as the cornerstone of appropriate breast cancer follow-up. All patients should have a careful history and physical examination performed by a physician experienced in the surveillance of cancer patients and in breast examination. Examinations should be performed every 3 to 6 months for the first 3 years, every 6 to 12 months for years 4 and 5, and annually thereafter. For those who have undergone breast-conserving surgery, a post-treatment mammogram should be obtained 1 year after the initial mammogram and at least 6 months after completion of radiation therapy. Thereafter, unless otherwise indicated, a yearly mammographic evaluation should be performed. Patients at high risk for familial breast cancer syndromes should be referred for genetic counseling. The use of CBCs, chemistry panels, bone scans, chest radiographs, liver ultrasounds, computed tomography scans, [18F]fluorodeoxyglucose-positron emission tomography scanning, magnetic resonance imaging, or tumor markers (carcinoembryonic antigen, CA 15-3, and CA 27.29) is not recommended for routine breast cancer follow-up in an otherwise asymptomatic patient with no specific findings on clinical examination. Careful history taking, physical examination, and regular mammography are recommended for appropriate detection of breast cancer recurrence.

Genetic predisposition to breast cancer: a surgical perspective.

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. 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. 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). 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.

Hereditary breast cancer associated with a germline BRCA2 mutation in identical female twins with similar disease expression

The relative contribution of heritable and nonheritable factors to disease expression in BRCA2 mutation carriers is largely unknown. This report describes a familial breast cancer syndrome in a pair of identical female twins. These twins showed an extremely high concordance in their clinical histories; both twins exhibited similar cancer-related risk factors, and developed breast cancer at the same age with the same disease stage and identical histological features. No differences were detected in hormone receptors status, p53, bcl-2, erbB-2 and LI Ki67 expression by immunohistochemistry. A BRCA2 exon 11 protein truncation test showed a lower molecular weight band than the one expected for a normal allele, in both twins. Sequence analysis of DNA showed a 6 bp insertion between nucleotides 4359-4360, which resulted in a premature stop codon at position 1378. The remarkable disease similarity observed in this identical twin pair is in accordance with an important role for heritable factors in disease expression among patients carrying BRCA germline mutations.

Breast cancer genes and the surgeon.

Two genes, called BRCA-1 and BRCA-2, have been identified that appear to be responsible for the majority of familial breast cancer syndromes. These genes now play a prominent role in the practice of the surgeon treating breast cancer. Additional genes, PTEN (Cowden disease), MSH1 or MLH2 (HNPCC), and p53 (Li-Fraumeni syndrome) are responsible for other breast cancer syndromes but have not yet entered the clinical arena on a large scale. The risk of breast and ovarian cancer by age 70 in a BRCA-1 mutation carrier is estimated at 55-75% and 16-26 %, respectively, overall, and as high as 87% and 44% in those with a strong family history. The cancer risks associated with BRCA-2 mutations appear to be somewhat lower than those of BRCA-1. BRCA mutations show a strong founder effect. This is best recognized in the Ashkenazi Jewish community, in which the incidence of one of three characteristic mutations is about 2%. In other ethnic groups the pattern of mutations is different, with over 100 distinct mutations throughout the genes having been described. Most mutations so far have been frame-shift or mis-sense mutations, although large deletions have also been described. Thus, in most situations, assessment of the whole coding sequence is required to confirm or exclude a mutation. Guidelines to suggest who is likely to be a mutation carrier are being clarified, but the appropriate management of someone who tests positive remains difficult. Prophylactic mastectomy and oophorectomy are likely to offer substantial gains in life expectancy to mutation carriers, especially for young women with a strong family history. Unfortunately, there are no currently available strategies to eliminate the risk of breast or ovarian cancer. The psychological impact of testing also remains poorly understood, and the danger of various forms of discrimination remain. These factors must be clearly understood by all parties prior to testing. The process of a dynamic, interactive informed consent--much more than a simple printed document--and also counseling are central to the testing process.

Characteristics of hereditary ovarian cancer

Ovarian cancer is the fifth major cause of cancer-related mortality among women. In Wielkopolska, higher incidence and mortality rates are observed compared to other regions of Poland. Ovarian cancer affects mainly women in their sixties and seventies. The etiology of this disease has not been fully understood yet. The factors contributing to increased risk of ovarian cancer occurrence include infertility, breast cancer diagnosed before the age of 45 and family history of ovarian cancer while childbearing and oral contraceptives are considered to be protective factors. Simultaneous genetic and epidemiological studies based on analyzing pedigrees of families with multiple cases of ovarian cancer and indicate a role of the genetic factor in ovarian cancer etiology. Familial forms of ovarian cancer which represent approximately 5–10% of all cases are associated with certain syndromes, including: familial breast and ovarian cancer syndrome related to mutations in BRCA1, familial breast cancer syndrome related to mutations in BRCA2 which can be accompanied by ovarian cancer, Lynch II syndrome characterized by the occurrence of ovarian cancer, colon cancer and endometrial cancer in the family as well as the syndrome of hereditary non-polypous colon cancer (HNPCC). Genetic ovarian cancer is most often diagnosed before the age of fifty. Identification of individuals with a high risk of genetic predisposition to developing ovarian cancer should be based on precise information collected during interviews with family members complemented by the data on personal risk factors. Women identified as members of high-risk groups can be offered genetic testing aimed at detecting asymptomatic carriers of mutations in genes predisposing to ovarian cancer. On the one hand, genetic tests represent a new, extremely powerful instrument for identifying individuals genetically predisposed to ovarian cancer, on the other hand, however, they create numerous problems. The two basic controversies which need clarifying are: who should be offered genetic testing and what preventive measures can be taken to help women carrying gene mutations increasing the risk of developing cancer, including ovarian cancer. Most issues related to genetic types of cancer (including ovarian) require further investigation and studies and currently proposed protocols are still widely discussed.

Germ-LineBRCA1Mutations in Jewish and Non-Jewish Women with Early-Onset Breast Cancer

Mutations in a germ-line allele of the BRCA1 gene contribute to the familial breast cancer syndrome. However, the prevalence of these mutations is unknown in women with breast cancer who do not have the features of this familial syndrome. We sought BRCA1 mutations in women who were given a diagnosis of breast cancer at an early age, because early onset is characteristic of a genetic predisposition to cancer. Clinical information and peripheral-blood mononuclear cells were obtained from 418 women from the Boston metropolitan area in whom breast cancer was diagnosed at or before the age of 40. A comprehensive BRCA1 mutational analysis, involving automated nucleotide sequencing and a protein-truncation assay, was undertaken in 30 of these women, who had breast cancer before the age of 30. In addition, the BRCA1 mutation 185delAG, which is prevalent in the Ashkenazi Jewish population, was sought with an allele-specific polymerase-chain-reaction assay in 39 Jewish women among the 418 women who had breast cancer at or before the age of 40. Among 30 women with breast cancer before the age of 30, 4 (13 percent) had definite, chain-terminating mutations and 1 had a missense mutation. Two of the four Jewish women in this cohort had the 185delAG mutation. Among the 39 Jewish women with breast cancer at or before the age of 40, 8 (21 percent) carried the 185delAG mutation (95 percent confidence interval, 9 to 36 percent). Germ-line BRCA1 mutations can be present in young women with breast cancer who do not belong to families with multiple affected members. The specific BRCA1 mutation known as 185delAG is strongly associated with the onset of breast cancer in Jewish women before the age of 40.

Radiation and Cancer

To the Editor.— Regular examination of breasts in women previously exposed to radiation, as suggested by Stoffer et al (1981;245:462), is excellent advice. They failed, however, to note the other known risk factors in development of breast cancer. 1 The patient described, and her family, may still be at risk for cancer development. She may have one of several types of familial breast cancer syndromes 2 or, more important, could be a person afflicted with the family cancer syndrome (FCS). 3 The patient displayed a potential for thyroid tumor as well as the actual development of bilateral breast cancer. No mention is made of investigation into other potential tumors in this 28-year-old woman or in other family members. Family cancer syndrome, described by Lynch et al, 3 recognizes groupings of specific cancers found in excess within certain families. In these families the predisposition to cancer seems to be inherited in