Modifiers of risk of hereditary breast and ovarian cancer

Hereditary breast and ovarian cancer is among the most commonly encountered adult genetic disease, and it is increasingly important that geneticists, oncologists, surgeons and gynaecologists are aware of the issues regarding risk assessment, prevention and management of women with inherited susceptibility to cancer. Genetic risk can be modified by external factors, but what are these factors, and how might our knowledge of them help us to better define the risks for individual women and to develop strategies for cancer prevention?     

Knowledge about breast cancer risk factors and hereditary breast cancer among early-onset breast cancer survivors

Little is known about knowledge levels regarding hereditary breast cancer among breast cancer survivors. This study explored, among women with early-onset breast cancer (<50 years): 1) knowledge regarding breast cancer risk factors and hereditary breast cancer; and 2) differences in knowledge based on risk for hereditary disease. Participants recruited from 34 Virginia hospitals responded to two questionnaires. The Family History Questionnaire assessed risk for hereditary breast cancer. The Knowledge, Attitudes, and Beliefs Questionnaire evaluated knowledge of general breast cancer risk factors and hereditary breast cancer. Of 314 respondents, 273 (87%) returned both questionnaires. A total of 137 (52%) participants met the study's criteria for hereditary breast cancer risk. Most participants knew common breast cancer-associated risk factors, including family history of breast cancer. Only 35% recognized family history of non-breast malignancies as a risk factor for breast cancer. Most participants recognized that prophylactic mastectomy does not eliminate breast cancer risk (63%), that not all women carrying a mutation develop disease (73%), and that men can develop breast cancer (96%). The majority selected 'I don't know' for knowledge of several characteristics of hereditary breast cancer, including: early-onset disease (54%); multifocal or bilateral disease (62%); risk transmission through fathers (58%); association with other cancer types (61%); and male breast cancer (70%). Knowledge regarding hereditary breast cancer did not vary between women with suspected hereditary disease and those with presumed sporadic disease. These data highlight the need for information regarding hereditary breast cancer for early-onset breast cancer survivors.     

Pathology of hereditary breast cancer

Background

Hereditary breast cancer runs in families where several members in different generations are affected. Most of these breast cancers are caused by mutations in the high penetrance genes BRCA1 and BRCA2 accounting for about 5% of all breast cancers. Other genes that include CHEK2, PTEN, TP53, ATM, STK11/LKB1, CDH1, NBS1, RAD50, BRIP1 and PALB2 have been described to be high or moderate penetrance breast cancer susceptibility genes, all contributing to the hereditary breast cancer spectrum. However, in still a part of familial hereditary breast cancers no relationship to any of these breast cancer susceptibility genes can be found. Research on new susceptibility genes is therefore ongoing.

Design

In this review we will describe the function of the today known high or moderate penetrance breast cancer susceptibility genes and the consequences of their mutated status. Furthermore, we will focus on the histology, the immunophenotype and genotype of breast cancers caused by mutations in BRCA1 and BRCA2 genes and the other high or moderate penetrance breast cancer susceptibility genes. Finally, an overview of the clinical implications of hereditary breast cancer patients will be provided.

Conclusion

This information leads to a better understanding of the morphological, immunohistochemical and molecular characteristics of different types of hereditary breast cancers. Further, these characteristics offer clues for diagnosis and new therapeutic approaches.     

Treatment of hereditary breast cancer

Mutations in BRCA1 and BRCA2 are well-established causes of hereditary breast cancer. As genetic testing becomes more widespread, increasing numbers of women are known to have mutations at or shortly after their breast cancer diagnosis. Current evidence is insufficient to mandate different local or systemic treatment based upon the presence of a germline mutation. The well-documented increased risk of contralateral second primary breast cancer and possibly of late ipsilateral second primary breast cancers may influence patient decision-making with regard to breast-conserving treatment.     

Breast cancer screening uptake in women at increased risk of developing hereditary breast cancer

This multicenter study assessed breast cancer screening uptake in 461 unaffected women at increased risk of developing breast cancer on the basis of family history who approached familial cancer clinics for advice about surveillance options. At the time of attending the clinic, 89% and 90% of participants were vigilant with respect to age- and risk-specific recommendations for mammography and clinical breast examination, respectively, and 51% reported practicing breast self-examination monthly or more frequently. The degree to which health outcomes are perceived to be under one's personal control (²=–2.09, p=0.0037) and breast cancer anxiety (²=8.11,p=0.044) were both associated with monthly or more frequent breast self-examination, while there were no associations with sociodemographic characteristics. A significantly lower percentage (56%) of women aged <30 were vigilant with respect to mammography recommendations, compared to 77%, 96% and 98% of women aged 30–39, 40–49 and >50, respectively (²=37.2,p<0.0001). These relatively low rates of mammographic screening in young women may reflect concerns about increased cancer risk associated with early and repeated radiation exposure or lack of sensitivity in young women with radiographically dense breasts. If mammographic screening is ultimately shown to lower mortality in women at high risk, there will be a strong case to promote screening in young women. The need for regular mammographic screening would then need to be highlighted and reinforced amongst young women and their referring physicians. Awareness amongst general practitioners, who are largely responsible for referral to screening services, would also need to be increased.     

Update on hereditary breast cancer

Women with BRCA1 or BRCA2 mutations are at substantial risk for breast and ovarian cancer. This review describes recent developments in the approach to hereditary breast cancer. Risk-reducing surgeries remain the most effective means of preventing breast cancer in mutation carriers. For women with breast tissue at risk, magnetic resonance imaging is rapidly becoming incorporated into screening programs. For affected women, management does not currently differ from that of women with sporadic breast cancer, although women may choose to undergo bilateral mastectomy. Preclinical data suggest that BRCA mutation-associated breast cancers may benefit from specific targeted therapeutic approaches.     

Screening for hereditary breast cancer

Most women at risk for hereditary breast cancer opt for intensive breast screening rather than risk-reducing mastectomy. For this to be a rational choice, the vast majority of tumors must be detected either while still in situ or at a very early stage of invasion. Annual screening mammography has low sensitivity in this population, in part due to the greater breast density of younger women, resulting in cancers being detected at a suboptimal stage. In six prospective comparative studies, the addition of annual contrast-enhanced magnetic resonance imaging (MRI) of the breast to mammography demonstrated greater than 90% sensitivity, more than twice that of mammography alone. In those studies that included ultrasound and clinical breast examination, additional cancers were rarely detected by these modalities. False positive rates were higher with the addition of MRI, but specificity improved on successive rounds of screening. Although long-term survival data are still lacking, there is mounting evidence that the addition of screening MRI to mammography detects hereditary breast cancers at an earlier stage and is thus estimated to be cost-effective, at least for women with BRCA mutations. This review will examine the literature and current screening recommendations.     

The prevention of hereditary breast cancer

In the past 10 years our knowledge of hereditary breast cancer, and specifically the breast cancer susceptibility genes BRCA1 and BRCA2, has dramatically increased, as has our understanding of prevention options for high-risk women. Effective strategies to reduce the risk of breast cancer include prophylactic mastectomy, prophylactic oophorectomy, and chemoprevention. In this article we review the current evidence regarding the efficacy of each of these management strategies.     

Clinicopathological features of hereditary breast cancer

The possible role of germline mutations ofBRCA1 andBRCA2 as causative agents of familial breast cancer was assessed. Their possible involvement in the carcinogenesis of hereditary breast cancer was investigated using 63 clinically suspect families. Twenty-one lineages (33.3%) had mutations in one of the twoBRCA genes. This relatively low incidence suggested that germline mutations in unknown genes are involved in the carcinogenesis of hereditary breast cancer in the Japanese population. However, the clinicopathological features characteristic of hereditary breast cancer, such as early disease onset, a high incidence of bilateral breast cancer, and a high incidence of multiple primary carcinomas in other organs were confirmed in the present study.     

The Distress Thermometer assessed in women at risk of developing hereditary breast cancer

Objectives: The Distress Thermometer (DT) is a promising instrument to get insight into distress experienced by cancer patients. At our Family Cancer Clinic the DT, including an adapted problem list, was completed by 100 women at increased risk of developing hereditary breast cancer (mean age 45.2 years; SD: 10.5). Additionally, the women filled in either the Hospital Anxiety and Depression Scale as psychological component (n=48) or the somatic subscale of the Symptom Checklist‐90 as somatic component (n=50) to identify associations with the DT‐score. Further, the women filled in an evaluation form. Results: The median score on the DT was 2 (range: 0–9). With regression analysis adjusted for age, the contribution of mood and somatic complaints, respectively, was investigated. The standardized regression coefficient for anxiety was 0.32 (ns), for depression 0.14 (ns) and for the somatic subscale 0.49 (p<0.001). The explained variance for anxiety and depression was 16%, and for somatic complaints 24%. The differences between the coefficients were not significant. Evaluation forms were returned by 73 women. In 50% of the cases, the physician had discussed the DT/problem list, which was appreciated by the majority of these women (80%). Sixty‐two percent of the women would recommend the use of the DT for other patients. Conclusion: The use of the DT/problem list seems promising for the current population, and was appreciated by the majority of the women. As mood and somatic complaints did not differ significantly in explaining the experienced distress, other candidate factors need to be examined. Copyright © 2009 John Wiley & Sons, Ltd.     

Reproductive factors in hereditary breast cancer

Background: An early age at menarche, a short menstrual cycle length, and a high age at first full term pregnancy or nulliparity are known risk factors for breast cancer. These risk factors have previously been reported to differ between breast cancer patients with and without a family history of breast cancer and also between breast cancer patients and controls. Methods: Self-administered questionnaires were filled out by 95 women belonging to 24 families with known BRCA1 mutations, 16 women belonging to nine families with known BRCA2 mutations, and 95 women belonging to 65 families with hereditary breast cancer where no BRCA1 or BRCA2 mutations could be detected. Thirty-nine women were BRCA1 mutation carriers and 56 women were BRCA1 negative, 11 women were BRCA2 carriers and five BRCA2 negative. All women were born between 1905 and 1979. Results: Age at menarche, physiological menstrual cycle length at age 30 or at current age in younger women (when not using oral contraceptives), age at first full term pregnancy, and nulliparity did not significantly differ between BRCA1 mutation carriers and BRCA1 negative women. Too few women were BRCA2 negative to serve as a control group. BRCA2 mutation carriers were therefore compared with BRCA1 negative and BRCA2 negative women. None of the above reproductive factors did significantly differ between BRCA2 mutation carriers and from BRCA1 and BRCA2 families. Women from non-BRCA1/BRCA2 hereditary breast cancer families had a higher age at menarche, but this was no longer significant after adjustment for other factors in a multivariate model. Conclusion: Our results suggest that reproductive risk factors of breast cancer are not related to BRCA1 or BRCA2 carrier status. There was also no indication that these factors differ in carriers of unknown susceptibility genes compared with non-carriers from BRCA1 and BRCA2 families.     

Brca2 hereditary breast cancer pathophenotype

Four BRCA2 hereditary breast cancer (HBC) families manifested significant excesses of tubular-lobular group (TLG) invasive carcinomas and lobular carcinoma in situ/atypical lobular hyperplasia in comparison to BRCA1-HBC cases.     

MicroRNA signatures in hereditary breast cancer

This study aims to identify signatures of miR associated with hereditary, BRCA1 or BRCA2 mutation positive breast cancer (BC), and non-hereditary BC, either sporadic (SBC) or non-informative (BRCAX). Moreover, we search for signatures associated with tumor stage, immunohistochemistry and tumor molecular profile. Twenty formalin fixed paraffin embedded (FFPE) BCs, BRCA1, BRCA2, BRCAX and SBC, five per group were studied. Affymetrix platform miRNA v.3.0 was used to perform miR expression analysis. ER, PR, HER2 and Ki67 protein expression was analyzed by immunohistochemistry. BRCA1, BRCA2 and RASSF1 methylation analysis, AURKA copy number variations, and BRCA1 and BRCA2 deletions, were studied by MLPA. We validated eight of the miR selected by the arrays in 77 BCs by qRT-PCR. The miR profiles associated with tumor features were studied applying the Sparse Partial Least Squares Discriminant Analysis. MiR discrimination capability to distinguish hereditary and non-hereditary BC was analyzed by the discriminant function. With 15 out of 1,733 hsa-miRs, it was possible to differentiate the four groups. BRCA1, BRCA2 and SBC were associated with clusters of hyper-expressed miRs, and BRCAX with hypo-expressed miRs. Hsa-miR-4417 and hsa-miR-423-3p expressions (included among the eight validated miRs) differentiated 70.1 % of hereditary and non-hereditary BCs. We found miR profiles associated with tumor features like node involvement, histological grade, ER, PR and HER2 expression. Regarding molecular parameters, we only found a weak association of miRs in BC harboring losses in AURKA. We conclude that array miR expression profiles can differentiate the four study groups using FFPE BC. However, miRs expression estimated by qRT-PCR differentiates only hereditary and non-inherited BCs. The miR expression array is a simple and rapid approach that could be useful to facilitate the identification of those SBC carrying genetic or epigenetic changes in BRCA genes responsible of BRCA-like phenotype. These patients could benefit from the treatment with PARP inhibitors.     

Prospective blinded surveillance screening of Swedish women with increased hereditary risk of breast cancer

Purpose

To evaluate the sensitivity and specificity of different screening modalities in women with a family history of breast cancer.

Methods

Our blinded, prospective, comparative cohort analysis included three types of screening, mammography, ultrasound, and clinical breast examination once per year for 6 years. Eligible patients for this study were healthy women with ≥ 17% lifetime risk of breast cancer or with a mutation in BRCA1 or BRCA2.

Results

A total of 632 women were screened between 2002 and 2012 (each for 6 years). During the study, 30 women were diagnosed with breast cancer, with 10 of these diagnoses occurring between screening visits, and six of the 10 diagnosed women were gene carriers. The clinical presentation for the women diagnosed with breast cancer was followed until 2017. No consistent patterns for the diagnostic capacity of the different screening modalities were found, although mammography showed low sensitivity, whereas ultrasound showed better sensitivity in three of the six rounds. The specificity was high in mammography and improved in ultrasound over time. Most importantly, clinical breast examination provided no additional information toward the diagnosis of breast cancer.

Conclusion

Neither mammography nor ultrasound performed yearly were sensitive enough as standalone modalities, although high specificity was confirmed. Our findings indicate that high risk (> 29% life time risk) individuals and gene carriers can be screened biannually, using the same protocol as used in mutation carriers. Our results also suggest that low-risk groups (< 20%) may continue to be referred to population mammography screening program, while clinical breast examination may be omitted in all risk groups, and could be optional in gene carriers.

     

Germline mutations in 40 cancer susceptibility genes among Chinese patients with high hereditary risk breast cancer

Multigene panel testing of breast cancer predisposition genes have been extensively conducted in Europe and America, which is relatively rare in Asia however. In this study, we assessed the frequency of germline mutations in 40 cancer predisposition genes, including BRCA1 and BRCA2, among a large cohort of Chinese patients with high hereditary risk of BC. From 2015 to 2016, consecutive BC patients from 26 centers of China with high hereditary risk were recruited (n = 937). Clinical information was collected and next-generation sequencing (NGS) was performed using blood samples of participants to identify germline mutations. In total, we acquired 223 patients with putative germline mutations, including 159 in BRCA1/2, 61 in 15 other BC susceptibility genes and 3 in both BRCA1/2 and non-BRCA1/2 gene. Major mutant non-BRCA1/2 genes were TP53 (n = 18), PALB2 (n = 11), CHEK2 (n = 6), ATM (n = 6) and BARD1 (n = 5). No factors predicted pathologic mutations in non-BRCA1/2 genes when treated as a whole. TP53 mutations were associated with HER-2 positive BC and younger age at diagnosis; and CHEK2 and PALB2 mutations were enriched in patients with luminal BC. Among high hereditary risk Chinese BC patients, 23.8% contained germline mutations, including 6.8% in non-BRCA1/2 genes. TP53 and PALB2 had a relatively high mutation rate (1.9 and 1.2%). Although no factors predicted for detrimental mutations in non-BRCA1/2 genes, some clinical features were associated with mutations of several particular genes.     

Management of hereditary breast and ovarian cancer

Hereditary breast and ovarian cancer (HBOC) syndrome represents 5?10% of all breast cancers. In Japan, the HBOC syndrome is frequently diagnosed in patients with breast cancer. Therefore, a treatment strategy combining a plan for existing breast cancer and for reduction of future breast and ovarian cancer risk is necessary. Breast cancer risk-reducing management involves three options—surveillance, chemoprevention, and risk-reducing mastectomy (RRM). RRM can prevent >90% of new breast cancers. Ovarian cancer risk management options are more limited, and risk-reduction salpingo-oophorectomy is the only option since there is no proven effective early detection method available. The local recurrence rate following breast-conserving surgery in BRCA1/2 mutation-associated breast cancer is not significantly higher than that in sporadic breast cancer. Furthermore, there is no difference in prognosis between surgical methods. Clinicians should inform patients that there are no data on long-term monitoring and fully discuss risks of re-developing breast cancer with patients when choosing the surgical method. In HBOC, BRCA1/2 mutations lead to failure of double-strand DNA break repair, with poly ADP-ribose polymerase (PARP) playing an important role in single-strand DNA nick repair. Use of PARP inhibitors in HBOC prevents DNA repair (synthetic lethality) leading to cell death. This review summarizes management of the HBOC syndrome based on recent evidence.