Current Women's Health Reviews - Volume 8, Issue 1, 2012

As Dr Russo and Dr Federico mentioned in their Editorial of this issue, breast cancer is the most common malignant tumor among women with approximately one million new cases per year worldwide. Disparities on the incidence of breast cancer among the rich and poor countries are still not fully understood. As Dr Awadelkarim and colleagues mentioned in their article, breast cancer incidence is lower in middle and low income countries, however, the majority of patients in Sub-Saharan countries present with locally advanced and metastatic disease. This lower incidence means that screening programs aimed at early detection in asymptomatic women would have a lower yield—i.e., substantially more women would need to be examined to find a true case of breast cancer [1]. Because the average age of breast cancer is generally lower in low-and-middle income countries (LMCs), it has been suggested that breast-cancer screening programs begin at an earlier age in these settings. However, the younger average age of breast cancer is mainly driven by the age distribution of the population, and the fact that there are fewer older women with breast cancer, rather than by higher age-specific incidence rates in younger women [1]. The hard work put in by the guest editors of this issue should be commended. They are looking for innovative and early markers of breast cancer which is of great importance particularly with the current controversies surrounding the use of mammography. The Canadian task force recently reported that women under 50 years of age at average risk should not have a mammogram; instead, mammography should be reserved only for women aged between 50 and 74 [2]. According to the Canadian experts, women should not receive clinical breast examinations or perform self-examinations at any age. The recommendations mirror those from the US Preventive Services Taskforce: in women who aren't at high risk, don't start routine mammography until age 50, screen only every two to three years, and stop routine clinical breast examination. The fact that both these national task forces have reached the same conclusion should give some confidence in the result, but there is no doubting the controversy. Nor are we dealing with a stationary target: new evidence is emerging all the time [3]. This is a new example of the need to gather new evidence through well-designed and well-performed research, along with the systematic review of the literature and the compilation of this evidence as a crucial methodology in guiding providers and consumers on the best practices, avoiding useless practices and to informing users on the expectations of using procedures and interventions.

Breast and Ovarian Cancer: The Power of Genome-Wide Association Studies Breast cancer (BC) is the most common malignant tumor among women with approximately one million new cases per year worldwide. One of the main risk factors for breast cancer is family history, suggesting that genetic factors are important determinants of disease risk. Familial germline mutations are considered responsible for 5% of all breast cancer cases. The two most important BC susceptibility genes, BRCA1 e BRCA2, were identified by linkage analysis and positional cloning in the 1990s. BRCA1 and BRCA2 mutations are uncommon, but confer high risk of breast and ovarian cancer and smaller risk for other tumors [1, 2]. It is estimated that BRCA1 and BRCA2 are involved in less than 25% of the familial risk of breast cancer, whereas mutations in other high-susceptibility genes (such as TP53, PTEN, STK11) or in moderate-susceptibility genes (such as ATM, PALB2, CHEK2, BRIP1) account only for about 5% of familial breast cancer. Several studies, performed on familial cases not associated with BRCA1 and BRCA2 germline mutations, have revealed the heterogeneous nature of the non-BRCA1/2 tumors [3]. Thus, most of the familial risk of BC can plausibly implicate a multiple combination of several low-penetrance susceptibility alleles, each conferring a small effect on BC risk. This model defined polygenic allows to evaluate not only the risk associated with different allelic variants but also their combined effects and the interactions with lifestyle and other factors. Several studies suggested that no one gene is responsible for a significant portion of BC susceptibility, strengthening the hypothesis of the polygenic model. Thus, despite the efforts made during the last years, the majority of familial cases is unexplained and other BC susceptibility genes still remain to be identified. The identification of new genes could have a significant impact in risk prediction [4]. Two main strategies have been used to identify several susceptibility genes: genetic linkage analyses in multiple cases of the familial non-BRCA1/2 tumors and Genome-Wide Association Studies (GWAS). While linkage studies, performed even in many families, have limited power to detect such genes, instead case-control association studies have provided the opportunity to better identify most common variants (allele frequencies ≥ 5 %) associated with cancer [5]. Genome Wide Association Studies represent a new powerful approach to identify low-penetrance alleles whose combined effects may be used for cancer risk prediction. The power of GWAS is to examine all or most of the genes in the genome of different individuals in order to evaluate the association of genetic variants at different loci on different chromosomes (LD) in large series of cases versus controls, analyzing a panel of hundred thousand SNPs (single nucleotide polymorphisms) simultaneously, to identify new alleles of susceptibility to cancer [6, 7]. In the past years, novel risk alleles for BC were identified by four recent GWA studies: Breast Cancer Association Consortium, Cancer Genetic Markers of Susceptibility, DeCode Islanda, Memorial Sloan-Kettering Cancer Center. Comparing the results obtained from four major studies of GWA, it has been highlighted a correlation of allele frequency of some SNPs located on the genes: FGFR2, TNRC9, MAP3K1, LSP1 and H19. The combined analysis of these GWA studies allowed to identify the main allelic variants showing a stronger statistical evidence of association with increased familial risk: rs2981582 lies in intron 2 of FGFR2, rs12443621 and rs8051542 within TNRC9, rs889312 lies in a region that contain MAP3K1 gene, rs3817198 lies in intron 10 of lymphocyte-specific protein 1 (LSP1) and rs2107425 within the H19 gene. New susceptibility allelic variants associated with BC risk were recently discovered through large replication studies in combination with the original GWAS data [8]. Family history represents the strongest risk factor for ovarian cancer (OC) with disease predisposing mutations identified in 15% of the tumors. Also, BRCA1 and BRCA2 germline mutations confer a high risk of OC for non-BRCA1/2 tumors. In population-based studies, BRCA1 and BRCA2 mutations are present in 5-15% of all OC cases [9]. In recent years, the research and identification of low-penetrance susceptibility loci played a key role in the etiology of OC. To date, a few low-penetrance genes that confer increased susceptibility to ovarian cancer have been isolated. In this perspective, numerous genetic association studies were performed to identify common ovarian cancer susceptibility variants. Allelic variants with the strongest evidence for an association with OC include SNPs on chromosomes 8q24, 9p22.2, 19p13, and 2q31, and the rs2854344 in the RB1 gene. The main involved pathways are DNA repair, cell cycle, sex steroid hormone and oncogenic pathway [10].....

Full sequence analysis of the BRCA1 and BRCA2 (BRCA1/2) tumour suppressor genes was introduced more than ten years ago. Unfortunately, a large number of non hot spot regions have been identified and the DNA sequence changes, resulting in an increased risk of developing breast and ovarian cancer, can occur throughout the entire length of the coding regions of these genes, leading to the necessity to perform highly complex sequence analyses. Genetic alteration research is generally performed using genomic DNA extracted from blood or saliva, with automated DNA sequencing representing the gold standard. However, some alternative approaches to direct sequencing do exist, and among these, the most common in widespread use are Denaturing High Performance Liquid Chromatography (DHPLC) and High Resolution Melting (HRM). Genetic testing for germline BRCA1/2 mutations can establish the presence or absence of cancer predisposing alterations related to the disease. The analyses can be interpreted in three possible ways: a mutation that clearly disrupts BRCA1/2 gene function; no variation in the DNA sequence; or a sequence variant of uncertain/unclassified significance (VUS) with unknown function and cancer risk. Indeed, the main problem facing current BRCA genetic analysis techniques is the correct interpretation of these variants. To overcome this difficulty, webbased databases have proven to be useful to link the results obtained from different laboratories, helping researchers and clinicians to correctly interpret the data. However, at this point in time, many questions are still open about analysis methods and, mainly, test results interpretation. In this article we will try to identify and correctly address these important issues.

Since the discovery of the familial breast cancer susceptibility genes BRCA1 and BRCA2, genetic counseling and molecular analysis in the identification of mutations responsible for the increased risk of breast and ovarian cancer have become crucial steps in the clinical practice. In fact, the identification of pathogenic BRCA1/2 mutations provides useful information about the risk of a second cancer in the proband, the possible presence of the same mutation in healthy relatives of the patient and the different preventative and therapeutic approaches. However, due to the high costs and some technical limitations, the cost effectiveness ratio of BRCA1/2 gene testing should be carefully evaluated in the different cases, considering the psychological implications related to this kind of analysis. In this review, the different criteria for the selection of patients, the role of genetic counseling and the different approaches for the molecular analysis will be discussed, in order to provide a picture of the different strategies aimed to increase the sensitivity and specificity of BRCA1/2 genetic testing.

A large number of cancer predisposing BRCA1/BRCA2 mutations have been reported, with a wide variety among populations. In some restricted groups, specific germline mutations in these tumor suppressor genes have been found with high predominance, due to a founder effect. We focused our review on the Italian founder mutations. The first Italian BRCA1 founder mutation, 5083del19, was found in Calabria: the presence of common allele in all carriers of this mutation (also in families with Calabrian origin living in other parts of Italy) confirmed its founder effect. The same BRCA1 mutation was identified in the Sicilian population, but only the haplotype analysis can reveal the common ancestor of these groups. Another BRCA1 founder mutation, 4843delC, was found in Sicily. Four distinct BRCA1 mutations are attributable to families original from Tuscany: 3348delAG, 3285delA, 1499insA and 5183delTGT; the latter has been shown to be a founder mutation from North-Eastern Italy. The first BRCA2 mutation was identified in Sardinia, 8765delAG, a mutation already described as a founder mutation in Jewish-Yemenite families and also in French-Canadian population but with independent origins of carriers in these three populations. BRCA2 3951del3 and BRCA1 917delTT have been described as founder mutations in Middle Sardinia and in South and Middle Sardinia, respectively. Studies regarding prevalence and penetrance of founder mutations can allow to quantify the degree of homogeneity within a population and can surely help the geneticist and oncologist to simplify their choices in the genetic testing on high-risk families, on the basis of their ethnical origin.

A heterogeneous phenotype for age of onset, for cancer development and for cancer spectrum, i.e. different penetrance, has been reported among individuals from families with an identified germline mutation in BRCA1 and BRCA2 genes. Genetic as well as non genetic factors could explain this variation in phenotype. Among genetic causes the type and position of the mutation, allelic variations as well as mutation in other genes could modify breast cancer risk and favour a different phenotype expression. In BRCA1/2 mutation carriers, several studies have been performed in order to evaluate the specific impact on cancer risk of different factors, such as diet, reproduction, anthropometric measures, hormones and environmental exposure. All together these factors can play the role of modifiers of risk in BRCA1/2 mutation carriers. In this chapter, all those factors have been reviewed as potential modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers Moreover, aspects of information and education on modifiers of risk during oncogenetic counseling have been covered.

Genetic screening of BRCA1 and BRCA2 genes is a recurrent practice in laboratories for counseling. In the last ∼20 years, investigators have identified mutations with a founder effect, but also a series of private variants. Multi-component models have been developed to understand if a variant is deleterious or neutral. However, these models are not sufficient to understand the roles of UVs. In this review, we report results from genetic analyses, studies in animal models and bioinformatic analyses. To combine evidences from different approaches, consortia have been created (such as ENIGMA). There is a need to develop a reliable multi-factorial model. Furthermore, indirect assays and bioinformatic tools have to be improved in order to support such a model.

The need to answer the question “how much of the familial risk is currently explained by the known genes?” has increased ,and although BRCA1 and BRCA2 are considered the two major breast cancer (BC) susceptibility genes, they do not justify the entire percentage of all hereditary BC cases. The current consensus is that other BC predisposing genes could explain at least a portion of the remaining non-mutated familial cases, including not only other highpenetrance BC genes, but also moderate and low-penetrance genes. Considering these three different categories of genes, a gap of risk estimation in breast cancer can be observed. Moreover, different researchers tried to give significance to the mutations identified in terms of family management but the way in which these common variants contribute to cancer is still largely unknown. It has been recently proposed that the ‘rare variant hypothesis’, a model in which the summation of the effects of a series of low frequency gene variants, could justify a great portion of the inherited susceptibility to relatively common human diseases, such as breast cancer, independently by their way of acting. However, this hypothesis is still debated due the fact that there is little or no evidence about the fitness effects of common, disease-associated variants.

Little is known about breast cancer in Sub-Saharan Africa, where the incidence of this neoplasm is estimated to be lower than in developed countries. Yet, as a result of several factors, among which demographic structures, lifestyle, reproductive, environmental and socio-economic factors, including traditional beliefs, and access to diagnostic facilities and medical care, the majority of the patients present with locally advanced and metastatic disease and early onset breast cancer is frequent in institutional cancer series. This review reports the current knowledge on hereditary breast cancer and early onset breast cancer in Sub-Saharan Africa as emerging from the available studies, with special emphasis on those conducted in Sudan.

Male breast cancer (MBC) is a rare disease compared with female breast cancer (FBC), but its incidence is increasing. Because of its rarity, MBC is often compared with FBC and our current understanding regarding MBC biology, natural history and treatment strategies has been largely extrapolated from the female counterpart. Based on age-frequency distribution, age-specific incidence rate patterns and prognostic factors profiles, MBC is considered similar to late-onset post-menopausal estrogen/progesterone receptors (ER/PR)-positive FBC. This suggests that common BC risk factors may affect both genders. Indeed, similar to BC in women, MBC is likely to be caused by the concurrent effects of different risk factors, including hormonal, environmental and genetic risk factors. However, clinical and pathological characteristics of MBC do not exactly overlap FBC. Compared with women, BC occurs in men later in life, is mostly represented by invasive ductal carcinoma with higher stage, lower grade and ER/PR expression. Although rare, MBC remains a substantial cause for morbidity and mortality in men, probably because of its occurrence in advanced age and delayed diagnosis. MBC treatment generally follows the same indications as post-menopausal FBC. BC mortality and survival rates have improved significantly over time for both male and female BC, but the improvement for male is smaller if compared to female patients, thus suggesting a delay or non-appropriate utilization of adjuvant therapy. Overall, much still needs to be learned about MBC and, because of its rarity, the main effort is to develop national and international consortia for moving forward in our understanding of MBC.

Germline mutations in the tumor suppressor genes BRCA1 and BRCA2 predispose to familial breast and/or ovarian cancer. The lifetime risk of members of families with genetic predisposition depends on the mutations of susceptibility genes. BRCA1 mutations seem to confer the highest risk of developing neoplastic diseases. Apart from breast and ovarian cancer mutations in BRCA, related pathways are supposed to confer a smaller risk for additional cancers (colon, melanoma, pancreas, lymphoma, prostate, liver). All these tumors have an inherited component not necessarily associated with genetic susceptibility to BRCA genes. To date he main focus of this review has been argued still with difficulty. Just a deeper and complete evaluation of the topic will allow to establish how much is the contribution of BRCA mutations in different types of cancers other than breast and ovary.

The aim of this review is to identify the evidence for the surveillance of women at high risk of breast cancer with the different modalities. The definition of high risk refers to the subpopulation of women with a family history of breast cancer, including both those with and without identified genetic mutations. The following topic has been evaluated: clinical breast examination (CBE), mammography, ultrasound and MRI accuracy of detecting breast cancer among women at high risk. The search was limited to full reports published in English and published between 1996 and March, 2010. We found consistent evidence that adding MRI provides a highly sensitive screening strategy (sensitivity range: 93-100%) compared to mammography alone (32-86%) or mammography plus ultrasound +/- CBE (26-93%). Three studies that compared MRI plus mammography versus mammography alone showed the sensitivity of MRI plus mammography as 93% (95% CI 86-100%) and the incremental sensitivity of MRI as 60%. Incremental sensitivity of MRI was lower when added to mammography plus ultrasound (43%) or to the combination of mammography, ultrasound plus CBE. Estimates of screening specificity with MRI were less consistent but suggested a 3-5-fold higher risk of patient recall for investigation of false positive results. No studies assessed whether adding MRI reduces patient mortality, interval or advanced breast cancer rates, even if we found strong evidence that MRI leads to the detection of earlier stage disease. This review suggests that a surveillance strategy would be accurate and effective in improving health outcomes for women at high risk of breast cancer, but randomized studies should be considered for a better evaluation of these topics.

The prospects for making a vast impact on the morbidity and mortality from breast cancer lie more likely in the area of chemoprevention. Tamoxifen was the first agent considered in a preventive setting. Different studies analyzed the role of tamoxifen in prevention and, although the first results were apparently contradictory, they showed notable reductions in breast cancer. In the same period, in the MORE trial, raloxifene unexpectedly produced a larger reduction of breast cancer than was seen for tamoxifen. This result led to other chemoprevention studies to establish the role of raloxifene. Particularly, the STAR trial showed that raloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer and has a lower risk of adverse event. At the same time, the third-generation aromatase inhibitors (AIs) have shown good efficacy in advanced breast cancer and a low toxicity profile. They offer another approach to prevention, which may be superior or complimentary to the use of Selective Estrogen Receptor Modifiers (SERMs). Currently no AIs have yet been fully evaluated. New studies comparing the different agents together are needed and further follow up of the existing chemoprevention trials are necessary to determine which women will truly benefit from this kind of prophylaxis.

Women with BRCA1/2 mutations are at increased risk of developing breast and ovarian cancer. Options to manage this risk are intensive surveillance, chemoprevention, and risk-reducing surgery which includes, risk reduction mastectomy (bilateral or contralateral) and risk reduction salpingo-oophorectomy. Here we reported an overview of the current literature regarding efficacy of risk-reduction surgery, its acceptability and psychological implications. We found that majority of studies reported that: risk-reduction surgery has been proven to be effective in reducing breast and ovarian cancer risk up to 90%, women who choose surgery have diminished anxiety about cancer risk, and experience few psychological difficulties, but physical complication and alteration in body image, sexual life are often reported. In conclusion, we could state that decisions about surgery are influenced by several factors, mostly psychological, women need to be counselled about the decision to undergo risk-reduction surgery and multidisciplinary approaches are needed. Potential negative effects should be discussed thoroughly with each woman considering this procedure. Careful psychological follow-up after the surgery should be scheduled.

The identification of BRCA1 and BRCA2 genes has led to the understanding of the molecular basis of the Hereditary Breast and Ovarian Cancer Syndromes and to the development of preventive strategies by the identification of individuals carriers of pathogenic germ-line mutations. In the last few years the study of the complex molecular scenario of breast and ovarian tumors arising in the BRCA1 and 2 setting has opened new exciting treatment perspectives on the basis of the important defects in DNA repair which are linked to BRCA1/2 related carcinogenesis. Early clinical trials have clearly demonstrated the translational value of preclinical research on Cisplatin or Poly-ADP-ribose inhibitors. A new treatment paradigma is now emerging which links cancer treatment to the carcinogenetic process and whose value will probably spread beyond the specific setting of inherited breast and ovarian cancer.