Almost 7 % of breast cancers are diagnosed among women age 40 years and younger in Western populations. Clinical outcomes among young women are worse. Early age-of-onset increases the risk of contralateral breast cancer, local and distant recurrence, and subsequent mortality. Breast cancers in young women (BCYW) are more likely to present with triple-negative (TNBC), TP53-positive, and HER-2 over-expressing tumors than among older women. However, despite these known differences in breast cancer outcomes and tumor subtypes, there is limited understanding of the basic biology, epidemiology, and optimal therapeutic strategies for BCYW. Several modifiable lifestyle factors associated with reduced risk of developing breast cancer have also been implicated in improved prognosis among breast cancer survivors of all ages. Given the treatment-related toxicities and the extended window for late effects, long-term lifestyle modifications potentially offer significant benefits to BCYW. In this review, we propose a model identifying three main areas of lifestyle factors  that may influence survival in BCYW. In addition, we provide a summary of mechanisms of action and a synthesis of previous research on each of these topics. BRCA1/BRCA2) [ Breast cancer is the most common cancer among women in Western populations with a lifetime cumulative incidence probability of one in nine . Approxi1/BRCA2) , 5 and aThere are four clinically relevant breast cancer phenotypes currently recognized : luminalHere we present a review of the epidemiologic literature on the associations between lifestyle factors, recurrence, and survival for BCYW, defined as a breast cancer diagnosed by age 40 years. The aim of this review is to provide an overview of the associations observed to date among BCYW and how they compare to those that have been observed in the general population of breast cancer survivors. In doing so, we have also aimed to identify gaps in the literature where additional research is needed in this population. BCYW is considered to be distinct from pre-menopausal breast cancer (average age at menopause among North American women is 51 years) , 15. HowDespite the acknowledged differences in clinical outcomes, tumor subtypes and treatment approaches in young women compared with older women, specific insights into the basic biology, epidemiology, and optimal therapeutic strategies for BCYW are relatively sparse. Several modifiable factors that have been associated with reduced risk of developing breast cancer may also be implicated in improved prognosis. Given the treatment-related toxicities, and the extended window for late effects, including cardiotoxic effects of systemic and radiation therapy –19, bonered labels) and the potentially beneficial impacts (green labels) of diet, physical activity, sleep, and non-steroidal anti-inflammatory drugs (NSAIDs) are included. The conceptual model provides a framework for this review as well as a roadmap for future research to integrate diet, nutrient levels, shared signaling between obesity and inflammation, and potential lifestyle interventions. Each of the three main areas is reviewed in the sections below.All of the factors included in our review affect the hypothesized pro-inflammatory state, and our conceptual model seeks to integrate the impact of lifestyle factors that have been implicated in modifying clinical outcomes following a diagnosis of breast cancer Fig. . The conThe cumulative incidence of breast cancer rises exponentially until age 40 years and then rises more linearly with age . IncidenYoung age at diagnosis is associated with reduced survival, even after controlling for differences in the distribution of prognostic features between older and younger women with breast cancer , 32–35. The absolute benefits of treatment, whether local or systemic, tend to be larger in younger women because of the higher proportion of aggressive disease , 42, butBRCA mutations in BCYW results in these women being offered novel combinations of systemic therapeutic agents more frequently than older women, particularly within clinical trials.Younger women also tend to receive more intensive radiation and systemic therapy despite an international expert panel advocating that young age alone should not be sufficient justification for aggressive therapy . Whole bPositive energy balance, as a consequence of excess caloric intake and/or insufficient energy expenditure, results in increased adipose tissue leading to overweight and/or obesity. Both obesity  and physp for trend = 0.087) and an inverse trend in ER-/PR-positive patients (p for trend = 0.081) among a general population of breast cancer patients [One of the biologic mechanisms through which obesity could affect cancer survival is by altering the insulin resistance (IR) pathway . Homeostpatients . In a mupatients .Excess adiposity may also impact cancer survival by altering levels of circulating adipokines, particularly elevating leptin, and decreasing adiponectin , 68. Lepn = 717) with 251 breast cancer deaths after a median follow-up of 10.4 years [n = 1,468 events, HR = 0.73, 95 % CI 0.66–0.82) and a 25 % reduction in breast cancer-specific mortality  compared with women performing <10 MET-hours/week [Physical activity has been consistently associated with improved survival and other breast cancer-specific outcomes in breast cancer patients , 78. Whi.4 years . The ris.4 years . This es.4 years ; those eurs/week . The magIn the only randomized controlled trial to date, Courneya et al.  reportedSeveral biologic mechanisms have been proposed for the beneficial effects of physical activity in cancer progression including changes in BMI and adiposity which are likely to impact the biologic pathways discussed above as well as altered levels of estrogens, androgens, sex hormone-binding globulin, and reduced levels of inflammatory markers .Inflammation represents a complex network of biologic responses and pathways mediated by cytokines, lymphocytes, acute-phase proteins, prostaglandins, and many other cellular components. Inflammation plays a pivotal role in the development and progression of breast cancer  and is cInflammatory cytokines including interleukins , tumor necrosis factor alpha (TNF-α), and interferon gamma (IFN-γ) are key inflammatory mediators of interest in breast cancer progression. Changes in inflammatory cytokine levels are observed in obese individuals and may represent critical mediators between energy imbalance and breast cancer survival . Elevatep < 0.001) [The immune system may play an important role in tumor control through both the elimination of immunogenic tumor cells (immunosurveillance) and to promote the outgrowth of less immunogenic tumor cell variants (immune editing) . In brea< 0.001) . The pre< 0.001) , 102. Co< 0.001) . No stud< 0.001) , 104. Th< 0.001)  has been< 0.001) . Immunot< 0.001) , 108, buAcute-phase proteins are produced by the liver in response to inflammatory cytokines. Elevated levels of serum amyloid A (SAA) and C-reactive protein (CRP) are associated with significantly increased risk of death among breast cancer patients  , 110. HoProstaglandins are lipid autacoids derived from arachidonic acid, an omega-6 fatty acid. They both sustain homeostatic functions and mediate pathogenic mechanisms, including the inflammatory response . ProstagSleep disturbance and insomnia are common and often persistent behavioral comorbidities following a diagnosis of cancer . Most slThere is considerable evidence regarding the role of dietary intake in breast cancer etiology, but relatively little research has focused on the role of these exposures in prognosis, particularly among BCYW. The World Cancer Research Fund states that “…in the absence of stronger evidence, we believe the best advice for cancer survivors is to follow our Recommendations for Cancer Prevention” . There iDietary fat intake has been extensively researched in relation to breast cancer risk, but the evidence remains inconclusive . DietaryThe literature on dietary fat and breast cancer survival has recently been thoroughly reviewed elsewhere . SeveralVitamin D is mostly synthesized in the skin by ultraviolet B radiation (only in the summer at higher latitudes), while dietary intake and supplements also contribute to overall vitamin D status, particularly in the winter in northern populations. The evidence to support an inverse association between breast cancer risk and vitamin D status is complex and uncertain , but theThe two main classes of phytoestrogens  are isoflavones and lignans. Isoflavones are found primarily in soy foods, while lignans are found in low concentrations in fiber-rich foods such as grains, legumes, seeds, fruits/vegetables, and in high concentration in flaxseeds . Many suFolate is a naturally occurring, water-soluble vitamin B . MandatoTo date, eight studies have evaluated the relationship between dietary or plasma folate levels and survival after breast cancer and findings have been inconsistent , 180–186The role of alcohol consumption in breast cancer development and progression generates great public interest and scientific debate. The exact mechanism of action remains to be elucidated, but alcohol is proposed to cause tissue damage and cancer progression is through the formation of acetaldehyde . AcetaldThe association between alcohol consumption and prognosis has not been directly evaluated in BCYW. However, a recent meta-analysis of prospective cohort data showed that for pre-menopausal women, high levels of alcohol consumption were associated with increased risk of breast cancer recurrence  . AnotherGiven the high rates of recurrence and poorer survival in BCYW, there is an urgent need to optimize lifestyle advice to improve outcomes for these women. Modifiable lifestyle factors offer an opportunity to complement conventional therapies provided to these women. The majority of the factors included in this review show common etiologic links in the progression of breast cancer through altered pathways ultimately leading to a pro-inflammatory state. We acknowledge that the list of factors is not exhaustive; however, the aim of this review is to provide an integrated view of the inter-relationship between the most promising candidate modifiable factors. In doing so, we provide a conceptual model for the inter-play between factors and their possible contributions to cancer progression and survival. This literature review has highlighted the paucity of data on the effect of these modifiable factors on breast cancer prognosis among young women. We propose that the potential for an impact on reducing recurrence and improving survival may be considerable. Additional research on this area will provide directions for lifestyle and clinical interventions that support beneficial behavioral change to improve outcomes in young women diagnosed with breast cancer. Future investigations should aim to maximize the integration of factors so that the relative impacts of multiple lifestyle factors can be assessed both independently and in combination. Furthermore, molecular and genetic markers may help to determine potentially relevant subgroups likely to experience maximal or minimal beneficial impact. Integrated study designs with appropriate biospecimen collections will support the assessment of the relative contributions of these exposures to the pathways proposed in our biologic model focused on survival in BCYW.


Chemoprevention or the now more preferred ‘cancer prevention’ is the long-term administration of a biological or chemical agent to reduce the risk of cancer. This approach has long been active in individuals at high risk of developing breast or colon cancer. The aim of this expert meeting was to review the current status of the field of cancer prevention and potential, emerging biomarkers specifically focusing on breast, colon, and lung cancer but also with sessions on ovary and prostate. Jack Cuzick started the meeting discussing the challenges in developing and validating biomarkers for cancer prevention. Breast cancer is escalating exponentially, and by 2020, there will be around 2 million new cases per year. There is an urgent need to identify high-risk populations and to identify minimally toxic preventative therapy. He discussed the known risk factors associated with breast cancer: family history, reproductive/hormonal factors and benign pathology. He touched on the genes that can predict risk, including the well-established BRCA1/2 as well as other more recent discoveries . He mentPowel Brown followed on with a presentation on biomarkers for Chemoprevention Trials: Filling the Gap Between the Bench and the Clinic. In order to test effective cancer preventive interventions we need to test promising prevention agents in preclinical models and in human prevention trials, measure drug-response biomarkers and also to identify surrogate endpoint biomarkers in animals that can then be used in Phase I and II cancer prevention trials in humans. A number of risk biomarkers have been identified which can also be used to monitor response to preventive drug treatment. These currently include mammographic breast density, blood hormone, and insulin growth factor levels and breast tissue precancerous changes called hyperplasia  and atypical hyperplasia .in vitro studies of bexarotene indicate that they are able to inhibit pre-malignant and breast cancer cell growth. The activity of bexarotene in breast cancer prevention was assessed in a biomarker-modulation trial, however, there was no significant difference in change of Ki67 index between bexarotene and placebo arms. Now other rexinoids are being tested to develop more effective and safer preventive drugs.Retinoids are promising preventive agents and Karen Brown went on to discuss the possibility of PARP inhibition as prevention. Breast cancer landmark studies have demonstrated the activity of PARP inhibitors in BRCA mutation carriers and in triple negative breast cancer. In fact, a PARP inhibitor biomarker-modulation trial is being planned. She concluded that future efforts should focus on developing accurate risk markers, drug-response markers, and surrogate endpoint biomarkers.Eva Szabo‘s talk was titled ‘Phase I–II chemoprevention trials: lessons from the NCI consortia experience’. The goal of early phase trials is to identify the ‘signal’ and thereafter to try understand the mechanism of action and to select high-risk participants.The NCI consortia have focused on intraepithelial neoplasia (IEN) as it is recognized as an identifier of high-risk population. She discussed the various Phase I and II trials and the information they provide. In imaging studies, which can be useful for monitoring response, e.g. CT-detected lung nodules, she pointed out that the problem is that if there is no biopsy there is no biological information.PI3K is a potential Molecular biomarker for lung dysplasia as the PI3K pathway is activated in smokers with dysplasia in airway (p < 0.001). Myo-inositol inhibited PI3K activation in normal bronchial airways in smokers, resulting in regression of dysplasia.Andrea De Censi discussed ‘Why the results of phase III trials have not been translated into clinical practice?’ To address this issue, several points were to be considered. First a prevention treatment has to be proposed only to high-risk subjects, it is not aimed at the general population.There are four main barriers to the development of chemo prevention drugs:Depending on the specific national health system the treatment may not be reimbursed, especially if it is an off label treatment (European countries except UK) or for new agents.Uncertainty of reimbursement for new agentsLimitations in current patent law and intellectual property protectionLimitations in emerging prevention science, evolving designs of clinical trials, and the process of drug approvalLimited public participation in clinical trials.Certainly there is the need for more awareness starting from the physician to reach the target population. It is quite difficult and takes time to explain the concept of the individual risk to people. And once the increased risk has been defined, how much is the ‘minimum effect’ required to consider a proposed treatment valid ?One criticism that the major prevention trials often come up against is that there is no evidence of mortality reduction. This is a debate which is difficult to resolve since in primary prevention the main aim is incidence, mortality is ‘too far away’ and would require countless subjects and years to be proven.One more topic is the lack of commercial interest and consequently it is very difficult to perform phase III clinical trials. One short-term goal could be the identification of an interim sign of efficacy, in order to encourage the responding subjects to continue treatment and to stop the one that may not benefit the individual.Probably the younger generation will be more favourable to prevention treatment.DIN/DCIS: more shade than light, discussed the fact that intra epithelia neoplasias present a problem in terms of diagnosis reproducibility especially for the DIN1a or flat epithelial atypia. In non-highly specialized centres the surgical strategies (DIN1a vs DIN1b) and the importance of the margins is still under discussion. Finally, the predictive and or prognostic factors are still unclear compared to other more invasive tumours.Giancarlo Pruneri, in his talk on It is important to recognize and distinguish types of DIN that tend to recur from those that do not. Multigene expression assays can be helpful in scoring these lesions into categories that predict recurrence risk. However, they do not appear to be significantly better compared to the standard biological assays carried out using standard immunohistochemistry.Proliferation matters: the ‘oncotype DX’ is an assay that harnesses the power of genomics to provide a more precise and accurate assessment of risk based on individual tumour biology. It encompasses a panel of 21 genes, many being proliferation genes within the tumour to determine a Recurrence Score. However, Ki67 expression may be just as informative and especially as DIN characterization has to be reproducible in all hospitals and not only in highly equipped labs, KI67, which is affordable worldwide, may be more appropriate.It is important to improve the reproducibility of Ki67 and this is a work in progress. We have shown that it was possible to train laboratories around the world using ‘web-based standard images’. After the training, the reproducibility among labs showed a significant trend for improvement.We have also shown that Ki-67 can be a good indicator of which patients with DIN2 may benefit from radiotherapy (RT). In patients with DIN2 with necrosis who underwent breast conservative surgery followed by RT versus no RT gave an HR of 0.18 (95% CI 0.07–0.46) whereas no difference was observed in the patients with a ki67 of <14%.Andrea De Censi discussed cancer adjacent intraepithelial neoplasia (IEN) as a target biomarker for screening new preventive agentsThe concept of the ‘cancerization field’ in mammary carcinogenesis postulates that around the tumour there are already present cells with genetic and epigenetic alterations that may cause a subsequent second cancer. The pre-surgical window of opportunity (WOP) trials is a powerful tool to test new and old drugs, not only on the tumour tissue, but also on adjacent tissue.The post-treatment tumour expression of Ki-67 has been shown, by the group of decency and by other groups to be correlated with disease-free survival and overall survival. Evaluated Ki-67 in adjacent IEN or atypical hyperplasia (AH) can be used as a biomarker for preventive activity. Two trials have shown that Lapatinib and Metformin decreased Ki-67 in both IEN and AH. Metformin seems particularly effective in HER2+ve and ER+ve subgroup.Patrizia Pasanisi discussed the use of ‘Hormones and Growth factors as markers of risk and prognosis in breast cancer’. Glucose levels, glycemic index, etc. have been associated with an increased breast cancer risk. This hypothesis has prompted research on dietary carbohydrates and their possible relationship to breast cancer risk. High glucose levels are associated with increased risk of breast cancer. Patrizia’s group assessed the effect of peri-diagnostic fasting blood glucose in women treated for BC in order to see if there is a link between serum glucose and prognosis. They retrospectively investigated 1,261 women diagnosed and treated for stage I-III BC at the National Cancer Institute, Milan, in 1996, 1999, and 2000. The risk of recurrence death was significantly higher in the increased glucose group compared to the reference. The increased risks remained for a follow-up of 9.5 years [Since a possible way for carbohydrates to be linked to breast cancer risk is through their effect on insulin levels, several lines of evidence suggest that insulin levels may directly or indirectly affect breast cancer risk.The association between obesity and breast cancer is in part related to oestrogen which is synthesized by adipose tissue in post-menopausal women. Oestrogen has long been a known risk factor for breast cancer. Obesity is also associated with high levels of insulin. Gunter at al demonstrated that hyperinsulinemia is an independent risk factor for breast cancer in post-menopausal women.Carbohydrates in our diets affect the body’s levels of blood glucose (blood sugar) and the hormone insulin. In post-menopausal women there is a correlation between high levels of oestrogen and androgens and breast cancer, whereas in pre-menopausal women only testosterone is associated. Three prevention trials were discussed the Cos2 (increasing activity), the DIANa-5 and the MeMeMe.role of mammographic density in risk prediction and response to treatment. Increased mammographic density is associated with a markedly increased risk of invasive breast cancer. In a study nested within the IBIS, a randomized prevention trial of tamoxifen versus placebo, Cuzick and colleagues [Jack Cuzick gave a second presentation on the lleagues  showed tbiomarkers of risk for ovarian cancer. Of all inherited ovarian cancers, BRCA2 is involved in 45% of cases. More than two out of three cases of ovarian cancer (Ov Ca) are diagnosed at an advanced stage (stage III-IV) and as survival is inversely correlated with clinical stage there is an urgent need for early diagnosis. The only real biomarker in Ov Ca screening is CA125. It is elevated in 47% of women with early-stage Ov Ca and in 80-90% of advanced stage Ov Ca. However, numerous, non-neoplastic conditions can cause an elevation in CA125 levels and so by itself is not a reliable biomarker. Furthermore, when used in combination with transvaginal ultrasound compared with usual care did not reduce ovarian cancer mortality. The only real preventative measure for individuals at high risk of developing OvCa is risk-reducing salpingo-oophorectomy (RRSO). It has been shown that in 122 BRCA1/2 women undergoing RRSO (5.7%) were found to have an early malignancy which originated in the distal fallopian tube.Dorella Franchi spoke about The human epididymis protein 4 (HE4) measurements in serum have been proposed for improving the specificity of laboratory identification of OvCa. The combination of HE4 and CA125  showed the highest sensitivity relative to any other dual combination of markers. It represents a potential tool to triage women with a pelvic mass to the appropriate treatment. Other serum biomarkers under evaluation were discussed, but these still need to be validated. To date, the best known chemoprevention agent for OvCa is the oral contraceptive, which gives a 46% risk reduction of ovarian cancer in the general population.genetic markers for CRC prevention. Risk alleles exist, but they are not sufficient to predict individual risk. Chemoprevention strategies include aspirin; 25% reduction in the incidence and 31% reduction in mortality. However, this benefit is only in patients with a PI3K. They are using a genotyping approach to subdivide the population into those who will benefit, but without the toxic side effects. Along with De Censi they are involved in the ASMET trial combining Aspirin and Metformin in the prevention of CRC. The aim is to identify tissue and circulating biomarkers.Dominique Scherer then talked about In conclusion, the heritable component of the CRC is not completely elucidated. Aspirin/NSAIDs have great potential for chemoprevention of CRC. The interaction between genetics and prevention strategies need to be considered and further investigated for personalized prevention strategies.Adriana Albini discussed the search for biomarkers of cancer angioprevention for clinical studies. Angiogenesis is an early event in multistage tumorigenesis and so needs to be prevented. She discussed some potential molecules for antiangiogenic treatment.Her group has recently discovered a tumour infiltrating NKs as a potential marker and a target for therapeutic and preventive approaches . The ideState-of-the-art and future perspectives in lung cancer chemoprevention. The first-generation lung cancer chemoprevention trials, including the ATBC lung cancer prevention study were limited due to the over simplistic interpretation of epidemiological data. These trials also suffered from the lack of intermediate biological endpoints and the exposure to known carcinogens within the trials. Second-generation chemoprevention trials need to be designed with more active and less toxic agents and the use of reliable biomarkers. The participants should be high-risk individuals. He discussed extensively the use of microRNAs as predictive and diagnostic markers of lung cancer and their use in improving the efficacy of screening. The only potentially active agent for chemoprevention in smokers is verenicline, whereas aspirin, metformin and miRNA modulators may be conceivable in former smokers. In the end, the best prevention for lung cancer incidence is to stop smoking.Ugo Pastorino discussed Fabrizio Bianchi gave us an introduction to microRNAs and the clinical validity of a microRNA-based blood test in lung cancer. miRNAs can act as either ‘downregulators’ or ‘enhancers’ of gene expression. He explained how miRNAs are deregulated in cancer and gave some examples of how miRNAs might induce tumour-promoting effects. miRNA secreted by cancer cells might affect the translational profile of surrounding normal cells or render self-promoting effects.The increase of tissue-specific miRNA in the blood and plasma of individuaks with tumours supports the use of miRNA as ‘disease biomarkers’. The main features arguing for the suitability of miRNAs as ‘liquid biomarkers’, i.e. stability and tissue-specific expression were discussed. Early detection of lung cancer is the main strategy to improve disease prognosis. Early diagnosis can be achieved with tomography-based screening in high-risk individuals, i.e. the COSMOS in IEO. However, concerns remain regarding the feasibility of large-scale population screening. The group of Bianchi has developed a blood test, based on the detection of serum miRNAs, that identifies early-stage non-small cell lung carcinomas (NSCLCs) in a population of asymptomatic high-risk individuals with ~80% accuracy. The test is based on the detection of 34 miRNAs. The test displays a number of features of clinical relevance that project its utility in programmes for the early detection of NSCLC and is being validated within the COSMOS II trial.Hector Hernandez-Vargas discussed Epigenetics as a source of prevention biomarkers. In particular, he is looking at DNA methylation as a biomarker in cancer prevention. An ideal biomarker should be able to predict an outcome with high sensitivity and specificity. In addition, it should be cost-efficient and not invasive. DNA methylation is a good as it is stable, its reported deregulation at early stages and its accessibility. However, there is still no widespread DNA methylation biomarker for cancer prevention and we still need to wait for new data coming from genome-wide analysis (GWAS).biomarker for the identification of men at high risk of aggressive prostate cancer: the past. Similarly, to other cancers in the screening age, we are observing a steep increase of incidence and a total stable percentage of mortality. Out of seven men with prostate cancer only one will die from it.Phillipe Autier spoke about PSA is currently the best biochemical marker for prostate cancer. More than the absolute concentration, its biological variation (within subject) can help to beter determine cancer risk, a single measurement can lead to more unnecessary biopsies. But PSA does not help to discriminate cancer aggressiveness.The PLCO Cancer Screening Trial concluded that there was no evidence of a mortality benefit in the screening intervention group.new avenues for biomarkers of potentially deadly prostate cancer. Which kind of tumour do we want to prevent?Massimo Maffezzini talked about The screening for prostate cancer has increased to nearly 50% of the diagnosis to low-grade cancer, does this represent success or over-diagnosis? Is the current treatment of low-grade prostate cancer, in fact, over treatment? Clearly there are prostate cancers that won’t cause disease-specific morbidity nor mortality during the patient’s life. Several clinical trials are ongoing to address this issue. The (short-term follow up of the) PRIAS study indicates that active surveillance is a reasonable strategy to reduce overtreatment.A greater research effort has to be focused on risk subjects stratification for a more personalized surveillance and intermediate biomarkers to test new preventive agents. Recognized and easily assessed risk factors are: age, race, family history, obesity, boldness, and PSA; new biomarkers under evaluation: Single nucleotide polymorphisms (rs 11672691), Cell Cycle Progression Score, miRNA (-23b/-27b).Active prevention is possible and so far the more effective agents are the 5-α reductase inhibitors. Non-steroidal anti-inflammatory drugs (NSAIDs and in particularly aspirin), SERMs, iNOS inhibitors, cell cycle blockers and apoptosis inducer are also potential agents to be studied in prostate cancer prevention.The aim of this meeting was to establish guidelines for biomarker discovery and validation relative to high-risk individuals. Five types of biomarkers were outlined:(a)Prognostic(b)Predictive(c)Risk biomarkers(d)Drug-response biomarkers(e)Diagnostic biomarkersScreening and biomarker discovery will be important in distinguishing aggressive from less aggressive disease. This is something that needs more work.in vitro systems and cells that represent precursor states to the agents under study. It will be important to measure drug-response biomarkers to assess effects of the drug in blood and tissue. Surrogate endpoint biomarkers need to be tested in animals that can then be used in Phase I and II cancer prevention trials in humans.To test effective cancer preventive interventions, these agents need to be tested in several preclinical models and in human prevention trials. The use of clinically achievable concentrations of agents is essential in preclinical models. It will be necessary to chronically expose In human prevention trials, Phase 3 trials need to demonstrate a reduction in mortality. They should also validate the surrogate biomarker. Biomarkers should be developed at the time of the clinical trial. It will also be important to show that the marker is efficacious in the  animal model. A biomarker should demonstrate an effect of the intervention on carcinogenesis-relevant pathways. Biopsies are necessary to understand the biology.Future studies will require multiple biomarkers, a single biomarker would be too naïve in a multifaceted disease. Circulating Free DNA has great potential as a surrogate tumour marker for monitoring efficacy and personalizing interventions.Finally, there was consensus that we need more money from the EU for clinical prevention trials. The proposal is to put forward a Horizon 2020 project to discover effective preventative agents and eventually an ERANET. There is a need to nest prevention into screening programs.


PLAGL1/ZAC1, H19-ICR1, IGF2-DMR2, KvDMR-ICR2, RB1, SNRPN-DMR1 and PEG3—in blood samples from 189 women with the most common type of invasive breast cancer , 41 women with in situ breast cancer  and 363 matched disease-free controls.Altered DNA methylation of imprinted genes has been implicated in a range of cancers. Imprinting is established early in development, and some are maintained throughout the life course in multiple tissues, providing a plausible mechanism linking known early life factors to cancer risk. This study investigated methylation status of seven imprinted differentially methylated regions—PEG3 methylation was associated with an elevated risk of IDC (odds ratio (OR) 1.065; 95 % confidence interval (CI) 1.002, 1.132; p = 0.042) and DCIS . The effect was stronger when in situ and invasive breast cancer were combined . DCIS breast cancer risk increased with higher KvDMR-ICR2 methylation  and lower PLAGL1/ZAC1 methylation . In a combined model, only KvDMR-ICR2 methylation remained significantly associated.There was no evidence that imprinted gene methylation levels varied with age (between 25 and 87 years old), weight or height. Higher These findings may help to improve our understanding of the aetiology of breast cancer and the importance of early life factors in particular. Imprinting methylation status also has the potential to contribute to the development of improved screening and treatment strategies for women with, or at risk of, breast cancer. BRCA1, BRCA2, TP53 and PTEN) only account for around 5–10 % of all cases , H19 [OMIM 103280], KvDMR [OMIM 604115], RB1 [OMIM 614041], SNRPN [OMIM 18227] and PEG3 [OMIM 601483]. A somatic region (DMR2) linked with IGF2 [OMIM 147470] was also selected for analysis. This DMR interacts with H19 on the methylated paternal allele . Aberrant PEG3 methylation in blood samples of women with breast cancer has recently been reported [PEG3 methylation, rather than the more subtle changes in average methylation reported here. The same study also reported differential outlier frequency of IGF2-DMR2 in blood samples [IGF2-DMR2 methylation was also increased in combined cases compared to controls in the study described here, but this effect only approached statistical significance. There are also reports of altered IGF2 methylation in breast tumours [Increased  cancers , as well cancers . Studiest tissue  and thatt tissue . PEG3 enreported  but this samples . Average tumours .PEG3 methylation in blood is associated with both DCIS and IDC separately in this study suggests that this change could contribute to the common origin and development pathway. This information could potentially contribute to the development of early biomarkers of breast cancer susceptibility.Cancer marker studies suggest a common origin and development pathway of the two main types of breast cancer, IDC and DCIS. Reports have identified that low-grade DCIS can transition to low-grade IDC and high-grade DCIS to high-grade IDC , 42. TheNot all women with DCIS will go on to develop invasive breast cancer. The risk of progression is estimated at 25–50 % for women with low-grade DCIS and 75 % for women with high-grade DCIS . A recenPLAGL1/ZAC1 methylation were linked with increasing risk of DCIS compared to both controls and IDC cases. When both genes were included in the same statistical model, only the significance for KvDMR-ICR2 methylation remained. Such findings have the potential to identify individuals with DCIS who are less likely to progress to invasive breast cancer. KvDMR-ICR2 regulates the CDKN1C/KCNQ1 domain, including the non-coding antisense KCNQ1OT1 RNA which silences genes on the paternal allele within this region. Downregulation of CDKN1C (which encodes p57(KIP2), a negative regulator of cell proliferation—OMIM 600856) has been associated with increased metastasis potential and poorer survival for breast cancer [KCNQ1OT1 methylation has been identified in tumour development and the imprinting disorder Beckwith-Wiedemann syndrome which is associated with tumour predisposition [CDKN1C or KCNQ1OT1. Further work on the links between KvDMR-ICR2 methylation and CDKN1C/KCNQ1OT1 gene expression in cancer would be instructive.An important clinical challenge is to identify which individuals can safely be left without treatment . This stt cancer , 47. Decposition . AlteredLinks between imprint signals in normal tissue (such as blood) and breast cancer risk are particularly relevant to the concept of ‘field cancerisation’ . This isThe differences in imprinting methylation described here are also relevant to observations linking breast cancer susceptibility to early development . A numbePEG3 and IGF2 methylation in the offspring [Interestingly, there is some evidence that methylation of imprinted genes may be modifiable by the early environment such as maternal nutrition before birth. One example of this is folic acid. This nutrient is metabolised through the pathway that provides methyl groups for DNA methylation, and its use in human pregnancy has been reported to influence ffspring . The metffspring , 31, 58.ffspring . From thPEG3 methylation within blood samples of both invasive and in situ breast cancer cases. Increased KvDMR-ICR2 methylation was observed in women with in situ breast cancer compared to both controls and invasive breast cancers. DNA methylation stability was confirmed for the seven selected imprinted gene regions within this cohort. The findings set out in this study suggest potential biomarkers for breast cancer risk.Altered DNA methylation has been shown to occur in tumours, with changes now being identified in non-tumour tissue such as blood samples. Imprinted gene methylation is particularly interesting to consider as these provide potential mechanistic routes to early life influences and non-genetic heritability of breast cancer. Using a case-control cohort of almost 600 women, we have observed increased The study was approved by the North of Scotland Research Ethics Committee (reference number 08/S0801/17), and all participants gave informed consent. Two thousand and one hundred seventy-two women were recruited between 2008 and 2013 from the Aberdeen Breast Clinic with 1168 breast cancer cases and 1004 disease-free controls. The breast cancer patients were newly diagnosed, with histological confirmation and without detectable metastatic disease. Blood samples were taken prior to surgical intervention. The disease-free women had attended the Aberdeen Breast Clinic with benign breast changes, none of which significantly increased their risk of breast cancer. Disease-free status was confirmed by clinical examination, mammography, breast ultrasonography and fine needle aspiration cytology where appropriate.BRCA1/2 mutations and those which have been identified at an increased risk of breast cancer were excluded from the analysis. The women were identified as having an increased risk of breast cancer if there was known family history, previous occurrence of atypical ductal hyperplasia, lobular carcinoma in situ or Hodgkin’s disease.Only European Caucasians were included in the study and women with known family history of n = 363) exceeded the number of cases (n = 230) but the groups remained well matched for the key variables of age, height, weight, body mass index (BMI) and menopausal status.Participant characteristics and pathological information including histological type, tumour size, tumour grade, lymph node status, hormone receptor status and HER2 expression status were recorded. Nottingham Prognostic Index was determined using tumour grade, tumour size and involvement of lymph nodes . In the Age, height, weight and BMI of the participants are summarised in Table PLAGL1/ZAC1, IGF2-DMR2, SNRPN-DMR1 and PEG3 assays [H19-ICR1, KvDMR-ICR2 and RB1 assays [H19-ICR1 assay; forward 5′-biotin-GGGTGATTATTGGAGTTGTTGAGGTGAG-3′, reverse 5′-TCCAATCCCAATTCAACCCACTC-3′ and sequencing primer 5′-CTAAACCACCATAAAAACTAT-3′ for the KvDMR-ICR2 assay; forward 5′-biotin-TGGGGTTAGGAGGTGAAAGTGG-3′, reverse 5′-CATATAAAACAACAACAAATCCCTTTCTAC-3′ and sequencing primer 5′-CCCTAAACCTACCTTCCC-3′ for the RB1 assay. Pyrosequencing was performed using the PyroMark MD Q96 Instrument  running PyroMark CpG software . The plates were prepared for pyrosequencing according to the manufacturers’ protocol. Only data which passed appropriate quality control thresholds were included for analysis.DNA was extracted from the blood using QIAamp DNA Mini Blood QIAcube kits , automated on a QIAcube . The DNA was quantified with SYBR® Green on a Rotergene Q  using DNA standards . The DNA samples were dispensed into 96-well plates by a QIAgility robotic system . Matched samples (breast cancer cases and disease-free controls) were positioned on the same plate to minimise any potential batch effects. The samples were treated with sodium bisulphite using Epitect® 96 Bisulfite kits . Published PCR primers designed for bisulphite-converted DNA were used for 3 assays –63. FAST1 assays . The prit test. Pairwise correlation was run to determine the relationship between CpG sites within each gene/region. CpG sites within each gene  were highly correlated with each other , and the average methylation for each of these genes/regions was used in subsequent analysis. Linear regression was used to determine the relationship between methylation and age, weight, height and body mass index in the disease-free control group.Data were analysed using STATA/SE version 13 . Subject characteristics of the entire cohort and pathological characteristics of breast cancer cases were compared using Student’s p values. Significance was set at *p < 0.05, **p < 0.01 and ***p < 0.001. Due to the severe effect of multiple comparison adjustments on false negative error rates and the exploratory nature of this research, such adjustments have been avoided to prevent this.Logistic regression was used to compare methylation levels in the cases  relative to the disease-free controls. IDC was also compared with DCIS. Logistic regression was used for other categorical outcomes (lymph node involvement and receptor status). Multinomial logistic regression was used to evaluate the link between methylation and NPI categories. All analyses were adjusted for appropriate covariates including menopausal status, age and weight (as stated in the tables and text). The results of regression analysis are presented with 95 % confidence intervals and


The purpose of this study is to determine the associations between statin use and breast cancer survival and risk by performing a systematic review and meta-analysis. We searched PubMed, Embase and Web of Science up to August 2015 for identifying relevant prospective or case-control studies, or randomized clinical trials. Five prospective studies involving 60,911 patients reported the association between statin use and breast cancer mortality. Eleven prospective studies, 12 case-control studies and 9 randomized clinical trials involving 83,919 patients reported the association between statin use and breast cancer risk. After pooling estimates from all available studies, there was a significantly negative association between pre-diagnosis statin use and breast cancer mortality : hazard ratio (HR) = 0.68, 95% confidence interval (CI) 0.54–0.84; for disease specific survival (DSS): HR = 0.72, 95% CI 0.53–0.99). There was also a significant inverse association between post-diagnosis statin use and breast cancer DSS , although the association with breast cancer OS did not reach statistical significance . Additionally, there was a non-linear relationship for the duration of post-diagnosis statin use with breast cancer specific mortality. On the other hand, with regards to the relationship between statin use and breast cancer risk, no significant association was detected. Our analyses suggest that although statin use may not influence breast cancer risk, the use of statin may be associated with decrease mortality of breast cancer patients. Further large-scale studies are warranted to validate our findings. Breast cancer remains the most common and death-causing cancer in females . In US iSimilarly, with regards to the risk of breast cancer development, laboratory studies have suggested statins to be potentially chemopreventive , 13, whiWe aim to conduct a comprehensive meta-analysis study to assess the associations between statin use and breast cancer survival and risk. Findings from such a study may help determine whether statins could be used for either chemotherapy or chemoprevention of breast cancer, at the aim of reducing health burden from this malignant disease.The detailed steps of our literature search and article screening were shown in Figure 2 = 89.7%; Table p for bias: 0.947) and Begg's test (p for bias: 1.000). The negative association was detected in studies focusing on general breast cancer patients, studies conducted in Europe and subgroup analysis according to follow up time  and Begg's test (p for bias: 0.806). The subgroup analyses based on disease subtype, study location and follow up time also largely revealed null associations, although in the strata of shorter than 4.3 years of follow up time, the association reached statistical significance  and Begg's test (p for bias: 1.000). This inverse association persisted in subgroup analysis of follow up time.Three studies reported the association between pre-diagnosis statin use and mortality of breast cancer patients , 8, 11, 2 = 82.3%; Table Similarly, we identified an inverse association between pre-diagnosis statin use and DSS of breast cancer patients, with a HR of 0.72 (95% CI 0.53–0.99). There was significant heterogeneity across studies  and Begg's test (p for bias: 0.906). The null association persisted in almost all strata of subgroup analyses according to study design and location , Web of Science, and Embase databases was conducted from each database's inception to January 2015 for studies published in English Controlled vocabulary and keywords were used to search for eligible studies. The detailed search strategy is described in the Studies were eligible if they (i) were case–control studies, prospective studies, or RCTs; (ii) evaluated the association between statin use and breast cancer risk or survival; (iii) presented relative risk (RR), odds ratio (OR), hazard ratio (HR) estimates with 95% confidence intervals (CI) or necessary data for determination. There was no restriction for sample size and follow-up duration. If there were several publications from the same study, we included the study with the most cases and relevant information, like our previous studies –78.A pair of investigators independently carried out the abstract screening, full text screening, and data extraction (Chao Tu and Lang Wu). Disagreements were resolved by discussion, with input from other investigators. Data extracted from each study included: the first author's last name, year of publication, study location, study design, characteristics of study population , and effect sizes of the associations. If multiple estimates of the association for the same outcome were reported, we used the estimate that was adjusted for the most appropriate covariates, like previous studies –81. In sThe quality assessment of included studies were performed according to the Newcastle-Ottawa Quality Assessment Scale (NOS) for observational studies , 83, and2 to evaluate the heterogeneity across studies, in which a I2 > 50% suggests high heterogeneity [Due to the relative rarity of breast cancer in the general population, ORs and HRs were deemed equivalent to RRs. We used RRs to represent measures of studies evaluating associations with breast cancer risk. For studies evaluating breast cancer survival, HRs were used since all involved studies used HRs as the estimation. We used the Iogeneity . We poologeneity  if thereogeneity . With reogeneity , 8, the For the dose-response analysis, we explored potential non-linear relationship between the duration of statin use and breast cancer mortality, using principles as previously published . For stuP-value of 0.05 was used to determine whether there was significant publication bias. All statistical analyses were performed with Stata .Publication bias was evaluated via Egger's test  and Begg


The Consequences of a BRCA Mutation in WomenA continuing education article for nurse practitioners, physician assistants, clinical nurse specialists, advanced degree nurses, oncology and hematology nurses, pharmacists, and physicians.Release date: May 15, 2015Expiration date: May 15, 2016Expected time to complete this activity as designed: 0.75 hoursMeniscus Educational Institute3131 Princeton Pike, Building 1, Suite 205ALawrenceville, NJ 08648Voice: 609-246-5000Fax: 609-449-7969E-mail: lrubin@meniscusedu.comJournal of the Advanced Practitioner in Oncology37 Main StreetCold Spring Harbor, NY 11724Voice: 631-692-0800Fax: 631-692-0805E-mail: claudine@harborsidepress.com2015, Meniscus Educational Institute. All rights reserved.© Janice Famorca-Tran, RN, MS, AOCNP®, CBCN®, NP-C, Texas OncologyGayle Roux, PhD, NP-C, FAAN, Texas Woman’s University College of NursingBRCA1 and BRCA2 genes are the only known causes of hereditary breast and ovarian cancer (HBOC) syndrome. These mutations account for 60% of hereditary breast cancer. Women with HBOC face many decision-making challenges and rely heavily on information and guidance provided by their oncology care providers. Therefore it is imperative that advanced practitioners (APs) in oncology be informed about the many facets surrounding HBOC. The purpose of this article to provide APs with a clinical overview and the most up-to-date information regarding risk assessment for these genetic mutations, genetic testing, psychological consequences associated with genetic testing, the importance of pre- and posttest counseling, and posttest risk-reduction strategies.Deleterious mutations inIntended AudienceThe activity’s target audience will consist of nurse practitioners, physician assistants, clinical nurse specialists, advanced degree nurses, oncology and hematology nurses, pharmacists, and physicians.After completing this educational activity, participants should be able to:Define hereditary breast and ovarian cancer syndrome (HBOC) and the genetic mutations associated with this conditionDescribe risk-reduction measures for individuals with HBOC and their families that may decrease the risk of developing cancers associated with HBOCList National Comprehensive Cancer Network testing criteria for HBOCDiscuss the role of the advanced practitioner in regards to genetic counseling in HBOCIdentify existing laws that govern the rights of BRCA-positive individualsDescribe some of the psychological issues facing HBOC patients and familiesStatement of Credit—Participants who successfully complete this activity  will receive a statement of credit.Physicians. The Meniscus Educational Institute is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.The Meniscus Educational Institute designates this journal article (2015-005-02-MJ) for a maximum of 0.75 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.Nurses. This activity (2015-005-02-NJ) for 0.75 contact hours is provided by the Meniscus Educational Institute.The Meniscus Educational Institute is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation.Provider approved by the California Board of Registered Nursing, Provider No. 13164, for 0.50 contact hours.Pharmacists. The knowledge-based accredited education lectures are intended for pharmacists involved in the care of cancer patients. This educational activity is sponsored by the Meniscus Educational Institute.The Meniscus Educational Institute is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. The ACPE Universal Activity Number assigned to this program, for 0.75 contact hours, is 0429-0000-15-005-H04-P.All individuals in positions to control the content of this program  are expected to disclose all financial relationships with commercial interests that may have a direct bearing on the subject matter of this continuing education activity. Meniscus Educational Institute has identified and resolved all conflicts of interest in accordance with the MEI policies and procedures. Participants have the responsibility to assess the impact (if any) of the disclosed information on the educational value of the activity.FacultyJanice Famorca-Tran, RN, MS, AOCNP®, CBCN®, NP-C, has nothing to disclose.Gayle Roux, PhD, NP-C, FAAN, has nothing to disclose.Lead Nurse PlannerWendy J. Smith, ACNP, AOCN®, has nothing to disclose.PlannersJeannine Coronna has nothing to disclose.Claudine Kiffer has nothing to disclose.Terry Logan, CHCP, has nothing to disclose.Pamela Hallquist Viale, RN, MS, CNS, ANP, has nothing to disclose.Content ReviewersGlenn Bingle, MD, PhD, FACP, has nothing to disclose.Margaret M. Fields, MSN, ACNP-BC, AOCNP®, has nothing to disclose.Allison A. Muller, PharmD, D.ABAT, has nothing to disclose.Wendy J. Smith, ACNP, AOCN®, has nothing to disclose.This activity has been designed to provide continuing education that is focused on specific objectives. In selecting educational activities, clinicians should pay special attention to the relevance of those objectives and the application to their particular needs. The intent of all Meniscus Educational Institute educational opportunities is to provide learning that will improve patient care. Clinicians are encouraged to reflect on this activity and its applicability to their own patient population.The opinions expressed in this activity are those of the faculty and reviewers and do not represent an endorsement by Meniscus Educational Institute of any specific therapeutics or approaches to diagnosis or patient management.This educational activity may contain discussion of published as well as investigational uses of agents that are not approved by the US Food and Drug Administration. For additional information about approved uses, including approved indications, contraindications, and warnings, please refer to the prescribing information for each product.To access the learning assessment and evaluation form online, visit www.meniscusce.comStatement of Credit: Participants who successfully complete this activity  will be able to download a statement of credit.BRCA1 and BRCA2 genes, known as hereditary breast and ovarian cancer (HBOC). An inherited mutation in either of these genes increases the probability of malignant transformation and cancer. This article provides a clinical overview of HBOC as well as risk-reduction measures that have the potential to decrease cancer development. The review of the literature highlights the psychological consequences, prophylactic measures, and potential postoperative complications. An examination of this public health issue increases our understanding of the challenges and decision-making processes faced by women with HBOC. Risk-reducing measures and effective strategies that can be implemented to assist these women and their families are discussed. Practice and research implications are outlined to improve health outcomes for these women. Patients’ rights as well as the costs associated with HBOC are also addressed.Approximately 5% to 10% of breast cancer cases and 11% to 18% of ovarian cancer cases are a result of a mutation in the BRCA1 and BRCA2 genes, otherwise known as hereditary breast and ovarian cancer .Approximately 5% to 10% of breast cancer cases and 11% to 18% of ovarian cancer cases are a result of a mutation in the BRCA mutation. Prophylactic measures and potential postoperative complications are discussed. An examination of this public health issue allows advanced practitioners (APs) to understand the challenges and decision-making processes faced by women with HBOC. Risk-reducing measures and effective strategies that can be implemented to assist these women and their families are identified. Practice and research implications are outlined to improve health outcomes for these women. Patient rights as well the costs associated with HBOC are also summarized.The purpose of this article is to provide a clinical overview of HBOC as well as risk-reduction measures that have the potential to decrease the probability of the development of these cancers. The review of the literature highlights the psychological consequences that can be associated with having a BRCA1 or BRCA2 gene. These genes produce tumor-suppressor proteins that help repair damaged DNA and aid in the stability of a cell’s genetic material. Mutations in the BRCA1 or BRCA2 gene are transmitted in an autosomal-dominant pattern in a family, meaning a mutation needs to occur in only one copy of the gene to increase a person’s risk of developing cancer. Therefore, each child of a parent who carries a mutation in one of these genes has a 50% chance of inheriting the mutation, consequently increasing the risk for cancer. Equally, the child also has a 50% chance of not inheriting the mutation; in that case, the risk for cancer becomes comparable to that of the general population.Hereditary breast and ovarian cancer is an inherited genetic condition associated with a mutation in the BRCA1 or BRCA2 gene . Mutations in the BRCA1 gene increase ovarian cancer risk to 39% by age 70, and BRCA2 gene mutations increase ovarian cancer risk to 10% to 17% by age 70 .A woman’s risk for breast cancer increases to 45% to 65% by age 70 if she carries a mutation in either the BRCA gene.There are other cancers associated with HBOC . However, for purposes of this article, only breast and ovarian cancers and their association with HBOC will be discussed. BRCA1 and BRCA2 mutations. The test requires a blood or buccal sample. Genetic counseling should be performed before pursuing screening and after the results are available . An increased likelihood of HBOC is suspected based on certain personal and family history characteristics and various clinical criteria. The NCCN has outlined criteria for further genetic risk evaluation  of the breast beginning at age 25 . The study was limited due to its small size of 19 participants, accounting for only 7% of the study population. Another limitation was that the study did not match its cases and controls based on oophorectomy status.mutation . In a stBRCA1 and BRCA2 mutations when tamoxifen was given as treatment for the initial breast cancer diagnosis. Due to the limitations of the study design, which was case controlled, and the small size of the subgroups, the optimal duration of tamoxifen for chemoprevention could not be determined.A second study performed by Advanced practitioners should be aware that tamoxifen use is currently approved for risk reduction in both premenopausal and postmenopausal women; however, raloxifene is approved for risk reduction in postmenopausal women only . Additionally, practitioners should warn individuals of the major risks of both raloxifene and tamoxifen, including uterine cancer, blood clots, and stroke .Oral Contraceptives: The use of oral contraceptives has demonstrated a reduction in the risk of ovarian cancer by up to 45% to 50% in BRCA1-mutation carriers and up to 60% in BRCA2-mutation carriers  on breast cancer risk has been examined in clinical studies. In the prospective study by BRCA mutation without RRSO or HRT were used as the referent group, HRT after RRSO was found not to significantly change the breast cancer risk associated with RRSO.BRCA1 mutation to compare the risks of breast cancer among those who used HRT and those who did not. A decrease in breast cancer risk was observed among those who took HRT compared with those who did not.A case-controlled study by Risk-Reducing Mastectomy: The NCCN (2014) recommends discussion of risk-reducing bilateral mastectomy (RRM) for those with a BRCA mutation. RRM has shown to substantially reduce the risk of breast cancer . Two options for mastectomy are available: total (simple) mastectomy and subcutaneous mastectomy. A total mastectomy removes the entire breast, whereas a subcutaneous mastectomy preserves the nipple-areolar complex.BRCA1 or BRCA2 mutations, no breast cancers were diagnosed in the women who underwent RRM during 3 years of prospective follow-up . The NCCN (2014) recommends RRSO ideally between 35 and 40 years of age, and upon completion of child bearing, or individualized based on the earliest age of onset of ovarian cancer in the family. Risk-reducing salpingo-oophorectomy is associated with an ovarian risk reduction of approximately 70% to 90% and reduction in breast cancer of at least 50% or greater .BRCA-positive women who did not undergo RRSO vs. those who did . Discovering one has a mutation in the BRCA1 or BRCA2 gene can elicit a variety of different emotions, both positive and negative.Although learning of one’s BRCA-positive mutation status. A study conducted by BRCA-positive. Of this sample, none was extremely anxious , 13% were moderately anxious , and 28% were somewhat anxious .Anxiety, distress, and worry are common psychological consequences experienced by women after discovery of their BRCA1 or BRCA2 mutation also may experience feelings of worry. This worry is often related to the chance of cancer recurrence , distress was exhibited in a sample of 214 women with a known BRCA-positive women revealed that only 26% of those individuals were still experiencing distress as a result of their test results .With RRSO, there is the potential for injury to internal organs such as the bowel, bladder, ureter, blood vessels, and nerves, although these complications are rare. Individuals with prior surgeries, a history of pelvic infection, endometriosis, or other causes of adhesive disease are at greater risk.Reproductive OptionsBRCA gene can have a significant impact on family planning decisions in those of reproductive age. Reproductive options such as prenatal diagnosis and preimplantation genetic diagnosis (PGD) should be offered to those who are concerned about the mutation status of their future offspring .Carrying a mutation in the Prenatal diagnosis refers to any medical procedure performed to assess the genetic predisposition of a fetus. Methods include amniocentesis and chorionic villous sampling (CVS). These tests pose the risk of miscarriage and potential fetal defects. If the fetus is found to be a carrier of the mutation, couples are confronted with the arduous decision regarding continuation or termination of pregnancy.Another available option is PGD. This procedure is used to test fertilized embryos for genetic disorders before uterine implantation, thereby offering the option to select unaffected embryos to be transferred to the uterus. This option avoids the risks associated with amniocentesis and CVS and the decision to terminate pregnancy .Family CommunicationBRCA-mutation result can be a complex and arduous process. The complexity can be largely influenced by the psychological outcomes of conveying these findings. Despite its complexity, communication regarding these results is vital so family members are aware of their cancer susceptibility. With this information, family members can pursue the necessary steps to obtain genetic testing. Several studies have examined the communication process between individuals with a positive mutation status and their family members.Family communication regarding a positive BRCA mutation are more likely to disseminate this information to their relatives. In the Patenaude and colleagues (2006) cohort sample of 68 women, 92% disclosed this information to their mother and 81%, to their father.Individuals with a Another study by BRCA mutation result with family members. There are many reasons surrounding the motivation to share a positive BRCA-mutation carrier discloses her results to family members. Nevertheless, disclosure of these results should be approached with sensitivity.There are strategies that can be implemented when a Hoskins and Werner-Lin (2011) have recommended several approaches. Conversations should focus on objective information about cancer risk in language understandable to everyone. Personal opinions should only be shared when asked. Hoskins and Werner-Lin (2011) also encouraged providing relatives with printed materials given to them by their health-care professionals. These materials provide a credible source to which family members can refer. They also stress that communication be tailored to individuals’ needs and considerations based on factors such as age, health history, risk tolerance, and coping strategies. After communication is made, family members should be encouraged to meet with a genetics counselor to discuss risks, recommendations for preventive care, and screening.Age-Related IssuesBRCA test results to at-risk children is approximated to be 50% , genetic counseling is the process of assisting individuals to understand and adapt to the medical, psychological, and familial implications of genetic contributions to disease. These individuals are specially trained to interpret family and medical histories to assess the risk of disease occurrence or recurrence. Genetic counseling is a vital component of the HBOC risk-assessment process.According to the NCCN (2014), genetic counselors educate individuals about the genetic, biologic, and environmental factors surrounding the risk of disease or an individual’s cancer diagnosis. This process promotes empowerment of the individual to make educated, informed decisions about genetic testing, cancer screening, and cancer prevention. Presentation of information should be tailored to the age and education of the person undergoing counseling, the individual’s personal exposure to the disease, the level of risk, and the social environment ., 2004.Genetic counseling involves both a pretest and posttest session with the individual. Pretest counseling should incorporate a discussion of why HBOC testing is being recommended and how the test results may impact medical management. Furthermore, the cancer risks associated with the specific gene mutation, the possibility of different test results, cost, and the likelihood of a positive result should be discussed. Confidentiality issues should encompass an explanation of the Genetic Information Nondiscrimination Act .Posttest counseling is performed to disclose test results. An interpretation of the test results and an assessment of the emotional and behavioral responses of the individual are also performed. The impact of the results on medical management and how the patient will be followed are discussed. Lastly, education about the dissemination of results to family members is emphasized .Clinical PracticeBRCA1 or BRCA2 mutation can elicit a variety of mixed emotions. Individuals in this position are confronted with the concerns that they are at a higher risk for developing breast or ovarian cancer. Adding to these individuals’ stress, there is the worry that this mutation may also affect their family members.The discovery that one is a carrier of the Although understanding the complex psychological processes that this population experiences is essential, APs must be able to look beyond the lens of the patient and identify the needs of family members. Family members who carry a mutation carry as much risk as the affected individual and should be screened as high risk until proven otherwise. By understanding the psychological responses of these women and their families as well as their perception of their cancer risk, APs can provide emotional support and direction as these individuals decide on risk-reducing strategies. Advanced practitioners may need to refer these individuals to a professional counselor or psychologist. Referral to a support group may also be beneficial, as these individuals can discuss their fears and anxieties with others who share the same emotions.BRCA status, APs should also direct these individuals for genetic counseling, as recommended by NCCN and the US Preventive Services Task Force . Genetic counselors are responsible for explaining the meaning of the individual’s genetic results with regard to their risks of occurrence of breast or ovarian cancer. The counselors will also guide these individuals on risk-reducing management measures with sensitivity to their family goals as well as their ethical and religious standards. By providing optimal psychological support and education, health-care professionals support these individuals to make informed decisions regarding risk-reducing strategies with which they feel comfortable.Prior to genetic testing and again upon receipt of an individual’s With the growth and advancement of genomic medicine, the need for genetic counseling and testing has also expanded. Advanced practitioners should ideally have some professional training in genetics when caring for patients at high risk for developing cancer due to a genetic mutation. Although APs have the opportunity to become certified in genetics to care for this population of patients, those without genetic certification can still be involved in the care of these patients with appropriate training and education. Advanced practitioners with this background can offer these patients comprehensive optimal care as they go through the genetics process. Current ResearchBRCA mutation is concentrated on individuals who are carriers of the BRCA mutation; however, there is little research focusing on the needs of family members of the affected individuals. Further research is needed to target this group of individuals so that appropriate interventions can be performed to meet their physiologic and psychological needs.Current research on the psychological consequences of a Because women are now beginning to seek more preventive measures to decrease their cancer risk, in large part based on the influence of the media, a more multidisciplinary effort to guide these individuals may make this journey less complex for them. Current research is focused on the clinician’s role in supporting these individuals. Further research is warranted to examine the benefits of the integration of other disciplines such as social workers, financial counselors, chaplain personnel, genetic counselors, and pharmacists. The integration of different disciplines will ensure that the practical needs of these individuals are also met, including insurance issues, financial coverage, medication education on chemoprevention, and spiritual guidance.Patients’ RightsBRCA-positive women. Because APs are often the first point of contact for them, having an accurate knowledge of this information is essential in ensuring that these women understand their rights.Laws and policies exist to govern the rights of The Health Insurance Portability and Accountability Act (HIPAA) acknowledges genetic information as protected health information (PHI) and indicates the protection for the confidentiality of PHI. This Act also provides restrictions on health-related information in making coverage decisions and in setting premiums by group health insurers. Furthermore, HIPAA states that genetic information in the absence of a diagnosis cannot be considered a preexisting condition. In the federal government, executive departments and agencies are prohibited from using protected genetic information as a basis for employment decisions .The GINA of 2008  prohibits a group or individual health insurer from discriminating against someone based on results from any type of genetic testing. These results cannot be used as a preexisting condition, nor can they be used to set rates or deny coverage for any services. This Act also prohibits genetic discrimination by employers but does not extend to long-term care insurance, life insurance, or disability insurance.BRCA-related cancer. The group recommends that primary care providers screen women who have family members with breast, ovarian, fallopian tube, or peritoneal cancer with one of several screening tools designed to identify a family history that may be associated with an increased risk for a mutation in the BRCA1 or BRCA2 gene (B recommendation). After receipt of the genetic test results, if a woman is found to be a carrier of a BRCA mutation, the USPSTF also recommends that she meet with a genetic counselor to understand her results as well as the implications and treatment options available to decrease her risk of breast and ovarian cancers .The USPSTF (2013), composed of an independent group of national experts in prevention and evidence-based medicine, has developed final recommendations on risk assessment, genetic counseling, and genetic testing for Cost of TestingBRCA analysis is approximated to cost between $1,500 and $4,000 without insurance coverage, with single-mutation site testing ranging from $300 to $400. Most insurance companies will cover the BRCA test provided an individual meets the guidelines set by NCCN to test for HBOC. Depending on each insurance company and its method of coverage, the cost may vary from individual to individual. Laboratories offer payment plans as well as financial hardship programs for uninsured and underinsured individuals.Because APs are often the first point of contact for patients, it is important that they are cognizant of the cost involved with genetic testing. A complete BRCA mutation can be overwhelming. These individuals are confronted with the decision as to whether or not to pursue prophylactic surgery to decrease their cancer risk. Fear, anxiety, distress, and worry are often felt when patients are struggling with this decision. These emotions are associated with the concerns of developing breast or ovarian cancer as well as the complications and long-term effects of risk-reducing surgery.The psychological and physiologic consequences of discovering one carries a BRCA mutation.Advanced practitioners play an essential role in educating this population about their risk of breast and ovarian cancers as well as measures to decrease this risk. Furthermore, the role of APs is also vital in providing these women emotional support with appropriate referral to a psychologist or support group as necessary. More importantly, APs should also be aware of the policies governing an individual’s rights, specifically with regard to insurance coverage, privacy, and preventive treatment. Being aware of this information will allow APs to accurately direct and educate this population of women so they are fully aware of the rights associated with carrying a


To date, there is limited and inconsistent epidemiologic evidence for associations of adolescent diet with mammographic breast density, a strong and consistent predictor of breast cancer. We investigated the association of adolescent fiber intake with mammographic density in premenopausal women.This study included 743 cancer-free premenopausal women  within the Nurses’ Health Study II cohort. Percent breast density, absolute dense and non-dense areas were measured from digitized film mammograms using a computer-assisted thresholding technique. Adolescent and adult diet were assessed with a food frequency questionnaire; energy-adjusted nutrient intakes were estimated for each food item. Information regarding breast cancer risk factors was obtained from baseline or biennial questionnaires closest to the mammogram date. We used generalized linear regression to quantify associations between quartiles of adolescent fiber intake and each of the breast density measures, adjusted for potential confounders. Associations were examined separately for total fiber intake; fiber from fruits, vegetables, legumes, and cereal; and food sources of fiber .p for trend = 0.64), absolute dense area (p for trend = 0.80), or non-dense area (p for trend = 0.75). Similarly, neither consumption of fiber from fruits, vegetables, legumes, or cereal nor specific sources of fiber intake  during adolescence were associated with any of the mammographic density phenotypes.In multivariable analyses, total fiber intake during adolescence was not associated with percent breast density (Our findings do not support the hypothesis that adolescent fiber intake is associated with premenopausal mammographic breast density. Mammographic breast density is a well-established and strong predictor of breast cancer risk –4. AppeaSome previous studies have suggested that higher fiber intake, particularly during earlier life, may be associated with a reduced risk of breast cancer later in life , 17. To Women included in this study were selected from participants of a breast cancer case-control study nested within the Nurses’ Health Study II (NHS II) cohort. This prospective cohort was established in 1989 and followed 116,430 female registered nurses in the United States who were 25–42 years old (NHS II) at enrollment. After administration of the initial questionnaire, information on breast cancer risk factors  and any diagnoses of cancer or other diseases was updated through biennial questionnaires .A nested case-control approach was originally used as an efficient design to examine the association between selected biomarkers and breast cancer risk within the NHS II cohort . Using iUsual dietary intake and alcohol consumption during the past year were assessed with a semi-quantitative food frequency questionnaire (FFQ) with approximately 130 items which was included in the 1991, 1995, 1999, 2003, and 2007 questionnaires . ResponsWe used energy-adjusted intake estimates in all the analyses. Total fiber intake, fiber from fruit, vegetables, cereal, and legumes were defined as quartiles based on the distribution in the study sample . Total nut intake included intake of peanuts and other nuts and categories were <1 time/month, 1–3 times/month, 1 time/week, and ≥2 times/week.Mammographic breast density was assessed in three batches approximately 2–3 years apart. To quantify breast density, the craniocaudal views of both breasts for the first two batches of mammograms in the NHS II were digitized at 261 μm per pixel with a Lumisys 85 laser film scanner . The third batch of NHS II mammograms was digitized using a VIDAR CAD PRO Advantage scanner  and comparable resolution of 150 dots per inch and 12-bit depth). The Cumulus software  was used for computer-assisted determination of the absolute dense area, non-dense area, and percent mammographic density on all mammograms . All NHSPercent breast density was measured as percentage of the total area occupied by epithelial/stromal tissue (absolute dense area) divided by the total breast area. Because breast densities of the right and left breast for an individual woman are strongly correlated , the aveInformation on breast cancer risk factors was obtained from the biennial questionnaires closest to the date of the mammogram. For exclusion from this analysis, women were considered to be postmenopausal if they reported: (1) no menstrual periods within the 12 months before blood collection with natural menopause, (2) bilateral oophorectomy, or (3) hysterectomy with one or both ovaries retained, and were 54 years or older for ever smokers or 56 years or older for never smokers , 44.We used generalized linear regression to examine the associations of total fiber intake; fiber from fruits, vegetables, legumes, and cereal; and food sources of fiber  with percent density, absolute dense and non-dense areas, while taking into account the correlation between matched controls . BecauseTo assess the overall trend for each of the types of the fiber intake, we used respective medians within each category. For nut consumption, the intake frequencies were first converted into servings and then the median servings in each quartile were used in the trend analysis. Statistical significance in all the analyses was assessed at 0.05 level. The analyses were performed using SAS software .2, and mean non-dense area of 146.2 cm2 as compared to 40.8 %, 90.9 cm2, and 144.7 cm2 in women from the lowest quartile, respectively. Distributions of breast cancer risk factors by the quartiles of total fiber intake are presented in Table In this study of 743 cancer-free premenopausal women, the average age at the mammogram was 44.9 years (range 34.0–55.0). Women in the highest total fiber intake quartile had a mean percent density of 41.2 %, mean absolute dense area of 94.4 cmp trend = 0.64), absolute dense area (p trend = 0.80), or non-dense area (p trend = 0.75) (Table p for trend = 0.05); however, this association was lacking a clear pattern . The results were similar with additional adjustment for adolescent total fiber intake. Neither specific types of fiber nor major sources of fiber intake  during adolescence were associated with any of the mammographic density phenotypes  Table . We founIn this study of cancer-free premenopausal women, we investigated the associations of adolescent fiber intake with mammographic density, a strong and consistent predictor of breast cancer. Adolescent fiber intake was not associated with any of breast density phenotypes. While we noted a borderline significant positive association between total nut intake during adolescence and absolute non-dense breast area, the lack of clear pattern of association suggests that this could be a chance finding. Our findings contribute to the very limited evidence on the association of adolescent fiber intake and premenopausal breast density.th quantile vs. 1st quantile = 0.78, p trend = 0.09) [p trend = 0.002) [Some, but not all, previous studies have suggested that higher fiber intake may be associated with a reduced risk of breast cancer , 47. A r = 0.09) . A recen= 0.002) . In the = 0.002) .Several biological mechanisms were suggested as a possible explanation for potential effects of dietary fiber on breast cancer risk, including its influence on circulating estrogen levels via inhibited intestinal reabsorption and increased fecal excretion as well as increased small intestine transit time leading to a slower glucose absorption and reduced insulin secretion . On the Very limited data exists on associations of adolescent or childhood fiber intake and breast density. Among 1161 cancer-free women participating in a British cohort , there was no statistically significant association between low-fat/high-fiber dietary pattern at age 4 years and adult percent density evaluated with computer-assisted thresholding method . A folloOur study is the largest study to date that systematically investigated associations of adolescent fiber intake with mammographic breast density in premenopausal women. We examined, for the first time, the associations of adolescent fiber intake with absolute dense and non-dense area. In addition to the total fiber intake, we examined associations of specific sources of fiber and food groups with breast density. The analysis used data from the Nurses’ Health Study II, an established cohort with more than 25 years of follow-up, ascertainment of disease status, and comprehensive information on breast cancer risk factors and breast density. While we found no statistically significant associations, with n = 743, we had sufficient statistical power (>80 %) to detect even modest effects  thuOur study has a few limitations. The examined associations are based on the density measures from a single mammogram, which might not be reflective of the woman’s lifelong density pattern; however, studies have suggested that a single measure can predict breast cancer risk for up to 10 years in both pre- and postmenopausal women , 55. DesWe investigated the associations of adolescent fiber intake with percent density, absolute dense and non-dense areas in premenopausal women. Our findings do not support the hypothesis that adolescent fiber intake is associated with premenopausal mammographic density. If observed associations with breast cancer risk are causal, then the effect may not be mediated through mammographic density.