Familial Breast Cancer Risk Research Articles

Weight change in breast cancer survivors compared to cancer-free women: a prospective study in women at familial risk of breast cancer.

This study prospectively examines weight gain in breast cancer survivors compared with cancer-free women from a familial risk cohort. Absolute and percent weight change over 4 years was compared among 303 breast cancer survivors and 307 cancer-free women matched on age and menopausal status, from the same familial risk cohort. Linear and logistic regression was used to estimate the association between survivor status and weight gain. Overall, breast cancer survivors gained significantly more weight [β = 3.06 pounds; 95% confidence intervals (CI), 0.94-5.17] than cancer-free women. Significant weight gain was observed in survivors diagnosed less than 5 years prior to baseline (β = 3.81 pounds; 95% CI, 1.22-6.29) and women with estrogen receptor (ER)-negative tumors (β = 7.26 pounds; 95% CI, 2.23-12.30). Furthermore, survivors treated with chemotherapy were 2.1 times more likely to gain at least 11 pounds during follow-up compared with cancer-free women (OR, 2.10; 95% CI, 1.21-3.63). Weight gain was even greater among survivors who took statins while undergoing chemotherapy treatment (Pinteraction = 0.01). This is the first study to demonstrate that weight gain is an important issue in breast cancer survivors with a familial risk. In the first five years posttreatment, breast cancer survivors gain weight at a faster rate than cancer-free women, particularly after chemotherapy and statin use but not after hormone therapy alone. Our findings provide support for the development of weight gain interventions for young breast cancer survivors with a familial risk.

MRI screening for breast cancer in women at high risk; is the Australian breast MRI screening access program addressing the needs of women at high risk of breast cancer?

Breast magnetic resonance imaging (MRI) screening of women under 50 years old at high familial risk of breast cancer was given interim funding by Medicare in 2009 on the basis that a review would be undertaken. An updated literature review has been undertaken by the Medical Services Advisory Committee but there has been no assessment of the quality of the screening or other screening outcomes. This review examines the evidence basis of breast MRI screening and how this fits within an Australian context with the purpose of informing future modifications to the provision of Medicare-funded breast MRI screening in Australia. Issues discussed will include selection of high-risk women, the options for MRI screening frequency and measuring the outcomes of screening.

A risk management model for familial breast cancer: A new application using Fuzzy Cognitive Map method

Breast cancer is the most deadly disease affecting women and thus it is natural for women aged 40–49 years (who have a family history of breast cancer or other related cancers) to assess their personal risk for developing familial breast cancer (FBC). Besides, as each individual woman possesses different levels of risk of developing breast cancer depending on their family history, genetic predispositions and personal medical history, individualized care setting mechanism needs to be identified so that appropriate risk assessment, counseling, screening, and prevention options can be determined by the health care professionals. The presented work aims at developing a soft computing based medical decision support system using Fuzzy Cognitive Map (FCM) that assists health care professionals in deciding the individualized care setting mechanisms based on the FBC risk level of the given women. The FCM based FBC risk management system uses NHL to learn causal weights from 40 patient records and achieves a 95% diagnostic accuracy. The results obtained from the proposed model are in concurrence with the comprehensive risk evaluation tool based on Tyrer–Cuzick model for 38/40 patient cases (95%). Besides, the proposed model identifies high risk women by calculating higher accuracy of prediction than the standard Gail and NSAPB models. The testing accuracy of the proposed model using 10-fold cross validation technique outperforms other standard machine learning based inference engines as well as previous FCM-based risk prediction methods for BC.

FANCM c.5791C>T nonsense mutation (rs144567652) induces exon skipping, affects DNA repair activity and is a familial breast cancer risk factor.

Numerous genetic factors that influence breast cancer risk are known. However, approximately two-thirds of the overall familial risk remain unexplained. To determine whether some of the missing heritability is due to rare variants conferring high to moderate risk, we tested for an association between the c.5791C>T nonsense mutation (p.Arg1931*; rs144567652) in exon 22 of FANCM gene and breast cancer. An analysis of genotyping data from 8635 familial breast cancer cases and 6625 controls from different countries yielded an association between the c.5791C>T mutation and breast cancer risk [odds ratio (OR) = 3.93 (95% confidence interval (CI) = 1.28-12.11; P = 0.017)]. Moreover, we performed two meta-analyses of studies from countries with carriers in both cases and controls and of all available data. These analyses showed breast cancer associations with OR = 3.67 (95% CI = 1.04-12.87; P = 0.043) and OR = 3.33 (95% CI = 1.09-13.62; P = 0.032), respectively. Based on information theory-based prediction, we established that the mutation caused an out-of-frame deletion of exon 22, due to the creation of a binding site for the pre-mRNA processing protein hnRNP A1. Furthermore, genetic complementation analyses showed that the mutation influenced the DNA repair activity of the FANCM protein. In summary, we provide evidence for the first time showing that the common p.Arg1931* loss-of-function variant in FANCM is a risk factor for familial breast cancer.

Prompting Primary Care Providers about Increased Patient Risk As a Result of Family History: Does It Work?

Electronic health records have the potential to facilitate family history use by primary care physicians (PCPs) to provide personalized care. The objective of this study was to determine whether automated, at-the-visit tailored prompts about family history risk change PCP behavior. Automated, tailored prompts highlighting familial risk for heart disease, stroke, diabetes, and breast, colorectal, or ovarian cancer were implemented during 2011 to 2012. Medical records of a cohort of community-based primary care patients, aged 35 to 65 years, who previously participated in our Family Healthware study and had a moderate or strong familial risk for any of the 6 diseases were subsequently reviewed. The main outcome measures were PCP response to the prompts, adding family history risk to problem summary lists, and patient screening status for each disease. The 492 eligible patients had 847 visits during the study period; 152 visits had no documentation of response to a family history prompt. Of the remaining 695 visits, physician responses were reviewed family history (n = 372, 53.5%), discussed family history (n = 159, 22.9%), not addressed (n = 155, 22.3%), and reviewed family history and ordered tests/referrals (n = 5, 0.7%). There was no significant change in problem summary list documentation of risk status or screening interventions for any of the 6 diseases. No change occurred upon instituting simple, at-the-visit family history prompts geared to improve PCPs' ability to identify patients at high risk for 6 common conditions. The results are both surprising and disappointing. Further studies should examine physicians' perception of the utility of prompts for family history risk.

Abstract P6-10-11: Longitudinal comparison of weight change in breast cancer survivors to cancer-free women: a prospective study in women with a familial risk of breast cancer

Abstract Background: Although postdiagnosis weight gain has been reported in breast cancer (BC) survivors from the general population, weight gain has not been studied in survivors with a familial BC risk who tend to be younger, treated with chemotherapy and more frequently diagnosed with an estrogen receptor (ER) negative BC. In addition, most studies of weight change in survivors have not included a comparison group of cancer-free women and therefore are unable to distinguish the impact of cancer or related treatment on weight gain versus increasing age. In this study we examine the change in weight among survivors compared to cancer-free women from the same high-risk cohort. Methods: In an ongoing prospective cohort of women at Johns Hopkins with a family history of BC, ovarian cancer, and/or a BRCA1/2 mutation, we identified 303 survivors of incident stage 0-III BC and 552 cancer-free women who were ≥ 20 years at enrollment, completed a baseline questionnaire and at least one follow-up questionnaire within 4 years. Linear and logistic regression was used to estimate change in self-reported weight from baseline to follow-up between survivors and cancer-free women. Survivors were categorized based on time between BC diagnosis and baseline, as well as BC treatment categories. Results: Greater than 60 percent of BC survivors were diagnosed under 50 years, and 22.3% had ER negative tumors. Neither weight nor body mass index (BMI) at baseline differed between survivors and cancer-free women; this was irrespective of tumor subtype. Survivors were more likely than cancer-free women to have ever used statins (19.5% in survivors vs. 14.9% in cancer-free women). Average change in weight during follow-up was 2.92 (95% CI 0.92, 4.91) pounds greater in survivors compared to cancer-free women after adjustment for age, baseline BMI, menopausal status, physical activity, statin use, and enrollment year. The greatest weight gain was observed in survivors diagnosed within 5 years prior to baseline, and treated with chemotherapy and not hormone therapy compared to cancer-free women. This group of survivors was 2.12 (95% CI 1.16, 3.90) times more likely than cancer-free women to have gained at least 11 lbs during follow-up. Further those survivors who had used statins gained significantly more weight compared to cancer-free statin users and non-users with and without cancer (p for interaction = 0.012); this increase in weight gain was largely driven by survivors who had received chemotherapy and statins (p for interaction = 0.008). Conclusion: In this study, BC survivors recently diagnosed and treated with chemotherapy were twice as likely to gain at least 11 lbs, compared to cancer-free women. This amount of weight gain has been linked to an increased risk of heart disease and diabetes in women. Therefore survivors in these categories may benefit from early interventions aimed to reduce weight gain. Intriguingly, we observed a statistically significant interaction for statin use on weight gain in chemotherapy-treated survivors, which may reflect an underlying biological interaction between these agents in BC survivors. Given the prevalence of statin use in this population, this needs to be explored further. Citation Format: Amy L Gross, Sarah A Davidovics, Deborah K Armstrong, Jennifer E Axilbund, Betty J May, Kala Visvanathan. Longitudinal comparison of weight change in breast cancer survivors to cancer-free women: a prospective study in women with a familial risk of breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-10-11.

Abstract P6-10-03: The contribution of common genetic variation to breast cancer risk among women receiving tamoxifen or raloxifene within the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 and P-2 trials

Abstract Purpose: Tamoxifen and raloxifene, are primary prevention strategies for women at high risk of breast cancer (Visvanathan, 2013). Recent advances in genetic studies of breast cancer risk have identified common susceptibility loci that explain 14% of familial risk for breast cancer in the general population (Michailidou, 2013). However, it is not known if these loci are risk factors for breast cancer among high-risk women treated with SERMs for breast cancer prevention. We hypothesized that the large risk reduction associated with SERMs, coupled with the fact that several breast cancer loci correlate with family history, may limit the contribution of these common genetic loci to breast cancer in this high risk population. We present the first report to evaluate 75 established breast cancer susceptibility loci, in the context of a polygenic risk score (PRS), as a risk factor for breast cancer among high risk women taking raloxifene and tamoxifen for breast cancer prevention. Methods: We conducted a matched case-control study of 594 cases (i.e., participants who developed breast cancer while on SERM therapy) and 1,171 matched controls selected from the 33,000 participants enrolled in the NSABP P-1 and P-2 breast cancer prevention trials. Genotypes of 75 single nucleotide polymorphisms (SNPs) were available from a genome-wide association study conducted at the RIKEN Center for Genomic Medicine. We formed a quantitative PRS from reported per-SNP odds ratios (OR) for the 75 susceptibility loci. Conditional logistic regression was used to examine the PRS as a risk factor for breast cancer and to assess whether the PRS and breast cancer association differed by treatment type, family history, or other clinical characteristics. Analyses also examined associations of PRS with invasive vs. in situ cancer and ER-positive vs. ER-negative cancer. Results: The PRS ranged from 3.98 to 7.74, and a one unit change in PRS was associated with a 42% increase in breast cancer (OR=1.42; 95% CI: 1.18-1.70; P = 0.0002). There was evidence of a stronger association of PRS with breast cancer among women with no first-degree family history (OR=1.62, 95% CI: 1.18-2.21) compared to those with a positive family history (OR=1.32, 95% CI: 1.06-1.66) (Pintx<0.05). The PRS also appeared a stronger risk factor for ER-positive (OR=1.59, 95% CI: 1.25-2.02, P < 0.0002) vs. ER-negative (OR=1.05, 95% CI: 0.68-1.62, P=0.84) breast cancer, although differences did not reach statistical significance (Pintx=0.10). PRS and breast cancer associations were similar across tamoxifen and raloxifene treatments, age at trial entry, 5-year predicted Gail model risk, hysterectomy status, BMI, presence of atypical hyperplasia and invasive vs. in situ cancer. Conclusion: A polygenic risk score composed of 75 loci was a risk factor for ER-positive breast cancer, especially in the absence of a first-degree family history of breast cancer. Further, the PRS associations with breast cancer were similar for women taking tamoxifen or raloxifene for prevention. These data suggest that common genetic variation adds information on risk of ER-positive breast cancer in a high-risk population receiving SERMs. Citation Format: Celine M Vachon, Daniel J Schaid, James N Ingle, Matthew P Goetz, Donald L Wickerham, Michiaki Kubo, Erin E Carlson, Soonmyung Paik, Norman Wolmark, Yusuke Nakamura, Liewei Wang, Richard M Weinshilboum, Fergus J Couch. The contribution of common genetic variation to breast cancer risk among women receiving tamoxifen or raloxifene within the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 and P-2 trials [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-10-03.

Abstract P6-10-17: Psychosocial adjustment, cancer worry and perceived risk in 6-13 year old girls from breast cancer families

Abstract Background: Many parents discuss familial and genetic risk of breast cancer (BC) with offspring. What girls know and perceive of BC risk and its psychosocial impact is unknown. Methods: In the multisite LEGACY Girls Study, 6-13 YO daughters and their parents/guardians from BC families (FH+) and families without BC (FH-) were recruited to examine early determinants of, and responses to BC risk. Parents/guardians completed surveys reporting on their daughters’ psychosocial adjustment (PSA). Mothers and daughters 10-13 YO completed surveys reporting their PSA and perceptions of breast cancer risk. We used linear and logistic regressions with variable selection. Results: 731 parents/guardians reported on their own and the PSA of 898 daughters (450 FH+, 448 FH-), and 447 girls (10-13 YO) completed surveys (227 FH+, 220 FH-). FH+ girls have lower somatization and internalizing behaviors by parent/guardian report than FH- girls (Table 1). Intrusive BC (IBC) worry, and avoidant BC (ABC) worry were significantly higher in FH+ girls. IBC worry (coef=0.8, p=0.04) and ABC worry (coef 1.8, p=0.007) were higher in daughters whose mother had BC. Daughter perceived stress (PS), anxiety, depression, somatization, and internalizing did not differ by mother BC history. In multivariable models, daughter-anxiety was associated with mother-anxiety (Coef 1.4, p<0.0001) and BRCA+ family (coef -13.5, p=0.040). Daughter-depression was associated with mother-anxiety (coef 1.0, p=0.009). Daughter-IBC worry was associated with mother-IBC worry (coef 0.2, p<0.001). Daughter-ABC worry was associated with mother-IBC worry (coef 0.2, p=0.002) and being FH+ (coef 1.3, p=0.02). Daughter-PS was associated with mother-depression (coef 0.2, p=0.003). Somatization was not associated with any variables in multivariable models. FH+ girls were more likely to report themselves at higher risk for BC, although many reported uncertainty about their own BC risk. Table 1Daughter Psychosocial AdjustmentFH+ Mean(SD)FH-Mean(SD)By parent/guardian reportn=437n=431Anxiety46.7 (30.3)49.1 (29.1)Depression51.2 (27.2)52.8 (27.3)Somatization43.9 (30.7)**50.3 (30.7)**Internalizing46.1 (29.6)*50.8 (29.1)*Daughter reportedn=228n=222Anxiety40.2 (28.5)42.4 (29.5)Depression32.4 (26.2)32.4 (27.7)Somatization36.5 (25.5)44.0 (27.7)Internalizing33.1 (25.5)34.0 (26.7)IBC Worry2.0 (3.4)**1.2 (2.4)**ABC Worry3.8 (5.8)**2.0 (4.3)**Perceived Stress4.8 (2.8)4.6 (2.8)Daughter Perceived BC Riskn=219n=209Higher risk for BC than peers85 (39%)**27 (13%)**Same risk as peers57 (26%)54 (26%)Lower risk than peers19 (9%)35 (17%)Responded 'not sure'58 (26)93 (45)* p<0.05, ** p<0.01 Conclusions: Pre-adolescent girls from BC families have lower somatization and internalizing behaviors by parent report, but higher self-reported BC worry. Daughter general anxiety, depression and BC worry are associated with corresponding mother affect. Some girls from BC families are aware of their increased risk and related research suggests this may increase with age. Understanding how PSA and BC worry changes over time and the impact on health and risk behaviors can inform interventions to optimize responses to growing up in families at familial and genetic risk for breast cancer. Citation Format: Angela R Bradbury, Linda Patrick-Miller, Brian Egleston, Lisa Schwartz, Colleen B Sands, Wendy Chung, Gord Glendon, Lisa Tuchman, Cindy Moore, Paula Rauch, Irene Andrulis, Saundra Buys, Caren J Frost, Esther M John, Theresa Keegan, Julia Knight, Mary Beth Terry, Mary Daly. Psychosocial adjustment, cancer worry and perceived risk in 6-13 year old girls from breast cancer families [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-10-17.

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers.

IntroductionIndividuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers.MethodsWe genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals.ResultsWe discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk.ConclusionsThis study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-015-0567-2) contains supplementary material, which is available to authorized users.

Facilitators and Challenges in Psychosocial Adaptation to Being at Increased Familial Risk of Breast Cancer.

Little is known about the process of psychosocial adaptation to familial risk in tested and untested individuals at increased familial risk of cancer. This paper presents findings from a qualitative study of 36 women participating in the Kathleen Cuningham Consortium for Research into Familial Breast cancer (kConFab) Psychosocial study. Facilitators and challenges in psychosocial adaptation were identified through semi-structured interviews. The women, who were either tested (carriers or non-carriers of breast cancer susceptibility mutations) or untested (ineligible for testing or eligible but delayed or declined testing), described personal, support network and healthcare characteristics that impacted on the adaptation process. Challenges in one domain could be overcome by facilitators in other domains and key differences relating to whether women had undergone testing, or not, were identified. Tested and untested women with an increased familial risk of breast cancer may benefit from support tailored to their mutation testing status in order to enhance adaptation.

Triple-modality screening trial for familial breast cancer underlines the importance of magnetic resonance imaging and questions the role of mammography and ultrasound regardless of patient mutation status, age, and breast density.

To evaluate the breast cancer screening efficacy of mammography, ultrasound, and magnetic resonance imaging (MRI) in a high-risk population and in various population subgroups. In a single-center, prospective, nonrandomized comparison study, BRCA mutation carriers and women with a high familial risk (> 20% lifetime risk) for breast cancer were offered screening with mammography, ultrasound, and MRI every 12 months. Diagnostic performance was compared between individual modalities and their combinations. Further comparisons were based on subpopulations dichotomized by screening rounds, mutation status, age, and breast density. There were 559 women with 1,365 complete imaging rounds included in this study. The sensitivity of MRI (90.0%) was significantly higher (P < .001) than that of mammography (37.5%) and ultrasound (37.5%). Of 40 cancers, 18 (45.0%) were detected by MRI alone. Two cancers were found by mammography alone (a ductal carcinoma in situ [DCIS] with microinvasion and a DCIS with < 10-mm invasive areas). This did not lead to a significant increase of sensitivity compared with using MRI alone (P = .15). No cancers were detected by ultrasound alone. Similarly, of 14 DCISs, all were detected by MRI, whereas mammography and ultrasound each detected five DCISs (35.7%). Age, mutation status, and breast density had no influence on the sensitivity of MRI and did not affect the superiority of MRI over mammography and ultrasound. MRI allows early detection of familial breast cancer regardless of patient age, breast density, or risk status. The added value of mammography is limited, and there is no added value of ultrasound in women undergoing MRI for screening.

Association of PALB2 sequence variants with the risk of familial and early-onset breast cancer in a South-American population.

BackgroundGermline mutations in PALB2 have been identified in approximately 1% of familial breast cancer (BC) in several populations. Nevertheless its contribution in the South-American population is unknown. The goal of this study was to determine the prevalence of PALB2 mutations in the Chilean population.Methods100 Chilean BRCA1/2-negatives familial BC cases were included for the PALB2 mutation analysis. We use conformational sensitive gel electrophoresis and direct sequencing. Using a case-control design, we studied the identified variants in 436 BC cases and 809 controls to evaluate their possible association with BC risk.ResultsNo pathogenic mutations were detected. We identified three variants, the variant c.1861C > A not previously described was found in one of the 436 cases and none of the 809 controls. The bioinformatic analyses indicate that this variant probably is not pathogenic. PALB2 c.1676A > G (rs152451A/G) and c.2993C > T (rs45551636C/T) variants were significantly associated with increased BC risk only in cases with a strong family history of BC (OR = 1.9 [CI 95% 1.3-2.8] p < 0.01 and OR = 3.3 [CI 95% 1.4-7.3] p < 0.01, respectively). The rs152451A/G-rs45551636C/T composite genotype produce increase of the BC risk in cases with a strong family history of BC (OR = 3.6 [CI 95% 1.7-8.0] p = 0.003). The rs152451-G/rs45551636-C and rs152451-G/rs45551636-T haplotypes were associated with an increased BC risk only in cases with a strong family history of BC (OR = 1.6 [CI 95% 1.0-2.5] p = 0.05 and OR = 3.7 [CI 95% 1.8-7.5] p < 0.001, respectively).ConclusionOur results suggest that PALB2 c.1676A > G and c.2993C > T play roles in BC risk in women with a strong family history of BC.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1033-3) contains supplementary material, which is available to authorized users.

Inherited variants in the inner centromere protein (INCENP) gene of the chromosomal passenger complex contribute to the susceptibility of ER-negative breast cancer.

The chromosomal passenger complex (CPC) plays a pivotal role in the regulation of cell division. Therefore, inherited CPC variability could influence tumor development. The present candidate gene approach investigates the relationship between single nucleotide polymorphisms (SNPs) in genes encoding key CPC components and breast cancer risk. Fifteen SNPs in four CPC genes (INCENP, AURKB, BIRC5 and CDCA8) were genotyped in 88 911 European women from 39 case-control studies of the Breast Cancer Association Consortium. Possible associations were investigated in fixed-effects meta-analyses. The synonymous SNP rs1675126 in exon 7 of INCENP was associated with overall breast cancer risk [per A allele odds ratio (OR) 0.95, 95% confidence interval (CI) 0.92-0.98, P = 0.007] and particularly with estrogen receptor (ER)-negative breast tumors (per A allele OR 0.89, 95% CI 0.83-0.95, P = 0.0005). SNPs not directly genotyped were imputed based on 1000 Genomes. The SNPs rs1047739 in the 3' untranslated region and rs144045115 downstream of INCENP showed the strongest association signals for overall (per T allele OR 1.03, 95% CI 1.00-1.06, P = 0.0009) and ER-negative breast cancer risk (per A allele OR 1.06, 95% CI 1.02-1.10, P = 0.0002). Two genotyped SNPs in BIRC5 were associated with familial breast cancer risk (top SNP rs2071214: per G allele OR 1.12, 95% CI 1.04-1.21, P = 0.002). The data suggest that INCENP in the CPC pathway contributes to ER-negative breast cancer susceptibility in the European population. In spite of a modest contribution of CPC-inherited variants to the total burden of sporadic and familial breast cancer, their potential as novel targets for breast cancer treatment should be further investigated.

A case-control study to assess the impact of mammographic density on breast cancer risk in women aged 40-49 at intermediate familial risk.

Mammographic density is a strong risk factor for breast cancer, but its potential application in risk management is not clear, partly due to uncertainties about its interaction with other breast cancer risk factors. We aimed to quantify the impact of mammographic density on breast cancer risk in women aged 40-49 at intermediate familial risk of breast cancer (average lifetime risk of 23%), in particular in premenopausal women, and to investigate its relationship with other breast cancer risk factors in this population. We present the results from a case-control study nested with the FH01 cohort study of 6,710 women mostly aged 40-49 at intermediate familial risk of breast cancer. One hundred and three cases of breast cancer were age-matched to one or two controls. Density was measured by semiautomated interactive thresholding. Absolute density, but not percent density, was a significant risk factor for breast cancer in this population after adjusting for area of nondense tissue (OR per 10 cm(2) = 1.07, 95% CI 1.00-1.15, p = 0.04). The effect was stronger in premenopausal women, who made up the majority of the study population. Absolute density remained a significant predictor of breast cancer risk after adjusting for age at menarche, age at first live birth, parity, past or present hormone replacement therapy, and the Tyrer-Cuzick 10-year relative risk estimate of breast cancer. Absolute density can improve breast cancer risk stratification and delineation of high-risk groups alongside the Tyrer-Cuzick 10-year relative risk estimate.

Breast-Cancer Risk in Families With Mutations in PALB2

Germline mutations in the BRCA1 and BRCA2 genes confer a marked increase in risk of breast cancer. Loss-of-function mutations have been identified in the PALB2 gene that also increase the risk of breast cancer. PALB2 interacts with BRCA1 and BRCA2 genes. In previous studies, the risk of breast cancer was estimated to be 2 to 4 times higher among carriers of PALB2 loss-of-function mutations as the risk among nonmutation carriers. Prior to the present study, the exact lifetime risk of breast cancer conferred by such mutations was unknown. The aim of this study was to obtain a robust estimate of the breast cancer risk associated with inherited loss-of-function mutations in PALB2. Data were collected for mutation carriers and their relatives from multiple centers worldwide. The risk of breast cancer was determined for 362 members from 154 families with PALB2 loss-of-function mutations A total of 311 women in these families had PALB2 mutations; 229 of these had breast cancer. The age-specific risk of breast cancer for mutation carriers was estimated using a modified segregation-analysis approach that allowed for the effects of inheritance patterns of disease and PALB2 genotype. Mutation carriers were divided into cohorts of women older than 60 years, between 40 and 60 years of age, and younger than 40 years. Compared with the general population, the risk of breast cancer for women who carried the PALB2 mutation was 8 to 9 times higher among those younger than 40 years, 6 to 8 times higher among those 40 to 60 years of age, and 5 times higher among those older than 60 years. The cumulative risk of breast cancer for female PALB2 mutation carriers was estimated to be 14% (95% confidence interval [CI], 9%–20%) by 50 years of age and 35% (95% CI, 26%–46%) by 70 years of age. Breast cancer risk among mutation carriers increased significantly as the birth cohort became more recent (P < 0.001); risk also was affected by other family factors (P = 0.04). By 70 years of age, the absolute risk of breast cancer for a woman who carried the PALB2 mutation ranged from 33% (95% CI, 25%–44%) if she had no family history of breast cancer to 58% (95% CI, 50%–66%) if she had a strong family history (≥2 first-degree relatives with breast cancer at 50 years of age). These data suggest that the level of breast cancer risk for a PALB2 mutation carrier, with or without a family history of breast cancer, is high. This level of risk may justify adding screening for PALB2 mutations to genetic testing panels used for BRCA1 and BRCA2.

Evaluation of genetic variations in miRNA-binding sites of BRCA1 and BRCA2 genes as risk factors for the development of early-onset and/or familial breast cancer.

Although genetic markers identifying women at an increased risk of developing breast cancer exist, the majority of inherited risk factors remain elusive. Mutations in the BRCA1/BRCA2 gene confer a substantial increase in breast cancer risk, yet routine clinical genetic screening is limited to the coding regions and intron- exon boundaries, precluding the identification of mutations in noncoding and untranslated regions. Because 3' untranslated region (3'UTR) polymorphisms disrupting microRNA (miRNA) binding can be functional and can act as genetic markers of cancer risk, we aimed to determine genetic variation in the 3'UTR of BRCA1/BRCA2 in familial and early-onset breast cancer patients with and without mutations in the coding regions of BRCA1/ BRCA2 and to identify specific 3'UTR variants that may be risk factors for cancer development. The 3'UTRs of the BRCA1 and BRCA2 genes were screened by heteroduplex analysis and DNA sequencing in 100 patients from 46 BRCA1/2 families, 54 non-BRCA1/2 families, and 47 geographically matched controls. Two polymorphisms were identified. SNPs c.*1287C>T (rs12516) (BRCA1) and c.*105A>C (rs15869) (BRCA2) were identified in 27% and 24% of patients, respectively. These 2 variants were also identified in controls with no family history of cancer (23.4% and 23.4%, respectively). In comparison to variations in the 3'UTR region of the BRCA1/2 genes and the BRCA1/2 mutational status in patients, there was a statistically significant relationship between the BRCA1 gene polymorphism c.*1287C>T (rs12516) and BRCA1 mutations (p=0.035) by Fisher's Exact Test. SNP c.*1287C>T (rs12516) of the BRCA1 gene may have potential use as a genetic marker of an increased risk of developing breast cancer and likely represents a non-coding sequence variation in BRCA1 that impacts BRCA1 function and leads to increased early-onset and/or familial breast cancer risk in the Turkish population.

Long-term outcomes of risk-reducing surgery in unaffected women at increased familial risk of breast and/or ovarian cancer.

This studyprospectively investigated long-term psychosocial outcomes for women who opted for risk-reducing mastectomy (RRM) and/or risk-reducing salpingo-oophorectomy (RRSO). Unaffected women from high-risk breast cancer families who had completed baseline questionnaires for an existing study and subsequently underwent RRM and/or RRSO, completed measures of perceived breast and ovarian cancer risk, anxiety, depression, cancer-related anxiety, body image, sexual functioning, menopausal symptoms, use of hormone replacement therapy and decision regret 3years post-surgery. Outcomes were compared to age- and risk-matched controls. Participants (N=233) were 17 women who had RRM (39 controls), 38 women who had RRSO (94 controls) and 15 women who had RRM+RRSO (30 controls). Women who underwent RRM and those who underwent RRM+RRSO reported reductions in perceived breast cancer risk and perceived breast and ovarian cancer risk respectively, compared to their respective controls. RRM women reported greater reductions in cancer-related anxiety compared with both controls and RRSO women. RRSO women reported more sexual discomfort than controls and more urogenital menopausal symptoms than controls and RRM only women. No differences in general anxiety, depression or body image were observed. Regret was associated with greater reductions in body image since surgery and more sexual discomfort, although overall regret levels were low. Women who undergo RRM experience psychological benefits associated with reduced breast cancer risk. Although women who undergo RRSO experience some deterioration in sexual and menopausal symptoms, they do not regret their surgery decision. It is vital that women considering these procedures receive detailed information about potential psychosocial consequences.

Wild-type genotypes of BRCA1 gene SNPs combined with micro-RNA over-expression in mammary tissue leading to familial breast cancer with an increased risk of distant metastases’ occurrence

Germ line deleterious mutations of BRCA1 gene are not the unique factor that could inactivate BRCA1 protein which leads to familial breast cancer onset with distant metastases' occurrence. The present research explores the role that could be assigned to BRCA1 SNPs to inactivate BRCA1 protein and therefore to the occurrence of familial breast cancer with an increased risk of distant metastases' occurrence. The presence or the absence of BRCA1 protein was first analyzed by applying the immunohistochemistry technique to the tumors with sporadic and familial breast cancer. Then, a case-control study was conducted including 40 patients with familial breast cancer, 46 ones with sporadic breast cancer and 34 healthy controls based on the genotyping of nine BRCA1 SNPs (c.442.58delT, c.2082C>T, c.2311T>C, c.2612C>T, c.3113A>G, c.3119G>A, c.3548A>G, c.4308T>C and 4837A>G) via direct sequencing. Finally, the functional role that could be assigned to these SNPs was focused upon. miRbase site was used as a bioinformatics tool to predict potential micro-RNAs (miRs) targeting SNPs that are associated with familial breast cancer according to the results of this research. These predicted miRs were confirmed by Q-PCR analysis and correlated with BRCA1 protein expression among patients along with potential distant metastases. Clinical outcome showed that distant metastasis concerned 45 % of familial breast cancer patients and 19.5 % with sporadic breast cancer. Analysis of BRCA1 protein expression revealed a negative staining among 46.6 % of familial breast cancer patients and only 16.6 % within sporadic breast cancer ones. The association of four variants was identified within BRCA1 gene (c.442.58 delT, c.2311T>C, c.2612C>T and c.4308T>C) to familial breast cancer across their wild genotypes. miR-1179 was selected as potential miR that targets the region of BRCA1 mRNA containing the c.2311T>C variant within the TT genotype. The expression of miR-1179 was significantly associated with familial breast cancer patients without BRCA1 deleterious mutations compared to those with sporadic breast cancer according to TT genotype along with BRCA1 negative staining and according to the occurrence of distant metastases. Combination between TT genotype of c.2311T>C and miR-1179 over-expression could generate a lack of BRCA1 protein leading to a high risk of familial breast cancer with distant metastases.

Partner and Localizer of BRCA-2 (PALB-2) Mutation Analysis Is Rapidly Being Adopted into Clinical Practice.

To the Editor, Breast-Cancer Risk in Families with Mutations in PALB2: A.C. Antoniou, S. Casadei, T. Heikkinen, et al. N Engl J Med. 2014;371:497-506. In a study published in N Engl J Med. August 2014, researchers from 14 centers in eight countries investigated information from 362 family members from 154 families who had an abnormal partner and localizer of BRCA2 (PALB2) gene, but did not have an abnormal BRCA1 or BRCA2 gene. Their aim was to demonstrate the importance of loss-of-function mutations in PALB2 as a cause of hereditary breast cancer. The study included 311 women with an abnormal PALB2 gene; 229 of these women had been diagnosed with breast cancer and 51 men with an abnormal PALB2 gene; seven of whom had been diagnosed with breast cancer. The researchers compared the breast cancer risk of the study population to the general population. They found out that overall, women with an abnormal PALB2 gene had a risk of breast cancer that was 9.47 times higher than average. Women with an abnormal PALB2 gene had a 14% risk of developing breast cancer by age 50 and a 35% risk of developing breast cancer by age 70. The average lifetime risk of breast cancer is about 12%. This increase in risk linked to an abnormal PALB2 gene was dependent on the women’s age and family history. They have demonstrated that the relative risk of breast cancer among PALB2 mutation carriers increased significantly as birth cohort became more recent (P<0.001). In women with an abnormal PALB2 gene, breast cancer risk was eight to nine times higher than average in women aged 20 to 39, six to eight times higher than average in women aged 40 to 60, and five times higher than average in women older than 60 years of age. By the age of 70, women with an abnormal PALB2 gene with no family history of breast cancer had a 33% risk of developing breast cancer whereas women with two or more first-degree relatives with breast cancer at 50 years of age had a 58% risk of developing the disease. The authors concluded that based on their estimates, breast cancer risk for a PALB2 mutation carrier, even in the absence of a family history of breast cancer, would be classified as high according to various guidelines. The researchers also reported that this level of risk may justify adding PALB2 to genetic testing for BRCA1 and BRCA2. A Genetic counselor’s perspective Partner and localizer of BRCA2 (PALB) is a gene whose protein facilitates the function of BRCA2 and interacts with BRCA1 to aid in repairing double strand and interstrand cross-link DNA damage. Biallelic PALB2 mutations cause Fanconi Anemia complement group N (FANCN) and monoallellic mutations in the PALB2 gene are associated with increased breast and pancreas cancer risks (1). PALB2 mutations may account for as much as 3% of familial breast cancer risk (2). A recent study of 362 members from PALB2 mutation positive families found that the risk for breast cancer in female mutation carriers ranged between 33% to 58% by age 70, with the higher risks relating to those women with a family history of early onset (<50) breast cancer in 2 first degree family members (3). The study also identified an 8 fold increase in male breast cancer risk and a 2 fold increase in ovarian cancer risk, both of which need to be confirmed in additional studies due a lack of statistical significance. These data suggest that female PALB2 mutation carriers may have breast cancer risks that are similar to those conferred by mutations in the BRCA2 gene. These findings suggest that women who carry PALB2 gene mutations may warrant similar breast cancer screening and prevention strategies as those offered to BRCA2 mutation carriers. PALB2 mutation analysis is available and is rapidly being adopted into clinical practice. As the data continues to accumulate it is likely that PALB2 mutation analysis will become a standard part of genetic testing in the realm of hereditary breast cancer predisposition. Whether testing will be done in addition to BRCA1/2 or as part of a larger breast cancer gene panel remains to be determined. In addition, more data will provide evidence to support the development of specific management guidelines to aid in the care of these at risk patients.

Abstract 1291: High and moderate penetrance germline mutations in a number of genes are responsible for a small proportion of familial breast cancer risk in BRCAx families

Abstract BRCA1 and BRCA2 (BRCA) testing is uninformative in approximately 80% of families with clinical features of inherited susceptibility to breast cancer. Early identification of the individuals at risk in BRCAx families may lead to enhanced screening and prevention strategies, and potentially improved overall survival as has been seen for carriers of BRCA1/2 mutations. A proportion of these families are likely explained by mutations in other high penetrance and moderate penetrance breast cancer susceptibility genes. Although multi-gene panels are now commercially available for clinical testing, only limited information is available on the spectrum of mutations in breast cancer susceptibility genes in specific subgroups of high-risk breast cancer patients. We performed whole exome sequencing in 278 BRCA1/2 negative individuals with high-risk familial breast cancer, defined as a proband and at least two first or second degree relatives with breast cancer. Samples included 232 individuals from 97 families and 49 unrelated individuals, for a total of 146 independent cases. Data were analyzed for identification of all variants in 18 known high and moderate penetrance breast cancer susceptibility genes, in addition to BRCA1 and BRCA2. Two of the 97 families and one of the 49 singletons (2% of independent cases) were found to have deleterious mutations in high penetrance genes, namely TP53 (2) and CDH1 (1). In addition, nine of 146 independent cases (6%) were found to have deleterious mutations in the other predisposition genes. Mutations in ATM and CHEK2 accounted for seven of the ten moderate penetrance mutations identified; additionally one family had a mutation in BLM, one in MRE11A, and one in PALB2. Furthermore, 15 of 146 independent cases (10%) were found to have variants of unknown significance (VUS) in one of eight genes. There were no deleterious mutations or VUS in eight of the 18 genes. Our data show that significant genetic heterogeneity exists in BRCAx families. Large-scale collaborative efforts will be required to attain sufficient power to understand how to appropriately apply these results clinically in cancer risk evaluation. Citation Format: Kara N. Maxwell, Lucia Guidugli, Kasmintan Schrader, Steven Hart, Vijai Joseph, Tinu Thomas, Xianshu Wang, Bradley Wubbenhorst, Robert Klein, Susan M. Domchek, Csilla Szabo, Susan Neuhausen, Jeffrey Weitzel, Katherine L. Nathanson, Kenneth Offit, Fergus Couch. High and moderate penetrance germline mutations in a number of genes are responsible for a small proportion of familial breast cancer risk in BRCAx families. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1291. doi:10.1158/1538-7445.AM2014-1291