Familial Breast Cancer Risk Research Articles

Blood arsenic levels and the risk of familial breast cancer in Poland.

Arsenic is recognized as a potent carcinogen at high concentrations, but the relationship between environmental arsenic and breast cancer risk has not well been studied. Most research has focused on the effect of arsenic in populations with high endemic exposure, and not in populations with arsenic levels within normal limits. We sought to determine if blood arsenic levels predict the risk of breast and other cancers risk among women in northern Poland. The cohort consisted of 1,702 healthy women, aged 40 and above, identified between 2010 and 2017. Blood arsenic level was determined by inductively coupled plasma mass spectrometry. After an average of 4.5 years of follow‐up (range 0.7–7.3 years), there were 110 incident cases of cancer diagnosed in the cohort, including 68 cases of breast cancer. Women in the highest quartile of arsenic had a highly significant 13‐fold increased risk of developing breast cancer, compared to women in the lowest quartile (hazard ratio [HR] = 13.2; 95% confidence interval [CI] 4.02–43.0). Results were similar for arsenic and all incident cancers (HR quartile 4 vs. quartile 1 = 13.3; 95% CI 4.78–37.0). If confirmed, our study suggests that the blood arsenic level may be a useful predictive marker of cancer risk in women.

Impact of genetic counseling on the uptake of contralateral prophylactic mastectomy among younger women with breast cancer

Background: Preoperative genetic testing affects the surgical decision-making among women with breast cancer. To avoid breast-conserving surgery and to offer the possibility of mastectomy with immediate reconstruction in high-risk patients, genetic testing for pathogenic variants in BRCA1 or BRCA2 and a pedigree-based familial breast cancer risk assessment was offered to younger women with breast cancer in Denmark. We evaluated the impact of the risk stratification through genetic counseling on the uptake of contralateral prophylactic mastectomy (CPM).Material and methods: The prospective cohort study included all women with unilateral breast cancer before the age of 45 who participated in a genetic counseling program during their primary diagnostics in the Central Denmark Region (2013–2018). Each patient was followed from the time of the genetic test result to the end of follow-up to estimate the long-term uptake of CPM as a competing risk-adjusted cumulative incidence. We compared the uptake of CPM between the various genetic risk categories, ages of onset, and family histories in a multivariable Cox proportional hazards regression model, reporting hazard ratios (HR) with two-sided 95% confidence intervals (CIs).Results: 156 females, aged 21–44, learned their genetic test result within a median of 92 days [interquartile range (IQR): 75–114]. The maximal follow-up was 3.8 years (median 1.8; IQR: 0.49–2.5), after which 33% (95% CI: 24–42%) of the patients had undergone CPM. The uptake of CPM was inversely associated with the age of onset (HR 0.92; 95% CI: 0.86–0.98) and significantly higher among BRCA carriers (HR 2.9; 95% CI: 1.3–6.8) and patients from the high risk of breast cancer families (HR 5.6; 95% CI: 1.9–16) compared to the lower genetic risk categories.Conclusion: The risk stratification obtained through genetic counseling had a considerable impact on the surgical decision-making among younger women with breast cancer at long-term follow-up.

Environmental and behavioural head and neck cancer risk factors.

The high incidence of head and neck cancer (HNC), significantly associated with living environment and behaviour, can be prevented more efficiently. The aim of this study was to evaluate the environmental and behavioural risk factors for HNC. Using a detailed questionnaire on social status, education, living and occupational environment exposures, family cancer and lifestyle, HNC patients (103 cases, 76.7% of men) were compared with control subjects (244 subjects, 73% of men) balanced by age: mean (standard deviation) 63.8 (9.3) and 63.8 (9.0) for cases and controls, respectively. The results of this study showed that smoking and low education were significant risk factors for HNC regardless of sex. Family HNC and breast cancer were significant predictors of HNC risk. The study confirmed previous results that smoking and low education are significantly associated with HNC. Additionally, results pointed to significant HNC and breast cancer risk in HNC patient's families that may have originated from passive smoking or a smoking habit stemming from social environments that support it. Better dissemination programmes regarding smoking risks for children and adults are needed, targeting not only individuals but also families.

MRI versus mammography for breast cancer screening in women with familial risk (FaMRIsc): a multicentre, randomised, controlled trial.

Approximately 15% of all breast cancers occur in women with a family history of breast cancer, but for whom no causative hereditary gene mutation has been found. Screening guidelines for women with familial risk of breast cancer differ between countries. We did a randomised controlled trial (FaMRIsc) to compare MRI screening with mammography in women with familial risk. In this multicentre, randomised, controlled trial done in 12 hospitals in the Netherlands, women were eligible to participate if they were aged 30-55 years and had a cumulative lifetime breast cancer risk of at least 20% because of a familial predisposition, but were BRCA1, BRCA2, and TP53 wild-type. Participants who were breast-feeding, pregnant, had a previous breast cancer screen, or had a previous a diagnosis of ductal carcinoma in situ were eligible, but those with a previously diagnosed invasive carcinoma were excluded. Participants were randomly allocated (1:1) to receive either annual MRI and clinical breast examination plus biennial mammography (MRI group) or annual mammography and clinical breast examination (mammography group). Randomisation was done via a web-based system and stratified by centre. Women who did not provide consent for randomisation could give consent for registration if they followed either the mammography group protocol or the MRI group protocol in a joint decision with their physician. Results from the registration group were only used in the analyses stratified by breast density. Primary outcomes were number, size, and nodal status of detected breast cancers. Analyses were done by intention to treat. This trial is registered with the Netherlands Trial Register, number NL2661. Between Jan 1, 2011, and Dec 31, 2017, 1355 women provided consent for randomisation and 231 for registration. 675 of 1355 women were randomly allocated to the MRI group and 680 to the mammography group. 218 of 231 women opting to be in a registration group were in the mammography registration group and 13 were in the MRI registration group. The mean number of screening rounds per woman was 4·3 (SD 1·76). More breast cancers were detected in the MRI group than in the mammography group (40 vs 15; p=0·0017). Invasive cancers (24 in the MRI group and eight in the mammography group) were smaller in the MRI group than in the mammography group (median size 9 mm [5-14] vs 17 mm [13-22]; p=0·010) and less frequently node positive (four [17%] of 24 vs five [63%] of eight; p=0·023). Tumour stages of the cancers detected at incident rounds were significantly earlier in the MRI group (12 [48%] of 25 in the MRI group vs one [7%] of 15 in the mammography group were stage T1a and T1b cancers; one (4%) of 25 in the MRI group and two (13%) of 15 in the mammography group were stage T2 or higher; p=0·035) and node-positive tumours were less frequent (two [11%] of 18 in the MRI group vs five [63%] of eight in the mammography group; p=0·014). All seven tumours stage T2 or higher were in the two highest breast density categories (breast imaging reporting and data system categories C and D; p=0·0077) One patient died from breast cancer during follow-up (mammography registration group). MRI screening detected cancers at an earlier stage than mammography. The lower number of late-stage cancers identified in incident rounds might reduce the use of adjuvant chemotherapy and decrease breast cancer-related mortality. However, the advantages of the MRI screening approach might be at the cost of more false-positive results, especially at high breast density. Dutch Government ZonMw, Dutch Cancer Society, A Sister's Hope, Pink Ribbon, Stichting Coolsingel, J&T Rijke Stichting.

Underdiagnosis is the main challenge in breast cancer screening.

In The Lancet Oncology, Sepideh Saadatmand and colleagues1 present the results of a multicentre, randomised, controlled trial that compared the performance of MRI plus mammography with that of mammography alone for breast cancer screening in women aged 30–55 years with familial risk of breast cancer, but without a documented mutation in a breast cancer susceptibility gene. Participants were randomly allocated to receive either annual MRI and clinical breast examination plus biennial mammography (MRI group) or annual mammography and clinical breast examination (mammography group).

Familial heterozygous hypobetalipoproteinemia and breast cancer risk: A systematic review and suggestions for further research.

The Breast JournalVolume 25, Issue 4 p. 763-765 COMMENTARY Familial heterozygous hypobetalipoproteinemia and breast cancer risk: A systematic review and suggestions for further research Eduardo Lima Pessoa MD, Corresponding Author Eduardo Lima Pessoa MD pessoaeduardo@hotmail.com orcid.org/0000-0002-8384-2734 Department of Radiation Oncology, Hospital do Servidor Público Estadual de São Paulo- Iamspe, São Paulo, Brazil Correspondence Eduardo Lima Pessoa MD, Hospital do Servidor Público Estadual de São Paulo-Iamspe, São Paulo, Brazil. Email: pessoaeduardo@hotmail.comSearch for more papers by this authorMarcelo Costa Vilella dos Reis MD, Marcelo Costa Vilella dos Reis MD Department of Radiation Oncology, Hospital do Servidor Público Estadual de São Paulo- Iamspe, São Paulo, BrazilSearch for more papers by this authorTatiana Sayuri Yamamoto MD, Tatiana Sayuri Yamamoto MD Department of Radiation Oncology, Hospital do Servidor Público Estadual de São Paulo- Iamspe, São Paulo, BrazilSearch for more papers by this authorMario Ribeiro Neto MD, Mario Ribeiro Neto MD Department of Radiation Oncology, Hospital do Servidor Público Estadual de São Paulo- Iamspe, São Paulo, BrazilSearch for more papers by this authorOdair Ferraro MD, Odair Ferraro MD Department of Gynecology and Obstetrics, Hospital do Servidor Público Estadual de São Paulo- Iamspe, São Paulo, BrazilSearch for more papers by this authorMaria José Alves MD, Maria José Alves MD Department of Radiation Oncology, Hospital do Servidor Público Estadual de São Paulo- Iamspe, São Paulo, BrazilSearch for more papers by this authorReginaldo Guedes Coelho Lopes PhD, Reginaldo Guedes Coelho Lopes PhD Department of Gynecology and Obstetrics, Hospital do Servidor Público Estadual de São Paulo- Iamspe, São Paulo, BrazilSearch for more papers by this author Eduardo Lima Pessoa MD, Corresponding Author Eduardo Lima Pessoa MD pessoaeduardo@hotmail.com orcid.org/0000-0002-8384-2734 Department of Radiation Oncology, Hospital do Servidor Público Estadual de São Paulo- Iamspe, São Paulo, Brazil Correspondence Eduardo Lima Pessoa MD, Hospital do Servidor Público Estadual de São Paulo-Iamspe, São Paulo, Brazil. Email: pessoaeduardo@hotmail.comSearch for more papers by this authorMarcelo Costa Vilella dos Reis MD, Marcelo Costa Vilella dos Reis MD Department of Radiation Oncology, Hospital do Servidor Público Estadual de São Paulo- Iamspe, São Paulo, BrazilSearch for more papers by this authorTatiana Sayuri Yamamoto MD, Tatiana Sayuri Yamamoto MD Department of Radiation Oncology, Hospital do Servidor Público Estadual de São Paulo- Iamspe, São Paulo, BrazilSearch for more papers by this authorMario Ribeiro Neto MD, Mario Ribeiro Neto MD Department of Radiation Oncology, Hospital do Servidor Público Estadual de São Paulo- Iamspe, São Paulo, BrazilSearch for more papers by this authorOdair Ferraro MD, Odair Ferraro MD Department of Gynecology and Obstetrics, Hospital do Servidor Público Estadual de São Paulo- Iamspe, São Paulo, BrazilSearch for more papers by this authorMaria José Alves MD, Maria José Alves MD Department of Radiation Oncology, Hospital do Servidor Público Estadual de São Paulo- Iamspe, São Paulo, BrazilSearch for more papers by this authorReginaldo Guedes Coelho Lopes PhD, Reginaldo Guedes Coelho Lopes PhD Department of Gynecology and Obstetrics, Hospital do Servidor Público Estadual de São Paulo- Iamspe, São Paulo, BrazilSearch for more papers by this author First published: 20 May 2019 https://doi.org/10.1111/tbj.13341Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume25, Issue4July/August 2019Pages 763-765 RelatedInformation

Effectiveness of interventions to identify and manage patients with familial cancer risk in primary care: a systematic review.

This systematic review evaluated the effectiveness of strategies to identify and manage patients with familial risk of breast, ovarian, colorectal and prostate cancer in primary care to improve clinical outcomes. MEDLINE, EMBASE, CINAHL and Cochrane library were searched from January 1980 to October 2017. We included randomised controlled trials (RCT) and non-randomised studies of interventions (NRSI). Primary outcomes were cancer incidence, cancer-related clinical outcomes or the identification of cancer predisposition; secondary outcomes were the appropriateness of referral, uptake of preventive strategies and cognitive and psychological effect. From 11,842 abstracts, 111 full texts were reviewed and three eligible studies (nine articles) identified. Two were cluster RCTs and one NRSI; all used risk assessment software. No studies identified our primary outcomes, with no consistent outcome across the three studies. In one RCT, intervention improved the proportion of genetic referrals meeting referral guidelines for breast cancer (OR 4.5, 95% CI 1.6 to 13.1). In the other RCT, there was no difference in screening adherence between the intervention and control group. However, there was borderline increased risk perception (OR 1.89, 95% CI 0.99 to 3.59) in the subgroup that under-estimated their colon cancer risk. In the NRSI, there was no change in psychological distress in patients at increased familial breast cancer risk, but population risk patients had reduced anxiety after intervention (state anxiety mean change - 3, 95% CI - 5 to - 2). Future studies should have better-defined comparator groups and longer follow-up and assess outcomes using validated tools.

14P - Outcomes of women at high familial risk for breast cancer in Australia: An 8-year single-centre experience

14P - Outcomes of women at high familial risk for breast cancer in Australia: An 8-year single-centre experience

Genetic Epidemiology of Breast Cancer in Latin America.

The last 10 years witnessed an acceleration of our understanding of what genetic factors underpin the risk of breast cancer. Rare high- and moderate-penetrance variants such as those in the BRCA genes account for a small proportion of the familial risk of breast cancer. Low-penetrance alleles are expected to underlie the remaining heritability. By now, there are about 180 genetic polymorphisms that are associated with risk, most of them of modest effect. In combination, they can be used to identify women at the lowest or highest ends of the risk spectrum, which might lead to more efficient cancer prevention strategies. Most of these variants were discovered in populations of European descent. As a result, we might be failing to discover additional polymorphisms that could explain risk in other groups. This review highlights breast cancer genetic epidemiology studies conducted in Latin America, and summarizes the information that they provide, with special attention to similarities and differences with studies in other populations. It includes studies of common variants, as well as moderate- and high-penetrance variants. In addition, it addresses the gaps that need to be bridged in order to better understand breast cancer genetic risk in Latin America.

Abstract P6-13-01: MRI breast cancer screening compared to mammography in women with a familial risk: A multicenter randomized controlled trial

Abstract Background: Screening guidelines for women with a family history of breast cancer without a known causative gene mutation differ per country. No randomized controlled trial has been performed to assess the optimal screening strategy for these women. Methods: In twelve centers, 1355 women aged 30–55 years with a cumulative lifetime risk of ≥20% without a BRCA1/2 mutation were randomized into two arms. From January 2011 until December 2017, women in the MRI-arm received yearly MRI-screening, clinical breast examination (CBE), and mammography every other year; and in the Mx-arm yearly mammography and CBE. Outcomes were number and stage of detected breast cancers, sensitivity, specificity and positive predictive value, and stratified by screening round and by mammographic density. Results: After on average 4.3 screening rounds per woman, in the MRI-arm (N=675) compared to the Mx-arm (N=680) more breast cancers were detected (41 versus 14, p<0.001), invasive cancers were smaller (median size 8 versus 17 mm, p=0.006) and less often node positive (20% versus 71.4%, p=0.019)(Table). In the MRI-arm, sensitivity was slightly higher (95.1% versus 92.9%, p=1), and specificity significantly lower (82% versus 90.1%, p<0.001), compared to the Mx-arm. After two rounds, specificity improved for both modalities (87.1% for MRI; 93.0% for Mx; p<0.001) and no ≥T2 tumors or interval cancers occurred in the MRI-arm. All tumors ≥T2 were in the two highest density categories. MRI detected more small invasive tumors than Mx across all density categories. Conclusions: In real-life practice the MRI-arm detected more, relevantly smaller, and far more often node negative tumors, and also at low density in women with a familial risk for breast cancer. Table 1Characteristics of participating women at baseline and of the detected breast cancers, according to study armParticipantsMRI-arm n=675Mx-arm n=680MRI-arm vs. Mx-arm p-valueMean age yr ± SD44.6 ± 6.244.7 ± 6.3 Premenopausal512 (76%)505 (74%) Previous Mx ≤ 2 yr536 (79 %)542 (80%) Previous Mx > 2 years ago23 ( 3%)29 ( 4%) Previous MRI ≤ 2 years ago62 ( 9%)81 (12%) Previous MRI > 2 years ago91 (14%)89 (13%) BI-RADS density category* I (entirely fat)88 (13%)92 (14%) II (scattered densities)248 (37%)229 (34%) III (heterogeneously dense)238 (35%)243 (36%) IV (extremely dense)98 (15%)102 (15%) Mean age at cancer detection49,6 ± 7.049,8 ± 4,70.74No cancer – no. (%)634 (94%)666 (98%) Invasive breast cancers – no. (%)25 (4%)7 (1%)<0.001 (noBC/inv BC/DCIS)DCIS – no. (%)16 (2%)7 (1%) Median size of invasive cancers8 mm17 mm0.006T1a/b15 (60%)1 (14%) T1c7 (28%)4 (57%)0.078 (T1a-b/T1c/≥ T2)≥ T23 (12%)2 (29%) Node pos5 (20%)5 (71%)0.019 (N+/-)Node negative20 (80%)2 (29%) DCIS grade 15 (31%)2 (29%) DCIS grade 28 (50%)4 (57%)1 (dcis gr1,2,3)DCIS grade 33 (19%)1 (14%) *Determined by radiologists, according to the fourth ACR BI-RADS edition Citation Format: Tilanus-Linthorst MM, Saadatmand S, Geuzinge AH, Rutgers EJ, Mann R, de Roy van Zuidewijn DB, Zonderland HM, Tollenaar RA, Lobbes MB, Ausems MG, van 't Riet M, Hooning MJ, Mares-Engelbert I, Luiten EJ, Heijnsdijk EA, Verhoef C, Karssemeijer N, Oosterwijk JC, Obdeijn I-M, de Koning HJ. MRI breast cancer screening compared to mammography in women with a familial risk: A multicenter randomized controlled trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-13-01.

Final Results of the Prospective FH02 Mammographic Surveillance Study of Women Aged 35–39 at Increased Familial Risk of Breast Cancer

BackgroundMany women who are at increased risk of breast cancer due to a mother or sister diagnosed with breast cancer aged under 40 do not currently qualify for surveillance before 40 years of age. There are almost no available data to assess whether mammography screening aged 35–39 years would be effective in this group, in terms of detection of breast cancer at an early stage or cost effective. MethodsA cohort screening study (FH02) with annual mammography was devised for women aged 35–39 to assess the sensitivity and screening performance and potential survival of women with identified tumours. Findings2899 women were recruited from 12/2006–12/2015. These women underwent 12,086 annual screening mammograms and were followed for 13,365.8 years. A total of 55 breast cancers in 54 women occurred during the study period (one bilateral) with 50 cancers (49 women) (15 CIS) adherent to the screening. Eighty percent (28/35) of invasive cancers were ≤2 cm and 80% also lymph node negative. Invasive cancers diagnosed in FH02 were significantly smaller than the comparable (POSH-unscreened prospective) study group (45% (131/293) ≤ 2 cm in POSH vs 80% (28/35) in FH02 p < 0.0001), and were less likely to be lymph-node positive (54% (158/290, 3 unknown) in POSH vs 20% (7/35) in FH02: p = 0.0002. Projected and actual survival were also better than POSH. Overall radiation dose was not higher than in an older screened population at mean dose on study per standard sized breast of 1.5 mGy. InterpretationMammography screening aged 35–39 years detects breast cancer at an early stage and is likely to be as effective in reducing mortality as in women at increased breast cancer risk aged 40–49 years.

Hereditary breast cancer; Genetic penetrance and current status with BRCA.

The most important cause of developing hereditary breast cancer is germline mutations occurring in breast cancer (BCs) susceptibility genes, for example, BRCA1, BRCA2, TP53, CHEK2, PTEN, ATM, and PPM1D. Many BC susceptibility genes can be grouped into two classes, high- and low-penetrance genes, each of which interact with multiple genes and environmental factors. However, the penetrance of genes can also be represented by a spectrum, which ranges between high and low. Two of the most common susceptibility genes are BRCA1 and BRCA2, which perform vital cellular functions for repair of homologous DNA. Loss of heterozygosity accompanied by hereditary mutations in BRCA1 or BRCA2 increases chromosomal instability and the likelihood of cancer, as well as playing a key role in stimulating malignant transformation. With regard to pathological features, familial breast cancers caused by BRCA1 mutations usually differ from those caused by BRCA2 mutations and nonfamilial BCs. It is essential to acquire an understanding of these pathological features along with the genetic history of the patient to offer an individualized treatment. Germline mutations in BRCA1 and BRCA2 genes are the main genetic and inherited factors for breast and ovarian cancer. In fact, these mutations are very important in developing early onset and increasing the risk of familial breast and ovarian cancer and responsible for 90% of hereditary BC cases. Therefore, according to the conducted studies, screening of BRCA1 and BRCA2 genes is recommended as an important marker for early detection of all patients with breast or ovarian cancer risk with family history of the disease. In this review, we summarize the role of hereditary genes, mainly BRCA1 and BRCA2, in BC.

Association of CDH1 and TERT Single-Nucleotide Polymorphisms with Susceptibility to Familial Breast Cancer Risk

Breast cancer (BC) is a multistep disease that is thought to result from an interaction between genetic background and environmental factors. In Iran, one of the strongest risk factors for developing BC is a positive family history of the disease. Recently, various polymorphisms of E-cadherin (CDH1) and TERT have been found to be associated with increased BC risk worldwide. This study aimed to analyze the association of CDH1 and TERT single-nucleotide polymorphisms with susceptibility to familial BC (FBC) risk in the Iranian patients. One hundred five patients with FBC and 110 non-FBC (NFBC) were genotyped to elucidate the potential association between CDH1 rs5030625 polymorphism and TERT rs2736098 polymorphism by polymerase chain reaction-restriction fragment length polymorphism. Then, results were evaluated by electrophoresis and Epi Info(™) 2012 software. A significant association was found between CDH1 rs5030625 GAGA genotype and FBC risk. Compared with the control group, the FBC patients had a lower frequency of GG genotype (69% vs. 85%) and a higher frequency of GAGA (5% vs. 2%, P < 0.02). Furthermore, the patients with FBC had a lower frequency of TERT rs2736098 GG genotype (38% vs. 49%, P = 0.001) and a higher frequency of rs2736098 AA genotype (12% vs. 5%, P = 0.001) compared with the NFBC. In contrast, the TERT rs2736098 GG genotype potentially increased the recurring risk of FBC (odds ratio = 3.17, P < 0.01). Allele genotypic frequencies in the FBC patients differed from those of the controls. Interestingly, tumors in FBC patients with rs2736098 GG genotype and rs5030625 GAGA exhibited higher mitotic activity, higher grade, lower estrogen receptor, and progesterone receptor than the other genotypes. In conclusion, CDH1 rs5030625 GAGA genotype and TERT rs2736098 GG genotype in combination with clinical parameters may be prognostic factors rather than susceptibility factors during the progression of FBC.

Breast cancer risk associated with BRCA1/2 variants in the Pakistani population.

Majority of the BRCA1 and BRCA2 mutations are associated with the risk of sporadic and familial breast cancer. Since these genes are significant in DNA repair mechanisms, we focused homology-directed DNA repair (HDDR) and BRCA complex. We selected BRCA1 variant (rs80356932, 4491C/T) and BRCA2 variant (rs80359182, 319T/C) from the interaction region of BRCA complex and studied in 100 breast cancer patients and 100 controls using tetra-ARMS-PCR. Here we show that BRCA1 and BRCA2 variants are significantly associated with high breast cancer risk (BRCA1 rs80356932; Genotype T/T OR 8.66, 95% CI 3.16-23.71, p < 0.0001; Allele-T, OR 2.48, 95% CI 1.62-3.81, p <0.0001 and BRCA2 rs80359182; Genotype C/C OR 4.32, 95% CI 1.95-9.53, p = 0.0001; Allele-C, OR 2.19, 95% CI 1.43-3.34, p = 0.0002). Additionally, bioinformatics analysis showed that BRCA2-tryptophan > arginine substitutions result in altered interaction of BRCA1/PALB2/BRCA2/protein complex and impaired HDDR pathway. We also observed that breast cancer risk was significantly increased in over-weighted and obese women. Our results indicate that high risk of breast cancer is significantly associated with BRCA1 and BRCA2 variants, and mutations may alter the protein interactions of BRCA complex that results in tumor genesis.

Evaluation of osteopenia and osteoporosis in younger breast cancer survivors compared with cancer-free women: a prospective cohort study

BackgroundOsteoporosis, an indicator of significant bone loss, has been consistently reported among older breast cancer survivors. Data are limited on the incidence of osteopenia, an earlier indicator of bone loss, and osteoporosis in younger breast cancer survivors compared with cancer-free women.MethodsWe prospectively examined bone loss in 211 breast cancer survivors (mean age at breast cancer diagnosis = 47 years) compared with 567 cancer-free women in the same cohort with familial risk for breast cancer. Multivariable-adjusted Cox proportional hazards models were used to estimate HRs and 95% CIs of osteopenia and/or osteoporosis incidence based on physician diagnosis.ResultsDuring a mean follow-up of 5.8 years, 66% of breast cancer survivors and 53% of cancer-free women reported having a bone density examination, and 112 incident cases of osteopenia and/or osteoporosis were identified. Breast cancer survivors had a 68% higher risk of osteopenia and osteoporosis compared to cancer-free women (HR = 1.68, 95% CI = 1.12–2.50). The association was stronger among recent survivors after only 2 years of follow-up (HR = 2.74, 95% CI = 1.37–5.47). A higher risk of osteopenia and osteoporosis was also observed among survivors aged ≤ 50 years, estrogen receptor-positive tumors, and those treated with aromatase inhibitors alone or chemotherapy plus any hormone therapy relative to cancer-free women.ConclusionsYounger breast cancer survivors are at higher risk for osteopenia and osteoporosis compared to cancer-free women. Studies are needed to determine effective approaches to minimize bone loss in this population.

Genetic Variants in pre-miR-146a, pre-miR-499, pre-miR-125a, pre-miR-605, and pri-miR-182 Are Associated with Breast Cancer Susceptibility in a South American Population.

Breast cancer (BC) is one of the most frequent tumors affecting women worldwide. microRNAs (miRNAs) single-nucleotide polymorphisms (SNPs) likely contribute to BC susceptibility. We evaluated the association of five SNPs with BC risk in non-carriers of the BRCA1/2-mutation from a South American population. The SNPs were genotyped in 440 Chilean BRCA1/2-negative BC cases and 1048 controls. Our data do not support an association between rs2910164:G>C or rs3746444:A>G and BC risk. The rs12975333:G>T is monomorphic in the Chilean population. The pre-miR-605 rs2043556-C allele was associated with a decreased risk of BC, both in patients with a strong family history of BC and in early-onset non-familial BC (Odds ratio (OR) = 0.5 [95% confidence interval (CI) 0.4–0.9] p = 0.006 and OR = 0.6 [95% CI 0.5–0.9] p = 0.02, respectively). The rs4541843-T allele is associated with increased risk of familial BC. This is the first association study on rs4541843 and BC risk. Previously, we showed that the TOX3-rs3803662:C>T was significantly associated with increased risk of familial BC. Given that TOX3 mRNA is a target of miR-182, and that both the TOX3 rs3803662-T and pri-miR-182 rs4541843-T alleles are associated with increased BC risk, we evaluated their combined effect. Risk of familial BC increased in a dose-dependent manner with the number of risk alleles (p-trend = 0.0005), indicating an additive effect.

Elucidating the Underlying Functional Mechanisms of Breast Cancer Susceptibility Through Post-GWAS Analyses.

Genome-wide association studies (GWAS) have identified more than 170 single nucleotide polymorphisms (SNPs) associated with the susceptibility to breast cancer. Together, these SNPs explain 18% of the familial relative risk, which is estimated to be nearly half of the total familial breast cancer risk that is collectively explained by low-risk susceptibility alleles. An important aspect of this success has been the access to large sample sizes through collaborative efforts within the Breast Cancer Association Consortium (BCAC), but also collaborations between cancer association consortia. Despite these achievements, however, understanding of each variant's underlying mechanism and how these SNPs predispose women to breast cancer remains limited and represents a major challenge in the field, particularly since the vast majority of the GWAS-identified SNPs are located in non-coding regions of the genome and are merely tags for the causal variants. In recent years, fine-scale mapping studies followed by functional evaluation of putative causal variants have begun to elucidate the biological function of several GWAS-identified variants. In this review, we discuss the findings and lessons learned from these post-GWAS analyses of 22 risk loci. Identifying the true causal variants underlying breast cancer susceptibility and their function not only provides better estimates of the explained familial relative risk thereby improving polygenetic risk scores (PRSs), it also increases our understanding of the biological mechanisms responsible for causing susceptibility to breast cancer. This will facilitate the identification of further breast cancer risk alleles and the development of preventive medicine for those women at increased risk for developing the disease.

Bi-allelic Recessive Loss-of-Function Variants in FANCM Cause Non-obstructive Azoospermia

Infertility affects around 7% of men worldwide. Idiopathic non-obstructive azoospermia (NOA) is defined as the absence of spermatozoa in the ejaculate due to failed spermatogenesis. There is a high probability that NOA is caused by rare genetic defects. In this study, whole-exome sequencing (WES) was applied to two Estonian brothers diagnosed with NOA and Sertoli cell-only syndrome (SCOS). Compound heterozygous loss-of-function (LoF) variants in FANCM (Fanconi anemia complementation group M) were detected as the most likely cause for their condition. A rare maternally inherited frameshift variant p.Gln498Thrfs∗7 (rs761250416) and a previously undescribed splicing variant (c.4387-10A>G) derived from the father introduce a premature STOP codon leading to a truncated protein. FANCM exhibits enhanced testicular expression. In control subjects, immunohistochemical staining localized FANCM to the Sertoli and spermatogenic cells of seminiferous tubules with increasing intensity through germ cell development. This is consistent with its role in maintaining genomic stability in meiosis and mitosis. In the individual with SCOS carrying bi-allelic FANCM LoF variants, none or only faint expression was detected in the Sertoli cells. As further evidence, we detected two additional NOA-affected case subjects with independent FANCM homozygous nonsense variants, one from Estonia (p.Gln1701∗; rs147021911) and another from Portugal (p.Arg1931∗; rs144567652). The study convincingly demonstrates that bi-allelic recessive LoF variants in FANCM cause azoospermia. FANCM pathogenic variants have also been linked with doubled risk of familial breast and ovarian cancer, providing an example mechanism for the association between infertility and cancer risk, supported by published data on Fancm mutant mouse models.

Knowledge of Genetic Counseling Among Patients With Breast Cancer and Their Relatives at a Nigerian Teaching Hospital.

Breast cancer prevalence continues to increase globally, and a significant proportion of the disease has been linked to genetic susceptibility. As we enter the era of precision medicine, genetics knowledge and skills are increasingly essential for achieving optimal cancer prevention and care. However, in Nigeria, patients with breast cancer and their relatives are less knowledgeable about genetic susceptibility to chronic diseases. This pilot study collected qualitative data during in-depth interviews with 21 participants. Of these, 19 participants were patients with breast cancer and two were relatives of patients with breast cancer. Participants were asked questions regarding their knowledge of breast cancer, views on heredity and breast cancer, and views on genetic counseling. Participants’ family histories were used as a basis with which to assess their hereditary risk of breast cancer. Participant responses were audio recorded and transcribed manually. The study evaluated patients’ and relatives’ knowledge of genetic counseling and the use of family history for the assessment of familial risk of breast cancer. This will serve as a guide to the processes of establishing a cancer risk assessment clinic.

Abstract B31: Creating a mobile device-based educational animation for African American women with hereditary breast cancer risk

Abstract Background: Women residing in predominantly African America (AA) communities on the south side of Chicago have a breast cancer (BC) mortality rate twice as high as women living in predominantly white communities on the north side of the city. The emerging precision health paradigm for BC control that bases screening and prevention on individual level of risk has the potential to narrow the mortality gap by providing effective enhanced screening and preventive measures to AA women at high risk. Implementing a precision medicine strategy will require cancer genetic risk assessment (CGRA) in the primary care setting and referral of women with familial BC risk for genetic counseling (GC). Our prior work with CGRA in primary care clinics in AA communities revealed that women with a family history of BC who meet criteria for genetic counseling are unlikely to attend a GC consultation even when they are referred by their primary care physician (PCP). We found a strong desire among AA women and their PCPs for culturally sensitive educational materials tailored to AA women at risk for hereditary BC to help them understand the purpose of genetic counseling. We are developing a scientific educational animation delivered on a mobile device platform that is designed to motivate AA women with familial BC risk to attend a genetic-counseling consultation. Methods: Scientific animations are an effective tool for educating individuals with low health literacy on the benefits of cancer screening. Scientific animations delivered on smart phones have been used successfully in low-resource countries to provide basic health information. The intervention will be a scientific animation that can be viewed on smart phones, which will be created through an iterative process and will incorporate key elements of culturally sensitive health behavior interventions. The initial step involves semistructured interviews to identify factors that motivated attendance or nonattendance at a GC consultation among AA women who meet national guidelines for genetic counseling based on family history of breast cancer and were referred for counseling by their PCP in an earlier study. The sample (n=20) includes both women who did and who did not attend a GC session. Themes identified in the qualitative interviews will be used to create the script for the animation. The script will be story-driven. We will conduct two “story circles” with a subgroup of women participating in the semistructured interviews. The story circle fosters a safe environment for learning across modes of intelligence, expertise, and praxis. Participants will be asked to relate their family's experience with breast cancer in a story format, and to describe how that story affected them. Findings from the story circles will augment themes identified in semistructured interviews to create a storyline, script, and artwork for the animation that is based on the participants' family experiences. We will then conduct focus groups with key stakeholders from local AA communities and AA women with family history of BC to elicit responses to the script, storyboards, and artwork, and revisions will be made as needed based on input from the focus groups. The animation is created in collaboration with the Scientific Animations without Borders, and we will test the final animation with the same participants who viewed the draft storyboards and artwork. Results: Semistructured interviews and the story circles will be completed by the end of July, 2017, and a draft of the script and initial artwork will be completed by September of 2017. Key themes and stories for the script and preliminary artwork for the animation will be presented. Conclusion: A technology-enabled, culturally sensitive scientific animation that motivates AA women with increased breast cancer risk to attend a genetic counseling consultation will facilitate implementation of a population-based, precision health approach to eliminating BC disparities. Citation Format: Zo Ramamonjiarivelo, DeLawnia Comer-Hagans, Ifeanyi Beverly Chukwudozie, Shirley Spencer, Vida Henderson, Barry Pittendrigh, Julia Bello-Bravo, Karriem S. Watson, Catherine Balthazar, Rupert Evans, Robert A. Winn, Angela Odoms-Young, Kent Hoskins. Creating a mobile device-based educational animation for African American women with hereditary breast cancer risk [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr B31.