Association Between BARD1 Polymorphisms, Immunological and Hormonal Markers, and Breast Cancer Risk in Iraqi Women

To determine whether frequent measurement of tumor markers triggers early detection of colorectal cancer recurrence. Of 1,651 consecutive patients undergoing colorectal cancer surgery between 2010 and 2016, 1,050 were included. CEA and CA 19-9 were considered to be postoperative tumor markers and were measured every 3months for 3years, and then every 6months for 2years. Sensitivity analysis of elevated CEA and CA19-9 levels and multivariate analysis of factors associated with elevated CEA and CA19-9 levels were performed. The proportion of triggers for detecting recurrence was determined. The median follow-up period was 5.3years. After applying the exclusion criteria, 1,050 patients were analyzed, 176 (16.8%) of whom were found to have recurrence. After excluding patients with persistently elevated CEA and CA19-9 levels before and after surgery from the 176 patients, 71 (43.6%) of 163 patients had elevated CEA levels and 35 (20.2%) of 173 patients had elevated CA19-9 levels. Sensitivity/positive predictive values for elevated CEA and CA19-9 levels at recurrence were 43.6%/32.3% and 20.2%/32.4%, respectively. Lymph node metastasis was a factor associated with both elevated CEA and CA19-9 levels at recurrence. Of the 176 patients, computed tomography triggered the detection of recurrence in 137 (78%) and elevated tumor marker levels in 13 (7%); the diagnostic lead interval in the latter 13 patients was 1.7months. Tumor marker measurements in surveillance after radical colorectal cancer resection contribute little to early detection, and frequent measurements are unnecessary for stage I patients with low risk of recurrence.

Objective To investigate the association between single Nucleotide polymorphisms (SNPs) of breast cancer susceptibility gene 1 interacting protein C-terminal helicase 1 (BACH1) gene and susceptibility of early-onset breast cancer in Uygur women in Xinjiang. Methods Detecting and analyzing BACH1 gene exon sites by DNA direct sequencing method and Snapshot genotyping technology, in 80 early-onset breast cancer cases and 240 cases of Uygur women (≤40 years). Results In breast cancer and control groups of Uygur women, the frequencies of genotypes of rs4986764、rs4986765 and c. 587A>G of BACHI gene showed differences between breast cancer and control groups (P=0.001, P=0.011, P=0.049), rs4986764 site of TC (OR=0.086), CC (OR=0.044)and TC+ CCdominant model (OR=0.058) significantly reduced the risk of breast cancer. rs4986765 site of GG (OR=5.617), AG+ GG dominant model (OR=4.254) and c. 587A>G site of GG (OR=7.590), AG+ GG dominant model (OR=7.590) significantly increased the risk of breast cancer. In addition, the SNP-SNP interactions of dominance-genotypes (TC+ CC, AG+ GG) reduced 0.4% risk of breast cancer. Conclusion SNP of rs4986764 of BACHl gene was associated with significantly reduces risk of early-onset breast cancer in Xinjiang women of Uygur, SNP of rs4986765 and c. 587A>G were associated with significantly increases risk of breast cancer in Uygur women. Key words: Breast cancer susceptibility gene 1 interacting protein C-terminal helicase 1 gene; Single nucleotide polymorphism; Uygur; Breast cancer

Unraveling Genes, Hormones, and Breast Cancer

Genome-Wide Association Studies have identified several loci associated with breast cancer (BC) in populations of different ethnic origins. One of the strongest associations was found in the FGFR2 gene, and MAP3K1 has been proposed as a low-penetrance BC risk factor. In this study, we evaluated the associations among FGFR2 SNPs rs2981582, rs2420946, and rs1219648; and MAP3K1 rs889312, with BC risk in 351 BRCA1/2-negative Chilean BC cases and 802 controls. All the SNPs studied were significantly associated with increased BC risk in familial BC and in non-familial early-onset BC, in a dose-dependent manner. Subjects with 3 risk alleles were at a significantly increased risk of BC compared with subjects with 0-2 risk alleles, in both familial BC and early-onset non-familial BC (OR = 1.47, 95 % CI 1.04-2.07, P = 0.026 and OR = 2.04 95 % CI 1.32-3.24, P < 0.001, respectively). In the haplotype analysis, the FGFR2 rs2981582 T / rs2420946 T / rs1219648 G haplotype (ht2) was associated with a significantly increased BC risk compared with the rs2981582 C / rs2420946 C / rs1219648 A haplotype in familial BC and in non-familial early-onset BC (OR = 1.32, 95 % CI 1.06-1.65, P = 0.012; OR = 1.46, 95 % CI 1.11-1.91, P = 0.004, respectively). When the FGFR2 ht2 and MAP3K1 rs889312 were evaluated as risk alleles, the risk of BC increased in a dose-dependent manner as the number of risk alleles increased (P trend <0.0001), indicating an additive effect. Nevertheless, there is no evidence of an interaction between FGFR2 ht2 and the MAP3K1 rs889312 C allele. These findings suggest that genetic variants in the FGFR2 and MAP3K1 genes may contribute to genetic susceptibility to BC.

Recent Genome-Wide Association Studies have identified several single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) among women of Asian, European, and African-American ancestry. Nevertheless, the contribution of these variants in the South American population is unknown. Furthermore, there is little information about the effect of these risk alleles in women with early BC diagnosis. In the present study, we evaluated the association between rs3803662 (TOX3, also known as TNRC9), rs13387042 (2q35), and rs13281615 (8q24) with BC risk in 344 Chilean BRCA1/2-negative BC cases and in 801 controls. Two SNPs, rs3803662 and rs13387042, were significantly associated with increased BC risk in familial BC and in non-familial early-onset BC. The risk of BC increased in a dose-dependent manner with the number of risk alleles (P-trend < 0.0001 and 0.0091, respectively). The odds ratios for BC in familial BC and in early-onset non-familial BC were 3.76 (95%CI 1.02-13.84, P = 0.046) and 8.0 (95%CI 2.20-29.04, P = 0.002), respectively, for the maximum versus minimum number of risk alleles. These results indicate an additive effect of the TOX3 rs3803662 and 2q35 rs13387042 alleles for BC risk. We also evaluated the interaction between rs3803662 and rs13387042 SNPs. We observed an additive interaction only in non-familial early-onset BC cases (AP = 0.72 (0.28-1.16), P = 0.001). No significant association was observed for rs13281615 (8q24) with BC risk in women from the Chilean population. The strongly increased risk associated with the combination of low-penetrance risk alleles supports the polygenic inheritance model of BC.

Breast cancer is the most commonly diagnosed invasive cancer among women both globally and within the United States and the number one cause of cancer-related deaths among women globally ([1, 2][1]). Less than 1% of diagnosed breast cancers occur in men ([2][2]) and, therefore, male breast cancer is

The increasing practice of hormonal infertility treatments (HITs) raised concerns about their effects on breast cancer (BC) risk. Available evidence reported conflicting results. The aim of this study was to assess the potential association between HITs and BC risk. The literature was searched through November 2014. Eligible studies included cohort studies reporting BC incidence in women undergone HITs. Data were analyzed with standard meta-analytic techniques. Subgroup analyses were performed by type of intervention (IVF vs. NO IVF), follow-up duration (<10 vs. >10 years), and type of control (population vs. infertile). 20 eligible studies (207.914 women, 2347 BC) were retrieved: no increased risk was detected (SRR = 1.05, 95 % CI 0.96-1.14), with a significant heterogeneity (I (2) = 59 %, p = 0.001) among studies. In the seven studies with the in vitro fertilization (IVF) procedure, no increase in BC risk was observed (SRR = 0.96, 95 % CI 0.80-1.14); in the three NO IVF studies, an increased BC risk was identified (SRR = 1.26, 95 %CI 1.06-1.50). A borderline interaction between type of intervention (IVF vs. NO IVF) and BC risk was observed (p = 0.06). An increased risk with longer follow-up (≥10 vs. <10 years) was detected (SRR = 1.13, 95 % CI 1.02-1.26 vs. SRR = 0.95, 95 % CI 0.85-1.06). Overall, HITs are not associated with an increased BC risk. In particular, no increased risk was observed in women undergoing IVF. Conversely, an increased in BC risk cannot be ruled out with older treatment protocols based on clomiphene. The long-term administration of clomiphene outside the current indications should be discouraged because of a possible increase in BC risk.

Background: The National Comprehensive Cancer Network (NCCN) currently recommends consideration of genetic testing for appropriate, high risk individuals when it will impact medical management of the individual or at-risk family members. Established NCCN testing criteria are based on family history, the presence of multiple primary cancers, and age of diagnosis. For breast cancer, women diagnosed before age 50 are eligible for genetic testing with limited family history; however, these criteria were developed based on high-risk breast cancer genes, such as BRCA1 and BRCA2. The growing use of gene panels has extended testing to include genes associated with a 2- to 4-fold increased risk for breast cancer. Although NCCN guidelines now include medical management recommendations for these genes, it is unclear whether current criteria appropriately identify candidates for testing who have pathogenic variants (PVs) in genes with moderate breast cancer risk. Here, we investigated the age of breast cancer diagnosis in women carrying PVs in genes with high or moderate breast cancer risk. Methods: Clinical testing was performed for 68,239 women with a personal diagnosis of breast cancer using a 25-gene hereditary cancer panel that includes genes with a high (BRCA1, BRCA2, PTEN, TP53) or moderate (PALB2, CHEK2, ATM, STK11, CDH1, NBN, BARD1) risk of breast cancer. The majority of women tested met current NCCN criteria for testing based on their personal and/or family cancer history. The proportion of women with a PV who were diagnosed &amp;lt;50 and &amp;lt;60 years of age was evaluated. Results: Overall, 5,231 women diagnosed with breast cancer were found to carry a PV in a gene with high or moderate breast cancer risk. 70.2% of women with PVs in genes with a high breast cancer risk were diagnosed with breast cancer before age 50, compared to only 55.5% of patients with PVs in genes with moderate breast cancer risk (see Table). However, similar proportions of women with PVs in genes with a high (89.3%) and moderate (80.2%) breast cancer risk were diagnosed before age 60 (see Table). GeneDiagnosed &amp;lt;50Diagnosed &amp;lt;60Moderate Breast Cancer RiskCHEK2458 (59.3%)629 (81.5%)PALB2337 (54.7%)507 (82.3%)ATM315 (52.4%)452 (75.2%)BARD168 (51.5%)111 (84.1%)NBN56 (52.3%)86 (80.4%)CDH124 (58.5%)33 (80.5%)STK114 (66.7%)6 (100%)Total1262 (55.5%)1824 (80.2%)High Breast Cancer RiskBRCA11086 (76.4%)1314 (92.4%)BRCA2901 (63.0%)1227 (85.8%)TP5361 (83.6%)68 (93.2%)PTEN28 (90.3%)31 (100%)Total2076 (70.2%)2640 (89.3%) Conclusions: Approximately half of the women with a PV in a moderate breast cancer risk gene identified here were diagnosed before age 50. This likely overestimates the proportion of moderate-risk PV carriers with early onset breast cancers, as current testing criteria are weighted towards diagnoses at young ages. Given that there are now medical management guidelines for patients who carry PVs in most of the moderate-risk breast cancer genes, it is important to consider whether current testing criteria developed for genes with a high breast cancer risk effectively identify women with PVs in moderate-risk genes. Citation Format: Gorringe H, Rosenthal E, Kidd J, Brown K, Manley S. Trends in age of breast cancer diagnosis for women with pathogenic variants in genes associated with increased breast cancer risk [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-08-04.

To the Editor: We previously published results from a small pilot study suggesting that young women with BRCA1/2 mutations who have used oral contraceptives (OCs) are at much increased risk of breast cancer. 1 BRCA1/2 mutations account for the majority of hereditary breast cancers, 2 so that if OCs are associated with a particularly high risk of breast cancer in BRCA1/2 mutation carriers, then we would expect this effect to be reflected in the extensive epidemiologic literature on OCs and breast cancer in women with a family history of breast cancer, in particular in young women. We have listed in Table 1 the studies that reported risk of early onset breast cancer (<45) associated with duration of OC use by stratum of family history of breast cancer.3–5 We estimated the odds ratios (ORs) of breast cancer in women with and without family history with and without long-term OC use using women with no family history who had not used OCs as a reference. These ORs were used to determine whether the interaction between family history and long-term OC use exceeds additivity.6 All three studies suggest an excess over additive effects for family history and long-term OC use in the youngest age group. In Rosenberg et al ’s study, the interaction was only apparent for women under age 35. A fourth study suggested no interaction between ever/never OC use and family history,7 but did not present data on duration of OC use. A fifth study suggested an interaction between family history and long-term OC use,8 but contained inadequate information for the odds ratios to be estimated. Table 1: The Effect of Family History of Breast Cancer and Long-Term Oral Contraceptive (OC) Use on Breast Cancer Risk in Young WomenThese data therefore suggest that family history modifies the effect of OC use on early onset breast cancer occurrence, and this result is supported by the finding that cell proliferation may be particularly increased in OC users with a family history of breast cancer. 9 These data thus support indirectly our finding that OC use increases breast cancer risk in young women with BRCA1/2 mutations. 1 It may be, however, that the results in the Table 1 are a biased sample of the studies that have data on the relation between OC use and breast cancer and how it is affected by family history. That is, a form of publication bias may exist in which authors are more likely to report on this particular relation to family history if the result indicates a positive effect. We, for example, did not report the data separately by family history in our report of a study of early breast cancer conducted in Los Angeles, where we found no effect modification by family history. 10 The question of whether family history modifies the effect of OC use on breast cancer in young women is important. The collaborative study on breast cancer 11 only reported the relative risk by family history in all ages combined. A further analysis of their data restricted to young women would help settle this issue. Giske Ursin Chaoyang Li Malcolm C. Pike

Fibroblast growth factor receptor 2 (FGFR2) plays an important role in tumor cell growth, invasiveness, motility, and angiogenesis. Several single-nucleotide polymorphisms (SNPs) in the second intron of the FGFR2 gene are associated with the risk of breast cancer. In this study, we determined whether these SNPs of the FGFR2 gene are associated with early onset of non-familial breast cancer in a Chinese Han population. Recruited were 118 female breast cancer patients who were less than or equal to 35 years of age and without a family history of breast cancer, and 104 age-matched healthy controls. Six SNPs of the second intron of the FGFR2 gene, including rs2981428C/A (i.e., a change at this particular site from nucleotide C to A), rs11200014G/A, rs2981579C/T, rs1219648A/G, rs2420946C/T, and rs2981582C/T, were detected using matrix-assisted laser desorption/ionization mass spectrometry. The data showed that the homozygotes at each minor allele, rs11200014 (AA), rs1219648 (GG), rs2420946 (TT), and rs2981582 (TT), were significantly associated with an increased risk of early-onset non-familial breast cancer. The haplotype containing rs11200014A, rs1219648G, rs2420946T and rs2981582T also exhibited a significantly higher distribution in patients compared to controls (OR=1.784, 95% CI=1.161-2.744). In stratified analyses, each of the above four SNPs conferred a significantly greater risk of estrogen receptor-positive breast cancer, compared to estrogen receptor-negative breast cancer that is more resistant to treatment. Our data demonstrate that these four SNPs of the FGFR2 gene are associated with the risk of breast cancer at a young age in Chinese Han women.

Background: Chronic stress as a result of residing in neighborhoods with higher levels of racial/ethnic segregation may increase a woman's risk of breast cancer. There is strong evidence of increased breast cancer risk due to social stress from animal models. Furthermore, epidemiologic studies have suggested links between racial/ethnic segregation and poor breast cancer outcomes. While a limited number of studies have demonstrated increased breast cancer risk and worse prognostic factors for African American women residing in neighborhoods with high racial/ethnic segregation compared to White women, no studies have examined this potential association in other racial/ethnic groups. Methods: Using data from the Multiethnic Cohort (MEC) (1993-2014), we examined the association between a neighborhood segregation typology of racial/ethnic compositions and incidence of primary, invasive breast cancer in a population-based sample of 101,811 African American, Japanese American, Latina, Native Hawaiian, and White women primarily residing in Los Angeles County, California and Hawaii. Segregation typology was based on the distribution of racial/ethnic groups across census tracts and linked to participants' geocoded baseline residential addresses. Hazard ratios (HRs) and 95% confidence intervals (CIs) for breast cancer risk were estimated using multivariable Cox proportional hazards regression adjusted for age, family history of breast cancer, reproductive and lifestyle risk factors for breast cancer, and stratified by state and self-reported race/ethnicity. For each state and racial/ethnic group, the reference typology was specific to co-ethnic residents. Results: A median follow-up of 20 years yielded 6,398 breast cancer cases. In California, African American women living in predominantly White neighborhoods had reduced risk of breast cancer (HR=0.68, 95%CI=0.46-0.99) compared to African American women living in predominantly Black neighborhoods. Among Latina women, compared to residents in predominately Latino neighborhoods, those in mixed White and Asian American/Pacific Islander (AAPI) (HR=1.54, 95%CI=1.05-2.25) and multiethnic White neighborhoods (HR=1.34, 95%CI=1.07-1.69) had increased risk of breast cancer. In Hawaii, Native Hawaiian women in predominantly AAPI neighborhoods had increased breast cancer risk (HR=1.20, 95%CI=1.04-1.38) compared to Native Hawaiian women in mixed White and AAPI neighborhoods. For Japanese American women in Hawaii, those living in mixed Native Hawaiian (HR=1.28, 95% CI=1.05-1.55) and multiethnic (HR=1.61, 95% CI=1.36-1.90) neighborhoods had higher breast cancer risk than those living in predominately Asian neighborhoods. Conclusion: This large-scale prospective study in a multiethnic population found differential associations between neighborhood racial/ethnic segregation and breast cancer risk by state of residence and self-reported race/ethnicity. Future research should aim to identify pathways through which segregation measures influence breast cancer risk in specific racial/ethnic populations. Citation Format: Meera Sangaramoorthy, Joseph Gibbons, Juan Yang, Katherine Lin, Yuqing Li, Jenna A Khan-Gates, Pushkar Inamdar, Christopher A. Haiman, Loïc Le Marchand, Lynne R Wilkens, Scarlett L. Gomez, Salma Shariff-Marco, Iona Cheng. Neighborhood segregation typology and breast cancer risk: The Multiethnic Cohort Study [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-175.

Background Early-onset cancer (diagnosed under 50 years of age) is generally more aggressive. Its rising incidence is a global concern. The associations between genetic risk, lifestyle, and the risk of early-onset cancer may inform preventive strategies. Methods We studied the association between genetic risk, lifestyle and early-onset cancers among 66308 white British participants enrolled in the UK Biobank before age 50. Genetic risk was assessed using sex-specific composite total cancer polygenic risk scores (PRSs). We calculated composite PRSs as weighted sums of previously-developed cancer site-specific PRSs using weights obtained from lasso regression. We considered a breast cancer-specific PRS for analyses on breast cancer among women. A health-associated lifestyle score (HLS) was calculated based on baseline smoking, BMI (men only), physical activity, alcohol intake, and diet. Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of early-onset total cancer and breast cancer across genetic risk and HLS groups in women and men. Results A total of 1247 incident invasive early-onset cancer cases (820 in women, 427 in men) were documented, including 386 cases of early-onset breast cancer. In multivariable-adjusted analyses with 2-year latency, higher genetic risk (highest vs. lowest tertile of PRS) was associated with significantly increased risks of early-onset total cancer in women (composite PRS HR=1.85; 95% CI, 1.50-2.29), early onset total cancer in men (composite PRS HR=1.94; 95% CI, 1.45-2.59), and early-onset breast cancer in women (breast-cancer PRS HR=3.06; 95% CI, 2.20-4.25). The HRs (95% CI) of early-onset total cancer in women and men, and early-onset breast cancer in women associated with adopting an unfavorable lifestyle (highest vs. lowest tertile of HLS) were 1.49 (0.99, 2.25), 1.14 (0.67, 1.95), and 1.78 (0.97, 3.24), respectively, in the total study population; 1.85 (1.02, 3.36), 3.27 (0.78, 13.72), and 1.67 (0.71, 3.90), respectively, in those with high genetic risk; 1.25 (0.60, 2.57), 1.11 (0.42, 2.89), and 1.66 (0.54, 5.11), respectively, in those with intermediate genetic risk; and 1.15 (0.44, 2.98), 1.16 (0.39, 3.40), and 2.10 (0.57, 7.75), respectively, in those with low genetic risk. Compared to individuals with both low genetic risk and a favorable lifestyle, those with high genetic risk and an unfavorable lifestyle had substantially increased risks of early-onset total cancer in women (3.07; 1.64-5.78) and men (2.18; 0.78-6.11), and significantly higher early-onset breast cancer risk in women (4.11; 1.56-10.85). Conclusion Genetic and lifestyle factors were independently associated with risks of early-onset total cancer and breast cancer. Compared to those with low genetic risk, individuals with a high genetic risk may benefit more from adopting a healthy lifestyle in preventing early-onset cancer. Citation Format: Yin Zhang, Yuxi Liu, Kathryn L. Penney, Sara Lindström, Peter Kraft. Genetic risk, health-associated lifestyle, and risk of early-onset total cancer and breast cancer: A prospective cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6141.

Purpose: To test whether genes located in GWAS-identified regions contain exonic variants that show novel gene-level associations with early-onset ER negative breast cancer risk. Background: Only a small portion of the expected genetic contribution to breast cancer risk has been identified by examining the effect of common variants using single-variant analyses. In contrast to single-variant analyses, sequencing studies combined with gene-based tests evaluate the collective effect of all variants in a gene. In regions identified as associated with disease in GWAS, sequencing combined with gene-based tests can potentially provide evidence whether exonic variation contributes to disease risk independently of the common variants already. However, these studies have not yet been widely implemented in breast cancer research. Methods: We selected 19 genes in 11 genomic regions in which previous GWA studies found associations between common variants and breast cancer. We sequenced the exons of each of these genes in 210 cases (women diagnosed with breast cancer before age 45 who did not carry a known BRCA-1 or BRCA-2 mutation and whose tumors were ER-), and 169 age-matched controls. We analyzed these exons using the variance-based SKAT-O test to determine if exonic variation in any of these 19 genes was associated with risk of developing breast cancer. To examine whether any association was driven by the known GWAS variant, we repeated the analysis, controlling for the common variant that single-variant association tests indicated was most strongly associated with breast cancer. To examine whether the association was driven by putative “functional” variants, we also repeated both analyses, including only non-synonymous variants that alter the amino acid sequence. Results: Exonic variants in three genes were collectively associated with breast cancer risk in our population of early-onset cases: ZMIZ1 (p = 2.07•10-4), FGF3 (p = 1.30•10-3), and ANKLE1 (p = 2.80•10-5). In all of these three genes, the associations persisted or even strengthened after adjusting for the top variant identified by GWAS in the region (ZMIZ1 p = 2.41•10-5; FGF3 p = 1.41•10-3; ANKLE1 p = 7.63•10-6). Functional variants in these three genes (restricted only to non-synonomous variants) also were collectively associated with risk (ZMIZ1 p = 2.65•10-5; FGF3 p = 4.52•10-5; ANKLE1 p = 6.52•10-5). These associations are similar after adjusting for the strongest single variant association identified by GWAS in the region (ZMIZ1 p = 5.10•10-4; FGF3 p = 7.74•10-5; ANKLE1 p = 9.42•10-5). Conclusions: Our results are consistent with the hypothesis that the exons of genomic regions identified through GWAS contain additional variants that contribute to ER- breast cancer risk. These results, that need to be independently validated in a larger study, contribute to our understanding of the genetic determinants that influence the risk of ER- early onset breast cancer. Citation Format: Molly Scannell Bryan, Muhammad G. Kibirya, Irene Andrulis, Jenny Chang-Claude, Habibul Ahsan, Brandon Pierce. Exon sequencing of candidate genes for early onset ER negative breast cancer risk reveals novel gene-level associations. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2787. doi:10.1158/1538-7445.AM2015-2787

The population-based case–control study CECILE investigated the impact of various menopausal hormone therapy (MHT) products on breast cancer (BC) risk in 1,555 postmenopausal women [1]. The case group (n = 739) included incident cases of in situ (!) or invasive BC in postmenopausal women. The control group (n = 816) included women from the general population within predefined quotas by age and socio-economic status (SES). While quotas by age were applied to obtain similar distributions by age among controls and among cases, quotas by SES in control women were applied to reflect the distribution by SES of women in the general population in the study area. Data of participants were obtained by a structured questionnaire during in-person interviews, and from pathology reports if applicable, respectively. Women were divided into current and past MHT user. MHTs were classified in estrogen-only therapy (ET), estrogen combined with progestin therapy (EPT) and tibolone. EPT was subdivided in three subtypes according to the progestogen constituent: natural micronized progesterone, progesterone derivatives, and testosterone derivatives. In comparison to never MHT users, any current or past MHT use (ET, EPT, tibolone) was not associated with an increased BC risk. However, in subanalysis BC risk was significantly increased for current use of EPT for 4 or more years (n = 73 cases and n = 56 controls, adjusted OR 1.55; 95 % CI 1.02–2.36). Within the group of current EPT users for 4 or more years, 14 cases had used estrogens combined with micronized progesterone (n = 17 controls), and 55 a combination with a synthetic progestogen (n = 34 controls), respectively. Compared to never MHT use, current use of EPT containing a synthetic progestogen for 4 or more years was associated with a significantly increased BC risk (adjusted OR 2.07; 95 % CI 1.26–3.39), but EPT containing micronized progesterone was not (adjusted OR 0.79; 95 % CI 0.37–1.71). 73 % of current MHT users started treatment within the first year of onset of menopause. Early EPT (n = 52 cases and n = 38 controls, adjusted OR 1.65; 95 % CI 1.02–2.69), but not early ET, starters had a significantly higher BC risk compared to never MHT users. In contrast, MHT initiation beyond 1 year after menopause was not associated with an increased BC risk. The authors concluded that: (1) ET and EPT containing natural progesterone did not increase BC risk whereas, (2) BC risk was increased in users of tibolone or EPT containing a synthetic progestogen, respectively, and that (3) MHT use early after onset of menopause was associated with an increased BC risk as compared to women who delay MHT beyond 1 or more years.

BackgroundMicroRNAs (miRNAs) are a novel class of endogenous, non-coding, single-stranded RNAs capable of regulating gene expression by suppressing translation or degrading mRNAs. Single nucleotide polymorphisms (SNP) can alter miRNA expression, resulting in diverse functional consequences. Previous studies have examined the association of miRNA SNPs with breast cancer (BC) susceptibility. The contribution of miRNA gene variants to BC susceptibility in South American women had been unexplored. Our study evaluated the association of the SNPs rs895819 in pre-miR27a, rs11614913 in pre-miR-196a2, rs6505162 in pre-miR-423, rs4919510 in miR-608, and rs2682818 in pre-mir-618 with familial BC and early-onset non-familial BC in non-carriers of BRCA1/2 mutations from a South American population.ResultsWe evaluated the association of five SNPs with BC risk in 440 cases and 807 controls. Our data do not support an association of rs11614913:C > T and rs4919510:C > G with BC risk. The rs6505162:C > A was significantly associated with increased risk of familial BC in persons with a strong family history of BC (OR = 1.7 [95 % CI 1.0–2.0] p = 0.05). The rs2682818:C > A genotype C/A is associated with an increased BC risk in non-familial early-onset BC. For the rs895819:A > G polymorphism, the genotype G/G is significantly associated with reduced BC risk in families with a moderate history of BC (OR = 0.3 [95 % CI 0.1–0.8] p = 0.01).ConclusionsThe contribution of variant miRNA genes to BC in South American women had been unexplored. Our findings support the following conclusions: a) rs6505162:C > A in pre-miR-423 increases risk of familial BC in families with a strong history of BC; b) the C/A genotype at rs2682818:C > A (pre-miR-618) increases BC risk in non-familial early-onset BC; and c) the G/G genotype at rs895819:A > G (miR-27a) reduces BC risk in families with a moderate history of BC.