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Background: Although germline genetics influences breast cancer incidence, published research only explains approximately half of the expected association. Moreover, the accuracy of prediction models remains low. For women who develop breast cancer early, the genetic architecture is less established. Methods: To identify loci associated with early-onset breast cancer, gene-based tests were carried out using exome array data from 3,479 women with breast cancer diagnosed before age 50 and 973 age-matched controls. Replication was undertaken in a population that developed breast cancer at all ages of onset. Results: Three gene regions were associated with breast cancer incidence: FGFR2 (P = 1.23 × 10−5; replication P < 1.00 × 10−6), NEK10 (P = 3.57 × 10−4; replication P < 1.00 × 10−6), and SIVA1 (P = 5.49 × 10−4; replication P < 1.00 × 10−6). Of the 151 gene regions reported in previous literature, 19 (12.5%) showed evidence of association (P < 0.05) with the risk of early-onset breast cancer in the early-onset population. To predict incidence, whole-genome prediction was implemented on a subset of 3,076 participants who were additionally genotyped on a genome wide array. The whole-genome prediction outperformed a polygenic risk score [AUC, 0.636; 95% confidence interval (CI), 0.614–0.659 compared with 0.601; 95% CI, 0.578–0.623], and when combined with known epidemiologic risk factors, the AUC rose to 0.662 (95% CI, 0.640–0.684). Conclusions: This research supports a role for variation within FGFR2 and NEK10 in breast cancer incidence, and suggests SIVA1 as a novel risk locus. Impact: This analysis supports a shared genetic etiology between women with early- and late-onset breast cancer, and suggests whole-genome data can improve risk assessment. Cancer Epidemiol Biomarkers Prev; 27(9); 1057–64. ©2018 AACR.

Breast cancer is the second leading cause of cancer mortality among women. Given its important role in DNA methylation and synthesis, one-carbon metabolism may affect breast cancer mortality. We used a population-based cohort of 1,508 women with breast cancer to investigate possible associations of dietary intake of B vitamins before diagnosis as well as nine polymorphisms of one-carbon metabolizing genes and subsequent survival. Women newly diagnosed with a first primary breast cancer in 1996 to 1997 were followed for vital status for an average of 5.6 years. Kaplan-Meier survival and Cox proportional hazard regression analyses were used to evaluate the association between dietary intakes of B vitamins (1,479 cases), genotypes (∼1,065 cases), and all-cause as well as breast cancer–specific mortality. We found that higher dietary intake of vitamin B1 and B3 was associated with improved survival during the follow-up period (Ptrend = 0.01 and 0.04, respectively). Compared with the major genotype, the MTHFR 677 T allele carriers have reduced all-cause mortality and breast cancer–specific mortality in a dominant model [hazard ratio (95% confidence interval): 0.69 (0.49-0.98) and 0.58 (0.38-0.89), respectively]. The BHMT 742 A allele was also associated with reduced all-cause mortality [hazard ratio, 0.70 (0.50-1.00)]. Estrogen receptor/progesterone receptor status modified the association between the MTHFR C677T polymorphism and survival (P = 0.05). The survival associations with one-carbon polymorphisms did not differ with the use of chemotherapy, although study power was limited for examining such effect modification. Our results indicate that one-carbon metabolism may be an important pathway that could be targeted to improve breast cancer survival. (Cancer Epidemiol Biomarkers Prev 2008;17(8):2109–16)

Background: To examine the effects of prediagnostic obesity and weight gain throughout the life course on survival after a breast cancer diagnosis, we conducted a follow-up study among a population-based sample of women diagnosed with first, primary invasive, and in situ breast cancer between 1996 and 1997 (n = 1,508). Methods: In-person interviews were conducted shortly after diagnosis to obtain information on height and weight at each decade of life from age 20 years until 1 year before diagnosis. Patients were followed to determine all-cause (n = 196) and breast cancer–specific (n = 127) mortality through December 31, 2002. Results: In multivariate Cox proportional hazards models, obese women had increased mortality due to breast cancer compared with ideal weight women among those who were premenopausal at diagnosis [hazard ratio (HR), 2.85; 95% confidence interval (95% CI), 1.30-6.23] and postmenopausal at diagnosis (HR, 1.91; 95% CI, 1.06-3.46). Among women diagnosed with premenopausal breast cancer, those who gained >16 kg between age 20 years and 1 year before diagnosis, compared with those whose weight remained stable (±3 kg), had more than a 2-fold elevation in all-cause (HR, 2.45; 95% CI, 0.96-6.27) and breast cancer–specific mortality (HR, 2.09; 95% CI, 0.80-5.48). Women diagnosed with postmenopausal breast cancer who gained more than 12.7 kg after age of 50 years up to the year before diagnosis had a 2- to 3-fold increased risk of death due to all-causes (HR, 2.69; 95% CI, 1.63-4.43) and breast cancer (HR, 2.95; 95% CI, 1.36-6.43). Conclusions: These results indicate that high levels of prediagnostic weight and substantial weight gain throughout life can decrease survival in premenopausal and postmenopausal breast cancer patients. (Cancer Epidemiol Biomarkers Prev 2007;16(9):1803–11)

Recent oral contraceptive (OC) use is associated with modestly higher breast cancer incidence among younger women, but its impact on survival is unclear. This study examined the relationship between OC use before breast cancer diagnosis and survival. A population-based sample of 1,264 women aged 20 to 54 years with a first primary invasive breast cancer during 1990 to 1992 were followed up for 8 to 10 years. OC and covariate data were obtained by interviews conducted shortly after diagnosis and from medial records. All-cause mortality was ascertained through the National Death Index (n = 292 deaths). Age- and income-adjusted hazard ratios (HR) and 95% confidence intervals (95% CI) were estimated by Cox regression methods. All-cause mortality was not associated with ever use of OCs or duration of use. Compared with nonusers, mortality estimates were elevated among women who were using OCs at diagnosis or stopped use in the previous year (HR, 1.57; 95% CI, 0.95-2.61). The HR for use of high-dose estrogen pills within 5 years before diagnosis was double that of nonusers (HR, 2.39; 95% CI, 1.29-4.41) or, if the most recent pill included the progestin levonorgestrel, compared with nonusers (HR, 2.01; 95% CI, 1.03-3.91). Because subgroup estimates were based on small numbers of OC users, these results should be cautiously interpreted. Overall, most aspects of OC use did not seem to influence survival, although there is limited evidence that OC use just before diagnosis, particularly use of some pill types, may negatively impact survival in breast cancer patients aged 20 to 54 years. (Cancer Epidemiol Biomarkers Prev 2007;16(9):1822–7)

Among postmenopausal women, obesity is linked to increased risk of breast cancer and poorer subsequent survival. For premenopausal women, obesity may reduce incidence, but less is known about its effect on prognosis, particularly for abdominal obesity. This study investigated whether general or abdominal obesity at diagnosis influenced survival in a cohort of young women with breast cancer. A population-based follow-up study was conducted among 1,254 women ages 20 to 54 who were diagnosed with invasive breast cancer between 1990 and 1992 in Atlanta or New Jersey. Women were interviewed within several months of diagnosis and asked about their weight and height at age 20 and in the year before diagnosis. Study personnel did anthropometric measures at the interview. With 8 to 10 years of follow-up, all-cause mortality status was determined using the National Death Index (n = 290 deaths). Increased mortality was observed for women who were obese [body mass index (BMI), ≥30] at the time of interview compared with women of ideal weight [BMI, 18.5-24.9; stage- and income-adjusted hazard ratio (HR), 1.48; 95% confidence interval (95% CI), 1.09-2.01]. A similar result was seen for the highest versus lowest quartile of waist-to-hip ratio (HR, 1.52; 95% CI, 1.05-2.19). Strong associations with mortality were found for women who were obese at age 20 (HR, 2.49; 95% CI, 1.15-5.37) or who were overweight/obese (BMI, ≥25) at both age 20 and the time of interview (HR, 2.22; 95% CI, 1.45-3.40). This study provides evidence that breast cancer survival is reduced among younger women with general or abdominal obesity. (Cancer Epidemiol Biomarkers Prev 2006;15(10):1871–7)

Selenium-dependent glutathione peroxidase (GPX1) is a cytosolic antioxidant enzyme that neutralizes H2O2 to water and oxygen ([1][1]). A GPX1 Pro→Leu polymorphism exists at codon 198, with the variant Leu allele being less responsive than the common Pro allele to the stimulation of enzyme activity

The variability in DNA repair capacity of the general population may depend in part upon common variants in DNA repair genes. X-ray repair cross complementing group 1( XRCC1) is an important DNA base excision repair gene and exhibits polymorphic variation. Using the Long Island Breast Cancer Study Project, a population-based casecontrol study, we evaluated the hypothesis that two common single nucleotide polymorphisms of XRCC1 (codon 194 Arg! !Trp and 399 Arg! !Gln) influence breast cancer susceptibility and interact with polycyclic aromatic hydrocarbon (PAH)-DNA adducts, cigarette smoking, and intake of fruits and vegetables and antioxidants. The available sample for genotyping included 1,067 cases and 1,110 controls. Genotyping was done by a high-throughput single-nucleotide extension assay with fluorescence polarization detection of the incorporated nucleotide. We observed no significant increases in risk among all subjects who were carriers of XRCC1 194Trp or 399Gln alleles. Among never smokers, we observed an increased risk of breast cancer in 399Gln carriers [odds ratio (OR), 1.3; 95% confidence interval (CI), 1.0-1.7). Further analysis indicated a suggestive weak additive interaction between the 399Gln allele and detectable PAH-DNA adducts (OR for exposure with mutant genotype, 1.9; 95% CI, 1.2-3.1). The estimated age-adjusted interaction contrast ratio (ICR) and 95% CI (ICR, 0.38; 95% CI, � � � 0.32 to 1.10) indicated that the departure from additivity was not statistically significant, but that there was some suggestion of a relative excess risk due to the interaction. In subjects with at least one copy of XRCC1 194Trp allele, there was a moderate interaction with high intake of fruits and vegetables (z35 half-cup servings per week of any fruits, fruit juices, and vegetables, OR, 0.58; 95% CI, 0.38-0.89; ICR, � � � � 0.49; 95% CI, � � � 0.03 to � � � � 0.95), and dietary plus supplement antioxidant intake with 33% to 42% decreases in breast cancer risk compared with those with the Arg194Arg genotype and low-intake individuals. These results do not show that the two genetic polymorphisms of XRCC1 independently influence breast cancer risk. However, there is evidence for interactions between the two XRCC1 single nucleotide polymorphisms and PAH-DNA adducts or fruit and vegetable and antioxidant intake on breast cancer risk. Further understanding of the biological function of XRCC1 variants and their interactions with PAH-DNA adducts, antioxidants, and other genes in the pathway are needed. (Cancer Epidemiol Biomarkers Prev 2005;14(2):336 – 42)

DNA repair is essential to an individual's ability to respond to damage caused by environmental carcinogens. Alterations in DNA repair genes may affect cancer risk by influencing individual susceptibility to environmental exposures. XPD, a gene involved in nucleotide excision repair, may influence individual DNA repair capacity particularly of bulky adducts. Using a population-based breast cancer case-control study that was specifically conducted to examine markers of environmental exposures, such as polycyclic aromatic hydrocarbons (PAH), on Long Island, NY, we examined whether XPD genotype modified the associations among PAH-DNA adducts, cigarette smoking, and breast cancer risk. Specifically, we examined the XPD polymorphism at exon 23, position 751 in 1,053 breast cancer cases and 1,102 population-based controls. The presence of at least one variant allele (Lys/Gln or Gln/Gln) was associated with a 20% increase in risk of breast cancer [odds ratio (OR), 1.21; 95% confidence interval (95% CI), 1.01-1.44]. The increase in risk for homozygosity of the variant allele (Gln/Gln) seemed limited to those with PAH-DNA adduct levels above the median(OR, 1.61; 95% CI, 0.99-2.63 for adducts above the median versus OR, 1.05; 95% CI, 0.64-1.74 for adductsbelow the median), although the multiplicative interaction was not statistically significant. The increasein risk for homozygosity of the variant allele (Gln/Gln) was only seen among current smokers (OR, 1.97; 95% CI, 1.02-3.81 for current smokers versus OR, 0.87; 95% CI, 0.57-1.32 for never smokers); the multiplicative interaction was statistically significant. Overall, this study suggests that those individuals with this polymorphism in the XPD gene may face an increased risk of breast cancer from PAH-DNA adducts and cigarette smoking.

Whether fruit, vegetable, and antioxidant micronutrient consumption is associated with a reduction in breast cancer incidence remains unresolved. To address this issue, we analyzed data from a large population-based case-control study, with consideration given to whether the associations varied with menopausal status or with clinical characteristics of the cases' disease. Study participants completed a modified Block food frequency questionnaire, which included assessment of the frequency and portion sizes of 13 fruits and fruit juices and 16 vegetables and the use of multiple and single vitamin supplements. Statistical analyses were done on 1,463 cases and 1,500 controls. Among postmenopausal women, reduced odds ratios [OR; 95% confidence intervals (95% CI)] were noted for the highest fifth, as compared with the lowest fifth, of intake of any vegetables [0.63 (0.46-0.86); P for trend0.01] and leafy vegetables [0.66 (0.50-0.86); P for trend = 0.03] after controlling for age and energy intake. Adjusted ORs (95% CIs) were also decreased for postmenopausal breast cancer in relation to high intake of carotenoids, alpha-carotene, beta-carotene, lutein, and particularly lycopene [0.66 (0.48-0.90); P for trend = 0.03]. Inverse associations for fruits and vegetables were stronger for postmenopausal women with estrogen receptor (ER)+ tumors (OR, 0.65; 95% CI, 0.51-0.82) than ER- tumors (OR, 0.92; 95% CI, 0.64-1.32), but results were less consistent for micronutrients. No similarly reduced associations were observed among premenopausal women. ORs did not appreciably differ by in situ or invasive breast cancer or by whether cases had begun chemotherapy. Our results support an inverse association for fruit and vegetable intake among postmenopausal but not premenopausal breast cancer, which may be more pronounced among women with ER+ tumors.

This study was undertaken to determine whether selected risk factors for esophageal and gastric cancer are associated with tumors that overexpress cyclin D1. Archived tumor tissue was available for 630 esophageal and gastric cancer patients who participated in a population-based case-control study. Patients were categorized into case groups based on whether protein overexpression of the cyclin D1 gene, as assessed by immunohistochemistry, was present (cyclin D1+, n = 285) or not (cyclin D1-, n = 345) in the tumor. The distribution of risk factors in each of these case groups was then compared with the distribution among the 695 controls. Multivariate-adjusted odds ratios (OR) for esophageal adenocarcinoma were reduced in relation to use of aspirin and other nonsteroidal anti-inflammatory drug (NSAID) use but only among patients with cyclin D1+ tumors (0.45, 95% confidence interval [CI] = 0.26, 0.79) and not among those with cyclin D1- tumors (1.12, 95% CI = 0.67, 1.86). A similar pattern was observed for gastric cardia adenocarcinomas. In contrast, ORs for esophageal squamous cell carcinoma and noncardia gastric adenocarcinomas in relation to NSAID use were reduced, regardless of cyclin D1 status. ORs did not vary with cyclin D1 status in relation to alcohol, body size, or cigarette smoking, with the following exception; for noncardia gastric adenocarcinomas the cyclin D1- tumors showed a 2-fold elevation in the OR with ever smoking. These data suggest that the reduction in risk associated with NSAID use may be restricted to those esophageal and gastric cardia adenocarcinomas that overexpress cyclin D1.

Cyclin D1, an important cell cycle regulator, is overexpressed in several human cancers including breast. Both estrogens and progestins activate the transcription of the gene; antiestrogens have been shown to reduce cyclin D1 protein levels. Cyclin D1 protein overexpression has been strongly associated with well-differentiated, estrogen receptor-positive tumors. Little is known, however, as to whether epidemiological risk factors are related to this molecularly defined subset of tumors. Using a population-based study of young women45 years in New Jersey, we analyzed whether oral contraceptives (OCs) and other risk factors were associated with the overexpression of cyclin D1 in breast cancer tissue. We measured cyclin D1 status in paraffin-embedded, archived tissue from 78.8% of the breast cancer cases using immunohistochemistry. Cyclin D1 was overexpressed in 33.7% of the cases (123 of 365). We used unordered polytomous logistic regression to estimate the odds ratios (ORs) for two case groups--(a) breast cancer with cyclin D1 overexpression (n = 123) and (b) breast cancer without overexpression (n = 242)--compared with 462 population-based controls. The multivariate-adjusted OR for ever use of OCs was 1.6 [95% confidence interval (CI), 1.0-2.5] for cases that overexpressed cyclin D1 and 1.0 (95% CI, 0.7-1.5) for those with no overexpression. Among women who started using OCs at least 20 years before the reference date, the OR was increased 2-fold for breast cancer with cyclin D1 overexpression (OR, 2.2; 95% CI, 1.2-4.0) but not for breast cancer without cyclin D1 overexpression (OR, 1.1; 95% CI, 0.7-1.8). If replicated, these findings suggest that early OC use may be associated with the subset of mammary tumors that overexpress cyclin D1.

Polycyclic aromatic hydrocarbons (PAH) are potent mammary carcinogens in rodents, but their effect on breast cancer development in women is not clear. To examine whether currently measurable PAH damage to DNA increases breast cancer risk, a population-based case-control study was undertaken on Long Island, NY. Cases were women newly diagnosed with in situ and invasive breast cancer; controls were randomly selected women frequency matched to the age distribution of cases. Blood samples were donated by 1102 (73.0%) and 1141 (73.3%) of case and control respondents, respectively. Samples from 576 cases and 427 controls were assayed for PAH-DNA adducts using an ELISA. The geometric mean (and geometric SD) of the log-transformed levels of PAH-DNA adducts on a natural scale was slightly, but nonsignificantly, higher among cases [7.36 (7.29)] than among controls [6.21 (4.17); P = 0.51]. The age-adjusted odds ratio (OR) for breast cancer in relation to the highest quintile of adduct levels compared with the lowest was 1.51 [95% confidence interval (CI), 1.04-2.20], with little or no evidence of substantial confounding (corresponding multivariate-adjusted OR, 1.49; 95% CI, 1.00-2.21). There was no consistent elevation in risk with increasing adduct levels, nor was there a consistent association between adduct levels and two of the main sources of PAH, active or passive cigarette smoking or consumption of grilled and smoked foods. These data indicate that PAH-DNA adduct formation may influence breast cancer development, although the association does not appear to be dose dependent and may have a threshold effect.