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Background: Adherence to dietary recommendations has been shown to be associated with reduced mortality in healthy populations. Little is known about the possible benefits of adherence to dietary recommendations among breast cancer survivors., Methods: Dietary information was collected using food frequency questionnaires at the 5-year postdiagnosis survey in 3,450 5-year breast cancer survivors from the Shanghai Breast Cancer Survival Study. Adherence scores to Chinese Food Pagoda (CHFP)-2007, CHFP-2016, modified Dietary Approaches to Stop Hypertension (DASH), and Healthy Eating Index 2015 (HEI-2015) were created. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for total mortality and breast cancer-specific events according to adherence scores., Results: Participants in the highest quartiles of CHFP-2007, CHFP-2016, and DASH had 25% to 34% lower risk of total mortality (HR, 0.66; 95% CI, 0.48-0.89 for CHFP-2007; HR, 0.75; 95% CI, 0.55-1.01 for CHFP-2016; HR, 0.66; 95% CI, 0.49-0.91 for DASH), and 36% to 40% lower risk of breast cancer-specific events (HR, 0.64; 95% CI, 0.44-0.93 for CHFP-2007; HR, 0.67; 95% CI, 0.45-0.99 for CHFP-2016; HR, 0.60; 95% CI, 0.40-0.90 for DASH) comparing with the lowest quartiles. Associations did not vary by known prognostic factors. HEI-2015 scores were not significantly associated with breast cancer outcomes., Conclusions: Higher adherence to CHFP and DASH dietary guidelines post-cancer diagnosis was associated with reduced risk of both overall death and breast cancer-specific recurrence or death among long-term breast cancer survivors., Impact: Our study highlights the importance of overall dietary quality among long-term breast cancer survivors., (©2019 American Association for Cancer Research.)

The transforming growth factor β (TGF-β) pathway plays an important role in breast cancer progression and in metabolic regulation and energy homeostasis. The prognostic significance of TGF-β interaction with obesity and physical activity in breast cancer patients remains unclear. We evaluated the expression of TGF-β type II receptor and pSmad2 immunohistochemically in breast cancer tissue from 1,045 patients in the Shanghai Breast Cancer Study (2002-2005). We found that the presence of nuclear pSmad2 in breast cancer cells was inversely associated with overall and disease-free survival, predominantly among participants with lower body mass index (BMI; weight (kg)/height (m) 2 ) and a moderate level of physical activity. However, the test for multiplicative interaction produced a significant result only for BMI (for disease-free survival and overall survival, adjusted hazard ratios were 1.79 and 2.05, respectively). In 535 earlier-stage (T1-2, N0) invasive cancers, nuclear pSmad2 was associated with improved survival among persons with higher BMI (overall survival: adjusted hazard ratio = 0.27, 95% confidence interval: 0.09, 0.86). The cytoplasmic pattern of TGF-β type II receptor expression in cancer cells was significantly associated with a lower survival rate but was not modified by BMI or physical activity. Our study suggests that the TGF-β pathway in tumor cells is involved in breast cancer prognosis and may be modified by BMI through pSmad2., (© The Author 2016. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To evaluate whether the genetic susceptibility of T2D was associated with overall survival (OS) and disease-free survival (DFS) outcomes for breast cancer (BC)., Methods: Included in the study were 6346 BC patients who participated in three population-based epidemiological studies of BC and were genotyped with either GWAS or Exome-chip. We constructed a genetic risk score (GRS) for diabetes using risk variants identified from the GWAS catalog (http://genome.gov/gwastudies) that were associated with T2D risk at a minimum significance level of P ≤ 5.0E-8 among Asian population and evaluated its associations with BC outcomes with Cox proportional hazards models., Results: During a median follow-up of 8.08 years (range, 0.01-16.95 years), 1208 deaths were documented in 6346 BC patients. Overall, the diabetes GRS was not associated with OS and DFS. Analyses stratified by estrogen receptor status (ER) showed that the diabetes GRS was inversely associated with OS among women with ER- but not in women with ER+ breast cancer; the multivariable adjusted HR was 1.38 (95% CI: 1.05-1.82) when comparing the highest to the lowest GRS quartiles. The association of diabetes GRS with OS varied by diabetes status (P for interaction <0.01). In women with history of diabetes, higher diabetes GRS was significantly associated with worse OS, with HR of 2.22 (95% CI: 1.28-3.88) for the highest vs. lowest quartile, particularly among women with an ER- breast cancer, with corresponding HR being 4.59 (95% CI: 1.04-20.28). No significant association between the diabetes GRS and OS was observed across different BMI and PR groups., Conclusions: Our study suggested that genetic susceptibility of T2D was positively associated with total mortality among women with ER- breast cancer, particularly among subjects with a history of diabetes. Additional studies are warranted to verify the associations and elucidate the underlying biological mechanism.

Menopausal symptoms have been suggested to be an indicator of better prognosis among patients treated for breast cancer, because women who experience these symptoms usually have a lower level of estrogen. We tested this hypothesis in a population-based, prospective cohort study involving 4,842 women with stage 0 to III primary breast cancer who were enrolled in the Shanghai Breast Cancer Survival Study between March 2002 and April 2006, were aged 20 to 75 years, and were recruited 6 months post-diagnosis. They were followed-up by in-person surveys and record linkages with the vital statistics registry. Cox regression analysis was used to evaluate the association of menopausal symptoms at baseline with breast cancer recurrence. Approximately 56% of patients experienced at least one menopausal symptom, including hot flashes, night sweats, and/or vaginal dryness at baseline. During a median follow-up period of 5.3 years, 720 women had a recurrence. Experiencing hot flashes or having ≥2 menopausal symptoms was associated with lower risk of recurrence among premenopausal women (hazard ratio [HR]=0.77, 95% confidence interval [CI]: 0.62-0.96 for hot flashes; 0.73, 0.56-0.96 for ≥2 menopausal symptoms). Lower recurrence risk in relation to hot flashes was also observed among women who were not overweight/obese (HR=0.78, 95% CI: 0.64-0.99), those with relatively low waist-to-hip ratio (WHR) (HR=0.77, 95% CI: 0.61-0.97), and those who used tamoxifen (HR=0.75, 95% CI: 0.58-0.98). Consistently experiencing multiple menopausal symptoms was associated with lower recurrence risk among women with low WHR or who used tamoxifen. This large, population-based cohort study of women with breast cancer confirms that experiencing menopausal symptoms is an indicator of favorable breast cancer prognosis.

Background: Recently, 41 new genetic susceptibility loci for breast cancer risk were identified in a genome-wide association study (GWAS) conducted in European descendants. Most of these risk variants have not been directly replicated in Asian populations., Methods: We evaluated nine of those nonreplication loci in East Asians to identify new risk variants for breast cancer in these regions. First, we analyzed single-nucleotide polymorphisms (SNP) in these regions using data from two GWAS conducted among Chinese and Korean women, including 5,083 cases and 4,376 controls (stage 1). In each region, we selected an SNP showing the strongest association with breast cancer risk for replication in an independent set of 7,294 cases and 9,404 controls of East Asian descents (stage 2). Logistic regression models were used to calculate adjusted ORs and 95% confidence intervals (CI) as a measure of the association of breast cancer risk and genetic variants., Results: Two SNPs were replicated in stage 2 at P < 0.05: rs1419026 at 6q14 [per allele OR, 1.07; 95% confidence interval (CI), 1.03-1.12; P = 3.0 × 10(-4)] and rs941827 at 10q25 (OR, 0.92, 95% CI, 0.89-0.96; P = 5.3 × 10(-5)). The association with rs941827 remained highly statistically significant after adjusting for the risk variant identified initially in women of European ancestry (OR, 0.88; 95% CI, 0.82-0.97; P = 5.3 × 10(-5))., Conclusion: We identified a new breast cancer risk variant at 10q25 in East Asian women., Impact: Results from this study improve the understanding of the genetic basis for breast cancer.

In a consortium including 23 637 breast cancer patients and 25 579 controls of East Asian ancestry, we investigated 70 single-nucleotide polymorphisms (SNPs) in 67 independent breast cancer susceptibility loci recently identified by genome-wide association studies (GWASs) conducted primarily in European-ancestry populations. SNPs in 31 loci showed an association with breast cancer risk at P < 0.05 in a direction consistent with that reported previously. Twenty-one of them remained statistically significant after adjusting for multiple comparisons with the Bonferroni-corrected significance level of <0.0015. Eight of the 70 SNPs showed a significantly different association with breast cancer risk by estrogen receptor (ER) status at P < 0.05. With the exception of rs2046210 at 6q25.1, the seven other SNPs showed a stronger association with ER-positive than ER-negative cancer. This study replicated all five genetic risk variants initially identified in Asians and provided evidence for associations of breast cancer risk in the East Asian population with nearly half of the genetic risk variants initially reported in GWASs conducted in European descendants. Taken together, these common genetic risk variants explain ~10% of excess familial risk of breast cancer in Asian populations.

Background: Genome-wide association studies (GWASs) have identified multiple genetic susceptibility loci for breast cancer. However, these loci explain only a small fraction of the heritability. Very few studies have evaluated copy number variation (CNV), another important source of human genetic variation, in relation to breast cancer risk., Methods: We conducted a CNV GWAS in 2623 breast cancer patients and 1946 control subjects using data from Affymetrix SNP Array 6.0 (stage 1). We then replicated the most promising CNV using real-time quantitative polymerase chain reaction (qPCR) in an independent set of 4254 case patients and 4387 control subjects (stage 2). All subjects were recruited from population-based studies conducted among Chinese women in Shanghai., Results: Of the 268 common CNVs (minor allele frequency ≥ 5%) investigated in stage 1, the strongest association was found for a common deletion in the APOBEC3 genes (P = 1.1×10(-4)) and was replicated in stage 2 (odds ratio =1.35, 95% confidence interval [CI] = 1.27 to 1.44; P = 9.6×10(-22)). Analyses of all samples from both stages using qPCR data produced odds ratios of 1.31 (95% CI = 1.21 to 1.42) for a one-copy deletion and 1.76 (95% CI = 1.57 to 1.97) for a two-copy deletion (P = 2.0×10(-24))., Conclusions: We provide convincing evidence for a novel breast cancer locus at the APOBEC3 genes. This CNV is one of the strongest common genetic risk variants identified so far for breast cancer.

Genome-wide association studies have identified approximately 20 susceptibility loci for breast cancer. A cumulative genetic risk score (GRS) was constructed from 10 variants with replicated associations among participants of the Shanghai Breast Cancer Genetics Study (Shanghai, China, 1996-1998 and 2002-2005). Interactions between the GRS and 11 breast cancer risk factors were evaluated. Among the 6,408 study participants, no evidence of effect modification was found with the GRS for age at menarche, age at menopause, age at first live birth/parity, total months of breastfeeding, family history of breast cancer, history of benign breast disease, hormone replacement therapy, body mass index, waist/hip ratio, or regular physical activity. The effect of the GRS was least homogeneous by duration of menstruation; further analysis indicated a nominally significant interaction with one genetic variant. The mitochondrial ribosomal protein S30 gene (MRPS30) rs10941679 was associated with breast cancer risk only among women with more than 30 years of menstruation (odds ratio = 1.15, 95% confidence interval: 1.05, 1.26). Although this multiplicative interaction reached a nominal significance level (P = 0.037), it did not withstand correction for multiple comparisons. In conclusion, this study revealed no apparent interactions between genome-wide association study-identified genetic variants and breast cancer risk factors in the etiology of this common cancer.

Background: The TGF-β signaling pathway plays a significant role in the carcinogenic process of breast cancer., Methods: We systematically evaluated associations of common variants in TGF-β signaling pathway genes with breast cancer risk using a multistage, case-control study among Asian women., Results: In the first stage, 341 single-nucleotide polymorphisms with minor allele frequencies ≥ 0.05 across 11 genes were evaluated among 2,926 cases and 2,380 controls recruited as a part of the Shanghai Breast Cancer Genetics Study (SBCGS). In the second stage, 20 SNPs with promising associations were evaluated among an additional 1,890 cases and 2,000 controls from the SBCGS. One variant, TGFBR2 rs1078985, had highly consistent and significant associations with breast cancer risk among participants in both study stages, as well as promising results from in silico analysis. Additional genotyping was carried out among 2,475 cases and 2,343 controls from the SBCGS, as well as among 5,077 cases and 5,384 controls from six studies in the Asian Breast Cancer Consortium (stage III). Pooled analysis of all data indicated that minor allele homozygotes (GG) of TGFBR2 rs1078985 had a 24% reduced risk of breast cancer compared with major allele carriers (AG or AA; OR, 0.76; 95% CI, 0.65-0.89; P = 8.42 × 10(-4))., Conclusion: These findings support a role for common genetic variation in TGF-β signaling pathway genes, specifically in TGFBR2, in breast cancer susceptibility., Impact: These findings may provide new insights into the etiology of breast cancer as well as future potential therapeutic targets., (©2012 AACR)

Background: Soy isoflavones have antiestrogenic and anticancer properties but also possess estrogen-like properties, which has raised concern about soy food consumption among breast cancer survivors., Objective: We prospectively evaluated the association between postdiagnosis soy food consumption and breast cancer outcomes among US and Chinese women by using data from the After Breast Cancer Pooling Project., Design: The analysis included 9514 breast cancer survivors with a diagnosis of invasive breast cancer between 1991 and 2006 from 2 US cohorts and 1 Chinese cohort. Soy isoflavone intake (mg/d) was measured with validated food-frequency questionnaires. HRs and 95% CIs were estimated by using delayed-entry Cox regression models, adjusted for sociodemographic, clinical, and lifestyle factors., Results: After a mean follow-up of 7.4 y, we identified 1171 total deaths (881 from breast cancer) and 1348 recurrences. Despite large differences in soy isoflavone intake by country, isoflavone consumption was inversely associated with recurrence among both US and Chinese women, regardless of whether data were analyzed separately by country or combined. No heterogeneity was observed. In the pooled analysis, consumption of ≥10 mg isoflavones/d was associated with a nonsignificant reduced risk of all-cause (HR: 0.87; 95% CI: 0.70, 1.10) and breast cancer-specific (HR: 0.83; 95% CI: 0.64, 1.07) mortality and a statistically significant reduced risk of recurrence (HR: 0.75; 95% CI: 0.61, 0.92)., Conclusion: In this large study of combined data on US and Chinese women, postdiagnosis soy food consumption of ≥10 mg isoflavones/d was associated with a nonsignificant reduced risk of breast cancer-specific mortality and a statistically significant reduced risk of recurrence.

Etiologic differences between subtypes of breast cancer defined by estrogen receptor (ER) and progesterone receptor (PR) status are not well understood. The authors evaluated associations of hormone-related factors with breast cancer subtypes in a population-based case-control study involving 1,409 ER-positive (ER+)/PR-positive (PR+) cases, 712 ER-negative (ER-)/PR-negative (PR-) cases, 301 ER+/PR- cases, 254 ER-/PR+ cases, and 3,474 controls aged 20-70 years in Shanghai, China (phase I, 1996-1998; phase II, 2002-2005). Polytomous logistic regression and Wald tests for heterogeneity across subtypes were conducted. Breast cancer risks associated with age at menarche, age at menopause, breastfeeding, age at first livebirth, waist-to-hip ratio, and oral contraceptive use did not differ by hormone receptor status. Among postmenopausal women, higher parity (≥2 children vs. 1) was associated with reduced risk (odds ratio (OR) = 0.69, 95% confidence interval (CI): 0.52, 0.91) and higher body mass index (BMI; weight (kg)/height (m)(2)) with increased risk (highest quartile: OR = 2.40, 95% CI: 1.65, 3.47) of the ER+/PR+ subtype but was unrelated to the ER-/PR- subtype (for parity, P(heterogeneity) = 0.02; for BMI, P(heterogeneity) < 0.01). Hormone replacement therapy (OR = 2.25, 95% CI: 1.40, 3.62) and alcohol consumption (OR = 1.59, 95% CI: 1.01, 2.51) appeared to be preferentially associated with the ER+/PR- subtype. These findings indicate that BMI, parity, hormone replacement therapy, and alcohol consumption may play different roles in subtypes of breast cancer. More research is needed to better understand the etiology of 2 relatively rare subtypes, ER+/PR- tumors and ER-/PR+ tumors.

It has been suggested that exercise following breast cancer diagnosis is inversely associated with mortality. However, controversy exists regarding the causality of such associations. We evaluated associations of exercise after breast cancer diagnosis with total mortality and recurrence/disease-specific mortality, accounting for conditions that restrict exercise participation. The analysis included 4,826 women with stage I to III breast cancer identified 6 months after diagnosis through the population-based Shanghai Cancer Registry and recruited into the study between 2002 and 2006. Exercise was assessed approximately 6, 18, and 36 months postdiagnosis, and metabolic equivalent (MET) scores were derived. Information on medical history, cancer diagnosis, treatments, quality of life (QOL), anthropometrics, and lifestyles were obtained by in-person interviews at 6 months postdiagnosis. Medical charts were abstracted to verify clinical information. During the median follow-up of 4.3 years, 436 deaths and 450 recurrences/cancer-related deaths were documented. After adjustment for QOL, clinical prognostic factors, and other covariates, exercise during the first 36 months postdiagnosis was inversely associated with total mortality and recurrence/disease-specific mortality with HRs of 0.70 (95% CI: 0.56-0.88) and 0.60 (95% CI: 0.47-0.76), respectively. Significant dose-response relationships between total and recurrence/disease-specific mortality rates and exercise duration and MET scores were observed (all values for P(trend) < 0.05). The exercise-mortality associations were not modified by menopausal status, comorbidity, QOL, or body size assessed at approximately 6 months postdiagnosis. An interaction between disease stage and hormone receptor status and total mortality was noted. Our study suggests that exercise after breast cancer diagnosis may improve overall and disease-free survival., (©2011 AACR.)

Background: Molecular classification of breast cancer is an important prognostic factor. The distribution of molecular subtypes of breast cancer and their prognostic value has not been well documented in Asians., Methods: A total of 2,791 breast cancer patients recruited for a population-based cohort study were evaluated for molecular subtypes of breast cancer by immunohistochemical assays. Data on clinicopathological characteristics were confirmed by centralized pathology review. The average follow-up of the patients was 53.4 months. Overall and disease-free survival by molecular subtypes of breast cancer were evaluated., Results: The prevalence of the luminal A, luminal B, human epidermal growth factor receptor 2 (HER2), and triple-negative subtypes were 48.6%, 16.7%, 13.7%, and 12.9%, respectively. The luminal A subtype was more likely to be diagnosed in older women (P = 0.03) and had a stronger correlation with favorable clinicopathological factors (smaller tumor size, lower histologic grade, and earlier TNM stage) than the triple-negative or HER2 subtypes. Women with triple-negative breast cancer had a higher frequency of family history of breast cancer than women with other subtypes (P = 0.048). The 5-year overall/disease-free survival percentages for the luminal A, luminal B, HER2, and triple-negative subtypes were 92.9%/88.6%, 88.6%/85.1%, 83.2%/79.1%, and 80.7%/76.0%, respectively. A similar pattern was observed in multivariate analyses. Immunotherapy was associated with improved overall and disease-free survival for luminal A breast cancer, but reduced disease-free survival (HR = 2.21, 95% CI, 1.09-4.48) for the HER2 subtype of breast cancer., Conclusions: The triple-negative and HER2 subtypes were associated with poorer outcomes compared with the luminal A subtype among these Chinese women. The HER2 subtype was more prevalent in this Chinese population compared with Western populations, suggesting the importance of standardized HER2 detection and anti-HER2 therapy to potentially benefit a high proportion of breast cancer patients in China.

Background: Self-reported information is an important tool for collecting clinical information for epidemiologic studies and in clinical settings where electronic medical records are not employed and shared., Methods: Using data collected from the Shanghai Breast Cancer Survival Study (SBCSS), a population-based, prospective cohort study of 5,042 women diagnosed with breast cancer in Shanghai, China, we compared the concordance of patient questionnaire responses to a survey administered approximately 6 months after cancer diagnosis with medical chart information obtained from the diagnostic hospitals for several disease and treatment-related variables., Results: Of 5,042 SBCSS participants, medical chart information was available for 4,948 women (98.1%). Concordance between patient self-reported and medical chart information was high for the majority of disease-related variables, including: diagnosing hospital (agreement: 98.7%, kappa: 0.99), type of surgery conducted (94.0%, 0.53), ER/PR status (94.5%, 0.91), and tumor position (98.2%, 0.97), as well as for important calendar dates, such as date of diagnosis, surgery, and first chemotherapy treatment. The 10 most commonly used chemotherapeutic drugs were all reported with agreement rates of at least 82%, with associated kappa values that ranged from 0.41 for calcium folinate to 0.76 for vinorelbine., Conclusions: Our study found high validity for patient self-reported information for a variety of disease and treatment-related variables, suggesting the utility of self-reports as an important source of clinical information for both epidemiological research and patient care.

In previous studies among 1,144 cases and 1,256 controls recruited in stage 1 of the Shanghai Breast Cancer Study (SBCS I; 1996-1998), 18 known or potentially functional single nucleotide polymorphisms (SNPs) in 16 genes were found to be associated with breast cancer risk. The authors evaluated these associations among 1,918 cases and 1,819 controls recruited in stage 2 of the SBCS (SBCS II; 2002-2005) using genetic effect models and subgroup analyses predetermined from SBCS I results. Five SNPs (AHR rs2066853, ATM rs1003623, ESR1 rs2234693, GSTP1 rs1695, and SHBG rs6259) showed generally consistent results in SBCS I and SBCS II and statistically significant associations with breast cancer risk in combined analyses, mostly in subgroups defined by age or menopausal status. Further, the relation between breast cancer risk and SHBG rs6259 was found to vary by body mass index (weight (kg)/height (m)(2)) (P for interaction = 0.003). The strongest reduction in risk associated with SHBG rs6259 was found for lean (body mass index <23) postmenopausal minor allele carriers (odds ratio = 0.6, 95% confidence interval: 0.5, 0.8; P = 4.6 × 10(-4)). This biologically plausible and highly significant finding provides strong evidence for a true association among Asian women. This study also highlights the value of gene-environment interaction analyses in evaluating genetic factors for complex diseases.

The fibroblast growth factor receptor 2 gene (FGFR2) has been associated with the risk of breast cancer in multiple ethnic populations, and its effect has been suggested to be hormone-dependent. A large, 2-stage, population-based case-control study was conducted in urban Shanghai, China, during the periods of 1996-1998 and 2002-2005. Exposure and genotyping information from 2,073 patients with breast cancer and 2,084 age-matched population controls was available for evaluation of the interactions between FGFR2 polymorphisms and exogenous estrogen exposure in the development of breast cancer. A logistic regression model was used to compute adjusted odds ratios and 95% confidence intervals. Of 20 genotyped and 25 imputed single nucleotide polymorphisms (SNPs), 22 were significantly associated with breast cancer. Three genotyped SNPs in close linkage disequilibrium, rs2303568, rs3135730, and rs1078806, and an imputed SNP of rs755793 in complete linkage disequilibrium with other 8 SNPs were observed to interact significantly with oral contraceptive (OC) use. The SNP-cancer association was evident only among OC users, and the OC use was only associated with the risk of breast cancer among carriers of these minor alleles at these loci. These findings suggest that genetic variants in FGFR2 may modify the role of OC use in causing breast cancer in Chinese women.

Background: In addition to mediating aspects of physiologic and pathologic angiogenesis, the VEGF family also contributes to carcinogenesis., Methods: We comprehensively characterized genetic variation across four VEGF family genes and evaluated associations with breast cancer risk with odds ratios (OR) and 95% CIs for participants of the two-stage case-control Shanghai Breast Cancer Genetics Study (SBCGS). Stage 1 evaluated 200 single nucleotide polymorphisms (SNP) across two VEGF ligands (VEGFA and VEGFC) and two VEGF receptors (FLT1/VEGFR1 and KDR/VEGFR2) among 2,079 cases and 2,148 controls. Five SNPs with promising associations were assessed in stage 2 among 4,419 cases and 1,851 controls., Results: Two SNPs were consistently associated with breast cancer risk across our two study stages and were significant in combined analyses. Compared with FLT1 rs9551471 major allele homozygotes (AA), reduced risks were associated with AG (OR = 0.92, 95% CI: 0.84-1.00) and GG (OR = 0.78, 95% CI: 0.64-0.95) genotypes (P(trend) = 0.005). Compared with VEGFA rs833070 major allele carriers (CC or CT), increased risk was associated with TT genotypes (OR = 1.26, 95% CI: 1.05-1.52, P = 0.016)., Conclusion: Results from our study indicate that common genetic variation in VEGFA and FLT1 (VEGFR1) may contribute to breast cancer susceptibility., Impact: Our findings provide clues for future studies on VEGF family genes in relation to cancer susceptibility and survival., (©2011 AACR.)

Background: Recent genome-wide association studies (GWAS), mostly conducted among women of European ancestry, have identified 16 single-nucleotide polymorphisms (SNP) associated with breast cancer., Methods: We evaluated these SNPs with the risk of breast cancer and further by estrogen receptor status in a population-based study of 6,498 cases and 3,999 controls in Chinese women. We also searched for novel genetic risk variants in four loci, 2q35, 5p12/MRPS30, 8q24.21, and 17q23.2/COX11, in a two-stage study. In stage I, 868 SNPs were analyzed in 2,073 cases and 2,084 controls. In stage II, 58 SNPs selected from stage I were evaluated, including 4,425 cases and 1,915 controls., Results: Statistically significant associations (P < 0.05) were observed for eight GWAS-identified SNPs, including rs4973768 (3p24/SLC4A7), rs889312 (5q11.2MAP3K1), rs2046210 (6q25.1), rs1219648 (10q26.13/FGFR2), rs2981582 (10q26.13/FGFR2), rs3817198 (11p15.5/LSP1), rs8051542 (16q12.1/TOX3), and rs3803662 (16q12.1/TOX3). Two additional SNPs, rs10941679 (5p12/MRPS30) and rs13281615 (8q24.21), showed a marginally significant association. Some of these associations varied by estrogen receptor status. In the fine-mapping analysis, five SNPs showed a consistent association with breast cancer risk in both stages: rs10169372 (2q35), rs283720 (8q24.21), rs10515083 (17q23.2/COX11), rs16955329 (17q23.2/COX11), and rs2787487 (17q23.2/COX11)., Conclusions: This study shows that approximately half of the SNPs initially reported from GWAS of breast cancer in European descendants can be directly replicated in Chinese. Our fine-mapping analyses revealed several candidates of risk variants that can be further evaluated in studies with a larger sample size., Impact: Findings from this study may help guide future fine-mapping studies to identify causal variants for breast cancer., ((c)2010 AACR.)

Background: Most of the genetic variants identified from genome-wide association studies of breast cancer have not been validated in Asian women. No risk assessment model that incorporates both genetic and clinical predictors is currently available to predict breast cancer risk in this population., Methods: We analyzed 12 single-nucleotide polymorphisms (SNPs) identified in recent genome-wide association studies mostly of women of European ancestry as being associated with the risk of breast cancer in 3039 case patients and 3082 control subjects who participated in the Shanghai Breast Cancer Study. All participants were interviewed in person to obtain information regarding known and suspected risk factors for breast cancer. The c statistic, a measure of discrimination ability with a value ranging from 0.5 (random classification) to 1.0 (perfect classification), was estimated to evaluate the contribution of genetic and established clinical predictors of breast cancer to a newly established risk assessment model for Chinese women. Clinical predictors included in the model were age at menarche, age at first live birth, waist-to-hip ratio, family history of breast cancer, and a previous diagnosis of benign breast disease. The utility of the models in risk stratification was evaluated by estimating the proportion of breast cancer patients in the general population that could be accounted for above a given risk threshold as predicted by the models. All statistical tests were two-sided., Results: Eight SNPs (rs2046210, rs1219648, rs3817198, rs8051542, rs3803662, rs889312, rs10941679, and rs13281615), each of which reflected a genetically independent locus, were found to be associated with the risk of breast cancer. A dose-response association was observed between the risk of breast cancer and the genetic risk score, which is an aggregate measure of the effect of these eight SNPs (odds ratio for women in the highest quintile of genetic risk score vs those in the lowest = 1.85, 95% confidence interval = 1.58 to 2.18, P(trend) = 2.5 x 10(-15)). The genetic risk score, the waist-to-hip ratio, and a previous diagnosis of benign breast disease were the top three predictors of the risk of breast cancer, each contributing statistically significantly (P < .001) to the full risk assessment model. The model, with a c statistic of 0.6295 after adjustment for overfitting, showed promise for stratifying women into different risk groups; women in the top 30% risk group accounted for nearly 50% of the breast cancers diagnosed in the general population., Conclusion: A risk assessment model that includes both genetic markers and clinical predictors may be useful to classify Asian women into relevant risk groups for cost-efficient screening and other prevention programs.

In a population-based cohort study of 5,014 women with stage 0-III breast cancer, we evaluated weight change patterns from diagnosis to 6, 18, and 36 months post-diagnosis. Patients were recruited to the study approximately 6 months after cancer diagnosis between 2002 and 2006 and followed through 36 months post-diagnosis. The medians of weight change from diagnosis to 6, 18, and 36 months post-diagnosis were 1.0, 2.0, and 1.0 kg, respectively. Approximately, 26% of survivors gained > or =5% of their at-diagnosis body weight during the first 6 months after diagnosis, while 37% and 33% of women gained the same percentage of weight at 18 and 36 months post-diagnosis. More weight gain was observed among women who had a more advanced disease stage, were younger, had lower body mass index at diagnosis, were premenopausal, or received chemotherapy or radiotherapy during the first 6 months after cancer diagnosis. Multivariate analyses indicated that age at diagnosis, body size, comorbidity, and disease stage independently predicted weight gain from diagnosis to 36 months post-diagnosis. In summary, weight gain is common over the first 3 years after breast cancer diagnosis among Chinese women. More research is needed to investigate measures to prevent weight gain in breast cancer survivors.

The authors evaluated the effect of regular exercise during the first 36 months after cancer diagnosis on quality of life (QOL) in a population-based cohort study of 1,829 Chinese women diagnosed with breast cancer. The women were identified between 2002 and 2004 and were invited to participate in the study about 6 months after cancer diagnosis. Exercise was assessed approximately 6, 18, and 36 months after diagnosis, and a metabolic equivalent task (MET) score in hours per week was derived. A cumulative, weighted exercise-MET score was created for regular exercise during the 36-month postdiagnosis period. QOL was evaluated at 6 and 36 months postdiagnosis. Multiple linear regression and mixed models were conducted to evaluate the association between regular exercise and QOL, with adjustment for clinical prognostic factors and other potential confounders. Both exercise-MET scores measured during the first 6 or 36 months postdiagnosis and the weighted exercise-MET score over the 36-month postdiagnosis period were positively associated with total QOL score and physical, psychological, and social well-being scores assessed at 36 months postdiagnosis (all P for trend < 0.05). Compared with nonregular exercisers, women with higher exercise-MET scores (> or =8.3 MET-hours/week) were more likely to have higher scores for total QOL and specific QOL domains (all P < 0.05). The exercise-QOL association remained stable over time after cancer diagnosis. This study suggests that regular exercise after breast cancer diagnosis improves QOL.

We hypothesized that NRH:quinone oxidoreductase 2 (NQO2) is a candidate susceptibility gene for breast cancer because of its known enzymatic activity on estrogen-derived quinones and its ability to stabilize p53. We performed case-control studies to investigate the contributions of genetic variants/haplotypes of the NQO2 gene to breast cancer risk. In the first hospital-based study (n = 1604), we observed significant associations between the incidence of breast cancer and a 29 bp-insertion/deletion polymorphism (29 bp-I/D) and the rs2071002 (+237A>C) polymorphism, both of which are located within the NQO2 promoter region. Decreased risk was associated with the D-allele of 29 bp-I/D [odds ratio (OR), 0.76; P = 0.0027] and the +237C-allele of rs2071002 (OR, 0.80; P = 0.0031). Specifically, the susceptibility variants within NQO2 were notably associated with breast carcinomas with wild-type p53 (the most significant P-value: 3.3 x 10(-6)). The associations were successfully replicated in an independent population set (familial/early-onset breast cancer cases and community-based controls, n = 1442). The combined P-values of the two studies (n = 3046) are 3.8 x 10(-7) for 29 bp-I/D and 2.3 x 10(-6) for rs2071002. Furthermore, we revealed potential mechanisms of pathogenesis of the two susceptibility polymorphisms. Previous work has demonstrated that the risk-allele I-29 of 29 bp-I/D introduces transcriptional-repressor Sp3 binding sites. Using promoter reporter-gene assays and electrophoretic-mobility-shift assays, our present work demonstrated that the other risk-allele, +237A-allele of rs2071002, abolishes a transcriptional-activator Sp1 binding site. Furthermore, an ex vivo study showed that normal breast tissues harboring protective genotypes expressed significantly higher levels of NQO2 mRNA than those in normal breast tissues harboring risk genotypes. Taken together, the data presented here strongly suggest that NQO2 is a susceptibility gene for breast carcinogenesis.

Green tea is a commonly consumed beverage in China. Epidemiological and animal data suggest tea and tea polyphenols may be preventive against various cancers, including breast cancer. Catechol-O-methyltransferase (COMT) catalyzes catechol estrogens and tea polyphenols. The COMT rs4680 AA genotype leads to lower COMT activity, which may affect the relationship between green tea consumption and breast cancer risk. We evaluated whether regular green tea consumption was associated with breast cancer risk among 3454 incident cases and 3474 controls aged 20-74 y in a population-based case-control study conducted in Shanghai, China during 1996-2005. All participants were interviewed in person about green tea consumption habits, including age of initiation, duration of use, brew strength, and quantity of tea. Odds ratios (OR) and 95% CI were calculated for green tea consumption measures and adjusted for age and other confounding factors. Compared with nondrinkers, regular drinking of green tea was associated with a slightly decreased risk for breast cancer (OR, 0.88; 95% CI, 0.79-0.98). Among premenopausal women, reduced risk was observed for years of green tea drinking (P-trend = 0.02) and a dose-response relationship with the amount of tea consumed per month was also observed (P-trend = 0.046). COMT rs4680 genotypes did not have a modifying effect on the association of green tea intake with breast cancer risk. Drinking green tea may be weakly associated with a decreased risk of breast cancer.

Background: Data from the Shanghai Breast Cancer Study were analyzed to evaluate the relationship between benign breast disease (BBD) and breast cancer among Chinese women with a self-report of physician-diagnosed BBD., Methods: Study participants consisted of 3,452 breast cancer cases and 3,474 population controls recruited by the Shanghai Breast Cancer Study. In-person interviews were conducted to collect information on demographics and suspected risk factors for breast cancer, including a detailed history of BBD. Unconditional logistic regression was used to derive adjusted odds ratios (OR(adj)) and 95% confidence intervals (CI) for the association between self-reported BBD and breast cancer., Results: Women with breast cancer were significantly more likely to have a self-reported history of BBD including lobular proliferation (OR(adj) = 1.6; 95% CI 1.4-1.8), fibroadenoma (OR(adj) = 1.9; 95% CI 1.6-2.3), and other BBD (OR(adj) = 1.6; 95% CI 1.3-2.1). Breast cancer risk was lower for surgically treated fibroadenoma as compared to non-surgically treated and higher for other BBDs that were surgically treated versus non-surgically treated., Conclusions: Our results suggest that personal history of BBD is associated with an increased risk of future breast cancer among women in China. Surgical intervention for fibroadenoma may reduce the risk.