Shanghai Breast Cancer Survival Study Research Articles

Association between chronic pain and quality of life in long-term breast cancer survivors: a prospective analysis.

Pain is a leading cause of disability worldwide and is highly prevalent among breast cancer survivors. Pain and quality of life (QOL) are associated in breast cancer patients undergoing active treatment, but little is known about the relationship between the two in long-term survivors. We evaluated associations between pain information collected during a 5-year post-diagnosis follow-up survey and QOL assessed by the SF-36 during a 10-year post-diagnosis survey for 2828 participants in the Shanghai Breast Cancer Survival Study. The mean overall QOL score was 78.7 for the entire study population and decreased as pain severity and frequency measured at the 5-year timepoint increased (none: 81.9, mild: 75.9, moderate/severe: 70.4, infrequent: 76.7, frequent: 72.3; P < 0.001). Significant inverse associations were found between pain and all QOL domains, including pain at 10-years post-diagnosis after multivariate adjustments. Concurrent pain was significantly and strongly associated with QOL. Most of the associations between 5-years post-diagnosis pain and QOL at 10-years post-diagnosis persisted after further adjustment for concurrent pain. Pain is associated prospectively and concurrently with poor QOL among long-term breast cancer survivors. Programs to manage pain are needed to improve QOL among breast cancer survivors.

Chronic pain and its correlates among long-term breast cancer survivors.

Chronic pain is a common symptom affecting quality of life for breast cancer survivors. However, its prevalence and correlate factors in long-term breast cancer survivors, particularly Asian women, are understudied. The reported study is to address these knowledge gaps. We evaluated pain severity and frequency, and their associations with clinical features and lifestyle factors among 3640 5-year breast cancer survivors who participated in the Shanghai Breast Cancer Survival Study. Demographic, clinical, and lifestyle information was collected at study enrollment, which occurred 6months post-diagnosis, and pain was assessed at the 5-year post-diagnosis follow-up survey. In total, 42% of participants reported experiencing pain. Pain is more prevalent among survivors with low educational attainment or low income. Multivariable polytomous regression analyses showed that pain was positively associated with metastasis or recurrence (moderate pain OR: 2.17, 95% CI: 1.45, 3.26, frequent pain OR: 1.92, 95% CI: 1.37, 2.70), triple negative status (infrequent pain OR: 1.36, 95% CI: 1.04, 1.78), obesity (frequent pain OR: 1.80, 95% CI: 1.41, 2.31), and multiple comorbidities. Exercise (OR: 0.65, 95%: 0.49, 0.88), chemotherapy (OR: 0.59, 95% CI: 0.41, 0.849), and HER2-positive and ER/PR-negative status (OR: 0.64, 95% CI: 0.43, 0.97) were inversely associated with moderate pain. Chronic pain is highly prevalent among long-term breast cancer survivors in China and was associated with obesity, physical inactivity, and several clinical factors. This study highlights the importance of promoting weight control and exercise to alleviate chronic pain.

Nut consumption in association with overall mortality and recurrence/disease-specific mortality among long-term breast cancer survivors.

High nut consumption is associated with reduced total and certain cause-specific mortality in general populations. However, its association with cancer outcomes among long-term breast cancer survivors remains unknown. We examined the associations of nut consumption (including peanuts and tree nuts), assessed at 5-year postdiagnosis, with overall survival (OS) and disease-free survival (DFS) among 3449 long-term breast cancer survivors from the Shanghai Breast Cancer Survival Study, applying Cox regression analysis. During a median follow-up of 8.27 years post dietary assessment, there were 374 deaths, including 252 breast cancer deaths. Among 3274 survivors without previous recurrence at the dietary assessment, 209 developed breast cancer-specific events, that is, recurrence, metastasis or breast cancer mortality. At 5-year post dietary assessment (ie, 10-year postdiagnosis), regular nut consumers had higher OS (93.7% vs 89.0%) and DFS (94.1% vs 86.2%) rates. After multivariable adjustment, nut consumption was positively associated with OS (Ptrend =.022) and DFS (Ptrend =.003) following a dose-response pattern, with hazard ratios (95% confidence interval) of 0.72 (0.52-1.05) for OS and 0.48 (0.31-0.73) for DFS, for participants with greater than median nut intake compared with nonconsumers. The associations did not vary by nut type. Stratified analyses showed that the associations were more evident among participants with a higher total energy intake for OS (Pinteraction =.02) and among participants with early stage (I-II) breast cancers for DFS (Pinteraction =.04). The nut-DFS associations were not modified by estrogen receptor/progesterone receptor status or other known prognostic factors. In conclusion, nut consumption was associated with better survival, particularly DFS, among long-term breast cancer survivors.

Prediction models for breast cancer prognosis among Asian women.

Robust and reliable prognosis prediction models have not been developed and validated for Asian patients with breast cancer, a rapidly growing yet understudied population in the United States. We used longitudinal data from the Shanghai Breast Cancer Survival Study, a population-based prospective cohort study (n = 5042), to develop prediction models for 5- and 10-year disease-free survival (DFS) and overall survival (OS). The initial models considered age at diagnosis, tumor grade, tumor size, number of positive nodes, TNM stage, chemotherapy, tamoxifen therapy, and estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status. We then evaluated whether the addition of modifiable lifestyle factors (physical activity, soy isoflavones intake, and postdiagnostic weight change) improved the models. All final models have been validated internally and externally in the National Cancer Database when applicable. Our final models included age at diagnosis, tumor grade, tumor size, number of positive nodes, TNM stage, chemotherapy, tamoxifen therapy, ER status, PR status, 6-month postdiagnostic weight change, interaction between ER status and tamoxifen therapy, and interaction between age and TNM stage. The internal validation yielded C-statistics of 0.76, 0.74, 0.78, and 0.75 for 5-year DFS, 10-year DFS, 5-year OS, and 10-year OS, respectively. The external validation yielded C-statistics of 5- and 10-year OS both at 0.78 for Chinese ethnicity, 0.79 for East Asian ethnicity, and 0.75 and 0.76 for all ethnic groups combined. We developed prediction models for breast cancer prognosis from a large prospective study. Our prognostic models performed very well in women from the United States-particularly in Asian American women-and demonstrated high prediction accuracy and generalizability.

Abstract GS2-05: Genome-wide association study identifies UACA as a modulator of breast cancer chemoresistance and survival

Abstract Prior studies suggest a strong genetic influence on breast cancer prognosis. Six genome-wide association studies (GWAS) on breast cancer prognosis have been published to date. However, none of the reported loci was replicated across studies and only two passed genome-wide significance (P &amp;lt; 5 x 10-8). In the Pathways Study, a prospective cohort of breast cancer survivors begun in Kaiser Permanente Northern California (KPNC) in 2006, we carried out a GWAS of overall survival (OS) in 3,973 patients. Trans-ethnic meta-GWAS identified an association with OS of a locus on chromosome 15 that almost reached genome-wide significance (P = 9.42 x 10-8). This locus spanned the UACA gene, a key regulator of tumor suppressor Par-4. We found that receipt of chemotherapy modified the effect of the UACA locus on OS (Pinteraction = 2.4 x 10-4). This observation led us to hypothesize that the UACA locus effect on OS may be specific to Par-4 dependent chemotherapies, which include anti-HER2 therapy and doxorubicin. We stratified patients into two groups, those who received Par-4 dependent chemotherapy agents versus other patients. In separate trans-ethnic meta-GWAS, the UACA locus was significantly associated with OS in patients taking Par-4 dependent chemotherapies (P = 1.27 x 10-9), while no association was observed in the other patients (P = 0.21). To evaluate whether the UACA gene may be responsible for this association, we performed a transcriptome-wide association study (TWAS) of OS in White patients taking Par-4 dependent chemotherapies. Higher UACA gene expression was significantly associated with OS (P = 4.68 x 10-7), the only gene reaching transcriptome-wide significance (P &amp;lt; 4.34 x 10-6). These results suggest that higher UACA expression may inhibit Par-4 induced apoptosis and lead to stronger chemoresistance and worse survival. We attempted to validate our findings in the independent KPNC Genetic Epidemiology Research on Aging (GERA) cohort. The GERA cohort included only 168 White patients with incident breast cancer after DNA collection who received Par-4 dependent chemotherapies. We found a non-significant association (hazard ratio (HR) = 1.46, P = 0.66) consistent with Pathways Study findings. However, the GERA cohort also included 1,983 prevalent breast cancer patients with biospecimen collection after diagnosis. In this group, the risk allele frequency in breast cancer survivors receiving Par-4 dependent chemotherapies was significantly lower than that in the White population (P = 5.50 x 10-3) while the risk allele frequency in the those not receiving these chemotherapies was similar to the population (P = 0.07). This is consistent with Pathways Study observations that the UACA locus risk allele significantly increased risk of mortality in patients taking Par-4 dependent chemotherapies. A higher mortality in breast cancer survivors carrying the risk allele would result in decreased risk allele frequency. We further validated our findings in Shanghai Breast Cancer Survival Study (SBCSS)and Shanghai Breast Cancer Study, which were conducted from 1996 to 2006 in urban Shanghai and recruited 5,575 breast cancer patients. In this independent Asian breast cancer population, the UACA locus was modestly associated with OS in the overall population (HR = 1.18, P = 0.012), and more significantly in 1,289 SBCSS patients who received anthracyclines (HR = 1.66, P = 1.55 x 10-4). This is the first human study suggesting the Par-4 pathway affects breast cancer patient survival with UACA a key modulator of treatment outcomes by anti-Her2 therapy and doxorubicin. Our findings suggest a path toward new predictive pharmacogenetic markers for personalized medicine targeting the Par-4 pathway for breast cancer treatment. Citation Format: Lawrence H Kushi, Qianqian Zhu, Emily Schultz, Jirong Long, Janise M Roh, Emily Valice, Cecile A Laurent, Li Yan, Isaac J Ergas, Warren Davis, Dilrini K Ranatunga, Marilyn L Kwan, Ping-Ping Bao, Wei Zheng, Xiao-Ou Shu, Christine B Ambrosone, Song Yao. Genome-wide association study identifies UACA as a modulator of breast cancer chemoresistance and survival [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS2-05.

Association between lincRNA expression and overall survival for patients with triple-negative breast cancer.

Long intergenic non-coding RNAs (lincRNAs) are increasingly recognized as important regulators for pathogenesis and/or prognosis of breast cancer, including triple-negative breast cancer (TNBC) subtype. However, few previous studies used RNA-sequencing (RNA-Seq) technology, and none included an independent replication. To systematically evaluate the association between expression of lincRNAs and TNBC survival, we examined lincRNA expression profiles in TNBC tissues using RNA-Seq data for 200 TNBC patients from the Shanghai Breast Cancer Survival Study (SBCSS) and Southern Community Cohort Study (SCCS). Twenty-five lincRNAs were found to be associated with overall survival (P < 0.05 and no significant heterogeneity across studies at Q statistic P > 0.1), and 61 lincRNAs were associated with disease-free survival (DFS). Among these, two lincRNAs (LINC01270 and LINC00449) were significantly associated with both worse overall survival and DFS and were expressed at significantly higher levels in tumor tissues compared with adjacent normal breast tissues (log2[Fold Change] > 0.5 and FDR < 0.05). We further evaluated the potential functions of LINC01270 and LINC00449 using in vitro functional experiments and found that siRNA-mediated knockdown of LINC01270 and LINC00449 expression significantly decreased cell viability, colony formation and cell migration ability in TNBC cells (P < 0.05). Evidence from observational studies and in vitro experiments indicates that LINC00449 and LINC01270 may be prognostic biomarkers for TNBC.

Adherence to Dietary Recommendations among Long-Term Breast Cancer Survivors and Cancer Outcome Associations.

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. 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. 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. 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. Our study highlights the importance of overall dietary quality among long-term breast cancer survivors.

Soy Food Consumption, Exercise, and Body Mass Index and Osteoporotic Fracture Risk Among Breast Cancer Survivors: The Shanghai Breast Cancer Survival Study.

BackgroundBreast cancer survivors have a high incidence of osteoporosis-related fractures; the associated factors are understudied. We investigated incidence of bone fracture and its associations with soy food consumption, exercise, and body mass index among breast cancer survivors.MethodsThis prospective study included 4139 stage 0–III breast cancer patients and 1987 pre-/perimenopausal and 2152 postmenopausal patients. Fractures were assessed at 18 months and at 3, 5, and 10 years after cancer diagnosis. Osteoporotic fractures were defined as fractures caused by falls from standing height and at sites associated with osteoporosis. Exercise and soy isoflavone intake were assessed at 6 and 18 months postdiagnosis. Weight and height were measured at baseline. Lifetable and Cox regression analyses were employed. All statistical tests were two sided.ResultsThe 10-year incidence for osteoporotic fractures was 2.9% and 4.4% for pre-/perimenopausal and postmenopausal patients, respectively. High soy isoflavone intake was associated with reduced risk among pre-/perimenopausal patients (hazard ratio [HR] = 0.22, 95% confidence interval [CI] = 0.09 to 0.53, for soy isoflavone mg/d ≥56.06 vs <31.31; Ptrend < .001) but not among postmenopausal patients (Pinteraction < .01). Overweight (vs normal weight) was a risk factor for pre-/perimenopausal patients (HR = 1.81, 95% CI = 1.04 to 3.14) but not for postmenopausal patients (HR = 0.67, 95% CI = 0.43 to 1.03; Pinteraction = .01). Exercise was inversely associated with osteoporotic fractures in postmenopausal patients (HR = 0.56, 95% CI = 0.33 to 0.97, for metabolic equivalents hours ≥12.6 vs <4.5) following a dose-response pattern (Ptrend = .035), an association not modified by menopausal status.ConclusionsOur findings, especially the novel association of soy food intake with osteoporotic fractures in breast cancer survivors, if confirmed, can help guide future strategies for fracture risk reduction in this vulnerable population.

Abstract 4254: Associations of sleep, quality of life and energy level with breast cancer mortality and recurrence: The Shanghai Breast Cancer Survival Study

Abstract Background: Sleep disorder is highly prevalent among breast cancer patients. Whether sleep disorder is associated with breast cancer prognosis has rarely been investigated. The objective of this study is to prospectively assess the association of self-reported sleep difficulty and sleep quality with total mortality and breast-cancer specific mortality/recurrence in the Shanghai Breast Cancer Survival Study. Methods: This study included 4,219 women with stage I-III breast cancer diagnosed at an age between 20 to 75 years. Information on sleep attributes was collected at approximately 18 months and 36 months after breast cancer diagnosis. Information on disease recurrence and survival status was obtained via in-person follow-up and via record linkage with vital statistics registry data. Cox proportional hazard model was used to derive hazard ratios (HR) and confidence intervals (CIs) for all-cause mortality and breast cancer-specific mortality/recurrence. Stratified analyses according to self-reported overall quality of life, depression and energy level assessed at 18 months were also conducted. Results: During a median follow-up of 9.8 years (range: 0.1-12.2 years), 757 deaths due to any causes and 672 breast cancer recurrences or related deaths were recorded after the 18-month post-diagnosis survey. Sleep difficulty and low sleep quality were not significantly associated with total or breast-cancer specific mortality/recurrence. The respective HRs were 0.98 (95% CI: 0.79, 1.22) and 1.01 (95% CI: 0.77, 1.31) for total mortality and 1.04 (95% CI: 0.82, 1.31) and 0.93 (95% CI: 0.69, 1.26) for breast cancer-specific mortality/recurrence. On the other hand, low quality of life, depression and low energy level were significantly associated with increased total mortality, with HRs of 3.19 (2.45, 4.15), 1.61 (1.21, 2.14) and 1.53 (1.23, 1.91), respectively. These three factors did not modify the association of sleep measurements with breast cancer outcomes (all P-interactions &amp;gt; 0.10). Conclusions: In a large population-based cohort study, we did not observe any significant association of sleep difficulty and poor sleep quality with increased risk of death and recurrence in breast cancer patients. Instead, low quality of life and energy level were found to be associated with disease prognosis and thus they could be important indicators for targeting population with poor breast cancer prognosis. Citation Format: Jingjing Zhu, Pingping Bao, Hui Cai, Liang Shi, Ying Zheng, Wei Zheng, Xiao-ou Shu. Associations of sleep, quality of life and energy level with breast cancer mortality and recurrence: The Shanghai Breast Cancer Survival Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4254.

Gene expression in triple-negative breast cancer in relation to survival

The identification of biomarkers related to the prognosis of triple-negative breast cancer (TNBC) is critically important for improved understanding of the biology that drives TNBC progression. We evaluated gene expression in total RNA isolated from formalin-fixed paraffin-embedded tumor samples using the NanoString nCounter assay for 469 TNBC cases from the Shanghai Breast Cancer Survival Study. We used Cox regression to quantify Hazard Ratios (HR) and corresponding confidence intervals (CI) for overall survival (OS) and disease-free survival (DFS) in models that included adjustment for breast cancer intrinsic subtype. Of 302 genes in our discovery analysis, 22 were further evaluated in relation to OS among 134 TNBC cases from the Nashville Breast Health Study and the Southern Community Cohort Study; 16 genes were further evaluated in relation to DFS in 335 TNBC cases from four gene expression omnibus datasets. Fixed-effect meta-analysis was used to combine results across data sources. Twofold higher expression of EOMES (HR 0.90, 95% CI 0.83-0.97), RASGRP1 (HR 0.89, 95% CI 0.82-0.97), and SOD2 (HR 0.80, 95% CI 0.66-0.96) was associated with better OS. Twofold higher expression of EOMES (HR 0.89, 95% CI 0.81-0.97) and RASGRP1 (HR 0.87, 95% CI 0.81-0.95) was also associated with better DFS. On the contrary, a doubling of FA2H (HR 1.14, 95% CI 1.06-1.22) and GSPT1 (HR 1.33, 95% CI 1.14-1.55) expression was associated with shorter DFS. We identified five genes (EOMES, FA2H, GSPT1, RASGRP1, and SOD2) that may serve as potential prognostic biomarkers and/or therapeutic targets for TNBC.

Associations of dietary intake and supplement use with post-therapy cognitive recovery in breast cancer survivors.

Cognitive impairment induced by cancer therapy is common and can be long lasting after completion of therapy. Little is known on factors that influence recovery from the impairment. We evaluated the associations of dietary intake and supplement use with post-therapy cognitive recovery in a large cohort of breast cancer survivors. This study included 1047 breast cancer patients aged 20-75 who were recruited to the Shanghai Breast Cancer Survival Study between 2002 and 2006 at approximately 6.5 months post-cancer diagnosis. Two cognitive assessments covering immediate memory, delayed memory, verbal fluency, and attention, were conducted at 18 and 36 months post-diagnosis. We used food frequency questionnaire to collect information on their dietary intake and supplement use between 18 and 36 months post-diagnosis. Linear regression models were used to examine the associations of dietary intake and supplement use with mean cognitive scores at 36 months post-diagnosis and with differences in cognitive scores between 18 and 36 months post-diagnosis. Higher vegetable, fruit and fish intake, supplementation with vitamin B and vitamin E, and tea drinking were associated with higher cognitive scores, while alcohol drinking was associated with lower cognitive scores at 36 months post-diagnosis. Vegetable intake was positively associated with improvement in verbal fluency, while tea drinking and fish oil supplementation were associated with greater improvements in delayed memory between 18 and 36 months post-diagnosis. Our results indicate that higher vegetable intake, tea drinking, and fish oil supplementation may help post-therapy cognitive recovery for cancer patients.

Time-varying effects of prognostic factors associated with long-term survival in breast cancer.

The impact of some prognostic factors on breast cancer survival has been shown to vary with time since diagnosis. However, this phenomenon has not been evaluated in Asians. In the present study, 4886 patients were recruited from the Shanghai Breast Cancer Survival Study, a longitudinal study of patients diagnosed during 2002-2006, with a median follow-up time of 11.2 years. Cox model incorporating time-by-covariate interactions was used to describe the time-varying effects of prognostic factors related to overall survival and disease-free survival. Age ≥65 years showed a progressively negative effect on breast cancer prognosis over time, whereas tumour size >2 cm had a lasting and constant impact. Age significantly modified the effects of the tumour grade, nodal status and oestrogen receptor (ER) status on breast cancer survival. The detrimental effect of poorly differentiated tumours was time limited and more obvious in patients aged 45-54 years. Having ≥4 positive lymph nodes had a persistent and negative impact on prognosis, although it attenuated in later years; the phenomenon was more prominent in the 55-64-year age group. ER-positive status was protective in the first 3 years after diagnosis but was related to a higher risk of recurrence in later years; the time-point when ER-positive status turned into a risk factor was earlier in younger patients. These results suggest that older age, positive lymph node status, larger tumour size and ER-positive status are responsible for late death or recurrence in Asian breast cancer survivors. Extended endocrine therapy should be given earlier in younger ER-positive patients.

Body mass index, waist-to-hip ratio and late outcomes: a report from the Shanghai Breast Cancer Survival Study

Obesity has been well studied in relation to breast cancer survival. However, the associations of post-diagnosis obesity and late outcomes (≥5 years after diagnosis) have been much less studied. A total of 4062 5-year disease-free patients were recruited from the Shanghai Breast Cancer Survival Study, a longitudinal study of patients diagnosed during 2002-2006. Cox proportional hazard model with restricted cubic spline were used to evaluate the potential non-linear associations of post-diagnosis body mass index (BMI) and waist-to-hip ratio (WHR) with late all-cause mortality and late recurrence. While no significant association was observed for post-diagnosis BMI or WHR with late recurrence; a U-shaped association was observed for the two measures with late all-cause death. Women with BMI of 25.0 kg/m2 or WHR of 0.83 were at the lowest risk of late all-cause mortality, whereas those with BMI beyond the range of 22.1–28.7 kg/m2 or WHR beyond the range of 0.81–0.86 had a higher risk. ER, stage or menopausal status did not modify the effect of post-diagnosis BMI or WHR on the outcomes. In conclusion, post-diagnosis BMI and WHR, as indicators of overall and central obesity respectively, were associated with late all-cause mortality in U-shaped pattern among long-term breast cancer survivors.

Abstract 2251: Tumor tissue gene expression in association with survival of triple-negative breast cancer

Abstract Triple-negative breast cancer (TNBC) is an aggressive type of cancer with limited treatment options. Previous studies have shown that gene expression profiles were associated with TNBC prognosis. Information on specific genes that are predictive of TNBC outcome is limited. Using data and samples from a cohort of 469 TNBC cases from Shanghai Breast Cancer Survival Study (SBCSS), we systematically evaluated expressions of 302 genes in tumor tissue with survival of TNBC. Genes included in the study are PAM50 genes, genes encoding drug metabolizing enzymes and, genes implicated in TNBC biology and progression based on literature reviews. Gene expression levels were measured in total RNA isolated from formalin-fixed paraffin-embedded breast cancer tissues using the NanoString nCounter assay. Cox regression was applied to evaluate disease-free survival (DFS) and overall survival (OS) in association with gene expression. Analysis was adjusted for known predictors of TNBC outcome, including age, disease stage, basal like subtype and DUSP4 gene expression. During a median follow-up of 5.3 years (range: 0.7-8.9 years), 100 deaths and 92 recurrences/breast cancer deaths were documented. Expression levels of 17 genes were significantly associated with OS, and 15 genes with DFS (P&amp;lt;0.05). The top 5 most significant genes are EOMES (Hazard Ratio, HR = 0.88; 95% Confidence Interval, 95% CI: 0.82-0.96), GZMK (HR = 0.91, 95% CI: 0.85-0.97), TUBB3 (HR = 1.12, 95% CI: 1.03-1.21), SIT1 (HR = 0.90, 95% CI: 0.83-0.98) and ZNF224 (HR = 0.89, 95% CI: 0.81-0.97) for OS, and TUBB3 (HR = 1.14, 95% CI: 1.05-1.24), KRT14 (HR = 1.08, 95% CI: 1.02-1.14), BAG1 (HR = 1.19, 95% CI: 1.05-1.35), CD44 (HR = 0.73, 95% CI: 0.58-0.92) and EOMES (HR = 0.89, 95% CI: 0.82-0.97) for DFS. Study is on-going to replicate the findings of this study. Citation Format: Shuyang Wang, Qiuyin Cai, Hui Cai, Pingping Bao, Jie Wu, Fei Ye, Wei Zheng, Ying Zheng, Xiao-Ou Shu. Tumor tissue gene expression in association with survival of triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2251. doi:10.1158/1538-7445.AM2017-2251

Long-term survival analysis of different breast cancer molecular subtypes: Shanghai Breast Cancer Survival Study

To analyze the survival of breast cancer molecular subtypes and to examine the effect of therapy on the long-term prognosis of different subtypes. This study included 3 586 breast cancer patients with estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2) information in Shanghai Breast Cancer Survival Study, a population-based prospective cohort study established in 2002. Molecular subtypes, based on immunohistochemistry were categorized as follows: Luminal A, Luminal B, HER2, and triple-negative subtype. Characteristics and clinical data were collected through questionnaires and medical records at baseline survey and sequential follow-up surveys. Survival rates of different molecular subtypes were analyzed and compared with Log-rank tests. Multiple Cox regression models were used to evaluate the effect of therapy on long-term prognosis of different molecular subtypes. Among the 3 586 cases, Luminal A, Luminal B, HER2 and triple-negative breast cancer subtypes accounted for 54.5%, 16.6%, 13.9%, and 14.9%, respectively. With a median follow-up of 10.3 years (ranging 0.6 to 12.8 years), the 10-year overall survival (OS) rates for the four subtypes were 82.7% (95% CI: 80.9% to 84.4%), 77.7% (95% CI: 74.1% to 80.8%), 76.3% (95% CI: 72.3% to 79.8%), and 74.8% (95% CI: 70.9% to 78.3%), respectively. The 10-year disease to free survival (DFS) rates were 79.0% (95% CI: 76.7% to 81.0%), 76.0% (95% CI: 71.9% to 79.5%), 73.6% (95% CI: 68.9% to 77.7%), and 74.5% (95% CI: 69.4% to 78.9%), respectively. Significant difference in survival among four subtypes was observed (Log-rank test, P<0.01). Multivariate Cox regression indicated that hormonal therapy can significantly reduce the long-term risk of total mortality and recurrence breast cancer specific mortality among Luminal A subtype patients. Adjuvant chemotherapy could improve the long-term prognosis of triple-negative breast cancer. No benefit from radiotherapy was observed for four subtypes of breast cancer in terms of long-term prognosis. Molecular subtypes based on ER/PR/HER2 could provide important information to predict breast cancer prognosis. The hormonal status was an important basis for individualized therapy and precision medicine.

Body mass index and weight change in relation to triple-negative breast cancer survival.

The aim of this study was to evaluate the influence of body mass index (BMI), weight change on triple-negative breast cancer (TNBC) prognosis in a population-based prospective cohort study. The current analysis included 518 participants diagnosed with TNBC in Shanghai Breast Cancer Survival Study. Weight at 1 year prior to cancer diagnosis, at diagnosis, and at 6, 18 and 36 months after cancer diagnosis and height at 6 months after cancer diagnosis were assessed. Disease-free survival (DFS) and overall survival (OS) were evaluated in relation to BMI and weight change using Cox proportional hazard models. Obesity (BMI ≥ 28.0 kg/m(2)) at 1-year pre-diagnosis was associated with higher risk of total mortality and recurrence/disease-specific mortality, with multivariate hazard ratios (HRs) of 1.79 (95 % CI 1.06-3.03) and 1.83 (95 % CI 1.05-3.21), respectively. The associations between BMI and TNBC prognosis attenuated over time from pre-diagnosis to post-diagnosis. Compared with stable weight (change within 5 %), weight loss ≥5 % at 18- or 36-month post-diagnosis was related with higher risk of total mortality and recurrence/disease-specific mortality. Respective multivariate HRs were 2.08 (95 % CI 1.25-3.46) and 1.42 (95 % CI 0.77-2.63) for OS, and 2.50 (95 % CI 1.45-4.30) and 2.17 (95 % CI 1.14-4.12) for DFS. However, the association of weight loss and OS/DFS attenuated after excluding patients whose weight was measured after recurrence. Weight gain ≥5 % at 18- or 36-month post-diagnosis was associated with a non-significant increased risk of death. The results showed that obesity pre-diagnosis and weight loss post-diagnosis was inversely associated with TNBC prognosis. Emphasis on maintaining stable weight after cancer diagnosis for TNBC patients may be considered.

Modifiable Lifestyle Factors and Triple-negative Breast Cancer Survival: A Population-based Prospective Study.

Very little is known about the effect of modifiable lifestyle factors on outcomes of triple-negative breast cancer. We examined this association in a population-based prospective cohort study of patients with triple-negative breast cancer. A total of 518 women with confirmed triple-negative breast cancer, recruited by the Shanghai Breast Cancer Survival Study, completed 6-, 18-, 36-, and 60-month postdiagnosis surveys. We applied Cox proportional hazard models to evaluate the associations. The mean age at diagnosis was 53.4 (standard deviation = 10.6) years old. After a median follow-up of 9.1 years (range: 0.6-11.8), 128 deaths and 112 recurrences were documented. Exercise during the first 60 months postdiagnosis was inversely associated with total mortality and recurrence/disease-specific mortality with adjusted hazard ratios (HRs) of 0.67 (95% confidence interval [CI] = 0.46, 0.96) and 0.58 (95% CI = 0.39, 0.86), respectively. Women with higher exercise-metabolic equivalent scores (≥7.6 metabolic equivalent-hours/week) and longer duration of exercise (≥2.5 hours/week) had lower risk of total and recurrence/disease-specific mortality than did nonexercisers. Compared with nontea drinkers, survival was better among women who were regular tea drinkers during the first 60 months for all cause (HR = 0.57, 95% CI = 0.34, 0.93) and recurrence/disease-specific mortality (HR = 0.54, 95% CI = 0.31, 0.96). There was no dose-response pattern for tea consumption. No interactions were observed for body mass index, menopausal status, and comorbidity. These findings show that postdiagnosis exercise and tea intake were associated with improved survival among women with triple-negative breast cancer.

ALDH1A1 mRNA expression in association with prognosis of triple-negative breast cancer

ALDH1 is a crucial element in the retinoic acid signaling pathway regulating the self-renewal and differentiation of normal stem cells, and may play an important role in cancer progression. However, research on ALDH1 gene expression and breast cancer prognosis has yielded conflicting results. We evaluated the association between tumor tissue ALDH1A1/ALDH1A3 mRNA expression and triple-negative breast cancer (TNBC) prognosis in the Shanghai Breast Cancer Survival Study (SBCSS, N=463), Nashville Breast Health Study (NBHS, N=86), and Southern Community Cohort Study (SCCS, N=47). Gene expression was measured in RNA isolated from breast cancer tissues. In the SBCSS, higher ALDH1A1 mRNA level was associated with improved disease-free (HR=0.87, 95% CI: 0.80-0.95, per log unit change) and overall survival (HR=0.85, 95% CI: 0.78-0.93 per log unit change) independent of age at diagnosis, TNM stage and treatment. We replicated the findings for overall survival in the NBHS and SCCS (HR = 0.27, 95% CI: 0.10-0.73) and for disease-free survival by a meta-analysis of four publicly-available gene expression datasets (HR = 0.86, 95% CI: 0.76-0.97). No significant association was found for ALDH1A3.Our study suggests high expression of ALDH1A1 mRNA in tumor tissues may be an independent predictor of a favorable TNBC outcome.

Abstract 2773: Association of ALDH1A1 gene expression with survival of triple-negative breast cancer

Abstract Aldehyde dehydrogenases (ALDH) are a family of enzymes that catalyze aldehyde into carboxylic acids via the NAD(P)+-dependent oxidation. Several ALDH family members have been identified in humans, including ALDH1A1, ALDH1A3, ALDH2, ALDH3A1, and ALDH4A1. ALDH1A1 is a crucial element in the retinoic acid signaling pathway regulating the self-renewal and differentiation of normal stem cells. It ALDH1A1 has been suggested as one of breast cancer stem cell markers and may play an important role in breast cancer prognosis. However, previous research on ALDH1A1 and breast cancer prognosis has yielded conflicting results. We analyzed the association between mRNA expression of ALDH1A1 in tumor tissues and survival of triple-negative breast cancer (TNBC: ER-/PR-/HER2-) using data and samples from three cohorts of breast cancer patients, including 469 cases from the Shanghai Breast Cancer Survival Study (SBCSS), 86 cases from the Nashville Breast Health Study (NBHS), and 47 cases from the Southern Community Cohort Study (SCCS). Gene expression levels were measured in total RNA isolated from microdissected archival formalin-fixed paraffin-embedded breast cancer tissues using Nanostring nCounter assays. The associations between ALDH1A1 mRNA expression levels and recurrence/breast cancer mortality and overall mortality were evaluated by multivariate survival analysis using the Cox regression model. Data from the SCCS and NBHS were combined in the analysis because both studies were conducted among US women and had a small sample size. The levels of ALDH1A1 mRNA expression were consistently and positively associated with disease free and overall survival independent of age at diagnosis and TNM stage in both Chinese and US women with TNBC. Compared to those with ALDH1A1 mRNA expression below the median, TNBC patients with ALDH1A1 mRNA expression above the median had a reduced risk of recurrence/breast cancer mortality (HR = 0.60, 95% CI: 0.39-0.92) and overall mortality (HR = 0.70, 95% CI: 0.47-1.05) in the SBCSS and reduced overall mortality in the SCCS/NBHS (HR = 0.27,95% CI: 0.10-0.74). Additional analyses of the SBCSS cohort stratified by basal-like breast cancer subtype showed that ALDH1A1 mRNA expression was similarly associated with reduced risk of recurrence/breast cancer mortality and total mortality in both basal-like and non-basal like TNBC patients, although the point estimates were not significant due to the smaller sample size. In addition, we found that patients with a higher tumor grade had a lower level of ALDH1A1 mRNA expression but did not observe an association with TNM stage. Our study suggests that the mRNA expression of ALDH1A1 in tumor tissue may be associated with favorable clinical outcomes in patients with TNBC. Further investigations are needed to understand the biological mechanism(s) underlying the observed association. Citation Format: Yan Liu, Qiuyin Cai, Ying Zheng, Michelle L. Baglia, Yinghao Su, Sarah Nechuta, Ping-Ping Bao, William Blot, Wei Zheng, Xiao-Ou Shu. Association of ALDH1A1 gene expression with survival of triple-negative breast cancer. [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 2773. doi:10.1158/1538-7445.AM2015-2773

Soy isoflavone intake and bone mineral density in breast cancer survivors.

Low bone mineral density (BMD) is common among breast cancer survivors due to acute estrogen deprivation. Soy food is a rich source of phytoestrogens, namely isoflavones, known to have both estrogenic and anti-estrogenic effects. The objective of the study was to assess the association between soy consumption and BMD in breast cancer survivors, which has not previously been evaluated. Forearm BMD was evaluated using dual-energy X-ray absorptiometry at 60 months post-diagnosis for 1,587 participants of the Shanghai Breast Cancer Survival Study. Soy intakes collected at 6, 18, and 36 months post-diagnosis were averaged, and the association with BMD, osteopenia, and osteoporosis was evaluated using linear and logistic regression. The mean (standard deviation) intake of isoflavones was 48.1 (28.0) mg/day. Soy intake was inversely associated with BMD and positively associated with osteoporosis. Compared with the lowest quartile, the highest quartile of soy isoflavone intake, ≥ 62.64 mg/day, was associated with a reduction of BMD by 1.95% [95% confidence interval (CI) -3.54, -0.36%] and an increased odds ratio of 1.69 for osteoporosis (95% CI 1.09, 2.61). The inverse association was predominantly seen among women who recently entered menopause (≤ 5 years). In contrast to observations from general populations, high soy intake (≥ 62.64 mg of soy isoflavone/day) was associated with lower proximal forearm BMD among breast cancer survivors, particularly during the early years of menopause. Our finding needs to be replicated, particularly in studies with more comprehensive bone density evaluation.