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Background The activation of insulin pathways is hypothesized to promote tumor growth and worsen breast cancer survival. Sugar-sweetened beverages (SSBs) can lead to a higher risk of insulin resistance and may affect survival. The authors prospectively evaluated the relation of postdiagnostic SSB and artificially sweetened beverage (ASB) consumption with mortality among women with breast cancer. Methods In total, 8863 women with stage I through III breast cancer were identified during follow-up of the Nurses' Health Study (NHS; 1980-2010) and Nurses' Health Study II (NHSII; 1991-2011). Women completed a validated food frequency questionnaire every 4 years after diagnosis and were followed until death or the end of follow-up (2014 for the NHS and 2015 for the NHSII). Multivariable Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of breast cancer-specific and all-cause mortality after adjusting for measures of adiposity and other potential predictors of cancer survival. Results With a median follow-up of 11.5 years, 2482 deaths were prospectively documented, including 1050 deaths from breast cancer. Compared with women who had no consumption, women who had SSB consumption after diagnosis had higher breast cancer-specific mortality (>1 to 3 servings per week: HR, 1.31 [95% CI, 1.09-1.58]; >3 servings per week: HR, 1.35 [95% CI, 1.12-1.62]; Ptrend = .001) and all-cause mortality (>1 to 3 servings per week: HR, 1.21 [95% CI, 1.07-1.37]; >3 servings per week: HR, 1.28 [95% CI, 1.13-1.45]; Ptrend = .0001). In contrast, ASB consumption was not associated with higher breast cancer-specific or all-cause mortality. Furthermore, replacing 1 serving per day of SSB consumption with 1 serving per day of ASB consumption was not associated with a lower risk of mortality. Conclusions Higher postdiagnostic SSB consumption among breast cancer survivors was associated with higher breast cancer-specific mortality and death from all causes.

Environmental information transparency signifies a transition from the top-down environmental management towards participatory governance. The cognitive pathways through which environmental informa...

Background: We investigated the associations of postdiagnostic dietary glycemic index (GI), glycemic load (GL), insulin index (II), and insulin load (IL) with breast cancer–specific and all-cause mortality. Methods: Among 8,932 women with stage I–III breast cancer identified in the Nurses' Health Study (NHS; 1980–2010) and NHSII (1991–2011), we prospectively evaluated the associations between postdiagnostic GI, GL, II, and IL, and breast cancer–specific and all-cause mortality. Participants completed a validated food frequency questionnaire every 4 years after diagnosis. Results: During follow-up by 2014 in the NHS and 2015 in the NHSII, 2,523 deaths, including 1,071 from breast cancer, were documented. Higher postdiagnostic GL was associated with higher risk of both breast cancer–specific mortality [HRQ5vsQ1 = 1.33; 95% confidence interval (CI) = 1.09–1.63; Ptrend = 0.008] and all-cause mortality (HRQ5vsQ1 = 1.26; 95% CI = 1.10–1.45; Ptrend = 0.0006). Higher all-cause mortality was also observed with higher postdiagnostic GI (HRQ5vsQ1 = 1.23; 95% CI = 1.08–1.40; Ptrend = 0.001), II (HRQ5vsQ1 = 1.20; 95% CI = 1.04–1.38; Ptrend = 0.005), and IL (HRQ5vsQ1 = 1.23; 95% CI = 1.07–1.42; Ptrend = 0.0003). The associations were not modified by insulin receptor or estrogen receptor status of the tumor, or body mass index. Conclusions: We found that higher dietary GL, reflecting postprandial glucose response, after a breast cancer diagnosis was associated with higher risk of breast cancer–specific mortality. Higher dietary GI, GL, II, and IL after a breast cancer diagnosis were associated with higher risk of death from any cause. Impact: These results suggest that carbohydrate quantity and quality may be important in breast cancer prognosis. See related commentary by McTiernan, p. 252

Leptomeningeal disease (LMD) is an increasingly common complication from solid tumor malignancies with a poor prognosis and limited treatment options. We conducted a single arm Phase II study of combined ipilimumab and nivolumab in patients with LMD from solid tumor malignancies (NCT02939300). Patients received manufacturer-specific dosing regimens of combined ipilimumab and nivolumab based on primary-tumor histology until definitive progression or unacceptable toxicity. The primary end point was rate of overall survival at 3 months (OS3). A Simon two-stage design was used to compare a null hypothesis OS3 of 18% against an alternative of 44%. Eighteen patients with diverse primary tumor histologies were enrolled and all received at least one dose of combined ipilimumab and nivolumab. Median follow up based on patients still alive was 8.0 months (range: 0.5 to 15.9 months). The study met its primary endpoint as 8 of 18 (OS3 0.44; 90% CI: 0.24 to 0.66) patients were alive at three months after enrollment. One third of patients experienced one (or more) grade-3 or higher adverse events possibly related to treatment. Two patients discontinued protocol treatment due to unacceptable toxicity (hepatitis and colitis, respectively). The most frequent adverse events overall included fatigue (N=7), nausea (N=6), fever (N=6), anorexia (N=6) and rash (N=6). Combined ipilimumab and nivolumab has an acceptable safety profile and demonstrates promising activity in LMD patients; this therapeutic approach should be studied in larger, multicenter clinical trials to validate these results as well as better identify patients who will benefit.

Leptomeningeal disease (LMD) is a common complication from solid tumor malignancies with a poor prognosis and limited treatment options. We present a single arm Phase II study of 18 patients with LMD receiving combined ipilimumab and nivolumab until progression or unacceptable toxicity (NCT02939300). The primary end point is overall survival at 3 months (OS3). Secondary end points include toxicity, cumulative time-to-progression at 3 months, and progression-free survival. A Simon two-stage design is used to compare a null hypothesis OS3 of 18% against an alternative of 44%. Median follow up based on patients still alive is 8.0 months (range: 0.5 to 15.9 months). The study has met its primary endpoint as 8 of 18 (OS3 0.44; 90% CI: 0.24 to 0.66) patients are alive at three months. One third of patients have experienced one (or more) grade-3 or higher adverse events. Two patients have discontinued protocol treatment due to unacceptable toxicity (hepatitis and colitis, respectively). The most frequent adverse events include fatigue (N = 7), nausea (N = 6), fever (N = 6), anorexia (N = 6) and rash (N = 6). Combined ipilimumab and nivolumab has an acceptable safety profile and demonstrates promising activity in LMD patients. Larger, multicenter clinical trials are needed to validate these results., Leptomeningeal metastases from solid tumors are a rare complication with a very poor prognosis. Here the authors report the efficacy and safety of combined ipilimumab and nivolumab in patients with leptomeningeal carcinomatosis.

The importance-performance analysis (IPA) has been developed and widely utilized to understand customer satisfaction and prioritize provision strategies based on the assumption that satisfaction is resultant from a preference (perceived importance) for a service and a relevant judgment of its performance. However, little work has been performed to examine to what degree different social groups are satisfied with diverse ecosystem services provided by urban rivers, being a unique yet underinvested public good. This study pioneers the IPA application to systematically analyze local communities' perceived importance of urban rivers' ecosystem services and their perceptions about how well those ecosystem services have been provided by urban rivers in Guangzhou (south China). We found notable importance-performance gaps for 10 out of 12 ecosystem services. The local residents were more dissatisfied with provision performance than the non-locals even though both groups of residents could explicitly recognize the importance of urban rivers' ecosystem services. Enhancement of water purification was ranked first amongst all ecosystem services by all respondents, irrespective of respondents' hukou status (Chinese household registration system) and residing environment. Thus, this ecosystem service should be prioritized in relevant management and restoration initiatives. These data provide an accurate picture of potential approaches for the improvement and prioritization of ecosystem services that would satisfy the respective target groups' needs. The IPA offers a mechanism to help match local residents' needs with ecosystem services provision. The IPA also has promise as a means of helping decision-makers and practitioners to communicate effectively with various social groups holding diverging expectations and levels of satisfaction. Such communication is essential to curate urban spaces enjoyed and appreciated by diverse social groups via inclusive urban ecosystem governance.

Governments worldwide have embraced mandatory environmental information disclosure as a vital and indispensable component of their strategies to improve environmental conditions. However, the pathways through which environmental information disclosure can effectively mobilize public support for environmental management initiatives is not well understood. On the basis of latent class modelling of discrete choice experiment survey data in Shaoguan city (Guangdong province, south China), we investigate the impacts of passive disclosure (public simply receive environmental information) and active disclosure (public purposefully interact with environmental information providers) on residents’ heterogeneous preferences pertaining to an urban river restoration project. We find that passive environmental information transparency could successfully motivate public participation and support, while active environmental information accessibility tends to hinder public participation. Respondents either act as non-supporters, or fail to lucidly convey their preferences, if they have directly contacted local authorities or attended environmental events to purposefully collect environmental information via two-way interactive communications. The positive and favourable effect of passive environmental information disclosure on public environmental participation is notable. Yet, if we fail to enhance the effectiveness of active environmental information disclosure, we will miss a unique opportunity to transform public environmental awareness and interest into a useful catalyst for aligning public support with governmental environmental management goals.

Planning and management of forest parks have been contentious and challenging, as multiple and sometimes conflicting uses must be accommodated, especially in urban and peri-urban areas. Methodologies are thus needed to explore and evaluate development and conservation initiatives as a crucial part of sustainable planning and management process. In China, urban forest parks have been increasingly established aiming at satisfying the recreational demand of citizens in tandem with preserving diverse natural resources to safeguard the ecological resilience and adaptability of urban ecosystems. The transition from the traditional focus on recreational use (emphasizing the improvement of visitors’ visual quality and landscape aesthetics) to multiple uses including ecological and biological preservation (highlighting the minimization of ecological vulnerability) poses an urgent challenge for the planning and management of urban forest parks worldwide. In this study, a geographic information system (GIS) combined with Analytic Hierarchy Process (AHP) approach is explored to objectively quantify and integrate the visual sensitivity and ecological sensitivity of the Tianzhu Mountain National Forest Park, Fujian province, South China. The visual sensitivity is evaluated based on three dimensions: slope, distance and visibility. And the ecological sensitivity is measured with regard to elevation, slope, aspect, forest type, and distance to river. By overlapping of the visual sensitivity and ecological sensitivity maps for the study site, three functional zones are pinpointed, including nature restoration/conservation zone (with high ecological sensitivity and low visual sensitivity or invisible), level 1 development zone (with high visual sensitivity and low/very low ecological sensitivity), as well as level 2 development zone (with moderate visual and ecological sensitivities). Compared with the existing long-term development plan, obvious discrepancies can be identified. Our results can provide scientific decision support for multiple use planning of the study site, and also demonstrate the efficacy of the proposed methodology, which is comprehensive yet convenient, for the sustainable planning of urban and peri-urban forest parks.

Background BCP is uncommon; however, the frequency is increasing due to trends in delayed childbearing. Studies have suggested that some systemic therapies, including doxorubicin and cyclophosphamide, can be delivered safely during pregnancy after the first trimester, whereas agents such as trastuzumab and endocrine therapy are contraindicated due to risk to the fetus. Data remain limited on the efficacy and safety of administering taxane chemotherapy or growth factor support during pregnancy. We retrospectively evaluated the safety of systemic therapies, including paclitaxel and GCSF, as well as clinical outcomes, in a multi-institutional cohort of patients (pts) with BCP. Methods Pts treated for BCP from 1996-2018 from 3 large academic institutions were included. Demographic, oncologic treatment, and obstetric/neonatal outcomes data were obtained from medical records. Disease-free survival (DFS) and overall survival (OS) were estimated by Kaplan-Meier; Log-rank test were used to compare different groups/outcomes. Associations were calculated by Fisher's exact test. Results A total of 114 pts diagnosed with BCP were included. The median age was 35 years (range 25-44) and median gestational age at diagnosis was 18 weeks (range 2-38). BCP was predominantly early stage at diagnosis (stage I 28.0%, stage II 53.5%) and ER+/HER2- negative (48.2%). Sixty-three (55.2%) women received chemotherapy, 13 (11.4%) received paclitaxel and 11 (9.6%) GCSF (daily or depot injections) while pregnant. A total of 78% of pts with HER-2-positive BCP (28/36) received trastuzumab after delivery (11% were treated before 2005 and 5.5% were T1a). With median follow-up of 67.7 months, median DFS (stage I-III) was 212.8 months (CI 95% 108.4-317.1), and median OS (stage I-IV) was not reached. Subgroup analysis suggested a higher DFS for pts diagnosed in the 1sttrimester compared to the 3rdtrimester among women with stage II-III (HR 0.25 CI 95% 0.09-0.70, p= 0.03). Among women who received paclitaxel, there was no significant increase in adverse obstetrical/neonatal outcomes: preterm delivery (23.1% vs 13.1%, p 0.39), low weight newborn (7.7% vs 9.1 %, p 1.0), congenital malformations (0% vs 6.1%, p 1.0) or acute neonatal adverse outcomes (7.7% vs 4.0%, p 0.51), which include NICU need and Apgar 5' Conclusion In this multi-institution cohort of BCP pts, despite a small number of pts, exposure to contemporary therapies including paclitaxel was not associated with unfavorable obstetrical/neonatal outcomes and these results suggest it is safe to administer during pregnancy under the care of a multidisciplinary team. Although not statistically significant, GCSF presented numerical worse outcomes and combining data from several cohorts would be helpful to provide confirmation of these findings. Citation Format: Exman P, Freret TS, Economy KE, Chen WY, Parsons HA, Lin NU, Moy B, Tung NM, Partridge AH, Mayer EL. Outcomes and safety of paclitaxel and granulocyte-colony stimulating factor (GCSF) in breast cancer in pregnancy (BCP) - A multi-institutional retrospective analysis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-17-02.

Blastoid and pleomorphic mantle cell lymphomas (MCLs) are variants of aggressive histology MCL (AH-MCL). AH-MCL can arise de novo (AH-DN) or transform from prior classic variant MCL (AH-t). This study is the first integrated analysis of clinical and genomic characteristics of AH-MCL. Patient characteristics were collected from diagnosis (AH-DN) and at transformation (AH-t). Survival after initial diagnosis (AH-DN) and after transformation (AH-t) was calculated. Regression tree analysis was performed to evaluate prognostic variables and in univariate and multivariate analyses for survival. Whole-exome sequencing was performed in evaluable biopsy specimens. We identified 183 patients with AH-MCL (108 were AH-DN, and 75 were AH-t; 152 were blastoid, and 31 were pleomorphic). Median survival was 33 months (48 and 14 months for AH-DN and AH-t, respectively; P = .001). Factors associated with inferior survival were age (≥72 years), AH-t category, Ki-67 ≥50% and poor performance status. AH-t had a significantly higher degree of aneuploidy compared with AH-DN. Transformed MCL patients exhibited KMT2B mutations. AH-MCL patients with Ki-67 ≥50% had exclusive mutations in CCND1, NOTCH1, TP53, SPEN, SMARCA4, RANBP2, KMT2C, NOTCH2, NOTCH3, and NSD2 compared with low Ki-67 (

We evaluated the relation of fruit and vegetable consumption, including specific fruits and vegetables, with incident breast cancer characterized by menopausal status, hormone receptor status and molecular subtypes. Fruit and vegetable consumption, cumulatively averaged across repeated, validated questionnaires, was examined in relation to risk of invasive breast cancer among 182,145 women initially aged 27-59 years in the Nurses' Health Study (NHS, 1980-2012) and NHSII (1991-2013). Cox proportional hazards regression, adjusted for known risk factors, was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) and assessed tumors by hormone receptor status and molecular subtypes. We prospectively documented 10,911 invasive breast cancer cases. Greater intake of total fruits and vegetables, especially cruciferous and yellow/orange vegetables, was associated with significantly lower breast cancer risk (>5.5 vs. ≤2.5 servings/day HR = 0.89, 95% CI = 0.83-0.96; ptrend = 0.006). Intake of total vegetables was especially associated with lower risk of estrogen receptor negative tumors (HR per 2 additional servings/day as a continuous variable = 0.84, 95%CI = 0.77-0.93; pheterogeneity = 0.02). Among molecular subtypes, higher intake of total fruits and vegetables (HR per 2 additional servings/day as a continuous variable) was most strongly associated with lower risk of human epidermal growth factor receptor 2 (HER2)-enriched (HR = 0.79, 95%CI = 0.67-0.93), basal-like (HR = 0.84, 95%CI = 0.72-0.97) and luminal A (HR = 0.94, 95%CI = 0.89-0.99), but not with luminal B tumors (pheterogeneity = 0.03). In conclusion, our findings support that higher intake of fruits and vegetables, and specifically cruciferous and yellow/orange vegetables, may reduce the risk of breast cancer, especially those that are more likely to be aggressive tumors.

Urban forests are important landscape components in cities around the world that offer multiple functionality, thereby serve as a nature-based solution to offsetting negative social-ecological effects brought by urbanization. While the recreational function, as a traditional focus of urban forests, has been primarily emphasized in Chinese cities, the emerging ecological civilization, as a national guiding institution, has gradually brought ecological dimension into urban forest construction and management. By combining statistical data and satellite image data covering 31 key-cities in mainland China, we attempt to quantitatively analyze the transition of urban forests with regard to two intertwined, critical dimensions: recreational potential (proxied by public park space per capita) and habitat potential (proxied by the percentage of core habitat that is not subject to significant disturbances and thus able to effectively maintain the ecological functionality of urban forest patches), to unveil possible synergies or tradeoffs between these two critical aspects for the period of 2011−2018. We found that overall urban forests’ recreation potential has increased, but their habitat potential has decreased. Economic growth is positively associated with recreation potential, but negatively associated with habitat potential. Results of this study revealed that the institutionalization of “ecological civilization” paradigm in China has not yet been successfully taken into urban forest domain. This calls for urban landscape policy and planning directed towards fostering synergistic effects between urban forests’ recreational function and habitat potential in order to essentially reconcile citizens’ recreational uses and the resilience of cities as complex socioecological systems. In this vein, the development of urban forest, as a visualized form of the mainstream yet subtle ecological civilization, can be further geared towards multi-functionality.

To evaluate the association between alcohol consumption and breast cancer risk in younger women, overall and by family history of breast cancer and folate intake, we prospectively followed 93,835 US women aged 27–44 years in Nurses’ Health Study II who had alcohol consumption data in 1991. Alcohol consumption and folate intake were measured by food frequency questionnaire every 4 years. We documented 2,866 incident cases of invasive breast cancer between 1991 and 2011. Alcohol consumption was not associated with breast cancer risk overall (for intake of ≥10 g/day vs. nondrinking, multivariate hazard ratio = 1.07, 95% confidence interval: 0.94, 1.22). When the association was stratified by family history and folate intake, a positive association between alcohol consumption and breast cancer was found among women with a family history and folate intake less than 400 μg/day (multivariate hazard ratio = 1.82, 95% confidence interval: 1.06, 3.12; P-trend = 0.08). Alcohol consumption was not associated with breast cancer in other categories of family history and folate intake (P-interaction = 0.55). In conclusion, in this population of younger women, higher alcohol consumption was associated with increased risk of breast cancer among those with both a family history of breast cancer and lower folate intake.

Urban streams could concurrently bring about both positive amenities accruing to the view of waterscape and negative disamenities associated with water pollution. In this paper, we focus on a specific question that has not yet been explicitly answered in the extant literature: how to estimate the cumulative impacts of urban streams (which refer to the combined impacts of amenities and disamenities of multiple sources) in high density and high-rise urban contexts. A typical residential apartment complex (comprised of a number of apartment units located in dozens of mid- to high-rise commercial apartment buildings on a contiguous land parcel) in Guangzhou, south China, is used as a case study. A detailed palette of natural amenities and environmental disamenities of two bifurcated streams are quantified via the generalized spatial two-stage least squares (GS2SLS) model. In this model, an originally constructed 3-D spatial connectivity matrix, cube contiguity, is applied to address, in a sophisticated manner, an array of endogenous, exogenous, and error interactions along both horizontal and vertical dimensions that inherently exist in the spatial context of high-rise housing markets. Our results from spatial hedonic models at the micro-neighborhood level demonstrate that homebuyers tend to evaluate urban streams’ chemical, physical, and ecological features holistically. A cumulative impact is also found, as homebuyers would like to pay an extra premium for an apartment located farther away from both polluted streams. This study advances the extant literature by contributing to a novel and effective extension of the conventional two-dimensional spatial matrix which can capture the long-ignored spatial correlation existing amongst apartment units located on contiguous floors, as well as a robust estimation of the demand of urban natural and environmental amenities in the gradually rising mid- and high-rise housing market in both developing and developed countries.

One of the major challenges facing river restoration in densely populated urban areas has been the disparity between the expectations of policy-makers and societal preferences. This study aimed to elicit public preferences and elucidate underlying sources of preference heterogeneity, using the Zenne River in central Brussels, Belgium, as a case study. A discrete choice experiment was administered to a representative sample of the Brussels population. Five attributes were specified, including water quality, ecological status, hydromorphological features of channels, recreational opportunities, and monetary cost. Our econometric analysis based on mixed logit models revealed that overall public would like to have a more natural river (open and naturalized channel, good water quality, and with rich species diversity), while achieving good water quality was the most preferred attribute. Respondents categorized as male, non-Belgian citizen, or not being a member of an environmental organization constituted an inclination to prefer the status quo. Belgian citizens showed a pronounced preference for good biodiversity, and being a member of an environmental organization could moderate the strong preference for good water quality. This study provided insights into the relative attractiveness of key attributes pertaining to river restoration, in general, and served as a useful input to the ongoing discussion concerning the future plan for the Zenne River in Brussels, specifically. Possible implications also exist for other urban river restorations in the rest of Europe, where the Water Framework Directive has become a major impetus for the expansion of freshwater ecosystem restoration from rural and peri-urban areas to densely populated urban areas. Particularly, the cultural heterogeneity of societal preferences should be tested and accounted for to compare the welfare impacts of river restoration and to facilitate benefit transfer, within and between river basins, in the Water Framework Directive implementation.

There is an increasing recognition of ecosystem services provided by urban trees and their importance to urban resilience and sustainability through the preservation and enhancement of biological diversity so as to withstand disturbances and retain ecosystem functions as well as guarantee the well-being of current and future urban dwellers. However, the heterogeneous perceptions that urban residents may hold towards various ecosystem services have seldom been investigated. This study made a unique contribution to the growing body of literature on urban ecosystem services by examining the unobserved heterogeneity in resident perceptions of ecosystem services provided by a distinctive bio-cultural asset, urban heritage trees, in Hong Kong, via a novel application of latent class factor analysis which allows for considering the multidimensionality of latent factors and increases model parsimony. A total of 1075 face-to-face interviews were conducted with a stratified sample of residents about their perceived importance of two categories of distinctive ecosystem services provided by urban heritage trees: biological benefits and cultural benefits. The results indicated that, on average, both biological and cultural benefits of urban heritage trees were perceived to be important. Nevertheless, six classes were identified on the basis of different levels of two latent class factors, which differed markedly with respect to individual’s perceived importance of ecosystem services provided by urban heritage trees, from fairly balanced to very divergent perceptions of biological services and cultural services. This heterogeneity was explained with covariates describing respondents’ sociodemographic characteristics and activities at heritage tree sites. The results have implications for optimally tailoring promoting and participatory approaches, fostering improved communications with the general public, and nurturing overall support for urban heritage tree conservation from heterogeneous resident groups in order to achieve urban resilience and sustainability.

Obesity is a well-established cause of postmenopausal breast cancer. However, early life adiposity is inversely associated with breast cancer incidence. To understand these conflicting relations, we use validated measures to assess adiposity in childhood and late adolescence, as well as weight change, in relation to total invasive breast cancer incidence and receptor subtypes. We conducted a prospective observational study among 74,177 women from the Nurses' Health Study from 1980-2012, with updated risk factors every 2 years during which 4965 incident invasive breast cancers occurred. Overall, weight at age 18 was inversely associated with both premenopausal (HR per 30 kg = 0.52, 95% CI = 0.39 – 0.71) and postmenopausal (HR per 30 kg = 0.81, 95% CI = 0.72 – 0.92) breast cancer which was largely explained by adiposity at age 10. Long-term weight gain from age 18 both during premenopause and postmenopause were positively associated with postmenopausal breast cancer risk. However, premenopausal weight gain was not related to premenopausal breast cancer risk. Furthermore, weight gain since age 18 was positively associated with ER+/PR+ postmenopausal breast cancer (HR per 30 kg = 1.50, 95% CI = 1.36 – 1.65) but not ER+/PR- (HR per 30 kg = 0.96, 95% CI = 0.78 – 1.19) or ER-/PR- (HR per 30 kg = 1.16, 95% CI = 0.95 – 1.42) postmenopausal breast cancer. Overall, 17% of ER+/PR+ postmenopausal breast cancer and 14% of total postmenopausal breast cancer are attributable to weight gain of > 5 kg since age 18. This article is protected by copyright. All rights reserved.

BACKGROUND Studies of obesity and survival among patients with breast cancer produce conflicting results, possibly because of heterogeneity by molecular subtype. METHODS This study examined whether the association of body mass index (BMI) at diagnosis with breast cancer recurrence and survival varied across subtypes defined by PAM50 (Prediction Analysis of Microarray 50) gene expression. Included were 1559 Kaiser Permanente Northern California members ages 18 to 79 years who had PAM50 assays and were diagnosed with American Joint Committee on Cancer stage I through III breast cancer from 1996 to 2013. Patients reported weight and height. Cox regression models were adjusted for age, menopause, race/ethnicity, stage, and chemotherapy. RESULTS Over a median of 9 years (maximum, 19 years), 378 women developed recurrent disease, and 312 died from breast cancer. Overall, BMI was not associated with breast cancer recurrence or survival when controlling for subtype (eg, the hazard ratio per 5 kg/m2 of BMI was 1.05 [95% confidence interval, 0.95-1.15] for breast cancer-specific death). However, associations varied by subtype. Among women with luminal A cancers, those who had class II/III obesity, but not class I obesity or overweight, had worse outcomes. When women who had a BMI ≥35 kg/m2 were compared with those who had a BMI from 18.5 to

Background: Breast cancer is a leading cause of cancer death in women. Sleep has been linked with mortality among cancer-free population; however, its association with survival among women with breast cancer is understudied. Methods: Breast cancer patients (N=3682) reported their average sleep duration post diagnosis. Subsamples also provided their pre-diagnosis sleep duration (n=1949) and post-diagnosis sleep difficulties (n=1353). Multivariate Cox models estimated hazard ratios (HR) and confidence intervals (CI) of all-cause, breast cancer, and non-breast cancer mortality. Results: At diagnosis, the mean age was 64.9 years and 91.7% were stage I or II. Women sleeping ⩾9 h per night post diagnosis had a strong higher risk of all-cause (multivariate HRs: MV-HR=1.37, CI=1.10–1.71), breast cancer (MV-HR=1.46, CI=1.02–2.07), and non-breast cancer mortality (MV-HR=1.34, CI=1.01–1.79), compared to women sleeping 8 h per night. Increased sleep duration post diagnosis (vs unchanged) and regular sleep difficulties (vs rare/none) were associated with a strong elevated risk of all-cause mortality (MV-HRincreased duration=1.35, CI=1.04–1.74; MV-HRregular difficulties=1.49, CI=1.02–2.19) and a moderate greater risk of breast cancer and non-breast cancer mortality. Conclusions: Various facets of sleep were associated with higher all-cause mortality risk. If replicated, these findings support evaluation of breast cancer patients' sleep duration and difficulties to identify those at risk for poorer outcomes.

This abstract was not presented at the symposium.

PurposeGreater protein intake has been associated with better breast cancer survival in several prospective studies, including among 1,982 women in the Nurses’ Health Study. We proposed to extend this previous finding. We hypothesized that protein, essential amino acid, branched-chain amino acid, and leucine intakes are associated with improved survival and that these associations are stronger in tumors expressing insulin receptor (IR).Patients and MethodsWe included 6,348 women diagnosed with stage I to III breast cancer between 1976 and 2004. There were 1,046 distant recurrences. Relative risks (RRs) and 95% CIs were calculated according to quintiles of updated postdiagnostic diet using adjusted Cox proportional hazards models based on follow-up until 2010.ResultsThere was an inverse association between energy-adjusted protein intake and recurrence. Multivariable RRs for increasing quintiles of intake compared with the lowest were 0.95 (95% CI, 0.79 to 1.15), 0.92 (95% CI, 0.76 to 1.11), 0.75 (95% CI, 0.61 to 0.91), and 0.84 (95% CI, 0.69 to 1.03; trend P = .02). For animal protein intake, the RRs were 0.88 (95% CI, 0.73 to 1.06), 0.85 (95% CI, 0.70 to 1.02), 0.75 (95% CI, 0.62 to 0.92), and 0.78 (95% CI, 0.63 to 0.95; trend P = .003). Neither essential amino acids, branched-chain amino acids, nor any individual amino acid stood out as being the source of the association. The association also did not differ by IR status. There was no clear association with any protein-containing foods.ConclusionWe found a modest survival advantage with higher intake of protein, regardless of IR status. There was no clear mechanism for this association, although it is consistent with prior studies. Our data suggest that there is likely no advantage for women with a history of breast cancer in restricting protein intake or protein-containing foods.

Background: Achieving a healthy weight is recommended for all breast cancer survivors. Previous research on postdiagnosis weight change and mortality had conflicting results. Methods: We examined whether change in body weight in the 18 months following diagnosis is associated with overall and breast cancer–specific mortality in a cohort of n = 12,590 stage I–III breast cancer patients at Kaiser Permanente using multivariable-adjusted Cox regression models. Follow-up was from the date of the postdiagnosis weight at 18 months until death or June 2015 [median follow-up (range): 3 (0–9) years]. We divided follow-up into earlier (18–54 months) and later (>54 months) postdiagnosis periods. Results: Mean (SD) age-at-diagnosis was 59 (11) years. A total of 980 women died, 503 from breast cancer. Most women maintained weight within 5% of diagnosis body weight; weight loss and gain were equally common at 19% each. Compared with weight maintenance, large losses (≥10%) were associated with worse survival, with HRs and 95% confidence intervals (CI) for all-cause death of 2.63 (2.12–3.26) earlier and 1.60 (1.14–2.25) later in follow-up. Modest losses (>5%– Conclusion: Large postdiagnosis weight loss is associated with worse survival in both earlier and later postdiagnosis periods, independent of treatment and prognostic factors. Impact: Weight loss and gain are equally common after breast cancer, and weight loss is a consistent marker of mortality risk. Cancer Epidemiol Biomarkers Prev; 26(1); 44–50. ©2016 AACR. See all the articles in this CEBP Focus section, “The Obesity Paradox in Cancer: Evidence and New Directions.”

IMPORTANCE: Although most chemotherapies are dosed on body surface area or weight, body composition (ie, the amount and distribution of muscle and adipose tissues) is thought to be associated with chemotherapy tolerance and adherence. OBJECTIVES: To evaluate whether body composition is associated with relative dose intensity (RDI) on anthracycline and taxane-based chemotherapy or hematologic toxic effects and whether lower RDI mediates the association of adiposity with mortality. DESIGN, SETTING, AND PARTICIPANTS: An observational cohort study with prospectively collected electronic medical record data was conducted at Kaiser Permanente Northern California, a multicenter, community oncology setting within an integrated health care delivery system. Participants included 1395 patients with nonmetastatic breast cancer diagnosed between January 1, 2005, and December 31, 2013, and treated with anthracycline and taxane-based chemotherapy. Data analysis was performed between February 25 and September 4, 2019. EXPOSURES: Intramuscular, visceral, and subcutaneous adiposity as well as skeletal muscle were evaluated from clinically acquired computed tomographic scans at diagnosis. MAIN OUTCOMES AND MEASURES: The primary outcome was low RDI (

Background Body composition from computed tomography (CT) scans is associated with cancer outcomes including surgical complications, chemotoxicity, and survival. Most studies manually segment CT scans, but Automatic Body composition Analyser using Computed tomography image Segmentation (ABACS) software automatically segments muscle and adipose tissues to speed analysis. Here, we externally evaluate ABACS in an independent dataset. Methods Among patients with non‐metastatic colorectal (n = 3102) and breast (n = 2888) cancer diagnosed from 2005 to 2013 at Kaiser Permanente, expert raters annotated tissue areas at the third lumbar vertebra (L3). To compare ABACS segmentation results to manual analysis, we quantified the proportion of pixel‐level image overlap using Jaccard scores and agreement between methods using intra‐class correlation coefficients for continuous tissue areas. We examined performance overall and among subgroups defined by patient and imaging characteristics. To compare the strength of the mortality associations obtained from ABACS's segmentations to manual analysis, we computed Cox proportional hazards ratios (HRs) and 95% confidence intervals (95% CI) by tertile of tissue area. Results Mean ± SD age was 63 ± 11 years for colorectal cancer patients and 56 ± 12 for breast cancer patients. There was strong agreement between manual and automatic segmentations overall and within subgroups of age, sex, body mass index, and cancer stage: average Jaccard scores and intra‐class correlation coefficients exceeded 90% for all tissues. ABACS underestimated muscle and visceral and subcutaneous adipose tissue areas by 1–2% versus manual analysis: mean differences were small at −2.35, −1.97 and −2.38 cm2, respectively. ABACS's performance was lowest for the

PURPOSE Cardiovascular disease (CVD) is a major source of morbidity and mortality among breast cancer survivors. Although body mass index (BMI) is associated with CVD risk, adipose tissue distribution may better identify patients with a high risk of CVD after breast cancer. METHODS Among 2,943 patients with nonmetastatic breast cancer without prior CVD, we used International Classification of Diseases (9th and 10th revisions) codes to identify incidence of nonfatal stroke, myocardial infarction, heart failure, or CVD death. From clinically acquired computed tomography scans obtained near diagnosis, we measured visceral adiposity (centimeters squared), subcutaneous adiposity (centimeters squared), and intramuscular adiposity (fatty infiltration into muscle [Hounsfield Units, scored inversely]). We estimated hazard ratios (HRs) and 95% CIs per SD increase in adiposity accounting for competing risks and adjusting for demographics, smoking, cancer treatment, and pre-existing CVD risk factors. RESULTS Mean (SD) age was 56 (12) years. Over a median follow-up of 6 years, 328 CVD events occurred. Each SD increase in visceral or intramuscular adiposity was associated with an increase in CVD risk (HR, 1.15 [95% CI, 1.03 to 1.29] and HR, 1.21 [95% CI, 1.06 to 1.37]), respectively). Excess visceral and intramuscular adiposity occurred across all BMI categories. Among normal-weight patients, each SD greater visceral adiposity increased CVD risk by 70% (HR, 1.70 [95% CI, 1.10 to 2.62]). CONCLUSION Visceral and intramuscular adiposity were associated with increased CVD incidence after breast cancer diagnosis, independent of pre-existing CVD risk factors and cancer treatments. The increased CVD incidence among normal-weight patients with greater visceral adiposity would go undetected with BMI alone. Measures of adipose tissue distribution may help identify high-risk patients and tailor CVD prevention strategies.

Author(s): Bradshaw, Patrick T; Cespedes Feliciano, Elizabeth M; Prado, Carla M; Alexeeff, Stacey; Albers, Kathleen B; Chen, Wendy Y; Caan, Bette J | Abstract: ObjectivePrevious studies of breast cancer survival have not considered specific depots of adipose tissue such as subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT).MethodsThis study assessed these relationships among 3,235 women with stage II and III breast cancer diagnosed between 2005 and 2013 at Kaiser Permanente Northern California and between 2000 and 2012 at Dana Farber Cancer Institute. SAT and VAT areas (in centimeters squared) were calculated from routine computed tomography scans within 6 (median: 1.2) months of diagnosis, covariates were collected from electronic health records, and vital status was assessed by death records. Hazard ratios (HRs) and 95% CIs were estimated using Cox regression.ResultsSAT and VAT ranged from 19.0 to 891ncm2 and from 0.484 to 454ncm2 , respectively. SAT was related to increased risk of death (127-cm2 increase; HR [95% CI]: 1.13 [1.02-1.26]), but no relationship was found with VAT (78.18-cm2 increase; HR [95% CI]: 1.02 [0.91-1.14]). An association with VAT was noted among women with stage II cancer (stage II: HR: 1.17 [95% CI: 0.99-1.39]; stage III: HR: 0.90 [95% CI: 0.76-1.07]; P interaction l 0.01). Joint increases in SAT and VAT were associated with mortality above either alone (simultaneous 1-SD increase: HR 1.19 [95% CI: 1.05-1.34]).ConclusionsSAT may be an underappreciated risk factor for breast cancer-related death.

Background: The Gail model and the model developed by Tyrer and Cuzick are two questionnaire-based approaches with demonstrated ability to predict development of breast cancer in a general population. Methods: We compared calibration, discrimination, and net reclassification of these models, using data from questionnaires sent every 2 years to 76,922 participants in the Nurses' Health Study between 1980 and 2006, with 4,384 incident invasive breast cancers identified by 2008 (median follow-up, 24 years; range, 1–28 years). In a random one third sample of women, we also compared the performance of these models with predictions from the Rosner–Colditz model estimated from the remaining participants. Results: Both the Gail and Tyrer–Cuzick models showed evidence of miscalibration (Hosmer–Lemeshow P < 0.001 for each) with notable (P < 0.01) overprediction in higher-risk women (2-year risk above about 1%) and underprediction in lower-risk women (risk below about 0.25%). The Tyrer–Cuzick model had slightly higher C-statistics both overall (P < 0.001) and in age-specific comparisons than the Gail model (overall C, 0.63 for Tyrer–Cuzick vs. 0.61 for the Gail model). Evaluation of net reclassification did not favor either model. In the one third sample, the Rosner–Colditz model had better calibration and discrimination than the other two models. All models had C-statistics Conclusions: Both the Gail and Tyrer–Cuzick models had some ability to discriminate breast cancer cases and noncases, but have limitations in their model fit. Impact: Refinements may be needed to questionnaire-based approaches to predict breast cancer in older and higher-risk women.

BACKGROUND Large social networks have been associated with better overall survival, though not consistently with breast cancer (BC)–specific outcomes. This study evaluated associations of postdiagnosis social networks and BC outcomes in a large cohort. METHODS Women from the After Breast Cancer Pooling Project (n = 9267) provided data on social networks within approximately 2 years of their diagnosis. A social network index was derived from information about the presence of a spouse/partner, religious ties, community ties, friendship ties, and numbers of living first-degree relatives. Cox models were used to evaluate associations, and a meta-analysis was used to determine whether effect estimates differed by cohort. Stratification by demographic, social, tumor, and treatment factors was performed. RESULTS There were 1448 recurrences and 1521 deaths (990 due to BC). Associations were similar in 3 of 4 cohorts. After covariate adjustments, socially isolated women (small networks) had higher risks of recurrence (hazard ratio [HR], 1.43; 95% confidence interval [CI], 1.15-1.77), BC-specific mortality (HR, 1.64; 95% CI, 1.33-2.03), and total mortality (HR, 1.69; 95% CI, 1.43-1.99) than socially integrated women; associations were stronger in those with stage I/II cancer. In the fourth cohort, there were no significant associations with BC-specific outcomes. A lack of a spouse/partner (P = .02) and community ties (P = .04) predicted higher BC-specific mortality in older white women but not in other women. However, a lack of relatives (P = .02) and friendship ties (P = .01) predicted higher BC-specific mortality in nonwhite women only. CONCLUSIONS In a large pooled cohort, larger social networks were associated with better BC-specific and overall survival. Clinicians should assess social network information as a marker of prognosis because critical supports may differ with sociodemographic factors. Cancer 2017;123:1228–1237. © 2016 American Cancer Society.

We evaluated individual grain-containing foods and whole and refined grain intake during adolescence, early adulthood, and premenopausal years in relation to breast cancer risk in the Nurses’ Health Study II. Grain-containing food intakes were reported on a baseline dietary questionnaire (1991) and every 4 years thereafter. Among 90,516 premenopausal women aged 27–44 years, we prospectively identified 3235 invasive breast cancer cases during follow-up to 2013. 44,263 women reported their diet during high school, and from 1998 to 2013, 1347 breast cancer cases were identified among these women. Cox proportional hazards regression was used to estimate relative risks (RR) and 95 % confidence intervals (95 % CI) of breast cancer for individual, whole and refined grain foods. After adjusting for known breast cancer risk factors, adult intake of whole grain foods was associated with lower premenopausal breast cancer risk (highest vs. lowest quintile: RR 0.82; 95 % CI 0.70–0.97; P trend = 0.03), but not postmenopausal breast cancer. This association was no longer significant after further adjustment for fiber intake. The average of adolescent and early adulthood whole grain food intake was suggestively associated with lower premenopausal breast cancer risk (highest vs lowest quintile: RR 0.74; 95 % CI 0.56–0.99; P trend = 0.09). Total refined grain food intake was not associated with risk of breast cancer. Most individual grain-containing foods were not associated with breast cancer risk. The exceptions were adult brown rice which was associated with lower risk of overall and premenopausal breast cancer (for each 2 servings/week: RR 0.94; 95 % CI 0.89–0.99 and RR 0.91; 95 % CI 0.85–0.99, respectively) and adult white bread intake which was associated with increased overall breast cancer risk (for each 2 servings/week: RR 1.02; 95 % CI 1.01–1.04), as well as breast cancer before and after menopause. Further, pasta intake was inversely associated with overall breast cancer risk. Our results suggest that high whole grain food intake may be associated with lower breast cancer risk before menopause. Fiber in whole grain foods may mediate the association with whole grains.

Background: In its 2014 position statement, ASCO concluded that obesity is associated with worse prognosis after cancer diagnosis. However in the same year, a comprehensive review by the World Cancer Research Fund concluded that there was limited evidence that greater body fatness increases risk of overall or breast cancer mortality, indicating that further investigation into lifestyle factors are needed. The After Breast Cancer (ABC) Pooling Project has reported, separately, significant mortality effects of pre-diagnosis BMI and of post-diagnosis physical activity (PA). We investigate whether the effect of BMI can be limited to subgroups characterized by comorbidities and physical activity. Methods: Data are from the three US cohorts that were harmonized in the ABCPP (n=9513) including: the Women's Healthy Eating and Living (WHEL), Life After Cancer Epidemiology (LACE), and Nurses' Health (NHS) studies. Stepwise delayed entry Cox proportional hazards models examined each lifestyle predictor (BMI, PA, and comorbidities assessed after diagnosis) sequentially and together in multivariate models for breast cancer and all-cause mortality. Results: In multivariate models without the other two target variables, PA was significantly associated with a 17% decrease in the risk of breast cancer mortality among women in the highest quartile of PA (MET hr/wk > 21.4), compared to the lowest quartile (MET hr/wk < 2.7) (HR=0.81,95% CI= 0.67,0.97). In the model with major comorbidities, there was a significant 40% increase in the risk of breast cancer mortality among women diagnosed with both diabetes and hypertension (HR=1.40, 95% CI= 1.01,1.93). In the model with BMI, there was no significant association with risk of breast cancer mortality. These results were essentially unchanged with all variables in a single model. For all-cause mortality, the PA-only model showed a significant PA effect with the hazard decreasing from 20% to 40% across quartiles (Q2 HR=0.80, 95% CI=0.71,0.90, Q4 HR=0.62, 95% CI=0.54,0.71). In the comorbidity-only model, both diabetes and hypertension significantly increased hazard of all-cause mortality 80% and 33%, respectively. Having both diagnoses was associated with a significant, 2.3 fold increase in all-cause mortality (HR=2.34, 95% CI= 1.95,2.81). In the BMI-only model, being underweight was associated with a significant 2.4 fold increase in risk of all-cause mortality, and there was a 20 and 37% increase in risk associated with being categorized as obese I or II (Obese I HR=1.23, 95% CI=1.07,1.40, Obese II HR=1.37, 95% CI=1.16,1.61). With all three variables in the model, the risk associated with being obese decreased and became non-significant (Obese I HR=1.06, Obese II HR=1.05), while the significance, strength, and direction of the association of comorbidities and PA with all-cause mortality remained constant. Conclusion: These data suggest that post-diagnosis comorbidities and lack of physical activity, rather than high BMI , are the important risk factors for all-cause and breast cancer specific mortality. While needing further validation, these suggest that physical activity interventions and monitoring treatment for comorbidities should become standard of care for breast cancer survivors. Citation Format: Nelson SH, Marinac CR, Patterson RE, Nachuta SJ, Caan BJ, Chen WY, Shu X-O, Pierce JP. Post-diagnosis physical activity and comorbidities, not BMI, explain mortality risk in the after breast cancer pooling project. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD4-08.

Although breast cancer risk increases with age, the importance of early events on breast cancer development is increasingly recognized. Compared to the plethora of studies on adult dietary exposures and breast cancer risk, the field of adolescent diet and breast cancer risk is still in its infancy. We review the data on breast cancer risk and diet during adolescence (defined as between ages 11 and 19) with a focus on the dietary exposures that have been investigated most in adult diet. The current literature suggests possible associations with dietary intake of soy and red meat and breast cancer risk. However, the lack of strong associations for other exposures may be due to methodological issues regarding precise measurement and a paucity of published studies. Overall, the area of early life exposures and cancer risk deserves more research and increased resources to advance the field.

The purpose of this study was to examine post-diagnosis BMI, very low physical activity, and comorbidities, as predictors of breast cancer-specific and all-cause mortality. Data from three female US breast cancer survivor cohorts were harmonized in the After Breast Cancer Pooling Project (n = 9513). Delayed entry Cox proportional hazards models were used to examine the impact of three post-diagnosis lifestyle factors: body mass index (BMI), select comorbidities (diabetes only, hypertension only, or both), and very low physical activity (defined as physical activity

Author(s): Kroenke, Candyce H; Michael, Yvonne L; Shu, Xiao-Ou; Poole, Elizabeth M; Kwan, Marilyn L; Nechuta, Sarah; Caan, Bette J; Pierce, John P; Chen, Wendy Y | Abstract: ObjectiveLarger social networks have been associated with better breast cancer survival. To investigate potential mediators, we evaluated associations of social network size and diversity with lifestyle and treatment factors associated with prognosis.MethodsWe included 9331 women from the After Breast Cancer Pooling Project who provided data on social networks within approximately two years following diagnosis. A social network index was derived from information about the presence of a spouse or intimate partner, religious ties, community participation, friendship ties, and numbers of living relatives. Diversity was assessed as variety of ties, independent of size. We used logistic regression to evaluate associations with outcomes and evaluated whether effect estimates differed using meta-analytic techniques.ResultsAssociations were similar across cohorts though analyses of smoking and alcohol included US cohorts only because of low prevalence of these behaviors in the Shanghai cohort. Socially isolated women were more likely to be obese (OR = 1.21, 95% CI:1.03-1.42), have low physical activity (l10 MET-hours/week, OR = 1.55, 95% CI:1.36-1.78), be current smokers (OR = 2.77, 95% CI:2.09-3.68), and have high alcohol intake (≥15 g/d, OR = 1.23, 95% CI:1.00-1.51), compared with socially integrated women. Among node positive cases from three cohorts, socially isolated women were more likely not to receive chemotherapy (OR = 2.10, 95% CI:1.30-3.39); associations differed in a fourth cohort. Other associations (nonsignificant) were consistent with less intensive treatment in socially isolated women. Low social network diversity was independently associated with more adverse lifestyle, but not clinical, factors.ConclusionsSmall, less diverse social networks measured post-diagnosis were associated with more adverse lifestyle factors and less intensive cancer treatment. Copyright © 2016 John Wiley a Sons, Ltd.

The first International Conference on Urban Tree Diversity hosted in June 2014 by the Swedish University of Agricultural Science in Alnarp, Sweden highlighted the need for a better understanding of the current state of urban tree diversity. Here we present and discuss a selection of urban tree diversity themes with the intention of developing and sharing knowledge in a research area that is gaining momentum. We begin by discussing the specific role of species diversity in ecosystem service provision and ecosystem stability. This is followed by exploring the urban conditions that affect species richness. Having determined that many ecosystem services depend on urban tree species diversity and that urban environments are capable of supporting high species diversity, we conclude by addressing how to govern for urban tree diversity.

Preclinical studies support an anticancer effect of statin drugs, yet epidemiologic evidence remains inconsistent regarding their role in breast cancer primary prevention. Here, we report an updated analysis of the association between statin use and breast cancer incidence in the Nurses' Health Study (NHS) cohort. Postmenopausal NHS participants without a cancer history were followed from 2000 until 2012 (n = 79,518). Data on statin use were retrieved from biennial questionnaires. We fit Cox regression models to estimate associations between longitudinal statin use and breast cancer incidence. Over 823,086 person-years of follow-up, 3,055 cases of invasive breast cancer occurred. Compared with never users, both former and current statin users had similar rates of invasive breast cancer incidence [former users: HRadj, 0.96; 95% confidence interval (CI), 0.82–1.1; current users: HRadj, 1.1; 95% CI, 0.92–1.3]. Associations did not differ by estrogen receptor (ER) status or histology (ductal vs. lobular carcinoma). Statin use was not associated with risk of invasive breast cancer, irrespective of histologic subtype and ER status. Statin drugs do not appear to modify processes involved in breast cancer initiation. Cancer Epidemiol Biomarkers Prev; 25(1); 201–6. ©2016 AACR.

Key Points Question Does vitamin D3 supplementation reduce the risk of developing advanced (metastatic or fatal) cancer among adults without a diagnosis of cancer at baseline? Findings In this secondary analysis of a randomized clinical trial with 25 871 patients, supplementation with vitamin D3 reduced the incidence of advanced (metastatic or fatal) cancer in the overall cohort, with strongest risk reduction in individuals with normal weight and no reduction among individuals with overweight or obesity. Meaning These findings suggest that vitamin D3 may reduce the risk of developing advanced cancer among adults without a diagnosis of cancer at baseline; this protective effect is apparent for those who have normal but not elevated body mass index., This secondary analysis of a randomized clinical trial evaluates the effect vitamin D on the incidence of advanced (metastatic or fatal) cancer among adults without cancer at baseline and examines possible effect modification by body mass index., Importance Epidemiologic and trial data suggest that vitamin D supplementation may reduce metastatic cancer and cancer mortality, reflecting shared biological pathways. Objective To follow up on the possible reduction in cancer death in the Vitamin D and Omega-3 Trial (VITAL) with an evaluation of whether vitamin D reduces the incidence of advanced (metastatic or fatal) cancer and an examination possible effect modification by body mass index. Design, Setting, and Participants VITAL is a randomized, double-blind, placebo-controlled, 2 × 2 factorial clinical trial of vitamin D3 (cholecalciferol, 2000 IU/d) and marine omega-3 fatty acids (1 g/d). This multicenter clinical trial was conducted in the United States; participants included men aged 50 years or older and women aged 55 years or older who were free of cancer and cardiovascular disease at baseline. Randomization took place from November 2011 through March 2014, and study medication ended on December 31, 2017. Data for this secondary analysis were analyzed from November 1, 2011, to December 31, 2017. Interventions Vitamin D3 (cholecalciferol, 2000 IU/d) and marine omega-3 fatty acids (1 g/d) supplements. Main Outcomes and Measures For the present analysis, the primary outcome was a composite incidence of metastatic and fatal invasive total cancer, because the main VITAL study showed a possible reduction in fatal cancer with vitamin D supplementation and effect modification by body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) for total cancer incidence reduction for individuals with normal BMI, but not for individuals with overweight or obesity. Secondary analyses included examination of BMI (

The vertical dimension of the residential apartment market has been largely overlooked in spatial hedonic studies. To adequately quantify the environmental impacts brought by various urban natural elements on apartment prices using spatial hedonic models, the selection of an appropriate weights matrix, which could adequately approximate complex spatial relationship amongst apartment units in high-rise housing markets, is an important methodological challenge. Using a micro high-rise neighbourhood in Guangzhou (China) as a case, we compare the model performance of a set of 3-D spatial weights matrices in capturing the environmental impacts of a polluted river running by the residential neighbourhood on apartment transaction prices. Three 3-D spatial weights schemes are examined, including distance-based, contiguity-based, and a hybrid distance-contiguity weights matrix. Our Monte Carlo simulations and empirical comparison consistently confirm that contiguity-based weights matrices outperform distance-based and hybrid weights alternatives. Adopting the appropriate second-order queen’s cube contiguity matrix in a 3-D Spatial Autoregressive Combined (SAC) model, the spatial heterogeneity of urban river’s environmental impacts along both horizontal and vertical dimensions is revealed. We find significant negative impacts associated with the proximity and visibility of the polluted river, which are strengthened for apartments located on the 10th floor and below. Our findings highlight the urgency of restoring polluted urban rivers and provide evidence-based information for local authorities and private housing developers to restore polluted rivers in order to improve environmental amenities.

TPS600 Background: In-vitro and in-vivo evidence suggest that aspirin may have an anti-tumor effect. Multiple epidemiologic studies have reported improved breast cancer survival among regular aspirin users compared to non-users. Pooled data from randomized trials of aspirin for cardiovascular disease have also reported a decreased risk of metastatic cancer among aspirin users. However, the exact benefits and risks for breast cancer survivors need to be confirmed in a randomized controlled trial. Even if the clinical effect were modest, the global impact would be substantial since aspirin is inexpensive and widely available. Methods: The primary objective is to compare the effect of 300 mg daily aspirin versus placebo upon invasive disease-free survival (iDFS) in high risk HER2 negative breast cancer patients. Secondary objectives include effects on overall survival, cardiovascular disease, toxicity, and adherence. A biospecimen repository will be created for correlative analyses including tumor collection at baseline and blood and urine samples and questionnaires assessing lifestyle factors associated with inflammation (pain, sleep, stress, and depression) at baseline and 2 years. Study design: Subjects will be randomized (1:1) to aspirin 300 mg vs placebo daily for 5 years in a double-blinded fashion. Stratification factors include hormone receptor (HR) status (positive vs negative), body mass index ( < or ≥ 30 kg/m2), and stage (II vs III). Subjects will be followed every 6 six months while on study drug, then annually for 10 years. Accrual goal is 2936 patients to reach 381 iDFS events. We have 80% power to detect HR 0.75 assuming 5-year iDFS on placebo of 77%. Eligibility: Eligible subjects include patients aged 18-70 diagnosed with a primary invasive HER2 negative breast cancer. If HR positive, tumors need to be node positive and diagnosed within the past 10 years. If HR negative, tumor can be node positive or T2-4N0 within 18 months of diagnosis. Subjects who are currently anticoagulated or those with a prior history of GI bleeding, atrial fibrillation, or myocardial infarction are excluded. Subjects who regularly use aspirin (defined as ≥ 5 days per week) need to stop 30 days prior to enrollment. Updated accrual numbers will be given at the time of presentation. Clinical trial information: NCT02927249 .

1510 Background: Epidemiologic data suggest that vitamin D supplementation may reduce cancer mortality. We tested whether vitamin D and/or omega-3 supplementation reduces the incidence of advanced stage cancer at diagnosis or lethal cancer, and whether body mass index (BMI) modifies these associations. Methods: The VITamin D and OmegA-3 TriaL (VITAL) is a randomized, placebo-controlled, 2x2 factorial trial of vitamin D3 (cholecalciferol, 2000 IU/day) and marine omega-3 fatty acids (1 g/day) that enrolled men aged ≥50 years and women aged ≥55 years free of cancer and cardiovascular disease at baseline. For this particular analysis, the primary outcome is a composite of metastatic and fatal invasive total cancer. Secondary analyses included examination of BMI (= 30 kg/m2) as effect modifiers of the observed associations. Results: VITAL randomized 25,871 participants, among whom 1,617 were diagnosed with invasive cancer over a median 5.3 year intervention period. No significant differences by treatment arm (vitamin D vs placebo: hazard ratio [HR]=0.96; 95% confidence interval, 0.88-1.06; p=0.47; omega-3 vs placebo; HR 1.03 [0.93-1.13]; p=0.56) were observed. However, a significant reduction in advanced cancers (metastatic or fatal) was found for those randomized to vitamin D, compared to placebo (226 assigned to vitamin D and 274 to placebo; HR 0.83 [0.69-0.99]; p=0.036). There was no difference by omega-3 assignment (246 assigned to omega-3 and 254 to placebo: HR 0.97 [0.81-1.15], p=0.72). When stratified by BMI, there was a significant reduction for the vitamin D arm in incident metastatic or fatal cancer among those with normal BMI (BMI=30: HR 1.05 [0.74-1.49]); p for interaction by BMI =0.03. There was no effect modification by BMI noted for the omega 3 arm. Conclusions: In a randomized clinical trial, supplementation with vitamin D, but not omega-3s, reduced incidence of advanced (metastatic or fatal) cancer in the overall cohort, with strongest risk reduction in normal weight individuals. Further research is needed to understand these findings. Clinical trial information: NCT01169259.

Fruits and vegetables contain many bioactive components that may contribute to improved survival after diagnosis of breast cancer, however, evidence to date is insufficient. We prospectively assessed the associations of postdiagnostic fruit and vegetable consumption with breast cancer–specific and all-cause mortality among 8,927 women with stage I–III breast cancer identified during follow-up of the Nurses' Health Study (NHS; 1980–2010) and NHSII (1991–2011), using a validated food frequency questionnaire completed every 4 years after diagnosis. We prospectively documented 2,521 deaths, including 1,070 from breast cancer through follow-up until 2014 in the NHS and 2015 in the NHSII. Total fruit and vegetable and total vegetable consumption was related to lower all-cause [HRQ5vsQ1, 0.82; 95% confidence interval (CI), 0.71–0.94; Ptrend = 0.004, and HRQ5vsQ1, 0.84; 95% CI, 0.72–0.97; Ptrend = 0.001, respectively], but not breast cancer–specific mortality. Total fruit consumption was not related to breast cancer–specific or all-cause mortality. Greater intake of green leafy and cruciferous vegetables was associated with lower all-cause mortality. Each 2 servings/week of blueberries was associated with a 25% (HR, 0.75; 95% CI, 0.60–0.94) lower breast cancer–specific and a 17% (HR, 0.83; 95% CI, 0.72–0.96) lower all-cause mortality. In contrast, higher fruit juice consumption was associated with higher breast cancer–specific (HRQ5vsQ1, 1.33; 95% CI, 1.09–1.63; Ptrend = 0.002) and all-cause mortality (HRQ5vsQ1, 1.19; 95% CI, 1.04–1.36; Ptrend = 0.003). Apple juice largely accounted for these higher risks and orange juice was not associated with risk. Higher postdiagnostic fruit and vegetable consumption among breast cancer survivors was not associated with breast cancer–specific mortality. However, our findings suggest that higher vegetable consumption, particularly green leafy and cruciferous vegetables, was associated with better overall survival among patients with breast cancer. Higher fruit juice consumption, but not orange juice, was associated with poorer breast cancer–specific and all-cause survival. Significance: A large-scale study shows that high fruit and vegetable consumption may be associated with better overall survival among breast cancer patients, while high fruit juice consumption may be associated with poorer porgnosis.

It is now recognized that compounds released from tumor cells can activate platelets, causing the release of platelet-derived factors into the tumor microenvironment. Several of these factors have been shown to directly promote neovascularization and metastasis, yet how the feedback between platelet releasate and the tumor cell affects metastatic phenotype remains largely unstudied. Here, we identify that breast tumor cells secrete high levels of interleukin 8 (IL-8, CXCL8) in response to platelet releasate, which promotes their invasive capacity. Furthermore, we found that platelets activate the Akt pathway in breast tumor cells, and inhibition of this pathway eliminated IL-8 production. We therefore hypothesized inhibiting platelets with aspirin could reverse the prometastatic effects of platelets on tumor cell signaling. Platelets treated with aspirin did not activate the Akt pathway, resulting in reduced IL-8 secretion and impaired tumor cell invasion. Of note, patients with breast cancer receiving aspirin had lower circulating IL-8, and their platelets did not increase tumor cell invasion compared with patients not receiving aspirin. Our data suggest platelets support breast tumor metastasis by inducing tumor cells to secrete IL-8. Our data further support that aspirin acts as an anticancer agent by disrupting the communication between platelets and breast tumor cells.

Although obesity has now been widely accepted to be an important risk factor for cancer survival, the associations between BMI and cancer mortality have not been consistently linear. Although morbid obesity has clearly been associated with worse survival, some studies have suggested a U-shaped association with no adverse association with overweight or lower levels of obesity. This ‘obesity paradox’ may be due to the fact that BMI likely incompletely captures key measures of body composition, including distribution of skeletal muscle and adipose tissue. Fat and lean body mass can be measured using clinically acquired computed tomography scans. Many of the earlier studies focused on patients with metastatic cancer. However, skeletal muscle loss in the metastatic setting may reflect end-stage disease processes. Therefore, this article focuses on the clinical implication of low skeletal muscle mass in early-stage non-metastatic breast and colorectal cancer where measures of body composition have been shown to be strong predictors of disease-free survival and overall survival and also chemotherapy toxicity and operative risk.

Importance Sarcopenia (low muscle mass), poor muscle quality (low muscle radiodensity), and excess adiposity derived from computed tomography (CT) has been related to higher mortality in patients with metastatic breast cancer, but the association with prognosis in patients with nonmetastatic breast cancer is unknown. Objective To evaluate associations of all 3 body composition measures, derived from clinically acquired CT at diagnosis, with overall mortality in nonmetastatic breast cancer. Design, Setting, and Participants This observational study included 3241 women from Kaiser Permanente of Northern California and Dana Farber Cancer Institute diagnosed from January 2000 to December 2013 with stages II or III breast cancer. We calculated hazard ratios (HRs) to evaluate the associations of all-cause mortality with sarcopenia, low muscle radiodensity, and total adipose tissue (TAT). Models were adjusted for sociodemographics, tumor characteristics, treatment, body mass index (BMI; calculated as weight in kilograms divided by height in meters squared), and other body composition measures. We also evaluated the cross-classification of categories of sarcopenia (yes/no) and tertiles of TAT, with outcomes. Main Outcomes and Measures Overall survival time and all-cause mortality. Results Median (range) age of 3241 women included in this study was 54 (18-80) years, and median follow-up was 6.0 years; 1086 patients (34%) presented with sarcopenia, and 1199 patients (37%) had low muscle radiodensity. Among patients with nonmetastatic breast cancer, those with sarcopenia showed higher overall mortality (HR, 1.41; 95% CI, 1.18-1.69) compared with those without sarcopenia. Patients in the highest tertile of TAT also showed higher overall mortality (HR, 1.35; 95% CI, 1.08-1.69) compared with those in the lowest tertile. Low radiodensity was not associated with survival. In analyses of sarcopenia and TAT, highest mortality was seen in patients with sarcopenia and high TAT (HR, 1.89; 95% CI, 1.30-2.73); BMI alone was not significantly related to overall mortality and did not appropriately identify patients at risk of death owing to their body composition. Conclusions and Relevance Sarcopenia is underrecognized in nonmetastatic breast cancer and occurs in over one-third of newly diagnosed patients. Measures of both sarcopenia and adiposity from clinically acquired CT scans in nonmetastatic patients provide significant prognostic information that outperform BMI and will help to guide interventions to optimize survival outcomes.

Lifestyle factors have been well studied in relation to breast cancer prognosis overall; however, associations of lifestyle and late outcomes (>5 years after diagnosis) have been much less studied, and no studies have focused on estrogen receptor-positive (ER+) breast cancer survivors, who may have high risk of late recurrence and mortality. We utilized a large prospective pooling study to evaluate the associations of lifestyle factors with late recurrence and all-cause mortality among 6,295 5-year ER+ Stage I-III breast cancer survivors. Pooled and harmonized data were available on clinical factors and lifestyle factors (pre- to post-diagnosis weight change, body mass index (BMI) (kg/m(2)), recreational physical activity, alcohol intake and smoking history), measured on average 2.1 years after diagnosis. Updated information for weight only was available. Study heterogeneity was evaluated by the Q-statistic. Multivariable Cox regression models were stratified by study. Adjusting for clinical factors and potential confounders, ≥ 10% weight gain and obesity (BMI, 30-34.99 and ≥ 35) were associated with increased risk of late recurrence (hazard ratios (95% confidence intervals): 1.24 (1.00-1.53), 1.40 (1.05-1.86) and 1.41 (1.02-1.93), respectively). Daily alcohol intake was associated with late recurrence, 1.28 (1.01-1.62). Physical activity was inversely associated with late all-cause mortality (0.81 (0.71-0.93) and 0.71 (0.61-0.82) for 4.9 to

Alcohol consumption is a consistent risk factor for breast cancer, although it is unclear whether the association varies by breast cancer molecular subtype. We investigated associations between cumulative average alcohol intake and risk of breast cancer by molecular subtype among 105,972 women in the prospective Nurses' Health Study cohort, followed from 1980 to 2006. Breast cancer molecular subtypes were defined according to estrogen receptor (ER), progesterone receptor, human epidermal growth factor 2 (HER2), cytokeratin 5/6, and epidermal growth factor status from immunostained tumor microarrays in combination with histologic grade. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). Competing risk analyses were used to assess heterogeneity by subtype. We observed suggestive heterogeneity in associations between alcohol and breast cancer by subtype (phet = 0.06). Alcohol consumers had an increased risk of luminal A breast cancers [n = 1,628 cases, per 10 g/day increment HR (95%CI) = 1.10(1.05-1.15)], and an increased risk that was suggestively stronger for HER2-type breast cancer [n = 160 cases, HR (95%CI) = 1.16(1.02-1.33)]. We did not observe statistically significant associations between alcohol and risk of luminal B [n = 631 cases, HR (95%CI) = 1.08(0.99-1.16)], basal-like [n = 254 cases, HR (95%CI) = 0.90(0.77-1.04)], or unclassified [n = 87 cases, HR (95%CI) = 0.90(0.71-1.14)] breast cancer. Alcohol consumption was associated with increased risk of luminal A and HER2-type breast cancer, but not significantly associated with other subtypes. Given that ERs are expressed in luminal A but not in HER2-type tumors, our findings suggest that other mechanisms may play a role in the association between alcohol and breast cancer.

In epidemiologic studies, alcohol consumption appears more strongly associated with risk of estrogen receptor (ER)-positive than ER-negative breast cancer. However, this association has not been assessed by other potentially relevant tumor markers, such as androgen receptor (AR) or insulin receptor (IR). In the prospective Nurses' Health Study cohort, we evaluated alcohol consumption and breast cancer risk by individual tumor marker expression (i.e., ER, progesterone receptor [PR], AR, and IR) while controlling for other markers and also assessed the joint effect of these receptors. During 26 years follow-up of 106,037 women, 2552 invasive breast cancers contributed to the analysis. When all four markers were considered simultaneously, no significant heterogeneity of the alcohol and breast cancer association was observed by any of the markers. However, each increment in one drink per day was associated with 10% (95% confidence interval [CI] = 4%, 15%) and 9% (95% CI = 4%, 15%) increased risk of AR-positive and ER-positive breast cancer, respectively, while no increased risk was observed among AR-negative or ER-negative tumors. The association was independent of PR and IR expression. Assessment of the joint expression of hormone receptors revealed a significantly increased risk among AR+/ER+/PR+ (hazard ratio [HR] per drink/day = 1.11, 95% CI = 1.06, 1.17) but not in other subgroups (e.g. , AR-/ER-/PR-: HR = 0.99; 95% CI = 0.88, 1.12). Our data suggest that the alcohol and breast cancer association may be more pronounced among ER-positive and/or AR-positive breast tumors. However, our data do not support an important role of IR in the association.

Protest response is a common aspect of contingent valuation (CV) studies, which has attracted growing attention from scholars worldwide. Distrust of government, understood as one of the major reasons for protest response, has been prevalent across transitional China experiencing dramatic changes in its economy, society and natural environment. Citizen distrust of government would significantly hinder the efficiency and validity of the contingent valuation method (CVM) application focusing on the provision of public environmental and ecological goods in China, as a large proportion of protest responses might be induced. Hitherto little has been done to link residents' trust in government to their environmental behaviors in developing and transitional economies like China where CVM has been increasingly applied to generate meaningful and reliable information for integrating both ecological and socioeconomic perspectives into policy decisions. This study aims to investigate the discrepancies between protest responses induced by distrust of government and non-protest responses, using the contingent valuation of heritage trees in Guangzhou as a case. The combination of a set of debriefing questions and several attitudinal questions is employed in the questionnaire. Based on logit analysis and discriminant analysis, it has been found that protestors who distrust government and non-protestors share similar salient values associated with urban heritage trees in Guangzhou, especially their distinctive historical and cultural values, in comparison with ordinary urban trees. Residents with low familiarity with heritage trees (who rarely visit sites with heritage trees, know little about management and conservation techniques, and consider present management to be ineffective) are likely to act as protesters with the "distrust of government" belief. Only if more opportunities are provided for residents to obtain access to urban heritage tree sites, more information (about urban heritage trees and other environmental and ecological goods) is disseminated, and more effective management is implemented, can better governmental trust be developed and stronger public participation and support secured. The results of this study can shed light on understanding protest responses in CV studies and improving the reliability and efficiency of CVM in China and other developing countries where a low level of trust in government prevails.

Heritage trees in cities represent special natural-cum-cultural assets of cities. They could contribute substantially to the quality of urban life and social welfare through the provision of an array of biological, aesthetical, environmental, and cultural benefits. The conservation of this rare and unique natural asset is a challenging endeavor in developing countries, such as China, where the intense pressures of rapid urbanization must be confronted. There is an urgent need to present these trees to the public in a way which reflects their true value to society. The present study estimated public willingness-to-pay (WTP) for the conservation of heritage trees in Guangzhou, south China by applying the contingent valuation method (CVM). The results revealed that the mean WTP was about RMB24.67 per household for common heritage tree species (with a 95% confidence interval of RMB17.46 to RMB31.88), and RMB31.26 per household for rare heritage tree species (with a 95% confidence interval of RMB21.60 to RMB40.97), respectively. Public WTP is insensitive to the rarity status of some heritage tree species, indicating that all old trees are considered as a special rare natural resource, and that there is also a general lack of publicity of the endangered status of those old trees. Analysis also showed that although people could ascribe high importance to the special cultural and biological values of urban heritage trees, it is the overall value of heritage trees, particularly the recreational value, that determines respondents’ decision ‘to pay’ or ‘not to pay’ for their conservation. This recognition of the importance of various values has no impact on respondents’ decision about ‘how much to pay’. Income level is the only significant socioeconomic variable in WTP function, indicating that respondents’ decision about ‘how much to pay’ is mainly based on their economic resources. Thus, it is necessary to foster public environmental awareness and responsibility in order to link individual moral obligation with conservation behavior in educational processes.