Publications by authors named "Wendy Y Chen"

113 Publications

Phase I study of JAK1/2 inhibitor ruxolitinib with weekly paclitaxel for the treatment of HER2-negative metastatic breast cancer.

Cancer Chemother Pharmacol 2021 Feb 14. Epub 2021 Feb 14.

Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA.

Purpose: Preclinical studies support the JAK2-STAT3 signaling pathway as a key driver in CD44+ CD24- "stem-cell-like" breast cancer cells. Ruxolitinib is an orally bioavailable JAK1/2 inhibitor. We aimed to identify the recommended phase 2 dose (RP2D) of ruxolitinib in combination with paclitaxel in patients with HER2-negative metastatic breast cancer (MBC).

Methods: Eligible patients had HER2-negative MBC and had received ≤ 3 chemotherapy regimens for advanced disease. Patients received oral ruxolitinib (10-25 mg bid) in a 3 + 3 dose escalation design in combination with weekly paclitaxel 80 mg/m in a 3-week cycle. The primary objective was to determine the maximum tolerated dose (MTD) and the RP2D.

Results: Nineteen patients received protocol therapy (mean age 52 years). Eight (42%) had triple-negative breast cancer and 11 (58%) had hormone receptor-positive disease; 12 (63%) had visceral disease. Ten (53%) patients had not received prior treatment for advanced disease. Patients received a median number of 5 cycles of combination therapy (range 1-12) and five patients continued single-agent ruxolitinib. The MTD of ruxolitinib was 25 mg bid when combined with paclitaxel, and the RP2D for the combination was 15 mg bid. Thirteen (68%) patients required dose reductions or holds. Most frequent toxicities reported of any grade were neutropenia (50%) and anemia (33%). There were no grade 4/5 toxicities attributed to study drug. Four (21%) patients had PR, 12 (63%) had SD and three (16%) had PD as their best response.

Conclusion: The combination of ruxolitinib and weekly paclitaxel was well tolerated with evidence of clinical activity. Further analysis of this combination is ongoing (NCT02041429).

Trial Registration: NCT02041429. Date of registration: January 22, 2014.
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http://dx.doi.org/10.1007/s00280-021-04245-xDOI Listing
February 2021

Partial attribute attendance in environmental choice experiments: A comparative case study between Guangzhou (China) and Brussels (Belgium).

J Environ Manage 2021 Feb 6;285:112107. Epub 2021 Feb 6.

Land, Environment, Economics and Policy Institute, University of Exeter, Rennes Drive, Exeter, EX4 4PU, United Kingdom.

Attribute non-attendance (ANA) in discrete choice experiment (DCE) exercises has attracted increasing, yet limited, scholarly attention. This paper attempts to investigate ANA in a comparative case study, with a focus on its patterns and their association with socioeconomic, behavioral and perceptual factors, as well as its impacts on willingness-to-pay (WTP) estimates. We deploy a four-level polytomous scale (always, often, seldom, and never considered) for respondents to state their various degrees of attribute attendance (SANA) in an identical DCE questionnaire about urban river restoration initiatives in two global cities with contrast socioeconomic contexts, yet similar request for restoring polluted and modified urban rivers, Guangzhou (south China) and Brussels (Belgium). The survey results reveal the existence of large proportions of partial attendance in two sampled cities. We use an extended mixed logit model, which incorporates separate parameters delineating each attribute's different attendance groups, to estimate respondents' average WTP values. We find that accounting for SANA could improve the goodness-of-fit of the model and affect the magnitude of mean WTP estimates. Respondents' attribute attendance level pertaining to various attributes is mainly associated with their perceived importance of urban rivers' ecosystem services, but may not be necessarily correlated with the strength of their preference for corresponding attributes as indicated by the mean WTP estimates. Whether this discontinuity between respondents' stated ANA levels and WTP estimates within Guangzhou sample questions the ability of DCEs to generate unbiased welfare estimation and policy guidance in developing countries calls for further studies.
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http://dx.doi.org/10.1016/j.jenvman.2021.112107DOI Listing
February 2021

Postdiagnostic Dietary Glycemic Index, Glycemic Load, Dietary Insulin Index, and Insulin Load and Breast Cancer Survival.

Cancer Epidemiol Biomarkers Prev 2021 Feb 20;30(2):335-343. Epub 2020 Nov 20.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.

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 [HR = 1.33; 95% confidence interval (CI) = 1.09-1.63; = 0.008] and all-cause mortality (HR = 1.26; 95% CI = 1.10-1.45; = 0.0006). Higher all-cause mortality was also observed with higher postdiagnostic GI (HR = 1.23; 95% CI = 1.08-1.40; = 0.001), II (HR = 1.20; 95% CI = 1.04-1.38; = 0.005), and IL (HR = 1.23; 95% CI = 1.07-1.42; = 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..
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0764DOI Listing
February 2021

Effect of Vitamin D3 Supplements on Development of Advanced Cancer: A Secondary Analysis of the VITAL Randomized Clinical Trial.

JAMA Netw Open 2020 11 2;3(11):e2025850. Epub 2020 Nov 2.

Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

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 (<25, 25 to < 30, and ≥30) as effect modifiers of the observed associations.

Results: Among 25 871 randomized VITAL participants (51% female; mean [SD] age, 67.1 [7.1] years), 1617 were diagnosed with invasive cancer over a median intervention period of 5.3 years (range, 3.8-6.1 years). As previously reported, no significant differences for cancer incidence by treatment arm were observed. However, a significant reduction in advanced cancers (metastatic or fatal) was found for those randomized to vitamin D compared with placebo (226 of 12 927 assigned to vitamin D [1.7%] and 274 of 12 944 assigned to placebo [2.1%]; HR, 0.83 [95% CI, 0.69-0.99]; P = .04). 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<25: HR, 0.62 [95% CI, 0.45-0.86]) but not among those with overweight or obesity (BMI 25-<30: HR, 0.89 [95% CI, 0.68-1.17]; BMI≥30: HR, 1.05 [95% CI, 0.74-1.49]) (P = .03 for interaction by BMI).

Conclusions And Relevance: In this randomized clinical trial, supplementation with vitamin D reduced the incidence of advanced (metastatic or fatal) cancer in the overall cohort, with the strongest risk reduction seen in individuals with normal weight.

Trial Registration: ClinicalTrials.gov Identifier: NCT01169259.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.25850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675103PMC
November 2020

Postdiagnostic Fruit and Vegetable Consumption and Breast Cancer Survival: Prospective Analyses in the Nurses' Health Studies.

Cancer Res 2020 11;80(22):5134-5143

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.

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 [HR, 0.82; 95% confidence interval (CI), 0.71-0.94; = 0.004, and HR, 0.84; 95% CI, 0.72-0.97; = 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 (HR, 1.33; 95% CI, 1.09-1.63; = 0.002) and all-cause mortality (HR, 1.19; 95% CI, 1.04-1.36; = 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.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-3515DOI Listing
November 2020

Evaluation of automated computed tomography segmentation to assess body composition and mortality associations in cancer patients.

J Cachexia Sarcopenia Muscle 2020 Oct 20;11(5):1258-1269. Epub 2020 Apr 20.

Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.

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 cm , respectively. ABACS's performance was lowest for the <2% of patients who were underweight or had anatomic abnormalities. ABACS and manual analysis produced similar associations with mortality; comparing the lowest to highest tertile of skeletal muscle from ABACS versus manual analysis, the HRs were 1.23 (95% CI: 1.00-1.52) versus 1.38 (95% CI: 1.11-1.70) for colorectal cancer patients and 1.30 (95% CI: 1.01-1.66) versus 1.29 (95% CI: 1.00-1.65) for breast cancer patients.

Conclusions: In the first study to externally evaluate a commercially available software to assess body composition, automated segmentation of muscle and adipose tissues using ABACS was similar to manual analysis and associated with mortality after non-metastatic cancer. Automated methods will accelerate body composition research and, eventually, facilitate integration of body composition measures into clinical care.
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http://dx.doi.org/10.1002/jcsm.12573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567141PMC
October 2020

Body Composition, Adherence to Anthracycline and Taxane-Based Chemotherapy, and Survival After Nonmetastatic Breast Cancer.

JAMA Oncol 2020 02;6(2):264-270

Division of Research, Kaiser Permanente Northern California, Oakland.

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 (<0.85), which is the ratio of delivered to planned chemotherapy dose, derived from infusion records; in addition, hematologic toxic effects were defined based on laboratory test values. To evaluate associations with overall and breast cancer-specific mortality, logistic regression models adjusted for age and body surface area were fit as well as Cox proportional hazards models adjusted for age, race/ethnicity, adiposity, Charlson comorbidity index score, and tumor stage and subtype. The mediation proportion was computed using the difference method.

Results: The mean (SD) age at diagnosis of the 1395 women included in the study was 52.8 (10.2) years. Greater visceral (odds ratio [OR], 1.19; 95% CI, 1.02-1.39 per SD) and intramuscular (OR, 1.16; 95% CI, 1.01-1.34 per SD) adiposity were associated with increased odds of RDI less than 0.85. Greater muscle mass was associated with a decreased odds of hematologic toxic effects (OR, 0.84; 95% CI, 0.71-0.98 per SD). Relative dose intensity less than 0.85 was associated with a 30% increased risk of death (hazard ratio, 1.30; 95% CI, 1.02-1.65). Lower RDI partially explained the association of adiposity with breast cancer-specific mortality (mediation proportion, 0.20; 95% CI, 0.05-0.55).

Conclusions And Relevance: Excess adiposity, presenting as larger visceral or intramuscular adiposity, was associated with lower RDI. Lower RDI partially mediated the association of adiposity with worse breast cancer-specific survival. Body composition may help to identify patients likely to experience toxic effects and subsequent dose delays or reductions, which could compromise chemotherapeutic efficacy.
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http://dx.doi.org/10.1001/jamaoncol.2019.4668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902178PMC
February 2020

Environmental amenities of urban rivers and residential property values: A global meta-analysis.

Sci Total Environ 2019 Nov 27;693:133628. Epub 2019 Jul 27.

Department of Geography, The University of Hong Kong, Pokfulam Road, Hong Kong.

Environmental amenities and disamenities of urban rivers and their capitalization in property prices have been a major subject of empirical investigation in the hedonic price method (HPM) literature for several decades. Primary studies across the globe have nonetheless adopted varying valuation scenarios and modelling approaches. And systematic variation has been shown in homeowners' marginal willingness-to-pay (WTP) for urban rivers' amenities and disamenities, ranging between -12.2% and 63.58% price premium. To identify which valuation scenarios, socio-economic variables, and modelling characteristics might affect the quantification of urban rivers' impacts on property values, we conducted a very first meta-analysis of existing evidence to extract additional information concerning the heterogeneity in WTP estimates pertaining to urban rivers' environmental amenities and disamenities. A total of 53 observations from 30 primary studies that adopted HPM to provide WTP estimates for three prominent valuation scenarios, i.e., proximity, view and water quality, were synthesized using a random effects model. Our meta-analysis results revealed several important factors in explaining the heterogeneity in empirical WTP estimates pertaining to urban rivers' environmental amenities/disamenities. First, while all three valuation scenarios could capture urban rivers' impacts on residential property values, river view was associated with the greatest premium, followed by river water quality, and river proximity the least. Second, we found that WTP estimates were significantly higher after the year of 2000, indicating the widespread and successful river restoration and rehabilitation projects in the 21st century has driven up homeowners' environmental perception and appreciation of urban rivers' amenities, especially their clear depreciation of negative environmental disamenities, to a high level. Third, our results showed that homeowners' valuation of urban rivers was not sensitive to the macro-geographical locations of their residences, suggesting a universal overall appreciation/depreciation of urban rivers across varying cultures and societies. Instead, household income level and population density should be systematically controlled if value transfer across countries is necessary. The findings of this meta-analysis could help refine urban rivers' attributes to be incorporated into HPM studies so as to adequately quantify people's sophisticated valuation of intertwined amenities and disamenities. On the practical front, our results supported two arguments from a very utilitarian point of view. First, it appears that the visual impacts might be prioritized for river restoration projects, such as through careful revegetation of riparian areas using native species. This could harbor rich diversity of ecological functions and in the meantime maximize environmental amenities that homeowners would like to pay for. And second, cost-effective river restoration in urbanized contexts should be prioritized in densely populated areas over places with relatively low population densities. This approach might maximize the number of people who can enjoy rivers for a given budget.
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http://dx.doi.org/10.1016/j.scitotenv.2019.133628DOI Listing
November 2019

Adipose Tissue Distribution and Cardiovascular Disease Risk Among Breast Cancer Survivors.

J Clin Oncol 2019 10 1;37(28):2528-2536. Epub 2019 Aug 1.

Kaiser Permanente Northern California, Oakland, CA.

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.
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http://dx.doi.org/10.1200/JCO.19.00286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001794PMC
October 2019

Low-dose radiation (4 Gy) with/without concurrent chemotherapy is highly effective for relapsed, refractory mantle cell lymphoma.

Blood Adv 2019 07;3(13):2035-2039

Department of Radiation Oncology.

Mantle cell lymphoma (MCL) generally exhibits an aggressive disease course with poor outcomes. Despite inherent radiosensitivity, radiation therapy (RT) is not commonly used for MCL. This study assesses the role of low-dose RT (LDRT) with concurrent chemotherapy in relapsed, multiply refractory MCL. From 2014 through 2018, 19 patients with relapsed, refractory MCL had 98 sites treated with 4 Gy. Median follow-up from initial LDRT was 15.4 months. Patients had received a median 7 courses of chemotherapy since diagnosis, and 58% were ibrutinib-refractory. Of the 98 sites, 76% were refractory to ongoing chemotherapy, and LDRT was delivered with concurrent chemotherapy for 76%. The complete response (CR) rate was 81% at a median 2.7 months post-LDRT. There were no differences in CR despite ibrutinib-refractory disease, prior chemotherapy courses (>5), or tumor size (>3 cm). There were no RT-related toxicities. Overall survival at 1 year following initial LDRT was 90%, and 1-year progression-free survival following last course was 55%. In summary, LDRT is effective for relapsed, multiply refractory MCL, and may be safely delivered with chemotherapy, to multiple sites, and repeatedly without issue. By treating active sites of disease, LDRT can provide durable local control, help achieve remission, and potentially bridge patients to subsequent novel therapies.
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http://dx.doi.org/10.1182/bloodadvances.2019030858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6616267PMC
July 2019

Adipose Tissue Distribution and Survival Among Women with Nonmetastatic Breast Cancer.

Obesity (Silver Spring) 2019 06 25;27(6):997-1004. Epub 2019 Apr 25.

Division of Research, Kaiser Permanente Northern California, Oakland, California, USA.

Objective: Previous studies of breast cancer survival have not considered specific depots of adipose tissue such as subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT).

Methods: This 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.

Results: SAT and VAT ranged from 19.0 to 891 cm and from 0.484 to 454 cm , respectively. SAT was related to increased risk of death (127-cm increase; HR [95% CI]: 1.13 [1.02-1.26]), but no relationship was found with VAT (78.18-cm 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 < 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]).

Conclusions: SAT may be an underappreciated risk factor for breast cancer-related death.
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http://dx.doi.org/10.1002/oby.22458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533153PMC
June 2019

Comparison of Questionnaire-Based Breast Cancer Prediction Models in the Nurses' Health Study.

Cancer Epidemiol Biomarkers Prev 2019 07 23;28(7):1187-1194. Epub 2019 Apr 23.

Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

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 < 0.001 for each) with notable ( < 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 ( < 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 <0.60 among women ages ≥70 years.

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.
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http://dx.doi.org/10.1158/1055-9965.EPI-18-1039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684099PMC
July 2019

Aspirin inhibits platelets from reprogramming breast tumor cells and promoting metastasis.

Blood Adv 2019 01;3(2):198-211

Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA.

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.
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http://dx.doi.org/10.1182/bloodadvances.2018026161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341186PMC
January 2019

Synthetic microbe communities provide internal reference standards for metagenome sequencing and analysis.

Nat Commun 2018 08 6;9(1):3096. Epub 2018 Aug 6.

Garvan Institute of Medical Research, Sydney, 2010, NSW, Australia.

The complexity of microbial communities, combined with technical biases in next-generation sequencing, pose a challenge to metagenomic analysis. Here, we develop a set of internal DNA standards, termed "sequins" (sequencing spike-ins), that together constitute a synthetic community of artificial microbial genomes. Sequins are added to environmental DNA samples prior to library preparation, and undergo concurrent sequencing with the accompanying sample. We validate the performance of sequins by comparison to mock microbial communities, and demonstrate their use in the analysis of real metagenome samples. We show how sequins can be used to measure fold change differences in the size and structure of accompanying microbial communities, and perform quantitative normalization between samples. We further illustrate how sequins can be used to benchmark and optimize new methods, including nanopore long-read sequencing technology. We provide metagenome sequins, along with associated data sets, protocols, and an accompanying software toolkit, as reference standards to aid in metagenomic studies.
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http://dx.doi.org/10.1038/s41467-018-05555-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6078961PMC
August 2018

Fruit and vegetable consumption and breast cancer incidence: Repeated measures over 30 years of follow-up.

Int J Cancer 2019 04 19;144(7):1496-1510. Epub 2018 Dec 19.

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

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; p = 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; p = 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 (p = 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.
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http://dx.doi.org/10.1002/ijc.31653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440478PMC
April 2019

Clinical implications of low skeletal muscle mass in early-stage breast and colorectal cancer.

Proc Nutr Soc 2018 11 4;77(4):382-387. Epub 2018 Jun 4.

Department of Medical Oncology,Dana Farber Cancer Institute,Boston, MA,USA.

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.
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http://dx.doi.org/10.1017/S0029665118000423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197885PMC
November 2018

Dairy Consumption in Adolescence and Early Adulthood and Risk of Breast Cancer.

Cancer Epidemiol Biomarkers Prev 2018 05;27(5):575-584

Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.

Carcinogenic exposure in early life may be critical for subsequent breast cancer risk. Dairy consumption was examined during adolescence and early adulthood in relation to incident breast cancer in the Nurses' Health Study II cohort. For the analyses of early adulthood dairy consumption, we included 90,503 premenopausal women ages 27 to 44 years in 1991 who reported dairy consumption using a validated food-frequency questionnaire. From 1991 to 2013, 3,191 invasive breast cancer cases were identified. In 1998, 44,264 women recalled adolescent dairy consumption. This subgroup of women was followed up from 1998 to 2013; 1,318 invasive breast cancer cases were identified. Multivariate hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using the Cox proportional hazard regression. Adolescent and early adulthood total dairy consumption was not associated with overall breast cancer risk (each serving/day during adolescence, total dairy HR = 1.02, 95% CI, 0.97-1.07; for early adulthood total dairy HR = 1.01, 95% CI, 0.97-1.04), as were intakes of calcium, vitamin D, and lactose. Adolescent consumption of total and high-fat dairy was associated with higher risk of estrogen and progesterone receptor negative (each serving/day: total dairy HR = 1.11, 95% CI, 1.00-1.24; high-fat dairy HR = 1.17, 95% CI, 1.04-1.31). However, higher adolescent high-fat dairy consumption was associated with lower risk of estrogen and progesterone receptor positive tumors (each serving/day HR = 0.91, 95% CI, 0.86-0.97). Our results suggest no overall association between dairy consumption during adolescence or early adulthood and breast cancer risk, but the findings may differ by hormone receptor status of tumors. Dairy consumption in adolescence or early adulthood may not be a significant predictor of breast cancer incidence. .
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http://dx.doi.org/10.1158/1055-9965.EPI-17-0345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943046PMC
May 2018

Association of Muscle and Adiposity Measured by Computed Tomography With Survival in Patients With Nonmetastatic Breast Cancer.

JAMA Oncol 2018 06;4(6):798-804

Dana Farber Cancer Institute, Boston, Massachusetts.

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.
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http://dx.doi.org/10.1001/jamaoncol.2018.0137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6584322PMC
June 2018

Sleep and survival among women with breast cancer: 30 years of follow-up within the Nurses' Health Study.

Br J Cancer 2018 03 9;118(6):e6. Epub 2018 Jan 9.

Department of Medicine, Channing Division of Network Medicine, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA 02115, USA.

This corrects the article DOI: 10.1038/bjc.2017.85.
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http://dx.doi.org/10.1038/bjc.2017.437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5877366PMC
March 2018

Role of Aspirin in Breast Cancer Survival.

Curr Oncol Rep 2017 Jul;19(7):48

Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.

Chemotherapy and hormonal therapy have significantly decreased breast cancer mortality, although with considerable side effects and financial costs. In the USA, over three million women are living after a breast cancer diagnosis and are eager for new treatments that are low in toxicity and cost. Multiple observational studies have reported improved breast cancer survival with regular aspirin use. Furthermore, pooled data from five large randomized trials of aspirin for cardiovascular disease showed that subjects on aspirin had decreased risk of cancer mortality and decreased risk of metastatic cancer. Although the potential mechanism for aspirin preventing breast cancer is not known, possible pathways may involve platelets, inflammation, cyclooxygenase (COX) 2, hormones, or PI3 kinase. This review article summarizes the current epidemiologic and clinical trial evidence as well as possible underlying mechanisms that justify current phase III randomized trials of aspirin to improve breast cancer survival.
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http://dx.doi.org/10.1007/s11912-017-0605-6DOI Listing
July 2017

Extensions of the Rosner-Colditz breast cancer prediction model to include older women and type-specific predicted risk.

Breast Cancer Res Treat 2017 Aug 6;165(1):215-223. Epub 2017 Jun 6.

Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Purpose: A breast cancer risk prediction rule previously developed by Rosner and Colditz has reasonable predictive ability. We developed a re-fitted version of this model, based on more than twice as many cases now including women up to age 85, and further extended it to a model that distinguished risk factor prediction of tumors with different estrogen/progesterone receptor status.

Methods: We compared the calibration and discriminatory ability of the original, the re-fitted, and the type-specific models. Evaluation used data from the Nurses' Health Study during the period 1980-2008, when 4384 incident invasive breast cancers occurred over 1.5 million person-years. Model development used two-thirds of study subjects and validation used one-third.

Results: Predicted risks in the validation sample from the original and re-fitted models were highly correlated (ρ = 0.93), but several parameters, notably those related to use of menopausal hormone therapy and age, had different estimates. The re-fitted model was well-calibrated and had an overall C-statistic of 0.65. The extended, type-specific model identified several risk factors with varying associations with occurrence of tumors of different receptor status. However, this extended model relative to the prediction of any breast cancer did not meaningfully reclassify women who developed breast cancer to higher risk categories, nor women remaining cancer free to lower risk categories.

Conclusions: The re-fitted Rosner-Colditz model has applicability to risk prediction in women up to age 85, and its discrimination is not improved by consideration of varying associations across tumor subtypes.
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http://dx.doi.org/10.1007/s10549-017-4319-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5560077PMC
August 2017

Reply to D.J. Beale.

J Clin Oncol 2017 06 6;35(16):1857-1858. Epub 2017 Mar 6.

Michelle D. Holmes, Channing Division of Network Medicine and Harvard T. H. Chan School of Public Health, Boston, MA; Jun Wang, University of Massachusetts Amherst, Amherst, MA; Susan E. Hankinson, Channing Division of Network Medicine, Boston and University of Massachusetts Amherst, Amherst, MA; Rulla M. Tamimi, Channing Division of Network Medicine and Harvard T. H. Chan School of Public Health, Boston, MA; and Wendy Y. Chen, Channing Division of Network Medicine and Dana-Farber Cancer Institute, Boston, MA.

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http://dx.doi.org/10.1200/JCO.2016.72.0862DOI Listing
June 2017

Alcohol Consumption and Breast Cancer Risk in Younger Women According to Family History of Breast Cancer and Folate Intake.

Am J Epidemiol 2017 Sep;186(5):524-531

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.
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http://dx.doi.org/10.1093/aje/kwx137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5860629PMC
September 2017

Identifying Societal Preferences for River Restoration in a Densely Populated Urban Environment: Evidence from a Discrete Choice Experiment in Central Brussels.

Environ Manage 2017 08 5;60(2):263-279. Epub 2017 May 5.

VITO, The Flemish Institute for Technological Research, Boeretang 200, 2400, Mol, Belgium.

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.
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http://dx.doi.org/10.1007/s00267-017-0885-5DOI Listing
August 2017

Sleep and survival among women with breast cancer: 30 years of follow-up within the Nurses' Health Study.

Br J Cancer 2017 04 30;116(9):1239-1246. Epub 2017 Mar 30.

Department of Medicine, Channing Division of Network Medicine, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA 02115, USA.

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-HR=1.35, CI=1.04-1.74; MV-HR=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.
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http://dx.doi.org/10.1038/bjc.2017.85DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5418457PMC
April 2017

Body mass index, PAM50 subtype, recurrence, and survival among patients with nonmetastatic breast cancer.

Cancer 2017 Jul 13;123(13):2535-2542. Epub 2017 Mar 13.

Division of Research, Kaiser Permanente Northern California, Oakland, California.

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/m 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/m were compared with those who had a BMI from 18.5 to <25 kg/m , the hazard ratio was 2.24 (95% confidence interval,1.22-4.11) for breast cancer-specific death and 1.24 (95% confidence interval, 1.00-1.54) for recurrence. There was no association within luminal B, basal-like or human epidermal growth factor over-expressing subtypes.

Conclusions: Among patients who had accurately classified breast cancer subtypes based on gene expression, a BMI ≥35 kg/m was adversely associated with outcomes only among those who had luminal A cancers. Research is needed into whether tailoring recommendations for weight management to tumor characteristics will improve outcomes. Cancer 2017;123:2535-42. © 2017 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474169PMC
July 2017

Weight and weight changes in early adulthood and later breast cancer risk.

Int J Cancer 2017 05;140(9):2003-2014

Siteman Cancer Center and Washington University School of Medicine, Saint Louis, MO, 63110.

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 4,965 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.
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http://dx.doi.org/10.1002/ijc.30627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5798241PMC
May 2017

Protein Intake and Breast Cancer Survival in the Nurses' Health Study.

J Clin Oncol 2017 01 7;35(3):325-333. Epub 2016 Nov 7.

Michelle D. Holmes, Susan E. Hankinson, Rulla M. Tamimi, and Wendy E. Chen, Brigham and Women's Hospital; Michelle D. Holmes and Rulla M. Tamimi, Harvard T.H. Chan School of Public Health; Wendy E. Chen, Dana-Farber Cancer Institute, Boston; and Jun Wang and Susan E. Hankinson, University of Massachusetts Amherst, Amherst, MA.

Purpose Greater 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 Methods We 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. Results There 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. Conclusion We 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.
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http://dx.doi.org/10.1200/JCO.2016.68.3292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5456374PMC
January 2017

Pooled analysis of active cigarette smoking and invasive breast cancer risk in 14 cohort studies.

Int J Epidemiol 2017 06;46(3):881-893

Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA.

Background: The 2014 US Surgeon General's report noted research gaps necessary to determine a causal relationship between active cigarette smoking and invasive breast cancer risk, including the role of alcohol consumption, timing of exposure, modification by menopausal status and heterogeneity by oestrogen receptor (ER) status.

Methods: To address these issues, we pooled data from 14 cohort studies contributing 934 681 participants (36 060 invasive breast cancer cases). Cox proportional hazard regression models were used to calculate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs).

Results: Smoking duration before first birth was positively associated with risk ( P -value for trend = 2 × 10 -7 ) with the highest HR for initiation >10 years before first birth (HR = 1.18, CI 1.12-1.24). Effect modification by current alcohol consumption was evident for the association with smoking duration before first birth ( P -value=2×10 -4 ); compared with never-smoking non-drinkers, initiation >10 years before first birth was associated with risk in every category of alcohol intake, including non-drinkers (HR = 1.15, CI 1.04-1.28) and those who consumed at least three drinks per day (1.85, 1.55-2.21). Associations with smoking before first birth were limited to risk of ER+ breast cancer ( P -value for homogeneity=3×10 -3 ). Other smoking timing and duration characteristics were associated with risk even after controlling for alcohol, but were not associated with risk in non-drinkers. Effect modification by menopause was not evident.

Conclusions: Smoking, particularly if initiated before first birth, was modestly associated with ER+ breast cancer risk that was not confounded by amount of adult alcohol intake. Possible links with breast cancer provide additional motivation for young women to not initiate smoking.
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http://dx.doi.org/10.1093/ije/dyw288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837778PMC
June 2017

Postdiagnosis social networks and breast cancer mortality in the After Breast Cancer Pooling Project.

Cancer 2017 Apr 12;123(7):1228-1237. Epub 2016 Dec 12.

Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts.

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.
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http://dx.doi.org/10.1002/cncr.30440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5360517PMC
April 2017