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Background CDK4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) have a well-established role in the management of hormone receptor-positive (HR+)/HER2- metastatic breast cancer (MBC). The benefit of continuing CDK4/6i beyond progression in combination with a different ET has not been confirmed. Preclinical data suggest synergy between CDK4/6i and PD-L1 inhibition. The PACE trial prospectively evaluates whether continuation of the CKD4/6i palbociclib beyond progression on prior CDK4/6i and aromatase inhibitor (AI), with a change in ET to fulvestrant, improves outcomes beyond change to fulvestrant alone, as well as explores the activity of the palbociclib, fulvestrant, and avelumab triplet. Methods PACE is a multicenter randomized open-label investigator-initiated phase II trial, open at 11 U.S. sites. Eligible patients (pts) had HR+/HER2- evaluable MBC with prior progression on AI and any CDK4/6i after > 6 months (mo) of therapy in the MBC setting, or during/within 12 mo in the adjuvant setting, with no more than 1 prior line of chemotherapy for MBC. Pts were randomized 1:2:1 to fulvestrant alone (F); fulvestrant and palbociclib (F+P); or fulvestrant, palbociclib, avelumab (F+P+A), with tumor assessments every 8 weeks. Blood for circulating tumor DNA (ctDNA) analysis was collected at baseline, at times of tumor assessments, and at progression. The primary objective was to evaluate progression-free survival (PFS) with F+P vs F; secondary objectives included PFS with F+P+A vs F, objective response rate (ORR) in all arms, and safety. A sample size of 220 patients was planned to provide 80% power to detect an improvement in PFS with HR 0.6154 with F+P vs F (6.5 vs 4 mo; α(1)=0.05). Results A total of 220 pts were randomized from 9/2017-2/2022 (F: n=55, F+P: n=111, F+P+A: n=54); median age 57 years (range 25-83), 85% non-Hispanic (7.7% non-Hispanic black), 8.6% Hispanic, 6.4% unknown. 40% had de novo MBC, 60% had visceral disease, and 14% bone-only disease. 16% had 1 prior line of chemotherapy for MBC, 90% had received prior palbociclib, 4.5% ribociclib, 4.1% abemaciclib, 1.4% palbociclib and ribociclib. Pts entered the trial after a median 19 mo of prior CDK4/6i plus AI (interquartile range 12-31 mo). A total of 10 (5%) pts received protocol therapy as first line ET for MBC, 169 (77%) as second line, and 41 (17%) as beyond second line. 88% entered the trial directly after progression on CDK4/6i. After a median follow-up of 24 mo, 18 pts remained on protocol treatment. PFS was not improved with F+P vs F (median 4.6 vs 4.8 mo; HR=1.11, 90% CI 0.79-1.55; 2-sided p=0.62). Median PFS was 8.1 mo with F+P+A (HR=0.75 vs F, 90% CI 0.50-1.12; 2-sided p=0.23). ORR was 7.3% (90%CI 1.5-13.0) with F, 9.0% F+P (4.5-13.5%) and 13.0% F+P+A (5.4-20.5%). No new safety signals have been observed. Analysis of ctDNA panel sequencing encompassing 70 genes from 184 baseline samples, including correlation with known and hypothesized resistance genes, will be presented. Conclusions For ER+/HER2- breast cancer, combining palbociclib with fulvestrant beyond progression on prior CDK4/6i and AI did not significantly improve PFS compared with using fulvestrant alone. The observed longer PFS when a PD-L1 inhibitor was added to fulvestrant plus palbociclib is an intriguing signal in this ER+ population. Translational studies of blood and tumor tissue are ongoing and will be presented. Citation Format: Erica L. Mayer, Yue Ren, Nikhil Wagle, Reshma Mahtani, Cynthia Ma, Angela DeMichele, Massimo Cristofanilli, Jane Meisel, Kathy D. Miller, Trevor Jolly, Elizabeth Riley, Rubina Qamar, Priyanka Sharma, Sonya Reid, Natalie Sinclair, Meredith Faggen, Caroline Block, Naomi Ko, Ann Partridge, Wendy Y. Chen, Michelle K. DeMeo, Victoria Attaya, Amanda Okpoebo, Yuan Liu, Eric Gauthier, Harold Burstein, Meredith Regan, Sara Tolaney. GS3-06 Palbociclib After CDK4/6i and Endocrine Therapy (PACE): A Randomized Phase II Study of Fulvestrant, Palbociclib, and Avelumab for Endocrine Pre-treated ER+/HER2- Metastatic Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS3-06.

Correlation between histology and molecular subtypes in triple negative breast cancer Authors: Tabata Alves Domingos, MD; 1* Roberto Bonfim Pimenta Peixoto, MD; 1* Ashka Patel, BS1,2; Krishan Taneja, PhD; 1 Wendy Y. Chen, MD, MPH; 4,5,6 Elizabeth A. Mittendorf, MD, PhD; 5,6,7 Alexa Zimbalist, MS; 3 Elizabeth M. Cespedes Feliciano, ScD SM; 3 Deborah A. Dillon, MD 1,2 *equal contribution Author Affiliations 1. Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115 2. Breast Oncology, Dana-Farber Brigham Cancer Center, Boston, MA 02215 3. Division of Research, Kaiser Permanente Northern California, Oakland, CA 94612 4. Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA 02115 5. Department of Medical Oncology Dana Farber Cancer Institute, Boston, MA 02215 6. Harvard Medical School, Boston, MA 02215 7. Division of Breast Surgery, Brigham and Women’s Hospital, Boston, MA 02215 Background Recently defined molecular subtypes of triple negative breast cancer (TNBC) show distinct clinical outcomes and suggest new therapeutic targets but have not been integrated into current pathologic classification systems. Here, we describe the histopathologic features of TNBC according to four molecular subtypes: basal-like immune activated (BLIA), basal-like immune suppressed (BLIS), luminal androgen receptor (LAR) and mesenchymal (MES), classified using the NanoString BC360 gene expression assay. Methods Stage II and III invasive breast cancers were identified in the Kaiser Permanente (KP) clinical pathology archives (2005-2015) and triple negative status was determined from the KP Northern California Cancer Registry data on immunohistochemistry. Selected slides were reviewed by two pathologists who recorded key histopathologic features [histologic subtype, presence of apocrine, metaplastic or micropapillary features, nuclear grade, mitotic score, and Tumor Infiltrating Lymphocytes (TILs)] and marked the best tumor areas for molecular analysis. TILs were evaluated according to the guidelines of the International TILs Working Group. Cases were macrodissected and evaluated using the NanoString BC360 gene expression assay. Histologic features were then summarized according to molecular subtype. Results Of 72 TNBCs, 60 were classified as Basal-like (83.3%), 7 as HER2-enriched (9.7%) and 5 as Luminal A (6.9%). 41 cases were classified as BLIA (56.9%), 14 as BLIS (19.4%), 13 as LAR (18.0%) and 4 as MES (5.5%). Both BLIA and BLIS tumors showed uniformly high nuclear grade and high mitotic score but differed significantly in TILs (BLIA average 32% vs BLIS average 9%; p value< 0.001, t-test for mean difference in TILs). The majority of LAR cases (69%) showed apocrine differentiation, not present in any other molecular subtype (p value< 0.001, chi-square test for presence of apocrine differentiation). LAR cases showed high nuclear grade but a lower average mitotic score (average score of 2) compared with the basal-like subtypes. TILs in LAR tumors were intermediate (17%) between BLIA and BLIS tumors. Of the 4 MES cases, all showed high nuclear grade. TILs in the MES cases were also intermediate (14%) between BLIA and BLIS tumors. Other histologic features, including lobular subtype, metaplastic and micropapillary features were not associated with specific triple negative molecular subtypes. Conclusion TILs are high in the BLIA molecular subtype (average 32%), low in the BLIS subtype (average 9%) and intermediate in LAR (average 17%) and MES (average 14%) subtypes. Apocrine features, if present in a TNBC, are a strong predictor of LAR molecular subtype. The inclusion of TILs and apocrine features (both easily derived from H&E slides) in routine pathology reporting could improve the classification of TNBC and aid in the identification of patients more likely to respond to specific therapies for the BLIA, BLIS and LAR subtypes, especially in resource-limited settings. Citation Format: Tabata Alves Domingos, Roberto Bonfim Pimenta Peixoto, Ashka Patel, Krishan Taneja, Wendy Y. Chen, Elizabeth A. Mittendorf, Alexa Zimbalist, Elizabeth M. Cespedes Feliciano, Deborah A. Dillon. Correlation between histology and molecular subtypes in triple negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-09-04.

Insulin resistance and hyperinsulinemia play important roles in the progression of multiple chronic disease and conditions. Diet modulates insulin response; however, evidence is limited regarding whether diets with higher insulinemic potential increase the risk of invasive breast cancer.We aimed to prospectively evaluate the association between a food-based empirical dietary index for hyperinsulinemia (EDIH) and the incidence of invasive breast cancer.We prospectively followed 76,686 women from the Nurses' Health Study (NHS; 1984-2016) and 93,287 women from the Nurses' Health Study II (NHSII; 1991-2017). Diet was assessed by food-frequency questionnaires every 4 y. The insulinemic potential of diet was evaluated using the previously established EDIH based on circulating C-peptide concentrations. Higher scores indicate higher insulinemic potential of the diet. Covariates included reproductive, hormonal, and anthropometric factors (height and BMI at age 18 y); race; socioeconomic status; total alcohol intake; total caloric intake; and physical activity.During 4,216,106 person-years of follow-up, we documented 10,602 breast cancer cases (6689 NHS, 3913 NHSII). In the pooled multivariable-adjusted analyses, women in the highest, compared with the lowest, EDIH quintile (Q) were at higher breast cancer risk (HRQ5 vs. Q1 = 1.15; 95% CI: 1.07, 1.24; P-trend 0.01). Although heterogeneity by estrogen receptor (ER) status was nonsignificant, the strongest association between EDIH and breast cancer was observed for ER-negative tumors (HRQ5 vs. Q1 = 1.21; 95% CI: 1.00, 1.46; P-trend = 0.02). Among tumor molecular subtypes, the strongest associations were observed for human epidermal growth factor receptor 2 (HER2)-enriched tumors (HRQ5 vs. Q1 = 1.62; 95% CI: 1.01, 2.61; P-trend = 0.02).A dietary pattern contributing to hyperinsulinemia and insulin resistance was associated with greater breast cancer risk, especially ER-negative and HER2-enriched tumors. Our findings suggest that dietary modifications to reduce insulinemic potential may reduce the risk of breast cancer.

Background: The relationships between PTEN loss and/or PIK3CA mutation and breast cancer prognosis remain controversial. We aim to examine the associations in large epidemiologic cohorts. Methods: We followed women with invasive breast cancer from the Nurses’ Health Studies with available data on tumor PTEN expression (n = 4,111) and PIK3CA mutation (n = 2,930). PTEN expression was evaluated by IHC and digitally scored (0%–100%). Pyrosequencing of six hotspot mutations of PIK3CA was performed. Results: We found loss of PTEN expression (≤10%) occurred in 17% of cases, and PIK3CA mutations were detected in 11% of cases. After adjusting for clinical and lifestyle factors, PTEN loss was not associated with worse breast cancer-specific mortality among all samples [HR, 0.85; 95% confidence intervals (CI), 0.71–1.03] or among estrogen receptor (ER)-positive tumors (HR, 0.99; 95% CI, 0.79–1.24). However, among ER-negative tumors, PTEN loss was associated with lower breast cancer-specific mortality (HR, 0.68; 95% CI, 0.48–0.95). PIK3CA mutation was not strongly associated with breast cancer-specific mortality (HR, 0.89; 95% CI, 0.67–1.17). Compared with tumors without PTEN loss and without PIK3CA mutation, those with alterations (n = 540) were not at higher risk (HR, 1.07; 95% CI, 0.86–1.34). However, women with both PTEN loss and PIK3CA mutation (n = 38) were at an increased risk of breast cancer-specific mortality (HR, 1.65; 95% CI, 0.83–3.26). Conclusions: In this large epidemiologic study, the PTEN-mortality association was more pronounced for ER-negative tumors, and the joint PTEN loss and PIK3CA mutation may be associated with worse prognosis. Impact: Further studies with a larger sample of ER-negative tumors are needed to replicate our findings and elucidate underlying mechanisms.

Background: Insulin resistance and hyperinsulinemia play important roles in the progression of multiple chronic disease and conditions. Diet modulates insulin response; however, evidence is limited regarding whether diet with higher insulinemic potential is associated with invasive breast cancer risk.Objectives: We prospectively evaluated the association between adherence to a food-based empirical dietary index for hyperinsulinemia (EDIH) and the incidence of invasive breast cancer.Methods: We prospectively followed 76,595 women from the Nurses’ Health Study (NHS, 1984-2016) and 93,295 women from the Nurses’ Health Study II (NHSII, 1991-2017). Diet was assessed by food frequency questionnaires every 4 years. The insulinemic potential of diet was evaluated using the EDIH that was pre-defined based on circulating C-peptide concentrations. Higher scores indicate higher insulinemic potential, while lower scores indicate lower insulinemic potential.Results: During 4,215,162 person-years of follow-up, we documented 10,595 breast cancer cases (6,639 NHS; 3,914 NHSII). Being in the highest, compared with the lowest, EDIH quintile was associated with higher breast cancer risk (HRQ5vsQ1 1.18; 95% CI 1.10, 1.27; P-trend Citation Format: Andrea Romanos-Nanclares, Walter C. Willett, Bernard A. Rosner, Rulla M. Tamimi, Fred K. Tabung, Michelle D. Holmes, Wendy Y Chen, A. Heather Eliassen. Insulinemic potential of diet and risk of total and subtypes of breast cancer among US women [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-09-06.

Background: PTEN loss and/or PIK3CA mutation are hypothesized to predict more aggressive tumor behavior and worse outcomes in women with breast cancer. However, the results of previous studies with small sample size have been conflicting. Methods: We followed pre- and postmenopausal women with invasive breast cancer from the Nurses’ Health Study (diagnosed 1976-2011) and Nurses’ Health Study II (1989-2011) with data available on PTEN cytoplasmic expression (n=4316, breast cancer-specific deaths=777) and/or PIK3CA mutation (n=2930, breast cancer-specific deaths=317). PTEN protein expression was evaluated by immunohistochemistry and scored as a digitally quantified continuous measure (1-100%). Polymerase chain reaction and pyrosequencing of six hot spot mutations of PIK3CA were performed on DNA extracted from formalin-fixed paraffin-embedded tumors. Information on other covariates was self-reported at baseline and repeatedly measured with follow-up questionnaires every two to four years. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between loss of PTEN expression and/or PIK3CA mutation and breast cancer-specific mortality were estimated using Cox proportional hazards regression models. Results: In this large epidemiological study, the loss of tumor cell PTEN cytoplasmic staining expression (≤10%) occurred in 17.6% of cases, and the overall mutation of PIK3CA occurred in 10.8% of cases. After adjusting for tumor characteristics, treatment, and lifestyle factors, the loss of PTEN expression (versus expression >10%) was not associated with worse breast cancer survival among overall samples (HR =0.85; 95%CI=0.71-1.03) and among estrogen receptor (ER)-positive tumors (HR =1.11; 95%CI=0.84-1.47). However, among women with ER-negative tumors, PTEN expression loss was strongly associated with lower breast cancer mortality (HR =0.68; 95%CI=0.48-0.96). Overall mutation status of PIK3CA was not associated with breast cancer mortality (HR =1.06; 95%CI=0.78-1.45). Combining PTEN and PIK3CA status, compared with tumors without PTEN loss and without PIK3CA mutation (wild type), those with PTEN loss and/or PIK3CA mutation were not at higher risk (HR =1.05; 95%CI=0.85-1.32). However, women with PTEN loss and PIK3CA mutation jointly (n=39, breast cancer-specific deaths=15) had increased breast cancer mortality (HR =2.05; 95%CI=1.07-3.94). Conclusion: This study is the largest to date examining PTEN and PIK3CA status and breast cancer survival, in which we found that the prognostic value of PTEN status differed by ER status, and the joint status of PTEN loss of expression and PIK3CA mutation was associated with worse breast cancer survival. Citation Format: Tengteng Wang, Yujing J Heng, Gabrielle M Baker, Vanessa C Bret-Mounet, Susan E Hankinson, Michelle D Holmes, Wendy Y. Chen, Walter C. Willett, Bernard A. Rosner, Rulla M Tamimi, A. Heather Eliassen. Loss of PTEN expression, PIK3CA mutations, and breast cancer survival in the Nurses’ health studies [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-12-02.

Background The expansion of hematopoietic stem cells carrying recurrent somatic mutations, termed clonal hematopoiesis (CH), is common in elderly individuals and is associated with increased risk of myeloid malignancy and all-cause mortality. Though chemotherapy is a known risk factor for developing CH, how myelosuppressive therapies affect the short-term dynamics of CH remains incompletely understood. Most studies have been limited by retrospective design, heterogeneous patient populations, varied techniques to identifying CH, and analysis of single timepoints. Methods We examined serial samples from 40 older women with triple-negative or hormone receptor–positive breast cancer treated on the prospective ADjuVANt Chemotherapy in the Elderly trial to evaluate the prevalence and dynamics of CH at baseline and throughout chemotherapy (6 and 12 weeks). Results CH was detected in 44% of patients at baseline and in 53% at any timepoint. Baseline patient characteristics were not associated with CH. Over the course of treatment, mutations exhibited a variety of dynamics, including emergence, expansion, contraction, and disappearance. All mutations in TP53 (n = 3) and PPM1D (n = 4), genes that regulate the DNA damage response, either became detectable or expanded over the course of treatment. Neutropenia was more common in patients with CH, particularly when the mutations became detectable during treatment, and CH was significantly associated with cyclophosphamide dose reductions and holds (P = .02). Conclusions Our study shows that CH is common, dynamic, and of potential clinical significance in this population. Our results should stimulate larger efforts to understand the biological and clinical importance of CH in solid tumor malignancies. Trial Registration ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT03858322). Clinical trial registration number: NCT03858322.

Associations between specific statins and invasive breast cancer incidence, in the Nurses' Health Study among new initiators of statins 2004-2012.

Background: 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.Methods: 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.Results: 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).Conclusions: 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.Impact: Dairy consumption in adolescence or early adulthood may not be a significant predictor of breast cancer incidence. Cancer Epidemiol Biomarkers Prev; 27(5); 575–84. ©2018 AACR.

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.

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.

Supplemental Figure S1. Post-Diagnosis Weight Change and Breast Cancer-Specific Mortality. Supplemental Table S1. Category of Weight Change and All-cause Mortality by Follow-Up Period. Supplemental Table S2. Average Association of Post-Diagnosis Weight Change and All-cause and Breast Cancer-Specific Mortality by Subgroup. Supplemental Table S3. Average Association of Post-Diagnosis Weight Change and Breast Cancer-Specific and All-cause Mortality by Immunohistochemistry.

Table S1: Definitions for early adulthood various dairy products subgroups.Table S2: Definitions for adolescent various dairy products subgroups. Table S3: Age-standardized characteristics in 1998 according to intake of total dairy products during adolescence among women enrolled in the Nurses’ Health Study II. Table S4. Hazard ratios (HR) and 95% confidence intervals (95% CI) for breast cancer according to adolescent dairy product items.Table S5. Hazard ratios (HR) and 95% confidence intervals (95% CI) for breast cancer according to quintile of early adulthood dairy products items. Table S6. Hazard ratios (HR) and 95% confidence intervals (95%CI) for breast cancer according to quintile of adolescent calcium, vitamin D, and lactose intake. Table S7. Hazard ratios (HR) and 95% confidence intervals (95% CI) for breast cancer according to quintile of early adulthood calcium, vitamin D, and lactose intake.

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.”

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Only two genome-wide association studies (GWAS) have been conducted to date to identify potential markers for total mortality after diagnosis of breast cancer. Here, we report the identification of two single-nucleotide polymorphisms (SNP) associated with total mortality from a two-stage GWAS conducted among 6,110 Shanghai-resident Chinese women with tumor–node–metastasis (TNM) stage I to IV breast cancer. The discovery stage included 1,950 patients and evaluated 613,031 common SNPs. The top 49 associations were evaluated in an independent replication stage of 4,160 Shanghai patients with breast cancer. A consistent and highly significant association with total mortality was documented for SNPs rs3784099 and rs9934948. SNP rs3784099, located in the RAD51L1 gene, was associated with total morality in both the discovery stage (P = 1.44 × 10−8) and replication stage (P = 0.06; P-combined = 1.17 × 10−7). Adjusted HRs for total mortality were 1.41 [95% confidence interval (CI), 1.18–1.68] for the AG genotype and 2.64 (95% CI, 1.74–4.03) for the AA genotype, when compared with the GG genotype. The variant C allele of rs9934948, located on chromosome 16, was associated with a similarly elevated risk of total mortality (P-combined = 5.75 × 10−6). We also observed this association among 1,145 patients with breast cancer of European ancestry from the Nurses’ Health Study (NHS; P = 0.006); the association was highly significant in a combined analysis of NHS and Chinese data (P = 1.39 × 10−7). Similar associations were observed for these two SNPs with breast cancer–specific mortality. This study provides strong evidence suggesting that the RAD51L1 gene and a chromosome 16 locus influence breast cancer prognosis. Cancer Res; 72(5); 1182–9. ©2012 AACR.

Summary Worldwide, a cocktail of climate change, urbanization, and population growth is increasing the vulnerability of coastal communities to flood risk. Recent experience in urban flood management from China’s Greater Bay Area shows that building “prevention” and “preparedness” into urban development plans is essential for climate adaptation and resilience.

Frequent typhoons significantly affect many coastal cities via intensive rainstorms, tidal surges and strong wind. Natural factors induced by human disturbance such as climate change and sea-level rise come alongside anthropogenic factors such as rapid urbanisation and land use/land cover change, leading to detrimental consequences such as urban floods. This short communication offers various lessons learnt by Ningbo municipality from two strong typhoons that hit the city directly, namely Fitow in 2013 and In-Fa in 2021. On the one hand, usage of “Big Data” and “Social Media” for better “Preparation” and “Prevention” reduced flood impacts noticeably. On the other hand, implementation of “Flood Insurance” sped up the “Recovery” processes. The successful “Preparation”, “Response” and “Recovery” helped Ningbo to enhance its flood resilience, and thus to reduce or avoid substantial impacts of injuries, household damages and the associated economic loss. These three key terms should be heeded in typhoon/flood governance in which various stakeholders are involved, and be incorporated into the city’s long-term strategic development plans to merge with the climate actions towards the 2030s and beyond. This will be vitally important in reducing climatic hazards and improving coastal flood resilience under the future climatic uncertainties in Asian coastal cities.

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.

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

China's Sponge City Programme (SCP) is one of the world's most ambitious sustainable urban drainage programmes. By 2030, Chinese cities must have 80% of their land drained by Blue–Green Infrastructure (BGI) to build critically needed flood resilience. Costs must be met from municipal and private finance, but BGI lacks the revenue streams of public assets like utilities, so has limited appeal to public–private partnerships. Finance options, including Green Bonds targeting institutional investors, and Payment for Urban Ecosystem Service schemes targeting local citizens and businesses, need developing. Green city branding could lever such finance but despite widespread use of green branding to attract investment, sponge branding strategies are immature, and alignment is needed in green branding between sponge project type (e.g., flagship and retrofit), financial instrument, and target financier, to develop differentiated brands that appeal to a diversity of SCP investors. With little grassroots input into city branding, and SCP problems of green gentrification, local support for SCP implementation may be at risk. This is concerning, because cities need local citizens and businesses to invest in the SCP to achieve the extensive retrofit needed, as retrofit (using small-scale BGI such as stormwater planters, de-paving, and raingardens) has little appeal for institutional investors.

Compelling epidemiologic data, supported by experimental evidence, suggest aspirin may improve survival in breast cancer patients. However, recent clinical trials showed a lack of protective effect, though length of intervention (18 months to 4.7 years) and follow-up (20 months to 4.7 years) were limited. We sought to examine the association between post-diagnostic aspirin use (frequency, dose, and duration), timing and age of initiation on breast cancer-specific mortality. Our study included 10,493 women diagnosed with stage I, II, or III invasive breast cancer. Participants were enrolled in the large, prospective Nurses’ Health Study (NHS) and NHSII in 1980 and 1989 prior to diagnosis and followed up through June 1, 2017. We collected information on frequency, dose and duration of aspirin use. Regular aspirin use was defined as using aspirin (standard- and low-dose) ≥2 days per week, and non-regular aspirin users were those who reported use of aspirin 70 years of age had increased risk of death due to breast cancer. Citation Format: Cheng Peng, Michelle D. Holmes, Wendy Y. Chen, Tengteng Wang, Kristen D. Brantley, Yujing Jan Heng, Pepper J. Schedin, Bernard A. Rosner, Walter C. Willett, Meir J. Stampfer, Rulla M. Tamimi, A. Heather Eliassen. Regular aspirin use, breast tumor characteristics and long-term breast cancer survival. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5758.

Background: Extreme adiposity has been associated with tumor progression and increased mortality after a breast cancer diagnosis, but the underlying mechanisms remain unclear. Pre-clinical and in vitro analyses suggest that higher levels of adiposity impair anti-tumor immunity, but studies in human breast cancer patients are lacking. Previously, we found that higher levels of subcutaneous adiposity had stronger associations with breast cancer outcomes than did higher levels of visceral adiposity or overall obesity measured by BMI, underscoring the importance of measuring adipose tissue distribution as well as overall body size to understand the adiposity-cancer link. Methods: We identified women with a first-primary, stage 2 or 3 invasive breast cancer diagnosed and treated at Kaiser Permanente Northern California between 2005 and 2015. Using diagnostic computed tomography scans collected as part of routine clinical care, we measured subcutaneous (SAT) and visceral adipose tissue (VAT) areas in cm2 at the third lumbar vertebra. We calculated body mass index (BMI) from clinically-collected height and weight. We isolated RNA from 251 FFPE breast tumors collected at biopsy or excision; these were a preliminary, random sample within each immunohistochemical subtype groups from an ongoing study that will analyze 1400 breast tumors. We verified RNA quality prior to performing NanoString BC 360™ assays to calculate the PAM50 molecular intrinsic subtype and measure the expression levels of genes related to immune cell abundance and anti-tumor immune activity. Using linear regression models, we examined the mean change in log2 gene expression (dependent variables) associated with each adiposity exposure (BMI, SAT and VAT as independent variables). Results: Mean (SD) age at diagnosis was 56 (13); a majority of women were either overweight (BMI 25- < 30-kg/m2: 30%) or obese (BMI>30-kg/m2: 35%), and most were diagnosed with stage 2 (61%) vs. stage 3 (39%) breast cancer with representation from each PAM50 subtype: n (%) Luminal A, 46 (18%) Luminal B, 56 (22%), HER2-overexpressing 26 (27%), and 82 (33%) basal-like. In unadjusted analyses, expression of genes related to macrophages, PD-1 and TIGIT increased with increasing subcutaneous adiposity, whereas expression of genes related to mast cells decreased (see Table 1). We found a similar (though non-significant) pattern for BMI. Associations with increasing visceral adiposity were closer to the null. After adjusting for PAM50 subtype, age and stage at diagnosis, only the association of increasing subcutaneous adiposity with increasing PD-1 expression remained statistically significant. Conclusion: Excess subcutaneous adiposity was associated with increased PD-1 expression, whereas excess visceral adiposity or obesity defined by BMI were not. These results from the first 251 samples of an ongoing study of 1400 tumors provide evidence from human breast cancer patients to demonstrate the importance of measuring body composition to assess adipose tissue distribution and support the hypothesis that excess adiposity impairs anti-tumor immunity. Association of Adiposity Measures with Immune-Related Gene Expression in the Breast Tumor Microenvironment (n=251 patients with stage 2-3 breast cancer at Kaiser Permanente Northern California) 195% Confidence Interval 2A 1-unit increase represents a doubling in the log expression level of the genes in the signature Citation Format: Deborah A. Dillon, Elizabeth M. Cespedes Feliciano, Alexa Zimbalist, En Cheng, Bette J. Caan, Wendy Y. Chen, Elizabeth A. Mittendorf, Roberto Bonfim Pimenta Peixoto, Tabata Alves Domingos, Krishan Taneja, Ashka Patel. Adiposity and immune-related gene expression in the breast tumor microenvironment [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-03-02.

Background: Dietary patterns promoting chronic inflammation, including the empirical dietary inflammatory pattern (EDIP), have been shown to strongly influence risk of weight gain, type 2 diabetes, cardiovascular disease, and colorectal cancer. However, it is unclear if this dietary pattern is associated with other tumors in which the mechanisms are not totally understood such as breast cancer. Methods: We prospectively followed 76,295 women from the Nurses’ Health Study (NHS, 1984-2016) and 91,078 women from the Nurses’ Health Study II (NHSII, 1991-2017). Diet was assessed by food frequency questionnaires (FFQs) every 4 years. The inflammatory potential of diet was evaluated using the previously established EDIP based on plasma C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor alpha receptor 2 (TNF-αR2). Higher scores indicate higher inflammatory potential of the diet. Results: During 4,153,676 person-years of follow-up, we documented 10,632 invasive breast cancer cases (6,807 NHS; 3,825 NHSII). In the pooled multivariable-adjusted analyses, women in the highest, compared with the lowest, EDIP quintile were at higher breast cancer risk (HRQ5vsQ1=1.12; 95% CI 1.05, 1.20; P-trend< 0.001). This association was attenuated after adjusting for weight change since age 18 y, although it remained significant (HRQ5vsQ1=1.07; 95% CI 1.00, 1.14; P-trend=0.01). In subtype analyses, we found evidence that the inflammatory potential of diet influenced breast cancer risk differentially by ER status (P-heterogeneity=0.038) and by molecular phenotype (P-heterogeneity=0.007), with the association between EDIP and breast cancer limited to ER-negative tumors (HRQ5vsQ1=1.31; 95% CI: 1.11, 1.55; P-trend=0.002; for ER-positive tumors, HR Q5vsQ1=1.03; 95% CI, 0.96, 1.12;P-trend=0.10) and basal-like tumors (HRQ5vsQ1=1.78; 95% CI: 1.19, 2.65; P-trend=0.004). Further adjustment for weight change since age 18 y did not materially alter the association for these subtypes. Conclusions: Dietary patterns with high potential to contribute to chronic systemic inflammation, based on higher EDIP scores, were associated with a modestly increased risk of breast cancer, which was more pronounced for ER-negative and basal-like breast tumors. Citation Format: Andrea Romanos-Nanclares, Walter C Willett, Bernard A Rosner, Daniel G Stover, Sarah Asad, Sagar Sardesai, Michelle D Holmes, Wendy Y Chen, Rulla M. Tamimi, Fred K Tabung, A Heather Eliassen. Proinflammatory Dietary Patterns and Risk of Total and Subtypes of Breast Cancer Among US Women [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-03-14.

Worldwide environmental information disclosure (EID) has been widely promoted as a policy approach to establish transparent governments, enhance public environmental awareness, and foster participatory environmental governance. While information disclosure and transparency are inherently incentivised within democratic regimes, how and through what pathways an increased flow of environmental information in the absence of democracy could lead to favourable public support for environmental/ecological projects remain under-investigated. Particularly, there exists very limited literature which compares how EID is associated with public environmental choices between different sociopolitical contexts. Taking Brussels (Belgium) and Guangzhou (China) as a comparative case, this study examines the association between citizens' perceived trustworthiness of various environmental information sources and their choice decisions regarding urban river restoration initiatives in contrasting socialpolitical contexts. Latent class modelling of two paralleled discrete choice experiments unveils a consistent classification of three distinctive groups for each city and also the combined sample, including Enthusiastic Supporters (Class 1, who are cost-insensitive and supportive of all proposed changes), Pragmatic Supporters (Class 2, who are cost-sensitive, prefer some changes they favour), and Non-Supporters (Class 3, who are unwilling to support the proposed initiatives). Incorporating respondents' trustworthiness in information sources as covariates in class membership likelihood function, respondents' membership is found to be associated solely with the most trusted information source, i.e., social contacts in Guangzhou, third parties in Brussels, and social contacts for the whole sample. Holding trust toward the most-trusted information source can increase the probability of being a member of Class 1, otherwise, more likely being a member of Class 3. Taken together with the insignificance of the variable denoting a respondent's city in explaining class membership, this study reveals that the variations in the EID levels (matured vs. emerging) and sociopolitical contexts (democratic vs. non-democratic) cannot significantly shape citizens' environmental decisions. Instead, it is respondents' perceived trustworthiness of information outlets that plays a positive role in their supportive decisions. These analytical results offer new insights about the role of EID in environmental governance and call for instilling institutional trust in China and relational trust in Belgium for facilitating effective communication and pro-environmental behaviours across the whole community.

Context Surface urban heat island intensity (SUHII) is a classical measure, which is sensitive to the selection of pixels/measurements representative of urban and rural areas, and overlooks pixel-level SUHII variation and thermodynamics of heterogeneous urban landscape. Accounting inter-pixel landscape heterogeneity in SUHII would capture inter-pixel thermodynamics and reveal complicated micro-thermal situations, contribute to assessment of potential heat risks at micro-pixel scale. Objectives This study develops [[EQUATION]] using pixel-based sharpening enhancement method. It integrates a pixel’s LST magnitude that reflects a city’s thermal context with local SUHII considering landscape variations and cognate thermal interactions of neighboring pixels. Methods [[EQUATION]] is constructed using MODIS LST product for Guangzhou (south China) in the summer season of 2015 through cloud-based GEE platform. Its effectiveness is tested using a bivariate choropleth map and Gaussian density curve with stepwise increments of the thermal influence from neighboring pixels. Results We found that (1) local SUHII variations are sensitive to the spatial configuration of a center pixel’s land use and that of its neighbors; (2) [[EQUATION]] makes more pronounced those spots that are heat per se (with higher original LST), but also receive additional heat load from adjacent pixels due to land-use homogeneity; (3) the effectiveness of [[EQUATION]] could be demonstrated by Gaussian density curve. Conclusions This paper proposed a new SHUII indicator, [[EQUATION]] , which models inter-pixel spatial variation of SHUI and highlights how neighboring pixels’ homogenous/heterogeneous land-use and associated thermal properties could affect center pixels’ thermal characteristics via either reinforcement or mitigation of heat load.

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.

Frequent typhoons are significantly affecting the coastal cities via intensive rainstorms, tidal surges and strong wind. Natural factors such as climate change and global sea-level rise come alongside anthropogenic factors such as rapid urbanisation and land use/land cover change leading to detrimental consequences such as urban floods. This short communication offers various lessons learnt by Ningbo municipality from two strong typhoons that hit the city directly, namely “Fitow” in 2013 and “In-Fa” in 2021. On the one hand, the usage of “Big Data” and “Social Media” for bettering “Preparation” and “Prevention” reduced flood impacts significantly. On the other hand, the implementation of “Flood Insurance” speed up the “Recovery” processes. The successful “Preparation”, “Response” and “Recovery” helped Ningbo to enhance its flood resilience, and thus substantial impacts of injuries, household damages and associated economic loss were avoided. These three key terms should be heeded in typhoon/flood governance in which various stakeholders are involved with, and be incorporated into the city’s long-term strategic development plans to merge with the climate actions towards 2030s and beyond. This will be vitally important in reducing climatic hazards and improving coastal flood resilience under the future climatic uncertainties in Asian coastal cities. (196 words)

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.

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.

Human health risks brought by fine atmospheric particles raise scholarly and policy awareness about the role of urban trees as bio-filters of air pollution. While a large number of empirical studies have focused on the characteristics of vegetation leaves and their effects on atmospheric particle retention, the dry deposition of particles on branches, which plays a significant role in capturing and retaining particles during the defoliation period and contributes substantially to total removal of atmospheric particles, is under-investigated. To fill in this knowledge gap, this case study examined the dry deposition velocities (V

Background: Type 2 diabetes (T2D) has been associated with increased risk of breast cancer. However, the role of metformin, the first-line anti-diabetic drug, in breast cancer carcinogenesis has not been elucidated completely. We aimed to examine further the association between the use of metformin and other anti-diabetic medication and breast cancer incidence within two large prospective cohort studies. Methods: We followed 184,437 women who participated in the Nurses’ Health Study (NHS;1994-2016) and the NHSII (1995-2017), with the baseline tied to the date metformin was introduced into the United States market. Information on T2D diagnosis, metformin, and other anti-diabetic medication, and other covariates were self-reported at baseline and repeatedly assessed by follow-up questionnaires every two to four years. Breast cancer cases were self-reported and confirmed by medical record review. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between metformin/other anti-diabetic medication use and breast cancer incidence were estimated using Cox proportional hazards regression models. Results: During 3,412,366 person-years of follow-up, we ascertained 9,442 incident invasive breast cancer cases, of which 720 were among women with T2D. Compared with women without T2D (n=168,498), similar risks of developing breast cancer were observed among those who ever used metformin (HR =0.95; 95%CI=0.79-1.13) and among those who received medications other than metformin (HR =1.11; 95%CI=0.91-1.37). Among women with T2D (n=15,939), compared with never metformin users, ever use of metformin overall was not associated with breast cancer (HR =0.90; 95%CI=0.72-1.13), but a lower risk of breast cancer was observed among past metformin users (HR =0.72; 95%CI=0.52-0.99). Longer duration of metformin use was not associated with risk of breast cancer (each 2-year interval: HR =0.98; 95%CI=0.93-1.03, p-trend=0.32). However, among women with substantial weight increase since age 18 (>25 kg), greater than 5 years of metformin use was associated with a lower risk of breast cancer (HR =0.62; 95%CI=0.43-0.89). Conclusion: Although we observed inverse associations among past metformin users, similar associations were not found among current users. Overall, metformin use was not strongly associated with the risk of developing breast cancer among the general cohort population or among women with T2D. Citation Format: Tengteng Wang, Jae H. Kang, Boyang Chai, Wendy Y. Chen, Michelle D. Holmes, Jennifer Erdrich, Edward L. Giovannucci, Frank B. Hu, Bernard A. Rosner, Rulla M. Tamimi, Walter C. Willett, A. Heather Eliassen. Metformin and other anti-diabetic medication use and breast cancer incidence in the Nurses’ Health Studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5902.

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.

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.

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.

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.

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 (