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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.

Supplementary Figure S1; Supplementary Table S1.

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Type II diabetes is associated with poor breast cancer prognosis. To study the association between a diabetes risk reduction diet (DRRD) and survival following breast cancer, we followed 8,482 women with breast cancer from two large cohort studies. Information on diet and other factors was repeatedly measured in validated questionnaires every two to four years. The DRRD includes 9 components: higher intakes of cereal fiber, coffee, nuts, whole fruits and polyunsaturated/saturated fat ratio; and lower glycemic index, trans fat, sugar-sweetened beverages, and red meat. Cumulative average DRRD score was calculated using repeated measures of postdiagnostic diet. Deaths were assessed by family members or via National Death Index. Multivariable-adjusted HRs and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. During a median of 14 years of follow-up since diagnosis, 2,600 deaths occurred among participants, 1,042 of which were due to breast cancer. Women with higher postdiagnostic DRRD score had a 20% lower risk of breast cancer–specific mortality (top vs. bottom quintile HR = 0.80; 95% CI = 0.65–0.97; Ptrend = 0.02) and 34% lower risk of all-cause mortality (HR = 0.66; 95% CI = 0.58–0.76; Ptrend < 0.0001). Compared with women who consistently had lower score (≤median) before and after diagnosis, those whose score improved from low to high had a lower risk of breast cancer–specific mortality (HR = 0.77; 95% CI = 0.62–0.95) and overall mortality (HR = 0.85; 95% CI = 0.74–0.97). These findings demonstrate that greater adherence to DRRD was associated with better survival, suggesting postdiagnosis dietary modification consistent with type II diabetes prevention may be important for breast cancer survivors.Significance:This study suggests that greater adherence to the diabetes risk reduction diet after diagnosis associates with improved survival outcomes among a large number of breast cancer survivors.

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.

Purpose: Androgen receptor (AR) is commonly expressed in breast cancers. However, the association between tumor AR status and breast cancer survival is uncertain. Hence, we examined the association between AR status and breast cancer survival in the Nurses' Health Study (NHS).Experimental Design: It was a prospective study of postmenopausal women enrolled in the Nurses' Health Study with stage I to III breast cancer diagnosed between 1976 and 1997 and followed from the date of diagnosis until January 1, 2008 or death. Analyses were conducted using Kaplan–Meier methods and Cox proportional hazard models, to determine the association of AR status with survival outcomes adjusting for covariates.Results: Among 1467 breast cancers, 78.7% were AR-positive (AR+). Among 1,164 estrogen receptor (ER)-positive cases, 88.0% were AR+. AR positivity was associated with a significant reduction in breast cancer mortality (HR, 0.68; 95% CI, 0.47–0.99) and overall mortality (HR, 0.70; 95% CI, 0.53–0.91) after adjustment for covariates. In contrast, among women with ER-negative tumors (303 cases), 42.9% were AR+. There was a nonsignificant association between AR status and breast cancer death (HR, 1.59; 95% CI, 0.94–2.68).Conclusions: The association of AR status and breast cancer survival is dependent on ER status. In particular, AR expression was associated with a more favorable prognosis among women with ER-positive tumors. Thus, determination of AR status may provide additional information on prognosis for postmenopausal women with breast cancer, and provide novel opportunities for targeted therapy. Clin Cancer Res; 17(7); 1867–74. ©2011 AACR.

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: Experimental evidence suggests that aspirin may inhibit breast tumor growth and reduce invasiveness of breast cancer cells. In large population-based studies (including our own), post-diagnostic aspirin use was associated with reduced breast cancer-specific and all-cause mortality. Here, we have extended our prior study with an additional 10 years of follow-up (3,785 more breast cancer cases) and investigation of the molecular underpinnings of the role of aspirin in breast cancer prognosis. Methods: Our study included 7,949 women diagnosed with stage I, II or III breast cancer from the Nurses’ Health Study (NHS) and NHSII. Cox proportional hazards regression was used to compute the multivariate hazard ratio (HR) for death, adjusting for tumor characteristics, treatment information and lifestyle factors. Post-diagnostic aspirin use was obtained at least 12 months after diagnosis and updated at every 2-year follow-up interval. We also evaluated the association between post-diagnostic aspirin use and survival according to tumor characteristics. Estrogen receptor (ER), insulin receptor (IR), PTEN, and Ki67 protein expression was evaluated by immunohistochemistry. PIK3CA mutation status was determined via polymerase chain reaction and pyrosequencing. In an exploratory analysis to identify functional enrichment of biologic pathways associated with long-term pre-diagnostic aspirin use (ever use of aspirin for ≥10 years with >2d/wk), we used a competitive gene-set testing procedure in a subgroup of cases with gene expression data (N=453). In this subset, we also computed the abundance of immune cell infiltration (B cell, CD4+ T cell, CD8+T cell, macrophage, neutrophil and dendritic cell) using Tumor IMmune Estimation Resource (TIMER). Results: During a median follow-up of 12 years after breast cancer diagnosis, we documented 2,502 deaths, including 1,373 from breast cancer. Compared with nonusers, women who regularly used aspirin after diagnosis had lower breast cancer-specific mortality: HR for 1, 2-5, 6-7 days of aspirin use per week were 0.65 (95% CI: 0.49, 0.86), 0.41 (95% CI: 0.29, 0.57) and 0.61 (95% CI: 0.47, 0.78) for, respectively (p-trend0.05). Long-term regular aspirin use before diagnosis was associated with the downregulation of pathways related to inflammation (INF-α, INF-γ, and TNF-α), PI3K—AKT—mTOR signaling (mTOR and PI3K—AKT), and other proliferation (E2F and myc targets) in primary breast tumors and/or normal-adjacent tissues (FDR≤0.05). Long-term regular aspirin use prior to diagnosis was also associated with higher CD8+T cell (mean±SD=0.20±0.02 for non-users and 0.21±0.02 for users, p=0.01) and macrophage (mean±SD=0.05±0.03 for non-users and 0.06±0.02 for users, p=0.0002) relative abundance in primary tumors. Conclusion: Regular aspirin use after breast cancer diagnosis was associated with lower risk of breast cancer-specific and total mortality. The association between aspirin and mortality did not differ by molecular characteristics of primary tumors. Long-term aspirin use prior to breast cancer diagnosis was associated with downregulation of inflammatory and proliferation pathways and higher immune cell infiltration of CD8+ T cells and macrophages in breast tumors. Taken together, our large-scale population-based analysis with long-term of follow-up highlight the potential benefit of aspirin as a secondary prevention strategy across different tumor molecular characteristics. Citation Format: Cheng Peng, Michelle D. Holmes, Tengteng Wang, Alexandra Harris, Wendy Chen, Kristen Brantley, Yujing J Heng, Vanessa C. Bret-Mounet, Gabrielle M Baker, Bernard Rosner, Walter Willett, Rulla Tamimi, A. Heather Eliassen. Regular aspirin use, breast tumor characteristics and long-term breast cancer survival [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 P3-12-01.

Background Physical activity is generally associated with better outcomes following diagnosis; however, few studies have evaluated change in pre- to postdiagnosis activity and repeated measures of activity by intensity and type. Methods We evaluated physical activity and survival following a breast cancer diagnosis in the Nurses’ Health Study and Nurses’ Health Study II (n = 9308 women, n = 1973 deaths). Physical activity was evaluated as updated cumulative average of metabolic equivalent of task (MET)-h/wk (assigned per activity based on duration and intensity) and change in pre- to postdiagnosis activity. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results Higher postdiagnosis activity was inversely associated with breast cancer–specific mortality in categories from ≥9 MET-h/wk (vs Conclusions Physical activity was associated with lower risk of death following diagnosis. Increased pre- to postdiagnosis activity corresponding to at least 1-3 h/wk of walking was associated with lower risk of death. These results provide further impetus for women to increase their activity after a breast cancer diagnosis, though reverse causation cannot be fully excluded.

Background We have developed a simple and globally applicable tool, the Global Diet Quality Score (GDQS), to measure diet quality. Objectives To test the utility of the GDQS, we examined the associations of the GDQS with weight change and risk of obesity in US women. Methods Health, lifestyle, and diet information were collected from women (n = 68,336) in the Nurses’ Health Study II (aged 27–44 y in 1991) through repeated questionnaires (1991–2015). The GDQS has 25 food groups (maximum = 49 points) and scoring higher points reflects a healthier diet. The association between GDQS change in 4-y intervals and concurrent weight change was computed with linear models adjusted for confounders. Results Mean ± SD weight gain across 4-y periods was 1.68 ± 6.26 kg. A >5-point improvement in GDQS was associated with −1.13 kg (95% CI: −1.19, −0.77 kg) weight gain compared with a score change of 5-point score decrease was associated with 1.13 kg (95% CI: 1.04, 1.22 kg) more weight gain in women aged 5-point increase and 1.32 (95% CI: 1.26, 1.37) for a >5-point decrease. Risk of obesity did not differ by age. Compared with other diet quality scores, the Alternate Healthy Eating Index-2010 had somewhat stronger associations than the GDQS (P

Background Key nutrient deficits remain widespread throughout sub-Saharan Africa (SSA) whereas noncommunicable diseases (NCDs) now cause one-third of deaths. Easy-to-use metrics are needed to track contributions of diet quality to this double burden. Objectives We evaluated comparative performance of a novel food-based Global Diet Quality Score (GDQS) against other diet metrics in capturing nutrient adequacy and undernutrition in rural SSA adults. Methods We scored the GDQS, Minimum Dietary Diversity–Women (MDD-W), and Alternative Healthy Eating Index–2010 (AHEI-2010) using FFQ data from rural men and nonpregnant, nonlactating women of reproductive age (15–49 y) in 10 SSA countries. We evaluated Spearman correlations between metrics and energy-adjusted nutrient intakes, and age-adjusted associations with BMI, midupper arm circumference (MUAC), and hemoglobin in regression models. Results Correlations between the GDQS and an energy-adjusted aggregate measure of dietary protein, fiber, calcium, iron, zinc, vitamin A, folate, and vitamin B-12 adequacy were 0.34 (95% CI: 0.30, 0.38) in men and 0.37 (95% CI: 0.32, 0.41) in women. The GDQS was associated (P

Background We have developed a diet quality metric intended for global use. To assess its utility in high-income settings, an evaluation of its ability to predict chronic disease is needed. Objectives We aimed to prospectively examine the ability of the Global Diet Quality Score (GDQS) to predict the risk of type 2 diabetes in the United States, examine potential differences of association by age, and compare the GDQS with other diet quality scores. Methods Health, lifestyle, and diet information was collected from women (n = 88,520) in the Nurses’ Health Study II aged 27–44 y at baseline through repeated questionnaires between 1991 and 2017. The overall GDQS consists of 25 food groups. Points are awarded for higher intake of healthy groups and lower intake of unhealthy groups (maximum of 49 points). Multivariable HRs were computed for confirmed type 2 diabetes using proportional hazards models. We also compared the GDQS with the Minimum Diet Diversity score for Women (MDD-W) and the Alternate Healthy Eating Index-2010 (AHEI-2010). Results We ascertained 6305 incident cases of type 2 diabetes during follow-up. We observed a lower risk of diabetes with higher GDQS; the multivariable HR comparing extreme quintiles of the GDQS was 0.83 (95% CI: 0.76, 0.91; P-trend

Background Poor diet quality is a major driver of both classical malnutrition and noncommunicable disease (NCD) and was responsible for 22% of adult deaths in 2017. Most countries face dual burdens of undernutrition and NCDs, yet no simple global standard metric exists for monitoring diet quality in populations and population subgroups. Objectives We aimed to develop an easy-to-use metric for nutrient adequacy and diet related NCD risk in diverse settings. Methods Using cross-sectional and cohort data from nonpregnant, nonlactating women of reproductive age in 10 African countries as well as China, India, Mexico, and the United States, we undertook secondary analyses to develop novel metrics of diet quality and to evaluate associations between metrics and nutrient intakes and adequacy, anthropometry, biomarkers, type 2 diabetes, and iteratively modified metric design to improve performance and to compare novel metric performance to that of existing metrics. Results We developed the Global Diet Quality Score (GDQS), a food-based metric incorporating a more comprehensive list of food groups than most existing diet metrics, and a simple means of scoring consumed amounts. In secondary analyses, the GDQS performed comparably with the Minimum Dietary Diversity - Women indicator in predicting an energy-adjusted aggregate measure of dietary protein, fiber, calcium, iron, zinc, vitamin A, folate, and vitamin B12 adequacy and with anthropometric and biochemical indicators of undernutrition (including underweight, anemia, and serum folate deficiency), and the GDQS also performed comparably or better than the Alternative Healthy Eating Index - 2010 in capturing NCD-related outcomes (including metabolic syndrome, change in weight and waist circumference, and incident type 2 diabetes). Conclusions The simplicity of the GDQS and its ability to capture both nutrient adequacy and diet-related NCD risk render it a promising candidate for global monitoring platforms. Research is warranted to validate methods to operationalize GDQS assessment in population surveys, including a novel application–based 24-h recall system developed as part of this project.

Type II diabetes is associated with poor breast cancer prognosis. To study the association between a diabetes risk reduction diet (DRRD) and survival following breast cancer, we followed 8,482 women with breast cancer from two large cohort studies. Information on diet and other factors was repeatedly measured in validated questionnaires every two to four years. The DRRD includes 9 components: higher intakes of cereal fiber, coffee, nuts, whole fruits and polyunsaturated/saturated fat ratio; and lower glycemic index, trans fat, sugar-sweetened beverages, and red meat. Cumulative average DRRD score was calculated using repeated measures of postdiagnostic diet. Deaths were assessed by family members or via National Death Index. Multivariable-adjusted HRs and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. During a median of 14 years of follow-up since diagnosis, 2,600 deaths occurred among participants, 1,042 of which were due to breast cancer. Women with higher postdiagnostic DRRD score had a 20% lower risk of breast cancer–specific mortality (top vs. bottom quintile HR = 0.80; 95% CI = 0.65–0.97; Ptrend = 0.02) and 34% lower risk of all-cause mortality (HR = 0.66; 95% CI = 0.58–0.76; Ptrend < 0.0001). Compared with women who consistently had lower score (≤median) before and after diagnosis, those whose score improved from low to high had a lower risk of breast cancer–specific mortality (HR = 0.77; 95% CI = 0.62–0.95) and overall mortality (HR = 0.85; 95% CI = 0.74–0.97). These findings demonstrate that greater adherence to DRRD was associated with better survival, suggesting postdiagnosis dietary modification consistent with type II diabetes prevention may be important for breast cancer survivors. Significance: This study suggests that greater adherence to the diabetes risk reduction diet after diagnosis associates with improved survival outcomes among a large number of breast cancer survivors.

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: It is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype. Methods: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer–specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype. Results: There was no evidence of heterogeneous associations between risk factors and mortality by subtype (Padj > 0.30). The strongest associations were between all-cause mortality and BMI ≥30 versus 18.5–25 kg/m2 [HR (95% confidence interval (CI), 1.19 (1.06–1.34)]; current versus never smoking [1.37 (1.27–1.47)], high versus low physical activity [0.43 (0.21–0.86)], age ≥30 years versus 0– Conclusions: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype. Impact: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.

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: 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.

Importance: Type 2 diabetes (T2D) is associated with poor breast cancer prognosis. Adherence to a dietary pattern associated with lower T2D risk may improve breast cancer outcomes. Objective: To evaluate the association between adherence to a diabetes risk reduction diet (DRRD) after diagnosis and survival outcomes following breast cancer. Method: We followed 8,320 women diagnosed with stage I-III breast cancer from two large prospective cohort studies, the Nurses’ Health Study (NHS; 1980-2014) and the NHSII (1991-2015). Information on diet and other covariates was repeatedly measured in validated follow-up questionnaires every two to four years. The DRRD adherence score includes 9 dietary components: higher intakes of cereal fiber, coffee, nuts, whole fruits and polyunsaturated:saturated fat ratio; and lower glycemic index of diet, lower intakes of trans fat, sugar-sweetened beverages/fruit juices, and red meat. Cumulative average DRRD score was calculated using repeated measures of diet after breast cancer diagnosis. Deaths were reported by family members or via the search of National Death Index, and cause of death was assigned by reviewing death certificates/medical records. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between DRRD score and breast cancer-specific and all-cause mortality were estimated using Cox proportional hazards models. Results: During a median of 16 years of follow-up after diagnosis, we ascertained 2,146 deaths, of which 948 were due to breast cancer. In the multivariable-adjusted models, women with higher post-diagnostic DRRD scores had a 17% lower risk of breast cancer-specific mortality (top vs. bottom quintile HR =0.83; 95%CI=0.67-1.02; p-trend=0.03) and 33% lower risk of all-cause mortality (HR =0.67; 95%CI=0.58-0.78; p-trend Conclusion: We found that greater adherence to the DRRD after breast cancer diagnosis was associated with better survival, suggesting dietary modification after diagnosis consistent with T2D prevention may be important to breast cancer survivors. Table 1. Multivariable HRs and 95% CIs for the association between post-diagnostic diabetes risk reduction diet score and mortality among breast cancer survivors using pooled data from NHS abd NHSII (N=8,320)Quintile 1Quintile 2Quintile 3Quintile 4Quintile 5p-trendMedian (IQR)20 (18-21)24 (23-25)27 (26-28)30 (29-31)34 (33-37)Breast cancer-specific mortalityNo. of events (n=948), 589,953 py207205184176176Model 11 (referent)0.97 (0.80-1.18)0.80 (0.65-0.97)0.79 (0.64-0.96)0.75 (0.61-0.92)0.0008Model 21 (referent)0.88 (0.72-1.07)0.76 (0.62-0.93)0.77 (0.63-0.95)0.83 (0.67-1.02)0.03Model 31 (referent)0.99 (0.81-1.20)0.82 (0.67-1.00)0.85 (0.69-1.04)0.86 (0.70-1.07)0.06All-cause mortalityNo. of events (n=2,146), 589,953 py506447476383334Model 11 (referent)0.83 (0.73-0.94)0.80 (0.71-0.91)0.67 (0.59-0.76)0.57 (0.50-0.65) Table 2. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between changes of diabetes risk reduction diet score before or after diagnosis and mortality among breast cancer survivors using pooled data from NHS abd NHSII (N=8,320)CharacteristicsHR (95% CI)Breast cancer-specific mortalityCross classified changesNo. of events (n=948), 589,953 pyLow to Low1 (referent)Low to High0.81 (0.65-1.00)High to Low0.97 (0.79-1.19)High to High0.87 (0.74-1.02)All-cause mortalityCross classified changesNo. of events (n=2,306), 589,953 pyLow to Low1 (referent)Low to High0.88 (0.76-1.02)High to Low0.99 (0.87-1.12)High to High0.80 (0.72-0.89) Citation Format: Tengteng Wang, Maryam Farvid, Jae Hee Kang, Michelle Holmes, Bernard Rosner, Rulla Tamimi, Walter Willett, A. Heather Eliassen. Diabetes risk reduction diet and survival following breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS2-09.

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

Neighborhood deprivation is linked with inflammation, which may explain poorer health across populations. Behavioral risk factors are assumed to largely mediate these relationships, but few studies have examined this. We examined three neighborhood contextual factors that could exert direct effects on inflammation: (1) neighborhood socioeconomic status, (2) an index of concentration at extremes (that measures segregation), and (3) surrounding vegetation (greenness).Using blood samples and addresses collected from prospective cohorts of 7,930 male (1990-1994) and 16,183 female (1986-1990) health professionals with at least one inflammatory marker, we prospectively linked neighborhood contextual factors to inflammatory biomarkers (adiponectin, C-reactive protein, interleukin-6, soluble tumor necrosis factor receptor-2). Log-transformed, z-scaled component measures were used to calculate an inflammation score. Neighborhood socioeconomic status and index of concentration of extremes were obtained from the 1990 decennial census and linked to participant addresses. Surrounding greenness was assessed from satellite data and focal statistics were applied to generate exposures within 270 m and 1230 m of the participants' address. We fit multiple linear regression models adjusting for demographic, clinical, and behavioral risk factors.Higher neighborhood socioeconomic status was associated with lower inflammation score in women (β for interquartile range increase = -27.7%, 95% CI: -34.9%, -19.8%) and men (β = -21.2%, 95% CI: -31.0%, -10.1%). Similarly, participants in neighborhoods with higher concentrations of high-income households were associated with lower inflammation score in women (β = -27.8%, 95% CI: -35.8%, -18.7%) and men (β = -16.4%, 95% CI: -29.7%, -0.56%). Surrounding greenness within 270 m of each participant's address was associated with lower inflammation score in women (β = -18.9%, 95% CI: -28.9%, -7.4%) but not men. Results were robust to sensitivity analyses to assess unmeasured confounding and selection bias.Our findings support the hypothesis that adverse neighborhood environments may contribute to inflammation through pathways independent of behavioral risk factors, including psychosocial stress and toxic environments.

BACKGROUND: Studies in women of European descent showed an inverse association of dietary vitamin A (retinol and carotenoids) intake with breast cancer risks, mainly in premenopausal women. OBJECTIVES: We examined whether higher compared with lower levels of dietary vitamin A are associated with reduced breast cancer risks among Black women by estrogen receptor (ER) and menopausal statuses. METHODS: In this pooled analysis, data were from 3564 breast cancer cases and 11,843 controls (mean ages = 56.4 and 56.3 years, respectively) in the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium. Dietary intake was assessed by FFQs. Multivariable logistic regressions were performed to estimate ORs and 95% CIs for study-specific quintiles of total vitamin A equivalents and individual carotenoids, and a pooled OR was estimated by a random-effect model. RESULTS: We observed an inverse association of total vitamin A equivalents with ER-positive breast cancer (quintiles 5 compared with 1: pooled OR: 0.82; 95% CI: 0.67–1.00; P-trend = 0.045). The association was seen among premenopausal women (pooled OR: 0.60; 95% CI: 0.43–0.83; P-trend = 0.004), but not among postmenopausal women (pooled OR: 0.99; 95% CI: 0.77–1.28; P-trend = 0.78). Additionally, there were inverse associations of dietary β-carotene (quintiles 5 compared with 1: pooled OR: 0.70; 95% CI: 0.51–0.95; P-trend = 0.08) and lutein (pooled OR: 0.63; 95% CI: 0.45–0.87; P-trend = 0.020) with ER-positive breast cancer among premenopausal women. There was no evidence for an association of total vitamin A equivalents or individual carotenoids with ER-negative breast cancer, regardless of menopausal status. CONCLUSIONS: Our findings on dietary vitamin A and breast cancer risks in Black women are consistent with observations in women of European descent and advance the literature showing an inverse association for ER-positive disease.

OBJECTIVE: To investigate the associations of different types of carbohydrate intake after breast cancer diagnosis with breast cancer-specific and all-cause mortality. METHODS: We prospectively assessed post-diagnostic intake of total sugar, added sugar, and natural sugar as well as carbohydrate from different sources, among 8,932 women with stage I-III breast cancer that were identified in the Nurses’ Health Study from 1980 to 2010 and Nurses’ Health Study II from 1991 to 2011. Participants completed a validated food frequency questionnaire every four years after diagnosis and were followed up for death. RESULTS: We prospectively documented 1,071 deaths due to breast cancer and 2,532 all-cause deaths, over a mean of 11.5 years of follow-up. After adjustment for confounding variables, greater post-diagnostic total sugar intake was suggestively associated with greater risk of breast cancer-specific mortality [hazard ratio (HR)(Q5vsQ1)=1.16, 95% confidence interval (CI)=0.95-1.41; P(trend)=0.02] and significantly associated with greater risk of all-cause mortality (HR(Q5vsQ1)=1.23, 95% CI=1.08-1.41; P(trend)=0.0001). Greater post-diagnostic added sugar intake was significantly associated with greater risk of all-cause mortality (HR(Q5vsQ1)=1.20, 95% CI=1.06-1.36; P(trend)=0.001). Post-diagnostic natural sugar (occurring in foods and not added as an ingredient) intake was not associated with mortality risk. Greater post-diagnostic fructose intake was significantly associated with greater risk of breast cancer-specific mortality (HR(Q5vsQ1)=1.34, 95% CI=1.10-1.64; P(trend)=0.005) and all-cause mortality (HR(Q5vsQ1)=1.16, 95% CI=1.02-1.32; P(trend)=0.01). High post-diagnostic intake of sucrose was associated with higher risk of breast cancer-specific and all-cause mortality. Increased post-diagnostic intake of carbohydrate from fruit juice was significantly associated with higher risk of breast cancer-specific and all-cause mortality and carbohydrate from vegetables was significantly associated with lower risk of all-cause mortality. High post-diagnostic intake of carbohydrate from potatoes was suggestively associated with higher risk of breast cancer-specific mortality and carbohydrate from refined grains was suggestively associated with higher risk of all-cause mortality. CONCLUSION: We found that higher total sugar intake, especially added sugar, sucrose, and fructose, as well as carbohydrate from fruit juice after a breast cancer diagnosis were associated with poorer prognosis. High post-diagnostic intake of carbohydrate from vegetables was associated with reduced risk of mortality.

PURPOSE: Increasingly epidemiological cohorts are being linked to claims data to provide rich data for healthcare research. These cohorts tend to be different than the general US population. We will analyze healthcare utilization of Nurses’ Health Study participants (NHS) to determine if studies of newly diagnosed incident early stage breast cancer can be generalized to the broader US Medicare population. METHODS: Analytic cohorts of fee-for-service NHS-Medicare linked participants and a 1:13 propensity matched SEER-Medicare cohort (SEER) with incident breast cancer in the years 2007–2011 were considered. Screening leading to, treatment-related, and general utilization in the year following early stage breast cancer diagnosis were determined using Medicare claims data. RESULTS: After propensity matching, NHS and SEER were statistically balanced on all demographics. NHS and SEER had statistically similar rates of treatments including chemotherapy, breast conserving surgery, mastectomy, and overall radiation use. Rates of general utilization include those related to hospitalizations, total visits, and ED visits were also balanced between the two groups. Total spending in the year following diagnosis were statistically equivalent for NHS and SEER ($36,180 vs. $35,399, p = 0.7045). CONCLUSIONS: NHS and the general female population had comparable treatment and utilization patterns following diagnosis of early stage incident breast cancers with the exception of type of radiation therapy received. This study provides support for the larger value of population-based cohorts in research on healthcare costs and utilization in breast cancer

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.

BACKGROUND: We examined the role of post-diagnostic coffee and tea consumption in relation to breast cancer-specific and all-cause mortality among women with breast cancer in prospective cohort studies. METHODS: We identified 8900 women with stage I–III breast cancer from 1980 through 2010 in the Nurses’ Health Study (NHS) and from 1991 through 2011 in the NHSII. Post-diagnostic coffee and tea consumption was assessed by a validated food frequency questionnaire every 4 years after diagnosis. RESULTS: During up to 30 years of follow-up, we documented 1054 breast cancer-specific deaths and 2501 total deaths. Higher post-diagnostic coffee consumption was associated with a lower breast cancer-specific mortality: compared with non-drinkers, >3 cups/day of coffee was associated with a 25% lower risk (hazard ratio (HR) = 0.75, 95% confidence interval (CI) = 0.59–0.96; P(trend) = 0.002). We also observed a lower all-cause mortality with coffee consumption: compared with non-drinkers, >2 to 3 cups/day was associated with a 24% lower risk (HR = 0.76, 95% CI = 0.66–0.87) and >3 cups/day was associated with a 26% lower risk (HR = 0.74, 95% CI = 0.63–0.87, P(trend) 3 cups/day was associated with a 26% lower risk (HR = 0.74, 95% CI = 0.58–0.95; P(trend) = 0.04). CONCLUSIONS: Among breast cancer survivors, higher post-diagnostic coffee consumption was associated with better breast cancer and overall survival. Higher post-diagnostic tea consumption may be related to better overall survival.

OBJECTIVES: No tool to measure diet quality on the global scale currently exist. At the same time, type 2 diabetes is a global issue for women, including those under age 50. As part of an effort to develop an instrument to assess diet quality, this analysis the ability of a global diet quality score to predict type 2 diabetes in women in a high-income country. Therefore, the objective of this analysis is to examine prospectively the association between the Global Diet Quality Score (GDQS) and risk of type 2 diabetes, and potential differences in association by age, among U.S. women. METHODS: Health, lifestyle, and diet information was collected from women (n = 88,520) in the Nurses’ Health Study II through repeated questionnaires between 1991 and 2017. The GDQS consisted of 25 food groups and points were awarded for higher intake of healthy groups and lower intake of unhealthy groups (maximum of 49 points). Multivariable hazard ratios (HR) were computed for confirmed type 2 diabetes using Cox proportional hazards models. RESULTS: We ascertained 6319 incident type 2 diabetes during follow-up. The multivariable HR comparing top to bottom quintile of GDQS was 0.83 (95% CI = 0.76–0.91, p trend

OBJECTIVES: We aimed to develop and evaluate an easily-tabulated metric that is sensitive to diet quality in diverse settings. In this analysis, we examined associations between a novel food-based metric – the Global Diet Quality Score (GDQS) - and diet quality using data from rural Africa. METHODS: The GDQS gives points for higher intake of 16 healthy food groups and lower intake of 9 unhealthy groups, based on 3 intake ranges for each group. We scored the GDQS using food frequency questionnaire (FFQ) data from 1613 men and 1710 nonpregnant nonlactating women ages 15–49 (median: 30) in 12 rural African villages participating in the Millennium Villages Project in 2006 to 2009. We evaluated associations between the GDQS and nutrient intakes calculated from the same FFQ, body mass index (BMI), mid-upper arm circumference (MUAC), hemoglobin, and an overall nutrient adequacy score ranging from 0 to 7 (1 point given for each of 7 nutrients meeting average requirements). Associations were also derived for GDQS submetrics (GDQS+ and GDQS−) computed using only healthy or unhealthy food groups, respectively, and simplified versions of the GDQS and submetrics (scored using 2 intake ranges for each food group). RESULTS: Moderate rank correlations were observed between the GDQS+ and energy-adjusted intakes of fiber (women: 0.43, men: 0.33), folate (0.40, 0.30), vitamin A (0.40, 0.34), and zinc (0.38, 0.30), exceeding correlations with the Minimum Dietary Diversity Score for Women (p for difference between metrics 0.05): women and men in the highest GDQS+ quintile had an OR of anemia of 0.25 (95% CI 0.09, 0.68) and 0.16 (95% CI 0.04, 0.46), respectively, relative to those in the lowest. Metrics were not associated with BMI or MUAC in adjusted analyses. CONCLUSIONS: The GDQS and submetrics were associated with nutrient intakes, hemoglobin, and reduced anemia in rural African adults. FUNDING SOURCES: Intake - Center for Dietary Assessment at FHI Solutions.

PURPOSE: To understand trends in the incidence and mortality of two human papillomavirus (HPV)-associated cancers, cervical and oropharyngeal cancer, in Massachusetts. METHODS: From 2004–2014, the Massachusetts Cancer Registry recorded 3,996 incident cases of oropharyngeal cancer and 2,193 incident cases of cervical cancer. Mortality data were obtained from the Massachusetts Registry of Vital Records and Statistics from 2008–2014. Rates were age-standardized to the 2000 US population and trends were assessed using joinpoint regression. RESULTS: While the incidence rate of cervical cancer (5.46 per 100,000) decreased by 2.41% annually (p=0.004), the incidence rate of oropharyngeal cancer among males (7.85 per 100,000) increased by 2.82% annually (p=0.0002). Mortality rates for both cancers decreased from 2008–2014 but were not statistically significant (Cervical −3.73% annually, p=0.29; Oropharyngeal −1.94% annually, p=0.44). CONCLUSION: The rising incidence rate of oropharyngeal cancer in men and the decreasing, but relatively high, incidence rate of cervical cancer in women highlight the need for further screening and prevention by HPV vaccination in Massachusetts.

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.

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

Background Young women with breast cancer tend to report lower quality of life and higher levels of stress than older women with breast cancer, and this may have implications for other psychosocial factors including finances. We sought to determine if stress, anxiety, and depression at diagnosis were associated with changes in household income over 12-months in young women with breast cancer in the United States. Methods This study was a prospective, longitudinal cohort study comprised of women enrolled in the Young and Strong trial. Of the 467 women aged 18–45 newly diagnosed with early-stage breast cancer enrolled in the Young and Strong trial from 2012 to 2013, 356 (76%) answered income questions. Change in household income from baseline to 12 months was assessed and women were categorized as having lost, gained, maintained the same household income Results Although most women maintained household income ≥$100,000 (37.1%) or the same household income Conclusions Baseline stress, anxiety, and depression were not associated with household income changes for young women with breast cancer. However, lower baseline household income was associated with losing household income. Some young survivors encounter financial and insurance problems in the first year after diagnosis, and further support for these women should be considered. Trial registration Clinicaltrials.gov, NCT01647607; date registered: July 23, 2012.

Background Overweight and obesity are on the rise in developing countries including sub-Saharan Africa. We undertook a four-country survey to show the collective burden of these health conditions as they occur currently in sub-Saharan Africa and to determine the differences between urban and rural populations and other socio-economic factors. Methods Participants were nurses in two hospitals in Nigeria (200), school teachers in South Africa (489) and Tanzania (229), and village residents in one peri-urban (297) and one rural location in Uganda (200) who completed a standardised questionnaire. Their height and weight were measured and body mass index calculated. Factor analysis procedure (Principal component) was used to generate a wealth index. Univariate and multivariate analyses with binary logistic regression models were conducted to examine the associations between potential correlates and the prevalence of overweight and obesity with 95 % confidence intervals. Results The prevalence of overweight and obese (combined) was 46 %, 48 %, 68 %, 75 % and 85 % in rural Uganda, peri-urban Uganda, Nigeria, Tanzania and South Africa (SA), respectively. Rural Uganda, Peri- urban Uganda, Nigeria, Tanzania and SA had obesity prevalence of 10 %, 14 %, 31 %, 40 % and 54 %, respectively (p =25 kg/m2 in Nigeria [Age > =45 - AOR = 9.11; 95 % CI: 1.72, 48.16] and SA [AOR = 6.22; 95 % CI: 2.75, 14.07], while marital status was predictor of BMI > =25 kg/m2 only in peri-urban Uganda. [Married - AOR = 4.49; 95 % CI: 1.74, 11.57]. Those in Nigeria [AOR = 2.56; 95 % CI: 1.45, 4.53], SA [AOR = 4.97; 95 % CI: 3.18, 7.78], and Tanzania [AOR = 2.68; 95 % CI: 1.60, 4.49] were more likely to have BMI > =25 kg/m2 compared with the rural and peri-urban sites. Conclusion The high prevalence of overweight and obesity in these sub-Saharan African countries and the differentials in prevalence and risk factors further highlights the need for urgent focused intervention to stem this trend, especially among women, professionals and urban dwellers.

Supplemental Digital Content is available in the text., Background: Growing evidence suggests that neighborhood contextual environment could influence risk factors and, therefore, incidence of lethal prostate cancer. We studied the association between neighborhood greenness and lethal prostate cancer incidence and assessed mediation by vigorous physical activity. Methods: A total of 47,958 participants were followed in the Health Professionals Follow-up Study from 1986 to 2014. Neighborhood greenness exposure was estimated using normalized difference vegetation index (NDVI) with 1 km resolution, assigned to home or work addresses at start of follow-up. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) were estimated using sequentially adjusted Cox models with individual and contextual prostate cancer risk factors as covariates. Analyses were compared among those whose addresses were constant over follow-up and stratified by population density and address type. Results: We observed 898 cases over 1,054,743 person-years. An interquartile range increase in NDVI was associated with 5% lower rate of lethal prostate cancer (aHR = 0.95, 95% CI = 0.88, 1.03), with stronger associations in nonmovers (aHR = 0.92, 95% CI = 0.85, 1.01). Inverse associations were observed among men in high (aHR = 0.90, 95% CI = 0.82, 0.99) but not low (aHR = 1.11, 95% CI = 0.95, 1.29, Phet = 0.086) population density areas, and those reporting from work (aHR = 0.87, 95% CI = 0.75, 1.01) but not home (aHR = 1.04, 95% CI = 0.91, 1.17, Phet = 0.10) addresses. There was no evidence of mediation by vigorous physical activity. Conclusion: We report inverse associations between neighborhood greenness and lethal prostate cancer when restricting to nonmovers and in high population density areas. Replication could confirm findings and clarify mechanisms.

Background: Black men with prostate cancer (CaP) experience excess mortality compared with White men. Residential greenness, a health promoting contextual factor, could explain racial disparities in mortality among men with CaP. Methods: We identified Pennsylvania Cancer Registry cases diagnosed between January 2000 and December 2015. Totally, 128,568 participants were followed until death or 1 January 2018, whichever occurred first. Residential exposure at diagnosis was characterized using the Normalized Difference Vegetation Index (NDVI) with 250 m resolution. We estimated hazard ratios (HRs) using Cox models, adjusting for area-level socioeconomic status, geographic healthcare access, and segregation. To determine whether increasing residential greenness could reduce racial disparities, we compared standardized 10-year mortality Black-White risk differences under a hypothetical intervention fixing NDVI to the 75th percentile of NDVI experienced by White men. Results: We observed 29,978 deaths over 916,590 person-years. Comparing men in the highest to lowest NDVI quintile, all-cause (adjusted HR [aHR]: 0.88, 95% confidence interval [CI]: 0.84, 0.92, Ptrend < 0.0001), prostate-specific (aHR: 0.88, 95% CI: 0.80, 0.99, Ptrend= 0.0021), and cardiovascular-specific (aHR: 0.82, 95% CI: 0.74, 0.90, Ptrend < 0.0001) mortality were lower. Inverse associations between an interquartile range increase in NDVI and cardiovascular-specific mortality were observed in White (aHR: 0.90, 95% CI: 0.86, 0.93) but not Black men (aHR: 0.97, 95% CI: 0.89, 1.06; Phet = 0.067). Hypothetical interventions to increase NDVI led to nonsignificant reductions in all-cause (−5.3%) and prostate-specific (−23.2%), but not cardiovascular-specific mortality disparities (+50.5%). Discussion: Residential greenness was associated with lower mortality among men with CaP, but findings suggest that increasing residential greenness would have limited impact on racial disparities in mortality.

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.

BACKGROUND: Despite preventive health benefits of the human papillomavirus (HPV) vaccination, uptake in the United States remains low. Twenty-four states have enacted legislation regarding HPV vaccination and education. One reason these policies have been controversial is because of concerns that they encourage risky adolescent sexual behaviors. Our aim in this study is to determine if state HPV legislation is associated with changes in adolescent sexual behaviors. METHODS: This is a difference-in-difference study in which we use data on adolescent sexual behaviors from the school-based state Youth Risk Behavior Surveillance System from 2001 to 2015. Sexual behaviors included ever having sexual intercourse in the last 3 months and condom use during last sexual intercourse. We compared changes in sexual behaviors among high school students before and after HPV legislation to changes among high school students in states without legislation. RESULTS: A total of 715 338 participants reported ever having sexual intercourse in the last 3 months, and 217 077 sexually active participants reported recent condom use. We found no substantive or statistically significant associations between HPV legislation and adolescent sexual behaviors. Recent sexual intercourse decreased by 0.90 percentage points (P = .21), and recent condom use increased by 0.96 percentage points (P = .32) among adolescents in states that enacted legislation compared with states that did not. Results were robust to a number of sensitivity analyses. CONCLUSIONS: Implementation of HPV legislation was not associated with changes in adolescent sexual behaviors in the United States. Concern that legislation will increase risky adolescent sexual behaviors should not be used when deciding to pass HPV legislation.

ObjectiveTo identify predominant dietary patterns in four African populations and examine their association with obesity.DesignCross-sectional study.Setting/SubjectsWe used data from the Africa/Harvard School of Public Health Partnership for Cohort Research and Training (PaCT) pilot study established to investigate the feasibility of a multi-country longitudinal study of non-communicable chronic disease in sub-Saharan Africa. We applied principal component analysis to dietary intake data collected from an FFQ developed for PaCT to ascertain dietary patterns in Tanzania, South Africa, and peri-urban and rural Uganda. The sample consisted of 444 women and 294 men.ResultsWe identified two dietary patterns: the Mixed Diet pattern characterized by high intakes of unprocessed foods such as vegetables and fresh fish, but also cold cuts and refined grains; and the Processed Diet pattern characterized by high intakes of salad dressing, cold cuts and sweets. Women in the highest tertile of the Processed Diet pattern score were 3·00 times more likely to be overweight (95 % CI 1·66, 5·45; prevalence=74 %) and 4·24 times more likely to be obese (95 % CI 2·23, 8·05; prevalence=44 %) than women in this pattern’s lowest tertile (both PConclusionsWe identified two major dietary patterns in several African populations, a Mixed Diet pattern and a Processed Diet pattern. The Processed Diet pattern was associated with obesity.

In sub-Saharan Africa, there are limited data on burden of non-alcohol substance abuse (NAS) and depressive symptoms (DS), yet potential risk factors such as alcohol and intimate partner violence (IPV) are common and NAS abuse may be the rise. The aim of this study was to measure the burden of DS and NAS abuse, and determine whether alcohol use and IPV are associated with DS and/or NAS abuse. We conducted a cross-sectional study at five sites in four countries: Nigeria (nurses), South Africa (teachers), Tanzania (teachers) and two sites in Uganda (rural and peri-urban residents). Participants were selected by simple random sampling from a sampling frame at each of the study sites. We used a standardized tool to collect data on demographics, alcohol use and NAS use, IPV and DS and calculated prevalence ratios (PR). We enrolled 1415 respondents and of these 34.6% were male. DS occurred among 383 (32.3%) and NAS use among 52 (4.3%). In the multivariable analysis, being female (PR = 1.49, p = 0.008), NAS abuse (PR = 2.06, p = 0.02) and IPV (PR = 2.93, p p p = 0.036) were protective of NAS but current smokers (OR = 2.98, p p = 0.024) were more likely to use NAS. Longitudinal studies should be done to establish temporal relationships with these risk factors to provide basis for interventions.

Background Nutrients involved in one-carbon metabolism - folate, vitamins B6 and B12, methionine, choline, and betaine - have been inversely associated with multiple cancer sites and may be related to skin cancer. However, there is a lack of research on the association between intake of these nutrients and cutaneous melanoma risk. The aim of this study was to examine the associations between intake of one-carbon metabolism nutrients and cutaneous melanoma risk in two large prospective cohorts. Methods The cohorts included 75,311 white women and 48,523 white men. Nutrient intake was assessed repeatedly by food frequency questionnaires and self-reported supplement use. We used Cox proportional hazards regression to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) and then pooled HRs using a random-effects model. Results Over 24–26 years of follow-up, we documented 1328 melanoma cases (648 men and 680 women). Higher intake of folate from food only, but not total folate, was associated with increased melanoma risk (pooled HR for top versus bottom quintile: 1.36; 95% CI: 1.13–1.64; P for trend = 0.001). The association was significant in men, but attenuated in women. Higher intake of vitamins B6 and B12, choline, betaine, and methionine were not associated with melanoma risk, although there was modest increasing trend of risk for vitamin B6 from food only (pooled HR for top versus bottom quintile: 1.18; 95% CI: 0.99–1.41; P for trend = 0.03). Conclusions We found some evidence that higher intake of folate from food only was associated with a modest increased risk of cutaneous melanoma. However, since other factors related to dietary folate intake may account for the observed association, our findings warrant further investigation.

The purpose of this study was to evaluate whether antihypertensive medication use, including long-term use, is associated with increased breast cancer incidence in women. We studied 210,641 U.S. registered nurses participating in the Nurses' Health Study (NHS) and Nurses' Health Study II (NHS II). Information on antihypertensive medication use was collected on biennial questionnaires in both cohorts, and breast cancer cases were ascertained during this period. Multivariable-adjusted Cox proportional hazard models were used to estimate relative risks of invasive breast cancer over follow-up (1988-2012 in NHS, 1989-2011 in NHS II) across categories of overall antihypertensive medication use and use of specific classes (diuretics, beta blockers, calcium channel blockers, and angiotensin-converting enzyme inhibitors). During follow-up, 10,012 cases of invasive breast cancer developed (6718 cases in NHS and 3294 in the NHS II). Overall, current use of any antihypertensive medication was not associated with breast cancer risk compared with past/never use in NHS (multivariable-adjusted relative risk = 1.00, 95 % CI = 0.95-1.06) or NHS II (multivariable-adjusted relative risk = 0.94, 95 % CI = 0.86-1.03). Furthermore, no specific class of antihypertensive medication was consistently associated with breast cancer risk. Results were similar when we considered hypertensive women only, and when we evaluated consistency and duration of medication use over time. Overall, antihypertensive medication use was largely unrelated to the risk of invasive breast cancer among women in the NHS cohorts.

PURPOSE: Ki67 is a proliferation marker commonly assessed by immunohistochemistry in breast cancer, and it has been proposed as a clinical marker for subtype classification, prognosis and prediction of therapeutic response. However, the clinical utility of Ki67 is limited by the lack of consensus on the optimal cut point for each application. METHODS: We assessed Ki67 by immunohistochemistry using Definiens digital image analysis (DIA) in 2,653 cases of incident invasive breast cancer diagnosed in the Nurses’ Health Study from 1976–2006. Ki67 was scored as continuous percentage of positive tumor cells, and dichotomized at various cut points. Multivariate hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox regression models for distant recurrence, breast cancer-specific mortality and overall mortality in relation to luminal subtypes defined with various Ki67 cut points, adjusting for breast cancer prognostic factors, clinico-pathologic features and treatment. RESULTS: DIA was highly correlated with manual scoring of Ki67 (Spearman correlation ρ=0.86). Mean Ki67 score was higher in grade-defined luminal B (12.6%), HER2-enriched (17.9%) and basal-like (20.6%) subtypes compared to luminal A (8.9%). In multivariable-adjusted models, luminal B tumors had higher breast cancer-specific mortality compared to luminal A cancer classified using various cut points for Ki67 positivity including the 14% cut point routinely reported in the literature (HR=1.38, 95% CI 1.11–1.72, p=0.004). There was no significant difference in clinical outcomes for ER- tumors according to Ki67 positivity defined at various cut points. CONCLUSIONS: Assessment of Ki67 in breast tumors by DIA was a robust and quantitative method. Results from this large prospective cohort study provide support for the clinical relevance of using Ki67 at the 14% cut point for luminal subtype classification and breast cancer prognosis.