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It remains unclear if pre‐diagnostic factors influence the developmental pathways of colorectal cancer (CRC) that could enhance tumor aggressiveness. This study used prospective data from 205,489 cancer‐free US health professionals to investigate the associations of 31 known or putative risk factors with the risk of aggressive CRC. Tumor aggressiveness was characterized by three endpoints: aggressive CRC (cancer that causes death within 5 years of diagnosis), fatal CRC, and tumor stage at diagnosis. The data augmentation method was used to assess the difference in the associations between risk factors and endpoints. We documented 3201 CRC cases, of which 899 were aggressive. The protective associations of undergoing lower endoscopy (hazard ratios [HR] 0.43, 95% confidence interval (CI) 0.37, 0.49 for aggressive versus HR 0.61, 95% CI 0.56, 0.67 for non‐aggressive) and regular use of aspirin (HR 0.70, 95% CI 0.61, 0.81 versus HR 0.84, 95% CI 0.77, 0.92) were stronger for aggressive than non‐aggressive CRC (pHeterogeneity <0.05). Lower intake of whole grains or cereal fiber and greater dietary inflammatory potential were associated with a higher risk of aggressive but not non‐aggressive CRC. The remaining risk factors showed comparable associations with aggressive CRC and non‐aggressive CRC. Aggressive cases were more likely to have KRAS‐mutated tumors but less likely to have distal or MSI‐high tumors (p <.007). Similar results were observed for fatal CRC and advanced tumor stages at diagnosis. These findings provide initial evidence for the role of pre‐diagnostic risk factors in the pathogenesis of aggressive CRC and suggest research priorities for preventive interventions. [ABSTRACT FROM AUTHOR]

We aimed to examine the association between the use of metformin and other anti‐diabetic medications and breast cancer incidence within two large prospective cohort studies. We followed 185,181 women who participated in the Nurses' Health Study (NHS; 1994–2016) and the NHSII (1995–2017), with baseline corresponding to the date metformin was approved for type 2 diabetes (T2D) treatment in the US Information on T2D diagnosis, anti‐diabetes medications, and other covariates was self‐reported at baseline and repeatedly assessed by follow‐up questionnaires every 2 years. Breast cancer cases were self‐reported and confirmed by medical record review. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between medication use and breast cancer were estimated using Cox proportional hazards regression models, adjusting for breast cancer risk factors. During 3,324,881 person‐years of follow‐up, we ascertained 9,192 incident invasive breast cancer cases, of which 451 were among women with T2D. Compared with women without T2D (n = 169,263), neither metformin use (HR = 0.97; 95% CI = 0.81–1.15) nor other anti‐diabetic medications use (HR = 1.11; 95% CI = 0.90–1.36) associated with significantly lower breast cancer incidence. Among women with T2D (n = 15,918), compared with metformin never users, metformin ever use was not significantly inversely associated with breast cancer (HR = 0.92; 95% CI = 0.74–1.15). Although we observed that past use of metformin was inversely associated with breast cancer in the T2D population (HR = 0.67; 95% CI = 0.48–0.94), current use (HR = 1.01; 95% CI = 0.80–1.27) and longer duration of metformin use were not associated with breast cancer (each 2‐year interval: HR = 1.01; 95% CI = 0.95–1.07). Overall, metformin use was not associated with the risk of developing breast cancer among the overall cohort population or among women with T2D. [ABSTRACT FROM AUTHOR]

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. What's new? Fruits and vegetables are rich in potentially anti‐carcinogenic nutrients including fiber, vitamins C and E, carotenoids, and other bioactive substances. However, many studies found no association between fruit and vegetable consumption and risk of breast cancer. In this analysis based on two large prospective cohorts, the authors found that higher total fruit and vegetable consumption during adulthood was associated with a modest, statistically significant lower invasive breast cancer incidence, with the strongest associations for ER‐negative, HER2‐enriched and basal‐like tumors. Higher intake of fruits and vegetables, and specifically cruciferous and yellow/orange vegetables, may reduce the risk of breast cancer, especially aggressive tumors. [ABSTRACT FROM AUTHOR]

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

Despite multiple hypotheses for a protective effect, epidemiologic findings are inconsistent regarding the association between physical activity and risk of ovarian cancer. Considering physical activity assessment at different times of life, including pre- and postmenopause, may be important for explaining these discrepancies. Therefore, we examined the risk of ovarian cancer according to total, premenopausal and postmenopausal physical activity among 85,462 women from the Nurses' Health Study and 112,679 women from the Nurses' Health Study II. Leisure-time physical activity was prospectively assessed about every 2-4 years using validated questionnaires, and characterized as metabolic equivalent task hours per week (MET-hr/week), which combines exercise duration and intensity. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for these associations. We identified 815 incident epithelial ovarian cancer cases during 24 years of follow-up. A modestly increased ovarian cancer risk was observed for high levels of total cumulative average physical activity and a suggestively increased risk for low activity. Compared to 3-9 MET-hr/week, HRs (95% CIs) were 1.26 (1.02, 1.55) for ≥27 MET-hr/week (equivalent to 1 hr/day of brisk walking) and 1.19 (0.94, 1.52) for <3 MET-hr/week. This association was limited to premenopausal physical activity [comparable HR (95% CI) of 1.50 (1.13, 1.97) and 1.29 (0.95, 1.75), respectively]. Postmenopausal physical activity was not associated with risk. Our data do not support a protective role of physical activity for ovarian cancer. The increased risk associated with physical activity during premenopausal years and the underlying etiology require further investigation. [ABSTRACT FROM AUTHOR]

Studies suggest that greater physical activity may reduce endometrial cancer risk. However, the role of the timing, duration and intensity of activity is unclear. We therefore examined recent and past recreational activities in relation to incident endometrial adenocarcinoma, and compared the importance of total and moderate- or vigorous-intensity activities as well as walking. We analyzed data from 71,570 women in the Nurses' Health Study, a prospective cohort that assessed activity in 1986, with updates every 2-4 years. Cox proportional hazards models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs). During follow-up from 1986 to 2008 (1.2 million person-years), 777 invasive endometrial adenocarcinoma cases were documented. In multivariable models, compared with <3 MET-hr/week (<1 hr/week walking), women engaged in moderate (9 to <18 MET-hr/week: RR = 0.61, 95% CI: 0.48-0.78) or high (≥27 MET-hr/week: RR = 0.73, 95% CI: 0.58-0.92) amounts of recent total recreational activity were at reduced risk ( p-trend = 0.001). Past total activity was not associated with risk. Greater recent moderate- or vigorous-intensity activity was associated with reduced risk (≥4 vs. 0 hr/week: RR = 0.65, 95% CI: 0.47-0.88, p-trend = 0.002). Among women who did not perform any vigorous activity, recent walking was associated with reduced risk (≥3 vs. <0.5 hr/week: RR = 0.65, 95% CI: 0.45-0.93, p-trend = 0.01), and faster walking pace was independently associated with risk reduction. After additional adjustment for body mass index, all associations were statistically non-significant. Greater recent physical activity, including activity of moderate duration and intensity such as walking, may reduce endometrial adenocarcinoma risk. This relation is largely mediated or confounded by body mass index. [ABSTRACT FROM AUTHOR]

Overweight and obesity are inversely related to the risk of breast cancer among premenopausal women. We assessed the association between adult weight change since age 18 years with the risk of breast cancer among premenopausal women to explore whether weight gain was associated with a decrease in risk and weight loss was associated with an increase in risk. A total of 56,223 premenopausal participants in the Nurses' Health Study and 109,385 premenopausal participants in the Nurses' Health Study II were prospectively followed for up to 32 years and 18 years, respectively, and weight change since age 18 years was assessed biennially. The incidence of invasive breast cancer was assessed throughout follow-up. Weight loss of 5 kg or more since age 18, maintained for at least 4 years, was related to lower incidence of premenopausal breast cancer, compared to maintaining a stable weight, but this relation was of borderline statistical significance (covariate-adjusted HR = 0.75; 95% CI 0.52-1.09). Weight gain since age 18 years was also inversely related to breast cancer incidence among premenopausal women (covariate-adjusted p for trend = 0.01), but the association weakened after controlling for weight at age 18 and did not reach statistical significance ( p for trend = 0.08). Although obesity and breast cancer among premenopausal women are inversely related, weight loss since age 18 years did not increase and weight gain did not significantly decrease the risk of premenopausal breast cancer among participants in the large prospective cohorts of NHS and NHS II. [ABSTRACT FROM AUTHOR]

While early-life body leanness is associated with increased breast cancer risk, early-life physical activity may protect against breast cancer. We examined whether the excess risk among lean girls is modified by their levels of prior, concurrent, or future physical activity. We conducted an analysis among 74,723 women in the Nurses' Health Study II (follow-up 1997-2011). Participants recalled their body size at ages 5, 10 and 20 years in 1989 using a 9-level pictogram (Level 1 most lean). In 1997, they reported adolescent levels of physical activity (ages 12-13 and 14-17 years). Cox proportional hazards models estimated the overall association of body size with breast cancer risk and assessed interactions of adolescent physical activity with body size at three different age periods (5-10, 10-20 and 20 years), adjusting for early-life and adult risk factors for breast cancer. Regardless of levels of adolescent physical activity, early-life body leanness (level 1-2 vs. 4.5+) was significantly associated with higher breast cancer risk. The association was slightly attenuated among those who were active (60+ MET-hr/wk) during adolescence compared to those who were inactive (<30 MET-hr/wk) (body size at ages 5-10 years: hazard ratio = 1.37, 95% confidence interval = 1.04-1.81 vs. 1.66, 1.29-2.12), but the interaction was not significant (p = 0.72). The results were similar for body size at three different age periods. Being lean during early life is a risk factor for breast cancer among both inactive and active girls. Adolescent physical activity did not significantly modify the association, although some interaction cannot be excluded., (© 2014 UICC.)

The breast is particularly vulnerable to carcinogenic influences during adolescence due to rapid proliferation of mammary cells and lack of terminal differentiation. We investigated consumption of adolescent red meat and other protein sources in relation to breast cancer risk in the Nurses' Health Study II cohort. We followed prospectively 44,231 women aged 33-52 years who, in 1998, completed a detailed questionnaire about diet during adolescence. Relative risks (RR) and 95% confidence intervals (95%CI) were estimated using Cox proportional hazard regression. We documented 1132 breast cancer cases during 13-year follow-up. In multivariable Cox regression models with major breast cancer risk factors adjustment, greater consumption of total red meat in adolescence was significantly associated with higher premenopausal breast cancer risk (highest vs. lowest quintiles, RR, 1.43; 95%CI, 1.05-1.94; Ptrend  = 0.007), but not postmenopausal breast cancer. Adolescent intake of poultry was associated with lower risk of breast cancer overall (RR, 0.76; 95%CI, 0.60-0.97; for each serving/day). Adolescent intakes of iron, heme iron, fish, eggs, legumes and nuts were not associated with breast cancer. Replacement of one serving/day of total red meat with one serving of combination of poultry, fish, legumes, and nuts was associated with a 15% lower risk of breast cancer overall (RR, 0.85; 95%CI, 0.74-0.96) and a 23% lower risk of premenopausal breast cancer (RR, 0.77; 95%CI, 0.64-0.92). In conclusion, higher consumption of red meat during adolescence was associated with premenopausal breast cancer. Substituting other dietary protein sources for red meat in adolescent diet may decrease premenopausal breast cancer risk., (© 2014 UICC.)