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Although postmenopausal hormone therapy (HT) use declined significantly after publication of the Women's Health Initiative (WHI) results, many women still continue taking HT for menopausal symptom relief. It is clear that the breast cancer risk associated with combination estrogen and progesterone therapy (EPT) is greater than that with estrogen therapy alone (ET), but questions still remain about the safety of longer term ET use. Studies since the WHI have tried to clarify whether various factors can modify the risk of HT, such as the age at initiation, dose, or type of HT or characteristics of the individual, such as family history of body mass index. At this point, the relative risks breast cancer associated with HT across various subgroups of women should still be considered similar, but absolute risks can vary significantly among women and this may inform individual decision making. For breast cancer survivors, systemic HT should be discouraged.

The 2008 Physical Activity (PA) Guidelines recommend engaging in at least 2.5 h (10 MET-hours/week) of moderate intensity PA per week (defined as 4 METs) to reduce risk of morbidity and mortality. This analysis was conducted to investigate whether this recommendation can be extended to breast cancer survivors. Data from four studies of breast cancer survivors measuring recreational PA from semi-quantitative questionnaires a median of 23 months post-diagnosis (interquartile range 18-32 months) were pooled in the After Breast Cancer Pooling Project (n = 13,302). Delayed entry Cox proportional hazards models were applied in data analysis with adjustment for age, post-diagnosis body mass index, race/ethnicity, menopausal status, TNM stage, cancer treatment, and smoking history. Engaging in at least 10 MET-hours/week of PA was associated with a 27% reduction in all-cause mortality (n = 1,468 events, Hazard Ratio (HR) = 0.73, 95% CI, 0.66-0.82) and a 25% reduction in breast cancer mortality (n = 971 events, HR = 0.75, 95% CI 0.65-0.85) compared with women who did not meet the PA Guidelines (

Some previous studies have found worse prognosis among cyclooxygenase-2 (COX-2)-expressing breast cancers. Aspirin and NSAIDs inhibit COX-2. Three studies, including ours, have reported a survival advantage among women with breast cancer who take either aspirin or NSAIDs. Through this study we hypothesized that in the Nurses’ Health Study (NHS), COX-2 expression would be associated with worse prognosis, and aspirin use would be associated with better survival particularly among women with COX-2 positive tumors. In this study we investigated 2,001 women presenting with invasive breast cancers stained for COX-2 by immunohistochemistry. Tumor prognostic factors were from medical records. Aspirin use was assessed at least 12 months after diagnosis and updated. Cause of death was identified from death certificates. Statistical analyses included logistic regression of prognostic factors with COX-2 status as the outcome, and proportional hazards regression with breast cancer death as the outcome. Tumor COX-2 expression was associated with higher diagnostic stage. Compared with stage I, the RR(95% CI) for stages II–IV were 1.16 (0.93–1.45), 1.68 (1.27–2.22), and 1.76 (0.93–3.32). COX-2 expression was associated with lobular compared with ductal histology (1.40 [1.02–1.92]), and estrogen receptor positive compared with negative (2.22 [1.66–2.95]). The RR(95% CI) of breast cancer death for current aspirin use was similar for women with COX-2-positive and COX-2-negative tumors; 0.64 (0.43–0.96) and 0.57 (0.44–0.74), respectively. In the NHS, COX-2 breast cancer expression was associated with higher stage at diagnosis. The survival benefit associated with aspirin use did not differ by COX-2 status. COX-2 breast cancer expression is associated with worse prognosis. If aspirin truly impacts breast cancer survival, then it is not solely via COX-2.

Introduction Ductal and lobular carcinomas are the two most common types of invasive breast cancer. Whether well-established risk factors are differentially associated with risk on the basis of histologic subtype is not clear. We prospectively investigated the association between a number of hormonal and nonhormonal exposures and risk defined by histologic subtype among 4,655 ductal and 659 lobular cases of postmenopausal breast cancer from the Nurses' Health Study. Methods Multivariate Cox proportional hazards regression stratified by histologic subtype and time period was used to examine the association between risk factors and the incidence of ductal and lobular subtypes. For each exposure, we calculated the P value for heterogeneity using a likelihood ratio test comparing models with separate estimates for the two subtypes versus a single estimate across subtypes. Results The associations with age at menarche (P-heterogeneity (het) = 0.03), age at first birth (P-het < 0.001) and postmenopausal hormone use (P-het < 0.001) were more strongly associated with lobular cancers. The associations with age, nulliparity, parity, age at menopause, type of menopause, alcohol intake, adult body mass index (BMI), BMI at age 18, family history of breast cancer and personal history of benign breast disease did not vary by subtype (P-het ≥ 0.08). Results were similar when we restricted the analyses to estrogen receptor-positive and progesterone receptor-positive tumors. Conclusions These data indicate that breast cancer is a heterogeneous disease, and the differential association with a number of risk factors is suggestive of etiologically distinct tumors. Epidemiological analyses should continue to take into account a modifying role of histology.

Landscape amenities and disamenities are important factors for households in making residence decision. This study presents a hedonic analysis of the amenity and disamenity effects arising from the heterogeneous urban landscape in a Chinese city. The sample is composed of 358 apartment characteristics and transaction data collected directly from home owners in the central built-up area of Shenzhen. Four types of urban landscapes were included, namely urban parks, residential gardens, Shenzhen Bay, and urban villages. We applied a three-dimensional model (availability, accessibility, and visibility) to estimate the amenity–disamenity effects of these urban landscape features. The results indicated that residential gardens were the most attractive landscape (an average increase of 17.2% of housing price) and urban villages had disamenity effects (a decrease of 3.72% for visibility and 2.5% for availability). The visibility of landscape was more valued than the accessibility. The lower weight accorded to the availability variable suggested: both benefits and possible negative impacts related to urban parks and Shenzhen Bay could be embodied in home buyers’ behaviour; and the unavoidability of urban villages. The findings could provide insights to the location and design of residential areas vis-a-vis amenity–disamenity landscape features in Chinese cities that are rapidly expanding and redeveloping.

Pegylated liposomal doxorubicin has activity in both breast and ovarian cancer. Preclinical data noted that ZD1839 acts synergistically with chemotherapy. Given the lack of cross-resistance between these two agents, a phase I trial was initiated examining the safety and efficacy of the combination of liposomal doxorubicin and ZD1839 in patients with recurrent gynecologic or metastatic breast cancer. Dose-limiting toxicity (DLT) was defined within the first two cycles of treatment. Escalating doses of liposomal doxorubicin were administered every 4 weeks with ZD1839. Pharmacokinetic analysis and correlative studies were performed. Thirty-five patients were enrolled in this study: six in each cohort. One DLT (febrile neutropenia) was observed in cohort 2. Dose level 3 was determined to be the maximum tolerated dose (MTD), and an additional ten patients were accrued. Serious adverse events (SAEs) included one patient with mental status changes believed secondary to disease progression and two central nervous system (CNS) bleeds believed to be unrelated to the combination of study agents. Toxicities were generally mild except for skin and gastrointestinal toxicity. No cardiac toxicity was observed. The best response to therapy included four partial responses and 20 patients with stable disease. Liposomal doxorubicin with ZD1839 is an active regimen but is associated with increased skin toxicity in patients with advanced breast and gynecologic cancer.

A functional promoter polymorphism in the progesterone receptor (PR) gene previously has been associated with an increased risk of postmenopausal breast cancer. Whether the relationship between genetic variation in PR and risk of breast cancer is modified by postmenopausal hormone (PMH) use is unknown. Thus, we conducted a case-control study nested within the prospective Nurses’ Health Study to evaluate if the risk of breast cancer associated with having the +331 A risk allele was modified by PMH use. Genotyping of this SNP was available for 1664 postmenopausal breast cancer cases and 2391 controls. Logistic regression was used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for breast cancer. Women who were carriers of one or both variant A alleles had a 31% increased risk of developing breast cancer (95%CI 1.04-1.65). PMH use significantly modified the association between the +331G/A polymorphism and risk (P-interaction

The monetary assessment of biodiversity measures the welfare damages brought by biodiversity losses and the cost-benefit analysis of conservation projects in a socio-economic context. The contingent valuation method could include motivational factors to strengthen economic analysis of nature conservation. This study analyzed Guangzhou residents’ motivations and willingness-to-pay (WTP) for an urban biodiversity conservation program in the National Baiyun Mountain Scenic Area (BMSA). The peri-urban natural site, offering refuge to some endemic species, is under increasing development pressures for recreational and residential use. A questionnaire survey was conducted in the Guangzhou metropolitan area during June to October 2007. We interviewed face-to-face 720 stratified sampled households to probe residents’ attitudes towards the city’s environmental issues, motivations for urban nature conservation, and WTP for biodiversity conservation. Principal component analysis identified five motivational factors, including environmental benefit, ecological diversity, nature-culture interaction, landscape-recreation function, and intergenerational sustainability, which illustrated the general economic values of urban nature. Logistic regression was applied to predict the probability of people being willing to pay for the urban biodiversity conservation in BMSA. The significant predictors of WTP included household income and the factor nature-culture interaction. The median WTP estimated RMB149/household (about US$19.5/household) per year and an aggregate of RMB291 million (approximately US$38.2 million) annually to support the urban conservation project. Including public motivations into contingent valuation presents a promising approach to conduct cost-benefit analysis of public projects in China.

Urban forests, composed of trees and other vegetation, are integral parts of urban ecosystems. Whether planted intentionally or left by default, urban forests appeared even in the earliest settlements. In urban areas, the constituent greenery provides a broad range of benefits, including opportunities for residents to have daily contact with nature, and to enjoy attractive landscapes and recreational activities (Grey and Deneke, 1986; Rowntree, 1986; Ulrich, 1986; Dwyer et al., 1992; Miller, 1997; Bolund and Hunhammar, 1999; Tyrvainen and Miettinen, 2000). In addition, vegetation in cities moderates microclimate extremes and reduces regional pollution (Botkin and Beveridge, 1997; Whitford et al., 2001). They contribute to an improved quality of urban life in many ways, even though these functions are often taken for granted by the public and some city authorities. The environmental benefits and natural functions provided by urban forests can be interpreted as ecosystem services, which are defined as benefits that the human population can derive, directly or indirectly, from ecosystem functions (Costanza et al., 1997). The urban population must rely mainly on services derived from external ecosystems, such as food and energy. However, the diversified benefits generated by urban forests, which are limited in comparison with the amount of imported ecosystem services, could be more instrumental in solving local environmental problems. They could significantly improve the quality of urban life, and play a paramount role in stabilizing and sustaining urban ecosystems (Daily, 1997; Bolund and Hunhammar, 1999; Jensen et al., 2000). Such ecosystem services, however, are not very tangible and generally not well understood or appreciated. Recent studies have generated a wealth of scientific information on the magnitude of their benefits. A more direct interpretation of these benefits for laypersons could promote their preservation and enhancement. A useful approach is to quantify these natural services, and then follow with a valuation of these nonmarket and noncommodity goods. The results could be translated into the universal language of monetary units, and be compared with alternatives to facilitate decision making related to natural resources or the environment. Valuation is inseparable from the choices and decisions humans have to make about ecosystems (Bingham et al., 1995; Costanza et al., 1997; Barbier et al., 1998; Costanza, 2000). Some studies have attempted to quantify the ecosystem services generated by urban

Background: Pre-S deletion mutant of hepatitis B virus (HBV) affects the expression of middle and small surface proteins, resulting in intracellular accumulation of large surface protein. The correlation between pre-S deletion mutant and risk of hepatocellular carcinoma (HCC) in hepatitis B virus carriers remains unclear. Methods: Using molecular assays, pre-S deletion mutant of HBV were determined in 266 patients with chronic HBV genotype B or C infection. They included 202 asymptomatic carriers and 64 HCC patients. Results: The overall prevalence of pre-S deletion mutant was 16.5%. Hepatocellular carcinoma (odds ratio [OR], 3.23; 95% confidence interval [CI], 1.23–8.48, P = 0.02) and genotype C (OR, 3.19; 95%CI, 1.54–6.62, P = 0.002) were independently associated with the presence of pre-S deletion mutant. The prevalence of pre-S deletion mutant was comparable between HCC patients with genotype B and C infection. Nevertheless, in asymptomatic carriers, patients with genotype C infection were significantly associated with the presence of pre-S deletion mutant compared to those with genotype B infection (20.8% vs 7.2%, P = 0.007). Compared with age- and genotype B-matched asymptomatic carriers, young HCC patients (

T he potential for breast cancer chemoprevention is supported by results from several large randomized trials of selective estrogen receptor modulators (SERMs), such as tamoxifen and raloxifene. Both tamoxifen and raloxifene have been shown to reduce the incidence of invasive breast cancer by approximately 50%, with the benefit confined to estrogen receptor-positive (ERþ) tumors. The first results from the National Surgical Adjuvant Breast and Bowel Project trial (NSABP P-1) of tamoxifen versus placebo for primary breast cancer prevention were published in 1998 and greeted with much fanfare. However, the use of tamoxifen for primary breast cancer prevention has been limited due to concerns regarding adverse effects (including uterine cancer and thromboembolic events) and the unfamiliarity of the majority of primary care providers with tamoxifen, which is primarily considered to be an oncology drug. Conversely, primary care providers are already familiar with raloxifene, which has been approved by the U.S. Food and Drug Administration for the prevention and treatment of osteoporosis in postmenopausal women. In addition, rates of adverse effects from placebo-controlled raloxifene trials appeared to be lower than those observed for tamoxifen (Table 1). These differences were confirmed in the large, randomized STAR trial (Study of Tamoxifen and Raloxifene), which reported a lower risk of thromboembolic events (relative risk [RR] of 0.70; 95% confidence interval [95%CI], 0.54– 0.91) and cataracts (RR of 0.79; 95% CI, 0.68–0.92) in the raloxifene arm compared with patients treated with tamoxifen. Although there was no statistically significant differences noted with regard to rates of uterine cancer (RR of 0.62; 95% CI, 0.35–1.08), raloxifene clearly had fewer effects on the uterus, with a lower incidence of uterine hyperplasia (RR of 0.16; 95% CI, 0.09–0.29) and fewer hysterectomies performed during follow-up (RR of 0.44; 95% CI, 0.35–0.56). In contrast to hormone replacement therapy, raloxifene did not appear to significantly increase the risk of cardiovascular disease. Rather than using a ‘‘one size fits all’’ approach to chemoprevention, we propose following the cardiovascular disease paradigm in which interventions are targeted according to the estimated risk of disease development. For cardiovascular disease, both biomarker Supported by Grant P01 CA 087969 from the National Cancer Institute.

We examined whether a history of smoking is associated with an increased risk of death from any cause or from breast cancer, among women diagnosed with breast cancer. This was a prospective observational study among 5,056 women from the Nurses' Health Study with Stages I-III invasive breast cancer diagnosed between 1978 and 2002 and for whom we had information on smoking, and who were followed until January 2002 or death, whichever came first. Subjects were classified as current, former or never smokers based upon smoking status at the biennial questionnaire immediately preceding the breast cancer diagnosis. In multivariate-adjusted analyses, compared with never smokers, women who were current smokers had a 43% increased adjusted relative risk (RR) [95% confidence interval (95% CI): 1.24-1.65] of death from any cause. A strong linear gradient was observed with the number of cigarettes per day smoked, p-trend

Purpose: Alcohol consumption is a consistent risk factor for breast cancer, although it is unclear whether the risk varies by molecular subtype of breast cancer. Alcohol may influence breast cancer risk via a steroid hormone pathway, or through non-hormonal pathways, including increasing susceptibility to DNA damage. Methods: We assessed the associations between alcohol intake and risk of breast cancer by molecular subtypes among 106,045 women in the prospective Nurses’ Health Study (NHS) cohort. Cumulative average alcohol intake was calculated from semi-quantitative food frequency questionnaires collected every 2-4 years. Breast cancer molecular subtypes were defined according to estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor 2 (HER2), cytokeratin 5/6 (CK5/6) and epidermal growth factor (EGFR) status from immunostained tumor microarrays in combination with histologic grade. Luminal A cases were ER-positive and/or PR-positive and HER2-negative and grade 1 or 2; Luminal B cases were either ER-positive and/or PR-positive and HER2-positive or ER-positive, PR-positive and HER2-negative with grade 3; HER2-type cases were ER-negative, PR-negative and HER2-positive; Basal-like cases were negative for ER and PR, and HER2 and positive for CK 5/6 and/or EGFR; Unclassified tumors lacked expression of all five markers. Cox proportional hazards models adjusted for age and breast cancer risk factors were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). Competing risk analyses were used to assess heterogeneity in associations across subtype. Results: A total of 2,624 cases of invasive breast cancer were diagnosed between 1980 and 2006. Alcohol consumers had an increased risk of Luminal A (n = 1,572 cases, per 10g/day increment HR (95%CI) = 1.10(1.04-1.15)) and an increased risk that was suggestively stronger for HER2-type (n = 166 cases, HR = 1.19(1.06-1.35)) breast cancer. We did not observe statistically significant associations between alcohol and risk of Luminal B (n = 534 cases, HR = 1.06(0.97-1.15)), basal-like (n = 259 cases, HR = 0.88(0.76-1.03)), or unclassified (n = 93 cases, HR = 0.88(0.69-1.12)) breast cancer. There was significant heterogeneity in associations between alcohol and breast cancer by subtype (phet = 0.006). Conclusion: Alcohol consumption was associated with increased risk of Luminal A and HER2-type. Given that hormone receptors are positive in Luminal A and negative in HER2-type, our findings suggest that both hormonal and non-hormonal mechanisms may play a role in the association between alcohol and breast cancer. Citation Format: Kelly A. Hirko, Wendy Y. Chen, Susan E. Hankinson, Walter C. Willett, Rulla M. Tamimi, A. Heather Eliassen, for the Nurses' Health Study research group. Alcohol consumption and risk of breast cancer by molecular subtype. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1885. doi:10.1158/1538-7445.AM2015-1885

1507 Background: Triple negative breast cancer (TNBC), defined as ER-/PR-/HER2-, has a poor prognosis and limited targeted treatment options. Modifiable lifestyle factors, including body mass index...

Breast cancer is a heterogeneous group of diseases and hormone receptor status defines important clinical and etiologic differences between breast cancer subtypes. This article reviews the epidemiologic data on differences in risk factor associations by hormone receptor status, and highlights the limitations of commonly used prediction models. The authors describe how receptor status information can be applied to risk analysis for screening and preventive therapies. It is increasingly being recognized that breast cancer does not represent a single homogeneous disease; instead, the hormone-receptor status defines important clinical and etiologic differences. We review the epidemiologic data on differences in risk-factor associations by hormone-receptor status and highlight major trends in the literature. We discuss the development and evaluation of breast cancer risk models, with a focus on the Rosner and Colditz model, which can separately estimate the risk of hormone-receptor-positive and hormone-receptor-negative breast cancers. We also discuss the clinical implications of accounting for hormone-receptor status in breast cancer risk-prediction models.

Background: Although short-term unopposed estrogen use does not seem to increase breast cancer risk, the effect of longer-term estrogen use remains unclear. We sought to assess the relationship between longer-term use of unopposed estrogen and the risk of invasive breast cancer over an extended follow-up period. Methods: Within the Nurses’ Health Study, a prospective cohort study, we observed 11 508 postmenopausal women who had a hysterectomy and reported information on estrogen use at baseline (1980). The study population was expanded every 2 years to include women who subsequently became postmenopausal and had a hysterectomy, so that 28 835 women were included in the final follow-up period (2000-2002). Estrogen use was assessed from self-reported data on biennial questionnaires. The main outcome was invasive breast cancer. Results: A total of 934 invasive breast cancers were included in the analysis. Breast cancer risk increased with duration of unopposed estrogen use among longer-term users with the highest risk seen in cancers positive for estrogen receptor (ER) and progesterone receptor (PR). The multivariate relative risks (RRs) and 95% confidence intervals (CIs) for breast cancer with current use of unopposed estrogen for less than 5 years, 5 to 9.9 years, 10 to 14.9 years, 15 to 19.9 years, and 20 years or longer were, respectively, 0.96 (95% CI, 0.75-1.22), 0.90 (95% CI, 0.73-1.12), 1.06 (95% CI, 0.87-1.30), 1.18 (95% CI, 0.95-1.48), and 1.42 (95% CI, 1.13-1.77) (P for trend .001). The risk of ER/PR breast cancers was noted to be statistically significant after 15 years of current use (RR, 1.48; 95% CI, 1.05-2.07). Conclusion: Users of unopposed estrogen were at increased risk of breast cancer but only after longerterm use.

Studies of the association between breast size, as a proxy for mammary gland mass, and breast cancer risk have given equivocal results. Most have been case-control studies with limited statistical power. We conducted a prospective analysis of the relation between breast size as measured by self-reported bra cup size and breast cancer risk among premenopausal women enrolled in the Nurses' Health Study II. Bra cup size at age 20 was assessed among 89,268 premenopausal women aged 29-47 in 1993. Subsequent incident cases of invasive breast cancer were assessed until 2001. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated with a Cox proportional hazards model adjusting for potential confounders and risk factors for breast cancer. During 622,732 person-years of follow-up, 803 premenopausal women were newly diagnosed with invasive breast cancer. For women with a BMI below 25 kg/m2, those with a bra cup size of "D or larger" had a significantly higher incidence of breast cancer than women who reported "A or smaller" (covariate adjusted HR=1.80; 95% CI 1.13-2.88; ptrend=0.01). There was no significant association among women with a BMI of 25 kg/m2 or higher. Stratifying by BMI at age 18 at a cutoff point of 21 kg/m2 gave similar results. Larger bra cup size at a young age is associated with a higher incidence of premenopausal breast cancer, though this association is limited to leaner women.

Regular physical activity is closely linked with an improved quality of life in women diagnosed as having breast cancer, and there is reason to believe that it extends survival. Activity also has been related to a lower risk of breast cancer. The question of whether the risk of dying from breast cancer is lowered by physical activity was addressed in an observational study of 2987 female nurses who took part in the Nurses' Health Study and who developed stage I to stage III breast cancer. Cancer mortality was related to the level of physical activity as quantified by the metabolic equivalent task (MET) hours per week, ranging from less than 3 to 24 or more MET-hours. The median follow-up interval was 8 years. A total of 463 deaths occurred during the study, 280 of them a result of breast cancer. Recurrences totaled 370 during this period. Physical activity was assessed a median of 38 months after breast cancer was diagnosed. Women who were relatively active had a lower body mass index, ate more protein, and were less likely to have gained weight between diagnosis and the time of assessment. Women with fewer than 3 MET-hours per week were likelier to have smoked before diagnosis than their more active counterparts. All levels of activity above 3 MET-hours per week were associated with a lower risk of an adverse breast cancer outcome. Compared with relatively inactive women, the multivariable relative risk (RR) of dying from breast cancer was 0.8 for 3 to 8.9 MET-hours per week; 0.5 for 9 to 14.9 MET-hours per week; 0.56 for 15 to 23 MET-hours per week; and 0.6 for 24 or more MET-hours per week. Similar trends were found for recurrence of breast cancer and for overall survival. Using a cutoff of 9 MET-hours per week, more active women had a RR of death of 0.63. Without adjusting for possibly confounding variables, the risk reduction for women with 9 or more MET-hours per week was 4% at 5 years and 6% at 10 years compared with those with fewer than 3 MET-hours per week. Overweight and normal-weight women benefited to a similar degree. Physical activity appeared to benefit women having stage I or stage II breast cancer, but those with stage III disease benefited the most. Both walking and vigorous activity (jogging, bicycling, calisthenics, and the like) contributed to a lower risk of dying from breast cancer. Adjusting for level of physical activity before diagnosis did not alter the findings. These findings support a role for physical activity after a diagnosis of breast cancer in lowering the risk of death from this cause. Benefit was most obvious for women who did the equivalent of walking 3 to 5 hours per week at an average pace. Lower mortality did not appear related to greater energy expenditure.

Purpose To determine whether weight prior to diagnosis and weight gain after diagnosis are predictive of breast cancer survival. Methods Patients included 5,204 Nurses' Health Study participants diagnosed with incident, invasive, nonmetastatic breast cancer between 1976 and 2000; 860 total deaths, 533 breast cancer deaths, and 681 recurrences (defined as secondary lung, brain, bone, or liver cancer, and death from breast cancer) accrued to 2002. We computed the change in body mass index (BMI) from before to the first BMI reported ≥ 12 months after the date of diagnosis. Cox proportional hazards models were used to evaluate associations of categories of BMI before diagnosis and of BMI change with time to event. We stratified by smoking, menopausal status, and breast cancer–related variables. Results In multivariate-adjusted analyses, weight before diagnosis was positively associated with breast cancer recurrence and death, but this was apparent only in never smokers. Similarly, among never-smoking women, those who gained between 0.5 and 2.0 kg/m2 (median gain, 6.0 lb; relative risk [RR], 1.35; 95% CI, 0.93 to 1.95) or more than 2.0 kg/m2 (median gain, 17.0 lb; RR, 1.64; 95% CI, 1.07 to 2.51) after diagnosis had an elevated risk of breast cancer death during follow-up (median, 9 years), compared with women who maintained their weight (test for linear trend, P = .03). Associations with weight were stronger in premenopausal than in postmenopausal women. Similar findings were noted for breast cancer recurrence and all-cause mortality. Conclusion Weight and weight gain were related to higher rates of breast cancer recurrence and mortality, but associations were most apparent in never-smoking women.

Risk appraisal instruments may be helpful in reinforcing prevention messages, although little is known about physician acceptance of such instruments.We explored perceived barriers to colon cancer risk counseling and responses to the colon cancer component of an Internet-based risk appraisal instrument.We qualitatively assessed provider perceptions of barriers to colon cancer prevention and screening, and their responses to the Harvard Cancer Risk Index using focus groups of primary care providers.Many providers commented that the risk appraisal instrument may be most helpful to reinforce messages by a health-care provider. The tool may increase awareness about modifiable risk factors for cancer and help patients prioritize changes as well as improve screening acceptance. With regard to barriers to counseling patients about colon cancer prevention and screening, providers expressed concerns that behaviors are too difficult to change. In addition, they were frustrated by limited time for prevention counseling and poor reimbursement.The Internet-based risk index was well accepted, although providers thought it would be most effective when used to complement provider messages about prevention. Use of an Internet-based risk index along with physician counseling could help improve cancer prevention practices and cancer screening acceptance.

Purpose To explore changes in physical and psychosocial function before and after breast cancer by age at diagnosis. Patients and Methods A total of 122,969 women from the Nurses' Health Study (NHS) and NHS 2, ages 29 to 71 years, who responded to pre- and postfunctional status assessments were included; 1,082 women were diagnosed with breast cancer between 1992 and 1997. Functional status was measured using the Medical Outcomes Study Short Form 36 (SF-36). Mean change in health-related quality of life (HRQoL) scores was computed across categories representing the combination of incident breast cancer (yes or no) and age at diagnosis (≤ 40, 41 to 64, or 65+ years). Results Compared with women ≤ 40 years without breast cancer, women with breast cancer experienced significant functional declines. Young (age ≤ 40) women who developed breast cancer experienced the largest relative declines in HRQoL (as compared with middle-aged and elderly women) in multiple domains including physical roles (−18.8 v −11.5 and −7.5 points, respectively), bodily pain (−9.0 v −2.7 and −2.7 points), social functioning (−11.3 v −4.3 and −4.4 points) and mental health (−3.1 v 0.0 and +0.4 points). Much of the decline in HRQoL among elderly (age ≥ 65) women with breast cancer was age related. Conclusion Young women may fare worse than middle-aged or elderly women in both physical and psychosocial dimensions after breast cancer diagnosis. The needs of women facing breast cancer may be better understood within a life stage framework.

To investigate the association between smoking and invasive breast cancers characterized by their estrogen receptor status in a large prospective study of mainly premenopausal women.112,844 women aged 25-42 years in 1989 were followed 10 years; questionnaire information on medical illnesses and risk factors was collected biennially and information on diet was collected in 1991 and 1995. During this period of follow-up (1,077,536 person-years), 1009 incident breast cancer cases were documented.In the multivariate-adjusted models, smoking status was not significantly related to overall breast cancer risk: compared with never smokers, the relative risks (RRs) were 1.18 [95% confidence interval (CI) 1.02-1.36] for past smokers and 1.12 (95% CI 0.92-1.37) for current smokers. Increasing duration of smoking before the first pregnancy was associated with a greater risk of breast cancer, although little increase was seen in the highest category: compared with never smokers, RRs were 1.42 (95% CI 1.10-1.83) for 15-19 years of smoking and 1.10 (95% CI 0.80-1.52) for/=20 years of smoking (P for trend = 0.01). Smoking was related most strongly to the risk of estrogen receptor-positive breast cancers. For women who had smoked for/=20 years, the RR of estrogen receptor-positive cancer was 1.37 (95% CI 1.07-1.74) and the RR of estrogen receptor-negative cancer was 1.04 (95% CI 0.71-1.53). For smoking before age 15, the RRs were 1.49 (95% CI 1.03-2.17) for estrogen receptor-positive cancer and 1.19 (95% CI 0.69-2.08) for estrogen receptor-negative cancer.Our results suggest that longer duration of smoking may be related to the risk of estrogen receptor-positive breast cancer but possibly less so for estrogen receptor-negative breast cancer.

Background: Evaluations of epidemiologic risk factors in relation to breast cancer classified jointly by estrogen receptor (ER) and progesterone receptor (PR) status have been inconsistent. To address this issue, we conducted a prospective evaluation of risk factors for breast cancer classi fied according to receptor status. Methods: During 1 029 414 person-years of follow-up of 66 145 women participating in the Nurses’Health Study from 1980 through 2000, we identified 2096 incident cases of breast cancer for which information on ER/PR status was available: 1281 were ER/ PR, 318 were ER/PR, 80 were ER/PR, and 417 were ER/PR .W efit a log-incidence model of breast cancer and used polychotomous logistic regression to compare coefficients for breast cancer risk factors in patients with different ER/PR status. To test for differences in risk factor odds ratios based on marginal ER/PR categories, we evaluated ER status controlling for PR status and vice versa. The predictive ability of our log-incidence model to discriminate between women who would develop ER/PR breast cancer and those who would not (and similarly for ER/ PR breast cancer) was evaluated by using receiver operator characteristic curve analysis. All statistical tests were two-sided. Results: We observed statistically significant heterogeneity among the four ER/PR categories for some risk factors (age, menopausal status, body mass index [BMI] after menopause, the one-time adverse effect of first pregnancy, and past use of postmenopausal hormones) but not for others (benign breast disease, family history of breast cancer, alcohol use, and height). The one-time adverse association of first pregnancy with incidence was present for PR but not for PR tumors after controlling for ER status (P .007). However, the association of BMI after menopause with incidence was present for PR but not PR tumors (P .005). Statistically significant differences in the incidence of ER and ER tumors were seen with age, both before and after menopause (P .003), and with past use of postmenopausal hormones (P .01). Area under the receiver operator characteristic curve, adjusted for age, was 0.64 (95% confidence interval [CI] 0.63 to 0.66) for ER/PR tumors and 0.61 (95% CI 0.58 to 0.64) for ER/PR tumors. Conclusions: Incidence rates and risk factors for breast cancer differ according to ER and PR status. Thus, to accurately estimate breast cancer risk, breast cancer cases should be divided according to the ER and PR status of the tumor. [J Natl Cancer Inst 2004;96:218 ‐28]

Carbohydrate intake, glycemic index, and glycemic load have been hypothesized to increase risk of breast cancer by raising insulin levels, but these associations have not been studied extensively. The insulin response to dietary carbohydrate is substantially greater among overweight women than among leaner women. Although fiber intake has been hypothesized to reduce the risk of breast cancer, data from early adult life are lacking. We examined dietary carbohydrate, glycemic index, glycemic load, and fiber in relation to breast cancer risk among 90655 premenopausal women in the Nurses' Health Study II aged 26-46 years in 1991. Diet was assessed with a food frequency questionnaire in 1991 and 1995. During 8 years of follow-up, we documented 714 incident cases of invasive breast cancer. Dietary carbohydrate intake, glycemic load, and glycemic index were not related to breast cancer risk in the overall cohort. However, the associations differed by body mass index (BMI): among women with BMI25 kg/m(2), the multivariate relative risks for the increasing quintiles of carbohydrate intake were 1.00 (referent), 0.87, 0.77, 0.66, and 0.62 [95% confidence interval, 0.40-0.97; P, test for trend = 0.02]; and among women with BMIor=25 kg/m(2), the corresponding relative risks were 1.00 (referent), 1.30, 1.35, 1.50, and 1.47 (95% confidence interval, 0.84-2.59; P, test for trend = 0.14; P, test for interaction = 0.02). Similar interaction with BMI was observed for glycemic load, but not for glycemic index. Intakes of total fiber and different types of fiber were not appreciably related to breast cancer risk. Our findings suggest that the associations between carbohydrate intake or glycemic load and breast cancer risk among young adult women differ by body weight. Our data do not support a strong association between fiber intake and breast cancer risk.

Physical activity appears to be inversely related to risk of breast cancer, yet the results remain inconsistent. To evaluate this relation among premenopausal women and examine variation in risk according to level of obesity and use of oral contraceptives (OCs), the authors examined data from the Nurses' Health Study II. During 10 years of follow-up, 849 cases of invasive premenopausal breast cancer were confirmed. Physical activity was assessed by self-report at baseline and during follow-up using a validated questionnaire. Total physical activity was unrelated to risk of breast cancer. Women engaging inor=27 metabolic equivalent (MET)-h week(-1) had a multivariate-adjusted relative risk (RR) of 1.04 (95% confidence interval (CI) 0.82-1.33) compared to those in the3 MET-h week(-1) category. Among women with a BMIor=30 kg m(-2), we observed a significant positive dose-response relation (P=0.04). Activity was unrelated to breast cancer risk at lower levels of BMI. A test for interaction between activity and BMI (30,or=30 kg m(-2)) was statistically significant (P=0.02). Among current OC users, higher activity was associated with a non-significantly lower risk of breast cancer (RR=0.59, 95% CI 0.30-1.16 foror=27 vs9 MET-h week(-1), P for linear trend=0.14). These results show no overall association between physical activity and risk of breast cancer among premenopausal women, but suggest that the effect of physical activity could be substantially modified by the underlying degree of adiposity. The potential interactions between physical activity, adiposity, and current use of OCs require further study.

Intakes of vitamins A, C, and E, folate, and carotenoids have been hypothesized to reduce the risk of breast cancer. However, previous epidemiological studies on these nutrients and breast cancer risk have been inconclusive, and have included primarily postmenopausal women. We examined the intake of these nutrients in relation to breast cancer risk among 90,655 premenopausal women ages 26-46 years in 1991 in the Nurses' Health Study II. Nutrient intake was assessed with a validated food-frequency questionnaire at baseline in 1991 and in 1995. During 8 years of follow-up from 1991 to 1999, we documented 714 incident cases of invasive breast cancer. Overall, none of the vitamins and carotenoids was strongly related to a reduced risk of breast cancer. However, intake of vitamin A, including preformed vitamin A and carotenoids, was associated with a reduced risk of breast cancer among smokers; participants in the highest quintile of total vitamin A intake had a multivariate relative risk of 0.28 (95% confidence interval 0.12-0.62; P, test for trend0.001; P, test for interaction0.001) compared with those in the lowest quintile of intake. We found no evidence that higher intakes of vitamins C and E, and folate in early adult life reduce risk of breast cancer. However, intake of vitamin A may be related to a reduced risk of breast cancer among smokers.

Background: Increasing evidence suggests that many breast cancers may be “overdiagnosed” due to intensive screening and would not cause harm if left untreated. More research is needed on risk factors for the most harmful tumors that go on to become lethal. Alcohol is the strongest dietary risk factor for breast cancer, but whether alcohol consumption increases risk of lethal breast cancer specifically is unknown. Methods: We assessed alcohol intake (drinks/week) in 88,759 women in the Nurses' Health Study (NHS; 1980-2010) and 93,911 women in the NHSII (1991-2009). Women reported beer, wine, and liquor intake on semi-quantitative food frequency questionnaires administered every four years. The main exposure was cumulative average alcohol consumption in grams/day; we also assessed baseline and updated current consumption. Breast cancer cases were confirmed with pathology reports and deaths were confirmed by next of kin or the National Death Index. We defined lethal cases as women with invasive breast cancer for whom the primary cause of death was breast cancer or a metastasis from breast cancer. Person-time for each participant was calculated from the date of return of the baseline questionnaire to the date of breast cancer diagnosis, date of any other cancer diagnosis, death from any cause, or the end of follow-up, whichever came first. We pooled the NHS and NHSII data and used Cox proportional hazards models adjusted for breast cancer risk factors. To determine whether the association differed for lethal versus nonlethal breast cancer, competing risks models were used; we conducted likelihood ratio tests to compare models assuming different versus the same associations of alcohol (defined continuously) with lethal and nonlethal tumors. We tested for an interaction between alcohol and folate intake using a likelihood ratio test. Results: 1,452 women developed lethal breast cancer over follow-up. Cumulative average alcohol intake was associated with higher risk of lethal breast cancer [hazard ratio (HR) per 10 g increase: 1.13 (95% CI: 1.07, 1.18, p-trend Conclusions: In these two prospective cohort studies, alcohol intake was positively associated with lethal breast cancer, but the association was not significantly different for lethal versus nonlethal breast cancer. Citation Format: Caroline E. Boeke, A. Heather Eliassen, Wendy Y. Chen, Michelle D. Holmes, Bernard Rosner, Walter C. Willett, Rulla M. Tamimi. Alcohol intake in relation to lethal breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1269. doi:10.1158/1538-7445.AM2014-1269

Background: The role of androgens in breast cancer etiology has been hypothesized but not confirmed. Androgen receptors (AR) have important physiological effects in normal breast development and are expressed in malignant breast tissue. Clinical studies indicate that AR may be a prognostic factor for breast cancer survival; however, studies addressing its role in breast cancer development are limited. Alcohol consumption, a confirmed breast cancer risk factor, has been hypothesized to exert its effect, at least partially, through the AR signaling pathway. We previously reported that alcohol consumption during adult life was positively associated with breast cancer risk (per 10 grams/day: hazard ratio [HR] = 1.10, 95% confidence interval [CI] = 1.07-1.12), and the association appeared stronger for estrogen receptor (ER) positive tumors. However, no epidemiologic studies have so far investigated alcohol and breast cancer risk according to AR status. Methods: We assessed this association in a prospective study of 105,858 women enrolled in the Nurses' Health Study. Alcohol consumption was first assessed through food frequency questionnaire at baseline (1980) and updated six times during follow-up; cumulative average alcohol use was calculated by averaging alcohol intake over time starting at baseline. Tumor AR status was determined through immunohistochemical staining using sections from a tumor tissue microarray (TMA); ER and progesterone receptor (PR) status was obtained from the TMA, or secondarily from the medical record pathology report. We applied a constrained competing risk survival model that allows for assessment of the alcohol and breast cancer association by AR status while controlling for ER and PR status, as well as other breast cancer risk factors. Results: During over 2.2 million person-years of follow-up from 1980 to 2006, 2706 invasive breast cancer cases with complete tumor marker data (i.e. AR, ER and PR) contributed to the analysis. When considering AR separately without adjustment of ER and PR status, alcohol consumption was positively associated with risk of invasive breast cancer among tumors expressing AR but not among AR-negative tumors (per 11 grams/day [equivalent to 1 drink/day] HR [95%CI]: 1.10 [1.05 - 1.16] and 1.02 [0.93 - 1.12], respectively; P-value for heterogeneity test = 0.14). After taking into account both ER and PR status, alcohol intake remained positively associated with risk of invasive breast cancer among AR-positive tumors but not among AR-negative tumors (per 11 grams/day HR [95%CI]: 1.10 [1.05 - 1.15] and 1.04 [0.96 - 1.12], respectively). However, the difference in relative risks between AR-positive and AR-negative tumors was not statistically significant (P-value for heterogeneity = 0.24). Conclusion: Our data suggest a positive association between alcohol intake and breast cancer risk for AR-positive tumors, but larger studies will be needed to confirm this. Citation Format: Jun Wang, Xuehong Zhang, Andrew H. Beck, Laura C. Collins, Wendy Chen, Rulla M. Tamimi, Aditi Hazra, Bernard Rosner, Susan E. Hankinson. Lifetime alcohol consumption and risk of breast cancer, by tumor androgen receptor expression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1270. doi:10.1158/1538-7445.AM2014-1270

Background: Estrogen-receptor (ER)+ breast cancers have a favorable prognosis in the first several years after diagnosis, with adjuvant endocrine therapies for treatment. However, in later years, ER+ breast cancer is associated with poorer prognosis compared to ER- breast cancer. Predictors of late recurrence in women with ER+ breast cancer, and in particular lifestyle factors, have been little studied. Using data from a pooling project of breast cancer survivor cohorts (After Breast Cancer Pooling Project), we prospectively evaluated the association of post-diagnosis lifestyle factors and comorbidities with late breast cancer outcomes. Methods: Analyses included 6,129 women diagnosed with stage I-III invasive ER+ breast cancer (1990-2004) from three US prospective cohorts, who survived disease-free for five years. Pooled and harmonized data were available for post-diagnosis lifestyle factors, comorbidities, cancer treatment, tumor characteristics, and socio-demographics. Late outcomes (defined as >5 years post-diagnosis) included breast cancer recurrence, breast cancer specific-mortality (BCSM), and all-cause mortality. Lifestyle factors and comorbidities were assessed at a mean of about 2 years post-diagnosis. Study heterogeneity was evaluated by the Q statistic. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression models stratified by study. Results: After a median follow-up of 6.9 years (11.9 years post-diagnosis), 645 deaths and 564 recurrences were documented. Five-year recurrence and all-cause mortality rates were 7.2% and 6.1%, respectively. Ten-year recurrence and all-causes mortality rates were 12.1% and 15.4%, respectively. In multivariable models, recreational physical activity (PA) of 10-MET h/wk was associated with reduced all-cause mortality (HR: 0.71, 95% CI: 0.60-0.84) and BCSM (HR: 0.77, 95% CI: 0.61-0.99), and non-significantly reduced recurrence risk (HR: 0.87, 95% CI: 0.73-1.03). Multivitamin and antioxidant vitamin supplement use were inversely associated with recurrence (HRs (95% CIs): 0.74 (0.62-0.87) and 0.75 (0.61-0.91), respectively). Current smoking was associated with increased risk of all-cause and BCSM ((HRs (95% CIs): 2.58 (1.99-3.35)) and 1.87 (1.22-2.88), respectively). Women with diabetes had increased risk of late outcomes (HRs 95% CIs: 1.35 (0.95-1.92) for recurrence, 1.86 (1.45-2.40) for all-cause mortality, and 1.75 (1.12-2.73) for BCSM. Hypertension was significantly associated with all-cause mortality only (HR: 1.42, 95% CI: 1.19-1.70). Obesity (BMI ≥30 kg/m2) was not associated with late outcomes. Conclusion: In this large study, post-diagnosis lifestyle factors were important predictors of late breast cancer outcomes. Our findings suggest PA and multivitamin use may improve long-term prognosis for ER-positive breast cancer. Citation Format: Sarah J. Nechuta, Wendy Y. Chen, Marilyn L. Kwan, Elizabeth M. Poole, Shirley W. Flatt, John P. Pierce, Bette J. Caan, Xiao Ou Shu. Lifestyle factors are associated with late breast cancer outcomes among 5-year survivors of estrogen-receptor positive breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2182. doi:10.1158/1538-7445.AM2014-2182

115 Background: Larger social networks have been associated with better breast cancer survival. To investigate potential mediators, we evaluated associations of social network size and diversity with lifestyle and treatment factors associated with prognosis. Methods: We included 9,331 women from the After Breast Cancer Pooling Project who provided data on social networks within two years following diagnosis. A social network index was derived from information about the presence of a spouse or intimate partner, religious ties, community participation, friendship ties, and numbers of relatives. Diversity was assessed as variety of ties, independent of size. We used logistic regression to evaluate associations with outcomes and evaluated whether effect estimates differed using meta-analytic techniques. Results: Associations of social networks and outcomes generally did not differ by cohort. Because of the low prevalence of smoking and alcohol consumption in the Shanghai cohort, however, analyses of smoking and alcohol included US cohorts only. Women who were socially isolated (small networks) were more likely to be obese (body mass index>30 kg/m2, OR=1.21, 95% CI:1.03-1.42) and have low physical activity (15 g/d alcohol, OR=2.43, 95% CI:1.60-3.69). Among node positive cases, socially isolated women were more likely not to receive chemotherapy (OR=1.52, 95% CI:1.03-2.25). By contrast, low network diversity, but not social network size, was associated with greater odds of not receiving adjuvant hormonal therapy (OR=1.52, 95% CI:1.03-2.23). Associations with surgery were nonsignificant. Conclusions: In a large pooled cohort, small, less diverse social networks measured post-diagnosis were associated with more adverse lifestyle factors and less intensive cancer treatment, which may help to explain poorer breast cancer prognosis in socially isolated women.

Objective To investigate the association between dietary protein sources in early adulthood and risk of breast cancer. Design Prospective cohort study. Setting Health professionals in the United States. Participants 88 803 premenopausal women from the Nurses’ Health Study II who completed a questionnaire on diet in 1991. Main outcome measure Incident cases of invasive breast carcinoma, identified through self report and confirmed by pathology report. Results We documented 2830 cases of breast cancer during 20 years of follow-up. Higher intake of total red meat was associated with an increased risk of breast cancer overall (relative risk 1.22, 95% confidence interval 1.06 to 1.40; Ptrend=0.01, for highest fifth v lowest fifth of intake). However, higher intakes of poultry, fish, eggs, legumes, and nuts were not related to breast cancer overall. When the association was evaluated by menopausal status, higher intake of poultry was associated with a lower risk of breast cancer in postmenopausal women (0.73, 0.58 to 0.91; Ptrend=0.02, for highest fifth v lowest fifth of intake) but not in premenopausal women (0.93, 0.78 to 1.11; Ptrend=0.60, for highest fifth v lowest fifth of intake). In estimating the effects of exchanging different protein sources, substituting one serving/day of legumes for one serving/day of red meat was associated with a 15% lower risk of breast cancer among all women (0.85, 0.73 to 0.98) and a 19% lower risk among premenopausal women (0.81, 0.66 to 0.99). Also, substituting one serving/day of poultry for one serving/day of red meat was associated with a 17% lower risk of breast cancer overall (0.83, 0.72 to 0.96) and a 24% lower risk of postmenopausal breast cancer (0.76, 0.59 to 0.99). Furthermore, substituting one serving/day of combined legumes, nuts, poultry, and fish for one serving/day of red meat was associated with a 14% lower risk of breast cancer overall (0.86, 0.78 to 0.94) and premenopausal breast cancer (0.86, 0.76 to 0.98). Conclusion Higher red meat intake in early adulthood may be a risk factor for breast cancer, and replacing red meat with a combination of legumes, poultry, nuts and fish may reduce the risk of breast cancer.

For years, experts have questioned whether cigarette smoking worsens the prognosis among women diagnosed with breast cancer. To date, most longitudinal studies have indicated that breast cancer survivors who smoke have increased risk of all-cause mortality but women who quit after diagnosis do not (1–8). However, it may be that the risk for former smokers is dependent upon the lifetime exposure to smoking, which is not captured by a simple question on current or former smoking. Therefore, the lack of association between former smoking and breast cancer prognosis could be an artifact of including former smokers with a wide range of lifetime exposure to cigarettes. Cohort studies of breast cancer survivors have been limited by sample size (range = 166–5056) (2–7,9,10), breast cancer–specific death events (range = 111–628) (2–7,9,10), and follow-up times that average less than a decade. In contrast, Doll et al. studied more than 34000 British doctors with nearly 5300 cancer deaths over several decades to expose the link between smoking and lung cancer (11). In addition to adequate study power, data on duration and intensity of smoking were needed to explain the lung cancer risk in major cohort studies (12,13). For example, the 50-year follow-up study of British doctors indicated that adults who smoke the equivalent of a pack a day appear to escape most health consequences if they quit smoking by age 35 (11). In 2010, more than 20% of US smokers quit successfully before age 30 (14); therefore a large proportion of former smokers are likely to be in this low-risk category. These data suggest that previous studies of smoking and breast cancer prognosis may have suffered from misclassification of the exposure or been underpowered to test this association. The objective of this study is to investigate the association of lifetime smoking behavior with breast cancer outcomes. We used data from the 3 US cohorts in the After Breast Cancer Pooling Project (ABCPP), which provides data on duration and intensity of smoking among almost 10000 breast cancer survivors who experienced more than 1700 breast cancer events. This much larger population and number of events compared with previously published studies provide us with the power to detect even moderate effect sizes (eg, 20%) among subgroups. To our knowledge, this is the largest examination of lifetime smoking and breast cancer outcomes conducted. Results of this analysis can inform clinicians about the impact of smoking cessation on breast cancer prognosis.

Dietary fats are not strongly associated with breast cancer incidence in general, but it is unknown whether fat intake influences risk of developing more aggressive, fatal breast cancer. We evaluated intake of total fat, specific types of fat (saturated, monounsaturated, polyunsaturated, trans fat; omega 3 polyunsaturated; animal and vegetable), and cholesterol prior to cancer diagnosis in relation to fatal breast cancer risk in 88,627 women in the Nurses’ Health Study (NHS; 1980-2008) and 93,372 women in the Nurses’ Health Study II (NHS II; 1991-2009). Diet was assessed every 4 years using a semi-quantitative food frequency questionnaire. Breast cancer cases were confirmed with pathology reports and deaths were confirmed using the National Death Index. We calculated cumulative average percent calories from fat intake and used substitution models to adjust for macronutrient composition. For cholesterol, we adjusted for total energy intake using the residual method. We defined fatal cases as women with breast cancer who died and had breast cancer listed as their primary cause of death. There were 1149 fatal breast cancer cases in NHS and 206 fatal cases in NHS II. After adjusting for multiple risk factors for breast cancer, neither total fat nor types of fat were associated with risk of fatal breast cancer in NHS or NHS II. For example, compared with those in the lowest quintile of saturated fat intake, those in the highest quintile had a hazard ratio (HR) of 1.02 (95% CI: 0.75, 1.38; p-trend=0.80) in NHS and 1.14 (0.61, 2.13; p-trend=0.61) in NHS II. In NHS there was a suggestive positive association between cholesterol and fatal breast cancer (Q5 vs. Q1 HR: 1.28, 95% CI: 1.02, 1.61; p-trend=0.04); this association did not persist in NHS II (0.73; 95% CI: 0.41, 1.32; p-trend=0.44) but should be examined further. Long-term pre-diagnosis dietary fat intake was not associated with fatal breast cancer in these two large prospective cohort studies. Cholesterol and percent calories from fat in relation to fatal breast cancer, Nurses” Health Study. Quartile 1 Quartile 2 Quartile 3 Quartile 4 Quartile 5 p-trend Nutrient HR HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) Total fat Number of cases 230 231 211 224 253 Macronutrient and age-adjusted 1.00 1.05 (0.87, 1.26) 0.92 (0.76, 1.11) 0.92 (0.76, 1.11) 0.92 (0.76, 1.11) 0.17 Multivariable adjusted 1.00 1.05 (0.87, 1.26) 0.92 (0.76, 1.11) 0.92 (0.76, 1.11) 0.89 (0.73, 1.08) 0.10 Saturated fat Number of cases 204 209 232 243 261 Macronutrient and age-adjusted 1.00 1.04 (0.85, 1.27) 1.10 (0.89, 1.36) 1.06 (0.84, 1.35) 1.04 (0.77, 1.42) 0.70 Multivariable adjusted 1.00 1.03 (0.84, 1.27) 1.09 (0.88, 1.36) 1.05 (0.83, 1.34) 1.02 (0.75, 1.38) 0.80 Cholesterol Number of cases 188 192 247 239 283 Macronutrient and age-adjusted 1.00 1.09 (0.88, 1.33) 1.32 (1.08, 1.61) 1.19 (0.96, 1.48) 1.36 (1.09, 1.71) 0.01 Multivariable adjusted 1.00 1.08 (0.88, 1.33) 1.30 (1.06, 1.59) 1.16 (0.94, 1.44) 1.28 (1.02, 1.61) 0.04 Citation Format: Caroline E. Boeke, A. Heather Eliassen, Wendy Y. Chen, Eunyoung Cho, Michelle D. Holmes, Bernard Rosner, Walter C. Willett, Rulla M. Tamimi. Dietary fat and cholesterol intake in relation to fatal breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 144. doi:10.1158/1538-7445.AM2013-144

Background: Body size early in life is inversely associated with incidence of pre and postmenopausal breast cancer, but its relationship with fatal breast cancer is unclear. We prospectively examined the association between childhood and adolescent body size and risk of fatal breast cancer. Methods: Study participants include 76,261 women from Nurses’ Health Study (NHS) and 112,388 from Nurses’ Health Study II (NHS II). Self-reported body size at ages 5, 10 and 20 years was assessed with a validated 9-figure drawing in 1988 (NHS) and 1989 (NHSII). The outcome was defined as invasive breast cancer that led to breast cancer death. Cause of death was obtained from death certificates. We observed 922 cases of incident fatal breast cancer over 20 years of follow-up. Cox proportional hazards regression was used to calculate hazard ratios (HR) and confidence intervals (CI) for body size at each age, average childhood (ages 5 & 10) and adolescent (ages 10 & 20) body size, and change in body size up to age 20. Fatal and non-fatal cases were censored at the date of diagnosis. Results: Women who were largest at age 5 were 32% less likely to develop fatal breast cancer as compared to women that were leanest (HR: 0.68, 95% CI: 0.50, 0.91; p-trend 0.15) or fatal vs. non-fatal (p-heterogeneity >0.20). Conclusion: Larger body size at ages 5, 10 and 20 is associated with lower risk of fatal breast cancer in adulthood independent of current BMI. The association does not appear to be driven by estrogen-related mechanisms. Cases N = 922 Person-years Age-adj. HR (95% CI) MV HR* (95% CI) MV +Current BMI HR (95% CI) Figure at age 5 years 1 370 1,034,245 1.00 (Reference) 1.00 (Reference) 1.00 (Reference) 2 243 922,357 0.92 (0.78, 1.09) 0.93 (0.79, 1.11) 0.93 (0.79, 1.10) 3 171 691,594 0.87 (0.73, 1.05) 0.89 (0.74, 1.07) 0.86 (0.71, 1.03) 4 84 390,941 0.72 (0.56, 0.91) 0.73 (0.57, 0.93) 0.69 (0.54, 0.87) ≥ 5 54 236,358 0.73 (0.55, 0.97) 0.73 (0.55, 0.98) 0.68 (0.50, 0.91) P for trend 0.001 0.002 Citation Format: Erica T. Warner, A. Heather Eliassen, Wendy Y. Chen, Michelle D. Holmes, Walter C. Willett, Rulla M. Tamimi. Childhood and adolescent body size and risk of fatal breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 130. doi:10.1158/1538-7445.AM2013-130

Background: The risk of breast cancer associated with longer-term use of both estrogen (ET) or estrogen + progesterone (E+P) hormone therapy (HT) cannot be determine from existing randomized controlled trials. Methods: The Nurses’ Health Study included 121,700 female registered nurses aged 30-55 in 1976 who have been followed with biennial questionnaires to medication use, risk factors and cancer incidence. Only postmenopausal women were included in this analysis. The main outcome was incidence of invasive breast cancer. We additionally evaluated the risk of fatal breast cancer (breast cancer diagnosis that resulted in breast cancer death). Results: During 1.57 million person-years of follow-up from 1980 through 2008, 5631 incident invasive breast cancers were diagnosed and 884 died of breast cancer. Breast cancer risk increased with duration of current E+P use without evidence for a plateau (e.g. RR 1.88 (95% CI 1.64-2.16) for 10-14.9 years and RR 2.35 (95% CI 1.90-2.92) for 15-19.9 years of use). More than 10 years of current ET use was also associated with increased breast cancer risk (RR 1.22 (95% CI 1.06-1.40) for 10-14.9 years and RR 1.43 (95% CI 1.22-1.68) for 15-19.9 years of use). Past E+P was also weakly associated with breast cancer risk. When the population was restricted to the same entry criteria as the Women's Health Initiative trial, we also observed a non-significant deceased risk of breast cancer HT with current ET use similar in magnitude to that seen in the trial (RR 0.61 (95% CI 0.63-1.05) for < 5 years and RR 0.93 (95% CI 0.76-1.14) for 5-9.9 years), but still observed an increased risk with current ET users of 15-19.9 years (RR 1.30 (95% CI 1.07-1.59). Effects were stronger for ER positive tumors and among thinner women. Results were similar when limited to women who underwent regular screening. Although breast cancer incidence was increased in these groups, there was no increase in the risk of fatal breast cancer with either E+P or ET use (RR 1.05 (95% CI 0.67-1.68) and RR 1.08 (0.80-1.46) for 10-19.9 years of current use respectively). Conclusions: Both past and current E + P users and current long-term ET users were at increased breast cancer risk. We did not observe an increase in fatal breast cancer with HT use. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-60. doi:1538-7445.AM2012-LB-60

Objective: Previous studies suggest a positive association between history of non-melanoma skin cancer (NMSC) and risk of subsequent cancer development. We prospectively investigate this association in both men and women. Methods: In two large cohorts in the US, the Health Professionals Follow-up Study (HPFS) and the Nurses’ Health Study (NHS), we prospectively examined the risks of primary cancer according to history of NMSC. In the HPFS, 876,094 person-years were followed up from June 1986 to June 2008. In the NHS, 2,358,185 person-years were followed up from June 1984 to June 2008. We documented 30,636 cancer cases after ongoing NMSC diagnosis. The median time (and range) of diagnosis between NMSC and subsequent cancer was 156 (3 - 342) months in the NHS, and 116 (3 - 259) months in the HPFS. Cox proportional hazard models were used to calculate relative risks (RRs) and 95% confidence intervals (CIs), adjusting for major cancer risk factors (e.g. age, smoking, body mass index, physical activity, etc). Results: A history of NMSC was associated with a higher risk of other primary cancers in men (RR = 1.15; 95% CI: 1.08, 1.21; P < 0.0001), and in women (RR = 1.25; 95% CI: 1.20, 1.31; P < 0.0001). For individual cancer sites, in men, a history of NMSC was associated with an increased risk of prostate cancer, non-Hodgkin lymphoma, and melanoma. In women, a history of NMSC was associated with an increased risk of breast cancer, endometrial cancer, ovarian cancer, lung cancer, non-Hodgkin lymphoma, renal cancer, melanoma, and oral cancer. Conclusions: Our prospective-cohort study provides evidence for an association between a history of NMSC and an increased risk of subsequent malignancies. Further studies are warranted to identify the potential mechanism underlying this relationship. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 636. doi:1538-7445.AM2012-636

Background: Fatigue is a common side effect of cancer treatment, but the longer terms effects of cancer diagnosis and treatment on fatigue are not well quantified. Study population: Participants from the prospective Nurses' Health Study who completed the Medical Outcomes Short-Form-36 (SF36) in 1992, 1996, and 2000. Outcomes: The 5-item Fatigue subscale from the SF36. A score of ≤ 50 is considered to represent fatigue: Results: 46,851 women without a history of cancer, 1015 women diagnosed with invasive breast cancer between 1984 and 1991, and 187 women diagnosed with in situ breast cancer between 1984 and 1991 were included in this analysis. All fatigue assessments were performed at least one year after diagnosis. Using the three time points, several fatigue trajectories were investigated including: persistently fatigued at all three time points, persistently non-fatigued at all time points, and developing fatigue over time. In age-adjusted analyses, the frequencies of the different fatigue trajectories were similar across the three groups: cancer free women, breast cancer survivors with invasive breast cancer, and survivors with in situ disease. That is, the chances of being persistently fatigued, persistently non-fatigued, or developing fatigue was similar across all three groups (p>0.09). Instead, the strongest predictor of fatigue trajectories was age. The prevalence of persistent fatigue and persistent non-fatigue varied strongly with age with a U-shaped curve (p Conclusions: After a cancer diagnosis, the prevalence of persistent fatigue or developing fatigue is similar comparing cancer-free women compared to breast cancer survivors. Self-assessments of fatigue appear to be more strongly related to age. Age needs to be carefully considered in all fatigue analyses and would provide a useful way to target interventions to improve fatigue. Citation Information: Cancer Prev Res 2011;4(10 Suppl):B22.

1502 Background: Although current use of hormone therapy (HT) is clearly associated with breast cancer risk, most studies have not seen an increased risk among past users of HT. However, the effect...

Background: Soy constituents possess anti-estrogenic and other anti-cancer properties. Soy food consumption has been associated with lower risk of development of breast cancer. However, the ability of soy isoflavones to bind to estrogen receptors, stimulate cell proliferation, and potentially interact with tamoxifen therapy, has raised concern about soy food consumption among breast cancer survivors. Two recent reports from China and one report from the US have suggested that postdiagnosis soy intake may improve prognosis among breast cancer survivors. Methods: We evaluated postdiagnosis soy food intake and breast cancer outcomes using data from the After Breast Cancer Pooling Project, which includes 18,312 women diagnosed with invasive primary breast cancer between ages 20 and 83 years and who participated in four prospective cohorts, three from the US and one from Shanghai, China. In two cohorts, information on soy food intake was assessed using food frequency questionnaires designed to capture soy food intake; two cohorts only collected information on two soy foods (tofu and soy milk), and multiple imputation was applied to derive total isoflavone intake based on information gathered by the US study with comprehensive assessment of soy intake. Delayed entry Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations of isoflavones with total mortality and breast cancer recurrence, adjusted for age at diagnosis, estrogen receptor/progesterone receptor status, stage, chemotherapy, radiotherapy, hormonal therapy, smoking, body mass index, exercise, race/ethnicity, and education and stratified by study. Analyses included 16,048 women with information on soy food intake. Results: After an average follow-up of 9.2 years, a total of 2,592 deaths and 2,622 recurrences were documented. Mean soy isoflavone intake (mg), as assessed at an average of 13 months postdiagnosis (range: 1-48 months), was 3.2 (standard deviation (SD)=5.8) for US women and 45.9 (SD=38.3) for Chinese women. Pooled analyses based on study-specific deciles showed that, compared with the lowest deciles, higher isoflavone intakes were associated with HRs in the range of 0.85-0.89 for mortality and 0.85-0.83 for recurrence (not all HRs were significant). Corresponding HRs restricted to only US cohorts ranged from 0.84-1.04 for mortality and 0.87-0.88 for recurrence, although none were significant. Using common cut-points for the pooled data including all cohorts, HRs (95% CIs) for the highest intake category (>23 mg/day) vs. the lowest (≤0.48 mg/day) were 0.91 (0.70-1.19) for mortality and 0.85 (0.66-1.11) for recurrence. Additional analyses conducted among non-Asian US women showed a similar pattern. Conclusions: Soy food consumption was not associated with an increased risk of mortality or cancer recurrence among breast cancer survivors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4665. doi:10.1158/1538-7445.AM2011-4665

Background: Of the two health-related quality of life domains measured by the SF-36 (mental health and physical health), the physical health score (PHS) has been associated with all cause mortality, and recently with additional breast cancer events. This PHS includes subscales for self-perceived physical functioning, general health, bodily pain, and role limitations due to physical problems and is known to be a marker for a number of co-morbidities. Methods: Three of the four cohorts that form the After Breast Cancer (ABC) Pooling Project measured health-related quality of life using the SF-36 after cancer diagnosis. These cohorts were the Women's Healthy Eating and Living (WHEL) Study, the Nurses’ Health Study (NHS), and the Shanghai Breast Cancer Survival Study (SBCSS). Using Cox proportional hazards models controlled for cancer stage and grade, we examined the relationship between PHS with disease-free and overall survival in 9387 early stage (I-III) breast cancer survivors. The post-diagnosis SF-36 measurement took place between 1991 and 2006 and the median follow-up time was 7.8 years. Poor physical health was defined as a non-normalized score of 76.4 as previously published by the WHEL study. We also report the association between PH and co-morbidities. Results: The pooled HR (95% CI) for additional breast cancer events was 1.27(1.12, 1.44) with significant findings in each of the two US cohorts: Nurses’ Health Study 1.31(1.07-1.61) and WHEL study 1.28(1.08-1.51). A similar effect size was seen in SBCSS only, with the measurement taken during or immediately after cancer treatment. However, mostly likely due to the much shorter follow-up in this study, it did not reach statistical significance (HR=1.22 95% CI 0.80-1.86). In all cohorts, low PHS was strongly associated with higher BMI. In overweight/obese WHEL participants, low compared to adequate PHS scores were significantly associated with much lower levels of physical activity (p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5021. doi:10.1158/1538-7445.AM2011-5021

Introduction: Overweight or obesity measured around breast cancer diagnosis has been consistently associated with decreased survival, however the data on post diagnosis weight gain and survival is sparser and less consistent. We conducted a pooled investigation of weight gain and survival using data from the After Breast Cancer Pooling Project (ABC Pooling Project). Methods: The ABC Pooling Project includes 18,336 breast cancer survivors from four prospective cohorts (three from the US and one from Shanghai, China) diagnosed between 1976 and 2006 with invasive primary breast cancer at ages 20-83 years. Delayed entry Cox proportional hazards models were used to estimate hazard ratios (HRs) and associated 95% confidence intervals (CIs) for the associations of weight gain with breast cancer death, death due to other causes and overall death, adjusted for age at diagnosis, race/ethnicity, menopausal status, hormone receptor status, stage, positive lymph nodes, smoking and treatment. Results: Average weight gain between pre-diagnosis and 18-48 months post diagnosis across all 4 cohorts was 1.6 kg and ranged from 0.9 – 3.4kg across individual cohorts. Moderate weight gain (3- 30(22.4%), while extreme weight gain (> 10kg) was slightly more prevalent among those with BMI over 30 compared to other BMI groups (8.6% for BMI >30 compared to 5.3% BMI < 25). Extreme weight gain when compared to women who remained weight stable (within 3 kg of pre-diagnosis weight) was significantly related to both overall death (HR 1.30, CI 1.07-1.58), death due to causes other than breast cancer (HR 1.65; 95% CI 1.15-2.36) but not to breast cancer death (1.17; 95% CI 0.93-1.49). Effects of extreme weight gain on overall death were predominantly seen in women whose BMI pre-diagnosis was < 25 (HR 1.48; 95% CI 1.09, 2.01), and in women who at study enrollment had no history of hypertension (HR 1.33; 95% CI 1.13, 1.71) or diabetes (HR 1.37 95% CI 1.10, 1.69). In contrast, effects of extreme weight gain on death due to causes other than breast cancer were seen predominantly in women whose pre-diagnosis BMI was between 25-30 and women who reported hypertension (HR 2.01; 95% CI 1.22-3.30) but not diabetes at baseline survey. Conclusion: Moderate weight gain of up to 10kg after a breast cancer diagnosis is more common among women who are normal or underweight than among women who are overweight or obese and does not result in poorer survival. Extreme weight gain of greater than 10kg occurs in less than 10% of the breast cancer survivors, is more frequent in obese women, and is associated with poor outcomes. Continued research into understanding both those most at risk for extreme weight gain and those most at risk for poorer outcomes due to extreme weight gain is warranted. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3722. doi:10.1158/1538-7445.AM2011-3722

Background: Night shift work has been classified by the International Agency for Research and Cancer and the World Health Organization as a probable carcinogen, presumably due to its effect on the melatonin pathway. Extensive laboratory and some human data also support that melatonin may influence breast cancer risk, although the mechanism is not clear. Both pharmacologic and physiologic doses of melatonin inhibit the growth of malignant cells of the breast in vitro and in animal models. Study Design: 95 postmenopausal women with a prior history of Stage 0-III breast cancer who had completed active cancer treatment (including hormonal therapy) were recruited to a double-blind randomized trial of 4 months of 3 mg melatonin daily compared to placebo. Endpoints included changes in breast cancer biomarkers, sleep, hot flashes, and mood. Results: 5 subjects on melatonin and 4 on placebo withdrew from the study or did not complete the 4 month assessment leaving 86 women (43 on placebo and 43 on melatonin) with evaluable data. Melatonin was well-tolerated without any grade 3/4 toxicity. At baseline, there was no statistical difference between the two arms for any of the endpoints or standard demographic characteristics. Mean age was 59 years (range 38-71) with mean 8 years since diagnosis. At 4 months, there were no statistically significant differences between the two groups for the biomarker endpoints (estradiol, IGF-1, IGFBP-3, or IGF-1/IGFBP-3 ratios), depressive symptoms, or hot flashes. However, subjects taking melatonin had significantly improved sleep quality, sleep duration, and total sleep scores compared with subjects taking placebo. Conclusions: Among postmenopausal women with a prior history of breast cancer, a 4 month course of 3 mg melatonin daily did not influence IGF-1, IGFBP-3 or estradiol levels. Effects of longer courses of melatonin and among premenopausal women are unknown. However, melatonin was effective in improving sleep quality among breast cancer survivors without any significant adverse effects. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-431.

572 Background: The Oncotype DX recurrence score (RS) independently predicts the likelihood of benefit from adjuvant chemotherapy. However, the clinical factors that influence chemotherapy recommendations in addition to RS are not well characterized. We sought to determine how clinicians integrate the RS and standard clinicopathologic data when choosing adjuvant chemotherapy. Methods: We identified women with ER+, HER2-, LN- breast cancer seen at DFCI in whom RS testing was performed between November 2004 and October 2008. Clinical and pathological characteristics, RS and chemotherapy treatment were identified from electronic medical records. A multivariable model was used to examine which factors drove the decision to administer chemotherapy. Results: RS was performed on 269 women with the following case distribution: RS low (30) 9%. Chemotherapy was given to 7% of women with low RS, compared to 42% and 86% of women with intermediate and high RS, respectively. Tumor grade, T stage, progesterone receptor expression and RS were associated with receipt of chemotherapy in univariate analyses but age, LVI and menopausal status were not. In a multivariable logistic regression model, tumor grade, size, and RS were independent predictors of chemotherapy administration. Conclusions: Oncotype DX RS plays a critical role in medical decision making for women with early stage breast cancer at this single academic institution. However, other tumor and clinical features independently contribute to chemotherapy decisions, suggesting that tailored treatment does, and should, integrate both traditional and molecular pathological factors. [Table: see text] No significant financial relationships to disclose.

Background The use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) is widespread for treatment of common symptoms such as headaches, muscular pain, and inflammation. In addition, the chemopreventive use of NSAIDs is increasingly common for heart disease and colon cancer. Evidence of a protective association with breast cancer risk has been inconsistent, and few data exist for premenopausal women. Methods We assessed the associations for use of aspirin, other NSAIDs, and acetaminophen with breast cancer risk among premenopausal women in the prospective Nurses' Health Study II. In total, 112 292 women, aged 25 to 42 years and free of cancer in 1989, were followed up until June 2003. Multivariate relative risks and 95% confidence intervals were calculated by Cox proportional hazards models, adjusting for age and other important breast cancer risk factors. Results Overall, 1345 cases of invasive premenopausal breast cancer were documented. Regular use of aspirin (≥2 times per week) was not significantly associated with breast cancer risk (relative risk, 1.07; 95% confidence interval, 0.89-1.29). Regular use of either nonaspirin NSAIDs or acetaminophen also was not consistently associated with breast cancer risk. Results did not vary by frequency (days per week), dose (tablets per week), or duration of use. Furthermore, associations with each drug category did not vary substantially by estrogen and progesterone receptor status of the tumor. Conclusion These data suggest that the use of aspirin, other NSAIDs, and acetaminophen is not associated with a reduced risk of breast cancer among premenopausal women.

Abstract #3137 Background: The epitholones are a new class of antineoplastic agents which are microtubule inhibitors with low susceptibility to several mechanisms of drug resistance. Ixabepilone (BMS-247550, aza-epothilone B) has demonstrated efficacy as monotherapy or in combination with capecitabine (in anthracycline- and taxane-pretreated metastatic breast cancer) and has recently been approved for use in refractory breast cancer. A multicenter NCI-sponsored study was conducted to analyze the safety and efficacy of the combination of ixabepilone with trastuzumab in patients with metastatic HER2-positive breast cancer. Methods: This phase II nonrandomized study enrolled two cohorts of patients. Cohort 1 received no prior chemotherapy or trastuzumab for metastatic disease and cohort two received one or two prior trastuzumab-containing regimens for metastatic disease. Patients in each cohort received the same treatment regimen of ixabepilone and trastuzumab. Patients received ixabepilone 40 mg/m2 as a 3-hour continuous infusion on day 1 of a 21-day cycle plus trastuzumab once every 21 days. For the initial treatment of trastuzumab, patients received 8 mg/kg IV, and for all subsequent trastuzumab treatments 6 mg/kg. Treatment was continued until disease progression or unacceptable toxicity. Endpoints included response rate (RR), time to progression (TTP), toxicity, and predictive biomarkers. Results: 39 women entered the study (median age 51, range 29-74) with 15 patients in cohort 1 and 24 patients in cohort 2. A median of 7 cycles of therapy were administered in each cohort. In cohort 1, there were 12 partial responses (PR), and 1 patient with stable disease for 5 months (SD). In cohort 2, there were 8 PRs and 9 patients with SD. Across both cohorts, the overall RR was 51%, with a clinical benefit rate (CR + PR + SD for at least 6 months) of 56%. Treatment-related toxicities included neuropathy (grade ≥2, 55%), myalgias (grade ≥2, 20%), anemia (grade ≥2, 18%), neutropenia (grade ≥2, 23%), and elevated transaminases (grade ≥2, 10%). There were no episodes of grade 2 or higher cardiac toxicity. Biomarker data will be presented. Conclusion: This represents the first study of the combination of ixabepilone with trastuzumab for the treatment of metastatic HER2-positive breast cancer. These results suggest that the combination has an encouraging response rate as first- and subsequent- line therapy for metastatic breast cancer. Clinically significant neuropathy was the major toxicity, and appeared to be cumulative. Based on these results, further evaluation of ixabepilone plus trastuzumab is warranted. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3137.