Dietary factors protective against breast cancer in Japanese premenopausal and postmenopausal women

Since components of the Japanese diet that might be responsible for the relatively low breast cancer incidence rates observed in Japan have not been clarified in detail, a case-referent study with reference to menopausal status was conducted using data from the hospital-based epidemiologic research program at Aichi Cancer Center (HERPACC). In total, 2,385 breast cancer cases were included, and 19,013 women, confirmed as free of cancer, were recruited as the reference group. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were determined by multiple logistic regression analysis. There were reductions in risk associated with high intake of milk and green-yellow vegetables (green leafy vegetables, carrots and pumpkins) among both pre- and postmenopausal women. The protective effects of the Japanese diet were more prominent among postmenopausal than premenopausal women. The adjusted OR of fish consumption (5 or more times per week vs. fewer than 3 times per month) was 0.75 (95% CI 0.57-0.98, p(trend) = 0.01) for postmenopausal breast cancer. A significant decrease in postmenopausal breast cancer risk was also observed for increasing intake of fruit (OR = 0.61, 95% CI 0.41-0.91). Thus, traditional Japanese dietary factors may protect against breast cancer development, especially among postmenopausal women.     

Androgens and breast cancer in premenopausal women

We investigated the role of androgens in premenopausal breast cancer by comparing serum testosterone, dihydrotestosterone, androstenedione, dehydroepiandrosterone sulfate, progesterone, sex-hormone-binding globulin-binding capacity, and urinary testosterone and androstanediol in 63 women with breast adenocarcinoma and 70 healthy controls of similar age. With variables dichotomized at the 75th percentile, the age-adjusted relative risk was 3.4 (95% confidence interval, 1.6-7.3) for high versus low levels of serum testosterone, 2.1 (0.9-4.8) for urinary testosterone, and 2.5 (1.1-5.9) for serum dihydrotestosterone. We observed no differences in other hormones. The strength of the associations changed markedly with increasing time to the onset of the next menses. The risk for testosterone and dihydrotestosterone, which was negligible in women with onset within 5 days of sampling, increased progressively to nearly 10-fold higher than in unstratified data in women with onset 10 days or more after sampling. This study provides arguments in favor of a role for increased androgenic activity in premenopausal breast cancer. It also suggests that unknown factors related to cycle length may be important in modulating the strength of the association with testosterone. The results are discussed also in reference to possible biases and inadequacies in study design.     

Impact of breast cancer family history on tumor detection and tumor size in women newly-diagnosed with invasive breast cancer

This study evaluated the impact of family history (FH) on tumor detection, the patient’s age and tumor size at diagnosis in breast cancer (BC). Furthermore, we investigated whether the impact of FH on these features was dependent on degree of relationship, number of relatives with a BC history, or the age of the affected relative at the time that her BC was diagnosed. Out of the entire cohort (n = 1,037), 244 patients (23.5 %) had a positive FH; 159 (15.3 %) had first-degree relatives affected with BC and 85 patients (8.2 %) had second-degree affected relatives. Compared to women who had no BC-affected relatives, the tumors of women who had positive FH were more often found by radiological breast examination (RBE: 31.7 %/27.2 %, p = 0.008), and they were smaller (general tumor size: 21.8 mm/26.4 mm, p = 0.003; size of tumors found by breast self-examination (BSE): 26.1 mm/30.6 mm, p = 0.041). However, this positive effect of increased use of BC screening and smaller tumor sizes was only observed in patients whose first-degree relatives were affected (comparison with second-degree affected relatives: RBE: 43.8 %/24.7 %; odds ratio 2.38, p = 0.007; general tumor size: 19.3 mm/26.3 mm; mean difference (MD) ?6.9, p = 0.025; tumor size found by BSE: 22.5 mm/31.0 mm; MD ?8.5, p = 0.044). When more second-degree relatives or older relatives were diagnosed with BC, the tumors of these patients were similarly often detected by RBE (relationship: 24.7 %/27.2 %, p = 0.641; age: 33.7 %/27.2 %, p = 0.177) and had similar tumor sizes (general size: 26.3 mm/26.4 mm, p = 0.960; BSE: 31.0 mm/30.6 mm, p = 0.902) as those of women without a FH. Women with a positive FH generally use mammography screening more often and perceive changes in the breast earlier than women without such history. The increased awareness of BC risk decreases if the relationship is more distant.     

Birth size in the most recent pregnancy and maternal mortality in premenopausal breast cancer by tumor characteristics

The main aim of this study was to investigate possible associations between measures of offspring size at birth in the most recent pregnancy before premenopausal breast cancer diagnosis and the risks of maternal breast cancer mortality, taking tumor characteristics into account. We also aimed to investigate if these associations are modified by age at childbirth, time since childbirth, parity, and age at diagnosis. We followed 6,019 women from their date of premenopausal breast cancer (diagnosed from 1992 to 2008) until emigration, death or December 31st, 2009, whichever occurred first. We used Cox proportional hazard regression models, adjusted for parity, age at diagnosis, and education level, to estimate associations between women pregnancy, cancer characteristics and offspring birth characteristics, and mothers’ mortality risk. In stratified analyses, mortality risks were estimated by tumor stage, ER or PR status. There was no association between offspring birth weight (HR = 1.00, 95 % CI 0.99–1.01, when used as a continuous variable), birth weight for gestational age or ponderal index, and premenopausal breast cancer mortality. Similarly, in analyses stratified by tumor stage, receptor status, and time difference between last pregnancy and date of diagnosis, we found no associations between birth size and breast cancer mortality. Our findings suggest that the hypothesis that “premenopausal breast cancer mortality is associated with offspring birth characteristics in the most recent pregnancy before the diagnosis” may not be valid. In addition, these associations are not modified by tumor characteristics.     

Physical activity and risk of breast cancer in premenopausal women

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 in >or=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 the <3 MET-h week(-1) category. Among women with a BMI >or=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 for >or=27 vs <9 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.     

Estrogen profiles of premenopausal women with breast cancer

Population surveys have demonstrated an inverse relationship between breast cancer incidence rates and the urine "estriol ratio," the concentration of estriol relative to the sum of the concentrations of estrone and estradiol. In this study, the urine estriol ratio was evaluated in premenopausal breast cancer patients and control women from Boston and San Francisco. Although at least 2 years had passed since last use of oral contraceptives, women with a history or oral contraceptive use for 19 months or longer excreted estrogen in low concentrations compared to nonusers and so were excluded. Among the remaining 73 cases and 55 controls, the cases had lower estriol ratios and higher estrone and estradiol levels than did controls. However, these differences, which averaged about 10%, were not statistically significant. Thus the hypothesis that a low estriol ratio is a cause of breast cancer is given only minimal support. Among women in their 40's, the excretion of estrogens is subject to many influences and is difficult to study. The many determinants of estrogen excretion, including age and oral contraceptive use, should be accommodated in the design of future studies of the estriol ratio.     

Plasma amino acid profiles are associated with biomarkers of breast cancer risk in premenopausal Japanese women

Objective

Recently, profiles of plasma amino acids have been utilized to detect diseases including breast cancer. However, there is a possibility that the amino acid status may be associated with the risk of breast cancer. We investigated the relationship of plasma levels of amino acids with levels of sex hormones and insulin-like growth factor (IGF)-1, which are relevant to the etiology of premenopausal breast cancer, in normal premenopausal women.

Methods

Participants were 350 Japanese women who had regular menstrual cycles less than 40-day long. Fasting plasma samples were assayed for estradiol, testosterone, dehydroepiandrosterone sulfate, sex-hormone-binding globulin (SHBG), and IGF-1. A total of 20 amino acids in plasma were quantified by liquid chromatography–mass spectrometry. Information on lifestyle and reproductive factors was obtained using a self-administered questionnaire.

Results

The plasma arginine level was significantly inversely correlated with plasma levels of total and free estradiol and IGF-1 after adjusting for age, body mass index, and phase of the menstrual cycle. Plasma leucine and tyrosine levels were significantly positively correlated with the free testosterone level. The ratio of plasma asparagine to the total amino acids was significantly positively correlated with SHBG level.

Conclusions

Plasma levels of some specific amino acids, such as arginine, leucine, tyrosine, and asparagine, were associated with the levels of sex hormones, SHBG, or IGF-1 in premenopausal women. However, the present cross-sectional study cannot provide a cause–effect relation. The implication of amino acids in the etiology of breast cancer needs to be addressed in future studies.     

Endogenous sex hormones and subsequent breast cancer in premenopausal women

Because of large intra-individual variation in hormone levels, few studies have investigated the relation of serum sex hormones to breast cancer (BC) in premenopausal women. We prospectively studied this relation, adjusting for timing of blood sampling within menstrual cycle. Premenopausal women (5,963), recruited to the Hormones and Diet in the Etiology of Breast Tumors (ORDET) cohort study, provided a blood sample in the 20-24th day of their menstrual cycle. After 5.2 years of follow-up, 65 histologically confirmed BC cases were identified and matched individually to 4 randomly selected controls. Sera, stored at -80 degrees C, were assayed blindly for dehydroepiandrosterone sulfate, total and free testosterone (FT), androstenedione, androstanediol-glucoronide, progesterone, 17-OH-progesterone, sex hormone-binding globulin, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Fifty-five cases had information for multivariate analyses. Compared to controls, BC cases had shorter cycles and intervals between blood sampling and bleeding, and lower LH and FSH. FT was significantly associated with BC risk: relative risk (RR; adjusted for age, body mass index and ovarian cycle variables) of highest vs. lowest tertile was 2.85 [95% confidence interval (CI) = 1.11-7.33, p for trend = 0.030]. Progesterone was inversely associated with adjusted RR for highest vs. lowest tertile of 0.40 (95% CI = 0.15-1.08, p for trend = 0.077), significantly so in women with regular menses, where adjusted RR was 0.12 (95% CI = 0.03-0.52, p for trend = 0.005). These findings support the hypothesis that ovarian hyperandrogenism associated with luteal insufficiency increases the risk of BC in premenopausal women.     

Dual effect of parity on breast cancer risk in African-American women

BACKGROUND: In the United States, breast cancer incidence is higher among African-American women than among white women before age 45 but lower at older ages. To explore whether differences in childbearing patterns can explain this observation, we assessed the relation of several childbearing variables to breast cancer risk in a large prospective cohort study of U.S. African-American women. METHODS: Black Women's Health Study participants were enrolled in 1995 and were followed by mailed questionnaires every 2 years (in 1997 and 1999). Of the 64,500 women enrolled, 56,725 (88%) completed at least one of the follow-up questionnaires. During 214,862 person-years of follow-up, participants reported 349 breast cancers, of which 128 were among women younger than 45 years and 221 were among women aged 45-70 years. Incidence rate ratios (IRRs) with 95% confidence intervals (CIs) were derived from age-stratified Cox regression models that adjusted for each of the childbearing variables (parity, age at first birth, and time since last birth). RESULTS: Compared with primiparity, high parity was associated with an increased risk of breast cancer among women younger than 45 years (IRR for four or more births = 2.4, 95% CI = 1.1 to 5.1) and a decreased risk among women aged 45 years and older (IRR = 0.5, 95% CI = 0.3 to 0.9). The IRR for late age at first birth compared with early age was 2.5 (95% CI = 1.1 to 5.8) among the younger women and was not elevated among older women. We found no statistically significant association of time since last birth with breast cancer risk among either younger or older women. CONCLUSIONS: Parity has a dual association with breast cancer risk in African-American women; among women younger than 45 years, parity is associated with an increased risk and among women 45 years and older it is associated with a decreased risk. This dual effect may explain some of the observed differences in breast cancer incidence rates among African-American and white women.     

Impact of established risk factors for breast cancer in nulligravid Japanese women

BACKGROUND: The mechanism by which pregnancy impacts breast cancer risk remains poorly understood. There is a need for detailed quantification of risk in nulliparous women. We therefore have undertaken a case-referent study of breast cancer employing data from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC), Japan, examining the impact of reproductive and anthropometric factors on breast cancer risk among nulligravid women compared with their parous counterparts. METHODS: In total, 2032 breast cancer cases were included, and 17848 women, confirmed as free of cancer, were recruited as a reference group. Odds ratios (OR) and 95% confidence intervals (95% CI) were determined by multiple logistic regression analysis. RESULTS: A protective effect of later age at menarche was observed among parous women, but it did not alter risk in nulligravid cases. The risk increment with a family history appeared to be most pronounced among premenopausal cases with no history of pregnancy (OR=2.68, 95% CI: 1.41-5.11). Among postmenopausal women, positive associations with height and current body mass index (BMI) in the nulligravid group were similar to those observed in the parous group. The present study indicated that age at menopause, family history in premenopausal women, and height and obesity in postmenopausal women seemed to exert more influence in nulligravid women. Formal tests for interaction between maternity status and these factors, however, did not prove statistically significant. CONCLUSION: Our findings suggest that established risk factors for breast cancer have an additive impact with nulligravid status. Thus, it is implied that obesity control for all women, including nulliparous individuals, is important from a practical viewpoint for primary breast cancer prevention.     

Plasma leptin levels and risk of breast cancer in premenopausal women

Body mass index (BMI) is inversely related to the risk of premenopausal breast cancer, but the underlying biological mechanisms of this association are poorly understood. Leptin, a peptide hormone produced primarily by adipocytes, is a potential mediator of the BMI association because BMI and total body fat are positively associated with circulating leptin levels and leptin and its receptor are overexpressed in breast tumors. We conducted a prospective case-control study nested within the Nurses' Health Study II cohort examining the association between plasma leptin levels in premenopausal women and breast cancer risk. Leptin was measured in blood samples collected between 1996 and 1999. The analysis included 330 incident breast cancer cases diagnosed after blood collection and 636 matched controls. Logistic regression models, controlling for breast cancer risk factors, were used to calculate ORs and 95% CIs. After adjustment for BMI at age 18, weight change since age 18 to blood draw, and other breast cancer risk factors, plasma leptin levels were inversely associated with breast cancer risk (OR for top vs. bottom quartile = 0.55; 95% CI = 0.31-0.99; P(trend) = 0.04). Adjustment for BMI at blood draw attenuated the association (OR = 0.69; 95% CI = 0.38-1.23; P(trend) = 0.26). Our results suggest that leptin may be inversely associated with breast cancer risk, but it is unclear whether any part of this association is independent of BMI.     

Individualization of breast cancer based on histopathological features and molecular alterations

Histopathological findings and molecular alterations well reflect the biological properties of individual primary breast carcinomas. Specifically, pT (size of the invasive component), pN (number of metastatic lymph nodes), histological or nuclear grade, lymphovascular invasion, hormone receptors, and HER2 (c-erbB-2) gene overexpresison or amplification are known to be effective markers for assessing the risk of operable primary breast carcinoma, albeit incompletely. It is expected that additional molecular markers and novel diagnostic tools will be developed in the future to facilitate a more accurate characterization of higher risk node-negative breast carcinomas. This article is based on a presentation delivered at Presidential Symposium 1, “Breast cancer: individualized diagnosis for tailored treatment,” held on 29 June 2007 at the 15th Annual Meeting of the Japanese Breast Cancer Society in Yokohama.     

Impact of sentinel node tumor burden on outcome of invasive breast cancer patients

Background

The tumor status of the axillary lymph nodes is one of the most important prognostic factors in women with early breast cancer (BC). Sentinel lymph node (SLN) biopsy has become the standard staging procedure for patients with invasive BC, largely replacing axillary lymph nodes dissection (ALND). The exact impact on prognosis of SLN tumor burden is still object of controversy. The aim of this study was to correlate the tumor burden in the SLN with the outcome in a large cohort of women.

Patients and methods

1040 consecutive patients with clinical stage I–III invasive BC were prospectively collected on our Institutional BC database from January 2001 to January 2007. Patients were stratified into the following four groups based on the tumor burden of the SLN: macrometastases, tumor deposit ≥2 mm; micrometastases, tumor deposit ≥0.2 mm and <2 mm; isolated tumor cells (ITC), isolated tumor cells or tumor deposit <0.2 mm; negative, in case of patients with no evidence of tumor.

Results

At a median follow-up of 8.5 years, the tumor burden of SLN metastases resulted significant predictor of DFS (P < 0.0001) and OS (P = 0.042). Multivariate analysis showed that the tumor burden of SLN metastases and Ki 67 proliferative index maintained the statistical significance.

Conclusion

Patients with SLN micrometastases or ITC, do not seem to have a worse DFS or OS compared with SLN negative cases. There is a significant decrease in DFS and OS in patients with macrometastatic disease in the SLN.     

Salivary oestradiol and progesterone levels in premenopausal women with breast cancer

The concentrations of oestradiol and progesterone have been measured in salivary specimens collected daily over a complete menstrual cycle in 12 patients with operable breast cancer and 12 normal control volunteers. There was no significant difference (P >0.05) for either hormone between these two groups. Both showed a mid-cycle rise in oestradiol levels followed by a smaller but sustained increase during the luteal phase. The progesterone concentration increased markedly during the luteal phase of the cycle.Total or non-protein bound oestradiol levels measured in blood samples from 19 normal women were both linearly correlated (P < 0.001) with the concentration of oestadiol in matched saliva samples. The amount of free oestradiol in blood was about twice that found in saliva.     

Differences in breast cancer risk factors by tumor marker subtypes among premenopausal Vietnamese and Chinese women.

We evaluated associations between reproductive and lifestyle risk factors with breast cancer tumor marker status in a case-control study. Cases were premenopausal women living in Vietnam and China who were eligible for a clinical trial of oophorectomy and tamoxifen as treatment for breast cancer (n = 682). Controls were nonrelative hospital visitors, matched on age to the cases (n = 649). Immunohistochemical analysis was used to identify the presence of estrogen receptor (ER) and progesterone receptor and the overexpression of HER-2/neu oncogene. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using unconditional logistic regression, adjusted for known confounders. Overall, 280 (61%) tumor samples were ER positive and 176 (38%) were ER negative. HER-2/neu overexpression was detected in 161 (35%) samples, whereas 286 (26%) samples were HER-2/neu negative. We observed an inverse trend between increasing parity and decreasing breast cancer risk (P = 0.002). Women ages > or =25 years at first birth had increased breast cancer risk compared with women ages <25 years at first birth (OR, 1.53; 95% CI, 1.20-1.95). Women who consumed alcohol had increased risk of breast cancer compared with women who did not (OR,1.85; 95% CI, 1.32-2.61). Compared with controls, OR estimates for breast cancer by parity and age at first birth were significantly associated with ER and/or HER-2/neu tumor status by Wald test (P < 0.05). Family history, age at menarche, cumulative lactation, body mass index, and education were not significantly related to breast cancer risk. Our findings support the hypothesis that some breast cancer risk factors differ by ER and HER-2/neu tumor marker subtypes.     

Cyclical tumour variations in premenopausal women with early breast cancer

The hormonal milieu at the time of tumour excision may have a significant impact on survival in premenopausal patients with breast cancer, with those undergoing surgery between days 3 and 12 of the menstrual cycle having a worse prognosis. To investigate possible mechanisms which might explain this finding, histological features of tumours from 363 patients included in two studies from Guy's Hospital have been reviewed. Axillary nodal involvement occurred in 71/115 (62%) of patients whose primary tumour was excised between days 3 and 12 of the cycle, compared with 116/248 (47%) of patients undergoing surgery at other phases of the cycle (χ² = 7.04, P < 0.01). Vascular invasion was observed in 54/115 (47%) of primary tumours removed between days 3 and 12 and 82/248 (33%) of tumours removed at other times (χ² = 6.47, P < 0.02). Multivariate analysis of factors influencing survival indicated that both axillary nodal status and phase of the cycle were highly significant independent predictors of prognosis.