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Ductal carcinoma in situ (DCIS) lesions are non-invasive tumours of the breast that are thought to precede most invasive breast cancers (IBCs). As individual DCIS lesions are initiated, grow and invade (i.e. become IBC), the size distribution of the DCIS lesions present in a given human population will evolve. We derive a differential equation governing this evolution and show, for given assumptions about growth and invasion, that there is a unique distribution which does not vary with time. Further, we show that any initial distribution converges to this stationary distribution exponentially quickly. Therefore, it is reasonable to assume that the stationary distribution governs the size of DCIS lesions in human populations which are relatively stable with respect to the determinants of breast cancer. Based on this assumption and the size data of 110 DCIS lesions detected in a mammographic screening programme between 1993 and 2000, we produce maximum likelihood estimates for certain growth and invasion parameters. Assuming that DCIS size is proportional to a positive power p of the time since tumour initiation, we estimate p to be 0.50 with a 95% confidence interval of (0.35, 0.71). Therefore, we estimate that DCIS lesions follow a square-root growth law and hence that they grow rapidly when small and relatively slowly when large. Our approach and results should be useful for other mathematical studies of cancer, especially those investigating biological mechanisms of invasion., (© The Authors 2013. Published by Oxford University Press on behalf of the Institute of Mathematics and its Applications. All rights reserved.)

Objective: To determine the factors associated with symptom-detected breast cancers in a population offered screening., Methods: We interviewed 1,459 Australian women aged 40-69, 946 with symptom-detected and 513 with mammogram-detected invasive breast cancers ≥ 1.1 cm in diameter about their personal, mammogram, and breast histories before diagnosis and reviewed medical records for tumor characteristics and mammogram dates, calculating ORs and 95% confidence intervals (CIs) for symptom- versus mammogram-detected cancers in logistic regression models., Results: Lack of regular mammograms (<2 mammograms in the 4.5 years before diagnosis) was the strongest correlate of symptom-detected breast cancer (OR = 3.04 for irregular or no mammograms). In women who had regular mammograms (≥ 2 mammograms in the 4.5 years before diagnosis), the independent correlates of symptom-detected cancers were low BMI (OR < 25 kg/m(2) vs. ≥ 30 kg/m(2) = 2.18, 95% CI 1.23-3.84; p = 0.008), increased breast density (available in 498 women) (OR highest quarter vs. lowest = 3.50, 95% CI 1.76-6.97; p (trend) = 0.004), high-grade cancer, and a larger cancer (each p < 0.01). In women who did not have regular mammograms, the independent correlates were age <50 years, a first cancer, and a ≥ 2-cm cancer. Smoking appeared to modify the association of symptom-detected cancer with low BMI (higher ORs for low BMI in current smokers) and estrogen receptor (ER) status (higher ORs for low BMI in ER cancers)., Conclusion: Women with low BMI may benefit from a tailored approach to breast cancer detection, particularly if they smoke.

Unlabelled: The evidence that mutations in the HFE gene for hemochromatosis are associated with increased cancer risk is inconsistent. The Melbourne Collaborative Cohort Study is a prospective cohort study that commenced recruitment in 1990. Participants born in Australia, New Zealand, the United Kingdom, or Ireland (n = 28,509) were genotyped for the HFE C282Y (substitution of tyrosine for cysteine at amino acid 282) variant. Incident cancers were ascertained from Australian cancer registries during an average of 14 years follow-up. Hazard ratios (HRs), confidence intervals (CIs), and P values were obtained from separate Cox regression analyses for colorectal, breast, and prostate cancers, all other solid cancers, and all cancers. Compared to those with no C282Y variant, C282Y homozygotes were at increased risk of colorectal cancer (HR = 2.28; 95% CI = 1.22, 4.25; P = 0.01) and female C282Y homozygotes were at increased risk of developing breast cancer (HR = 2.39; 95% CI = 1.24, 4.61; P = 0.01), but male C282Y homozygotes were not at increased risk for prostate cancer (HR = 0.96; 95% CI = 0.43, 2.15; P = 0.92). C282Y/H63D compound heterozygotes were not at increased risk for colorectal cancer (HR = 1.27; 95% CI = 0.80, 2.01), breast cancer (HR = 1.16; 95% CI = 0.74, 1.84), or prostate cancer (HR = 1.08; 95% CI = 0.68, 1.70)., Conclusion: HFE C282Y homozygotes have twice the risk of colorectal and breast cancer compared with those individuals without the C282Y variant.

Background: Mortality/incidence predictions are used for allocating public health resources and should accurately reflect age-related changes through time. We present a new forecasting model for estimating future trends in age-related breast cancer mortality for the United States and England-Wales., Methods: We used functional data analysis techniques both to model breast cancer mortality-age relationships in the United States from 1950 through 2001 and England-Wales from 1950 through 2003 and to estimate 20-year predictions using a new forecasting method., Results: In the United States, trends for women aged 45 to 54 years have continued to decline since 1980. In contrast, trends in women aged 60 to 84 years increased in the 1980s and declined in the 1990s. For England-Wales, trends for women aged 45 to 74 years slightly increased before 1980, but declined thereafter. The greatest age-related changes for both regions were during the 1990s. For both the United States and England-Wales, trends are expected to decline and then stabilize, with the greatest decline in women aged 60 to 70 years. Forecasts suggest relatively stable trends for women older than 75 years., Conclusions: Prediction of age-related changes in mortality/incidence can be used for planning and targeting programs for specific age groups. Currently, these models are being extended to incorporate other variables that may influence age-related changes in mortality/incidence trends. In their current form, these models will be most useful for modeling and projecting future trends of diseases for which there has been very little advancement in treatment and minimal cohort effects (eg. lethal cancers).

Rates of large breast cancers should decrease in a population that is offered mammography screening, but women continue to present with them. We sought an explanation in a population-based epidemiological study of 1,459 women diagnosed with invasive breast cancer in 2002-2003 in Australia; breast cancers were > or =2 cm in 766 women (53%) and 11-1.9 cm in a comparison group (693, 47%). We interviewed the women about their personal, mammogram and breast histories in the years before diagnosis and collected biological characteristics of tumors and mammogram dates from medical records. The strongest correlate of breast cancer size at diagnosis was the method of detection: the odds of a > or =2 cm breast cancer was substantially lower for detection by a screening mammogram (OR = 0.27, 95% CI 0.21-0.34; p < 0.001) than for detection after a breast symptom. Higher BMI (ORs approximately 1.6 for > or =25 kg/m(2)), higher cancer grade (ORs of 1.6 for moderate, 2.89 for high grade) and lobular type (OR 2.09, 95% CI 1.45-3.0) were also independent correlates (p < 0.001) of a > or =2 cm breast cancer. HRT use strongly reduced the odds but only in cancers detected after a breast symptom (OR = 0.49, 95% CI 0.33-0.74; p = 0.002), not in those detected by a screening mammogram. As assessed from their proportional contribution to > or =2 cm breast cancers in our study population, lack of mammogram detection, BMI > or =25 kg/m(2) and moderate or high grade of the cancer were the most important factors with population attributable fractions of 42%, 11% and 29% respectively; the first 2 are amenable to intervention., ((c) 2008 Wiley-Liss, Inc.)

It is possible that the performance of mammographic screening would be improved if it is targeted at women at higher risk of breast cancer or who are more likely to have their cancer missed at screening, through more intensive screening or alternative screening modalities. We conducted a case-control study within a population-based Australian mammographic screening program (1,706 invasive breast cancers and 5,637 randomly selected controls). We used logistic regression to examine the effects of breast density, age, and hormone therapy use, all known to influence both breast cancer risk and the sensitivity of mammographic screening, on the risk of small (15 mm) screen-detected and interval breast cancers. The risk of small screen-detected cancers was not associated with density, but the risk of large screen-detected cancers was nearly 3-fold for the second quintile and approximately 4-fold for the four highest density categories (third and fourth quintiles and the two highest deciles) compared with the lowest quintile. The risk of interval cancers increased monotonically across the density categories [highest decile odds ratio (OR), 4.65; 95% confidence interval (95% CI), 2.96-7.31]. The risk of small and large screen-detected cancers, but not interval cancers, increased with age. After adjusting for age and density, hormone therapy use was associated with a moderately elevated risk of interval cancers (OR, 1.43; 95% CI, 1.12-1.81). The effectiveness of the screening program could be improved if density were to be used to identify women most likely to have poor screening outcomes. There would be little additional benefit in targeting screening based on age and hormone therapy use.

Accurate estimates of future age-specific incidence and mortality are critical for allocation of resources to breast cancer control programmes and evaluation of screening programmes. The purpose of this study is to apply functional data analysis techniques to model age-specific breast cancer mortality time trends, and forecast entire age-specific mortality functions using a state-space approach. We use annual unadjusted breast cancer mortality rates in Australia, from 1921 to 2001 in 5 year age groups (45 to 85+). We use functional data analysis techniques where mortality and incidence are modelled as curves with age as a functional covariate varying by time. Data are smoothed using non-parametric smoothing methods then decomposed (using principal components analysis) to estimate basis functions that represent the functional curve. Period effects from the fitted coefficients are forecast then multiplied by the basis functions, resulting in a forecast mortality curve with prediction intervals. To forecast, we adopt a state-space approach and an automatic modelling framework for selecting among exponential smoothing methods.Overall, breast cancer mortality rates in Australia remained relatively stable from 1960 to the late 1990s, but have declined over the last few years. A set of four basis functions minimized the mean integrated squared forecasting error and account for 99.3 per cent of variation around the mean mortality curve. Twenty year forecasts suggest a continuing decline, but at a slower rate, and stabilizing beyond 2010. Forecasts show a decline in all age groups with the greatest decline in older women. The proposed methods have the potential to incorporate important covariates such as hormone replacement therapy and interventions to represent mammographic screening. This would be particularly useful for evaluating the impact of screening on mortality and incidence from breast cancer., (Copyright (c) 2005 John Wiley & Sons, Ltd.)

Background and Methodology: Late 'age at menopause' is a recognised risk factor for postmenopausal breast cancer and is also associated with decreased use of hormone replacement therapy (HRT). When investigating the association between HRT use and breast cancer risk it is therefore necessary to adjust for the potential confounder, 'age at menopause'. 'Age at menopause', however, cannot be determined for women with a hysterectomy and ovarian conservation. Using data on 13 357 postmenopausal women in whom 396 cases of invasive breast cancer were diagnosed during 9 years of follow-up from the Melbourne Collaborative Cohort Study, we compared the estimates of relative risk of HRT use for breast cancer for three different methods of dealing with missing data: complete-case analysis, single imputation and multiple imputation., Results: 'Age at menopause' was missing for 17% of the data. Both HRT use and 'age at menopause' were significant risk factors for breast cancer, although 'age at menopause' only marginally confounded the estimates of risk for HRT. Women with 'age at menopause' missing did not represent a random sample of the population. Complete-case analyses resulted in higher estimates of the risk associated with HRT use compared with the different methods of imputation., Discussion and Conclusions: We recommend that analyses investigating the association between HRT and breast cancer should present the results in two ways: excluding women with 'age at menopause' missing and including the women using multiple imputation. For both methods, estimates of risk, with and without the adjustment of 'age at menopause', should be given.

Background: At least one-third of primary breast cancers in Australia are discovered by population-based mammographic screening. The aim of this study was to determine whether there were any differences in the surgical treatment of women diagnosed with breast cancer by BreastScreen Victoria between urban and rural populations and to investigate temporal changes in their pattern of care., Methods: An analysis of women diagnosed with breast cancer (invasive and non-invasive) by BreastScreen Victoria from 1993 to 2000 was conducted. Descriptive analyses of the proportion of women undergoing each surgical treatment type over time were carried out. Logistic regression was used to assess the effect of urban-rural residence on each treatment outcome while accounting for possible confounding factors., Results: Rural women with invasive breast cancer were less likely to undergo breast-conserving surgery (BCS) compared with urban women (odds ratio, 0.42; 95% confidence interval, 0.35-0.50). The same was also true for rural women with ductal carcinoma in situ (odds ratio, 0.53; 95% confidence interval, 0.29-0.96). This difference was independent of patient and tumour characteristics, including tumour size, surgeon caseload, patient's age and socioeconomic status. It also persisted over time despite a steady overall increase in use of BCS for both invasive and non-invasive cancers over the study period., Conclusions: Among Victorian women with screen-detected breast cancer, urban women consistently had higher rates of BCS compared with rural women despite increased overall adoption of BCS. Reasons for this disparity are still unclear and warrant further investigation.

Background: Ductal carcinoma in situ represents about 20% of all tumours diagnosed within mammographic screening programs. The natural history of DCIS is poorly understood, as it cannot be observed directly. Estimates of the proportion of DCIS that progress to invasive cancer, as well as factors that may influence progression, are important for clinical management. Here we review various sources of evidence regarding the natural history of DCIS., Methods: We identified relevant publications of studies on: follow-up studies of DCIS initially misdiagnosed as benign, studies of recurrence of DCIS as invasive cancer, autopsy studies, studies of risk factors for DCIS, animal studies and studies that used mathematical models to study growth of DCIS and invasive cancer. Data sources included the MEDLINE data base, searches of articles cited in key reviews and editorials., Results: The most direct evidence regarding the progression of DCIS to invasive cancer comes from studies where DCIS was initially misdiagnosed as benign and treated by biopsy alone. These studies suggest that between 14-53% of DCIS may progress to invasive cancer over a period of 10 or more years. The reported prevalence of undiagnosed DCIS in autopsy studies, of approximately 9%, has been used to suggest a larger reservoir of DCIS may exist in the population. All types of study designs reviewed had limitations that may bias the estimate of progression in either direction., Conclusion: The available evidence suggests not all DCIS will progress to invasive cancer in the medium term but precise estimates of progression are not possible given the limitations of the data. Mathematical modelling of various scenarios of progression and studies of genetic factors involved in progression may shed further light on the natural history of DCIS.

Evidence that the insulin pathway may be involved in breast carcinogenesis has increased the interest in dietary factors that influence insulin secretion and resistance. We investigated dietary carbohydrate, fibre, glycaemic index (GI) and glycaemic load (GL) in a prospective study of 324 breast cancers diagnosed in 12,273 post-menopausal women. Although an increase of 1 standard deviation in carbohydrate was marginally associated with risk of breast cancer, relative risk (RR) 1.31 (95% CI, 0.98, 1.75), there were no significant associations with fibre, 1.08 (0.92, 1.26), GI, 0.98 (0.88, 1.10) or GL, 1.19 (0.93, 1.52) or with carbohydrate foods (bread, rice, pasta). The RR for carbohydrate and localized disease was elevated, 1.40 (1.02, 1.92), but like those for fibre, GI and GL did not differ significantly between localized and non-localized disease. RRs for grade I, but not grade II or III, tumours were elevated for fibre, 1.38 (1.08, 1.75), carbohydrate, 1.56 (1.08, 2.25) and GL, 1.41 (1.01, 1.98) but not for GI, 0.84 (0.65, 1.09). The RRs for fibre and oestrogen receptor (ER) positive (+) and progesterone receptor (PR) positive (+) tumours, 1.36 (1.10, 1.67), differed significantly from those for ER positive (+) and PR negative (-) tumours, 1.01 (0.61, 1.69) and ER-/PR- tumours, 0.65 (0.43, 0.99), p = 0.005. Our data do not support a strong role for GI and GL in breast carcinogenesis but suggest that increased intake of fibre and carbohydrate may be associated with the diagnosis of cancers of more favourable prognosis.

Objective: To determine factors that may modify the association between hormone therapy (HT) and breast cancer risk., Design: Prospective cohort study (the Melbourne Collaborative Cohort Study) of 24,479 women aged 40 to 69 years. History of HT use was collected at baseline and 4 years later by questionnaire. By June 2002, 336 cases of breast cancer were diagnosed among 13,444 women postmenopausal at baseline. Association of breast cancer risk with history of HT use was analyzed using proportional hazards models., Results: The hazard ratio (HR) for recent HT use (current or stopped within the last year) was elevated (HR 1.51; 95% CI, 1.16-1.98) but was not significantly increased for past HT users (HR 1.19; 95% CI, 0.86-1.64). Recent HT use was associated with better differentiated tumors but was not more likely to be associated with estrogen receptor-positive / progesterone receptor-positive tumors. There was little evidence of interactions between recent HT use and body mass index, alcohol intake, parity, and smoking, although the HR for recent HT use in categories of alcohol consumption was greatest in women consuming the most alcohol (HR 2.37; 95% CI, 1.45-3.88 for those consuming > or = 10 g/d versus HR 1.33; 95% CI, 0.85-2.08 for nondrinkers, P interaction = 0.32)., Conclusions: The risk of breast cancer for recent users of HT in this Australian population is increased by approximately 50%. Our results suggest that any potential modifying effect of the association between HT and breast cancer risk by factors such as alcohol intake and body mass index is likely to be modest.

Objective: To evaluate the effect of dietary folate intake on the relation between alcohol consumption and breast cancer risk., Design: Prospective cohort study., Setting: Melbourne, Australia., Participants: 17,447 Anglo-Australian women resident in Melbourne, aged 40-69 years at recruitment in 1990-4, and followed up until 31 December 2003., Main Outcome Measure: Invasive breast cancers diagnosed during follow-up and ascertained through the Victorian cancer registry., Results: 537 invasive breast cancers were diagnosed. Compared with lifetime abstainers, the hazard ratio for breast cancer in women who consumed an average of 40 g or more of alcohol daily at baseline was 1.41 (95% confidence interval 0.90 to 2.23). No direct association was found between dietary folate intake and risk of breast cancer, but a high folate intake mitigated the excess risk associated with alcohol. The estimated hazard ratio of an alcohol consumption of 40 g/day or more was 2.00 (1.14 to 3.49) for women with intakes of 200 mug/day of folate and 0.77 (0.33 to 1.80) for 400 mug/day of folate (P = 0.04 for interaction between alcohol and folate)., Conclusions: An adequate dietary intake of folate might protect against the increased risk of breast cancer associated with alcohol consumption.

Objective: We examine to what extent the lower mammographic sensitivity found in hormone replacement therapy (HRT) users can be explained by any association of HRT use with higher mammographic density and more difficult to detect cancers., Methods: We used logistic regression to estimate the odds of a false-negative screen (a breast cancer diagnosed in the 24 months after a negative screening examination) for HRT users and to estimate, and adjust for, mammographic density (measured on a continuous scale, blinded, using a reliable, computer-assisted method), tumor characteristics (size, grade, and morphology), and potential confounders (age, symptom status, family history, and prior screening) among women ages > or =55 years who attended BreastScreen Victoria for first round screening mammography in 1994 and 1995 (1,086 breast cancers) and for subsequent round screening (471 breast cancers) in 1995 and 1996., Results: After adjusting for confounders, HRT users were more likely to have a false-negative screen [first round: odds ratio (OR), 1.99; 95% confidence interval (95% CI), 1.4-2.9; subsequent round: OR, 2.29; 95% CI, 1.4-3.8]. This effect was modestly attenuated by adjusting for mammographic density (first round: OR, 1.54; 95% CI, 1.0-2.3; subsequent round: OR, 1.97; 95% CI, 1.2-3.3). Adjusting for tumor characteristics resulted in a modest increase in the odds of a false negative at first round but had no effect at subsequent round., Conclusions: Mammographic density only partly explains the effect of HRT on sensitivity. Further research needs to clarify whether hyperemic breast tissue changes affect cancer detectability in HRT users as well as the possibility that the quality of mammography may be poor in some HRT users.

Introduction: AIB1, located at 20q12, is a member of the steroid hormone coactivator family. It contains a glutamine repeat (CAG/CAA) polymorphism at its carboxyl-terminal region that may alter the transcriptional activation of the receptor and affect susceptibility to breast cancer through altered sensitivity to hormones., Methods: We evaluated this repeat polymorphism in the context of early-onset disease by conducting a case-control study of 432 Australian women diagnosed with breast cancer before the age of 40 years and 393 population-based control individuals who were frequency matched for age. Genotyping was performed using a scanning laser fluorescence imager., Results: There were no differences in genotype frequencies between cases and control individuals, or between cases categorized by family history or by BRCA1 and BRCA2 germline mutation status. There was no evidence that the presence of one or two alleles of 26 glutamine repeats or fewer was associated with breast cancer (odds ratio = 1.03, 95% confidence interval = 0.73-1.44), or that women with alleles greater than 29 repeats were at increased risk of breast cancer. Exclusion of women who carried a BRCA1 or BRCA2 mutation (24 cases) and non-Caucasian women (44 cases) did not alter the risk estimates or inferences. We present raw data, including that on mutation carriers, to allow pooling with other studies., Conclusion: There was no evidence that risk of breast cancer depends on AIB1 CAG/CAA polymorphism status, even if affected women carry a mutation in BRCA1 or BRCA2.

Introduction: Because CYP17 can influence the degree of exposure of breast tissues to oestrogen, the interaction between polymorphisms in this gene and hormonal risk factors is of particular interest. We attempted to replicate the findings of studies assessing such interactions with the -34T-->C polymorphism., Methods: Risk factor and CYP17 genotyping data were derived from a large Australian population-based case-control-family study of 1,284 breast cancer cases and 679 controls. Crude and adjusted odds ratio (OR) estimates and 95% confidence intervals (CIs) were calculated by unconditional logistic regression analyses., Results: We found no associations between the CYP17 genotype and breast cancer overall. Premenopausal controls with A2/A2 genotype had a later age at menarche (P < 0.01). The only associations near statistical significance were that postmenopausal women with A1/A1 (wild-type) genotype had an increased risk of breast cancer if they had ever used hormone replacement therapy (OR 2.40, 95% CI 1.0 to 5.7; P = 0.05) and if they had menopause after age 47 years (OR 2.59, 95% CI 1.0 to 7.0; P = 0.06). We found no associations in common with any other studies, and no evidence for interactions., Conclusion: We observed no evidence of effect modification of reproductive risk factors by CYP17 genotype, although the experiment did not have sufficient statistical power to detect small main effects and modest effects in subgroups. Associations found only in subgroup analyses based on relatively small numbers require cautious interpretation without confirmation by other studies. This emphasizes the need for replication in multiple and large population-based studies to provide convincing evidence for gene-environment interactions.

Background: Studies of postmenopausal breast cancer have reported positive associations with body size and composition but it is uncertain whether these are due to non-adipose, adipose mass, or central adiposity, and whether they are limited to subgroups defined by age or tumor characteristics., Methods: In a prospective cohort study of women ages 27 to 75, body measurements were taken directly; fat mass and fat-free mass being estimated by bioelectrical impedance analysis, and central adiposity by waist circumference. Among 13,598 women followed on average for 9.1 years, 357 invasive breast cancers were ascertained via the population cancer registry. Data were obtained on estrogen receptor and progesterone receptor status, grade, and stage., Results: Estimates of body size such as fat-free mass [hazard ratio per 10 kg increase = 1.45, 95% confidence interval (CI) 1.16-1.82], fat mass (hazard ratio per 10 kg increase = 1.18, 95% CI, 1.06-1.31), and waist circumference (hazard ratio per 10 cm increase = 1.13, 95% CI, 1.03-1.24) were associated with breast cancer risk. There was no association with risk before 15 years postmenopause. About 15 years after menopause, risk increased sharply and remained elevated. There was some evidence that this association might be stronger for estrogen receptor-positive and poorly differentiated tumors but no evidence that it differed by stage., Conclusion: Given that elements of body size and composition are positively associated with breast cancer risk, although not until 15 or more years postmenopause, it is possible that women could reduce risk by maintaining ideal body weight after menopause.

Objective: The evidence for the effectiveness of screening is strongest for women ages 50 to 69 years; however, there is variation in the target age group for screening programs between different countries. In particular, there is uncertainty over whether women should continue screening once they reach age 70. We therefore investigated incidence rates for invasive and in situ breast cancer by age as well as prognostic features of tumors within a screening program., Methods: We studied 474,808 women who attended BreastScreen Victoria from January 1, 1993 to December 31, 2000. Of these women, 5,301 were diagnosed with invasive cancer and 1,127 were diagnosed with ductal carcinoma in situ. We used generalized additive models to model age-incidence rates for invasive cancers and ductal carcinoma in situ separately by users and nonusers of hormone replacement therapy at most recent screen. Nonparametric trends for ordered groups and regression methods were used to investigate trends in size, grade, and nodal involvement for invasive tumors by type of attendance and time since previous negative screen for age group., Results: The incidence of ductal carcinoma in situ among women with a previous negative screen clearly declined after age 70 irrespective of hormone replacement therapy use. At subsequent screen, the age-incidence curve for invasive breast cancer flattened at ages 60 to 75 years and then increased only for women taking hormone replacement therapy. Tumor size at diagnosis declined with age at both first round (P = 0.15) and subsequent round (P = 0.08). The proportion of poorly differentiated tumors also decreased with age, with the smallest proportion of grade III tumors diagnosed in women ages > or = 75 years (P = 0.09 for first screen and P = 0.05 for subsequent screen). The presence of positive nodes at diagnosis declined with age (P < 0.001) for both first and subsequent screening rounds., Conclusion: Older age is associated with more favorable prognostic tumor features and a lower incidence of ductal carcinoma in situ among subsequent attenders of screening. When making decisions regarding continuing screening, older women and their physicians should also consider the presence of other comorbid conditions that may mitigate any impact of screening on mortality.

The HER2 gene controls cellular function and has prognostic significance in breast cancer. The I655V polymorphism was associated with increased risk of breast cancer in Chinese women under the age of 45 years and in women with a first-degree family history of the disease. These associations, however, have not been confirmed in several studies of older women. We conducted a population-based case-control-family study of the I655V polymorphism using 409 Australian women with breast cancer diagnosed before the age of 40 years and 299 controls frequency matched for age. The I655V polymorphism was more common in cases (P = 0.01). A recessive model, in which homozygotes were associated with an adjusted odds ratio of 2.8 (95% confidence interval 1.3-6.2; P = 0.005), gave the best fit under parsimony. Although the biological role of the I655V polymorphism is not known, large independent studies of early onset breast cancer are warranted to attempt to replicate this finding.

Unlabelled: One of the primary adverse effects of long-term use of hormone replacement therapy (HRT) is a modest increase in the risk of breast cancer. Breast tumours that develop in women using HRT have been shown to have prognostically favourable histological features but it is unclear if this is the case for both short- and long-term use., Methods: We evaluated the association between HRT use with tumour size and histologic grade in a cohort of women aged over 55 years (n = 2200) diagnosed with invasive breast cancer at subsequent screen in BreastScreen Victoria (BSV), Australia between 1993 and 2000. BSV biennially screens women aged over 40 years with the target age group 50-69 years. Multiple linear regression was used to examine predictors of log-transformed tumour size and multinomial logistic regression was used to evaluate associations of HRT with tumour grade., Results: Short-term users of HRT (< or = 5 years), were approximately 50% less likely to develop poorly-differentiated breast tumours OR 0.48 95% CI (0.28-0.82) or node-positive tumours OR 0.57 95% CI (0.35-0.94) than non-users. Long-term users of HRT (> 5 years) were also less likely to develop poorly-differentiated tumours OR 0.36 95% CI (0.24-0.56) but were not more likely to be node-positive than women not on HRT. Duration of HRT use was not significantly associated with tumour size., Conclusion: HRT use, regardless of duration, was associated with breast tumours that were better differentiated and not significantly larger than women not on HRT, although only short-term use was associated with fewer node-positive tumours.

There is concern that exposures to the environmental chemicals polychlorinated biphenyls (PCBs) may contribute to breast cancer risk. An individual's susceptibility to the effects of PCBs may be partially determined by polymorphisms in the gene encoding the biotransformation enzyme cytochrome P450 1A1 (CYP1A1). PCB exposure induces CYP1A1 activity, and PCBs themselves or other xenobiotics can be metabolized to carcinogenic intermediates in the presence of the variant genotype. A previous case-control study provided evidence of an interaction between high exposures to PCBs and the CYP1A1-exon 7 polymorphism (the A to G transition at nucleotide 4889), leading to a significant increase in postmenopausal breast cancer risk. We examined the interaction of PCBs with the CYP1A1-MspI (the T to C transition at nucleotide 6235) and exon 7 polymorphisms among 367 breast cancer case-control pairs (293 postmenopausal pairs) in the Nurses' Health Study. Although there was no independent association of either the CYP1A1 variants or PCBs with breast cancer risk, the relative risk among the postmenopausal women with plasma PCB levels in the highest third of the distribution in the control group and at least one exon 7 variant allele compared with women who were homozygous for the wild-type allele and who had PCB levels in the lowest third was 2.78 (95% confidence interval, 0.99-7.82). The majority of studies have concluded that exposure to PCBs is unlikely to be a major cause of breast cancer, but these findings indicate that further studies of genetically susceptible populations are warranted.