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Biomedical subjects

Dorota M Gertig

Publications and source records attributed to Dorota M Gertig.

At least 19 recordsLinked to original sources

Forecasting age-specific breast cancer mortality using functional data models.

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.

Aged↗

Dietary carbohydrate, fibre, glycaemic index, glycaemic load and the risk of postmenopausal breast cancer.

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.

Adult↗

Body size and composition and colon cancer risk in women.

Studies of colon cancer risk in males have reported strong positive associations with obesity, particularly with central adiposity. The association has been weaker and less consistent for women. In a prospective cohort study of women, body measurements were taken directly; fat mass and fat-free mass being estimated by bioelectrical impedance analysis and central adiposity by waist circumference and waist-to-hip ratio (WHR). Among 24,072 women followed on average for 10.4 years, 212 colon cancers were ascertained via the population cancer registry. We reviewed medical records of all cases and classified them according to anatomic site and stage. The central adiposity measures of WHR (hazard ratio per 0.1 unit increase = 1.31, 95% confidence interval (CI) 1.08-1.58) and waist circumference (hazard ratio per 10 cm increase = 1.14, 95% CI 1.02-1.28) were positively associated with colon cancer risk. There was little or no association between other anthropometric measures and risk of colon cancer. There was some evidence that the associations were stronger for proximal tumors, but no evidence that risk differed by stage for any of the anthropometric measures. Central adiposity appears to be associated with colon cancer risk in women.

Abdominal Fat↗

Body size and composition and risk of rectal cancer (Australia).

BACKGROUND: Although body mass index has been shown to be associated with colon cancer, studies of rectal cancer risk have generally reported no association. The relationship between rectal cancer risk and central adiposity, overall fat mass, and fat-free mass is unknown. METHODS: In a prospective cohort study of people aged 27-75 years, body measurements were taken directly; fat mass and fat-free mass being estimated by bioelectrical impedance analysis and central adiposity by waist circumference and waist-to-hip ratio. Among 16,867 men and 24,247 women followed on average for 10.3 years, 229 rectal cancers were ascertained via the population cancer registry. RESULTS: When comparing the highest tertile with the lowest tertile, weight (hazard ratio = 1.4, 95% confidence interval (CI) 1.1-2.0), waist circumference (hazard ratio = 1.4, 95% CI 1.0-1.9), fat mass (hazard ratio = 1.4, 95% CI 1.0-2.0) and percent fat (hazard ratio = 1.4, 95% CI 1.0-2.0) were positively associated with rectal cancer risk. There was no evidence that risk differed by sex for any of the anthropometric measures. CONCLUSIONS: Waist circumference and fat mass may be weakly related to risk of rectal cancer.

Adiposity↗

Urban-rural differences in the management of screen-detected invasive breast cancer and ductal carcinoma in situ in victoria.

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.

Adult↗

Does dietary folate intake modify effect of alcohol consumption on breast cancer risk? Prospective cohort study.

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.

Adult↗

CYP17 genetic polymorphism, breast cancer, and breast cancer risk factors: Australian Breast Cancer Family Study.

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.

Adult↗

The AIB1 glutamine repeat polymorphism is not associated with risk of breast cancer before age 40 years in Australian women.

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.

Acetyltransferases↗

Hormone replacement therapy, percent mammographic density, and sensitivity of mammography.

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.

Aged↗

Body size and composition and colon cancer risk in men.

BACKGROUND: Several studies of male colon cancer have found positive associations with body size and composition. It is uncertain whether this relationship is due to non-adipose mass, adipose mass, distribution of adipose mass such as central adiposity, or all three. METHODS: In a prospective cohort study of men aged 27-75 at recruitment in 1990-1994, body measurements were taken by interviewers. Fat mass and fat-free mass (FFM) were estimated from bioelectrical impedance analysis. Waist circumference and waist-to-hips ratio (WHR) estimated central adiposity. Incident colon cancers were ascertained via the population cancer registry. Altogether, 16,556 men contributed 145,433 person-years and 153 colon cancers. RESULTS: Rate ratios (RRs) comparing men in the fourth quartile with those in the first quartile were as follows: FFM 2.3 [95% confidence interval (CI) 1.4-3.7]; height 1.9 (95% CI 1.1-3.1); waist circumference 2.1 (95% CI 1.3-3.5); WHR 2.1 (95% CI 1.3-3.4); fat mass 1.8 (95% CI 1.1-3.0); and body mass index 1.7 (95% CI 1.1-2.8). When continuous measures of FFM and WHR were modeled together, the RR for FFM per 10 kg was 1.37 (95% CI 1.04-1.80) and the RR for WHR per 0.1 unit was 1.65 (95% CI 1.28-2.13). After adjustment for FFM and WHR, the RRs for fat mass and body mass index were no longer statistically significant. CONCLUSION: Male colon cancer appears to be related to body size and composition by two different pathways, via central adiposity and via non-adipose mass.

Adipose Tissue↗

Incidence of invasive breast cancer and ductal carcinoma in situ in a screening program by age: should older women continue screening?

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.

Age Factors↗

Body size and composition and risk of postmenopausal breast cancer.

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.

Adipose Tissue↗

Duration of hormone replacement therapy, breast tumour size and grade in a screening programme.

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.

Aged↗

The HER2 I655V polymorphism and risk of breast cancer in women < age 40 years.

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.

Adult↗

Body size and composition and prostate cancer risk.

Reported associations between body measurements and the risk of prostate cancer are weak and inconsistent, possibly because some measures used do not differentiate between adipose and nonadipose tissue, body components that would theoretically have different associations with prostate cancer. Some studies have addressed this problem by estimating lean body mass from subjects' age, height, and weight. In a prospective cohort study of men 27-75 years of age at recruitment in 1990-1994, body measurements were taken by trained interviewers. Nonadipose and adipose mass were calculated from bioelectric impedance analysis. Incident prostate cancers were ascertained by use of the population cancer registry. Altogether 16,336 men contributed 113,535 person-years and 477 cancers, of which 79 were "aggressive," to the analysis. We found no overall association between prostate cancer and any anthropometric measurement. Analysis stratified by cancer aggressiveness revealed modest associations between measures of adiposity and the risk of aggressive disease. On the basis of the WHO cut points and compared with men in the normal range of body mass index, the risk ratio for obese men was 2.2 (95% confidence interval, 1.2-4.1). For each 10-kg increase in fat mass, the risk ratio was 1.4 (95% confidence interval, 1.0-1.8). Energy imbalance may play a role in the development of aggressive prostate cancer.

Adult↗

Public health aspects of genetic screening for hereditary haemochromatosis in Australia.

Hereditary haemochromatosis (HH) is an inherited disorder of iron absorption. It meets several of the key public health principles for population-based screening and is considered to be a test-case for public health genetics. However, there has been relatively little debate in the public health or wider community regarding the merits of population-based genetic screening for HH. Genetic susceptibility to HH occurs in about 1:200 people and although mortality is low (age-standardised rate 2.75/million), there are potentially serious clinical manifestations of iron overload. Regular venesection is a simple and effective treatment for early stage iron overload. DNA-based testing is available and iron overload may be identified using serum transferrin saturation and ferritin tests. However, there are important gaps in knowledge relevant to screening for HH. The limited data on penetrance of HFE genotypes, and thus the uncertain probability that genetically susceptible individuals will develop clinically significant disease, is a major impediment to population-based genetic screening. Clinical evidence supports treating early-stage disease but no randomised controlled trials of the effectiveness of screening in reducing the burden of disease have been conducted. In addition, the natural history of early stages of HH and factors that may modify progression are unclear. Two intemational consensus panels on HH concluded that there is insufficient evidence for population-based screening at present. We present recommendations to advance the debate on screening for HH in Australia.

Australia↗

Polychlorinated biphenyls, cytochrome P450 1A1, and breast cancer risk in the Nurses' Health Study.

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.

Adult↗