Genotypes and haplotypes in the insulin-like growth factors, their receptors and binding proteins in relation to plasma metabolic levels and mammographic density.

BACKGROUND: Increased mammographic density is one of the strongest independent risk factors for breast cancer. It is believed that one third of breast cancers are derived from breasts with more than 50% density. Mammographic density is affected by age, BMI, parity, and genetic predisposition. It is also greatly influenced by hormonal and growth factor changes in a woman's life cycle, spanning from puberty through adult to menopause. Genetic variations in genes coding for hormones and growth factors involved in development of the breast are therefore of great interest. The associations between genetic polymorphisms in genes from the IGF pathway on mammographic density and circulating levels of IGF1, its binding protein IGFBP3, and their ratio in postmenopausal women are reported here. METHODS: Samples from 964 postmenopausal Norwegian women aged 55-71 years were collected as a part of the Tromsø Mammography and Breast Cancer Study. All samples were genotyped for 25 SNPs in IGF1, IGF2, IGF1R, IGF2R, IGFALS and IGFBP3 using Taqman (ABI). The main statistical analyses were conducted with the PROC HAPLOTYPE procedure within SAS/GENETICS (SAS 9.1.3). RESULTS: The haplotype analysis revealed six haploblocks within the studied genes. Of those, four had significant associations with circulating levels of IGF1 or IGFBP3 and/or mammographic density. One haplotype variant in the IGF1 gene was found to be associated with mammographic density. Within the IGF2 gene one haplotype variant was associated with levels of both IGF1 and IGFBP3. Two haplotype variants in the IGF2R were associated with the level of IGF1. Both variants of the IGFBP3 haplotype were associated with the IGFBP3 level and indicate regulation in cis. CONCLUSION: Polymorphisms within the IGF1 gene and related genes were associated with plasma levels of IGF1, IGFBP3 and mammographic density in this study of postmenopausal women.

Different measures of smoking exposure and mammographic density in postmenopausal Norwegian women: a cross-sectional study.

BACKGROUND: Recent cohort studies have suggested an increased risk of breast cancer with long duration of smoking, and with smoking initiation before first birth. Cigarette smoking may have both carcinogenic effects and antiestrogenic effects on the breast tissue. We decided to examine the relationship between different measures of smoking exposure and mammographic density. METHODS: Lifetime smoking history was collected through interview and questionnaires among 907 postmenopausal participants in the Tromsø Mammography and Breast Cancer study. The mammograms were obtained from the governmental Norwegian Breast Cancer Screening Program. Mammograms were classified according to the percentage and absolute mammographic densities using a previously validated computer-assisted method. RESULTS: Sixty-five percent of the women reported having ever smoked cigarettes, while 34% were current smokers. After adjustment for age, age at first birth, parity, age at menopause, postmenopausal hormone therapy use, and body mass index, smoking was inversely associated with both measures of mammographic density (both trends P < 0.01). Both current smokers and former smokers had significantly lower adjusted mean percentage mammographic density compared with never smokers (P = 0.003 and P = 0.006, respectively). An inverse dose-response relationship with mammographic density was found between both the number of cigarettes and the number of pack-years smoked among current smokers. Current smokers who smoked 11 cigarettes or more daily had a 3.7% absolute (36% relative difference) lower percentage mammographic density compared with current smokers who smoked seven cigarettes or less daily (P = 0.008). When former smokers were stratified according to time since smoking cessation, we found that women who had stopped smoking less than 24 years ago had a significantly lower mean percentage mammographic density compared with never smokers (P < 0.001). CONCLUSION: We found modest inverse dose-response associations between numbers of cigarettes and of pack-years smoked and both measures of mammographic density among current smokers. Former smokers who had stopped smoking less than 24 years ago also had a statistically significantly lower mean percentage mammographic density when compared with never smokers. These findings are consistent with an antiestrogenic effect of cigarette smoking on the breast tissue.

Endogenous sex hormones, prolactin and mammographic density in postmenopausal Norwegian women.

The associations between endogenous sex hormone levels and breast cancer risk in postmenopausal women are well established. Mammographic density is a strong risk factor for breast cancer, and possibly an intermediate marker. However, the results from studies on the associations between endogenous sex hormones and mammographic density are conflicting. The authors examined the associations between circulating levels of sex hormones, sex hormone binding globulin (SHBG) and prolactin and mammographic densities among postmenopausal women not currently using postmenopausal hormone therapy (HT). The authors also examined if insulin-like growth factor-I (IGF-I) levels influenced the association between estrogen and mammographic density. Altogether, 722 postmenopausal participants in the Norwegian governmental mammographic screening program had endogenous hormone concentrations measured. Mammograms were classified according to percent and absolute mammographic density using a previously validated computer-assisted method. After adjustment for age, number of children, age at menopause, body mass index and HT use, both plasma concentrations of SHBG (p-trend = 0.003) and estrone (p-trend = 0.07) were positively associated with percent mammographic density. When the analyses were stratified according to median IGF-I concentration, the weak association between estrone and mammographic density was strengthened among women with IGF-I levels below median, while the association disappeared among women with over median IGF-I levels (p for interaction = 0.02). In summary, the authors found a positive association between plasma SHBG levels and mammographic densities among 722 postmenopausal Norwegian women not currently using HT. Further, the authors found a positive but weak association between plasma estrone concentration and mammographic density, which appeared to be modified by IGF-I levels.

Insulin-like growth factor and mammographic density in postmenopausal Norwegian women.

Insulin-like growth factor-I (IGF-I) is associated with breast cancer risk among premenopausal women but rarely among postmenopausal women. Recent data from two European studies suggested an increased risk of breast cancer with increasing levels of IGF-I among women >50 years old or among postmenopausal hormone therapy users >or=55 years old. Mammographic density is one of the strongest risk factors, and possibly an intermediate marker, for breast cancer. We examined the relationship between IGF and mammographic density among postmenopausal women overall and according to hormone therapy use. Altogether, 977 postmenopausal participants in the Norwegian governmental mammographic screening program had IGF concentrations measured by ELISA. Mammograms were classified according to percent and absolute mammographic densities using a previously validated computer-assisted method. After adjustment for age, number of children, age at menopause, body mass index, and hormone therapy use, both plasma IGF-I concentration (P(trend) = 0.02) and IGF-I/IGF binding protein 3 ratio (P(trend) = 0.02) were positively associated with percent mammographic density. The magnitudes of differences in percent mammographic density between women in the lowest and highest quartiles of IGF-I concentrations were 1.5% absolute difference and 21% relative difference. These associations were similar with absolute mammographic density as the outcome variable. When the analyses were stratified according to hormone therapy use, the associations between IGF-I and mammographic density were significant among noncurrent users (P(trend) = 0.03). In conclusion, we found a positive but weak association between plasma IGF-I concentrations and both percent and absolute mammographic densities among postmenopausal women. These associations were found among noncurrent hormone therapy users but not among current users.

Different types of postmenopausal hormone therapy and mammographic density in Norwegian women.

Postmenopausal hormone therapy (HT) is associated with increased risk of breast cancer. The HTs used in Scandinavia is associated with higher risk estimates than those used in most other countries. Mammographic density is one of the strongest risk factors for breast cancer, and possibly an intermediate marker for breast cancer. We decided to examine the relationship between use of different types of HT and mammographic density in Norwegian women. Altogether, 1,007 postmenopausal participants in the governmental mammographic screening program were asked about current and previous HT use. Mammograms were classified according to percent and absolute mammographic density. Overall, current users of HT had on average 3.6% higher mean percent mammographic density when compared with never users (p < 0.001). After adjustment for age at screening, number of children and BMI in a multivariate model, women using the continuous estradiol (E(2)) plus norethisterone acetate (NETA) combination had a mean percent mammographic density significantly higher than never users (6.1% absolute difference). Those using the continuous E(2) plus NETA combination had an 4.8% (absolute difference) higher mean percent mammographic density after <5 years of use when compared with never users, while the corresponding number for >or=5 years of use was 7% (p-trend < 0.001). We found similar associations when absolute mammographic density was used as the outcome variable. In summary, our study shows a statistical significant positive dose-response association between current use of the continuous E(2) plus NETA combination and both measures of mammographic density.

Plasma levels of leptin and mammographic density among postmenopausal women: a cross-sectional study.

INTRODUCTION: Obesity has been linked to increased risk of breast cancer in postmenopausal women. Increased peripheral production of estrogens has been regarded as the main cause for this association, but other features of increased body fat mass may also play a part. Leptin is a protein produced mainly by adipose tissue and may represent a growth factor in cancer. We examined the association between leptin plasma levels and mammographic density, a biomarker for breast cancer risk. METHODS: We included data from postmenopausal women aged 55 and older, who participated in a cross-sectional mammography study in Tromsø, Norway. Mammograms, plasma leptin measurements as well as information on anthropometric and hormonal/reproductive factors were available from 967 women. We assessed mammographic density using a previously validated computer-assisted method. Multiple linear regression analysis was applied to investigate the association between mammographic density and quartiles of plasma leptin concentration. Because we hypothesized that the effect of leptin on mammographic density could vary depending on the amount of nondense or fat tissue in the breast, we also performed analyses on plasma leptin levels and mammographic density within tertiles of mammographic nondense area. RESULTS: After adjusting for age, postmenopausal hormone use, number of full-term pregnancies and age of first birth, there was an inverse association between leptin and absolute mammographic density (P(trend) = 0.001). When we additionally adjusted for body mass index and mammographic nondense area, no statistically significant association between plasma leptin and mammographic density was found (P(trend) = 0.16). Stratified analyses suggested that the association between plasma leptin and mammographic density could differ with the amount of nondense area of the mammogram, with the strongest association between leptin and mammographic absolute density in the stratum with the medium breast fat content (P(trend) = 0.003, P for interaction = 0.05). CONCLUSION: We found no overall consistent association between the plasma concentration of leptin and absolute mammographic density. Although weak, there was some suggestion that the association between leptin and mammographic density could differ with the amount of fat tissue in the breast.

Percentage density, Wolfe's and Tabár's mammographic patterns: agreement and association with risk factors for breast cancer.

INTRODUCTION: The purpose of this report was to classify mammograms according to four methods and to examine their agreement and their relationship to selected risk factors for breast cancer. METHOD: Mammograms and epidemiological data were collected from 987 women, aged 55 to 71 years, attending the Norwegian Breast Cancer Screening Program. Two readers each classified the mammograms according to a quantitative method (Cumulus or Madena software) and one reader according to two qualitative methods (Wolfe and Tabár patterns). Mammograms classified in the reader-specific upper quartile of percentage density, Wolfe's P2 and DY patterns, or Tabár's IV and V patterns, were categorized as high-risk density patterns and the remaining mammograms as low-risk density patterns. We calculated intra-reader and inter-reader agreement and estimated prevalence odds ratios of having high-risk mammographic density patterns according to selected risk factors for breast cancer. RESULTS: The Pearson correlation coefficient was 0.86 for the two quantitative density measurements. There was moderate agreement between the Wolfe and Tabár classifications (Kappa = 0.51; 95% confidence interval 0.46 to 0.56). Age at screening, number of children and body mass index (BMI) showed a statistically significant inverse relationship with high-risk density patterns for all four methods (all P < 0.05). After adjustment for percentage density, the Wolfe classification was not associated with any of the risk factors for breast cancer, whereas the association with number of children and BMI remained statistically significant for the Tabár classification. Adjustment for Wolfe or Tabár patterns did not alter the associations between these risk factors and percentage mammographic density. CONCLUSION: The four assessments methods seem to capture the same overall associations with risk factors for breast cancer. Our results indicate that the quantitative methods convey additional information over the qualitative methods.

Plasma levels of enterolactone and percentage mammographic density among postmenopausal women.

AIMS: Certain phytoestrogens, such as lignans, may protect against developing breast cancer. Enterolactone is a lignan metabolite produced by the intestinal flora from dietary precursors such as whole grains, vegetables, and fruits. Enterolactone has been shown to have weak estrogenic and antiestrogenic properties. We decided to examine the association between plasma levels of enterolactone and mammographic density, a biomarker for breast cancer risk. METHODS: We included data from postmenopausal women ages 55 and older who participated in a cross-sectional mammogram study in Tromsø, Norway. Mammograms, plasma enterolactone measurements, as well as information on anthropometric and hormonal/reproduction factors were available on 616 women. We assessed mammographic density using a previously validated computer-assisted method. We estimated correlation coefficients and conducted multiple regression analyses. RESULTS: Mean mammographic density increased slightly across quartiles of enterolactone; the women in the highest quartile had, on average, 3.1% (absolute difference) higher percentage mammographic density compared with the lowest quartile (P(trend) < 0.01). After adjustment for age, body mass index, number of full-term pregnancies, age at first birth, and use of postmenopausal hormone therapy, the mean difference in density was reduced to 2.0% (P(trend) = 0.05). Results were similar when restricted to the 454 current hormone nonusers. The fully adjusted statistical model explained 28.3% of the total variability in mammographic percentage density, with body mass index contributing 18.2% and enterolactone only 0.9%. CONCLUSION: In our study, higher levels of enterolactone were associated with slightly higher percentage mammographic density. Our results suggest that if higher enterolactone levels reduce the risk of developing breast cancer in postmenopausal women, then this effect is not through lowering mammographic density.

Effects of exemestane administered for 2 years versus placebo on bone mineral density, bone biomarkers, and plasma lipids in patients with surgically resected early breast cancer.

PURPOSE: To evaluate potential detrimental effects of exemestane on bone and lipid metabolism. PATIENTS AND METHODS: Postmenopausal women with early breast cancer were randomly assigned to exemestane 25 mg daily or placebo for 2 years in a double-blind setting. Primary objective was to evaluate the effect of exemestane on bone mineral density. Secondary objectives were effects on bone biomarkers, plasma lipids, coagulation factors, and homocysteine. Planned size was 128 patients. RESULTS: One hundred forty-seven patients were enrolled. All patients completed their 24-month visit except for those discontinuing treatment at an earlier stage. The mean annual rate of bone mineral density loss was 2.17% v 1.84% in the lumbar spine (P = .568) and 2.72% v 1.48% in the femoral neck (P = .024) in the exemestane and placebo arm, respectively. The mean change in T-score after 2 years was -0.21 for exemestane and -0.11 on placebo in the hip, and -0.30 and -0.21, respectively, in the lumbar spine. Exemestane significantly increased serum level and urinary excretion of bone resorption, but also bone formation markers. Except for a modest reduction in high-density lipoprotein cholesterol (P < .001) and apolipoprotein A1 (P = .004), exemestane had no major effect on lipid profile, homocysteine levels, or coagulation parameters. CONCLUSION: Exemestane modestly enhanced bone loss from the femoral neck without significant influence on lumbar bone loss. Except for a 6% to 9% drop in plasma high-density lipoprotein cholesterol, no major effects on serum lipids, coagulation factors, or homocysteine were recorded. Bone mineral density should be assessed according to the US Preventive Services Task Force guidelines.

[Should complementary therapies be offered in hospitals?]. / Tilbud om komplementaer behandling i sykehus?

BACKGROUND: This study compares attitudes among oncology professionals to whether complementary therapies should be offered in integrated units affiliated with departments of oncology. MATERIAL AND METHODS: In June 2002 a questionnaire on alternative and complementary medicine was distributed among 156 physicians, 414 nurses, 164 radiation therapists and 94 administrative staff members in the five Norwegian university hospitals responsible for cancer treatment. 61% returned the questionnaire. RESULTS: More than half of the physicians (56%) and most of the other health care workers (85-93%) had a positive attitude to departments of integrative medicine. If the service was provided, about half of the physicians expressed the opinion that the cost of treatment should be covered by the patient. By contrast, more than 80% of nurses, clerks and therapeutic radiographers answered that the cost had to be covered by public funding. Most oncology professionals, including the physicians, felt that the decision on the type of treatment to be offered to patients should be made in collaboration between patients, complementary therapists and oncology health care workers. However, one third of the physicians thought that treatment decisions had to be made by health care workers only. INTERPRETATION: In general, this survey demonstrated a positive attitude towards integrated units offering complementary therapies, also among oncologists. However, major differences among professions were found.

Oral capecitabine in anthracycline- and taxane-pretreated advanced/metastatic breast cancer.

An open-label, non-randomized, compassionate-use study was carried out to investigate the effects of oral capecitabine at a dose of 1 250 mg/m2 twice daily on days 1 to 14 every 21 days in anthracycline- and taxane-pretreated advanced/metastatic breast cancer patients. Forty-eight patients were enrolled from April 2000 to December 2001. Twenty-four patients (50%) had metastases to the liver, 18 to bone, 13 to lung, 10 to regional lymph nodes, 8 to pleura, 7 to the thoracic wall, 5 to skin, 3 to the mediastinum, 1 to breast and 1 had metastasis to the abdomen. Thirty-three patients (69%) had metastases to more than one site. Median age of the patients was 55 years (range 35-74). Three patients had an ECOG performance status (PS) of 0, 32 PS 1 and 13 PS 2, respectively. Fourteen patients (29%; 95% CI 16 to 42%) obtained a partial response (PR) while 16 (33%) had stable disease (SD) as the best response, of whom 6 had stabilization for more than 24 weeks. This gives a clinical benefit (PR + SD > 24 weeks) of 42% (95% CI 28 to 56). Dose reduction was necessary in 29% of the patients. Median dose reduction was 25%. Grades 2 and 3 hand-foot syndrome (PPE) was observed in 17 patients (36%). Eleven patients experienced grades 2 and 3 gastrointestinal toxicity, and haematological toxicity grade 3 was observed in 3 patients (6%). Median time to progression was 107 days (CI 95% 85 to 129), and median overall survival was 281 days (CI 95% 164 to 398). Third-line, oral capecitabine in anthracycline- and taxane-pretreated metastatic breast cancer appears to be effective and has an acceptable toxicity profile.