Validation of the Skåne University Hospital nomogram for the preoperative prediction of a disease-free axilla in patients with breast cancer.

BACKGROUND: Axillary staging via sentinel lymph node biopsy (SLNB) is performed for clinically node-negative (N0) breast cancer patients. The Skåne University Hospital (SUS) nomogram was developed to assess the possibility of omitting SLNB for patients with a low risk of nodal metastasis. Area under the receiver operating characteristic curve (AUC) was 0.74. The aim was to validate the SUS nomogram using only routinely collected data from the Swedish National Quality Registry for Breast Cancer at two breast cancer centres during different time periods. METHOD: This retrospective study included patients with primary breast cancer who were treated at centres in Lund and Malmö during 2008-2013. Clinicopathological predictors in the SUS nomogram were age, mode of detection, tumour size, multifocality, lymphovascular invasion and surrogate molecular subtype. Multiple imputation was used for missing data. Validation performance was assessed using AUC and calibration. RESULTS: The study included 2939 patients (1318 patients treated in Lund and 1621 treated in Malmö). Node-positive disease was detected in 1008 patients. The overall validation AUC was 0.74 (Lund cohort AUC: 0.75, Malmö cohort AUC: 0.73), and the calibration was satisfactory. Accepting a false-negative rate of 5 per cent for predicting N0, a possible SLNB reduction rate of 15 per cent was obtained in the overall cohort. CONCLUSION: The SUS nomogram provided acceptable power for predicting a disease-free axilla in the validation cohort. This tool may assist surgeons in identifying and counselling patients with a low risk of nodal metastasis on the omission of SLNB staging.

Aesthetic outcome following breast-conserving surgery assessed by three evaluation modalities in relation to health-related quality of life.

BACKGROUND: The aim of this study was to compare the agreement between three different methods for evaluation of aesthetic outcome following breast-conserving surgery and adjuvant radiotherapy: a patient questionnaire, panel evaluation of photographs and the software BCCT.core. A further aim was to examine how these modalities predict health-related quality of life as measured by the validated Breast-Q™ questionnaire. METHODS: At 1-year follow-up after breast-conserving surgery, patients completed a study-specific questionnaire. Postoperative photographs were evaluated using the software BCCT.core. A panel of three healthcare professionals assessed preoperative and postoperative photographs. Agreement between methods was assessed using Spearman's correlation coefficients (rs ). The Breast-Q™ questionnaire was sent to study participants. The ability of the different evaluation methods to predict Q-scores for the health-related quality-of-life (HRQoL) domains satisfaction with breasts and psychosocial well-being was investigated using receiver operating characteristic (ROC) curves. RESULTS: A total of 532 patients undergoing breast-conserving surgery were examined before surgery. At 1-year follow-up, 334 patients completed the study-specific questionnaire. Postoperative photographs from 310 patients were evaluated using BCCT.core. The panel of healthcare professionals assessed photographs from 215 patients. Agreement between the different evaluation modalities was poor. The strongest agreement was noted between the panel evaluation for symmetry and BCCT.core results (rs = 0·59, P < 0·001). The Breast-Q™ questionnaire was returned by 348 patients. Patient satisfaction ratings at 1-year follow-up best predicted long-term HRQoL measured using the Breast-Q score, both in terms of satisfaction with breasts (area under the curve (AUC) 0·80, P < 0·001) and psychosocial well-being (AUC 0·73, P < 0·001). CONCLUSION: There is currently no ideal method for evaluating aesthetic outcome after breast-conserving surgery and adjuvant radiotherapy. These results emphasize the use of patient-related outcome measures.

Survival and risk of breast cancer recurrence after breast reconstruction with deep inferior epigastric perforator flap.

BACKGROUND: Women who undergo autologous breast reconstruction have been reported to have an increased risk of breast cancer recurrence compared with those who have mastectomy alone. It has been suggested that more extensive surgery possibly activates dormant micrometastases. The aim of this study was to evaluate whether delayed unilateral deep inferior epigastric perforator (DIEP) flap reconstruction after mastectomy increases the risk of breast cancer recurrence or affects mortality among women previously treated for breast cancer. METHODS: This was a matched retrospective cohort study including women with a previous unilateral invasive breast cancer who received a delayed DIEP flap breast reconstruction and a control cohort of individually matched women with unilateral breast cancer who underwent mastectomy but no autologous breast reconstruction. Matching criteria comprised: year of diagnosis (+/-3 years), age at diagnosis (+/-5 years), type of cancer and demographic region. The primary endpoints were local recurrence or distant metastasis, and overall mortality was a secondary endpoint. Absolute risk of recurrent disease and mortality was analysed, and relative risks were estimated using Cox proportional hazards analysis. RESULTS: There were 225 women in the DIEP cohort and 450 in the no-DIEP cohort. The median follow-up time was 125 months. There was no difference in absolute risk of recurrence between the cohorts. The hazard ratio for breast cancer recurrence in DIEP versus no-DIEP cohorts was 0·76 (95 per cent c.i. 0·47 to 1·21). CONCLUSION: There is no increased risk in breast cancer recurrence after delayed DIEP flap reconstruction compared with mastectomy alone.

Thyroid function and survival following breast cancer.

BACKGROUND: Thyroid function has been associated with breast cancer risk, and breast cancer cell growth and proliferation. It is not clear whether thyroid function affects prognosis following breast cancer but, if so, this could have an important clinical impact. The present study analysed prospectively collected measurements of free tri-iodothyronine (T3), free thyroxine (T4), thyroid-stimulating hormone (TSH) and thyroid peroxidase antibodies (TPO-Ab) in relation to breast cancer survival. METHODS: The Malmö Diet and Cancer Study is a prospective cohort study of 17 035 women in Sweden. Study enrolment was conducted between 1991 and 1996. Patients with incident breast cancer were identified through record linkage with cancer registries until 31 December 2006. Information on vital status was collected from the Swedish Cause of Death Registry, with the endpoint breast cancer mortality (31 December 2013). Hazard ratios (HRs) with 95 per cent confidence intervals (c.i.) were obtained by Cox proportional hazards analysis. RESULTS: Some 766 patients with incident breast cancer were identified, of whom 551 were eligible for analysis. Compared with patients in the first free T4 tertile, breast cancer mortality was lower among those in the second tertile (HR 0·49, 95 per cent c.i. 0·28 to 0·84). There was an indication, although non-significant, of lower breast cancer mortality among patients in the second TSH tertile (HR 0·63, 0·37 to 1·09) and in those with positive TPO-Ab status (HR 0·61, 0·30 to 1·23). Free T3 showed no clear association with mortality. CONCLUSION: In the present study, there was a positive association between free T4 levels and improved breast cancer survival.

The association between the intake of specific dietary components and lifestyle factors and microscopic colitis.

BACKGROUND/OBJECTIVES: The incidence of microscopic colitis (MC) has increased over the previous decades. In addition to smoking and drugs, currently unidentified environmental factors may have a role. The aim of this study was to determine whether specific dietary or other lifestyle factors were associated with the development of MC. SUBJECT/METHODS: The population-based cohort Malmö Diet and Cancer Study of 28 095 individuals was examined. Information about dietary habits was collected by a modified diet history method. Data on anthropometry were measured, and socio-economic and lifestyle factors were collected by questionnaires. Cases of MC were identified in medical registers. Associations were estimated using Cox regression analysis. RESULTS: During a 22-year period, 135 patients were diagnosed with MC. Intakes of protein, carbohydrates, sucrose, saturated fat, monounsaturated fat, polyunsaturated fat, omega-3 or omega-6 fatty acids, fibre and zinc were not associated with MC. We could verify the previously reported association between MC and smoking (hazard ratio (HR): 2.29; 95% confidence interval (CI): 1.66-3.84) and the female gender (HR: 3.57; 95% CI: 2.22-5.74). High alcohol consumption was associated with an increased risk for MC (HR: 1.89 for the highest quartile; 95% CI: 0.82-4.33, P for trend=0.032). In a post hoc analysis, alcohol intake including all patients independently of consumption seemed to reduce the smoking-related risk. CONCLUSIONS: Despite a large cohort and a long follow-up period, we could not detect any dietary risk factors for MC. The aetiological mechanisms behind the positive impact of smoking and alcohol on MC risk should be investigated.

Serum vitamin D (25OHD3) levels and the risk of different subtypes of breast cancer: A nested case-control study.

BACKGROUND: Previous studies regarding the association between serum 25-hydroxyvitamin D (25OHD3) and breast cancer risk have not been conclusive. The aim of this study was to investigate the potential association between pre-diagnostic serum 25OHD3 levels and the risk of different subtypes of breast cancer. MATERIALS AND METHODS: The study was based on The Malmö Diet and Cancer Study recruiting 17,035 women from 1991 to 1996. A total of 764 incident breast cancers with matched controls were analysed for 25OHD3 in samples collected at baseline, before diagnosis. A logistic regression analysis was used to calculate odds ratios with 95% confidence intervals for tertiles of 25OHD3 in relation to different subtypes of breast cancer, i.e. defined according to tumour type, tumour size, lymph node involvement, histological grade, oestrogen receptor (ER) status, progesterone receptor (PgR) status, Ki67, cyclin D1 and p27. RESULTS: As compared to the 1st tertile of 25OHD3, the second tertile had a statistically significantly lower risk of ER negative tumours, PgR negative tumours and tumours with a high expression of Ki67, A similar pattern was seen in relation to large tumours (≥21 mm), grade III tumours, and tumours with low p27 expression, but these associations did not reach statistical significance. The third tertile had a similar risk as the first tertile. CONCLUSIONS: We found that women with low levels of 25OHD3, as compare to women in the middle tertile, had a high risk of breast tumours with an unfavourable prognosis.

Liposuction of Postmastectomy Arm Lymphedema Decreases the Incidence of Erysipelas.

The objective of this study was to assess erysipelas incidence before and after liposuction treatment for patients suffering from post-mastectomy lymphedema. A prospective cohort study of 130 patients at Skåne University Hospital in Malmö, Sweden with postmastectomy arm lymphedema, who had poor outcomes from prior conservative treatment and clinical signs of subcutaneous adipose tissue hypertrophy, underwent liposuction between 1993-2012. Pre- and postoperative incident data on erysipelas were available for all of them. Mean duration of lymphedema prior to liposuction was 8.8 years (range1-38, standard deviation (SD) 7.0 years). Mean age at liposuction was 63 years (range 39-89, SD 10 years). Total pre-liposuction observation years were 1147, and total post-liposuction observation years were 983. Erysipelas incidence dropped significantly (p<0.001) from 0.47 attacks/year (range 0-5.0, SD 0.8 attacks/year) to 0.06 attacks/year (range 0-3.0, SD 0.3 attacks/year) after liposuction, a reduction of 87%. Also, compared to 76 patients who experienced at least 1 erysipelas episode preoperatively, only 13 patients experienced erysipelas postoperatively. Of the 54 patients who did not have erysipelas preoperatively, 6 patients had erysipelas postoperatively. The total number of erysipelas attacks observed decreased from 534 to 60 bouts after liposuction. The excess arm volume of 1607 ml (range 570-3950, SD 707) was reduced to -43 ml (range -945 to 1390, SD 379) after 6 months and was maintained during the postoperative follow-up period of, at most, 18 years. Our data suggest that liposuction can significantly reduce incidence of erysipelas in patients with post mastectomy arm lymphedema who prior to the intervention suffered one or more attacks.

CD4+ CD56+ natural killer T-like cells secreting interferon-γ are associated with incident coronary events.

BACKGROUND: CD3(+) CD56(+) natural killer T (NKT)-like cells are a subset of T cells characterized by expression of NK receptors and potent antitumour activity. It has also been suggested that they have a role in autoimmune disease, and levels of NKT-like cells are elevated in patients with coronary disease. OBJECTIVES: To investigate whether high levels of CD3(+) CD56(+) NKT-like cells are associated with an increased incidence of cardiovascular disease and a lower incidence of cancer. METHODS: This was a prospective study including 700 subjects participating in the baseline investigation of the Malmö Diet and Cancer study between 1991 and 1994. Leucocytes obtained at the baseline investigation and stored at -140 °C were thawed and CD3(+) CD56(+) cells analysed by flow cytometry. The incidence rates of cancer and coronary events during a mean follow-up of 15 years were determined through national registers. RESULTS: Subjects in the lowest tertile of interferon (IFN)-γ-expressing CD4(+) CD56(+) cells were found to have an increased risk of incidence of coronary events (log-rank test: P < 0.05). This association remained significant after controlling for age, sex, smoking, body mass index, hypertension, diabetes and the Th1/Th2 and Th1/Treg cell ratios in a Cox proportional hazards regression model (hazard ratio 1.98, 95% confidence interval 1.24-3.16), but not when the LDL/HDL ratio was included in the model. There were no associations between CD3(+) CD56(+) NKT-like cells and incident cancer. CONCLUSIONS: The present results could not confirm the hypothesis that low levels of CD3(+) CD56(+) NKT-like cells are associated with a higher incidence of cancer and a lower incidence of cardiovascular disease. However, we found that low levels of IFN-γ-expressing CD3(+) CD4(+) CD56(+) NKT-like cells were associated with an increased incidence of coronary events and that this association may be dependent on lipoproteins.

Gene variance in the nicotinic receptor cluster (CHRNA5-CHRNA3-CHRNB4) predicts death from cardiopulmonary disease and cancer in smokers.

BACKGROUND: Genetic variation in the cluster on chromosome 15, encoding the nicotinic acetylcholine receptor subunits (CHRNA5-CHRNA3-CHRNB4), has shown strong associations with tobacco consumption and an additional risk increase in smoking-related diseases such as chronic obstructive pulmonary disease (COPD), peripheral artery disease and lung cancer. OBJECTIVES: To test whether rs1051730 (C/T), a tag for multiple variants in the CHRNA5-CHRNA3-CHRNB3 cluster, is associated with a change in risk of smoking-related mortality and morbidity in the Malmö Diet and Cancer study, a population-based prospective cohort study. METHODS: At baseline participants were classified as current (n = 6951), previous (n = 8426) or never (n = 9417) smokers. Cox-proportional hazards models were used to determine the correlation between rs1051730 and incidence of first COPD, tobacco-related cancer, other cancer and cardiovascular disease (CVD), and total mortality due to these causes, during approximately 14 years of follow-up. RESULTS: Amongst current smokers there were 480 first incident COPD events, 852 tobacco-related cancers, 810 other cancers and 1022 CVD events. A total of 1508 deaths occurred, including 500 due to CVD, 102 due to respiratory diseases and 677 due to cancer. In adjusted additive models, an increasing number of T alleles were associated with a gradual increase in total mortality, incident COPD and tobacco-related cancer, even after adjustment for smoking quantity. No significant associations were observed amongst never smokers. CONCLUSION: Our data suggest that gene variance in the CHRNA5-CHRNA3-CHRNB4 cluster is associated with an increased risk of death, incidence of COPD and tobacco-related cancer in smokers. These findings indicate an individual susceptibility to tobacco use and its complications; this may be important when targeting and designing smoking cessation therapies.

Steroid hormone measurements from different types of assays in relation to body mass index and breast cancer risk in postmenopausal women: Reanalysis of eighteen prospective studies.

Epidemiological studies have examined breast cancer risk in relation to sex hormone concentrations measured by different methods: "extraction" immunoassays (with prior purification by organic solvent extraction, with or without column chromatography), "direct" immunoassays (no prior extraction or column chromatography), and more recently with mass spectrometry-based assays. We describe the associations of estradiol, estrone and testosterone with both body mass index and breast cancer risk in postmenopausal women according to assay method, using data from a collaborative pooled analysis of 18 prospective studies. In general, hormone concentrations were highest in studies that used direct assays and lowest in studies that used mass spectrometry-based assays. Estradiol and estrone were strongly positively associated with body mass index, regardless of the assay method; testosterone was positively associated with body mass index for direct assays, but less clearly for extraction assays, and there were few data for mass spectrometry assays. The correlations of estradiol with body mass index, estrone and testosterone were lower for direct assays than for extraction and mass spectrometry assays, suggesting that the estimates from the direct assays were less precise. For breast cancer risk, all three hormones were strongly positively associated with risk regardless of assay method (except for testosterone by mass spectrometry where there were few data), with no statistically significant differences in the trends, but differences may emerge as new data accumulate. Future epidemiological and clinical research studies should continue to use the most accurate assays that are feasible within the design characteristics of each study.

Adherence to the mediterranean diet and risk of breast cancer in the European prospective investigation into cancer and nutrition cohort study.

Epidemiological evidence suggests that the Mediterranean diet (MD) could reduce the risk of breast cancer (BC). As evidence from the prospective studies remains scarce and conflicting, we investigated the association between adherence to the MD and risk of BC among 335,062 women recruited from 1992 to 2000, in ten European countries, and followed for 11 years on average. Adherence to the MD was estimated through an adapted relative Mediterranean diet (arMED) score excluding alcohol. Cox proportional hazards regression models were used while adjusting for BC risk factors. A total of 9,009 postmenopausal and 1,216 premenopausal first primary incident invasive BC were identified (5,862 estrogen or progesterone receptor positive [ER+/PR+] and 1,018 estrogen and progesterone receptor negative [ER-/PR-]). The arMED was inversely associated with the risk of BC overall and in postmenopausal women (high vs. low arMED score; hazard ratio [HR] = 0.94 [95% confidence interval [CI]: 0.88, 1.00] ptrend = 0.048, and HR = 0.93 [95% CI: 0.87, 0.99] ptrend = 0.037, respectively). The association was more pronounced in ER-/PR- tumors (HR = 0.80 [95% CI: 0.65, 0.99] ptrend = 0.043). The arMED score was not associated with BC in premenopausal women. Our findings show that adherence to a MD excluding alcohol was related to a modest reduced risk of BC in postmenopausal women, and this association was stronger in receptor-negative tumors. The results support the potential scope for BC prevention through dietary modification.

Alcohol dehydrogenase and aldehyde dehydrogenase gene polymorphisms, alcohol intake and the risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition study.

BACKGROUND/OBJECTIVES: Heavy alcohol drinking is a risk factor of colorectal cancer (CRC), but little is known on the effect of polymorphisms in the alcohol-metabolizing enzymes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) on the alcohol-related risk of CRC in Caucasian populations. SUBJECTS/METHODS: A nested case-control study (1269 cases matched to 2107 controls by sex, age, study centre and date of blood collection) was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC) to evaluate the impact of rs1229984 (ADH1B), rs1573496 (ADH7) and rs441 (ALDH2) polymorphisms on CRC risk. Using the wild-type variant of each polymorphism as reference category, CRC risk estimates were calculated using conditional logistic regression, with adjustment for matching factors. RESULTS: Individuals carrying one copy of the rs1229984(A) (ADH1B) allele (fast metabolizers) showed an average daily alcohol intake of 4.3 g per day lower than subjects with two copies of the rs1229984(G) allele (slow metabolizers) (P(diff)<0.01). None of the polymorphisms was associated with risk of CRC or cancers of the colon or rectum. Heavy alcohol intake was more strongly associated with CRC risk among carriers of the rs1573496(C) allele, with odds ratio equal to 2.13 (95% confidence interval: 1.26-3.59) compared with wild-type subjects with low alcohol consumption (P(interaction)=0.07). CONCLUSIONS: The rs1229984(A) (ADH1B) allele was associated with a reduction in alcohol consumption. The rs1229984 (ADH1B), rs1573496 (ADH7) and rs441 (ALDH2) polymorphisms were not associated with CRC risk overall in Western-European populations. However, the relationship between alcohol and CRC risk might be modulated by the rs1573496 (ADH7) polymorphism.

Neuropeptide levels in Dercum's disease (adiposis dolorosa).

Dercum's disease (adiposis dolorosa) is characterised by adiposity and chronic pain in the adipose tissue. It has been proposed that conditions encompassing chronic pain have altered concentrations of neuropeptides involved in pain transmission. The aim of this investigation was to examine whether patients with Dercum's disease have abnormal concentrations of different neuropeptides. In cerebrospinal fluid (CSF) and in plasma (P) from 53 patients with Dercum's disease substance P-like immunoreactivity (SP-LI), neuropeptide Y-like immunoreactivity (NPY-LI), ß-endorphin-like immunoreactivity (ß-END-LI), calcitonin gene-related peptidelike immunoreactivity (CGRP-LI), met-enkephalin-like immunoreactivity (m-ENK-LI), vasoactive intestinal polypeptide-like immunoreactivity (VIP-LI), somatostatin (SOM-LI), γ2-melanocyte-stimulating hormone-like immunoreactivity (γ2-MSH-LI), and dynorphin-like immunoreactivity (DYN-LI) were measured. Three of the substances were also measured in a control group. The CSF concentration of SP was statistically significantly lower in the Dercum group than in the control group, whereas NPY-LI and b-END-LI were borderline statistically significantly lower and higher, respectively, in Dercum patients compared to controls. Compared with reference values, CSF-MSH-LI levels were slightly elevated and CSF-NPY-LI levels were slightly lowered in the Dercum group. The other substances in both CSF and plasma were within the reference values with a high degree of statistical significance. In conclusion, altered levels of neuropeptides that have previously been seen in different pain conditions cannot clearly be demonstrated in Dercum's disease.

Metabolic risk factors and skin cancer in the Metabolic Syndrome and Cancer Project (Me-Can).

BACKGROUND: Little is known about the associations of metabolic aberrations with malignant melanoma (MM) and nonmelanoma skin cancer (NMSC). OBJECTIVES: To assess the associations between metabolic factors (both individually and combined) and the risk of skin cancer in the large prospective Metabolic Syndrome and Cancer Project (Me-Can). METHODS: During a mean follow-up of 12 years of the Me-Can cohort, 1728 (41% women) incident MM, 230 (23% women) fatal MM and 1145 (33% women) NMSC were identified. Most NMSC cases (76%) were squamous cell carcinoma (SCC) (873, 33% women). Hazard ratios (HRs) were estimated by Cox proportional hazards regression for quintiles and standardized z-scores (with a mean of 0 and SD of 1) of body mass index (BMI), blood pressure, glucose, cholesterol, triglycerides and for a combined metabolic syndrome score. Risk estimates were corrected for random error in the measurements. RESULTS: Blood pressure per unit increase of z-score was associated with an increased risk of incident MM cases in men and women [HR 1·17, 95% confidence interval (CI) 1·04-1·31 and HR 1·18, 95% CI 1·03-1·36, respectively] and fatal MM cases among women (HR 2·39, 95% CI 1·58-3·64). In men, all quintiles for BMI above the reference were associated with a higher risk of incident MM. In women, SCC NMSC risk increased across quintiles for glucose levels (P-trend 0·02) and there was a trend with triglyceride concentration (P-trend 0·09). CONCLUSION: These findings suggest that mechanisms linked to blood pressure may be involved in the pathogenesis of MM. SCC NMSC in women could be related to glucose and lipid metabolism.

Helicobacter pylori infection assessed by ELISA and by immunoblot and noncardia gastric cancer risk in a prospective study: the Eurgast-EPIC project.

BACKGROUND: In epidemiological studies, Helicobacter pylori infection is usually detected by enzyme-linked immunosorbent assay (ELISA). However, infection can spontaneously clear from the mucosa during the progression of atrophy and could lead to substantial under-detection of infection and underestimation of its effect on gastric cancer (GC) risk. Antibodies detected by western blot are known to persist longer after the loss of the infection. METHODS: In a nested case-control study from the Eurogast-EPIC cohort, including 88 noncardia GC cases and 338 controls, we assessed the association between noncardia GC and H. pylori infection comparing antibodies detected by western blot (HELICOBLOT2.1) to those detected by ELISA (Pyloriset EIA-GIII(®)). RESULTS: By immunoblot, 82 cases (93.2%) were H. pylori positive, 10 of these cases (11.4%) were negative by ELISA and only 6 cases (6.8%) were negative by both ELISA and immunoblot. Multivariable odds ratio (OR) for noncardia GC comparing immunoglobulin G positive versus negative by ELISA was 6.8 [95% confidence interval (CI) 3.0-15.1], and by immunoblot, the OR was 21.4 (95% CI 7.1-64.4). CONCLUSIONS: Using a western blot assay, nearly all noncardia GC were classified as H. pylori positive and the OR was more than threefold higher than the OR assessed by ELISA, supporting the hypothesis that H. pylori infection is a necessary condition for noncardia GC.

Combined effect of low-penetrant SNPs on breast cancer risk.

BACKGROUND: Although many low-penetrant genetic risk factors for breast cancer have been discovered, knowledge about the effect of multiple risk alleles is limited, especially in women <50 years. We therefore investigated the association between multiple risk alleles and breast cancer risk as well as individual effects according to age-approximated pre- and post-menopausal status. METHODS: Ten previously described breast cancer-associated single-nucleotide polymorphisms (SNPs) were analysed in a joint European biobank-based study comprising 3584 breast cancer cases and 5063 cancer-free controls. Genotyping was performed using MALDI-TOF mass spectrometry, and odds ratios were estimated using logistic regression. RESULTS: Significant associations with breast cancer were confirmed for 7 of the 10 SNPs. Analysis of the joint effect of the original 10 as well as the statistically significant 7 SNPs (rs2981582, rs3803662, rs889312, rs13387042, rs13281615, rs3817198 and rs981782) found a highly significant trend for increasing breast cancer risk with increasing number of risk alleles (P-trend 5.6 × 10(-20) and 1.5 × 10(-25), respectively). Odds ratio for breast cancer of 1.84 (95% confidence interval (CI): 1.59-2.14; 10 SNPs) and 2.12 (95% CI: 1.80-2.50; 7 SNPs) was seen for the maximum vs the minimum number of risk alleles. Additionally, one of the examined SNPs (rs981782 in HCN1) had a protective effect that was significantly stronger in premenopausal women (P-value: 7.9 × 10(-4)). CONCLUSION: The strongly increasing risk seen when combining many low-penetrant risk alleles supports the polygenic inheritance model of breast cancer.

Tumour-related factors and prognosis in breast cancer detected by screening.

BACKGROUND: Breast cancer detected by screening has an unexplained prognostic advantage beyond stage shift compared with cancers detected clinically. The aim was to investigate biological factors in invasive breast cancer, with reference to mode of detection and rate of death from breast cancer. METHODS: Histology, oestrogen receptor α and ß, progesterone receptor, human epidermal growth factor receptor (HER) 2, cyclin D1, p27, Ki-67 and perinodal growth were analysed in 466 tumours from a prospective cohort, the Malmö Diet and Cancer Study. Using logistic regression, odds ratios were calculated to investigate the relationship between tumour characteristics and mode of detection. The same tumour factors were analysed in relation to standard prognostic features. Death from breast cancer was analysed using Cox regression with adjustments for standard tumour factors; differences following adjustment were analysed by means of Freedman statistics. RESULTS: None of the biological tumour characteristics varied with mode of detection of breast cancer. After adjustment for age, tumour size, axillary lymph node involvement (ALNI) and grade, women with cancer detected clinically had an increased risk of death from breast cancer (hazard ratio 2·48, 95 per cent confidence interval 1·34 to 4·59), corresponding to a 37·2 per cent difference compared with the unadjusted model. Additional adjustment for biological tumour factors studied caused only minor changes. CONCLUSION: None of the biological tumour markers investigated explained the improved prognosis in breast cancer detected by screening. None of the factors was related to ALNI, suggesting that other mechanisms may be responsible for tumour spread.

Oral contraceptive use and reproductive factors and risk of ovarian cancer in the European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: It is well established that parity and use of oral contraceptives reduce the risk of ovarian cancer, but the associations with other reproductive variables are less clear. METHODS: We examined the associations of oral contraceptive use and reproductive factors with ovarian cancer risk in the European Prospective Investigation into Cancer and Nutrition. Among 327,396 eligible women, 878 developed ovarian cancer over an average of 9 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard models stratified by centre and age, and adjusted for smoking status, body mass index, unilateral ovariectomy, simple hysterectomy, menopausal hormone therapy, and mutually adjusted for age at menarche, age at menopause, number of full-term pregnancies and duration of oral contraceptive use. RESULTS: Women who used oral contraceptives for 10 or more years had a significant 45% (HR, 0.55; 95% CI, 0.41-0.75) lower risk compared with users of 1 year or less (P-trend, <0.01). Compared with nulliparous women, parous women had a 29% (HR, 0.71; 95% CI, 0.59-0.87) lower risk, with an 8% reduction in risk for each additional pregnancy. A high age at menopause was associated with a higher risk of ovarian cancer (>52 vs ≤ 45 years: HR, 1.46; 95% CI, 1.06-1.99; P-trend, 0.02). Age at menarche, age at first full-term pregnancy, incomplete pregnancies and breastfeeding were not associated with risk. CONCLUSION: This study shows a strong protective association of oral contraceptives and parity with ovarian cancer risk, a higher risk with a late age at menopause, and no association with other reproductive factors.

Circulating sex hormones and breast cancer risk factors in postmenopausal women: reanalysis of 13 studies.

BACKGROUND: Breast cancer risk for postmenopausal women is positively associated with circulating concentrations of oestrogens and androgens, but the determinants of these hormones are not well understood. METHODS: Cross-sectional analyses of breast cancer risk factors and circulating hormone concentrations in more than 6000 postmenopausal women controls in 13 prospective studies. RESULTS: Concentrations of all hormones were lower in older than younger women, with the largest difference for dehydroepiandrosterone sulphate (DHEAS), whereas sex hormone-binding globulin (SHBG) was higher in the older women. Androgens were lower in women with bilateral ovariectomy than in naturally postmenopausal women, with the largest difference for free testosterone. All hormones were higher in obese than lean women, with the largest difference for free oestradiol, whereas SHBG was lower in obese women. Smokers of 15+ cigarettes per day had higher levels of all hormones than non-smokers, with the largest difference for testosterone. Drinkers of 20+ g alcohol per day had higher levels of all hormones, but lower SHBG, than non-drinkers, with the largest difference for DHEAS. Hormone concentrations were not strongly related to age at menarche, parity, age at first full-term pregnancy or family history of breast cancer. CONCLUSION: Sex hormone concentrations were strongly associated with several established or suspected risk factors for breast cancer, and may mediate the effects of these factors on breast cancer risk.

Primary brain tumours and specific serum immunoglobulin E: a case-control study nested in the European Prospective Investigation into Cancer and Nutrition cohort.

BACKGROUND: Case-control studies suggest that patients with allergic diseases have a lower risk of developing glioma but not meningioma or schwannoma. However, those data can be differentially biased. Prospective studies with objective measurements of immunologic biomarkers, like immunoglobulin E (IgE), in blood obtained before cancer diagnosis could help to clarify whether an aetiological association exists. METHODS: The present case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) measured specific serum IgE as a biomarker for the most common inhalant allergens in 275 glioma, 175 meningioma and 49 schwannoma cases and 963 matched controls using the ImmunoCAP specific IgE test. Subjects with an IgE level ≥0.35 kUA/l (kilo antibody units per litre) were classified as sensitized by allergens. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by adjusted conditional logistic regression models for each tumour subtype. The effect of dose-response relationship was assessed in five increasing IgE level categories to estimate P-values for trend. RESULTS: The risk of glioma was inversely related to allergic sensitization (OR = 0.73; 95% CI 0.51-1.06), especially pronounced in women (OR = 0.53; 95% CI 0.30-0.95). In dose-response analyses, for high-grade glioma, the lowest OR was observed in sera with the highest IgE levels (P for trend = 0.04). No association was seen for meningioma and schwannoma. CONCLUSION: The results, based on serum samples prospectively collected in a cohort study, provide some support for the hypothesis that individuals with allergic sensitization are at reduced risk of glioma and confirm results from previous case-control studies.