BACKGROUND:An increased risk of breast cancer for relatives of breast cancer patients has been demonstrated in many studies, and having a relative diagnosed with breast cancer at an early age is an indication for breast cancer screening. This indication has been derived from estimates based on data from cancer-prone families or from BRCA1/2 mutation families, and might be biased because BRCA1/2 mutations explain only a small proportion of the familial clustering of breast cancer. The aim of the current study was to determine the predictive value of a family history of cancer with regard to early onset of female breast cancer in a population based setting.METHODS:An unselected sample of 1,987 women with and without breast cancer was studied with regard to the age of diagnosis of breast cancer.RESULTS:The risk of early-onset breast cancer was increased when there were: (1) at least 2 cases of female breast cancer in first-degree relatives (yes/no; HR at age 30: 3.09; 95% CI: 128-7.44), (2) at least 2 cases of female breast cancer in first or second-degree relatives under the age of 50 (yes/no; HR at age 30: 3.36; 95% CI: 1.12-10.08), (3) at least 1 case of female breast cancer under the age of 40 in a first- or second-degree relative (yes/no; HR at age 30: 2.06; 95% CI: 0.83-5.12) and (4) any case of bilateral breast cancer (yes/no; HR at age 30: 3.47; 95%: 1.33-9.05). The positive predictive value of having 2 or more of these characteristics was 13% for breast cancer before the age of 70, 11% for breast cancer before the age of 50, and 1% for breast cancer before the age of 30.CONCLUSION:Applying family history related criteria in an unselected population could result in the screening of many women who will not develop breast cancer at an early age.

A three-stage genome-wide association study recently identified single nucleotide polymorphisms (SNPs) in five loci (fibroblast growth receptor 2 (FGFR2), trinucleotide repeat containing 9 (TNRC9), mitogen-activated protein kinase 3 K1 (MAP3K1), 8q24, and lymphocyte-specific protein 1 (LSP1)) associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. We also evaluated their influence on overall survival in 13,527 cases from 13 studies. All participants were of European or Asian origin. rs2981582 in FGFR2 was more strongly related to ER-positive (per-allele OR (95%CI) = 1.31 (1.27-1.36)) than ER-negative (1.08 (1.03-1.14)) disease (P for heterogeneity = 10(-13)). This SNP was also more strongly related to PR-positive, low grade and node positive tumors (P = 10(-5), 10(-8), 0.013, respectively). The association for rs13281615 in 8q24 was stronger for ER-positive, PR-positive, and low grade tumors (P = 0.001, 0.011 and 10(-4), respectively). The differences in the associations between SNPs in FGFR2 and 8q24 and risk by ER and grade remained significant after permutation adjustment for multiple comparisons and after adjustment for other tumor characteristics. Three SNPs (rs2981582, rs3803662, and rs889312) showed weak but significant associations with ER-negative disease, the strongest association being for rs3803662 in TNRC9 (1.14 (1.09-1.21)). rs13281615 in 8q24 was associated with an improvement in survival after diagnosis (per-allele HR = 0.90 (0.83-0.97). The association was attenuated and non-significant after adjusting for known prognostic factors. Our findings show that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER-positive and ER-negative disease are biologically distinct. Understanding the etiologic heterogeneity of breast cancer may ultimately result in improvements in prevention, early detection, and treatment.

To show differences and similarities between risk estimation models for breast cancer in healthy women from BRCA1/2-negative or untested families. After a systematic literature search seven models were selected: Gail-2, Claus Model, Claus Tables, BOADICEA, Jonker Model, Claus-Extended Formula, and Tyrer–Cuzick. Life-time risks (LTRs) for developing breast cancer were estimated for two healthy counsellees, aged 40, with a variety in family histories and personal risk factors. Comparisons were made with guideline thresholds for individual screening. Without a clinically significant family history LTRs varied from 6.7% (Gail-2 Model) to 12.8% (Tyrer–Cuzick Model). Adding more information on personal risk factors increased the LTRs and yearly mammography will be advised in most situations. Older models (i.e. Gail-2 and Claus) are likely to underestimate the LTR for developing breast cancer as their baseline risk for women is too low. When models include personal risk factors, surveillance thresholds have to be reformulated. For current clinical practice, the Tyrer–Cuzick Model and the BOADICEA Model seem good choices.

Purpose: To describe patient, tumor, and family histories of cancer in a hospital-based cohort of patients with ovarian cancer and to identify the predictive value of these characteristics for (non)carrying a BRCA1 or BRCA2 mutation. Methods: Women diagnosed with invasive ovarian cancer between 1999 and 2003 in the west region of The Netherlands and unselected for age at diagnosis or cancer family history were included. Information was gathered on patient and tumor characteristics; p53; HER-2/neu, and KI-67 protein-expression; BRCA1/2 mutations; and family histories of cancer. Prediction tests were constructed using multivariate analyses. Results: Our study included 85 women (mean age at diagnosis, 57.6 years; standard deviation, 11.0 years). Six of these women had been previously or concurrently diagnosed with another tumor. Of the ovarian cancers, 41 (48.2%) were in an early stage (FIGO I or II). Five pathogenic mutations (6.1%) and six unclassified variants (7.3%) were identified in BRCA1/2; when the total sensitivity of the mutation scanning was taken into account, it was estimated to reflect seven pathogenic mutations (8.5%) and eight unclassified variants (9.8%). Sixty-nine women (81.2%) had at least one relative with cancer. A personal history of breast cancer and a family history of breast, ovarian, or uterine/endometrioid cancer were found to predict the presence of pathogenic mutations. Conclusion: As the combination of a personal history of breast cancer and a family history of breast, ovarian, or uterine/endometrioid cancer had good predictive value for the presence of a pathogenic BRCA1/2 mutation, the presented prediction test is a useful instrument to identify those women eligible for DNA testing.

Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies. We used 227,876 SNPs that were estimated to correlate with 77% of known common SNPs in Europeans at r2 > 0.5. SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer (P < 10(-7)). Four of these contain plausible causative genes (FGFR2, TNRC9, MAP3K1 and LSP1). At the second stage, 1,792 SNPs were significant at the P < 0.05 level compared with an estimated 1,343 that would be expected by chance, indicating that many additional common susceptibility alleles may be identifiable by this approach.

INTRODUCTION:Seven SNPs in five genomic loci were recently found to confer a mildly increased risk of breast cancer.METHODS:We have investigated the correlations between disease characteristics and the patient genotypes of these SNPs in an unselected prospective cohort of 1,267 consecutive patients with primary breast cancer.RESULTS:Heterozygote carriers and minor allele homozygote carriers for SNP rs889312 in the MAP3K1 gene were less likely to be lymph node positive at breast cancer diagnosis (P = 0.044) relative to major allele homozygote carriers. Heterozygote carriers and minor allele homozygote carriers for SNP rs3803662 near the TNCR9 gene were more likely to be diagnosed before the age of 60 years (P = 0.025) relative to major allele homozygote carriers. We also noted a correlation between the number of minor alleles of rs2981582 in FGFR2 and the average number of first-degree and second-degree relatives with breast cancer and/or ovarian cancer (P = 0.05). All other disease characteristics, including tumour size and grade, and oestrogen or progesterone receptor status, were not significantly associated with any of these variants.CONCLUSION:Some recently discovered genomic variants associated with a mildly increased risk of breast cancer are also associated with breast cancer characteristics or family history of breast cancer and ovarian cancer. These findings provide interesting new clues for further research on these low-risk susceptibility alleles.

OBJECTIVE:To describe health outcomes reported by patients with rheumatoid arthritis (RA), i.e., pain, disability and health-related quality of life, as a function of disease duration in a longitudinal approach, and to compare the course of patient-reported health outcomes by a longitudinal versus a cross-sectional approach.METHODS:Data were collected with 4 series of questionnaires between 1997 and 2002 among patients with RA (maximum number = 882) of varying disease duration. The course of patient-reported health outcomes as a function of disease duration was evaluated using both longitudinal data and cross-sectional data of the first series.RESULTS:The course of RA shows a different pattern for various health outcomes. We observed similar trends in health outcomes in this large patient sample using the longitudinal and the cross-sectional approach.CONCLUSION:Although longterm consequences of RA are preferably assessed in longer duration followup studies, cross-sectional studies, including patients with a broad range of disease durations, seem to provide fairly reliable estimates of the course of health outcomes.

Objective. To assess the predictive value of selected sociodemographic characteristics, rheumatoid arthritis (RA)-specific clinical factors, and comorbidity with respect to patient-reported health outcomes, i.e., pain, disability, and health-related quality of life, among patients with RA. Methods. Data were collected between 1997 and 2002 among 882 patients with RA of varying disease duration using questionnaires and clinical examinations. Health outcomes were evaluated over 5 years as a function of disease duration by means of random intercept linear regression. Then we selected the 10% of patients with the poorest and best health outcomes during the 5 years of followup compared to others with equal disease duration. Separate multivariate logistic regression analyses were conducted to identify factors associated with poor and good outcomes. Results. Sociodemographic characteristics seemed to be less important in the prediction of health outcomes. After RA-specific clinical factors, comorbidity appeared to be a major predictive factor for health outcomes. In particular, psychological comorbidity, i.e., depressive symptomatology, was a consistent predictive factor with respect to all health outcomes. Conclusion. Assessment of comorbidity needs to be incorporated into the management of RA in order to prevent poor outcomes and to adapt therapies to the specific situation of individual patients. Periodic routine screening for and monitoring of somatic and psychological comorbidity should be included in clinical practice.

Purpose: We assessed the cost-effectiveness of mammography screening for women under the age of 50, from breast cancer families without proven BRCA1/BRCA2 mutations, because current criteria for screening healthy women from breast cancer families are not evidence-based. Methods: We did simulation studies with mathematical models on the cost-effectiveness of mammography screening of women under the age of 50 with breast cancer family histories. Breast cancer screening was simulated with varying screening intervals (6, 12, 18, and 24 months) and screening cohorts (starting at ages 30, 35, 40, and 45, and continuing to age 50). Incremental costs of screening were compared with those of women ages 50 to 52 years, the youngest age group currently routinely screened in the nationwide screening program of the Netherlands, to determine cost-effectiveness. Sensitivity analyses were done to explore the effects of model assumptions. The cost-effectiveness of breast cancer screening for women over the age of 50 was not debated. Results: The most effective screening interval was found to be 12 months, which, however, seems only to be cost-effective in a small group of women under the age of 50 with at least two affected relatives, including at least one affected in the first degree diagnosed under the age of 50. Significantly, early breast cancer screening never seemed to be cost-effective in women with only one affected first-degree or second-degree relative. Conclusion: Annual breast cancer screening with mammography for women under the age of 50 seems to be cost-effective in women with strong family histories of breast cancer, even when no BRCA1/BRCA2 mutation was found in affected family members. (Cancer Epidemiol Biomarkers Prev 2006;15(3):429–36)

Objective: To study the associations between disability and health‐related quality of life (HRQoL), respectively, and radiographic joint damage, disease activity, pain, and depressive symptoms among patients with rheumatoid arthritis (RA). Methods: Data were collected through questionnaires and clinical examinations at baseline (1997) and at 2 years' follow‐up among patients with RA (n = 307). Disability was measured with a validated Dutch questionnaire, derived from the Health Assessment Questionnaire (HAQ), and HRQoL with a validated Dutch version of the RAND‐36, using physical (PCS) and mental (MCS) component summary scales. Multivariate linear regression analyses were performed to assess the relationship between disability or HRQoL and radiographic damage, disease activity, pain, and depressive symptoms. Results: Pain, with respect to disability and PCS, and depressive symptoms, with respect to MCS, were more important predictors than radiographic damage and disease activity. Conclusions: Daily RA practice needs to be broadened by regular assessment of disease burden from the patients' perspectives. Patient‐reported measures, such as disability or HRQoL, should be incorporated for monitoring health outcomes of individual patients and for initiating and evaluating therapy.

We have developed a multiplexed and miniaturized TB serological assay with the aim of identifying (combinations of) antigens that maximally discriminate between TB and non-TB patients. It features a microarray accommodating 54 TB antigens, less than 1 μl serum consumption and an indirect immunofluorescence detection protocol. With a panel of 20 TB and 80 non-TB sera we ranked combinations of TB antigens with respect to sensitivity and specificity of TB detection by means of logistic step-forward regression analysis. The highest-ranking TB antigen combination had an area-under-the-curve of the receiver–operator-characteristics (ROC) of 0.95. We also identified an antigen that on its own provided good specificity and sensitivity of TB detection (Ara6–BSA; area-under-the-ROC curve: 0.90). These area-under-the-ROC curve values are exceptionally high for a serological TB assay. We conclude that TB antigen microarrays permit rapid identification of TB antigens that, either alone or in combination, discriminate maximally between TB and non-TB patients and that such identification provides an excellent starting point for developing point-of-care diagnostic assays.

Breast cancer is the most common cancer among women in Western countries. From a clinical point of view, discriminating between women with a high breast cancer risk and those with a low risk is of utmost importance, and proper breast cancer screening and counseling strategies are key in reducing mortality. Recently, a breast cancer risk prediction model incorporating familial risk factors was published in this Journal, the Tyrer model [1]. Tyrer et al. provided a two locus genetic model with the rst gene representing both BRCA1 and BRCA2, and the second chosen to give as good a t as possible to the observed risk from family history, in combination with the population incidence of breast cancer. At the same time our group modelled a similar breast cancer prediction model, the Jonker model [2]. Our genetic model encompassed three susceptibility loci, viz. BRCA1, BRCA2 as two separate genes, and a third hypothetical gene BRCAu. The values of this third gene were similarly chosen, i.e. to explain the remaining familial breast cancer risk not explained by BRCA1 and BRCA2, with the complete model explaining all observed breast cancer incidence in the population. Despite these similarities there were also di erences. For example, the Tyrer model incorporated personal risk factors, whereas the Jonker model did not. Also, the two models were t on di erent data sources. The Tyrer model was t on a cohort in which daughters of breast

Risk estimation in breast cancer families is often estimated by use of the Claus tables. We analyzed the family histories of 196 counselees; compared the Claus tables with the Claus, the BRCA1/2, the BRCA1/2/ models; and performed linear regression analysis to extend the Claus tables with characteristics of hereditary breast cancer. Finally, we compared the Claus extended method with the Claus, the BRCA1/2, and the BRCA1/2/u models. We found 47% agreement for Claus table versus Claus model; 39% agreement for Claus table versus BRCA1/2 model; 48% agreement for Claus table versus BRCA1/2/u model; 37% agreement for Claus extended method versus Claus model; 44% agreement for Claus extended model versus BRCA1/2 model; and 66% agreement for Claus extended method versus BRCA1/2/u model. The regression formula (Claus extended method) for the lifetime risk for breast cancer was 0.08 + 0.40 (*) Claus Table + 0.07 (*) ovarian cancer + 0.08 (*) bilateral breast cancer + 0.07 (*) multiple cases. This new method for risk estimation, which is an extension of the Claus tables, incorporates information on the presence of ovarian cancer, bilateral breast cancer, and whether there are more than two affected relatives with breast cancer. This extension might offer a good alternative for breast cancer risk estimation in clinical practice.

OBJECTIVE:To identify health care aspects of inadequate quality in rheumatoid arthritis (RA) care from the perspective of patients, and to study to what extent patients' perspectives on quality of care are associated with patient characteristics.DESIGN:Cross-sectional questionnaire survey performed in 1999.SETTING:Secondary and tertiary rheumatology outpatient clinics.STUDY PARTICIPANTS:A random sample (n = 683) of patients diagnosed with rheumatoid arthritis according to the 1987 revised American College of Rheumatology criteria. Patients varied widely with respect to age (mean 61.5 years) and disease duration (mean 10.7 years).MAIN OUTCOME MEASURES:Using the method of the QUOTE-questionnaire, patients' were asked to rate the importance to them of 29 aspects of care, and to rate the performance of five different health care providers [i.e. rheumatologist, general practitioner (GP), physiotherapist, home nurse, and formal home help] relating to these aspects. To identify aspects of inadequate quality, patients' performance ratings were weighted by importance ratings within each health care service. Inadequate performance on an extremely important aspect was found to be a more serious quality problem than an inadequate performance on an aspect that was less important to patients. Using regression analyses, the association between patients' quality ratings and patient characteristics was assessed.RESULTS:Several aspects of inadequate quality were identified, namely in the field of knowledge of rheumatism and particularly for GPs, physiotherapists, home nurses, and formal home help, and in the field of information on medication and treatment for rheumatologists and GPs. Furthermore, for the majority of the importance and performance ratings, we found no association with patient-related characteristics.CONCLUSIONS:Our study demonstrated that the quality of care could be improved further from the perspective of patients. These findings may be used for making health care more responsive to patients' needs.

OBJECTIVE:To describe the extent of somatic comorbid conditions in patients with rheumatoid arthritis (RA) and to assess the influence of comorbidity on health-related quality of life (HRQOL).METHODS:A 2-year followup study on health and HRQOL was conducted among 679 patients with RA with varying disease duration. Data were collected by means of questionnaires and clinical examinations at baseline and at 2-year followup. Comorbidity was measured by a self-administered questionnaire including 17 chronic diseases. HRQOL was assessed with the RAND-36. The effect of incident comorbid conditions on HRQOL was investigated with linear regression analyses.RESULTS:At least one comorbid condition was reported at baseline by 56% of patients. Significant differences in prevalence rates with the Dutch population were found. The effect of comorbidity on HRQOL depended on both the type of comorbid condition and the dimension of HRQOL. Gastrointestinal (GI) diseases, cancer, dizziness with falling (and less severe chronic pulmonary disease and heart complaints) resulted in significant adverse changes in HRQOL. For the other conditions under study no influence could be detected.CONCLUSION:Our results indicate that measuring comorbidity by a summary count, assuming an overall equally large effect of each comorbid condition, may not reveal the real effect. With respect to clinical practice, our results emphasize the relevance for health care providers to be aware of specific comorbid conditions exposing patients with RA at risk for additional impairment of HRQOL, and to be aware of interactions with RA that may be unique.

Objective. To multidimensionally assess fatigue in rheumatoid arthritis (RA) and to evaluate the impact of fatigue on health-related quality of life (HRQOL).Methods. The study was conducted in 1999 among 490 RA patients with varying disease duration. Fatigue was measured with the Multidimensional Fatigue Inventory (MFI-20) and HRQOL with a validated Dutch version of the RAND 36-Item Health Survey. We evaluated the impact of fatigue on HRQOL by multiple linear regression analyses taking into account RA-related pain and depressive symptoms.Results. Different aspects of fatigue selectively explained different dimensions of HRQOL. The MFI-20 was entered last to the linear regression models, resulting in an additional increase of explained variance of 1% (mental health) to 14% (vitality).Conclusion. The multidimensional portrayal of RA-related fatigue can be used to develop intervention strategies targeted to specific aspects of fatigue. Fatigue, supplementary to RA-related pain and depressive symptoms, appears to be a feasible and treatable target in the clinical management of RA to increase HRQOL.

OBJECTIVETo assess the prevalence of unmet health care demands among rheumatoid arthritis (RA) patients, and to determine if these unmet demands indicate underuse.METHODSA total of 679 patients with RA participated in a questionnaire survey and clinical examination. Unmet health care demands and health care use were assessed for orthopedic care, allied health care, home care, and psychosocial care. Indications for underuse were determined by comparing health outcomes of patients with unmet health care demands and of health care users.RESULTSOf the 679 patients, 28.7% had an unmet demand for 1 of the 4 services: 13.4% for allied health care, 9.7% for orthopedic care, 9.4% for home care, and 6.2% for psychosocial care. Underuse of allied health care, home care and psychosocial care was observed.CONCLUSIONUnmet demands for health care are frequent among RA patients. Most unmet demands indicate underuse. Health care professionals should therefore be more responsive to the demands of patients.

The identification of an increasing number of variants of uncertain clinical significance (VUCS) in genetic testing for hereditary breast cancer poses serious problems for genetic counseling, because no data are available about the psychosocial impact of discussing such an unclear risk message. The current study is the first to present data on how test applicants actually understand and cope with such a result if communicated by a geneticist. We compared 10 women who received a VUCS result with 34 women who carried the deleterious mutation, 37 women who did not carry the deleterious mutation or 'true negatives,' and 160 women who received a so-called inconclusive result before and after test disclosure. Women, with whom a VUCS result was discussed, reported quite a high level of comprehension of the result. In addition, compared with the pretest measures, they did not report a higher level of perceived risk (p = 0.58) and even reported a decrease in breast cancer distress (p = 0.03). They were very comparable to women who received an inconclusive result on all post-disclosure measures. Our results suggest that discussing a VUCS result in genetic counseling does not give rise for concern.