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Introduction: The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline\ud mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have\ud utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of\ud uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of\ud Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological\ud predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical\ud modeling.\ud Methods: Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for\ud invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565\ud BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of\ud mutation status by histopathological markers were derived using a Mantel-Haenszel approach.\ud Results: ER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to\ud 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years\ud or older (LR = 4.13 (3.70 to 4.62)) versus younger than 50 years (LR = 3.16 (2.96 to 3.37)). For BRCA2, ER-positive grade 3\ud phenotype modestly predicted positive mutation status irrespective of age (LR = 1.7-fold), whereas ER-negative grade 3\ud features modestly predicted positive mutation status at 50 years or older (LR = 1.54 (1.27 to 1.88)). Triple-negative tumor\ud status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR = 3.73 (3.43 to 4.05)) and\ud 50 years or older (LR = 4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years\ud or older (LR = 1.79 (1.42 to 2.24)).\ud Conclusions: These results refine likelihood-ratio estimates for predicting BRCA1 and BRCA2 mutation status by using\ud commonly measured histopathological features. Age at diagnosis is an important variable for most analyses, and grade is\ud more informative than ER status for BRCA2 mutation carrier prediction. The estimates will improve BRCA1 and BRCA2\ud variant classification and inform patient mutation testing and clinical management.

Background: Several toxicologic and epidemiologic studies have produced evidence that occupational exposure to polycyclic aromatic hydrocarbons (PAH) is a risk factor for ischemic heart disease (IHD). However, a clear exposure-response relation has not been demonstrated. Methods: We studied a relation between exposure to PAH and mortality from IHD (418 cases) in a cohort of 12,367 male asphalt workers from Denmark, Finland, France, Germany, Israel, The Netherlands and Norway. The earliest follow up (country-specific) started in 1953 and the latest ended in 2000, averaging 17 years. Exposures to benzo(a)pyrene were assessed quantitatively using measurement-driven exposure models. Exposure to coal tar was assessed in a semiquantitative manner on the basis of information supplied by company representatives. We carried out sensitivity analyses to assess potential confounding by tobacco smoking. Results: Both cumulative and average exposure indices for benzo(a)pyrene were positively associated with mortality from IHD. The highest relative risk for fatal IHD was observed for average benzo(a)pyrene exposures of 273 ng/m 3 or higher, for which the relative risk was 1.64 (95% confidence interval = 1.13-2.38). Similar results were obtained for coal tar exposure. Sensitivity analysis indicated that even in a realistic scenario of confounding by smoking, we would observe approximately 20% to 40% excess risk in IHD in the highest PAH-exposure categories. Conclusions: Our results lend support to the hypothesis that occupational PAH exposure causes fatal IHD and demonstrate a consistent exposure-response relation for this association. Copyright © 2005 by Lippincott Williams & Wilkins.

Background: Previously, small studies have found that BRCA1 and BRCA2 breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization. Methods: We used data from 4,325 BRCA1 and 2,568 BRCA2 mutation carriers to analyze the pathology of invasive breast, ovarian, and contralateral breast cancers. Results: There was strong evidence that the proportion of estrogen receptor (ER)-negative breast tumors decreased with age at diagnosis among BRCA1 (P-trend = 1.2 × 10−5), but increased with age at diagnosis among BRCA2, carriers (P-trend = 6.8 × 10−6). The proportion of triple-negative tumors decreased with age at diagnosis in BRCA1 carriers but increased with age at diagnosis of BRCA2 carriers. In both BRCA1 and BRCA2 carriers, ER-negative tumors were of higher histologic grade than ER-positive tumors (grade 3 vs. grade 1; P = 1.2 × 10−13 for BRCA1 and P = 0.001 for BRCA2). ER and progesterone receptor (PR) expression were independently associated with mutation carrier status [ER-positive odds ratio (OR) for BRCA2 = 9.4, 95% CI: 7.0–12.6 and PR-positive OR = 1.7, 95% CI: 1.3–2.3, under joint analysis]. Lobular tumors were more likely to be BRCA2-related (OR for BRCA2 = 3.3, 95% CI: 2.4–4.4; P = 4.4 × 10−14), and medullary tumors BRCA1-related (OR for BRCA2 = 0.25, 95% CI: 0.18–0.35; P = 2.3 × 10−15). ER-status of the first breast cancer was predictive of ER-status of asynchronous contralateral breast cancer (P = 0.0004 for BRCA1; P = 0.002 for BRCA2). There were no significant differences in ovarian cancer morphology between BRCA1 and BRCA2 carriers (serous: 67%; mucinous: 1%; endometrioid: 12%; clear-cell: 2%). Conclusions/Impact: Pathologic characteristics of BRCA1 and BRCA2 tumors may be useful for improving risk-prediction algorithms and informing clinical strategies for screening and prophylaxis. Cancer Epidemiol Biomarkers Prev; 21(1); 134–47. ©2011 AACR.

Background: Immunohistochemical markers are often used to classify breast cancer into subtypes that are biologically\ud distinct and behave differently. The aim of this study was to estimate mortality for patients with the major subtypes of\ud breast cancer as classified using five immunohistochemical markers, to investigate patterns of mortality over time, and to\ud test for heterogeneity by subtype.\ud Methods and Findings: We pooled data from more than 10,000 cases of invasive breast cancer from 12 studies that had\ud collected information on hormone receptor status, human epidermal growth factor receptor-2 (HER2) status, and at least\ud one basal marker (cytokeratin [CK]5/6 or epidermal growth factor receptor [EGFR]) together with survival time data.\ud Tumours were classified as luminal and nonluminal tumours according to hormone receptor expression. These two groups\ud were further subdivided according to expression of HER2, and finally, the luminal and nonluminal HER2-negative tumours\ud were categorised according to expression of basal markers. Changes in mortality rates over time differed by subtype. In\ud women with luminal HER2-negative subtypes, mortality rates were constant over time, whereas mortality rates associated\ud with the luminal HER2-positive and nonluminal subtypes tended to peak within 5 y of diagnosis and then decline over time.\ud In the first 5 y after diagnosis the nonluminal tumours were associated with a poorer prognosis, but over longer follow-up\ud times the prognosis was poorer in the luminal subtypes, with the worst prognosis at 15 y being in the luminal HER2-positive\ud tumours. Basal marker expression distinguished the HER2-negative luminal and nonluminal tumours into different subtypes.\ud These patterns were independent of any systemic adjuvant therapy.\ud Conclusions: The six subtypes of breast cancer defined by expression of five markers show distinct behaviours with\ud important differences in short term and long term prognosis. Application of these markers in the clinical setting could have\ud the potential to improve the targeting of adjuvant chemotherapy to those most likely to benefit. The different patterns of\ud mortality over time also suggest important biological differences between the subtypes that may result in differences in\ud response to specific therapies, and that stratification of breast cancers by clinically relevant subtypes in clinical trials is\ud urgently required.

Background We compared performance of different exposure assessment approaches in a cohort study of cancer risk among European asphalt workers. Methods Three bitumen fume exposure indices (duration of exposure (years), average exposure (mg/m3) and cumulative exposure (mg/m3*years)) and two latency models (with and without a 15 year lag) were considered for an association between lung cancer mortality and bitumen fume. Results There was no association between lung cancer risk and either duration or cumulative exposure. However, there was the suggestion of an increase in lung cancer risk accompanying rise in average exposure. Only models with average bitumen fume exposure (with or without lag) improved model fit, albeit to the same extent. Conclusions Constructing quantitative indices of exposure intensity was justified because they produced the greatest improvement in fit of models that explored possible relationship between bitumen fume exposure and lung cancer risk. The identified associations require further investigation. Am. J. Ind. Med. 43:40–48, 2003. © 2003 Wiley‐Liss, Inc.

Background We compared performance of different exposure assessment approaches in a cohort study of cancer risk among European asphalt workers. Methods Three bitumen fume exposure indices (duration of exposure (years), average exposure (mg/m3) and cumulative exposure (mg/m3*years)) and two latency models (with and without a 15 year lag) were considered for an association between lung cancer mortality and bitumen fume. Results There was no association between lung cancer risk and either duration or cumulative exposure. However, there was the suggestion of an increase in lung cancer risk accompanying rise in average exposure. Only models with average bitumen fume exposure (with or without lag) improved model fit, albeit to the same extent. Conclusions Constructing quantitative indices of exposure intensity was justified because they produced the greatest improvement in fit of models that explored possible relationship between bitumen fume exposure and lung cancer risk. The identified associations require further investigation. Am. J. Ind. Med. 43:40–48, 2003. © 2003 Wiley‐Liss, Inc.

Background An increased risk of lung cancers among asphalt workers has been suggested in epidemiological studies based on large scale statistical analyses. Methods In a multi‐country study of 29,820 male workers employed in road paving, asphalt mixing and roofing, 32,245 ground and building construction workers and 17,757 other workers from Denmark, Finland, France, Germany, Israel, the Netherlands, Norway, and Sweden, with mortality that was documented from 1953–2000. Exposures to bitumen fume, coal tar, 4–6 ring polycyclic aromatic hydrocarbons, organic vapor, diesel exhaust, asbestos, and silica dust were assessed via a job‐exposure matrix. Standardized mortality ratios (SMRs) and 95% confidence intervals (CIs) based on national mortality rates, as well as relative risks (RRs) based on Poisson regression models were calculated. Results The SMR of lung cancer among workers exposed to bitumen fume (1.08, 95% CI 0.99–1.18) was comparable to that of non‐exposed workers (SMR 1.05, 95% CI 0.92–1.19). In a sub‐cohort of bitumen‐exposed workers without exposure to coal tar, the SMR of lung cancer was 1.23 (95% CI 1.02–1.48). The analysis based on the semi‐quantitative, matrix‐based exposures in the whole cohort did not suggest an increased lung cancer risk following exposure to bitumen fume. However, in an analysis restricted to road pavers, based on quantitative estimate of bitumen fume exposure, a dose‐response was suggested for average level of exposure, applying a 15‐year lag, which was marginally reduced after adjustment for co‐exposure to coal tar. The results for cancer of the head and neck were similar to those of lung cancer, although they were based on a smaller number of deaths. There was no clear suggestion of an association with bitumen fume for any other neoplasm. Conclusions The results of the analysis by bitumen fume exposure do not allow us to conclude on the presence or absence of a causal link between exposure to bitumen fume and risk of cancer of the lung and the head and neck. Am. J. Ind. Med. 43:28–39, 2003. © 2003 Wiley‐Liss, Inc.

Background An exposure matrix (EM) for known and suspected carcinogens was required for a multicenter international cohort study of cancer risk and bitumen among asphalt workers. Methods Production characteristics in companies enrolled in the study were ascertained through use of a company questionnaire (CQ). Exposures to coal tar, bitumen fume, organic vapor, polycyclic aromatic hydrocarbons, diesel fume, silica, and asbestos were assessed semi‐quantitatively using information from CQs, expert judgment, and statistical models. Exposures of road paving workers to bitumen fume, organic vapor, and benzo(a)pyrene were estimated quantitatively by applying regression models, based on monitoring data, to exposure scenarios identified by the CQs. Results Exposures estimates were derived for 217 companies enrolled in the cohort, plus the Swedish asphalt paving industry in general. Most companies were engaged in road paving and asphalt mixing, but some also participated in general construction and roofing. Coal tar use was most common in Denmark and The Netherlands, but the practice is now obsolete. Quantitative estimates of exposure to bitumen fume, organic vapor, and benzo(a)pyrene for pavers, and semi‐quantitative estimates of exposure to these agents among all subjects were strongly correlated. Semi‐quantitative estimates of exposure to bitumen fume and coal tar exposures were only moderately correlated. EM assessed non‐monotonic historical decrease in exposures to all agents assessed except silica and diesel exhaust. Conclusions We produced a data‐driven EM using methodology that can be adapted for other multicenter studies. Am. J. Ind. Med. 43:3–17, 2003. © 2003 Wiley‐Liss, Inc.

Background Inhalation of bitumen fumes is potentially carcinogenic to humans. Methods We conducted a study of 29,820 male workers exposed to bitumen in road paving, asphalt mixing and roofing, 32,245 ground and building construction workers unexposed to bitumen, and 17,757 workers not classifiable as bitumen workers, from Denmark, Finland, France, Germany, Israel, the Netherlands, Norway, and Sweden, with mortality follow‐up during 1953–2000. We calculated standardized mortality ratios (SMRs) and 95% confidence intervals (CIs) based on national mortality rates. Poisson regression analyses compared mortality of bitumen workers to that of building or ground construction workers. Results The overall mortality was below expectation in the total cohort (SMR 0.92, 95% CI 0.90–0.94) and in each group of workers. The SMR of lung cancer was higher among bitumen workers (1.17, 95% CI 1.04–1.30) than among workers in ground and building construction (SMR 1.01, 95% CI 0.89–1.15). In the internal comparison, the relative risk (RR) of lung cancer mortality among bitumen workers was 1.09 (95% CI 0.89–1.34). The results of cancer of the head and neck were similar to those of lung cancer, based on a smaller number of deaths. There was no suggestion of an association between employment in bitumen jobs and other cancers. Conclusions European workers employed in road paving, asphalt mixing and other jobs entailing exposure to bitumen fume might have experienced a small increase in lung cancer mortality risk, compared to workers in ground and building construction. However, exposure assessment was limited and confounding from exposure to carcinogens in other industries, tobacco smoking, and other lifestyle factors cannot be ruled out. Am. J. Ind. Med. 43:18–27, 2003. © 2003 Wiley‐Liss, Inc.

Background An increased risk of lung cancers among asphalt workers has been suggested in epidemiological studies based on large scale statistical analyses. Methods In a multi‐country study of 29,820 male workers employed in road paving, asphalt mixing and roofing, 32,245 ground and building construction workers and 17,757 other workers from Denmark, Finland, France, Germany, Israel, the Netherlands, Norway, and Sweden, with mortality that was documented from 1953–2000. Exposures to bitumen fume, coal tar, 4–6 ring polycyclic aromatic hydrocarbons, organic vapor, diesel exhaust, asbestos, and silica dust were assessed via a job‐exposure matrix. Standardized mortality ratios (SMRs) and 95% confidence intervals (CIs) based on national mortality rates, as well as relative risks (RRs) based on Poisson regression models were calculated. Results The SMR of lung cancer among workers exposed to bitumen fume (1.08, 95% CI 0.99–1.18) was comparable to that of non‐exposed workers (SMR 1.05, 95% CI 0.92–1.19). In a sub‐cohort of bitumen‐exposed workers without exposure to coal tar, the SMR of lung cancer was 1.23 (95% CI 1.02–1.48). The analysis based on the semi‐quantitative, matrix‐based exposures in the whole cohort did not suggest an increased lung cancer risk following exposure to bitumen fume. However, in an analysis restricted to road pavers, based on quantitative estimate of bitumen fume exposure, a dose‐response was suggested for average level of exposure, applying a 15‐year lag, which was marginally reduced after adjustment for co‐exposure to coal tar. The results for cancer of the head and neck were similar to those of lung cancer, although they were based on a smaller number of deaths. There was no clear suggestion of an association with bitumen fume for any other neoplasm. Conclusions The results of the analysis by bitumen fume exposure do not allow us to conclude on the presence or absence of a causal link between exposure to bitumen fume and risk of cancer of the lung and the head and neck. Am. J. Ind. Med. 43:28–39, 2003. © 2003 Wiley‐Liss, Inc.

Item does not contain fulltext Work in the asphalt industry has been associated with nonmalignant respiratory morbidity and mortality, but the evidence is not consistent. A historical cohort of asphalt workers included 58,862 men (911,209 person-years) first employed between 1913 and 1999 in companies applying and mixing asphalt in Denmark, Finland, France, Germany, Israel, the Netherlands, and Norway. The relations between mortality from nonmalignant respiratory diseases (including the obstructive lung diseases: chronic bronchitis, emphysema, and asthma) and specific chemical agents and mixtures were evaluated using a study-specific exposure matrix. Mortality from obstructive lung diseases was associated with the estimated cumulative and average exposures to polycyclic aromatic hydrocarbons and coal tar (p values of the test for linear trend = 0.06 and 0.01, respectively). The positive association between bitumen fume exposure and mortality from obstructive lung diseases was weak and not statistically significant; confounding by simultaneous exposure to coal tar could not be excluded. The authors lacked data on smoking and full occupational histories. In conclusion, exposures to polycyclic aromatic hydrocarbons, originating from coal tar and possibly from bitumen fume, may have contributed to mortality from obstructive lung diseases among asphalt workers, but confounding and bias cannot be ruled out as an explanation for the observed associations.

Background An exposure matrix (EM) for known and suspected carcinogens was required for a multicenter international cohort study of cancer risk and bitumen among asphalt workers. Methods Production characteristics in companies enrolled in the study were ascertained through use of a company questionnaire (CQ). Exposures to coal tar, bitumen fume, organic vapor, polycyclic aromatic hydrocarbons, diesel fume, silica, and asbestos were assessed semi‐quantitatively using information from CQs, expert judgment, and statistical models. Exposures of road paving workers to bitumen fume, organic vapor, and benzo(a)pyrene were estimated quantitatively by applying regression models, based on monitoring data, to exposure scenarios identified by the CQs. Results Exposures estimates were derived for 217 companies enrolled in the cohort, plus the Swedish asphalt paving industry in general. Most companies were engaged in road paving and asphalt mixing, but some also participated in general construction and roofing. Coal tar use was most common in Denmark and The Netherlands, but the practice is now obsolete. Quantitative estimates of exposure to bitumen fume, organic vapor, and benzo(a)pyrene for pavers, and semi‐quantitative estimates of exposure to these agents among all subjects were strongly correlated. Semi‐quantitative estimates of exposure to bitumen fume and coal tar exposures were only moderately correlated. EM assessed non‐monotonic historical decrease in exposures to all agents assessed except silica and diesel exhaust. Conclusions We produced a data‐driven EM using methodology that can be adapted for other multicenter studies. Am. J. Ind. Med. 43:3–17, 2003. © 2003 Wiley‐Liss, Inc.

Luminal breast cancers express estrogen (ER) and/or progesterone (PR) receptors and respond to hormone therapies. Basal-like “triple negative” cancers lack steroid receptors but are cytokeratin (CK) 5-positive and require chemotherapy. Here we show that more than half of primary ER+PR+ breast cancers contain an ER−PR−CK5+ “luminobasal” subpopulation exceeding 1% of cells. Starting from ER+PR+ luminal cell lines, we generated lines with varying luminal to luminobasal cell ratios and studied their molecular and biological properties. In luminal disease, luminobasal cells expand in response to antiestrogen or estrogen withdrawal therapies. The phenotype and gene signature of the hormone-resistant cells matches that of clinical triple negative basal-like and claudin-low disease. Luminobasal cell expansion in response to hormone therapies is regulated by Notch1 signaling and can be blocked by γ-secretase inhibitors. Our data establish a previously unrecognized plasticity of ER+PR+ luminal breast cancers that, without genetic manipulation, mobilizes outgrowth of hormone-resistant basal-like disease in response to treatment. This undesirable outcome can be prevented by combining endocrine therapies with Notch inhibition.

Stromal tumour infiltrating lymphocytes (sTILs) are a strong prognostic marker in triple negative breast cancer (TNBC). Consistency scoring sTILs is good and was excellent when an internet-based scoring aid developed by the TIL-WG was used to score cases in a reproducibility study. This study aimed to evaluate the reproducibility of sTILs assessment using this scoring aid in cases from routine practice and to explore the potential of the tool to overcome variability in scoring. Twenty-three breast pathologists scored sTILs in digitized slides of 49 TNBC biopsies using the scoring aid. Subsequently, fields of view (FOV) from each case were selected by one pathologist and scored by the group using the tool. Inter-observer agreement was good for absolute sTILs (ICC 0.634, 95% CI 0.539–0.735, p &lt, 0.001) but was poor to fair using binary cutpoints. sTILs heterogeneity was the main contributor to disagreement. When pathologists scored the same FOV from each case, inter-observer agreement was excellent for absolute sTILs (ICC 0.798, 95% CI 0.727–0.864, p &lt, 0.001) and good for the 20% (ICC 0.657, 95% CI 0.561–0.756, p &lt, 0.001) and 40% (ICC 0.644, 95% CI 0.546–0.745, p &lt, 0.001) cutpoints. However, there was a wide range of scores for many cases. Reproducibility scoring sTILs is good when the scoring aid is used. Heterogeneity is the main contributor to variance and will need to be overcome for analytic validity to be achieved.

Contains fulltext : 58820.pdf (Publisher’s version ) (Closed access) To assess the variability of oestrogen receptor (ER) testing using immunocytochemistry, centrally stained and unstained slides from breast cancers were circulated to the members of the European Working Group for Breast Screening Pathology, who were asked to report on both slides. The results showed that there was almost complete concordance among readers (kappa=0.95) in ER-negative tumours on the stained slide and excellent concordance among readers (kappa=0.82) on the slides stained in each individual laboratory. Tumours showing strong positivity were reasonably well assessed (kappa=0.57 and 0.4, respectively), but there was less concordance in tumours with moderate and low levels of ER, especially when these were heterogeneous in their staining. Because of the variation, the Working Group recommends that laboratories performing these stains should take part in a external quality assurance scheme for immunocytochemistry, should include a tumour with low ER levels as a weak positive control and should audit the percentage positive tumours in their laboratory against the accepted norms annually. The Quick score method of receptor assessment may also have too many categories for good concordance, and grouping of these into fewer categories may remove some of the variation among laboratories.

Contains fulltext : 57809.pdf (Publisher’s version ) (Closed access) AIMS: To evaluate aspects of the current practice of sentinel lymph node (SLN) pathology in breast cancer via a questionnaire based survey, to recognise major issues that the European guidelines for mammography screening should address in the next revision. METHODS: A questionnaire was circulated by mail or electronically by the authors in their respective countries. Replies from pathology units dealing with SLN specimens were evaluated further. RESULTS: Of the 382 respondents, 240 European pathology units were dealing with SLN specimens. Sixty per cent of these units carried out intraoperative assessment, most commonly consisting of frozen sections. Most units slice larger SLNs into pieces and only 12% assess these slices on a single haematoxylin and eosin (HE) stained slide. Seventy one per cent of the units routinely use immunohistochemistry in all cases negative by HE. The terms micrometastasis, submicrometastasis, and isolated tumour cells (ITCs) are used in 93%, 22%, and 71% of units, respectively, but have a rather heterogeneous interpretation. Molecular SLN staging was reported by only 10 units (4%). Most institutions have their own guidelines for SLN processing, but some countries also have well recognised national guidelines. CONCLUSIONS: Pathological examination of SLNs throughout Europe varies considerably and is not standardised. The European guidelines should focus on standardising examination. They should recommend techniques that identify metastases > 2 mm as a minimum standard. Uniform reporting of additional findings may also be important, because micrometastases and ITCs may in the future be shown to have clinical relevance.