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Beta‐blockers have shown antineoplastic effects in laboratory studies but epidemiologic evidence in relation to contralateral breast cancer (CBC) is sparse. We investigated postdiagnosis beta‐blocker use and risk of CBC in a cohort of 52 723 women with breast cancer by using nationwide Danish health registers and the Danish Breast Cancer Group database. We defined postdiagnosis beta‐blocker use as a time‐varying covariate starting 1 year after a second prescription was redeemed. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for CBC associated with beta‐blocker use compared to nonuse. We identified 1444 women with CBC of whom 209 women were beta‐blocker users. We found an overall HR of 1.08 (95% CI: 0.93‐1.27) for beta‐blocker use and risk of CBC with no substantial variation according to cumulative amount, intensity or selectivity of beta‐blocker use. Hence, our cohort study of women with breast cancer did not sustain a protective effect of beta‐blocker use on risk of CBC, irrespective of beta‐blocker type. [ABSTRACT FROM AUTHOR]

Aims: Anthracycline-based chemotherapy improves survival in breast cancer patients but is associated with increased risk of heart failure (HF). However, the risk of late-onset HF is debatable and mainly based on observational studies. The aim of this study was to evaluate the effect of anthracycline-based chemotherapy on long-term risk of clinical HF.Methods and Results: Between 1990 and 1998 the Danish Breast Cancer Cooperative Group (DBCG) 89D trial randomized 980 Danish women with early breast cancer to adjuvant cyclophosphamide, epirubicin, and fluorouracil or cyclophosphamide, methotrexate, and fluorouracil. Incident HF was the primary endpoint obtained from Danish administrative registries. Follow-up ended at December 2014. The risk of HF was evaluated in a cumulative incidence analysis and a Fine-Gray proportional hazards model. Median follow-up time was 16.9 years [interquartile range (IQR) 3.7-20.9]. In the epirubicin treatment group, 23 new cases of HF were identified vs. 9 in the non-epirubicin group corresponding to incidence rates per 1000 patient-years of 3.7 [95% confidence interval (CI) 2.5-5.6] vs. 1.4 (95% CI 0.7-2.7). The cumulative incidence of HF was higher in the epirubicin treatment group compared with the non-epirubicin group (P < 0.01), yielding a hazard ratio of 3.00 (95% CI 1.39-6.49, P < 0.01) for HF associated with epirubicin. The median dose of epirubicin was 451.9 mg/m2 (IQR 400.0-523.5).Conclusions: Anthracycline-based chemotherapy is associated with a three-fold increased risk of late-onset clinical HF relative to non-anthracycline chemotherapy in this randomized clinical trial, but overall risk is low. [ABSTRACT FROM AUTHOR]

In a formal prospective‐retrospective analysis of the phase III SBG0102 clinical trial randomizing metastatic breast cancer patients to gemcitabine‐docetaxel or to single agent docetaxel, patients with basal‐like tumors by PAM50 gene expression had significantly better overall survival in the gemcitabine arm. By immunohistochemistry (IHC), triple negative status was not predictive, but more specific biomarkers have since become available defining basal‐like by nestin positivity or loss of inositol‐polyphosphate‐4‐phosphate (INPP4B). Here, we evaluate their capacity to identify which patients benefit from gemcitabine in the metastatic setting. Nestin and INPP4B staining and interpretation followed published methods. A prespecified statistical plan evaluated the primary hypothesis that patients with basal‐like breast cancer, defined as "nestin+ or INPP4B−", would have superior overall survival on gemcitabine‐docetaxel when compared to docetaxel. Interaction tests, Kaplan–Meier curves and forest plots were used to assess prognostic and predictive capacities of biomarkers relative to treatment. Among 239 cases evaluable for our study, 36 (15%) had been classified as basal‐like by PAM50. "Nestin+ or INPP4B−" was observed in 41 (17%) of the total cases and was significantly associated with PAM50 basal‐like subtype. Within an estimated median follow‐up of 13 years, patients assigned as IHC basal "nestin+ or INPP4B‐" had significantly better overall survival on gemcitabine‐docetaxel versus docetaxel monotherapy (HR = 0.31, 95%CI: 0.16–0.60), whereas no differences were observed for other patients (HR = 0.99), p‐interaction < 0.01. In the metastatic setting, women with IHC basal breast cancers defined as "nestin+ or INPP4B‐" have superior overall survival when randomized to gemcitabine‐containing chemotherapy compared to docetaxel alone. These findings need to be validated using larger prospective‐retrospective phase III clinical trials series. What's new? Preclinical findings support a potentially larger role of nucleoside analogues like gemcitabine in the treatment of basal‐like breast cancers when compared to other subtypes. However, immunohistochemistry (IHC) "triple negative" (ER‐/PR‐/HER2‐) status was previously found to be a poor surrogate for the basal‐like gene expression subtype and lacks predictive significance for gemcitabine benefit. This study provides evidence that the recently‐optimized IHC marker panel defining basal by nestin positivity or INPP4B negativity predicts a significant improvement in overall survival in metastatic breast cancer patients treated with gemcitabine. The findings offer an opportunity to more accurately identify basal‐like patients and tailor better chemotherapies. [ABSTRACT FROM AUTHOR]

Laboratory studies suggest that inhibition of the cyclooxygenase (COX)‐2 enzymes inhibits breast cancer development. We aimed to evaluate whether postdiagnosis use of COX‐2 selective or other nonaspirin nonsteroidal anti‐inflammatory drugs (NSAIDs) reduce the risk of contralateral breast cancer (CBC) among Danish breast cancer patients. From the clinical database of the Danish Breast Cancer Group, we identified 52,723 women diagnosed with breast cancer between 1996 and 2012. Data on nonaspirin NSAID use, CBC and potential confounding variables were obtained from nationwide registries. We defined postdiagnosis use (two or more prescriptions) as a time‐varying covariate with a one‐year lag. Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for CBC associated with nonaspirin NSAID use. During a median follow‐up of 4.8 years (interquartile range: 2.3–9 years), 1,444 patients were diagnosed with CBC. Overall, postdiagnosis use of nonaspirin NSAID was associated with an adjusted HR for CBC of 0.98 (95% CI: 0.87–1.11). The HRs did not vary substantially with duration or intensity of nonaspirin NSAID use. Moreover, similar associations were found for COX‐2 selective (HR: 1.02; 95% CI: 0.85–1.23) and nonselective (HR: 0.96; 95% CI: 0.82–1.13) nonaspirin NSAIDs. In conclusion, our nationwide cohort study of breast cancer patients does not suggest a reduced risk of CBC with nonaspirin NSAID use regardless of the COX‐2 selectivity. What's new? Nonsteroidal anti‐inflammatory drugs (NSAIDs) inhibit cyclooxygenase‐2 (COX‐2) enzymes, levels of which are increased in a significant proportion of breast cancers. Little is known, however, about whether NSAID use is protective against breast cancer. Herein, the authors examined the potential preventive effects of non‐aspirin NSAID use in a nationwide cohort of more than 52,700 Danish breast cancer patients at risk of primary tumor development in the contralateral breast. No association was detected between overall postdiagnosis use of nonaspirin NSAIDs and contralateral breast cancer. The data further indicate that neither COX‐2‐selective nor non‐selective, nonaspirin NSAIDs reduce contralateral breast cancer risk. [ABSTRACT FROM AUTHOR]

Long-term breast cancer trends in incidence in the United States (US) show rising estrogen receptor (ER)-positive rates and falling ER-negative rates. We hypothesized that these divergent trends reflect etiologic heterogeneity and that comparable trends should be observed in other countries with similar risk factor profiles. Therefore, we analyzed invasive female breast cancers in Denmark, a country with similar risk factors as the US. We summarized the overall trend in age-standardized rates with the estimated annual percentage change (EAPC) statistic (1993-2010) and used age-period-cohort models to estimate age-specific EAPCs, cohort rate ratios and projections for future time periods (2011-2018). In Denmark, the overall rate of ER-positive cancers rose between 1993 and 2010 by 3.0% per year (95% CI: 2.8-3.3% per year), whereas the overall rate of ER-negative cancers fell by 2.1% per year (95% CI: −2.5 to −1.6% per year). The ER-positive rate increased fastest among postmenopausal women and the ER-negative rate decreased fastest among premenopausal women, reflecting that cohorts born after 1944 were at relatively higher risk of ER-positive tumors and lower risk of ER-negative tumors. If current trends continue, ER-positive cancers will increase at least 13% by 2018 in Denmark, ER-negative cancers will fall 15% by 2018, and breast cancer overall will increase at least 7% by 2018. Divergent ER-specific trends are consistent with distinct etiologic pathways. If trends in known risk factors are responsible, the Danish and US experience may foreshadow a common pattern worldwide. [ABSTRACT FROM AUTHOR]

Axillary lymph node dissection (ALND) in breast cancer patients with positive sentinel nodes is under debate. We aimed to establish two models to predict non-sentinel node (NSN) metastases in patients with micrometastases or isolated tumor cells (ITC) in sentinel nodes, to guide the decision for ALND. A total of 1,577 breast cancer patients with micrometastases and 304 with ITC in sentinel nodes, treated by sentinel lymph node dissection and ALND in 2002-2008 were identified in the Danish Breast Cancer Cooperative Group database. Risk of NSN metastases was calculated according to clinicopathological variables in a logistic regression analysis. We identified tumor size, proportion of positive sentinel nodes, lymphovascular invasion, hormone receptor status and location of tumor in upper lateral quadrant of the breast as risk factors for NSN metastases in patients with micrometastases. A model based on these risk factors identified 5% of patients with a risk of NSN metastases on nearly 40%. The model was however unable to identify a subgroup of patients with a very low risk of NSN metastases. Among patients with ITC, we identified tumor size, age and proportion of positive sentinel nodes as risk factors. A model based on these risk factors identified 32% of patients with risk of NSN metastases on only 2%. Omission of ALND would be acceptable in this group of patients. In contrast, ALND may still be beneficial in the subgroup of patients with micrometastases and a high risk of NSN metastases. [ABSTRACT FROM AUTHOR]

Abstract: The Estrogen Receptor (ER) is an established predictive marker for the selection of adjuvant endocrine treatment in early breast cancer. During the 1990s Immunohistochemistry (IHC) replaced cytosol based assays for determination of ER status. This study examined the association between ER protein level determined by two different methods and ESR1 gene copy number. From 289 primary high-risk breast cancer patients, randomized in the Danish Breast Cancer Cooperative Group (DBCG) 77C trial, results from cytosolic ER levels were available from ligand binding assays. Archival tumor tissue was retrieved from 257 patients. ESR1/CEN-6 ratio was analyzed successfully by Fluorescence In Situ Hybridization (FISH) in 220 (86%) patients. ESR1 amplification (ESR1/CEN-6 ≥ 2.00) was observed in 23% of the patients and ESR1 deletion (ESR1/CEN-6 < 0.80) was observed in 32%. Further, we identified ESR1 gain (ratio ESR1/CEN-6 from 1.30 to 1.99) in 19% of the patients. A positive correlation of ESR1 FISH with both ER-cytosol and ER IHC was found (p < 0.0001). Amplification and gain of the ESR1 gene are associated with higher ER protein content measured by ligand binding assay and a more intense nuclear staining by IHC compared to tumors with normal ESR1 gene status. Major variations in ER measured by ligand binding assay and IHC are observed within all ESR1 copy number subgroups and other mechanisms than gene copy number seem to contribute to the ER protein content in the tumors. [Copyright &y& Elsevier]

Abstract: The clinical benefit of anthracyclines has been connected to HER2 status, TOP2A status and centromere 17 copy numbers (CEN-17). Data from a clinical trial randomizing patients to anthracyclines was used to assess whether the number of CEN-17 in breast cancers may predict incremental responsiveness to anthracyclines besides what is obtained when used relatively to TOP2A and HER2. As cut sections of paraffin-embedded tissue are prone to truncation of nuclei, strict definition of ploidy levels is lacking. We therefore used normal breast tissue to assist define ploidy levels in cut sections. Fluorescence in situ hybridization (FISH) with centromere 17 (CEN-17) and TOP2A was performed on 120 normal breast specimens. The diploid CEN-17 copy number was reduced from the expected two signals in whole nuclei to an average of 1.68 signals per nucleus in cut sections of normal breast. Ploidy levels determined in normal breast were applied to data on 767 patients with known HER2 and TOP2A status randomized to anthracyclines in the DBCG 89D trial. CEN-17 ploidy levels were in cut sections from the 767 breast cancer patients established as: Haploid: ≤1.25 (10%), diploid: 1.26–2.09 (60%), triploid: 2.10–2.93 (21%), tetraploid: 2.94–3.77 (5%) or higher ploidy: ≥3.78 (4%). Amplification of HER2 and deletion of TOP2A were frequently observed in tumors with a high ploidy level. In univariate analyses increasing ploidy was associated with decreased disease-free survival (DFS) (P =0.0001) and overall survival (OS) (P <0.0001). However, in multivariate analysis CEN-17 was not established as an independent prognostic factor and was neither a statistically significant predictor of benefit from CEF (Cyclophosphamide/Epirubicin/5-Fluorouracil) compared to CMF (Cyclophosphamide/Methotrexate/5-Fluorouracil) (P Interaction 0.39 for DFS and 0.67 for OS). In conclusion, CEN-17 levels do not independently from TOP2A/CEN-17 ratio identify breast cancer patients who achieve an incremental benefit from adjuvant anthracyclines. [Copyright &y& Elsevier]

Tvedskov TF, Bartels A, Jensen M-B, Paaschburg B, Kroman N, Balslev E, Brünner N. Evaluating TIMP-1, Ki67 and HER2 as markers for non-sentinel node metastases in breast cancer patients with micrometastases to the sentinel node. APMIS 2011; 119: 844-52. The aim was to investigate whether the biochemical prognostic markers TIMP-1, Ki67, and HER2 could predict metastatic spread to non-sentinel nodes (NSN) in breast cancer patients with micrometastases to sentinel node (SN). We included all breast cancer patients with micrometastases to SN operated between 2001 and 2007 at the Department of Breast Surgery, Herlev Hospital. The study was designed as a matched case-control study with 25 cases with micrometastases to SN and, in addition, metastatic spread to NSN and 50 matched controls with micrometastases to SN, but without NSN metastases. Patient and tumor characteristics were retrieved from the Danish Breast Cancer Cooperative Group database. Immunohistochemical analyses of TIMP-1 and Ki67 and measurements of HER2 on formalin-fixed paraffin-embedded tumor tissue were performed. No significant differences in the immunoreactivity of TIMP-1 and Ki67 were found between patients with and without NSN metastases. Six of seven HER2 positive patients did not have NSN metastases, but the results did not reach statistical significance. Despite being prognostic markers in breast cancer, TIMP-1 and Ki67 could not predict NSN metastases in women with micrometastatic disease to SN. Larger studies are needed to further validate HER2 as a marker for NSN metastases in these patients. [ABSTRACT FROM AUTHOR]

The article discusses the 25-year results of Danish Breast Cancer Cooperative Group (DBCG) 77-B trial, which evaluates the efficacy of breast cancer medication therapy such as oral cyclophosphamide and the combination of cyclophosphamide, methotrexate, and fluorouracil (CMF). The study gathered data from 1,146 premenopausal patients with breast cancer and taking cancer medication. The study showed that CMF and cyclophosphamide improved the disease-free survival of the patients for 25 years.