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Jorgensen J.T.,Dx Rx Institute | Moller S.,Danish Breast Cancer Cooperative Group | Rasmussen B.B.,Herlev Hospital | Winther H.,Dako Denmark | And 2 more authors.
American Journal of Clinical Pathology | Year: 2011

The present study was done to investigate the concordance between the HER2 status measured by immunohistochemical analysis (HercepTest, DAKO, Carpinteria, CA) and fluorescence in situ hybridization (FISH; HER2 FISH pharmDx, DAKO) in a large study cohort (n = 681) of patients with high-risk breast cancer. A high agreement between immunohistochemical and FISH results was demonstrated. For the whole study population, the agreement between the 2 assays was 93.1% with a corresponding κ coefficient of 0.85. When the equivocal immunohistochemical 2+ cases were excluded from the analysis (n = 79), the agreement increased to 95.0% with a κ coefficient of 0.90. When the cutoff value for amplified/nonamplified cases in the HER2 FISH assay was increased from 2.0 to 2.2 as recommended in the American Society of Clinical Oncology/College of American Pathologists guidelines, the concordance between the 2 assays was 94.3% with a κ coefficient of 0.87 in the whole study population. When the equivocal immunohistochemical 2+ cases were excluded from this analysis, the concordance is similar (95.7% with a κ coefficient of 0.91). © American Society for Clinical Pathology.


Tvedskov T.F.,Copenhagen University | Jensen M.-B.,Danish Breast Cancer Cooperative Group | Balslev E.,Herlev Hospital | Ejlertsen B.,Copenhagen University | Kroman N.,Copenhagen University
European Journal of Cancer | Year: 2011

Purpose: To estimate the size and therapeutic consequences of stage migration after introduction of sentinel lymph node dissection (SLND) in breast cancer treatment in Denmark. Patients and methods: We compared the distribution of lymph node metastases in breast cancer patients operated in 1993-1996 and 2005-2008; before and after introducing SLND. The study was based on data from the national Danish Breast Cancer Cooperative Group (DBCG) database. Results: We included 24,051 patients in the study; 10,231 patients from the first period and 13,820 from the second period. The proportion of patients having macrometastases was not significantly different in the two periods, whereas the proportion of patients with micrometastases increased from 5.1% to 9.0% (P < 0.0001). However, this only resulted in an estimated change, from 7.8% to 8.8%, in the proportion of patients offered adjuvant systemic treatment due to positive nodal status as the only high-risk criterion, when using today's criteria for risk-allocation. In addition, we found that negative hormone receptor status was associated to negative nodal status when adjusted for confounders (odds ratios (OR) 0.83, P < 0.0001). Conclusion: Introduction of SLND in breast cancer treatment in Denmark has resulted in a stage migration on 4% due to identification of more micrometastases. However, this stage migration has only minor impact on patients offered adjuvant systemic treatment because nodal status today is less important in risk-allocation. © 2010 Elsevier Ltd. All rights reserved.


Teilum D.,Brystkirurgisk Klinik PBB | Bjerre K.D.,Danish Breast Cancer Cooperative Group | Tjonneland A.M.,Danish Cancer Society | Kroman N.,Brystkirurgisk Klinik PBB
BMJ Open | Year: 2012

Background: Vitamin D has been suggested to influence the incidence and prognosis of breast cancer, and studies have found better overall survival (OS) after diagnosis for breast cancer in summer-autumn, where the vitamin D level are expected to be highest. Objective: To compare the prognostic outcome for early breast cancer patients operated at different seasons of the year. Design: Open population-based cohort study. Setting: Danish women operated 1978-2010. Cases: 79 658 adjusted for age at surgery, period of surgery, tumour size, axillary lymph node status and hormone receptor status. Statistical analysis: The association between OS and season of surgery was analysed by Cox proportional hazards regression models, at survival periods 0-1, 0-2, 0-5 and 0-10 years after surgery. A two-sided p value <0.05 was considered statistical significant. Results: Only after adjustment for prognostic factors that may be influenced by vitamin D, 1-year survival was close to significantly associated season of surgery. 2, 5 and 10 years after surgery, the association between OS and season of surgery was not significant. Limitations: Season is a surrogate measure of vitamin D. Conclusions: The authors found no evidence of a seasonal variation in the survival after surgery for early breast cancer. Lack of seasonal variation in this study does not necessarily mean that vitamin D is of no importance for the outcome for breast cancer patients.


Jorgensen C.L.T.,Herlev University Hospital | Jorgensen C.L.T.,Danish Breast Cancer Cooperative Group | Nielsen T.O.,Vancouver Coastal Health Research Institute | Bjerre K.D.,Danish Breast Cancer Cooperative Group | And 5 more authors.
Acta Oncologica | Year: 2014

Background. In vitro studies suggest basal breast cancers are more sensitive to gemcitabine relative to other intrinsic subtypes. The main objective of this study was to use specimens from a randomized clinical trial to evaluate whether the basal-like subtype identifies patients with advanced breast cancer who benefit from gemcitabine plus docetaxel (GD) compared to single agent docetaxel (D). Material and methods. From patients randomly assigned to GD or D, RNA was isolated from archival formalin-fixed, paraffin-embedded primary breast tumor tissue and used for PAM50 intrinsic subtyping by NanoString nCounter. Statistical analyses were prespecified as a formal prospective-retrospective clinical trial correlative study. Using time to progression (TTP) as primary endpoint, overall survival (OS) and response rate as secondary endpoints, relationships between subtypes and outcome after chemotherapy were analyzed by the Kaplan-Meier method, and Cox proportional hazards regression models. Data analysis was performed independently by the Danish Breast Cancer Cooperative Group (DBCG) statistical core and all statistical tests were two-sided. Results. RNA from 270 patients was evaluable; 84 patients (31%) were classified as luminal A, 97 (36%) luminal B, 43 (16%) basal-like, and 46 (17%) as HER2-enriched. PAM50 intrinsic subtype was a significant independent prognostic factor for both TTP (p = 0.014) and OS (p = 0.0003). Response rate was not different by subtype, and PAM50 was not a predictor of TTP by treatment arm. PAM50 was however a highly significant predictor of OS following GD compared to D (pinteraction = 0.0016). Patients with a basal-like subtype had a significant reduction in OS events [hazard ratio (HR) = 0.29, 95% confidence interval (CI) = 0.15-0.57; pinteraction = 0.0006]. Conclusion. A significantly improved and clinically important prolongation of survival was seen from the addition of gemcitabine to docetaxel in advanced basal-like breast cancer patients. © 2014 Informa Healthcare.


Tvedskov T.F.,Copenhagen University | Jensen M.-B.,Danish Breast Cancer Cooperative Group | Lisse I.M.,Herlev Hospital | Ejlertsen B.,Copenhagen University | And 2 more authors.
International Journal of Cancer | Year: 2012

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. Copyright © 2012 UICC.


Tvedskov T.F.,Copenhagen University | Jensen M.-B.,Danish Breast Cancer Cooperative Group | Balslev E.,Herlev Hospital | Kroman N.,Copenhagen University
Acta Oncologica | Year: 2014

Background. Benefit from axillary lymph node dissection in sentinel node positive breast cancer patients is under debate. Based on data from 1820 Danish breast cancer patients operated in 2002-2008, we have developed two models to predict high risk of non-sentinel node metastases when micrometastases or isolated tumor cells are found in sentinel node. The aim of this study was to validate these models in an independent Danish dataset. Material and methods. We included 720 breast cancer patients with micrometastases and 180 with isolated tumor cells in sentinel node operated in 2009-2010 from the Danish Breast Cancer Cooperative Group database. Accuracy of the models was tested in this cohort by calculating area under the receiver operating characteristic curve (AUC) as well as sensitivity and specificity. Results. AUC for the model for patients with micrometastases was comparable to AUC in the original cohort: 0.63 and 0.64, respectively. The sensitivity and specificity for predicting risk of non-sentinel node metastases over 30% was 0.36 and 0.81, respectively, in the validation cohort. AUC for the model for patients with isolated tumor cells decreased from 0.73 in the original cohort to 0.60 in the validation cohort. When dividing patients with isolated tumor cells into high and low risk of non-sentinel node metastases according to number of risk factors present, 37% in the high-risk group had non-sentinel node metastases. Specificity and sensitivity was 0.48 and 0.88, respectively, in the validation cohort when using this cut-point. Conclusion. In this independent dataset, the model for patients with micrometastases was robust with accuracy similar to the original cohort, while the model for patients with isolated tumor cells was less accurate. The models may be used to identify patients where axillary lymph node dissection should still be considered. © 2014 Informa Healthcare.


Ahern T.P.,Harvard University | Pedersen L.,Aarhus University Hospital | Tarp M.,Aarhus University Hospital | Cronin-Fenton D.P.,Aarhus University Hospital | And 6 more authors.
Journal of the National Cancer Institute | Year: 2011

Background Accumulating evidence suggests that statins affect diseases other than cardiovascular disease, including cancer, and that these effects may depend on the lipid solubility of specific statins. Though many studies have reported an association between statin use and breast cancer incidence, the relationship between statin use and breast cancer recurrence has not been well studied. Methods We conducted a nationwide, population-based prospective cohort study of all female residents in Denmark diagnosed with stage I-III invasive breast carcinoma who were reported to the Danish Breast Cancer Cooperative Group registry between 1996 and 2003 (n = 18769). Women were followed for a median of 6.8 years after diagnosis. Prescriptions for lipophilic and hydrophilic statins were ascertained from the national electronic pharmacy database. Associations between statin prescriptions and breast cancer recurrence were estimated with generalized linear models and Cox proportional hazards regression with adjustment for age and menopausal status at diagnosis; histological grade; estrogen receptor status; receipt of adjuvant therapy; type of primary surgery received; pre-diagnosis hormone replacement therapy; and co-prescriptions of aspirin, angiotensin-converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs, or anticoagulants. All statistical tests were two-sided.ResultsMost prescriptions for lipophilic statins in the study population were for simvastatin. Exclusive simvastatin users experienced approximately 10 fewer breast cancer recurrences per 100 women after 10 years of follow-up (adjusted 10-year risk difference =-0.10, 95% confidence interval =-0.11 to-0.08), compared with women who were not prescribed a statin. Exclusive hydrophilic statin users had approximately the same risk of breast cancer recurrence as women not prescribed a statin over follow-up (adjusted 10-year risk difference = 0.05, 95% confidence interval =-0.01 to 0.11). ConclusionsSimvastatin, a highly lipophilic statin, was associated with a reduced risk of breast cancer recurrence among Danish women diagnosed with stage I-III breast carcinoma, whereas no association between hydrophilic statin use and breast cancer recurrence was observed. © 2011 The Author.


Njor S.H.,Copenhagen University | Olsen A.H.,University of Tromsø | Blichert-Toft M.,Danish Breast Cancer Cooperative Group | Schwartz W.,University of Southern Denmark | And 2 more authors.
BMJ (Online) | Year: 2013

Objective To use data from two longstanding, population based screening programmes to study overdiagnosis in screening mammography. Design Population based cohort study. Setting Copenhagen municipality (from 1991) and Funen County (from 1993), Denmark. Participants 57 763 women targeted by organised screening, aged 56-69 when the screening programmes started, and followed up to 2009. Main outcome measures Overdiagnosis of breast cancer in women targeted by screening, assessed by relative risks compared with historical control groups from screening regions, national control groups from non-screening regions, and historical national control groups. Results In total, 3279 invasive breast carcinomas and ductal carcinomas in situ occurred. The start of screening led to prevalence peaks in breast cancer incidence: relative risk 2.06 (95% confidence interval 1.64 to 2.59) for Copenhagen and 1.84 (1.46 to 2.32) for Funen. During subsequent screening rounds, relative risks were slightly above unity: 1.04 (0.85 to 1.27) for Copenhagen and 1.14 (0.98 to 1.32) for Funen. A compensatory dip was seen after the end of invitation to screening: relative risk 0.80 (0.65 to 0.98) for Copenhagen and 0.67 (0.55 to 0.81) for Funen during the first four years. The relative risk of breast cancer accumulated over the entire follow-up period was 1.06 (0.90 to 1.25) for Copenhagen and 1.01 (0.93 to 1.10) for Funen. Relative risks for participants corrected for selection bias were estimated to be 1.08 for Copenhagen and 1.02 for Funen; for participants followed for at least eight years after the end of screening, they were 1.05 and 1.01. A pooled estimate gave 1.040 (0.99 to 1.09) for all targeted women and 1.023 (0.97 to 1.08) for targeted women followed for at least eight years after the end of screening. Conclusions On the basis of combined data from the two screening programmes, this study indicated that overdiagnosis most likely amounted to 2.3% (95% confidence interval -3% to 8%) in targeted women. Among participants, it was most likely 1-5%. At least eight years after the end of screening were needed to compensate for the excess incidence during screening.


PubMed | University of British Columbia and Danish Breast Cancer Cooperative Group
Type: | Journal: Clinical cancer research : an official journal of the American Association for Cancer Research | Year: 2016

Luminal A breast cancers have better prognosis than other molecular subtypes. Luminal A cancers may also be insensitive to adjuvant chemotherapy, although there is little high-level evidence to confirm this concept. The primary hypothesis in this formal prospective-retrospective analysis was to assess interaction between subtype (Luminal A vs. other) and treatment (chemotherapy vs. not) for the primary endpoint (10-year invasive disease-free survival) of a breast cancer trial randomizing women to adjuvant chemotherapy, analyzed in multivariate Cox proportional hazards models using the Wald interaction test.The Danish Breast Cancer Cooperative Group 77B clinical trial randomized 1,072 premenopausal women to no systematic treatment (control), levamisole, cyclophosphamide, or cyclophosphamide-methotrexate-fluorouracil arms. All arms included radiotherapy but no endocrine therapy. Researchers with no access to clinical data performed intrinsic subtype analysis on tissue microarrays using published immunohistochemical methods based on estrogen receptor, progesterone receptor, HER2, Ki67, and basal markers.Patients (n = 709) had tissue available; chemotherapy benefit in these patients was similar to the original trial (HR, 0.56). Immunohistochemistry classified 165 as Luminal A, 319 Luminal B, 58 HER2-enriched, and 82 core basal (among 91 triple-negative). Patients with Luminal A breast tumors did not benefit from chemotherapy [HR, 1.06; 95% confidence interval (CI), 0.53-2.14; P = 0.86], whereas patients with non-luminal A subtypes did (HR, 0.50; 95% CI, 0.38-0.66; P < 0.001; PIn a prospective-retrospective analysis of a randomized trial, patients with Luminal A breast cancers did not benefit from adjuvant cyclophosphamide-based chemotherapy. Clin Cancer Res; 1-8. 2016 AACR.


PubMed | Aarhus University Hospital, Danish Breast Cancer Cooperative Group and Western General Hospital
Type: Journal Article | Journal: Journal of surgical oncology | Year: 2016

The association between margin width and ipsilateral breast tumour recurrence (IBTR, defined as invasive recurrence) was investigated in a population-based nationwide cohort of 11,900 patients undergoing breast-conserving therapy for invasive cancer.The median follow-up was 4.9 years. The cumulative incidence of IBTR at 5 and 9 years was 2.4% and 5.9%, respectively. A final positive margin increased the risk of IBTR (HR 2.51; 95% CI 1.02-6.23). No decrease in IBTR with a wider negative margin compared to a narrow but negative margin was observed in the adjusted analysis of margin width (>0 to <2mm vs. 2 to <5mm vs. 5mm (reference): HR 1.54 (CI 95% 0.81-2.93) vs. 0.95 (CI 95% 0.56-1.62) vs. 1). However, few patients had narrow margins. The factors associated with increased IBTR were young age (P<0.001), >4 positive lymph nodes (P=0.008) and re-excision (P=0.003). A reduced risk of IBTR was observed with chemotherapy (P<0.001), boost radiation (P=0.023) and ER positivity (P<0.001).An overall low rate of IBTR was observed. A final positive margin was associated with a more than twofold risk of IBTR. There was no evidence for better local control with wider margins, but the data were insufficient to show whether narrow margins were as good as wider negative margins in terms of local control. J. Surg. Oncol. 2016;113:609-615. 2016 Wiley Periodicals, Inc.

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