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Preclinical studies suggest that some effects of conventional chemotherapy, and in particular, gemcitabine, are mediated through enhanced antitumor immune responses. The objective of this study was to use material from a randomized clinical trial to evaluate whether patients with preexisting immune infiltrates responded better to treatment with gemcitabine + docetaxel (GD) compared to docetaxel alone. Formalin fixed, paraffin-embedded breast cancer tissues from SBG0102 phase 3 trial patients randomly assigned to treatment with GD or docetaxel were used. Immunohistochemical staining for CD8, FOXP3, LAG3, PD-1, PD-L1 and CD163 was performed. Tumor infiltrating lymphocytes (TILs) and tumor associated macrophages were evaluated. Prespecified statistical analyses were performed in a formal prospective-retrospective design. Time to progression was primary endpoint and overall survival secondary endpoint. Correlations between biomarker status and endpoints were evaluated using the Kaplan–Meier method and Cox proportional hazards models. Biomarker data was obtained for 237 patients. There was no difference in treatment effect according to biomarker status for the whole cohort. In planned subgroup analysis by PAM50 subtype, in non-luminal (basal-like and HER2E) breast cancers FOXP3 was a significant predictor of treatment effect with GD compared to docetaxel, with a HR of 0.22 (0.09–0.52) for tumors with low FOXP3 compared to HR 0.92 (0.47–1.80) for high FOXP3 TILs (Pinteraction = 0.01). Immune biomarkers were not predictive of added benefit of gemcitabine in a cohort of mixed breast cancer subtypes. However, in non-luminal breast cancers, patients with low FOXP3+ TILs may have significant benefit from added gemcitabine.

Background Cell culture studies have disclosed that the mitotic Aurora kinase A is causally involved in both tamoxifen and aromatase inhibitor resistant cell growth and thus may be a potential new marker for endocrine resistance in the clinical setting. Material and methods Archival tumor tissue was available from 1323 Danish patients with estrogen receptor (ER) positive primary breast cancer, who participated in the Breast International Group (BIG) 1-98 trial, comparing treatment with tamoxifen and letrozole and both in a sequence. The expression of Aurora A was determined by immunohistochemistry in 980 tumors and semi quantitively scored into three groups; negative/weak, moderate and high. The Aurora A expression levels were compared to other clinico-pathological parameters and outcome, defined as disease-free survival (DFS) and overall survival (OS). Results High expression of Aurora A was found in 26.9% of patients and moderate in 57.0%. High expression was significantly associated with high malignancy grade and HER2 amplification. High Aurora A expression was significantly more frequent in ductal compared to lobular carcinomas. We found no significant association between Aurora A expression and DFS or OS and no evidence of interaction between Aurora A expression and benefits from tamoxifen versus letrozole. Conclusions Aurora A expression in breast tumors was associated with high malignancy grade III and with HER2 amplification. A trend as a prognostic factor for OS was found in patients with high Aurora A expression. No predictive property was observed in this study with early breast cancer.

The Prosigna-PAM50 risk of recurrence (ROR) score has been validated in randomized clinical trials to predict 10-year distant recurrence (DR) in hormone receptor-positive breast cancer. Here, we examine the ability of Prosigna for predicting DR at 10 years in a subgroup of postmenopausal breast cancer patients with special histological subtypes.Using the population based Danish Breast Cancer Group database, follow-up data were collected on all patients diagnosed from 2000 to 2003 with estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2) normal breast cancer who by nationwide guidelines were treated with 5 year of endocrine therapy (N = 2558). Among patients with 1 to 3 positive lymph nodes or a tumor size20 mm, we identified 1570 with invasive ductal carcinoma (IDC) and 89 with special histological subtypes (apocrine, medullary, mucinous, papillary, secretory, tubular, neuroendocrine) who were tested with Prosigna. Fine and Gray models were applied to determine the prognostic value of the Prosigna-PAM50 ROR score for DR special subtypes as compared to IDC.Median follow-up for DR was 9.2 year and for OS 15.2 year. The 10-year DR rate for the special subtypes was 9.2% (95% CI: 4.0% to 17.2%) as compared to 13.7% (95% CI: 11.9% to 15.7%) for IDC. The 10-year OS was 74.2% (95% CI: 63.7% to 82.0%) for the special subtypes and 75.4% (95% CI: 73.2% to 77.4%) for IDC. Prosigna showed a statistical significant association of the continuous ROR score with risk of DR for both IDC and the special subtypes (IDC: p .0001; special subtypes: p = .01).In the present study, we demonstrated that Prosigna-PAM50 continuous ROR score added significant prognostic information for 10-year DR in postmenopausal patients with special subtypes (tumor size20 mm or 1 to 3 positive lymph nodes) and ER-positive, HER2-normal early breast cancer.

Axillary lymph node status has for long been the most important prognostic factor in patients with primary breast cancer [1]. Axillary lymph node dissection (ALND) provides the most accurate stagin...

The Copenhagen Breast Cancer Trial (CBCT) randomly assigned patients with early breast cancer to two years of tamoxifen or placebo and we evaluated the effect over the following four decades.Between 1975 and 1978, 327 patients with primary breast cancer were randomly assigned to two years of daily placebo or tamoxifen. Survival statistics was collected from the Danish Civil Registration System.The five-year invasive breast cancer recurrence (BCR) rate was 43.2% in the placebo arm and 31.9% in the tamoxifen arm. Compared with the placebo arm the hazard ratio for a BCR event was 0.73 in the tamoxifen arm (p = .07). With an estimated median follow-up on overall survival of 40.9 years, 154 and 145 patients had died in the placebo and tamoxifen arm, respectively. After adjustment for baseline characteristics a significant reduction in mortality was obtained from tamoxifen (HR 0.79; p = .04).Two years of adjuvant tamoxifen resulted in a sustained reduction in mortality in pre- and postmenopausal high-risk breast cancer patients with long-term follow-up data.

AIM OF DATABASE: Danish Breast Cancer Cooperative Group (DBCG), with an associated database, was introduced as a nationwide multidisciplinary group in 1977 with the ultimate aim to improve the prognosis in breast cancer. Since then, the database has registered women diagnosed with primary invasive nonmetastatic breast cancer. The data reported from the departments to the database included details of the characteristics of the primary tumor, of surgery, radiotherapy, and systemic therapies, and of follow-up reported on specific forms from the departments in question.DESCRIPTIVE DATA: From 1977 through 2014, ~110,000 patients are registered in the nationwide, clinical database. The completeness has gradually improved to more than 95%. DBCG has continuously prepared evidence-based guidelines on diagnosis and treatment of breast cancer and conducted quality control studies to ascertain the degree of adherence to the guidelines in the different departments.CONCLUSION: Utilizing data from the DBCG database, a long array of high-quality DBCG studies of various designs and scope, nationwide or in international collaboration, have contributed to the current updating of the guidelines, and have been an instrumental resource in the improvement of management and prognosis of breast cancer in Denmark. Thus, since the establishment of DBCG, the prognosis in breast cancer has continuously improved with a decrease in 5-year mortality from ~37% to 15%.

Background We examined time trends in axilla management among patients with early breast cancer in European clinical settings. Material and methods EUROCANPlatform partners, including population-based and cancer center-specific registries, provided routinely available clinical cancer registry data for a comparative study of axillary management trends among patients with first non-metastatic breast cancer who were not selected for neoadjuvant therapy during the last decade. We used an additional short questionnaire to compare clinical care patterns in 2014. Results Patients treated in cancer centers were younger than population-based registry populations. Tumor size and lymph node status distributions varied little between settings or over time. In 2003, sentinel lymph node biopsy (SLNB) use varied between 26% and 81% for pT1 tumors, and between 2% and 68% for pT2 tumors. By 2010, SLNB use increased to 79–96% and 49–92% for pT1 and pT2 tumors, respectively. Axillary lymph node dissection (ALND) use for pT1 tumors decreased from between 75% and 27% in 2003 to 47% and 12% in 2010, and from between 90% and 55% to 79% and 19% for pT2 tumors, respectively. In 2014, important differences in axillary management existed for patients with micrometastases only, and for patients fulfilling the ACOSOG Z0011 criteria for omitting ALND. Conclusion This study demonstrates persisting differences in important aspects of axillary management throughout the recent decade. The results highlight the need for international comparative patterns of care studies in oncology, which may help to identify areas where further studies and consensus building may be necessary.

Omission of chemotherapy may affect mortality in postmenopausal high-risk women despite appropriate adjuvant endocrine therapy for estrogen receptor (ER) positive breast cancer. The aim of this study was to determine how all-cause mortality rate in these patients compares to that of the general female population. Furthermore, to identify a subset without excess mortality using clinical and pathological characteristics.From the population-based database of the Danish Breast Cancer Cooperative Group we included 6529 postmenopausal patients with ER positive high-risk breast cancer who in 1996 through 2004 by nationwide guidelines were allocated to five years of tamoxifen, an aromatase inhibitor (AI) or both in sequence. Multivariate categorical and fractional polynomials (MFP) models were used to construct prognostic subsets by clinicopathologic characteristics.In a multivariate model excess mortality was inversely (p0.0001) associated with increasing age at surgery while recurrence-free survival (RFS) was not. Non-adherence to endocrine therapy was associated with excess mortality (p = 0.0008) while treatment with an AI was associated with a less pronounced mortality excess (p = 0.03). A prognostic standard mortality rate (SMR) index (PSI) was built using the regression coefficients obtained in the MFP model, and the same risk factors were used to construct a flowchart algorithm. Both allocated 75% to a group with increased all-cause mortality as compared to the general female population, but the SMR was significantly increased (SMR 1.38; 95% CI 1.16-1.65) in 462 patients who were allocated to low-risk group by the Flowchart algorithm and to a high-risk group by PSI.Only one quarter of postmenopausal ER positive breast cancer patients are free of excess mortality when omitting adjuvant chemotherapy. Patients should be informed about importance of adherence to adjuvant endocrine therapy and inclusion of an AI. A PSI may better guide recommendations regarding adjuvant chemotherapy.

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.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.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.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.

The Danish Breast Cancer Group (DBCG) was established in 1977 by innovative and visionary clinicians and researchers diagnosing, treating and investigating breast cancer. The vision was to gather a...

Background. Taxanes used in adjuvant therapy for breast cancer are neurotoxic, and thereby being a potential risk factor for persistent pain after breast cancer treatment (PPBCT) and sensory disturbances. The purpose was to compare patients treated with cyclophosphamide, epirubicin and fl uorouracil (CEF) and cyclophosphamide and epirubicin docetaxel (CE T) in relation to PPBCT, sensory disturbances, peripheral sensory disturbances and functional impairment. Material and methods. A comparative nationwide cross-sectional questionnaire study on two cohorts treated with CEF respectively CE T, based on the Danish Breast Cancer Cooperative Groups database. Inclusion criteria: women treated with chemotherapy as adjuvant treatment for primary breast cancer, age 18 – 69 years, without recurrence. Results. One thousand two hundred and forty-one patients allocated to CEF in 2005 – 2006 and 1652 patients allocated to CE T in 2007 – 2008 were included. Six hundred and sixty-four (53%) with CEF and 861 (53%) patients with CE T reported pain. In the multivariate analysis including available risk factors, CE T did not confer an increased risk of PPBCT, OR 0.95 (95% CI 0.81 – 1.11), p 0.52, compared to CEF. Patients treated with CE T had a lower risk of sensory disturbances in the area of surgery compared with CEF, OR 0.75 (95% CI 0.62 – 0.90), p 0.002. More CE T patients reported peripheral sensory disturbances in the hands, OR 1.56 (95%CI 1.27 – 1.92), p 0.0001, and in the feet, OR 2.0 (95% CI 1.66 – 2.42) p 0.0001, compared to CEF. There was no difference in functional impairment (p 0.62). Conclusion. Docetaxcel as adjuvant treatment for breast cancer does not increase the risk of PPBCT, sensory disturbances in the surgical area or functional impairment, but increase risk for peripheral sensory disturbances.

A significant reduction in the risk of recurrence and death was achieved three decades ago with adjuvant chemotherapy in patients with operable breast. The major pivotal trials used oral cyclophosphamide (C) days 1-14 with intravenous methotrexate (M) and fluorouracil (F) on days 1 and 8, repeated every 28 days. The classical CMF has later been modified as concerns dose and schedule, without formal comparisons in randomised trials between the classical CMF and the modifications.Classical CMF was used in the first adjuvant chemotherapy trial performed by the Danish Breast Cancer Cooperative Group (DBCG), and two succeeding randomised trials in premenopausal patients with node positive breast cancer used three-weekly or four-weekly intravenous CMF in one of the treatment arms.Between November 1977 and January 2001 these trials included 2 213 patients who in addition to surgery and radiotherapy received CMF. Ten-year disease-free survival (DFS) rates were 48% following classical CMF, 45% following four-weekly and 47% following three-weekly CMF. Major differences in patient characteristics were observed across these three cohorts, and a multivariate analysis was performed adjusting for the known prognostic factors. In the adjusted analysis a 30% increase in the risk of recurrence was observed for two the intravenous regimens as compared to classical CMF. As concerns survival a significant 40% increase in the risk of death was observed with the four-weekly regimen, while a similar risk of death was observed with the three-weekly intravenous. Classical CMF was associated with a higher risk of amenorrhoea, and this may at least in part explain an observed interaction between age and efficacy.This cross trial comparison suggests a detrimental effect in premenopausal patients with node positive breast cancer when shifting from classical CMF to intravenous regimens with lower dose-intensity. Caution is required in the interpretation of these results due to the non-experimental study design.

Udgivelsesdato: 2008-null BACKGROUND: Randomised studies have shown that breast conserving surgery followed by radiotherapy is associated with a prognosis similar to mastectomy alone. This formed the basis for recommending breast conserving surgery combined with radiotherapy as a standard treatment for suited breast cancer patients in Denmark. PATIENTS AND METHODS: To evaluate the results of this treatment, we performed a nationwide population-based follow-up study of patients aged less than 75 years treated in Denmark from 1989 to 1998 based on the database of Danish Breast Cancer Cooperative Group. RESULTS: At 15 years of follow-up, the Kaplan-Meier estimate of overall survival was 69% among 3 758 patients who received the recommended treatment. Within the first 10 years of follow-up, the cumulative incidences of loco-regional recurrences, distant metastases or other malignant disease, or death as a first event were 9.0, 19.9, and 6.0% respectively, when analysed in a competing risk setting. The risk of loco-regional recurrences was significantly decreased in patients aged 50 years or more and increased with increasing tumour size. There was a pronounced beneficial effect of adjuvant radiotherapy with those not receiving radiotherapy having a hazard ratio of 3.52 (95% CI 2.21-5.61). The effect of resection margins was significant for loco-regional recurrences only in node negative patients. CONCLUSION: In conclusion, the present study shows that results similar to those from randomised clinical trials can be obtained when breast conserving treatment is applied as a standard treatment in an entire population.

Estrogen is an established growth factor in breast cancer and it has been hypothesized that pregnancy associated estrogens may increase the risk of recurrence of breast cancer. In 1997 we published a population-based Danish study indicating no negative prognostic effect of pregnancy after breast cancer treatment. The present study is a ten-year update.Danish Breast Cancer Cooperative Group has since 1977 collected population-based data on tumour characteristics, treatment regimes, and follow-up status on Danish women with breast cancer. Pregnancy history was added from the Danish Civil Registration System, the National Birth Registry, and the National Induced Abortion registry. Cox regression was used to estimate the risk ratio of dying among women with a pregnancy after breast cancer treatment compared with women without such experience.In all, 10 236 women with primary breast cancer aged 45 years or less at the time of diagnosis were followed for 95 616 person years. Among these, 371 women experienced pregnancy after treatment of breast cancer. In a multivariate analysis that included age at diagnosis, stage of disease, and pregnancy history prior to diagnosis, women who had a full-term pregnancy subsequent to breast cancer treatment were found to have a reduced risk of dying (relative risk: 0.73; 95% confidence interval: 0.54-0.99) compared with other women with breast cancer. The effect was not significantly modified by age at diagnosis, tumour size, nodal status, or pregnancy history before diagnosis of breast cancer. Neither spontaneous abortions nor induced abortions subsequent to breast cancer treatment had a negative impact on prognosis.In line with our previous study, but based on more than twice the patient material, we found no evidence that a pregnancy after treatment of breast cancer has a negative influence the prognosis.

Udgivelsesdato: 2008 In addition to nationwide standardized pathology forms for operable primary invasive breast cancer, the Danish Breast Cancer cooperative Group (DBCG) in 1982 introduced pathology forms for breast cancer in situ (CIS). The histological reporting form was used primarily for ductal cancer in situ (DCIS) treated with wide local excision. The form however, also provided information on lobular carcinoma in situ (LCIS), atypia and benign lesions. In 1989 the reporting form for DCIS was extended and now provided information on histological subtype, malignancy grade, growth pattern and both Estrogen receptor (ER) and Progesteron receptor (PR) status. Also mastectomy specimens were included. In 2004 the previous malignancy grading was replaced by the Van Nuys classification, and information on microcalcifications was introduced. The axillary status now included the sentinel node technique only. In 2006 the pleomorphic subtype of LCIS was added to histological subtypes. The present work reviews the DBCG guidelines and recommendations concerning CIS adding a brief characterization of the Danish CIS population. It also refers to the introduction of modern molecular pathology and distinction between low-risk and high-risk CIS lesions. A major point is that without the thirty years of outstanding efforts by the DBCG, future research would not be able to meet expectations.

Udgivelsesdato: 2008-null Introduction. Since 30 years, DBCG (Danish Breast Cancer Cooperative Group) has maintained a clinical database allowing the conduct of quality control studies, of randomised trials, examination of the epidemiology of breast cancer and of prognostic and predictive factors. Material and methods. The original database included patients with invasive breast cancer, but has later been expanded to patients with in situ breast cancer and hereditary breast and ovarian cancer families. Results. The multidisciplinary cooperative group has provided successive treatment guidelines and 70% of the 77284 registered patients have been enrolled and received treatment according to these guidelines. The standard treatments and the randomised trials included in the DBCG programmes are all briefly described. Among high-risk patients 48% have participated in randomised trials, and the results of these trials have largely been implemented in the next generation of treatment guidelines. Records within the clinical database of archival tumour tissue have established a basis for translational research and epidemiologic research has been enabled through linkage to other healthcare registries. Discussion. The joint conception of the multidisciplinary breast cancer group and a clinical database has provided improvements in the management of breast cancer patients and has enabled recruitment of patients onto randomised trials.

Data from 4 771 patients with tumor diameters ≤ 10 mm were analyzed. Results of surgery and pathoanatomical examinations indicated that nodal status was related to diameter, but not to number of nodes removed. More axillary metastases were found in group T1b tumors than in T1a. In 8% of tumors, at least 4 positive nodes were identified. Mean number of positive nodes was related to number of nodes removed, and when 10 or more nodes were removed a significantly lower axillary recurrence rate and better recurrence-free survival were demonstrated, confirming that axillary surgery has two goals: staging and regional disease control. Age, receptor status, grade and histological type, but not tumor location, were related to prognosis. In accordance with the classical prognostic factors, it was not possible to define a patient group where axillary surgery was superfluous. We conclude that proper staging and regional control renders a full axillary level I.II dissection necessary.