Search

BACKGROUND AND PURPOSE: The increase in the risk of heart disease from incidental exposure of the heart during radiotherapy for breast cancer has been estimated previously from retrospective data in Danish and Swedish women. Here we present an analysis of the Danish material updated with new cases and controls, extended follow-up period, and with refined dose estimates using simulator films or CT data MATERIAL AND METHODS: From the database of the Danish Breast Cancer Cooperative Group, we identified 531 women diagnosed with early-stage breast cancer from 1977 to 2005, who developed subsequent ischemic heart disease (cases) and matched them to 1069 controls without heart disease after radiotherapy. Data were available for precise dose estimation for 196 cases and 413 controls receiving tangential photon techniques.RESULTS: The median of the mean heart doses for the women receiving tangential radiotherapy was 2.41 Gy for left- and 0.68 Gy for right-sided radiotherapy. The mean heart dose was higher for cases than controls (0.84 Gy and 0.71 Gy, respectively; p

Background The natural history of breast cancer among BRCA2 carriers has not been clearly established. In a previous study from Iceland, positive ER status was a negative prognostic factor. We sought to identify factors that predicted survival after invasive breast cancer in an expanded cohort of BRCA2 carriers. Methods We studied 608 women with invasive breast cancer and a pathogenic BRCA2 mutation (variant) from four Nordic countries. Information on prognostic factors and treatment was retrieved from health records and by analysis of archived tissue specimens. Hazard ratios (HR) were estimated for breast cancer-specific survival using Cox regression. Results About 77% of cancers were ER-positive, with the highest proportion (83%) in patients under 40 years. ER-positive breast cancers were more likely to be node-positive (59%) than ER-negative cancers (34%) (P P = 0.03); thereafter, the effect was adverse (HR = 1.91; 95% CI 1.07–3.39, P = 0.03). The adverse effect of positive ER status was limited to women who did not undergo endocrine treatment (HR = 2.36; 95% CI 1.26–4.44, P = 0.01) and patients with intact ovaries (HR = 1.99; 95% CI 1.11–3.59, P = 0.02). Conclusions The adverse effect of a positive ER status in BRCA2 carriers with breast cancer may be contingent on exposure to ovarian hormones.

Estrogen receptor positive (ER+) breast cancer constitutes almost 85% of all breast cancer patients and are a genetically highly heterogenic group. Data on the association of somatic alterations to outcome and prognosis are however sparse. In this neoadjuvant endocrine phase II trial including postmenopausal breast cancer patients with ER+, HER2 normal breast cancer, we investigated the rate of pathogenic mutations before and after treatment as well as the association with treatment response and survival. Pretreatment and posttreatment tumour samples from 109 patients treated with neoadjuvant letrozole were collected and analysed with Next Generation Sequencing utilizing a panel of 12 genes (ALK, BRAF, EGFR, ERBB2, ERBB3, ESR1, KIT, KRAS, NRAS, PDGFRA, PIK3CA, and RAF1). Residual disease was assessed by a modified Miller Payne scale and the Residual Cancer Burden index. Survival data were collected prospectively. Among the 109 patients, 52 had at least one pathogenic mutation in the pretreatment sample and 60 in the posttreatment sample. The most frequently mutated gene was PIK3CA, followed by EGFR and KRAS. Twelve different pathogenic PIK3CA mutations were identified, primarily in exon 20 and exon 9. An altered PIK3CA mutation profile from the pre- to the posttreatment specimen was significantly associated to improved pathological outcome. Overall and Disease-Free Survival benefits in PIK3CA mutated patients was observed. Considerable heterogeneity was identified both among patients and between pre- and posttreatment samples. PIK3CA has the potential to be a predictive biomarker. To further assess the implications of a treatment related altered PIK3CA mutation profile, more data are needed.

Purpose The Prosigna-PAM50 risk of recurrence (ROR) score has documented clinical utility for the prediction of 10-year distant recurrence (DR). The present study investigated the value of Prosigna-PAM50 for predicting 10-year DR and overall survival after 5 years of endocrine treatment for postmenopausal patients with invasive lobular carcinoma. Patients and Methods Using the Danish Breast Cancer Group database, we identified patients with a diagnosis from 2000 to 2003 of estrogen receptor-positive, human epidermal growth factor receptor 2-negative invasive ductal (n = 1570) or lobular (n = 341) cancer > 20 mm or 1 to 3 positive lymph nodes and applied multivariate Cox models. Results The median follow-up for DR was 9.3 years and for overall survival 15.2 years. Of the 341 lobular and 1570 ductal cases, 140 (41%) and 349 (22%) were classified as low ROR, with a 10-year DR rate of 7.7% (95% confidence interval [CI], 3.7%-13.6%) and 3.5% (95% CI, 1.8%-6.2%), respectively. The 10-year DR rate for the intermediate ROR group for those with lobular cancer was 18% (95% CI, 10.1%-27.9%) compared with 9.7% (95% CI, 6.7%-13.4%) for those with ductal cancer. Luminal B tumors had a significantly worse outcome than luminal A tumors in both lobular (hazard ratio, 1.89; 95% CI, 1.03%-3.45%; P = .04) and ductal (hazard ratio, 3.18; 95% CI, 2.29%-4.43%; P Conclusion Prosigna PAM-50 provides significant prognostic information beyond the clinicopathologic factors in patients with invasive lobular breast cancer. Those with lobular cancer had worse 10-year DR rates compared with those with ductal cancer in the same ROR category. Our results could have an effect on the treatment decisions regarding the addition of chemotherapy for those in the intermediate ROR group.

Background: Stromal Tumour Infiltrating Lymphocytes (sTILs) has been established as a predictive biomarker for response to neoadjuvant chemotherapy irrespective of subtype. While increased sTIL levels is associated with prolonged survival among patients with triple-negative and HER2 positive breast cancer increased sTILs has in Estrogen Receptor positive (ER+) breast cancer been suggested to be an adverse prognostic factor. It has been hypothesised that differences in the cellular composition of immune cells may explain the dissimilarity in prognostic impact according to breast cancer subtype. Here, we report data from a neoadjuvant phase II study, treating postmenopausal patients with primary ER+, HER2 negative, operable breast cancer with letrozole for four months by the Danish Breast Cancer Group (DBCG). We analysed the association of sTILs, and changes in sTILs during neoadjuvant endocrine treatment (NET), with pathological response and correlation with other clinicopathological variables such as Ki67, as potential biomarkers for risk-stratification of patients following NET. Method: 113 postmenopausal patients with ER+, HER2 negative breast cancer were treated with NET for four months. Endpoint was pathological response assessed by a modified Miller Payne scale and the Residual Cancer Burden (RCB) score. Pretherapeutic core biopsies and post therapeutic surgical specimens were assessed centrally for the percentage of sTILs on HE sections according to the International TILs working group guidelines. sTILs association to pathological response were assessed with univariate logistic regression. Odds Ratio (OR) was estimated with a 95 % confidence interval. Correlation of sTILs and Ki67 were tested with Pearson´s correlation coefficient. Changes in sTILs with a paired t-test. Level of significance was set to 5 %. Results: sTILs concentration increased with mean 6.8 % (p The correlation between pre-therapeutic sTILs and Ki67 was moderate (Pearson 0.4; p = 0.0004), however the association grew stronger post treatment (Pearson 0.5; p Conclusion: Increased sTILs activity during NET was associated with poor treatment response. An increase in sTILs during NET could be considered indictive for potential immunogenic tumours, suggesting that patients with increasing sTIL in residual disease after NET might derive benefit from the addition of immunotherapy. We found a significant correlation between sTILs and Ki67 levels. Ki67 has been established as a window of opportunity biomarker for antiproliferative response. Combining biomarkers of antiproliferative response such as Ki67 with biomarkers of immunogenetic significance might be important to determine optimal combination of adjuvant therapy. A window of opportunity study with an aromatase inhibitor could show if it is feasible to detect a rise in sTILs early enough to guide adjuvant treatment in the perioperative setting. Citation Format: Signe Korsgaard Skriver, Maj-Britt Jensen, Ann Soegaard Knoop, Bent Ejlertsen, Anne-Vibeke Laenkholm. Changes in tumour infiltrating lymphocytes during neoadjuvant endocrine therapy and possible clinical implications for guiding therapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-10-18.

The DBCG89D trial randomized high-risk early breast cancer patients to adjuvant CMF (cyclophosphamide, methotrexate and fluorouracil) or CEF (cyclophosphamide, epirubicin and fluorouracil). Prosigna assays were performed by researchers with no access to clinical data. Time to distant recurrence (DR) was the primary endpoint, time to recurrence (TR) and overall survival (OS) secondary. Among the 980 Danish patients enrolled, Prosigna results were obtained in 686. Continuous ROR score was associated with DR for CMF (adjusted hazard ratio (HR) 1.20, 95% CI 1.09–1.33), and for CEF (HR 1.04, 95% CI 0.92–1.18), Pinteraction = 0.06. DR was significantly longer in CEF compared to CMF treated patients with Her2-enriched tumors (HR 0.58, 95% CI 0.38–0.86), but not in patients with luminal tumors. Heterogeneity of treatment effect was significant for TR and OS. In this prospective-retrospective analysis, patients with Her2-enriched breast cancer derived substantial benefit from anthracycline chemotherapy whereas anthracyclines are not an essential component of chemotherapy for patients with luminal subtypes. The benefit of CEF vs. CMF correlated with increasing ROR Score.

Background: The prognostic value of tumour-infiltrating lymphocytes (TILs) in breast cancer is well-established. However, the investigation of specific T-cell subsets exclusively in BRCA-associated breast cancer is sparse. Methods: Tumour tissues from 414 BRCA-mutated breast cancer patients were analysed by immunohistochemistry and digital image analysis for expression of CD4, CD8 and FOXP3 immune markers. Distribution of CD4-, CD8- and FOXP3-positive cells and clinicopathological characteristics were assessed according to groups of low or high expression. The prognostic value was evaluated as continuous variables in univariate and multivariate analyses of overall survival and disease-free survival. Results: Both CD4 and CD8 expression are associated with histological diagnosis, tumour grade and oestrogen and progesterone receptor expression status. CD4 expression is associated with BRCA gene status. A high percentage of tumour-infiltrating CD4-, CD8- or FOXP3-positive cells is significantly associated with lower mortality in BRCA1- and BRCA2-associated breast cancer and CD8-positive cells are associated with disease-free survival. No heterogeneity according to BRCA gene status was found for the prognostic value of the immune markers. Conclusions: The results support a prognostic role of specific T-cell subsets in BRCA-associated breast cancer and the promising potential of targeting the immune system in the treatment of these patients.

To determine the incidence and risk factors of sentinel lymph node (SN) and non-SN metastases in patients with microinvasive breast cancer (MIBC, T1mic). This to identify MIBC patients in whom axillary staging can be safely omitted. The Danish Breast Cancer Group database was used to identify a total of 409 women with breast cancer ≤ 1 mm who underwent sentinel lymph node biopsy (SLNB) between 2002 and 2015. After validation, 233 patients were eligible for the analysis. The incidence rates of SN and non-SN metastases were determined. The associations between clinicopathological variables and a positive SN [pN1, pN1mi, or pN0(i+)] were analyzed using univariate and multivariate designs. Of 233 patients with MIBC, only 9 (3.9%) had SN macrometastases. An additional 18 (7.7%) and 23 (9.9%) had SN micrometastases and isolated tumor cells (ITCs), respectively. Of patients with SN macrometastases, two (22.2%) had non-SN macrometastases. In the adjusted analysis, a positive SN was associated with younger age (P = 0.0001) and a positive human epidermal growth factor 2 receptor (HER2) status (P = 0.03). The low incidence of SN macrometastases

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: Women treated for breast cancer (BC) often suffer genitourinary syndrome of menopause. These symptoms may be alleviated by vaginal or systemic hormonal treatment. However, there are concerns that hormonal treatment increases the risk of recurrence of breast cancer and death. Methods: Longitudinal data from a national cohort of postmenopausal women treated for early stage estrogen receptor positive non-metastatic BC from 1997 to 2004 was used in this observational study. Vaginal estrogen therapy (VET) or systemic hormonal replacement therapy (HRT) was assessed by cross-linking to the nationwide prescription database. Mortality and risk of recurrence associated with use of VET and HRT compared to non-use were assessed using multivariate models adjusted for potential confounders. Findings: Among 8461 women, who had not received VET or HRT before BC diagnosis, 1957 and 133 used VET and HRT, respectively, after diagnosis. The adjusted relative risk of recurrence with a median follow-up of 9·8 years was 1·08 (95% CI 0·89-1·32) for VET and 1·05 (95% CI 0·62-1·78) for HRT compared with never use. The adjusted hazard ratio (HR) for overall mortality, with a median follow-up of 15·2 years, were 0·78 (95% CI 0·71-0·87) and 0·94 (95% CI 0·70-1·26) for VET and HRT compared with never use. Analyses stratified by type of adjuvant endocrine therapy revealed an increased risk of recurrence of 1·39 (95% CI 1·04-1·85) associated with VET use during adjuvant treatment among women treated with aromatase inhibitors, without increased mortality (HR=0·94 (95% CI 0·70-1·26)). Interpretation: In postmenopausal women treated for early stage estrogen receptor positive BC, use of VET after diagnosis was associated with increased risk of recurrence but not mortality in patients receiving adjuvant aromatase inhibitors. The use of VET in patients treated with tamoxifen or no adjuvant endocrine therapy was not associated with increased risk of recurrence or mortality. Funding: Breast Friends Declaration of Interest: SC has received support from Breast Friends for the present manuscript. MJ has received institutional grants from Samsung BIOEPIS, Nanostring Technologies and Oncology Venture and has received support for attending scientific meeting from Novartis. PC has received honoraria and support for attending scientific meeting from Roche Denmark. BE has received institutional grants from AstraZeneca, Pfizer, Roche, Novartis, Samsung BIOEPIS, Nanostring Technologies and Oncology Venture and has received support for attending scientific meeting from MSD. FC and DCF declared no conflicts of interest. Ethical Approval: The Danish Data Protection Board approved the study and data were accessed through a secure server at Statistics Denmark (https://www.dst.dk), and only Danish research environments are granted authorization.

PurposePremenopausal women diagnosed with estrogen receptor (ER) positive breast cancer are prescribed 5–10 years of endocrine therapy to prevent or delay recurrence. Many women who initiate endocrine therapy fail to complete the recommended course of treatment. In this study, we evaluated the association between early discontinuation of adjuvant endocrine therapy and breast cancer recurrence in a cohort of premenopausal women.Patients and MethodsWe identified 4,503 premenopausal ER+ breast cancer patients who initiated adjuvant endocrine therapy and were registered in the Danish Breast Cancer Group clinical database (2002–2011). Women were excluded if they had a recurrence or were lost to follow-up less than 1.5 years after breast cancer surgery. Endocrine therapy was considered complete if the patient received at least 4.5 years of treatment or discontinued medication less than 6 months before recurrence. Exposure status was updated annually and modeled as a time-dependent variable. We accounted for baseline and time-varying confounders via time-varying weights, which we calculated from multivariable logistic regression models and included in regression models to estimate hazard ratios (HR) and accompanying 95% confidence intervals (CI) associating early discontinuation with breast cancer recurrence.ResultsOver the course of follow-up, 1,001 (22%) women discontinued endocrine therapy. We observed 202 (20%) recurrences among those who discontinued endocrine therapy, and 388 (11%) among those who completed the recommended treatment. The multivariable-adjusted estimated rate of recurrence was higher in women who discontinued endocrine therapy relative to those who completed their treatment (HR=1.67, 95% CI 1.25, 2.14).ConclusionThese results highlight the importance of clinical follow-up and behavioral interventions that support persistence of adjuvant endocrine therapy to prevent breast cancer recurrence.

BACKGROUND: The presence of tumour-infiltrating lymphocytes (TILs) is associated with response to neoadjuvant chemotherapy among patients with triple-negative and HER2-positive breast cancer. However, the significance of TILs is less clear in luminal breast cancer. Here, we in postmenopausal patients with primary oestrogen receptor-positive (ER+), HER2 normal, operable breast cancer assessed the importance of inducing TILs during 4 months of letrozole on response in a neoadjuvant phase II study.METHODS: Participants were postmenopausal women with ER+, HER2 normal operable breast cancer assigned to 4 months of neoadjuvant letrozole. Pretreatment core biopsies and surgical specimens were assessed centrally for the percentage of TILs on haematoxylin and eosin-stained slides according to the International Immuno-Oncology Biomarker Working Group on Breast Cancer guidelines. Pathological response was assessed by the Residual Cancer Burden (RCB) index and a modified Miller-Payne grading system and was analysed according to change in TILs.RESULTS: Tumour specimens were available from 106 of the 112 patients treated per protocol. TIL concentration increased with mean 6.8 percentage point (p < 0.0001) during treatment (range - 39 to 60). An increase in TILs was significantly associated with pathological response with OR = 0.71 (95% CI 0.53-0.96; p = 0.02) per 10% absolute increase for pathological response and correspondingly OR = 0.56 (95% CI 0.40-0.78; p = 0.0007) for lower RCB index per 10% increase.CONCLUSION: Increasing TILs during letrozole was significantly associated with a poor treatment response. An increase in TILs during endocrine therapy might imply immunogenicity, and these patients could be targetable by immunotherapy.TRIAL REGISTRATION: ClinicalTrials.govNCT00908531, registered 27 May 2009.

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.

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.

PURPOSE: How a second breast cancer diagnosis affects survival in comparison with unilateral breast cancer (UBC) is unclear. Prognostic factors for contralateral breast cancer (CBC) are also not well established. We aimed to investigate the survival pattern after CBC with particular focus on time between first and second breast cancer diagnosis and age at CBC diagnosis.METHODS: Within the nationwide Danish Breast Cancer Cooperative Group database, we identified 68,466 breast cancer patients diagnosed during 1978-2012. Patients who subsequently developed CBC were identified in a previously established database (N = 3004). Patients were followed for breast cancer-specific death in the Danish Register of Causes of Death until 2015. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazard regression models. Cumulative breast cancer mortality from date of CBC was estimated using the Aalen-Johansen method.RESULTS: Compared with UBC patients, the rate of dying from breast cancer was more than twofold higher following a CBC diagnosis, after adjustment for age, period, tumor characteristics, and treatment of the first breast cancer (HR 2.48; 95% CI 2.31-2.66). Short time interval (CONCLUSION: Breast cancer-specific mortality rates were markedly higher after compared with before a CBC diagnosis. We found higher breast cancer-specific mortality after CBC associated with a short interval between diagnoses among patients diagnosed with CBC before age 70 years.

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

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.

Purpose Administration of anthracycline and taxane therapy in the adjuvant setting is considered a standard for breast cancer. We evaluated a non-anthracycline-based regimen in TOP2A-normal patients. Patients and Methods In this multicenter, open-label, phase III trial, 2,012 women with early TOP2A-normal breast cancer and at least one high-risk factor were randomly assigned to receive six cycles of docetaxel (75 mg/m2) and cyclophosphamide (600 mg/m2) every 3 weeks (DC) or three cycles of epirubicin (90 mg/m2) and cyclophosphamide (600 mg/m2) followed by three cycles of docetaxel (100 mg/m2; EC-D). The primary end point was disease-free survival (DFS) after a median of 5 years of follow-up. Secondary end points were patient-reported toxicity, overall survival (OS), and distant disease-free survival. Results At a median estimated potential follow-up of 69 months, 5-year DFS was 87.9% (95% CI, 85.6% to 89.8%) in the EC-D arm and 88.3% (95% CI, 86.1% to 90.1%) in the DC arm. There was no significant difference in the risk of DFS events (hazard ratio [HR], 1.00; 95% CI, 0.78 to 1.28; P = 1.00), distant disease-free survival (HR, 1.12; 95% CI, 0.86 to 1.47; P = .40), or mortality (HR, 1.15; 95% CI, 0.83 to 1.59; P = .41) in the intent-to-treat analysis. A significant interaction between menopausal status and treatment group was observed for DFS ( P = .04) but not for OS ( P = .07). Patients with grade 3 tumors derived most benefit from DC, and patients with grade 1 to 2 tumors derived most benefit from EC-D (DFS: interaction P = .02; and OS: interaction P = .03). Patients receiving EC-D reported significantly more stomatitis, myalgia or arthralgia, vomiting, nausea, fatigue, and peripheral neuropathy, whereas edema was more frequent after DC. Conclusion This study provides evidence to support no overall outcome benefit from adjuvant anthracyclines in patients with early TOP2A-normal breast cancer. Purpose Administration of anthracycline and taxane therapy in the adjuvant setting is considered a standard for breast cancer. We evaluated a non-anthracycline-based regimen in TOP2A-normal patients. Patients and Methods In this multicenter, open-label, phase III trial, 2,012 women with early TOP2A-normal breast cancer and at least one high-risk factor were randomly assigned to receive six cycles of docetaxel (75 mg/m2) and cyclophosphamide (600 mg/m2) every 3 weeks (DC) or three cycles of epirubicin (90 mg/m2) and cyclophosphamide (600 mg/m2) followed by three cycles of docetaxel (100 mg/m2; EC-D). The primary end point was disease-free survival (DFS) after a median of 5 years of follow-up. Secondary end points were patient-reported toxicity, overall survival (OS), and distant disease-free survival. Results At a median estimated potential follow-up of 69 months, 5-year DFS was 87.9% (95% CI, 85.6% to 89.8%) in the EC-D arm and 88.3% (95% CI, 86.1% to 90.1%) in the DC arm. There was no significant difference in the risk of DFS events (hazard ratio [HR], 1.00; 95% CI, 0.78 to 1.28; P = 1.00), distant disease-free survival (HR, 1.12; 95% CI, 0.86 to 1.47; P = .40), or mortality (HR, 1.15; 95% CI, 0.83 to 1.59; P = .41) in the intent-to-treat analysis. A significant interaction between menopausal status and treatment group was observed for DFS ( P = .04) but not for OS ( P = .07). Patients with grade 3 tumors derived most benefit from DC, and patients with grade 1 to 2 tumors derived most benefit from EC-D (DFS: interaction P = .02; and OS: interaction P = .03). Patients receiving EC-D reported significantly more stomatitis, myalgia or arthralgia, vomiting, nausea, fatigue, and peripheral neuropathy, whereas edema was more frequent after DC. Conclusion This study provides evidence to support no overall outcome benefit from adjuvant anthracyclines in patients with early TOP2A-normal breast cancer.

Background Preclinical studies have shown both pro- and antineoplastic effects of antihistamines. Here, we evaluated the effect of H1 antihistamines on contralateral breast cancer (CBC) risk, and whether cationic amphiphilic (CAD) antihistamines could increase the sensitivity to chemotherapy. Methods From the Danish Breast Cancer Group clinical database, we identified all women aged ≥20 years with a first-time diagnosis of breast cancer during 1996–2012. Information on drug use, CBC and potential confounding factors was retrieved from nationwide registries. Using Cox proportional hazard regression models, we calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for CBC associated with H1-antihistamine use. Results We identified 52,723 patients with breast cancer with a total of 310,583 person-years of follow-up. Among them, 1444 patients developed a new primary tumour in the contralateral breast. Post-diagnosis use of H1 antihistamines (≥2 prescriptions) was not strongly associated with CBC risk (HR 1.08, 95% CI: 0.90–1.31) compared with non-use ( Conclusions Taken together, our findings do not suggest any association of H1-antihistamine use with CBC development.

Objectives Randomized clinical trials do not include a population that truly reflects a real-world population, due to their inclusion and exclusion criteria. This leads to concerns about the applicability of these studies in a clinical practice. In the present study, we aim to describe the clinical and demographic characteristics, treatment patterns, and clinical outcomes in a population of patients with HER2-positive metastatic breast cancer who received pertuzumab and trastuzumab as first-line treatment in a real-world setting. Methods The database of the Danish Breast Cancer Group was used to assemble data on patients included in the period April 2013 to August 2017. The primary endpoints were overall survival (OS) and progression-free survival (PFS). Results A cohort of 291 patients with a median age of 58 years was registered. Hereof 112 (38%) patients with de novo disease (primary disseminated) and 179 (62%) with recurrence. The median follow-up for OS was 24.1 months. The median OS was 41.8 months (95% CI, 37.7 to NE) and the median PFS was 15.8 months (95% CI, 14.0 to 19.9). For de novo patients alone, the median OS was not reached whereas the median PFS was 17.9 months (95% CI, 14.3 to 27.3). Hazard ratios for patients receiving vinorelbine showed comparable results as for the whole population. Conclusion This heterogeneous patient population in a real-world setting had a PFS comparable with what could be expected from the related randomized trial. The de novo patients had better OS and PFS as compared to patients with recurrence., Highlights • Patients with HER2-positive metastatic breast cancer. • Pertuzumab and trastuzumab as first-line treatment in a real-world setting. • A cohort of 291 patients; 112 with de novo disease and 179 with recurrence. • Median OS; 41.8 months and median PFS; 15.8 months. • PFS comparable with what could be expected from the related randomized trial.

OBJECTIVES: This study sought to evaluate the long-term risk of developing heart failure (HF) in patients receiving trastuzumab therapy.BACKGROUND: Trastuzumab has improved the prognosis in patients with HER2-positive breast cancer, but it can induce left ventricular dysfunction with reduced ejection fraction or HF during treatment. The long-term risk of HF is less well described.METHODS: In a nationwide Danish retrospective cohort study, 9,901 patients scheduled for adjuvant treatment for early-stage breast cancer were identified in the Danish Breast Cancer Cooperative Group database. Of these, 8,812 patients (25% HER2-positive; 51.7 ± 8.5 years of age) received chemotherapy including anthracycline; and if they were HER2 positive, trastuzumab was added. The primary endpoint was a diagnosis of HF assessed before and after 18 months in a landmark analysis to distinguish short- and long-term risks.RESULTS: Median follow-up was 5.4 years (interquartile range [IQR]: 4.1 to 6.8 years). In the trastuzumab group, 60 patients had HF by 9 years versus 51 in the group who were treated with chemotherapy alone, corresponding to incidence rates per 1,000 patient years of 5.3 (95% confidence interval [CI]: 4.1 to 6.8) versus 1.4 (95% CI: 1.1 to 1.8), respectively. The cumulative incidence of HF was higher in the trastuzumab group at both the short- and long-term (p < 0.01), yielding adjusted hazard ratios of 8.7 (95% CI: 4.6 to 16.5; p < 0.01) for early HF and 1.9 (95% CI: 1.2 to 3.3; p = 0.01) for late HF associated with trastuzumab treatment.CONCLUSIONS: Trastuzumab treatment is associated with a 2-fold increased risk of late HF compared with chemotherapy treatment alone.

Summary Approximately 3% to 5% of breast cancer patients are BRCA1 or BRCA2 germline mutation carriers. In this study, we correlated the distribution of intrinsic molecular subtypes according to failure pattern in a Danish cohort of BRCA germline–mutated breast cancer patients. Tumor tissues from 425 BRCA germline–mutated breast cancer patients were analyzed by immunohistochemistry for hormone receptor status, proliferation index (Ki-67), and HER2. Surrogate intrinsic molecular subtypes were assigned according to approximated St Gallen criteria. Annual hazard rates (AHR) were calculated for death and local or distant relapse, contralateral breast cancer, new primary cancer other than breast cancer, or death as first event (disease-free event). Luminal A–like subtype was observed with a frequency of 9% and 35% for BRCA1 and BRCA2, respectively, and for both BRCA1 and BRCA2 patients, the luminal B–like subtype was more frequent than the luminal A–like subtype (BRCA1 21% and BRCA2 40% luminal B–like). No events or deaths were observed for luminal A–like subtype during the first 2.5 and 0 to 5 years, respectively. AHRs for luminal B–like tumors were 5.34% (95% confidence interval [CI], 1.49-1.19) and 1.76% (95% CI, 0.36-3.16) for disease-free event and death, respectively, and those for basal-like were 6.58% (95% CI, 2.98-10.18) and 4.54% (95% CI, 2.69-6.40). A substantial proportion of BRCA carriers had luminal A–like subtype, and these were mainly BRCA2 carriers. Luminal A–like subtype was significantly associated with low AHR the first 5 years after surgery. This study warrants further exploration of the impact of the molecular intrinsic subtypes on survival in BRCA-mutated breast cancer patients.

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.

577 Background: Increasingly, HER2-positive early breast cancer (EBC) is treated by NACT combined with trastuzumab and pertuzumab followed by surgery. Ontruzant is registered as a biosimilar trastuzumab based on the totality of evidence including a randomized phase III study of NACT+Herceptin versus NACT+Ontruzant demonstrating similar pCR-rates (Pivot et al. J Clin Oncol 2018;36:968). However, no data exist for the efficacy of the combination of NACT with pertuzumab+Ontruzant (p+O). This investigator-initiated study was conducted to assess real world efficacy in HER2-positive EBC patients treated with NACT+p+O based on data from DBCG. DBCG has since 1977 provided guidelines for treatment of breast cancer and collected data from Danish hospital departments of surgery, pathology, and oncology prospectively on NACT, date and type of surgery and patho-anatomic findings. Methods: From the DBCG database, information was extracted for consecutive patients with unilateral early HER2-positive breast cancer registered to have received NACT+p+O from September 1, 2018 to August 31, 2019. pCR was defined as absence of residual invasive tumor in the breast and axillary lymph nodes (ypT0/Tis ypN0(i-)). Results: 215 patients received NACT+p+O. Median age was 54.8 years (range 24-81). NACT used, in combination with concurrent p+O, was cyclophosphamide+epirubicin followed by paclitaxel (62% on 6 cycles and 35% on 8 cycles) or other chemotherapy followed by paclitaxel (3%). Overall, 56% of patients achieved a pCR (Table). 68% of node-positive patients before receiving NACT+p+O had tumor-free axillary nodes after completing NACT+p+O. Conclusions: Real-world data from a nationwide population based study demonstrated a pCR-rate with NACT+p+O comparable to that seen in clinical studies with NACT+p+Herceptin (Chen et al. BMC Cancer 2019;19:973). pCR-rate was highly dependent on estrogen receptor (ER)-status and malignancy grade but not on clinical nodal status and tumor size. 68% of patients with cN+ converted to ypN0(i-). [Table: see text]

Purpose Luminal breast cancer has a long natural history, with recurrences continuing beyond 10 years after diagnosis. We analyzed long-term follow-up (LTFU) of efficacy outcomes and adverse events in the Breast International Group (BIG) 1-98 study reported after a median follow-up of 12.6 years. Patients and Methods BIG 1-98 is a four-arm, phase III, double-blind, randomized trial comparing adjuvant letrozole versus tamoxifen (either treatment received for 5 years) and their sequences (2 years of one treatment plus 3 years of the other) for postmenopausal women with endocrine-responsive early breast cancer. When pharmaceutical company sponsorship ended at 8.4 years of median follow-up, academic partners initiated an observational, LTFU extension collecting annual data on survival, disease status, and adverse events. Information from Denmark was from the Danish Breast Cancer Cooperative Group Registry. Intention-to-treat analyses are reported. Results Of 8,010 enrolled patients, 4,433 were alive and not withdrawn at an LTFU participating center, and 3,833 (86%) had at least one LTFU report. For the monotherapy comparison of letrozole versus tamoxifen, we found a 9% relative reduction in the hazard of a disease-free survival event with letrozole (hazard ratio [HR], 0.91; 95% CI, 0.81 to 1.01). HRs for other efficacy end points were similar to those for disease-free survival. Efficacy of letrozole versus tamoxifen for contralateral breast cancer varied significantly over time (0- to 5-, 5- to 10-, and > 10-year HRs, 0.62, 0.47, and 1.35, respectively; treatment-by-time interaction P = .005), perhaps reflecting a longer carryover effect of tamoxifen. Reporting of specific long-term adverse events seemed more effective with national registry than with case-record reporting of clinical follow-up. Conclusion Efficacy end points continued to show trends favoring letrozole. Letrozole reduced contralateral breast cancer frequency in the first 10 years, but this reversed beyond 10 years. This study illustrates the value of extended follow-up in trials of luminal breast cancer.

Observational studies of aspirin use and breast cancer risk have provided inconsistent results. The occurrence of contralateral breast cancer (CBC) among breast cancer survivors may serve as a useful high-risk model to identify preventive drug effects. Using this model, we examined the association between post-diagnosis use of low-dose aspirin and risk of CBC. We identified all women recorded with a first primary breast cancer in the Danish Breast Cancer Cooperative Group Database between 1996 and 2012. Information on drug use, tumor and patient characteristics, treatment, and CBC was obtained from nationwide registries. In the main analysis, we defined time-varying post-diagnosis low-dose aspirin use as two or more prescriptions filled during follow-up and applied a one-year exposure lag. Cox proportional hazard regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between post-diagnosis low-dose aspirin use and CBC risk. Among 52,723 breast cancer patients, 1,444 women developed CBC during a median follow-up of 4.8 years. The adjusted HR for CBC associated with post-diagnosis use of low-dose aspirin was 0.91 (95% CI: 0.75-1.09). We observed no substantial variation in HRs according to pattern of low-dose aspirin use or estrogen receptor status of the first or the contralateral breast cancer. In conclusion, this large nationwide cohort study of breast cancer survivors does not provide strong evidence suggesting an association between post-diagnosis use of low-dose aspirin and risk of CBC.

Objectives Unexplained axillary metastases have been detected in some patients with ductal carcinoma in situ (DCIS), possibly because of occult invasion or iatrogenic tumor cell displacement. The significance of these metastases is unknown and brings into questions the need for upstaging and axillary surgery. What are the risk factors for sentinel lymph node (SN) and non-SN metastases, including the risk of iatrogenic displacement of tumor cells in relation to an excisional biopsy, in patients diagnosed with DCIS? Methods Nationwide data on 1787 women diagnosed with DCIS between 2001 and 2015 were retrieved from the Danish Breast Cancer Group database. The association of clinicopathological variables with a positive SN (isolated tumor cells (ITCs), micro- or macrometastases) was evaluated using univariate and multivariate analyses. Results Of the 1787 patients, 71 (4.0%) had a positive SN: 15 (0.8%) had macrometastases, 42 (2.4%) had micrometastases, and 14 (0.8%) had ITCs. Five patients with a positive SN also had a positive non-SN. In adjusted analysis, a positive SN was associated with younger age (P = 0.036), increased size (P = 0.002), palpability (P = 0.0004) and surgical excisional biopsy (P Conclusions The overall risk of a positive SN in patients with DCIS on final pathology is low and less than 9% of these patients had positive non-SNs. This argues against using axillary lymph node dissection in this group. The odds of positive SN after surgical excisional biopsies showed more than a four-fold increase, indicating iatrogenic tumor cell displacement. It is questioned whether these patients should be upstaged and classified as having invasive carcinoma.

Background: The PAM50-based (Prosigna) risk of recurrence (ROR) score and intrinsic subtypes are prognostic for women with high-risk breast cancer. We investigate the predictive ability of Prosigna regarding the effectiveness of cyclophosphamide-based adjuvant chemotherapy in premenopausal patients with high-risk breast cancer. Methods: Prosigna assays were performed on the NanoString platform in tumors from participants in Danish Breast Cancer Group (DBCG) 77B, a four-arm trial that randomized premenopausal women with high-risk early breast cancer to no systemic treatment, levamisole, oral cyclophosphamide (C) or cyclophosphamide, methotrexate and fluorouracil (CMF). Results: In total, this retrospective analysis included 460 women (40% of the 1146 randomized patients). The continuous Prosigna ROR score was prognostic in the no systemic treatment group (unadjusted P

BACKGROUND: Statins have demonstrated antineoplastic effects in breast cancer cell lines, particularly in oestrogen receptor (ER)-negative cell lines. However, epidemiological studies have not supported a preventive effect of statin use against breast cancer. Therefore, we examined the association between statin use and contralateral breast cancer (CBC) risk among women with breast cancer.METHODS: We identified 52,723 women with non-metastatic breast cancer during 1996-2012 from the Danish Breast Cancer Group database. We defined time-varying post-diagnosis statin use as minimum two prescriptions lagged by 1 year. Cox regression analyses were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for CBC associated with statin use.RESULTS: Statin use was associated with a lower CBC risk (HR = 0.88; 95% CI = 0.73-1.05). The inverse association was strongest for long-term use overall (HR = 0.64; 95% CI = 0.43-0.96), although the HR specifically for long-term consistent use and high-intensity use approached unity. Among ER-negative breast cancer patients, statin use was associated with a CBC risk reduction (HR = 0.67; 95% CI = 0.45-1.00).CONCLUSIONS: We found some indication that statins reduce the risk of CBC. Further evaluations are needed to disentangle the equivocal results for long-term use and to establish if ER-negative breast cancer patients may benefit most from statin use.

Purpose The PAM50-based Prosigna risk of recurrence (ROR) score has been validated in randomized clinical trials to predict 10-year distant recurrence (DR). The value of Prosigna for predicting DR was examined in a comprehensive nationwide Danish cohort consisting of postmenopausal women with hormone receptor–positive early breast cancer treated with 5 years of endocrine therapy alone. Patients and Methods Using the population-based Danish Breast Cancer Cooperative Group database, follow-up data were collected on all patients diagnosed from 2000 through 2003 who, by nationwide guidelines, were treated with endocrine therapy for 5 years. Primary tumor blocks from 2,740 patients were tested with Prosigna and, after determination of human epidermal growth factor receptor 2 (HER2) status, data from 2,558 hormone receptor–positive/HER2-negative samples were analyzed, including 1,395 node-positive patients. Fine and Gray models were applied to determine the prognostic value of ROR for DR. Results Median follow-up for recurrence was 9.2 years. Twenty-six percent of the node-positive patients were classified as low ROR (n = 359) with a DR risk of 3.5% (95% confidence interval [CI], 1.9% to 6.1%) versus a DR risk of 22.1% (95% CI, 18.6% to 25.8%) at 10 years for patients classified as high ROR (n = 648). Node-negative patients classified as low and high ROR had a risk of DR of 5.0% (95% CI, 2.9% to 8.0%) and 17.8% (95% CI, 14.0% to 22.0%), respectively. Luminal B tumors (n = 947; DR risk, 18.4% [95% CI: 15.7% to 21.3%]) had a significantly worse outcome than luminal A tumors (n = 1,474,;DR risk, 7.6% [95% CI: 6.1% to 9.2%]; P < .001). Conclusion Prosigna ROR score improved the prediction of outcome in this nationwide Danish population. In a real-world setting, Prosigna can reliably identify node-negative patients and a significant proportion of patients with one to three positive nodes who can be spared treatment with adjuvant chemotherapy.

Purpose Evidence supporting the clinical utility of predictive biomarkers of anthracycline activity is weak, with a recent meta-analysis failing to provide strong evidence for either HER2 or TOP2A. Having previously shown that duplication of chromosome 17 pericentromeric alpha satellite as measured with a centromere enumeration probe (CEP17) predicted sensitivity to anthracyclines, we report here an individual patient–level pooled analysis of data from five trials comparing anthracycline-based chemotherapy with CMF (cyclophosphamide, methotrexate, and fluorouracil) as adjuvant chemotherapy for early breast cancer. Patients and Methods Fluorescent in situ hybridization for CEP17, HER2, and TOP2A was performed in three laboratories on samples from 3,846 of 4,864 eligible patients from five trials evaluating anthracycline-containing chemotherapy versus CMF. Methodologic differences did not affect HER2-to-CEP17 ratios but necessitated different definitions for CEP17 duplication: > 1.86 observed copies per cell for BR9601, NEAT, Belgian, and DBCG89D trials and > 2.25 for the MA.5 trial. Results Fluorescent in situ hybridization data were available in 89.3% (HER2), 83.9% (CEP17), and 80.6% (TOP2A) of 3,846 patient cases with available tissue. Both CEP17and TOP2A treatment-by-marker interactions remained significant in adjusted analyses for recurrence-free and overall survival, whereas HER2 did not. A combined CEP17 and TOP2A–adjusted model predicted anthracycline benefit across all five trials for both recurrence-free (hazard ratio, 0.64; 95% CI, 0.51 to 0.82; P = .001) and overall survival (hazard ratio, 0.66; 95% CI, 0.51 to 0.85; P = .005). Conclusion This prospectively planned individual-patient pooled analysis of patient cases from five adjuvant trials confirms that patients whose tumors harbor either CEP17 duplication or TOP2A aberrations, but not HER2 amplification, benefit from adjuvant anthracycline chemotherapy.

INTRODUCTION: Neoadjuvant endocrine treatment (NET) is a low-toxicity approach to achieve operability in locally advanced breast cancer, and to facilitate breast conservation in early breast cancer, particular in patients with highly estrogen receptor (ER) positive and HER2-negative disease. Here, we report the results obtained by neoadjuvant letrozole in patients with early breast cancer in a phase-II design.MATERIAL AND METHODS: A total of 119 postmenopausal women with ER-positive, HER2-negative operable breast cancer were assigned to four months of neoadjuvant letrozole before definitive surgery. Sentinel node or diagnostic fine needle aspiration cytology procedure was performed prior to treatment and the women were assessed prior, at two months, and before surgery with clinical examination, mammography and ultrasonography. Surgical specimens were examined for pathological response. Primary outcome was pathological and clinical response.RESULTS: The per protocol population consisted of 112 patients. Clinical response was evaluated in 109 patients and pathological response in 108. Overall a mean decrease in tumor size was 15% (p ≤ .0001). One patient had complete pathological response and 55% of patients had partial pathological response. ER at 100%, ductal subtype, tumor size below 2 cm and lymph node-negative status was significantly associated with a better response to NET and malignancy grade 3 with a poorer response to NET. One patient progressed during treatment and received neoadjuvant chemotherapy. Eight patients received adjuvant chemotherapy due to lack of response.CONCLUSION: Neoadjuvant aromatase inhibitor therapy is an acceptable strategy in selected postmenopausal patients with ER-rich and HER2-negative early breast cancer with ductal histology and should be considered when chemotherapy either isn't indicated or feasible.

1533Background: Gene expression profiling assays are not commonly used for therapy selection for breast cancer patients with germline BRCA mutations but a complete molecular characterization could ...

Safety of pregnancy in women with history of estrogen receptor (ER)–positive breast cancer remains controversial. In this multicenter case–control study, 333 patients with pregnancy after breast cancer were matched (1:3) to 874 nonpregnant patients of similar characteristics, adjusting for guaranteed time bias. Survival estimates were calculated using the Kaplan-Meier analysis; groups were compared with the log-rank test. All reported P values were two-sided. At a median follow-up of 7.2 years after pregnancy, no difference in disease-free survival was observed between pregnant and nonpregnant patients with ER-positive (hazard ratio [HR] = 0.94, 95% confidence interval [CI] = 0.70 to 1.26, P = .68) or ER-negative (HR = 0.75, 95% CI = 0.53 to 1.06, P = .10) disease. No overall survival (OS) difference was observed in ER-positive patients (HR = 0.84, 95% CI = 0.60 to 1.18, P = .32); ER-negative patients in the pregnant cohort had better OS (HR = 0.57, 95% CI = 0.36 to 0.90, P = .01). Abortion, time to pregnancy, breastfeeding, and type of adjuvant therapy had no impact on patients’ outcomes. This study provides reassuring evidence on the long-term safety of pregnancy in breast cancer survivors, including those with ER-positive disease.

BACKGROUND:Over the past 40 years the Danish Breast Cancer Cooperative Group (DBCG) has made significant contributions to improve outcome and to make treatment of patients with early breast cancer more tolerable through nationwide and international trials evaluating loco-regional and systemic treatments. These trials have been instrumental to establish standards for the treatment of early breast cancer.METHODS:The DBCG 82 trials had a global impact by documenting that the significant gain in loco-regional recurrence from postmastectomy radiation added to systemic therapy was associated with a reduction in distant recurrence and mortality in high-risk pre- and postmenopausal patients. The DBCG trials comparing breast conserving surgery and radiotherapy with mastectomy and more recently the trial of internal mammary node irradiation also had a major impact of practice. The trials initiated by the DBCG 40 years ago on tamoxifen and cyclophosphamide based chemotherapy became instrumental for the development of adjuvant systemic therapy not only due to their positive results but by sharing these important data with other members of the Early Breast Cancer Trialist' Collaborative Group (EBCTCG). Trials from the DBCG have also been important for highlighting the relative importance of anthracyclines and taxanes in the adjuvant setting. Furthermore, DBCG has made a major contribution to the development of aromatase inhibitors and targeted adjuvant treatment for human epidermal growth factor receptor 2 positive breast cancers.RESULTS:The substantial impact of these treatment improvements is illustrated by a 46.7% 10-year overall survival of early breast cancer patients treated in 1978-1987 compared to 71.5% for patients treated 2008-2012.CONCLUSIONS:The trials conducted and implemented by the DBCG appear to have a major impact on the substantial survival improvements in breast cancer. BACKGROUND: Over the past 40 years the Danish Breast Cancer Cooperative Group (DBCG) has made significant contributions to improve outcome and to make treatment of patients with early breast cancer more tolerable through nationwide and international trials evaluating loco-regional and systemic treatments. These trials have been instrumental to establish standards for the treatment of early breast cancer.METHODS: The DBCG 82 trials had a global impact by documenting that the significant gain in loco-regional recurrence from postmastectomy radiation added to systemic therapy was associated with a reduction in distant recurrence and mortality in high-risk pre- and postmenopausal patients. The DBCG trials comparing breast conserving surgery and radiotherapy with mastectomy and more recently the trial of internal mammary node irradiation also had a major impact of practice. The trials initiated by the DBCG 40 years ago on tamoxifen and cyclophosphamide based chemotherapy became instrumental for the development of adjuvant systemic therapy not only due to their positive results but by sharing these important data with other members of the Early Breast Cancer Trialist' Collaborative Group (EBCTCG). Trials from the DBCG have also been important for highlighting the relative importance of anthracyclines and taxanes in the adjuvant setting. Furthermore, DBCG has made a major contribution to the development of aromatase inhibitors and targeted adjuvant treatment for human epidermal growth factor receptor 2 positive breast cancers.RESULTS: The substantial impact of these treatment improvements is illustrated by a 46.7% 10-year overall survival of early breast cancer patients treated in 1978-1987 compared to 71.5% for patients treated 2008-2012.CONCLUSIONS: The trials conducted and implemented by the DBCG appear to have a major impact on the substantial survival improvements in breast cancer.

BACKGROUND:Since 40 years, Danish Breast Cancer Cooperative Group (DBCG) has provided comprehensive guidelines for diagnosis and treatment of breast cancer. This population-based analysis aimed to describe the plurality of modifications introduced over the past 10 years in the national Danish guidelines for the management of early breast cancer. By use of the clinical DBCG database we analyze the effectiveness of the implementation of guideline revisions in Denmark.METHODS:From the DBCG guidelines we extracted modifications introduced in 2007-2016 and selected examples regarding surgery, radiotherapy (RT) and systemic treatment. We assessed introduction of modifications from release on the DBCG webpage to change in clinical practice using the DBCG clinical database.RESULTS:Over a 10-year period data from 48,772 patients newly diagnosed with malignant breast tumors were entered into DBCG's clinical database and 42,197 of these patients were diagnosed with an invasive carcinoma following breast conserving surgery (BCS) or mastectomy. More than twenty modifications were introduced in the guidelines. Implementations, based on prospectively collected data, varied widely; exemplified with around one quarter of the patients not treated according to a specific guideline within one year from the introduction, to an almost immediate full implantation.CONCLUSIONS:Modifications of the DBCG guidelines were generally well implemented, but the time to full implementation varied from less than one year up to around five years. Our data is registry based and does not allow a closer analysis of the causes for delay in implementation of guideline modifications. BACKGROUND: Since 40 years, Danish Breast Cancer Cooperative Group (DBCG) has provided comprehensive guidelines for diagnosis and treatment of breast cancer. This population-based analysis aimed to describe the plurality of modifications introduced over the past 10 years in the national Danish guidelines for the management of early breast cancer. By use of the clinical DBCG database we analyze the effectiveness of the implementation of guideline revisions in Denmark.METHODS: From the DBCG guidelines we extracted modifications introduced in 2007-2016 and selected examples regarding surgery, radiotherapy (RT) and systemic treatment. We assessed introduction of modifications from release on the DBCG webpage to change in clinical practice using the DBCG clinical database.RESULTS: Over a 10-year period data from 48,772 patients newly diagnosed with malignant breast tumors were entered into DBCG's clinical database and 42,197 of these patients were diagnosed with an invasive carcinoma following breast conserving surgery (BCS) or mastectomy. More than twenty modifications were introduced in the guidelines. Implementations, based on prospectively collected data, varied widely; exemplified with around one quarter of the patients not treated according to a specific guideline within one year from the introduction, to an almost immediate full implantation.CONCLUSIONS: Modifications of the DBCG guidelines were generally well implemented, but the time to full implementation varied from less than one year up to around five years. Our data is registry based and does not allow a closer analysis of the causes for delay in implementation of guideline modifications.

BACKGROUND:Observational studies have pointed at a better survival after breast conserving surgery (BCS) compared with mastectomy. The aim of the present study was to evaluate whether this remains true when more extensive tumor characteristics and treatment data were included.METHODS:The cohort included patients registered after primary surgery for early invasive breast cancer in the database of the Danish Breast Cancer Cooperative Group, in the period 1995-2012. The cohort was divided into three groups: (i) patients who primarily had a mastectomy, (ii) patients treated by BCS, and (iii) patients who primarily had BCS and then mastectomy [intention to treat (ITT) by BCS]. The association between overall mortality and standard mortality ratio (SMR) and risk factors was analyzed in univariate and multivariate Poisson regression models.RESULTS:A total of 58,331 patients were included: 27,143 in the mastectomy group, 26,958 in the BCS group, and 4230 in the BCS-ITT group. After adjusting for patient and treatment characteristics, the relative risk (RR) was 1.20 (95% CI: 1.15-1.25) after mastectomy and 1.08 (95% CI: 1.01-1.15) after BCS first and then mastectomy, as compared to BCS. Statistically significant interactions were not observed for age, period of treatment, and nodal status, but patients with Charlson's Comorbidity Index (CCI) score 2+ had no increased mortality after mastectomy, as opposed to patients with CCI 0-1. Loco-regional radiation therapy (RT) in node positive patients did not reduce the increased risk associated with mastectomy [RR = 1.28 (95% CI 1.19-1.38)].CONCLUSION:Patients assigned to BCS have a better survival than patients assigned to mastectomy. Residual confounding after adjustment for registered characteristics presumably explained the different outcomes, thus consistent with selection bias. Diversities in RT did not appear to explain the observed difference in survival after BCS and mastectomy. BACKGROUND: Observational studies have pointed at a better survival after breast conserving surgery (BCS) compared with mastectomy. The aim of the present study was to evaluate whether this remains true when more extensive tumor characteristics and treatment data were included.METHODS: The cohort included patients registered after primary surgery for early invasive breast cancer in the database of the Danish Breast Cancer Cooperative Group, in the period 1995-2012. The cohort was divided into three groups: (i) patients who primarily had a mastectomy, (ii) patients treated by BCS, and (iii) patients who primarily had BCS and then mastectomy [intention to treat (ITT) by BCS]. The association between overall mortality and standard mortality ratio (SMR) and risk factors was analyzed in univariate and multivariate Poisson regression models.RESULTS: A total of 58,331 patients were included: 27,143 in the mastectomy group, 26,958 in the BCS group, and 4230 in the BCS-ITT group. After adjusting for patient and treatment characteristics, the relative risk (RR) was 1.20 (95% CI: 1.15-1.25) after mastectomy and 1.08 (95% CI: 1.01-1.15) after BCS first and then mastectomy, as compared to BCS. Statistically significant interactions were not observed for age, period of treatment, and nodal status, but patients with Charlson's Comorbidity Index (CCI) score 2+ had no increased mortality after mastectomy, as opposed to patients with CCI 0-1. Loco-regional radiation therapy (RT) in node positive patients did not reduce the increased risk associated with mastectomy [RR = 1.28 (95% CI 1.19-1.38)].CONCLUSION: Patients assigned to BCS have a better survival than patients assigned to mastectomy. Residual confounding after adjustment for registered characteristics presumably explained the different outcomes, thus consistent with selection bias. Diversities in RT did not appear to explain the observed difference in survival after BCS and mastectomy.

Background: Following loco-regional treatment for early breast cancer accurate prognostication is essential for communicating benefits of systemic treatment. The aim of this study was to determine time to recurrence and long-term mortality rates in high risk patients according to patient characteristics and subtypes as assigned by immunohistochemistry panels. Patients and methods: In November 1977 through January 1983, 2862 patients with tumors larger than 5 cm or positive axillary nodes were included in the DBCG 77 trials. Archival tumor tissue from patients randomly assigned to no systemic treatment was analyzed for ER, PR, Ki67, EGFR and HER2. Intrinsic subtypes were defined as follows: Luminal A, ER or PR >0%, HER2-negative, PR >10% and Ki67 0%, (PR ≤10% or HER2-positive or Ki67 ≥ 14%); HER2E, ER 0%, PR 0%, HER2 positive; Core basal, ER 0%, PR 0%, HER2 negative and EGFR positive. Multivariate categorical and fractional polynomials (MFP) models were used to construct prognostic subsets by clinicopathologic characteristics. Results: In a multivariate model, mortality rate was significantly associated with age, tumor size, nodal status, invasion, histological type and grade, as well as subtype classification. Conclusions: With 35 years of follow-up, in this population of high-risk patients with no systemic therapy, no subgroup based on a composite prognostic score and/or molecular subtypes could be identified without excess mortality as compared to the background population.

Background Adjuvant treatment in breast cancer patients especially with aromatase inhibitors (AIs) has adverse effects on bone metabolism resulting in an increased occurrence of fractures. In order to demonstrate this occurrence, long-term follow-up studies are necessary. From several national registries in Denmark, it is possible to link data from different sources and analyze this issue. Methods A study cohort of 68,842 breast cancer patients prospectively diagnosed and registered in the Danish Breast Cancer Cooperative Group's database during the period 1995-2012 formed the basis of the analysis. These data were matched with data on all types of fractures from the Danish National Patient Register and vital data from the Danish Civil Registration System. Results After data cleaning 66,502 patients were available for analysis and 16,360 of these had incurred 20,341 fractures with 13,182 patients having just one fracture. These fractures were distributed over 214 specific fracture sites. An extended multivariable Cox regression model revealed significant association between the occurrence of fractures and age, menopause, Charlson comorbidity index (CCI) and endocrine therapy such that late menopause and tamoxifen treatment were associated with a lower occurrence and AI treatment, age and CCI were associated with a higher occurrence of fractures. Conclusion Before advising adjuvant therapy with AIs fragile patients with chronic diseases should receive special attention in order to reduce the incidence of fractures in this vulnerable group of patients.

Transcriptome analysis enables classification of breast tumors into molecular subtypes that correlate with prognosis and effect of therapy. We evaluated the clinical benefits of molecular subtyping compared to our current diagnostic practice.Molecular subtyping was performed on a consecutive and unselected series of 524 tumors from women with primary breast cancer (n = 508). Tumors were classified by the 256 gene expression signature (CIT) and compared to conventional immunohistochemistry (IHC) procedures.More than 99% of tumors were eligible for molecular classification and final reports were available prior to the multidisciplinary conference. Using a prognostic standard mortality rate index (PSMRi) developed by the Danish Breast Cancer Group (DBCG) 39 patients were assigned with an intermediate risk and among these 16 (41%) were furthermore diagnosed by the multi-gene signature assigned with a luminal A tumor and consequently spared adjuvant chemotherapy. There was overall agreement between mRNA derived and IHC hormone receptor status, whereas IHC Ki67 protein proliferative index proved inaccurate, compared to the mRNA derived index. Forty-one patients with basal-like (basL) subtypes were screened for predisposing mutations regardless of clinical predisposition. Of those 17% carried pathogenic mutations.Transcriptome based subtyping of breast tumors evidently reduces the need for adjuvant chemotherapy and improves identification of women with predisposing mutations. The results imply that transcriptome profiling should become an integrated part of current breast cancer management.

Objectives The risk of axillary metastases in breast cancer patients with only ductal carcinoma in situ (DCIS) is low. Thus, axillary staging with sentinel lymph node biopsy (SLNB) should only be used according to the current guidelines to avoid over-treatment and unnecessary morbidity. In the present study, the use of SLNB in patients with DCIS was evaluated nationally and compared across Danish departments. Material and methods A register-based study was conducted using the Danish Breast Cancer Group database. The use of SLNB in DCIS patients according to year of diagnosis, age at diagnosis, size of lesion, Van Nuys classification, palpability, location and department of surgery was evaluated. The chi-squared test was used to test differences between the groups. Results Data from 2618 Danish female patients diagnosed with DCIS between 2004 and 2015 were included; 54.3% of patients underwent SLNB. The use of SLNB increased from 26.6% in 2004 to 65.1% in 2015. A total of 1877 (71.7%) patients underwent breast-conserving surgery (BCS), and 577 (22.0%) underwent mastectomy, of which 43.9% and 86.0% respectively had a concomitant SLNB. The SLNB was performed in 23.8% of 454 patients not included by the guidelines. The use of SLNB in combination with BCS differed significantly between departments ranging from 19.7% to 63.8%. A significant difference in the use of SLNB with BCS and mastectomy according to department capacity (high-volume departments versus low-volume departments) was observed. Conclusion The use of SLNB in patients with DCIS and adherence to the Danish national guidelines varies among Danish breast surgery departments. To optimise the axillary treatment of patients with DCIS, an improved compliance to the national DCIS guidelines is necessary.

Adjuvant endocrine therapy has significantly improved survival of estrogen receptor α (ER)-positive breast cancer patients, but around 20% relapse within 10 years. High expression of ER-stimulated proteins like progesterone receptor (PR), Bcl-2 and insulin-like growth factor receptor I (IGF-IR) is a marker for estrogen-driven cell growth. Therefore, patients with high tumor levels of these proteins may have particularly good prognosis following adjuvant endocrine therapy.Archival tumor tissue was available from 1323 of 1396 Danish breast cancer patients enrolled in BIG 1-98, a randomized phase-III clinical trial comparing adjuvant letrozole, tamoxifen or a sequence of the two drugs. Immunohistochemical staining for ER, HER-2, PR, Bcl-2 and IGF-IR was performed and determined by Allred scoring (ER, PR and Bcl-2) or HercepTest (HER-2 and IGF-IR).Data on all five markers were available from 969 patients with ER-positive, HER-2-negative tumors. These patients were classified in ER activity groups based on the level of PR, Bcl-2 and IGF-IR. High ER activity profile was found in 102 patients (10.5%) and compared with the remaining patients, univariate and multivariate analysis revealed HR (95% CI) and p values for disease-free survival (DFS) of 2.00 (1.20-3.22), 0.008 and 1.70 (1.01-2.84), 0.04 and for the overall survival (OS) of 2.33 (1.19-4.57), 0.01 and 1.90 (0.97-3.79), 0.06, respectively. The high ER activity profile did not disclose difference in DFS or OS according to treatment with tamoxifen or letrozole (p = .06 and .09, respectively).Stratifying endocrine-treated patients in ER activity profile groups disclosed that patient with high ER activity profile (10.5%) had significantly longer DFS and OS, and the profile was an independent marker for DFS. High ER activity is a marker for estrogen-driven tumor growth. We suggest further analyses to disclose whether the ER activity profile or other markers associated with estrogen-driven growth may be used to identify ER-positive high-risk breast cancer patients who can be spared adjuvant chemotherapy.

To compare the rate of positive resection margins between radioactive seed localization (RSL) and wire-guided localization (WGL) after breast conserving surgery (BCS).WGL is the current standard for localization of nonpalpable breast lesions in BCS, but there are several difficulties related to the method.From January 1, 2014 to February 4, 2016, patients with nonpalpable invasive breast cancer or DCIS visible on ultrasound were enrolled in this randomized, multicenter, open-label clinical trial, and randomly assigned to RSL or WGL. The primary outcome was margin status after BCS. Secondary outcomes were duration of the surgical procedure, weight of surgical specimen, and patients' pain perception. Analyses were performed by intention-to-treat (ITT) and per protocol.Out of 444 eligible patients, 413 lesions representing 409 patients were randomized; 207 to RSL and 206 to WGL. Twenty-three did not meet inclusion criteria, chose to withdraw, or had a change in surgical management and were excluded. The remaining 390 lesions constituted the ITT population. Here, resection margins were positive in 23 cases (11.8%) in the RSL group compared with 26 cases (13.3%) in the WGL group (P = 0.65). The per-protocol analysis revealed no difference in margin status (P = 0.62). There were no significant differences in the duration of the surgical procedure (P = 0.12), weight of the surgical specimen (P = 0.54) or the patients' pain perception (P = 0.28).RSL offers a major logistic advantage, as localization can be done several days before surgery without any increase in positive resection margins compared with WGL.

We examined the association between the hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status of women with primary breast cancer and the risk of axillary lymph node (ALN) involvement at the time of diagnosis. Information on 20,009 women diagnosed with primary breast cancer between 2008 and 2012 was retrieved from the Danish Breast Cancer Cooperative Group database. The associations between clinical and pathological variables and ALN involvement at the time of diagnosis were evaluated in univariate and multivariate regression analyses, as well as the significance of tumor subtypes in ALN involvement. The risk of ALN metastases at the time of diagnosis was significantly reduced in HR-negative patients compared to HR-positive patients [adjusted odds ratio (OR) 0.69; 95 % CI 0.63–0.76; P = 0.0009]. A HER2-positive status was associated with an increased risk of ALN involvement at diagnosis compared to a HER2-negative status (OR 1.37; 95 % CI 1.24–1.50; P