Capecitabine monotherapy as first-line treatment in advanced HER2-normal breast cancer - a nationwide, retrospective study.

Background and purpose: Capecitabine can be used as first-line treatment for advanced breast cancer. However, real-world data on efficacy of capecitabine in this setting is sparse. The purpose of the study is to evaluate outcomes of patients with Human Epidermal Growth Factor Receptor (HER2)-normal advanced breast cancer treated with capecitabine monotherapy as first-line treatment. MATERIAL AND METHODS: The study utilized the Danish Breast Cancer Group (DBCG) database and was conducted retrospectively across all Danish oncology departments. Inclusion criteria were female patients, with HER2-normal advanced breast cancer treated with capecitabine monotherapy as the first-line treatment from 2010 to 2020. The primary endpoints were overall survival (OS) and progression-free survival (PFS). RESULTS: A total of 494 patients were included. Median OS was 16.4 months (95% confidence interval [CI]: 14.5-18.0), and median PFS was 6.0 months (95% CI: 5.3-6.7). Patients with estrogen receptor (ER)-positive disease had significantly longer OS (median: 22.8 vs. 10.5 months, p < 0.001) and PFS (median: 7.4 vs. 4.9 months, p = 0.003), when compared to ER-negative patients. Stratifying by age, patients under 45 years displayed a median PFS of 4.1 months, while those aged 45-70 years and over 70 years had median PFS of 5.7 and 7.2 months, respectively (p = 0.01). INTERPRETATION:  In this nationwide study, the efficacy of capecitabine as a first-line treatment for HER2-normal advanced breast cancer is consistent with other, mainly retrospective, studies. However, when assessed against contemporary and newer treatments, its effectiveness appears inferior to alternative chemotherapies or targeted therapies.

Incidence and survival of primary metastatic breast cancer in Denmark; implication of breast cancer screening, classification, and staging practice.

BACKGROUND: Primary metastatic breast cancer (pMBC) accounts for 5-10% of annual breast cancers with a median survival of 3-4 years, varying among subtypes. In Denmark, the incidence of breast cancer increased until 2010, followed by a stabilisation. Several factors influencing pMBC incidence and survival, including screening prevalence, staging methods, and classification standards, remain pivotal but inadequately documented. MATERIAL AND METHOD: This retrospective observational study involving pMBC patients diagnosed between 2000 and 2020 encompassed all Danish oncology departments. Data from the Danish Breast Cancer Group database and the National Patient Register included diagnosis specifics, demographics, treatment, and follow-up. RESULTS: Between 2000 and 2020, 3,272 patients were diagnosed with pMBC, a rise from 355 patients in 2000-2004 to 1,323 patients in 2015-2020. The increase was particularly observed in patients aged 70 years or older. Changes in tumour subtypes were observed, notably with a rise in human epidermal growth factor receptor 2 (HER2)-positive cases but a steady distribution of estrogen receptor (ER) status. Diagnostic practices changed over the two decades, with 6% evaluated with PET/CT (positron emission tomography-computed tomography) or CT (computed tomography) with a bone evaluation in 2000-2004 and 65% in 2015-2020. Overall survival (OS) improved from 23 months in 2000-2004 to 33 months in 2015-2020. In patients with ER-positive and HER2-positive disease, the multivariable model showed improved survival by year of diagnosis, and further, patients with ER-negative/HER2-negative disease fared worse the first 2 years after diagnosis. INTERPRETATION: Our study delineates changes in the treatment and survival of pMBC over two decades. Stage migration, screening introduction, and changes in registration practice, however, prevent a valid assessment of a possible causal relationship.

High inter-laboratory variability in the assessment of HER2-low breast cancer: a national registry study on 50,714 Danish patients.

BACKGROUND: Considering the recent advancements in the treatment of breast cancer with low expression of human epidermal growth factor receptor 2 (HER2), we aimed to examine inter-laboratory variability in the assessment of HER2-low breast cancer across all Danish pathology departments. METHODS: From the Danish Breast Cancer Group, we obtained data on all women diagnosed with primary invasive breast cancer in 2007-2019 who were subsequently assigned for curatively intended treatment. RESULTS: Of 50,714 patients, HER2 score and status were recorded for 48,382, among whom 59.2% belonged to the HER2-low group (score 1+ or 2+ without gene amplification), 26.8% had a HER2 score of 0, and 14.0% were HER2 positive. The proportion of HER2-low cases ranged from 46.3 to 71.8% among pathology departments (P < 0.0001) and from 49.3 to 65.6% over the years (P < 0.0001). In comparison, HER2 positivity rates ranged from 11.8 to 17.2% among departments (P < 0.0001) and from 12.6 to 15.7% over the years (P = 0.005). In the eight departments with the highest number of patients, variability in HER2-low cases increased from 2011 to 2019, although the same immunohistochemical assay was used. By multivariable logistic regression, the examining department was significantly related to both HER2 score 0 and HER2 positivity (P < 0.0001) but showed greater dispersion in odds ratios in the former case (range 0.25-1.41 vs. 0.84-1.27). CONCLUSIONS: Our data showed high inter-laboratory variability in the assessment of HER2-low breast cancer. The findings cast doubt on whether the current test method for HER2 is robust and reliable enough to select HER2-low patients for HER2-targeted treatment in daily clinical practice.

Adjuvant chemotherapy in patients with ER-negative/HER2-negative, T1abN0 breast cancer: a nationwide study.

PURPOSE: The purpose of this study was to examine the effect of chemotherapy on invasive disease-free survival (iDFS) and overall survival (OS) in a nationwide cohort of patients with estrogen receptor (ER)-negative/human epidermal growth factor receptor 2 (HER2)-negative, T1abN0 breast cancer. METHODS: Patients with ER-negative/HER2-negative, T1abN0 breast cancer registered in the Danish Breast Cancer Group database between 2007 and 2016 were identified. The effect of adjuvant chemotherapy on iDFS and OS was analyzed with Cox proportional hazards analysis. RESULTS: In total, 296 patients were included in the statistical analyses. Of these, 235 (79.4%) received chemotherapy and 61 patients (20.6%) did not. Patients treated with chemotherapy were significantly younger, had a significantly higher proportion of grade 3 tumors, T1b tumors, and tumors of ductal subtype. With 7.7 years of median follow-up, treatment with chemotherapy was associated with a significant improvement in OS in the adjusted analysis, Hazard Ratio 0.35 (95% Confidence Interval (0.15-0.81), p = 0.02), chemotherapy vs. no chemotherapy. In the unadjusted analyses, patients with both T1a and T1b tumors had significantly improved OS with chemotherapy. At 5 years, OS was 100% vs. 94.4% and 93.8% vs. 81.3% for patients with T1a and T1b tumors, respectively, chemotherapy vs. no chemotherapy. With 4.9 years of median follow-up, iDFS was not significantly improved with chemotherapy. CONCLUSION: Patients with ER-negative/HER2-negative, T1abN0 breast cancer had significantly improved OS when treated with chemotherapy. This improvement was significant in patients with both T1a and T1b tumors, respectively. The effect was, however, limited in patients with T1a tumors.

Identifying recurrent breast cancer patients in national health registries using machine learning.

BACKGROUND: More than 4500 women are diagnosed with breast cancer each year in Denmark, however, despite adequate treatment 10-30% of patients will experience a recurrence. The Danish Breast Cancer Group (DBCG) stores information on breast cancer recurrence but to improve data completeness automated identification of patients with recurrence is needed. METHODS: We included patient data from the DBCG, the National Pathology Database, and the National Patient Registry for patients with an invasive breast cancer diagnosis after 1999. In total, relevant features of 79,483 patients with a definitive surgery were extracted. A machine learning (ML) model was trained, using a simplistic encoding scheme of features, on a development sample covering 5333 patients with known recurrence and three times as many non-recurrent women. The model was validated in a validation sample consisting of 1006 patients with unknown recurrence status. RESULTS: The ML model identified patients with recurrence with AUC-ROC of 0.93 (95% CI: 0.93-0.94) in the development, and an AUC-ROC of 0.86 (95% CI: 0.83-0.88) in the validation sample. CONCLUSION: An off-the-shelf ML model, trained using the simplistic encoding scheme, could identify recurrence patients across multiple national registries. This approach might potentially enable researchers and clinicians to better and faster identify patients with recurrence and reduce manual patient data interpretation.

Evaluation of tumor-infiltrating lymphocytes, PD-L1, and PIK3CA mutations and association with prognosis in HER2-positive early stage breast cancer.

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) have predictive and prognostic potential in HER2-positive breast cancer (HER2+ BC). Programmed death-ligand 1 (PD-L1) is an immune checkpoint protein, with important roles in the tumor microenvironment, possibly in both tumor and immune cells (ICs), providing rationale for targeting with immune-checkpoint therapy. PIK3CA mutations are oncogenic, activating mutations, which are also of relevance in breast cancer. Herein, we investigate the frequency of TILs, PD-L1 and PIK3CA mutations, and whether these factors influence outcome, in early HER2+ BC. MATERIALS AND METHODS: Stromal TILs (sTILs) and PD-L1 expressions were assessed using full tumor-sections and TMA, respectively, from 236 patients with HER2+ BC. TILs were assessed, according to a standardized method, as continuous measurement and according to three predefined categories: low (0-10%), intermediate (11-59%), and high (60-100%). PD-L1 immunohistochemistry (Ventana SP263) was evaluated and positivity defined as ≥1% expression in tumor and ICs. PIK3CA mutations (exons 9 and 20) were determined by pyrosequencing. RESULTS: Fourteen percent of patients had high sTILs and 25% had a PIK3CA mutation. PD-L1 expression was more frequent in ICs (68%) than tumor cells (24%). Patients with low sTILs had a significantly worse overall survival (multivariate: HR 2.80; 95% CI 1.36-5.78; p = .02). DISCUSSION: Patients with low sTILs had a significantly poorer survival, despite adequate treatment with adjuvant therapy.

Real-world survival of Danish patients with HER2-positive metastatic breast cancer.

BACKGROUND: The purpose was to investigate the treatment flow of patients with HER2-positive metastatic breast cancer (mBC), progression-free survival (PFS) and overall survival (OS) across treatment lines and adherence to guidelines (defined as trastuzumab, pertuzumab and chemotherapy first line, where 85% received vinorelbine as backbone and T-DM1 second line). Furthermore, we identified clinical markers to predict the risk of developing brain metastases. MATERIAL AND METHODS: Patients with HER2-positive mBC, diagnosed between 01.01.2014-31.12.2019, registered in the database of the Danish Breast Cancer Group were included in this real-word study. Clinical follow-up was assessed until 01.10.2020 and complete follow-up for overall survival until 01.10.2021. Survival data were analyzed using the Kaplan-Meier method with guidelines adherence analyzed as a time-varying covariate, and the risk of CNS metastasis was estimated by the cumulative incidence function. RESULTS: 631 patients were included. 329 (52%) patients followed the guidelines. The median OS for all patients was 42.3 months (95% Cl, 38.2-48.4), and significantly higher for the patients who followed guidelines; NA (95% CI, 78.2-NA). The median PFS for all patients was 13.4 months (95% Cl, 12.1-14.8), 6.6 (95% Cl, 5.8-7.6) and 5.8 (95% Cl, 4.9-6.9) for first, second and third line of treatment, respectively. Patients with ER-negative mBC had a higher risk of developing brain metastases and patients with high tumor burden had a higher risk of developing brain metastases with an adjusted HR of 0.69 (95% CI, 0.49-0.98), p = 0.047 and 2.69 (95% CI, 1.45-5.00), p = 0.002, respectively. CONCLUSION: We found that only half of the patients with HER2-positive mBC, received first and second-line treatment according to national guidelines. Patients receiving treatment according to guidelines had a significantly higher median OS compared to patients who did not. We also found that patients with ER-negative disease or high tumor burden had a significantly higher risk of developing brain metastases.

A retrospective, non-interventional study of breast cancer patients diagnosed with ER+/HER2 negative, locally advanced or metastatic breast cancer treated with palbociclib in Denmark.

BACKGROUND: The recommended first-line treatment for advanced, ER+/HER2 negative breast cancer is a CDK 4/6 inhibitor in combination with an endocrine backbone. This study investigated the use of palbociclib, as first- or second-line therapy for advanced breast cancer patients in a real-world setting. MATERIAL AND METHODS: This retrospective, population-based study included all Danish, advanced breast cancer patients with ER+/HER2 negative disease who initiated first- or second-line treatment with palbociclib from January 1st, 2017, until December 31st, 2020. The primary outcomes were PFS and OS. RESULTS: The study included 1054 advanced breast cancer patients with a mean age of 66.8 years. Median OS was 51.7 months (95% CI, 44.9-54.6) for all patients in the first-line setting (n = 728) and median PFS was 24.3 months (95% CI, 21.7-27.8). Patients treated in second line (n = 326) had a median OS of 32.5 months (95% CI, 29.9-35.9) and a median PFS of 13.6 months (95% CI, 11.5-15.7). In first-line setting, the PFS and OS were significantly different for endocrine sensitive patients treated with AI (aromatase inhibitor) (n = 423) vs. fulvestrant (n = 158) as endocrine backbone to palbociclib (median PFS AI 31.3 months vs fulvestrant 19.9 months, p = 0.002 and median OS AI 56.9 months vs. fulvestrant 43.6 months, p = 0.001). In endocrine resistant patients (n = 145), no statistically significant difference in PFS was shown (median PFS AI 21.5 months vs. fulvestrant 12.0 months, p = 0.09), whereas OS was significantly different (median OS AI 43.5 months vs. fulvestrant 28.8 months, p = 0.02). CONCLUSION: In this real-world study, treatment with palbociclib combination therapy met the standards of efficacy set by the phase III trials, PALOMA-2 and PALOMA-3, and the standards set by real-world studies in other countries. The study showed significantly different outcomes in terms of PFS and OS in endocrine sensitive patients comparing AI vs. fulvestrant as endocrine backbone to palbociclib as first-line therapy.

A nationwide observational study in heavily pretreated metastatic HER2-positive breast cancer patients.

BACKGROUND: Current guidelines in HER2-positive metastatic breast cancer (mBC) recommend the combination of trastuzumab and a chemotherapeutic agent for 3rd line or later treatments. This study aims to describe the treatment of HER2-positive mBC in 3rd line or later after previous treatment with T-DM1 for mBC in a real-world setting. MATERIAL AND METHODS: This observational population-based study included all women diagnosed with HER2-positive mBC in Denmark, previously treated with T-DM1 in the metastatic setting. Patients were included on the date of progression leading to initiation of 3rd line treatment if the patient had received T-DM1 in 1st or 2nd line. If the patient received T-DM1 in 3rd line or later the inclusion was based on the date of progression on T-DM1. The primary end points were overall survival (OS) and progression-free survival (PFS). RESULTS: The study included 272 women with a mean age of 59 (27-86) and a median of 3 (2-11) treatment lines prior to inclusion. At index, all patients had received T-DM1 and 167 (62%) patients had received pertuzumab in the metastatic setting. During follow-up 183 patients received chemotherapy. Of these patients, 120 received chemotherapy combined with trastuzumab, 50 received chemotherapy combined with other HER2-targeted therapy, and 13 received chemotherapy as monotherapy. The remaining 89 patients received either HER2-targeted monotherapy (41), endocrine therapy (31), experimental treatment (10), or no treatment (7). Median PFS was 5.5 months (95% CI, 4.8-6.5) and median OS was 18.5 months (95% CI, 16.2-21.3). CONCLUSION: In this real-world study, we found that patients were treated with a wide variety of anti-cancer agents with modest efficacy. However, patients in this study did not have access to newer therapies like tucatinib and T-DXd.

Benefit of adjuvant chemotherapy and trastuzumab in patients with HER2-positive, node-negative breast tumors ≤ 10 mm: a nationwide study.

PURPOSE: The purpose of this study was to evaluate the effect of chemotherapy and trastuzumab on invasive disease-free survival (iDFS) and overall survival (OS) in patients with human epidermal growth factor receptor 2 (HER2) positive, T1abN0 breast cancer. METHODS: In the Danish Breast Cancer Group database, patients with HER2-positive, T1abN0 tumors diagnosed between 2007 and 2016 were identified. Cox proportional hazards analysis was performed to analyze the association between adjuvant chemotherapy and trastuzumab and iDFS and OS. RESULTS: Of 605 patients included in the analyses, 465 patients received chemotherapy and trastuzumab and 140 patients did not. Chemotherapy and trastuzumab did not improve iDFS or OS significantly in adjusted analyses. 5-year iDFS was 92.3% vs. 89.9%, Hazard ratio (HR) 1.01 (p = 0.98), and 5-year OS was 97.4% vs. 94.3%, HR 0.60 (p = 0.15), chemotherapy and trastuzumab vs. no chemotherapy/trastuzumab. In unadjusted analyses, significant treatment benefit on OS was found in patients with T1b tumors. The largest absolute treatment benefits were found in patients with T1b tumors and estrogen receptor (ER) negative tumors, respectively, whereas treatment effects in patients with T1a tumors and ER-positive tumors, respectively, were limited. CONCLUSION: Adjuvant chemotherapy and trastuzumab did not improve OS or iDFS significantly in patients with HER2-positive, T1abN0 breast cancers in adjusted analyses. In unadjusted analyses, significant OS benefit was found in patients with T1b tumors. The largest absolute benefit was observed in patients with T1b tumors and ER-negative tumors, respectively, whereas the effect was limited in patients with T1a tumors and ER-positive tumors, respectively.

Interventions supporting cancer patients in making decisions regarding participation in clinical trials - a systematic review.

OBJECTIVES: Existing research on the perspectives of patients with cancer and health care professionals indicates that patient decision making on cancer clinical trial participation is a complex process and may be poorly understood, possibly compromising their decision to participate. This systematic review investigates interventions that support patients in their decision-making processes regarding whether to participate or not and assesses the qualities of the interventions, measures used and related outcomes. METHODS: Six databases were systematically searched and only studies evaluating interventions that support the decision making of adult patients offered to enter a cancer clinical trial were included. Ten articles met the criteria and were analysed using a narrative synthesis approach. RESULTS: The research focus of the included studies reflected the multifactorial nature of what constitutes support for patient decision making in terms of entering a cancer clinical trial. However, most interventions were based on the hypothesis that more information leads to support in decision making, and did not take other factors, such as the relationship to the clinical staff or relatives, the patients' strong hope for therapeutic benefit or other existential needs into account. The interventions were primarily based on a specific tool, executed once, which seems to imply that decisions need only to be supported once and not at several time points throughout the decision process, and did not assess the importance of a patient's family- or social relations. Moreover, few interventions focused on the patients' counselling experience or assessed patient preferences in relation to decision making. CONCLUSIONS: The findings demonstrate a lack of research on interventions to support patients' decision making that takes other factors, apart from improving knowledge of trials, into account. Limited evidence exists on the effectiveness of decision support interventions to improve the experience of support in adult patients with cancer. Interventions that take patient preferences in relation to decision making and the social context of decision processes into account need to be developed and assessed.

Tumour-infiltrating lymphocytes and response to neoadjuvant letrozole in patients with early oestrogen receptor-positive breast cancer: analysis from a nationwide phase II DBCG trial.

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.

Induction of PIK3CA alterations during neoadjuvant letrozole may improve outcome in postmenopausal breast cancer patients.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Synchronous bilateral breast cancer: a nationwide study on histopathology and etiology.

PURPOSE: The aim of the present study was to describe histopathologic characteristics of synchronous bilateral breast cancer (SBBC), and by comparing SBBC to unilateral breast cancer (UBC), identify possible etiological mechanisms of SBBC. METHODS: Patients with primary SBBC (diagnosed within 4 months) and UBC diagnosed in Denmark between 1999 and 2015 were included. Detailed data on histopathology were retrieved from the Danish Breast Cancer Group database and the Danish Pathology Register. Associations between bilateral disease and the different histopathologic characteristics were evaluated by odds ratios and estimated by multinomial regression models. RESULTS: 1214 patients with SBBC and 59,221 with UBC were included. Patients with SBBC more often had invasive lobular carcinomas (OR 1.29; 95% CI 1.13-1.47), a clinically distinct subtype of breast cancer, than UBC patients. Further, they were older than UBC patients, more often had multifocal cancer (OR 1.13; 95% CI 1.01-1.26), and a less aggressive subtype than UBC patients. Invasive lobular carcinoma was associated with having multiple tumors in breast tissue-both in the form of bilateral disease and multifocal disease, and this association was independent of laterality. No similar pattern was observed for other tumor characteristics. CONCLUSION: We identified two etiological mechanisms that could explain some of the occurrence of SBBC. The high proportion of less aggressive carcinomas and higher age of SBBC compared to UBC patients suggests that many are diagnosed at a subclinical stage as slow-growing tumors have a higher probability of simultaneous diagnosis. The high proportion of invasive lobular carcinoma observed in bilateral and multifocal disease, being independent of laterality, suggests that these patients have an increased propensity to malignant tumor formation in breast tissue.

Breast cancer mortality in synchronous bilateral breast cancer patients.

BACKGROUND: Evidence suggests that patients with synchronous bilateral breast cancer (SBBC), diagnosed within 4 months, have an inferior prognosis compared to unilateral breast cancer (UBC) patients. Using data from nationwide Danish clinical databases, this cohort study investigated whether the inferior prognosis could be explained by SBBC patients having a more aggressive disease, or whether the prognosis could be explained by the fact that they have two simultaneous cancers. METHODS: Patients were diagnosed from 1999-2015. The main outcome was excess mortality, subtracting background population mortality from observed mortality. Differences between SBBC and UBC patients were evaluated by rate ratios (RR) and estimated by Poisson regression. RESULTS: In total, 1214 SBBC and 59 177 UBC patients were included. SBBC patients had a significantly higher excess mortality than UBC patients after adjustment for age and period (RR = 1.73; 95% CI:1.44-2.08; p < 0.01) and after adjusting for characteristics of the worst tumour as traditionally done (RR = 1.31; 95% CI:1.08-1.57; p = 0.01). However, adjusting for characteristics of both tumours, using a more advanced competing risks model, no difference was observed (RR = 1.01; 95% CI:0.83-1.22; p = 0.93). CONCLUSIONS: Our study does not support that the inferior prognosis in SBBC patients is due to having more aggressive tumours per se, but rather the combined effect of having two simultaneous cancers.

Routine surveillance for symptomatic toxicities with real-time clinician reporting in Danish breast cancer patients-Organization and design of the first national, cluster randomized trial using the Patient-Reported Outcomes version of Common Terminology Criteria for Adverse Events (PRO-CTCAE).

The Patient-Reported Outcomes version of Common Terminology Criteria for Adverse Events (PRO-CTCAE) was developed by the National Cancer Institute to capture patient self-reports of symptomatic toxicities during cancer treatment. The aim of this short communication is to describe the design of a national study, which examine the effect of using patients' electronic PRO-CTCAE reporting with real-time feedback to clinicians on treatment events for breast cancer patients receiving adjuvant chemotherapy. The study's end-points are defined as dose reduction, hospitalization, and febrile neutropenia. This is the first report on the impact of PRO-CTCAE in a national breast cancer population during chemotherapy treatment.

Predicting efficacy of epirubicin by a multigene assay in advanced breast cancer within a Danish Breast Cancer Cooperative Group (DBCG) cohort: a retrospective-prospective blinded study.

PURPOSE: Anthracyclines remain a cornerstone in the treatment of primary and advanced breast cancer (BC). This study has evaluated the predictive value of a multigene mRNA-based drug response predictor (DRP) in the treatment of advanced BC with epirubicin. The DRP is a mathematical method combining in vitro sensitivity and gene expression with clinical genetic information from > 3000 clinical tumor samples. METHODS: From a DBCG cohort, 140 consecutive patients were treated with epirubicin between May 1997 and November 2016. After patient informed consent, mRNA was isolated from archival formalin-fixed paraffin-embedded primary breast tumor tissue and analyzed using Affymetrix arrays. Using time to progression (TTP) as primary endpoint, the efficacy of epirubicin was analyzed according to DRP combined with clinicopathological data collected retrospectively from patients' medical records. Statistical analysis was done using Cox proportional hazards model stratified by treatment line. RESULTS: Median TTP was 9.3 months. The DRP was significantly associated to TTP (P = 0.03). The hazard ratio for DRP scores differing by 50 percentage points was 0.55 (95% CI -0.93, one-sided). A 75% DRP was associated with a median TTP of 13 months compared to 7 months following a 25% DRP. Multivariate analysis showed that DRP was independent of age and number of metastases. CONCLUSION: The current study prospectively validates the predictive capability of DRP regarding epirubicin previously shown retrospectively allowing the patients predicted to be poor responders to choose more effective alternatives. Randomized prospective studies are needed to demonstrate if such an approach will lead to increased overall survival.

Forty years of landmark trials undertaken by the Danish Breast Cancer Cooperative Group (DBCG) nationwide or in international collaboration.

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.

Mortality and recurrence rates among systemically untreated high risk breast cancer patients included in the DBCG 77 trials.

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 < 14%; Luminal B, ER or PR >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.

Molecular subtyping of breast cancer improves identification of both high and low risk patients.

BACKGROUND: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.