Residual Axillary Metastases in Node-Positive Breast Cancer Patients After Neoadjuvant Treatment: A Register-Based Study.

BACKGROUND: Lymph node (LN) metastasis after neoadjuvant chemotherapy (NACT) generally warrants axillary lymph node dissection, which opposes guidelines of upfront surgery in many cases. We investigated the risk of having additional metastases in the axilla when the LNs removed by targeted axillary dissection (TAD) harbored metastases after NACT. We aimed to identify subgroups suitable for de-escalated axillary treatment. METHODS: This register-based study used data from the Danish Breast Cancer Cooperative Group database. Data were analyzed with logistic regression models. The primary outcome was the metastatic burden in non-TAD LNs in patients with positive TAD LNs after NACT. RESULTS: Among 383 patients, < 66.6% positive TAD LNs (adjusted odds ratio [OR] 0.34, 95% confidence interval [CI] 0.17-0.62), only isolated tumor cells (ITCs) [OR 0.11, 95% CI < 0.01-0.82], and breast pathological complete response (pCR) [OR 0.07, 95% CI < 0.01-0.56] were associated with a low risk of having more than three positive non-TAD LNs. In 315 patients with fewer than three positive non-TAD LNs, the proportion of positive TAD LNs (OR 0.45, 95% CI 0.27-0.76 for 33.3-66.6% vs. > 66.6%), size of the TAD LN metastasis (OR 0.14, 95% CI 0.04-0.54 for ITC vs. macrometastasis), tumor size at diagnosis (OR 0.30, 95% CI 0.15-0.64 for 20-49 mm vs. ≥ 50 mm) and breast pCR (OR 0.38, 95% CI 0.15-0.96) were associated with residual LN metastases in the axilla. CONCLUSIONS: Breast pCR or ITC only in TAD LNs can, with reasonable certainty, preclude more than three positive non-TAD LNs. Additionally, patients with only ITCs in the TAD LN had a low risk of having any non-TAD LN metastases after NACT. De-escalated axillary treatment may be considered in both subgroups.

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.

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.

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.

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.

Use of beta-blockers and risk of contralateral breast cancer.

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

Tumour-infiltrating CD4-, CD8- and FOXP3-positive immune cells as predictive markers of mortality in BRCA1- and BRCA2-associated breast cancer.

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.

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.

The role of H1 antihistamines in contralateral breast cancer: a Danish nationwide cohort study.

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 (<2 prescriptions). Use of CAD antihistamines among patients receiving chemotherapy was not associated with a decrease in CBC risk. CONCLUSIONS: Taken together, our findings do not suggest any association of H1-antihistamine use with CBC development.

Breast cancer survival in Nordic BRCA2 mutation carriers-unconventional association with oestrogen receptor status.

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 < 0.001). The survival analysis included 584 patients. Positive ER status was protective in the first 5 years from diagnosis (multivariate HR = 0.49; 95% CI 0.26-0.93, 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.

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.

Adherence to treatment guidelines and survival in older women with early-stage breast cancer in Denmark 2008-2012.

Objectives: The aims of this study were to compare patients 70 years or older with younger patients, to examine whether Danish patients with early-stage breast cancer aged 70 years or more received treatment according to guidelines, the reasons for deviating from the guidelines, and to analyze whether such deviations affected survival.Methods: From the Danish Breast Cancer Cooperative Group (DBCG) database we identified 23,247 women diagnosed with early-stage breast cancer in Denmark from 2008 to 2012. 17,391 were aged less than 70 years and 5856 were 70+ years. We reviewed medical charts of 441 patients aged 70+ years from Funen (a region of Denmark) to ascertain whether treatment was given according to the guidelines of DBCG and if not, the reason for deviating. Overall survival was analyzed by Cox proportional hazards models.Results: Up to age 80 years most women (94%) had surgery according to guidelines, decreasing to 41% in women aged 85+ years, the main reason for omitting surgery being patients' requests. Patients with breast cancer over the age of 80 years did not have an excess mortality compared with the general population in Funen. Compared with women who had surgery according to guidelines, women who did not have surgery had a significantly higher risk of dying with a hazard ratio (HR) of 8.38 (95% Confidence Intervals (CI) 4.46-15.8) if they were less than 80 years and HR = 2.56 (95% CI 1.63-4.01) if they were 80 years or more (p = .003 for interaction).Conclusions: Adherence to treatment according to guidelines decreases with increasing age, mainly for patients aged 80+ years. Our results suggest that surgery is important for the survival of patients aged less than 80 years.

Nonaspirin NSAIDs and contralateral breast cancer risk.

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.

Basal biomarkers nestin and INPP4B predict gemcitabine benefit in metastatic breast cancer: Samples from the phase III SBG0102 clinical trial.

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.

Sentinel and non-sentinel lymph node metastases in patients with microinvasive breast cancer: a nationwide study.

PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: The low incidence of SN macrometastases < 4% suggests omission of axillary staging in MIBC patients without staging at primary surgery, especially in older (≥ 50 years) HER2- patients. Still, the relatively high proportion of patients with non-SN macrometastases indicates that axillary treatment might be considered in SN positive patients, especially in younger HER2+ MIBC patients.