Prognostic Value of Pretreatment Plasma C-Reactive Protein in Patients with Early-Stage Breast Cancer.

BACKGROUND: Breast cancer incidence is now the highest among all cancers and accountable for 6.6% of all cancer-related deaths worldwide. Studies of the prognostic utility of plasma C-reactive protein (CRP) measurement in early-stage breast cancer have given discrepant results. METHODS: We identified 6,942 patients in the Danish Breast Cancer Cooperative Group database with early-stage breast cancer diagnosed between 2002 and 2016 who had a measure of pretreatment plasma CRP. Outcomes were recurrence-free interval and survival for a period up to 10 years. We analyzed associations with plasma CRP using Fine-Gray proportional subdistribution hazards model with recurrence-free interval. Data on plasma CRP were analyzed per doubling of concentration and in relation to CRP levels of <3 mg/L, 3 to 10 mg/L, and >10 mg/L and stratified according to standard clinical parameters in sensitivity analyses. RESULTS: A doubling of the plasma CRP concentration was associated with increased risk of recurrence (multivariate adjusted HR, 1.05; 95% CI, 1.01-1.08) and shorter survival (HR, 1.13; 95% CI, 1.09-1.16) in multivariate analyses. Survival was shorter in patients with plasma CRP levels of 3 to 10 and >10 mg/L versus <3 mg/L, with multivariate adjusted HRs of 1.30; 95% CI, 1.17-1.45 and 1.65; 95% CI, 1.39-1.95, respectively. CONCLUSIONS: Elevated plasma CRP measured before treatment in patients with early-stage breast cancer is an independent biomarker of increased risk of recurrence and early death. IMPACT: CRP measures before treatment might be used to individualize follow-up of patients with early-stage breast cancer.

Metronomic treatment of vinorelbine with oral capecitabine is tolerable in the randomized Phase 2 study XeNa including patients with HER2 non-amplified metastatic breast cancer.

BACKGROUND: Metronomic treatment is hypothesized to be less toxic and more effective as compared to standard maximal tolerable dosing treatment in metastatic cancer disease. MATERIAL AND METHODS: We tested the metronomic treatment principle with vinorelbine in a randomized phase 2 setting combined with standard capecitabine treatment in the XeNa trial with Clinical Trials.gov identifier number: NCT0141771. 120 patients with disseminated HER2 non-amplified breast cancer were included. Randomization was between Arm A: vinorelbine 60 mg/m2 day 1 + day 8 in the first cycle followed by 80 mg/m2 day 1 + day 8 in the following cycles or Arm B: vinorelbine 50 mg three times a week. Capecitabine 1000 mg/m2 twice a day for days 1-14 was administered in both arms. RESULTS: The treatment was generally well-tolerated. The response rate (RR) was 24% (arm A) versus 29% (arm B) (p = .67). The clinical benefit rate (CBR) 46.8% (arm A) versus 51.7% (arm B) (p = .72). We found a median progression-free survival (PFS) of 7.1 months (95% confidence interval [CI] 3.9-10.3) in arm A and 6.3 months (95% CI 4.1-8.5) in arm B (p = .25) whereas median overall survival (OS) was 23.3 months (95% CI 20.2-26.4) in arm A and 22.3 months (95% CI 14.3-30.3) in arm B (p = .76). CONCLUSIONS: We confirmed that the combination of vinorelbine and capecitabine was well tolerated. Metronomic treatment can be used with acceptable adverse events (AEs), but we did not find significant difference in the effect compared to the standard treatment.

Prediction of fulvestrant efficacy in patients with advanced breast cancer: retrospective-prospective evaluation of the predictive potential of a multigene expression assay.

BACKGROUND: Fulvestrant is a selective oestrogen receptor (ER) degrader used as monotherapy and combination therapy for ER positive HER2 negative advanced breast cancer (ABC) in postmenopausal women. The drug response predictor (DRP), is a mathematical algorithm based on the expression of multiple genes in the tumour. The fulvestrant DRP algorithm has previously shown effect in BC. In this study, we investigated the DRP's potential in predicting fulvestrant benefit. METHOD: Among 695 patients with ABC prospectively included in a Danish Breast Cancer Cooperative Group (DBCG) cohort we retrospectively included 226 patients who received fulvestrant as monotherapy. The DRP result was based on mRNA extracted from tumour biopsies and analysed using Affymetrix array. Primary endpoint was time to progression (TTP). RESULTS: For patients who received fulvestrant in line one to four and were previously unexposed to adjuvant endocrine therapy, we identified a hazard ratio (HR) of 0.44 (90% confidence interval (90% CI) upper limit of 1.08, one sided p = 0.066) for a predicted positive vs negative outcome. A weaker association was seen when including patients exposed to adjuvant endocrine treatment or received fulvestrant in fifth or later lines. Exploratory analyses showed that the DRP was efficient when using recent biopsies for DRP estimate and among recently treated patients. CONCLUSION: The DRP showed a potential in predicting fulvestrant treatment but was not significant in the overall analysis. Use of older biopsies, long-term endocrine treatment and multiple therapies between biopsy used for analysis and fulvestrant treatment, probably affect the predictive accuracy.

The NAME trial: a direct comparison of classical oral Navelbine versus Metronomic Navelbine in metastatic breast cancer.

Chemotherapy for metastatic breast cancer (MBC) is in general given in cycles of maximum tolerated doses to potentially maximize the therapeutic outcome. However, when compared with targeted therapies for MBC, conventional and dose intensified chemotherapy has caused only modest survival benefits during the recent decades, often compromising the quality of life considerably. Navelbine is an antineoplastic agent that has shown efficacy in the treatment of a variety of cancer types, including breast cancer. Early clinical trials involving both breast cancer and lung cancer patients suggest that metronomic dosing of Navelbine might be at least as effective as classical administration (once weekly, etc.). The NAME trial compares these two strategies of Navelbine administration in MBC patients.

Adjuvant Cyclophosphamide and Docetaxel With or Without Epirubicin for Early TOP2A-Normal Breast Cancer: DBCG 07-READ, an Open-Label, Phase III, Randomized Trial.

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.

DBCG-IMN: A Population-Based Cohort Study on the Effect of Internal Mammary Node Irradiation in Early Node-Positive Breast Cancer.

PURPOSE: It is unknown whether irradiation of the internal mammary lymph nodes improves survival in patients with early-stage breast cancer. A possible survival benefit might be offset by radiation-induced heart disease. We assessed the effect of internal mammary node irradiation (IMNI) in patients with early-stage node-positive breast cancer. PATIENTS AND METHODS: In this nationwide, prospective population-based cohort study, we included patients who underwent operation for unilateral early-stage node-positive breast cancer. Patients with right-sided disease were allocated to IMNI, whereas patients with left-sided disease were allocated to no IMNI because of the risk of radiation-induced heart disease. The primary end point was overall survival. Secondary end points were breast cancer mortality and distant recurrence. Analyses were by intention to treat. RESULTS: A total of 3,089 patients were included. Of these, 1,492 patients were allocated to IMNI, whereas 1,597 patients were allocated to no IMNI. With a median of 8.9 years of follow-up time, the 8-year overall survival rates were 75.9% with IMNI versus 72.2% without IMNI. The adjusted hazard ratio (HR) for death was 0.82 (95% CI, 0.72 to 0.94; P = .005). Breast cancer mortality was 20.9% with IMNI versus 23.4% without IMNI (adjusted HR, 0.85; 95% CI, 0.73 to 0.98; P = .03). The risk of distant recurrence at 8 years was 27.4% with IMNI versus 29.7% without IMNI (adjusted HR, 0.89; 95% CI, 0.78 to 1.01; P = .07). The effect of IMNI was more pronounced in patients at high risk of internal mammary node metastasis. Equal numbers in each group died of ischemic heart disease. CONCLUSION: In this naturally allocated, population-based cohort study, IMNI increased overall survival in patients with early-stage node-positive breast cancer.

Carcinoma of the nasal cavity and paranasal sinuses in Denmark 1995-2004.

OBJECTIVE: To evaluate the treatment outcome for sino-nasal carcinomas in Denmark from 1995-2004 and compare the results to the previous Danish survey covering 1982-1991. DESIGN: Retrospective follow-up. MATERIALS AND METHODS: In the five Danish head and neck oncology centres, charts of all consecutive patients with sino-nasal carcinomas were reviewed and data extracted to a common database. Altogether 242 patients from the period 1995-2004 were identified. Of these 162 (67%) were male and 80 (33%) female. Histologies included squamous cell carcinoma (55%), adenocarcinoma (28.5%), adenoid-cystic carcinoma (5.0%), undifferentiated carcinoma (4.5%), transitiocellular carcinoma (1.7%), mucoepidermoid carcinoma (0.8%), neuroendocrine carcinoma (2.5%), small cell carcinomas (1.2%) and carcinomas not otherwise specified (0.8%). Treatments included radiotherapy alone 79 (33%), surgery alone 29 (12%), combined surgery and radiotherapy 96 (40%), palliative/no treatment 38 (16%). A total of 204 (86%) patients were treated with curative intent. RESULTS: Of the 204 patients treated with curative intent, 94 (46%) relapsed. Most failures were in T-site (63, 30%). N-site failures were 10 (5%) and M-site failures six (3%). Failure occurring in T+N-site, T+M-site, N+M-site and T+N+M-site were seven (3%), two (1%), one (0.5%) and five (3%) respectively. The 5-year actuarial local, nodal and loco-regional control rates were 55 + or - 4%, 86 + or - 3%, 49 + or - 4%, respectively. The overall 5-year actuarial survival rate for the entire cohort was 47 + or - 3%, and the corresponding cancer-specific 5-year actuarial survival rate was 57 + or - 3%. Female gender, nasal cavity tumour, adenocarcinoma and low clinical stage were significant positive prognostic factors in univariate analysis. A Cox multivariate analysis showed that only tumour site and clinical stage were independent significant prognostic factors. CONCLUSION: The current series has confirmed stage and tumour site as independent prognostic factors. Compared to the previous Danish survey covering the period 1982-1991, the overall survival and cancer-specific survival rates have improved significantly.

Fertility pattern does not explain social gradient in breast cancer in denmark.

The present study was undertaken to assess the impact of reproductive behavior on the social class gradient in breast cancer occurrence in Denmark. Objectives were to study whether the gradient across socioeconomic groups could be explained by fertility differences, whether the gradient across educational groups could be explained by fertility differences and whether the effect of socioeconomic group on breast cancer incidence and mortality could be explained by education and vice versa. We studied 674,084 women aged 20-39 at the census on 9 November 1970 for whom we had complete data on fertility history. The cohort was followed up for breast cancer incidence and mortality until 8 November 1998. Fertility history varied considerably across socioeconomic group, where 38% of the academics were childless at the age of 30, in contrast to only 8% of women in agriculture. The academics had the highest risk of breast cancer and women in agriculture had the lowest risk. For incidence, the gradient in the relative risks was 1.74, which changed to 1.49 when fertility history was incorporated and to 1.29 when school education was also taken into account. For school education, women with > or = 12 years of schooling had the highest risk and women with < or = 7 years of schooling had the lowest risk. For incidence, the gradient in the relative risk was 1.38, which changed to 1.26 when fertility history was incorporated and to 1.22 when socioeconomic group was also taken into account.

Use of census data for construction of fertility history for Danish women.

BACKGROUND: Modern epidemiology increasingly uses data on families. The authors constructed an extended fertility database for women born in Denmark from 1930 onwards by supplementing the existing Fertility Database with household data from the 1970 census. METHODS: A fertility history was constructed for all women participating in the 1970 census, but aiming for complete data only for women aged 20-39. The fertility history of these women prior to the 1970 census was constructed from the census data including 1,648,813 persons coded as children. An algorithm was used transforming household information into fertility history data by matching women and children according to family position. Children for whom the algorithm gave no match were searched for in the Fertility Database; children not found in the Fertility Database either were searched for manually. The fertility history after the 1970 census was retrieved from the Fertility Database. RESULTS: Using data from the census 1970, 98.5% of the children were linked to a mother, and 99.6% of these links were estimated to be correct, corresponding to 98.1% of the children being linked correctly. In total, 964,720 children of women aged 20-39 in 1970 were identified, which was equivalent to 96.6% of the expected live-born children, and to 99.1% of the expected surviving children. CONCLUSION: Census household data proved to be an excellent data source for construction of fertility histories.

Socioeconomic status and breast cancer in Denmark.

BACKGROUND: Breast cancer is the most frequent cancer in women and the incidence has increased over time. Our objectives were to study: (1) the socioeconomic differences in breast cancer incidence and mortality in Denmark, (2) how different socioeconomic groups have contributed to the increasing incidence, (3) whether the diverging trend between breast cancer incidence and mortality reflects different socioeconomic distributions of breast cancer cases and breast cancer deaths, and (4) to compare measures of socioeconomic status based on own and spouses' occupation, respectively. We addressed these questions by studying the socioeconomic distribution of breast cancer incidence and breast cancer mortality in Danish women during the last 25 years. METHODS: In all 1 402 225 women in Denmark were individually followed up for death, emigration, and incident breast cancer in 1970-1995. Of the 1 402 225 women included in the study, 730 549 were economically active in 1970, and 480 379 women were both married and economically active. Socioeconomic status was assessed based on the occupation in 1970. RESULTS: For all women classified by their own socioeconomic group, the standardized incidence (SIR) and the standardized mortality ratios (SMR) were highest in academics (SIR = 1.39, SMR = 1.29), and lowest in women in agriculture (SIR = 0.77, SMR = 0.75). For married, economically active women classified by their own socioeconomic group the SIR and SMR were highest in academics (SIR = 1.40, SMR = 1.44) and lowest in women in agriculture (SIR = 0.76, SMR = 0.76). Classified by their husbands' socioeconomic group, the SIR and SMR were highest in women married to academics (SIR = 1.21, SMR = 1.16) and lowest in women married to men in agriculture (SIR = 0.79, SMR = 0.79). From 1970 to 1995, the risk of developing breast cancer increased by 38% in women aged 50-64. All social groups contributed to this increase, the increase being 45% in unskilled workers, and 26% in academics. CONCLUSION: During the last quarter of the 20th century academics had the highest risk of breast cancer in Denmark. The size of the social gradient in breast cancer occurrence depended on the measure used. The time trends in social distribution will result in breast cancer becoming more frequent.