Adjuvant endocrine therapy compromises bone health in patients with breast cancer, causing osteopenia, osteoporosis, and fractures. Antiresorptive treatments such as bisphosphonates prevent and counteract these side-effects. In this trial, we aimed to investigate the effects of the anti-RANK ligand antibody denosumab in postmenopausal, aromatase inhibitor-treated patients with early-stage hormone receptor-positive breast cancer.
In this prospective, double-blind, placebo-controlled, phase 3 trial, postmenopausal patients with early hormone receptor-positive breast cancer receiving treatment with aromatase inhibitors were randomly assigned in a 1:1 ratio to receive either denosumab 60 mg or placebo administered subcutaneously every 6 months in 58 trial centres in Austria and Sweden. Patients were assigned by an interactive voice response system. The randomisation schedule used a randomly permuted block design with block sizes 2 and 4, stratified by type of hospital regarding Hologic device for DXA scans, previous aromatase inhibitor use, and baseline bone mineral density. Patients, treating physicians, investigators, data managers, and all study personnel were masked to treatment allocation. The primary endpoint was time from randomisation to first clinical fracture, analysed by intention to treat. As an additional sensitivity analysis, we also analysed the primary endpoint on the per-protocol population. Patients were treated until the prespecified number of 247 first clinical fractures was reached. This trial is ongoing (patients are in follow-up) and is registered with the European Clinical Trials Database, number 2005-005275-15, and with ClinicalTrials.gov, number NCT00556374.
Between Dec 18, 2006, and July 22, 2013, 3425 eligible patients were enrolled into the trial, of whom 3420 were randomly assigned to receive denosumab 60 mg (n=1711) or placebo (n=1709) subcutaneously every 6 months. Compared with the placebo group, patients in the denosumab group had a significantly delayed time to first clinical fracture (hazard ratio [HR] 0·50 [95% CI 0·39-0·65], p
Notes
Comment In: Lancet. 2015 Aug 1;386(9992):409-1026040500
Department of Oncology-Pathology, Radiumhemmet, Karolinska Institutet, Karolinska University Hospital, 17176, Stockholm, Sweden, theodoros.foukakis@ki.se.
Treatment of metastatic breast cancer (MBC) has evolved during the last decades but it is largely unknown whether this has led to improved survival in the general MBC population. Based on the regional, population-based breast cancer registry, we identified 5,463 patients diagnosed with MBC in Stockholm County during 1979-2004. Patients were divided into five cohorts based on the year of first MBC diagnosis and observed and relative survival were compared across the cohorts after adjustment for potential confounders. A significant trend of better survival over time was demonstrated for patients 60 years or younger (P
Department of Public Health and Caring Sciences, Section of Caring Sciences, Uppsala University, Uppsala Science Park, SE-751 83 Uppsala, Sweden. claudia.lampic@pubcare.lu.se
The main aims of this study were to investigate the extent to which women with recently diagnosed primary breast cancer (N = 29) and matched control subjects without cancer (N = 29) differ in perceived attainment and importance of life values and to study prospectively life value ratings during 1 year in a large group of recent attendees at mammography screening (N = 706). Life values were assessed by a study-specific version of a life value questionnaire, including ratings of the perceived attainment and importance of seven life value dimensions. Women with a recent diagnosis of primary breast cancer were found to attribute significantly more importance to positive relations than healthy controls. No other differences between these groups were found regarding the attainment or importance of life values. Perceptions of life values were found to vary as a function of age, marital or cohabitation status, and parenthood, and to be stable over a 9-month period in screening attendees. The implications of the current findings for the understanding of women's psychological adaptation to breast cancer are discussed.
Compared to middle-aged women, young women with breast cancer have a higher risk of systemic disease. We studied expression of proliferation markers in relation to age and subtype and their association with long-term prognosis.
Distant disease-free survival (DDFS) was studied in 504 women aged
From January 1, 1983, through December 31, 1992, a total of 4610 patients entered a randomized trial that compared mortality among patients receiving 2 years of adjuvant tamoxifen therapy with that in patients receiving 5 years of adjuvant tamoxifen therapy, 4175 of whom were recurrence free after 2 years of tamoxifen therapy. Among the 2046 patients randomly assigned to the 5-year group all-cause mortality, breast cancer-specific mortality, and the incidence of contralateral breast cancer were reduced, compared with those among 2129 patients randomized in the 2-year group, but the incidence of endometrial cancer was increased. In addition, mortality from coronary heart disease was statistically significantly reduced in the 5-year group, compared with that in the 2-year group (hazard ratio = 0.67, 95% confidence interval = 0.47 to 0.94; P = .022 [two-sided Wald test]). Ten years after surgery, 2.1% of the patients in the 5-year group and 3.5% of those in the 2-year group had died from coronary heart disease. No statistically significant increases in mortality from other heart diseases, cerebrovascular diseases, or other vascular diseases were observed.
Dose-tailoring of FEC adjuvant chemotherapy based on leukopenia is feasible and well tolerated. Toxicity and dose intensity in the Scandinavian Breast Group phase 3 adjuvant Trial SBG 2000-1.
The SBG 2000-1 trial is a randomised study that investigates if dose-tailored adjuvant FEC therapy based on the individual's leukocyte nadir value can improve outcome. The study has included 1535 women with medium and high-risk breast cancer.
After a first standard dosed FEC course (5-fluorouracil 600 mg/m(2), epirubicin 60 mg/mg(2) and cyclophosphamide 600 mg/m(2)), patients who did not reach leukopenia grade III or IV were randomised to standard doses (group standard) or doses tailored to achieve grade III leukopenia (group tailored) at courses 2-7. Patients who achieved leukopenia grade III or more after the first course were not randomised but continued on standard doses (group registered).
Both planned and actually delivered number of courses (seven) were the same in all three arms. The relative dose intensity was increased by a factor of 1.31 (E 1.22, C 1.43) for patients in the tailored arm compared to the expected on standard dose. Ninety percent of the patients in the tailored arm achieved leukopenia grade III-IV compared with 29% among patients randomised to standard dosed therapy. Dose tailoring was associated with acceptable acute non-haematological toxicity with more total alopecia, nausea, vomiting and fatigue.
Dose tailoring according to leukopenia was feasible. It led to an increased dose intensity and was associated with acceptable excess of acute non-haematological toxicity.
Ductal carcinoma in situ of the breast with different histopathological grades and corresponding new breast tumour events: analysis of loss of heterozygosity.
Department of Oncology-Pathology, Radiumhemmet Cancer Centre Karolinska, Karolinska Institute and Hospital, S-171 76 Stockholm, Sweden. johanna.smeds@cck.ki.se
To compare chromosomal alterations in ductal carcinoma in situ (DCIS) of different histopathological grades and to study aberrations between primary DCIS and corresponding ipsi- or contralateral new in situ or invasive tumours, a study was undertaken of the pattern of loss of heterozygosity (LOH) at chromosomal regions in which LOH has previously been described in invasive breast cancer. LOH was analysed using 19 microsatellite markers located on chromosomes 3p, 6q, 8p, 8q, 9p, 11p, 11q, 16q, 17p, and 17q in 30 women with a primary DCIS. Eleven women with DCIS of grade 1 and 19 with grade 3 according to the EORTC classification system were included. In six patients LOH was also analysed in a subsequent new breast cancer. Fractional allelic loss (FAL, the ratio of chromosomal arms where allelic loss was detected divided by the total number of chromosomal arms with informative markers) was statistically significantly higher in grade 1 DCIS compared with grade 3 (p=0.02) for the 19 loci, indicating that the amount of allelic loss does not correlate with increasing aggressiveness of the studied tumours. Also observed was a complete heterogeneity of LOH in the primary DCIS and their corresponding new events, suggesting that these events probably developed from genetically divergent clones.
Effect of Tailored Dose-Dense Chemotherapy vs Standard 3-Weekly Adjuvant Chemotherapy on Recurrence-Free Survival Among Women With High-Risk Early Breast Cancer: A Randomized Clinical Trial.
Standard dosing of chemotherapy based on body surface area results in marked interpatient variation in pharmacokinetics, toxic effects, and efficacy. Whether tailored dosing can improve outcomes is unknown, as is the role of dose-dense adjuvant chemotherapy.
To determine whether tailored dose-dense adjuvant chemotherapy improves the outcomes of early breast cancer compared with a standard 3-weekly chemotherapy schedule.
A randomized, open-label, phase 3 trial of women aged 65 years and younger who had surgery for nonmetastatic node-positive or high-risk node-negative breast cancer at 86 sites in Sweden, Germany, and Austria between February 20, 2007, and September 14, 2011.
Patients were randomized 1:1 either to 4 cycles of leukocyte nadir-based tailored and dose-dense adjuvant epirubicin and cyclophosphamide every 2 weeks followed by 4 cycles of tailored dose-dense docetaxel every 2 weeks, or to standard-interval chemotherapy with 3 cycles of fluorouracil and epirubicin-cyclophosphamide every 3 weeks followed by 3 cycles of docetaxel every 3 weeks.
The primary end point was breast cancer recurrence-free survival (BCRFS). Secondary end points included 5-year event-free survival (EFS), distant disease-free survival (DDFS), overall survival (OS), and rates of grade 3 or 4 toxic effects.
Among 2017 randomized patients (1006 in the tailored dose-dense group and 1011 in the control group; median [IQR] age, 51 [45-58] years; 80% with hormone receptor-positive tumors; 97% with node-positive disease), 2000 received study treatment (=1 cycle of chemotherapy; 1001 in the tailored dose-dense group and 999 in the control group). After a median follow-up of 5.3 years (IQR, 4.5-6.1 years), 269 BCRFS events were reported, 118 in the tailored dose-dense group and 151 in the control group (HR, 0.79; 95% CI, 0.61-1.01; log-rank P?=?.06; 5-year BCRFS, 88.7% vs 85.0%). The tailored dose-dense group had significantly better EFS than the control group (HR, 0.79; 95% CI, 0.63-0.99; P?=?.04; 5-year EFS, 86.7% vs 82.1%). The groups did not differ in OS (HR, 0.77; 95% CI, 0.57-1.05; P?=?.09; 5-year OS, 92.1% vs 90.2%) or DDFS (HR, 0.83; 95% CI, 0.64-1.08; P?=?.17; 5-year DDFS, 89.4% vs 86.7%). Grade 3 or 4 nonhematologic toxic effects occurred in 527 (52.6%) in the tailored dose-dense group and 366 (36.6%) in the control group.
Among women with high-risk early breast cancer, the use of tailored dose-dense chemotherapy compared with standard adjuvant chemotherapy did not result in a statistically significant improvement in breast cancer recurrence-free survival. Nonhematologic toxic effects were more frequent in the tailored dose-dense group.
Efficacy and safety of controlled ovarian stimulation using GnRH antagonist protocols for emergency fertility preservation in young women with breast cancer-a prospective nationwide Swedish multicenter study.
How efficacious and safe are the current approaches to controlled ovarian stimulation (COS) aimed at fertility preservation (FP) in women with breast cancer (BC)?
In women with BC undergoing COS aiming at egg/embryo cryopreservation, letrozole-based protocols and those randomly started were equally effective compared with conventional COS, and the overall survival was similar between the women that proceeded to FP and those who did not.
Cryopreservation of oocytes and embryos is an established method for FP in women with BC. Recent improvements to COS protocols include concomitant use of letrozole, random-cycle start day of stimulation and the use of GnRHa for the egg maturation trigger. To date, limited sample size of the available studies has not allowed investigation of differences in the efficacy of the different approaches to COS for FP in this patient population.
A prospective multicenter study with national coverage including 610 women with BC counseled between 1 January 1995 and 30 June 2017 at six Swedish FP regional programs.
After counseling, 401 women elected to undergo COS. Treatments differed in the use or not of concomitant letrozole, a conventional or random-cycle day COS initiation and the use of hCG versus GnRHa trigger for oocyte maturation. Numbers of cryopreserved oocytes and embryos were defined as primary outcome. Pregnancy attempts, reproductive outcomes and long-term survival, investigated by the linking of individuals of the cohort to the total population register of the Swedish Tax Agency (up to 25 November 2018), were evaluated.
Using letrozole or not resulted in similar numbers of oocytes and embryos cryopreserved (meanoocytes?=?9.7 versus 10 and meanembryos 4.0 versus 5.3, respectively), similar to COS with random versus conventional start (meanoocytes 9.0 versus 10.6 and meanembryos 4.8 versus 4.8). In COS with letrozole, a GnRHa trigger was associated with a higher number of oocytes retrieved (P?
INTRODUCTION: Adjuvant breast cancer therapy significantly improves survival, but overtreatment and undertreatment are major problems. Breast cancer expression profiling has so far mainly been used to identify women with a poor prognosis as candidates for adjuvant therapy but without demonstrated value for therapy prediction. METHODS: We obtained the gene expression profiles of 159 population-derived breast cancer patients, and used hierarchical clustering to identify the signature associated with prognosis and impact of adjuvant therapies, defined as distant metastasis or death within 5 years. Independent datasets of 76 treated population-derived Swedish patients, 135 untreated population-derived Swedish patients and 78 Dutch patients were used for validation. The inclusion and exclusion criteria for the studies of population-derived Swedish patients were defined. RESULTS: Among the 159 patients, a subset of 64 genes was found to give an optimal separation of patients with good and poor outcomes. Hierarchical clustering revealed three subgroups: patients who did well with therapy, patients who did well without therapy, and patients that failed to benefit from given therapy. The expression profile gave significantly better prognostication (odds ratio, 4.19; P = 0.007) (breast cancer end-points odds ratio, 10.64) compared with the Elston-Ellis histological grading (odds ratio of grade 2 vs 1 and grade 3 vs 1, 2.81 and 3.32 respectively; P = 0.24 and 0.16), tumor stage (odds ratio of stage 2 vs 1 and stage 3 vs 1, 1.11 and 1.28; P = 0.83 and 0.68) and age (odds ratio, 0.11; P = 0.55). The risk groups were consistent and validated in the independent Swedish and Dutch data sets used with 211 and 78 patients, respectively. CONCLUSION: We have identified discriminatory gene expression signatures working both on untreated and systematically treated primary breast cancer patients with the potential to spare them from adjuvant therapy.
