Elisabet Lidbrink

Tailored fluorouracil, epirubicin, and cyclophosphamide compared with marrow-supported high-dose chemotherapy as adjuvant treatment for high-risk breast cancer: a randomised trial

BACKGROUND Chemotherapy drug distribution varies greatly among individual patients. Therefore, we developed an individualised fluorouracil, epirubicin, cyclophosphamide (FEC) regimen to improve outcomes in patients with high-risk early breast cancer. We then did a randomised trial to compare this individually tailored FEC regimen with conventional adjuvant chemotherapy followed by consolidation with high-dose chemotherapy with stem-cell support. METHODS 525 women younger than 60 years of age with high-risk primary breast cancer were randomised after surgery to receive nine cycles of tailored FEC to haematological equitoxicity with granulocyte colony-stimulating factor (G-CSF) support (n=251), or three cycles of FEC at standard doses followed by high-dose chemotherapy with cyclophosphamide, thiotepa, and carboplatin (CTCb), and peripheral-blood stem-cell or bone-marrow support (n=274). Both groups received locoregional radiation therapy and tamoxifen for 5 years. The primary outcome measure was relapse-free survival, and analysis was by intention to treat. FINDINGS At a median follow-up of 34.3 months, there were 81 breast-cancer relapses in the tailored FEC group versus 113 in the CTCb group (double triangular method p=0.04). 60 deaths occurred in the tailored FEC group and 82 in the CTCb group (log-rank p=0.12). Patients in the CTCb group experienced more grade 3 or 4 acute toxicity compared with the tailored FEC group (p<0.0001). Two treatment-related deaths (0.7%) occurred in the CTCb group. Six patients in the tailored FEC group developed acute myeloid leukaemia and three developed myelodysplastic syndrome. INTERPRETATION Tailored FEC with G-CSF support resulted in a significantly improved relapse-free survival and fewer grade 3 and 4 toxicities compared with marrow-supported high-dose chemotherapy with CTCb as adjuvant therapy of women with high-risk primary breast cancer.

Randomized study of mammography screening--preliminary report on mortality in the Stockholm trial.

SummaryIn March 1981, 40,318 women in Stockholm, aged 40–64, entered a randomized trial of breast cancer screening by single-view mammography alone versus no intervention in a control group of 20,000 women. The attendance rate during the first screening round was 81 per cent and the cancer detection rate was 4.0 per 1000 women. The detection the rate fell to 3.1 per 1000 in the second round, which was completed in October 1985. During 1986 the controlled design of the study was broken and the contro women were invited once to screening which was completed the same year. A total of 428 cases of breast cancer were thus diagnosed in the study group and 439 in the adjusted control group. After a mean follow-up of 7.4 years the number of breast cancer deaths in the study and control groups was 39 and 30 respectively. The relative risk of breast cancer death (screening versus control) was 0.71 (95 per cent confidence interval: 0.4–1.2). Among women older than 50 years at entry the relative risk was 0.57 (95 per cent confidence interval: 0.3–1.1). Cancer deaths among women under 50 were few and perhaps because of this no mortality reduction was seen in this age group. The estimate of mortality reduction lies between the results from two earlier Swedish randomized controlled trials.

Clinically Used Breast Cancer Markers Such as Estrogen Receptor, Progesterone Receptor, and Human Epidermal Growth Factor Receptor 2 Are Unstable Throughout Tumor Progression

PURPOSE To investigate whether hormonal receptors and human epidermal growth factor receptor 2 (HER2) change throughout tumor progression, because this may alter patient management. PATIENTS AND METHODS The study cohort included female patients with breast cancer in the Stockholm health care region who relapsed from January 1, 1997, to December 31, 2007. Either biochemical or immunohistochemical (IHC)/immunocytochemical (ICC) methods were used to determine estrogen receptor (ER), progesterone receptor (PR), and HER2 status, which was then confirmed by fluorescent in situ hybridization for IHC/ICC 2+ and 3+ status. Results ER (459 patients), PR (430 patients), and HER2 (104 patients) from both primary tumor and relapse were assessed, revealing a change in 32.4% (McNemars test P < .001), 40.7% (P < .001), and 14.5% (P = .44) of patients, respectively. Assessment of ER (119 patients), PR (116 patients), and HER2 (32 patients) with multiple (from two to six) consecutive relapses showed an alteration in 33.6%, 32.0%, and 15.7% of patients, respectively. A statistically significant differential overall survival related to intraindividual ER and PR status in primary tumor and relapse (log-rank P < .001) was noted. In addition, women with ER-positive primary tumors that changed to ER-negative tumors had a significant 48% increased risk of death (hazard ratio, 1.48; 95% CI, 1.08 to 2.05) compared with women with stable ER-positive tumors. CONCLUSION Patients with breast cancer experience altered hormone receptor and HER2 status throughout tumor progression, possibly influenced by adjuvant therapies, which significantly influences survival. Hence, marker investigations at relapse may potentially improve patient management and survival.

FACT: An Open-Label Randomized Phase III Study of Fulvestrant and Anastrozole in Combination Compared With Anastrozole Alone as First-Line Therapy for Patients With Receptor-Positive Postmenopausal Breast Cancer.

PURPOSE To compare the effect of therapy with anastrozole versus a combination of fulvestrant and anastrozole in women in first relapse of endocrine-responsive breast cancer. PATIENTS AND METHODS Postmenopausal women, or premenopausal women receiving a gonadotropin-releasing hormone agonist, with estrogen receptor- and/or progesterone receptor-positive disease at first relapse after primary treatment of localized disease were open-label randomly assigned to a fulvestrant loading dose (LD) regimen followed by monthly injection plus 1 mg of anastrozole daily or to 1 mg of anastrozole daily alone. The primary end point was time to progression (TTP). RESULTS In all, 514 women were randomly assigned to fulvestrant plus anastrozole (experimental arm; n = 258) or anastrozole (standard arm; n = 256). Approximately two thirds had received adjuvant antiestrogens, but only eight individuals had received an aromatase inhibitor. Median TTP was 10.8 and 10.2 months in the experimental versus standard arm, respectively (hazard ratio [HR] = 0.99; 95% CI, 0.81 to 1.20; P = .91); median overall survival was 37.8 and 38.2 months, respectively (HR = 1.0; 95% CI, 0.76 to 1.32; P = 1.00). Incidences of prespecified adverse events (AEs) were similar. Hot flashes were more common in the experimental arm: 63 patients (24.6%) versus 35 patients (13.8%) in the standard arm (P = .0023). Death owing to AEs was reported in 11 (4.3%) and five patients (2.0%) in the experimental versus standard arm, respectively. CONCLUSION Fulvestrant (250 mg + LD regimen) in combination with anastrozole offered no clinical efficacy advantage over anastrozole monotherapy in this population of individuals with a relatively high proportion of previous adjuvant antiestrogen exposure.

Followup after 11 years – update of mortality results in the Stockholm mammographic screening trial

Results from several randomised mammography screening trials haveshown that it is possible to reduce mortalityin breast cancer by mammographic screening at leastfor women above 50 years of age. Thepurpose of this article is to present dataon mortality in breast cancer in study andcontrol groups of the Stockholm trial after 11years of followup, to analyse which age groupbenefits most from screening. In March 1981, 40,318women in Stockholm, aged 40 through 64 years,entered a randomized trial of breast cancer screeningby single view mammography alone, versus no interventionin a control group of 20 000 women.Two screening rounds were performed and the attendancerate was over 80% in the two rounds.During 1986 the control group was invited onceto screening. Totally 428 and 217 cases ofbreast cancer were diagnosed in the study andcontrol groups respectively. After a mean follow-up of11.4 years a nonsignificant mortality reduction of 26%was observed for the whole study group, witha relative risk (RR) of death in breastcancer of 0.74 (CI(confidence interval)=0.5–1.1). Forwomen aged 50–64 years a significant 38% mortalityreduction was observed with a RR of 0.62(CI=0.38–1.0). For women aged 40–49 yearsno effect on mortality was found, with aRR of death in breast cancer of 1.08(CI=0.54–2.17). The breakpoint for benefit inthis study seemed to be at 50 yearsof age when 5-year age groups were analysed,but this tendency is uncertain because of thelow statistical power in the analysis of theyounger age groups. Long screening intervals, the useof single-view mammography, and the fact that morethan 50% of the women in age group40–49 years were still below 50 years ofage when the study was closed, were allfacts that could have influenced the results inage group 40–49 years. Larger studies are neededto answer the question whether mammographic screening canbe successful in younger age groups.

TP53 status for prediction of sensitivity to taxane versus non-taxane neoadjuvant chemotherapy in breast cancer (EORTC 10994/BIG 1-00): a randomised phase 3 trial

BACKGROUND TP53 has a crucial role in the DNA damage response. We therefore tested the hypothesis that taxanes confer a greater advantage than do anthracyclines on breast cancers with mutated TP53 than in those with wild-type TP53. METHODS In an open-label, phase 3 study, women (age <71 years) with locally advanced, inflammatory, or large operable breast cancers were randomly assigned in a 1:1 ratio to either a standard anthracycline regimen (six cycles of intravenous fluorouracil 500 mg/m², epirubicin 100 mg/m², and cyclophosphamide 500 mg/m² every 21 days [FEC100], or fluorouracil 600 mg/m², epirubicin 75 mg/m², cyclophosphamide 900 mg/m² [tailored FEC] starting on day 1 and then every 21 days) or a taxane-based regimen (three cycles of docetaxel 100 mg/m², intravenously infused over 1 h on day 1 every 21 days, followed by three cycles of intravenous epirubicin 90 mg/m² and docetaxel 75 mg/m² on day 1 every 21 days [T-ET]) at 42 centres in Europe. Randomisation was by use of a minimisation method that stratified patients by institution and initial tumour stage. The primary endpoint was progression-free survival (PFS) according to TP53 status. Analysis was by intention to treat. This is the final analysis of this trial. The study is registered with ClinicalTrials.gov, number NCT00017095. FINDINGS 928 patients were enrolled in the FEC group and 928 in the T-ET group. TP53 status was not assessable for 183 (20%) patients in the FEC group and 204 (22%) patients in the T-ET group mainly because of low tumour-cell content in the biopsy. 361 primary endpoint events were recorded in the FEC group and 314 in the T-ET group. In patients with TP53-mutated tumours, 5-year PFS was 59·5% (95% CI 53·4-65·1) in the T-ET group (n=326) and 55·3% (49·2-60·9) in the FEC group (n=318; hazard ratio 0·84, 98% CI 0·63-1·14; p=0·17). In patients with TP53 wild-type tumours, 5-year PFS was 66·8% (95% CI 61·4-71·6) in the T-ET group (n=398) and 64·7% (59·6-69·4) in the FEC group (n=427; 0·89, 98% CI 0·68-1·18; p=0·35). For all patients, irrespective of TP53 status, 5-year PFS was 65·1% (95% CI 61·6-68·3) in the T-ET group and 60·8% (57·3-64·2) in the FEC group (0·85, 98% CI 0·71-1·02; p=0·035). At the sites using FEC100 versus T-ET, the most common grade 3 or 4 adverse events were febrile neutropenia (75 [9%] of 803 vs 173 [21%] of 809, respectively), and neutropenia (653 [81%] vs 730 [90%], respectively). At the sites using tailored FEC versus T-ET, the most common grade 3 or 4 adverse events were febrile neutropenia (ten [8%] of 118 vs 26 [22%] of 116, respectively), and neutropenia (100 [85%] vs 115 [99%], respectively). Two patients died of toxicity during or within 30 days of chemotherapy completion and without disease relapse (one in each group). INTERPRETATION Although TP53 status was prognostic for overall survival, it was not predictive of preferential sensitivity to taxanes. TP53 status tested by use of the yeast assay in this patient population cannot be used to select patients for an anthracycline-based chemotherapy versus a taxane-based chemotherapy. FUNDING US National Cancer Institute, La Ligue Nationale Contre le Cancer, European Union, Pharmacia, and Sanofi-Aventis.

HER2 status in a population-derived breast cancer cohort: discordances during tumor progression

This retrospective study investigates the correlation of intra-individual HER2 status between primary breast cancers and corresponding recurrences in a population derived cohort. The REMARK criteria were used as reference. In 151 breast cancer patients, primary tumors were analyzed for HER2 status on histopathology sections using immunohistochemistry (IHC) confirmed by fluorescence in situ hybridization (FISH) for IHC 2+ and 3+. Recurrences (loco regional and distant) were investigated by aspiration cytology, using HER2 immunocytochemistry (ICC) or FISH (ICC in 84 patients and FISH in 102 patients). In the 151 patients, sites of recurrence were bone/bone marrow 30%, liver 16%, local recurrence 18%, lung/pleura 10%, axillary lymph nodes 9%, skin (non-local) 7%, supra clavicular lymph nodes 5%, and other sites 7%. In 15 patients (10%) HER2 status changed, 7 of 108 patients (6%) from HER2 negative to HER2 positive and 8 of 43 (19%) from HER2 positive to HER2 negative. Intra-patient agreement in HER2 status was 76% (95% CI 64–87%), and the disagreement was 10% (95% CI 5–15%). The multivariable Cox analysis showed a significantly increased risk of dying in the patient group with changed HER2 status compared to patients with concordant positive HER2 status. Overall survival HR is 5.47 (95% CI 2.01–14.91) and survival from relapse HR is 3.22 (95% CI 1.18–8.77). The unstable status for HER2 in breast cancer is clinically significant and should motivate more frequent testing of recurrences.

Vaccination with a plasmid DNA encoding HER-2/neu together with low doses of GM-CSF and IL-2 in patients with metastatic breast carcinoma: a pilot clinical trial

BackgroundAdjuvant trastuzumab (Herceptin) treatment of breast cancer patients significantly improves their clinical outcome. Vaccination is an attractive alternative approach to provide HER-2/neu (Her2)-specific antibodies and may in addition concomitantly stimulate Her2-reactive T-cells. Here we report the first administration of a Her2-plasmid DNA (pDNA) vaccine in humans.Patients and MethodsThe vaccine, encoding a full-length signaling-deficient version of the oncogene Her2, was administered together with low doses of GM-CSF and IL-2 to patients with metastatic Her2-expressing breast carcinoma who were also treated with trastuzumab. Six of eight enrolled patients completed all three vaccine cycles. In the remaining two patients treatment was discontinued after one vaccine cycle due to rapid tumor progression or disease-related complications. The primary objective was the evaluation of safety and tolerability of the vaccine regimen. As a secondary objective, treatment-induced Her2-specific immunity was monitored by measuring antibody production as well as T-cell proliferation and cytokine production in response to Her2-derived antigens.ResultsNo clinical manifestations of acute toxicity, autoimmunity or cardiotoxicity were observed after administration of Her2-pDNA in combination with GM-CSF, IL-2 and trastuzumab. No specific T-cell proliferation following in vitro stimulation of freshly isolated PBMC with recombinant human Her2 protein was induced by the vaccination. Immediately after all three cycles of vaccination no or even decreased CD4+ T-cell responses towards Her2-derived peptide epitopes were observed, but a significant increase of MHC class II restricted T-cell responses to Her2 was detected at long term follow-up. Since concurrent trastuzumab therapy was permitted, λ-subclass specific ELISAs were performed to specifically measure endogenous antibody production without interference by trastuzumab. Her2-pDNA vaccination induced and boosted Her2-specific antibodies that could be detected for several years after the last vaccine administration in a subgroup of patients.ConclusionThis pilot clinical trial demonstrates that Her2-pDNA vaccination in conjunction with GM-CSF and IL-2 administration is safe, well tolerated and can induce long-lasting cellular and humoral immune responses against Her2 in patients with advanced breast cancer.Trial registrationThe trial registration number at the Swedish Medical Products Agency for this trial is Dnr151:785/2001.

Model Describing the Relationship Between Pharmacokinetics and Hematologic Toxicity of the Epirubicin-Docetaxel Regimen in Breast Cancer Patients

PURPOSE The aims of the present study were (1) to characterize the pharmacokinetics of both component drugs and (2) to describe the relationship between the pharmacokinetics and the dose-limiting hematologic toxicity for the epirubicin (EPI)/docetaxel (DTX) regimen in breast cancer patients. PATIENTS AND METHODS Forty-four patients with advanced disease received EPI and DTX every 3 weeks for up to nine cycles. The initial doses (EPI/DTX) were 75/70 mg/m(2). Based on leukocyte (WBC) and platelet counts, the subsequent doses were, stepwise, either escalated (maximum, 120/100 mg/m(2)) or reduced (minimum, 40/50 mg/m(2)). Hematologic toxicity was monitored in all patients, whereas pharmacokinetics was studied in 16 patients. A semiphysiological model, including physiological parameters as well as drug-specific parameters, was used to describe the time course of WBC count following treatment. RESULTS In the final pharmacokinetic model, interoccasion variability was estimated to be less than interindividual variability in the clearances for both drugs. The sum of the individual EPI and DTX areas under concentration-time curve correlated stronger to WBC survival fraction than did the corresponding sum of doses. A pharmacokinetic-pharmacodynamic (PK-PD) model with additive effects of EPI and DTX could adequately describe the data. CONCLUSION The final PK-PD model might provide a tool for calculation of WBC time course, and hence, for prediction of nadir day and duration of leukopenia in breast cancer patients treated with the EPI/DTX regimen.

Improvements in patient satisfaction at an outpatient clinic for patients with breast cancer

The present study prospectively investigated changes in patient satisfaction at an outpatient clinic for patients with breast cancer. Consecutive patients were asked to anonymously complete a questionnaire after their medical examination. The questionnaire consisted of 12 multiple-choice items concerning waiting time, interpersonal skills of physician and nurse, continuity of care, length of medical visit, communication and expectations. Finally, patients were asked for suggestions for improvements at the clinic in an open-ended question. The first measurement was conducted in 2000/2001 and the last in 2004, and between the two points of assessments efforts to develop care were introduced. Statistically significant improvements were found in eight of the 12 items: waiting time, length of medical visit, information, expectations and continuity of care. In conclusion, the questionnaire captured positive changes in patient satisfaction between the two measurements. Further changes for the better were still requested concerning continuity of care despite reported improvement.