WITHDRAWN: Combined epirubicin and vinorelbine as first-line therapy in metastatic breast cancer: a pilot study performed by the Danish Breast Cancer Cooperative Group.

The publisher regrets that this is an accidental duplication of an article that has already been published in The Breast, 12 (2003) 42-50, doi:10.1016/S0960-9776(02)00180-7. The duplicate article has therefore been withdrawn.

Axillary staging during surgery for breast cancer.

BACKGROUND: Axillary lymph node status remains the single most important prognostic parameter in patients with breast cancer. In approximately half of operations sentinel lymph node biopsy cannot be employed and axillary dissection is indicated. Retrieval of ten nodes has hitherto been considered sufficient, but it remains questionable whether the removal of more lymph nodes might improve staging. METHODS: Data from 31 679 breast cancer operations in Denmark were analysed. RESULTS: The number of axillary lymph nodes retrieved was an independent and strong predictor of node positivity. The more lymph nodes retrieved, the better the staging of the disease; this was evident for all sizes of tumour. Dissection of 20 or more nodes rather than ten to 14 increased the probability of node positivity from 14.2 to 25.9 per cent for 1-5-mm tumours, from 38.6 to 47.9 per cent for 11-20-mm tumours, and from 80.6 to 90.0 per cent for tumours with diameter greater than 50 mm. CONCLUSION: The number of metastatic lymph nodes increased as more nodes were retrieved. These findings underline the need for high-quality specialist surgical and pathological services in breast cancer treatment.

Treatment of anthracycline extravasation with Savene (dexrazoxane): results from two prospective clinical multicentre studies.

BACKGROUND: The purpose of this study was to assess the efficacy and tolerability of i.v. dexrazoxane [Savene (EU), Totect (US)] as acute antidote in biopsy-verified anthracycline extravasation. PATIENTS AND METHODS: Two prospective, open-label, single-arm, multicentre studies in patients with anthracycline extravasation were carried out. Patients with fluorescence-positive tissue biopsies were treated with a 3-day schedule of i.v. dexrazoxane (1000, 1000, and 500 mg/m(2)) starting no later than 6 h after the incident. Patients were assessed for efficacy (the possible need for surgical resection) and toxicity during the treatment period and regularly for the next 3 months. RESULTS: In 53 of 54 (98.2%) patients assessable for efficacy, the treatment prevented surgery-requiring necrosis. One patient (1.8%) required surgical debridement. Thirty-eight patients (71%) were able to continue their scheduled chemotherapy without postponement. Twenty-two patients (41%) experienced hospitalisation due to the extravasation. Mild pain (10 patients; 19%) and mild sensory disturbances (nine patients; 17%) were the most frequent sequelae. Haematologic toxicity was common as expected from the fact that the extravasation occurred during a chemotherapy course. Other toxic effects were transient elevation of alanine aminotransferases, nausea, and local pain at the dexrazoxane injection site. CONCLUSION: Dexrazoxane proved to be an effective and well-tolerated acute treatment with only one out of 54 assessable patients requiring surgical resection (1.8%).

Reduced mortality for women with mammography-detected breast cancer in east Denmark and south Sweden.

The 5-year relative survival from breast cancer in Denmark is 10 percentage points lower than in Sweden. This difference has been demonstrated previously as being caused partly by more involved lymph nodes and larger tumours in Denmark. Sweden has had nationwide mammography-screening coverage since 1991, whereas this is still in its infancy in Denmark. In the search for an explanation for the remaining survival difference, patient delay was a likely candidate. This study compared patient delay and mammography-detection between two national regions. Data on patient delay and mammography were obtained from hospital records from 1989 and 1994, and analysed using Cox proportional hazard analysis of death within the first 5 years, with the factors age, country, delay/mammography detection and established patho-anatomic variables. A comparison of patient delay and mammography detection in 1989 and 1994 showed more mammography-detected tumours in south Sweden and more women with long delay in east Denmark. Mammography detection, but not long patient delay, had a significant effect on the death hazard when adjusting for patho-anatomic risk factors. The hazard ratio was not eliminated in 1989, but in 1994, the hazard ratio between east Denmark and south Sweden was reduced from 1.3 to 1.1. In conclusion, patient delay did not appear to have any effect on 5-year survival when adjusting for patho-anatomic factors, but tumour detection by mammography affected survival favourably and partly explained the survival difference between east Denmark and south Sweden.

Can the survival difference between breast cancer patients in Denmark and Sweden 1989 and 1994 be explained by patho-anatomical variables?--a population-based study.

Analyses of data from cancer registries have shown a 10% unit difference in 5-year relative survival between Danish and Swedish patients with breast cancer. This study investigates the effect of age and patho-anatomic variables on this survival difference. Hospital records were collected for women over 40 years of age diagnosed in 1989 or 1994 in east Denmark and south Sweden; patho-anatomical variables and survival were compared between 2289 Danish and 1715 Swedish women. Tumours were smaller, node-negative axillae more frequent and well-differentiated tumours almost 10% more frequent in Sweden. A superior 5-year relative survival in Sweden was found in the 50- to 79-year age group. The adjusted hazard rate ratio between countries was 1.7 in 1989 and 1.3 in 1994. Conditional survival after surviving the first 5 years was similar for the two countries. Adjusting for patho-anatomical variables reduced but did not eliminate the higher risk of death among the Danish patients. Higher population death rates could explain some but not all of the residual elevated risk for Danish women.

Combined epirubicin and vinorelbine as first-line therapy in metastatic breast cancer: a pilot study performed by the Danish Breast Cancer Cooperative Group.

This pilot study investigated the tolerability and efficacy of increasing doses of epirubicin and vinorelbine as first-line chemotherapy for metastatic breast cancer. Acute toxicity was manageable at all dose levels for combinations of epirubicin 60-90 mg/m2 on day 1 and vinorelbine 15-25 mg/m2 on days 1 and 8 repeated every 3 weeks. Myelotoxicity was the most frequent toxic event, with a significant increase in grade 4 leukopenia from 0% at dose level 1 (60+15 mg/m2) to 26% at dose level 6 (90+25 mg/m2). Signs of acute or chronic cardiotoxicity grades 2-4 were seen in 15% of the patients and included arrhythmia and decreased function. No significant association was established between dose and nonhematological toxicity. Objective responses were observed in 49 of the 99 evaluable patients (49.5%, 95% CI 39.9-59.2), 18 being complete and 31 partial responses. Responses were observed at all six dose levels. In conclusion, acute toxicity was manageable at all dose levels for combinations of epirubicin 60-90 mg/m2 on day 1 and vinorelbine 15-25 mg/m2 on days 1 and 8. In the treatment of advanced breast cancer, improvement of the antitumor efficacy by the addition of vinorelbine to epirubicin remains to be demonstrated in a randomized phase III trial.

Immunoassays of urokinase (uPA) and its type-1 inhibitor (PAI-1) in detergent extracts of breast cancer tissue.

Two immunoassays for quantitation of the biological markers uPA and PAI-1 were evaluated for their use with detergent extracts of breast cancer tissue. Both assays were based on murine monoclonal capture antibodies and rabbit polyclonal detector antibodies. Horseradish peroxidase-conjugated goat anti-rabbit antibodies enabled measurement of the bound antigen. The detection limit of the uPA assay was 13 pg/ml, with a linear dose-response relationship up to 350 pg/ml. The assay detected free uPA as well as uPA in complex with PAI-1 and/or with its receptor. The detection limit of the PAI-1 assay was 50 pg/ml, with a linear dose-response relationship up to 1500 pg/ml. The assay detected both free PAI-1 and uPA:PAI-1 complex. Both assays were validated for detergent extracts using immunoabsorption and recovery tests. Highly significant associations between tumour tissue uPA and PAI-1 levels and prognosis were verified in a cohort of 164 lymph node-negative primary breast cancer patients. It is concluded that the two immunoassays are well-suited for the quantitation of uPA and PAI-1 in detergent extracts of breast cancer tissues.

Results of randomised studies of the EORTC Soft Tissue and Bone Sarcoma Group (STBSG) with two different ifosfamide regimens in first- and second-line chemotherapy in advanced soft tissue sarcoma patients.

The aim of this phase II study was to evaluate the efficacy and toxicity of two regimens of ifosfamide in metastatic soft tissue sarcoma patients given as first- and second-line chemotherapy. Two different schedules of ifosfamide were investigated in a randomised manner: Ifosfamide was given either at a dose of 5 g/m(2) over 24 h (5 g/m(2)/1 day), every 3 weeks or at a dose of 3 g/m(2) per day, administered over 4 h on three consecutive days (3 g/m(2)/3 days), every 3 weeks. Both schedules were given as first-line or second-line chemotherapy. A total of 182 patients was entered, 103 in first- and 79 in second-line, of whom 8 patients were ineligible, 5 in the first- and 3 in the second-line study. Most patients had a leiomyosarcoma, 46 of the 98 in the first-line and 34 of the 76 in the second-line. The two study arms were well balanced in both the first- and second-lines with respect to sex, age and performance status. In first-line treatment, 5 g/m(2)/1 day yielded five partial responses (PR) (Response Rate (RR) 10%), versus 12 PR (RR 25%) for the 3 g/m(2)/3 days. As second-line treatment, the 24-h infusion yielded: one CR and one PR (RR 6%) and the 3-day schedule one CR and two PR (RR 8%). Survival did not differ between the two regimens. The major World Health Organization (WHO) grade 3 and 4 toxicities encountered were: leucopenia in 19% of all courses in the first-line and 32% in the second-line with the 5 g/m(2)/1 day, while for the 3 g/m(2)/3 days schedule the rates were 57 and 63% respectively. Grade 3 or 4 infections were seen in 4% of patients treated with 5 g/m(2)/1 day first-line and 10% of patients given 3 g/m(2)/3 days, both as first- and second-lines. No such infections were seen in patients receiving 5 g/m(2)/1 day as second line treatment. In advanced soft-tissue sarcomas in the first-line, ifosfamide 3 g/m(2), given over 4 h on three consecutive days, is an active regimen with acceptable toxicity while the 5 g/m(2) over 24 hours schedule resulted in a disappointing response rate.

BRCA1 and BRCA2 mutation status and cancer family history of Danish women affected with multifocal or bilateral breast cancer at a young age.

INTRODUCTION: A small fraction of breast cancer is the result of germline mutations in the BRCA1 and BRCA2 cancer susceptibility genes. Mutation carriers frequently have a positive family history of breast and ovarian cancer, are often diagnosed at a young age, and may have a higher incidence of double or multiple primary breast tumours than breast cancer patients in general. OBJECTIVES: To estimate the prevalence and spectrum of BRCA1 and BRCA2 mutations in young Danish patients affected with bilateral or multifocal breast cancer and to determine the relationship of mutation status to family history of cancer. SUBJECTS: From the files of the Danish Breast Cancer Cooperative Group (DBCG), we selected 119 breast cancer patients diagnosed before the age of 46 years with either bilateral (n=59) or multifocal (n=61) disease. METHODS: DNA from the subjects was screened for BRCA1 and BRCA2 mutations using single strand conformation analysis (SSCA) and the protein truncation test (PTT). Observed and expected cancer incidence in first degree relatives of the patients was estimated using data from the Danish Cancer Registry. RESULTS: Twenty four mutation carriers were identified (20%), of whom 13 had a BRCA1 mutation and 11 carried a BRCA2 mutation. Two mutations in BRCA1 were found repeatedly in the material and accounted for seven of the 24 (29%) mutation carriers. The mutation frequency was about equal in patients with bilateral (22%) and multifocal breast cancer (18%). The incidence of breast and ovarian cancer was greatly increased in first degree relatives of BRCA1 and BRCA2 mutation carriers, but to a much lesser degree in relatives of non-carriers. An increased risk of cancer was also noted in brothers of non-carriers. CONCLUSIONS: A relatively broad spectrum of germline mutations was observed in BRCA1 and BRCA2 and most of the mutations are present in other populations. Our results indicate that a diagnosis of bilateral and multifocal breast cancer is predictive of BRCA1 and BRCA2 mutation status, particularly when combined with information on the patients' age at diagnosis and family history of breast/ovarian cancer.

Risk of late-stage breast cancer after a childbirth.

A pregnancy may lead to hormone-induced growth of breast tumors. The authors investigated whether women in the first years after childbirth had a higher incidence of breast cancer and, in particular, a higher incidence of late-stage tumors (i.e., a large tumor, nodal involvement, or histologic grading II + III). The study was based on a population-based cohort of 1.5 million Danish women born between 1935 and 1978. Between 1978 and 1994, 10,790 incident cases of breast cancer were identified in a nationwide cancer registry. Overall, uniparous and biparous mothers experienced a transient increased risk that did not appear to be attributable to delayed cancer diagnosis. The risk of being diagnosed with a tumor whose diameter was larger than 5 cm was, on average, 53% higher during the first 10 years after birth compared with later. The risk of tumors of less than 2 cm was not significantly associated with time since the latest birth. In conclusion, after a childbirth, mothers experience a transient increased risk of breast cancer and, in particular, a relatively high risk of late-stage disease. This finding suggests that pregnancy-related factors transiently induce a high growth rate in cells that are already malignant and stimulate new tumor growth.

A modified Nottingham prognostic index for breast cancer patients diagnosed in Denmark 1978-1994.

Stage of disease at diagnosis is a predictor of breast cancer survival. We used data from the Danish Cancer Register and the Danish Breast Cancer Cooperative Group to study stage distribution in 0-69-year-old Danish breast cancer patients diagnosed in 1978-1994. We constructed a modified Nottingham Prognostic Index (NPI) calculated from the number of excised and positive lymph nodes, malignancy grade and tumour diameter. This NPI could be calculated for 63% of the patients, and among these the stage distribution improved during the study period. The proportion of patients with a poor prognostic score decreased from 27% to 20%. Based on a comparison of the crude 3-year survival of patients with an NPI score and those without, it seems probable that the stage of disease at diagnosis on average improved in Danish breast cancer patients below age 70 during the 1980s and the early 1990s.

Impact of axillary dissection on staging and regional control in breast tumors < or = 10 mm--the DBCG experience. The Danish Breast Cancer Cooperative Group (DBCG), Rigshisoutalet, Copenhagen, Denmark.

Data from 4771 patients with tumor diameters < or = 10 mm were analyzed. Results of surgery and pathoanatomical examinations indicated that nodal status was related to diameter, but not to number of nodes removed. More axillary metastases were found in group T1b tumors than in T1a. In 8% of tumors, at least 4 positive nodes were identified. Mean number of positive nodes was related to number of nodes removed, and when 10 or more nodes were removed a significantly lower axillary recurrence rate and better recurrence-free survival were demonstrated, confirming that axillary surgery has two goals: staging and regional disease control. Age, receptor status, grade and histological type, but not tumor location, were related to prognosis. In accordance with the classical prognostic factors, it was not possible to define a patient group where axillary surgery was superfluous. We conclude that proper staging and regional control renders a full axillary level I-II dissection necessary.

Do clinical databases render population-based cancer registers obsolete? The example of breast cancer in Denmark.

OBJECTIVE: Clinical databases have been invented to monitor treatment outcomes, therapies or diseases, often in great detail. The traditional population-based cancer registry has been invented to collect a minimum of information about all incident cancers. Do clinical databases render population-based cancer registers obsolete as sources of cancer cases for epidemiological study? METHODS: We compared the study base of first incident breast cancer cases in Denmark in 1978-1994 known from the national cancer register and from the national clinical database on breast cancer patients. The clinical database is used for monitoring protocoled treatment. RESULTS: Combining the two data sources we found 48,522 first primary breast cancers in Denmark 1978-1994. Of these, 37,640 were included in both data sources, 2151 were included only in the clinical database, and 8731 were included only in the cancer register. A major part of the difference between the two data sources was due to treatment-focused data collection in the clinical database, and a minor part due to differences in the registration of second primaries, date of diagnosis and invasiveness. CONCLUSIONS: Cancer incidence data are sensitive to registration procedures and definitions. Clinical cancer databases cannot generally replace the traditional cancer register as a reliable data source for incident cancer cases in a national population.

Combined endocrine treatment of elderly postmenopausal patients with metastatic breast cancer. A randomized trial of tamoxifen vs. tamoxifen + aminoglutethimide and hydrocortisone and tamoxifen + fluoxymesterone in women above 65 years of age.

The efficacy of combined endocrine therapy with tamoxifen (TAM), aminoglutethimide (AG), and hydrocortisone (H) or tamoxifen and fluoxymesterone (FLU) was evaluated against treatment with tamoxifen alone in 311 patients above 65 years of age with a first recurrence of a metastatic breast cancer. A total of 279 patients were eligible. The response rates were assessed for 258 fully evaluable patients and were the following for the TAM (N = 94), the TAM+AG+H (N = 83), and the TAM+FLU (N = 81) groups, respectively, PR: 14, 18, and 21%, and CR: 20, 11, and 23%. The overall response rates are not statistically different (p = 0.30). The 95% CL of difference in response rates for TAM vs. TAM+AG+H are -9-19% and for TAM vs. TAM+FLU -4-25%. Time to treatment failure was comparable with median values of 9.2, 7.7, and 9.2 months in the TAM, TAM+AG+H, and TAM + FLU group, respectively (p = 0.17). The corresponding figures for survival are median times of 22.0, 24.1, and 21.1 months with a p-value of 0.62. Toxicity was more pronounced in both the combined treatment groups, and could in most instances be attributed to treatment with either AG+H or FLU. Currently, new specific aromatase inhibitors with lesser toxicity than AG are being evaluated in combination with TAM for treatment of primary and metastatic breast cancer. In conclusion, the simultaneous use of TAM and AG +H or FLU does not seem to improve the therapeutic efficacy in elderly postmenopausal patients with metastatic disease. So far, combined endocrine therapy in this group of patients should only be used in the context of clinical trials.

alpha-fetoprotein levels in maternal serum during pregnancy and maternal breast cancer incidence.

BACKGROUND: A full-term pregnancy is associated with a reduced risk of breast cancer, but the underlying biologic mechanism has not been elucidated. During pregnancy, maternal serum levels of alpha-fetoprotein, an estradiol-binding protein, rise sharply. In culture, alpha-fetoprotein inhibits the growth of estrogen-sensitive cells, including estrogen-sensitive breast cancer cells. Thus, we investigated whether a high level of alpha-fetoprotein in maternal serum during pregnancy is associated with a reduced risk of breast cancer. METHODS: From a population-based cohort of 42057 pregnant women in Denmark, enrolled in an alpha-fetoprotein-screening program from 1978 through 1996, we obtained a complete reproductive history, vital status, and a possible diagnosis of breast cancer (in 117 women) to the end of follow-up on September 1, 1998. RESULTS: During pregnancy, women with an alpha-fetoprotein level greater than or equal to the median value had a 41% lower risk of breast cancer than women with an alpha-fetoprotein level below the median value (relative risk [RR] = 0.59; 95% confidence interval [CI] = 0.41-0. 85). RRs for breast cancer by mother's age at childbirth were as follows: 29 years or younger, RR = 0.21 (95% CI = 0.08-0.56); 30-34 years, RR = 0.61 (95% CI = 0.32-1.14); 35-37 years, RR = 0.96 (95% CI = 0.49-1.89); and 38 years or older, RR = 0.71 (95% CI = 0.29-1. 75) (P for trend =.02). Further analyses suggested that high levels of alpha-fetoprotein were associated with a reduced incidence of aggressive disease. The most striking finding was that women with high levels of serum alpha-fetoprotein, compared with women with low levels of serum alpha-fetoprotein, showed a particularly reduced incidence of large tumors (>2 cm; RR = 0.24 [95% CI = 0.11-0.50]). CONCLUSION: A high level of alpha-fetoprotein in maternal serum during any pregnancy is associated with a low overall incidence of breast cancer and, in particular, with a low incidence of advanced breast cancer at diagnosis. This association appears particularly strong for a pregnancy occurring at a young age.

Factors influencing the effect of age on prognosis in breast cancer: population based study.

OBJECTIVE: To investigate whether young age at diagnosis is a negative prognostic factor in primary breast cancer and how stage of disease at diagnosis and treatment influences such an association. DESIGN: Retrospective cohort study based on a population based database of patients with breast cancer containing detailed information on tumour characteristics, treatment regimens, and survival. SETTING: Denmark. SUBJECTS: 10 356 women with primary breast cancer who were less than 50 years old at diagnosis. MAIN OUTCOME MEASURES: Relative risk of dying within the first 10 years after diagnosis according to age at diagnosis after adjustment for known prognostic factors and expected mortality. RESULTS: Overall, young women with low risk disease who did not receive adjuvant treatment had a significantly increased risk of dying; risk increased with decreasing age at diagnosis (adjusted relative risk: 45-49 years (reference): 1; 40-44 years: 1.12 (95% confidence interval 0.89 to 1.40); 35-39 years: 1.40 (1.10 to 1.78); <35 years: 2.18 (1.64 to 2.89). However, no similar trend was seen in patients who received adjuvant cytotoxic treatment. The increased risk in younger women who did not receive adjuvant treatment compared with those who did remained when women were grouped according to presence of node negative disease and by tumour size. CONCLUSION: The negative prognostic effect of young age is almost exclusively seen in women diagnosed with low risk disease who did not receive adjuvant cytotoxic treatment. These results suggest that young women with breast cancer, on the basis of age alone, should be regarded as high risk patients and be given adjuvant cytotoxic treatment.

Variations in prognostic factors in primary breast cancer throughout the menstrual cycle.

AIMS: We investigated whether menstrual cycle dependent variations in prognostic factors are detectable in malignant breast tissue. METHODS: Since 1977 the Danish Breast Cancer Cooperative Group has collected population-based information about primary clinical data, treatment regimens and follow-up status on Danish women with breast cancer. Information about last menstrual periods prior to surgery was obtained from files recorded at the time of admission for primary surgery. Included in this study were 1060 patients self-reported to be regularly menstruating and with a menstrual period within 6 weeks of surgery and who were operated in a single-step procedure. None of the patients were current users of exogenous hormones at the time of surgery. Variations of prognostic factors throughout the menstrual cycle were evaluated. RESULTS: Overall, no significant correlation between endogenous hormone fluctuations and oestrogen receptor (ER) status and progesterone receptor (PgR) status were found. Furthermore, we observed no cycle-dependent variation for mitotic index, lymph node involvement or tumour size. CONCLUSIONS: The classical prognostic factors in breast cancer did not differ significantly throughout the menstrual cycle in the present study.