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.

Incidence of new primary cancers after adjuvant tamoxifen therapy and radiotherapy for early breast cancer.

The incidence of new primary cancers was evaluated in 3538 postmenopausal patients who had received surgical treatment for primary breast cancer. Of these patients, 1828 with a low risk of recurrence received no further treatment. High-risk patients were randomly assigned to one of two groups. The first group (n = 846) received postoperative radiotherapy, while the second group (n = 864) received radiotherapy plus tamoxifen at a dose of 30 mg given daily for 48 weeks. The median observation time was 7.9 years. In comparison with the number of new cancers in the general population, the number of new cancers in the three groups was elevated mostly due to a high number of cancers of the contralateral breast and of colorectal cancers in the high-risk groups. The cumulative risk of nonlymphatic leukemia was increased among patients who received postoperative radiotherapy (P = .04). Cancer incidence in the high-risk tamoxifen-treated group relative to that in the high-risk group not treated with tamoxifen was not significant (1.3). No protective effect of tamoxifen on the opposite breast was seen (rate ratio for breast cancer = 1.1), but a tendency to an elevated risk of endometrial cancer was observed (rate ratio = 3.3; 95% confidence interval = 0.6-32.4). Continued and careful follow-up of women treated with tamoxifen is necessary to clarify the potential cancer-suppressive or cancer-promoting effects of this drug.

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.

Adjuvant radiotherapy and risk of contralateral breast cancer.

BACKGROUND: The risk of contralateral breast cancer is increased twofold to fivefold for breast cancer patients. A registry-based cohort study in Denmark suggested that radiation treatment of the first breast cancer might increase the risk for contralateral breast cancer among 10-year survivors. PURPOSE: Our goal was to assess the role of radiation in the development of contralateral breast cancer. METHODS: A nested case-control study was conducted in a cohort of 56,540 women in Denmark diagnosed with invasive breast cancer from 1943 through 1978. Case patients were 529 women who developed contralateral breast cancer 8 or more years after first diagnosis. Controls were women with breast cancer who did not develop contralateral breast cancer. One control was matched to each case patient on the basis of age, calendar year of initial breast cancer diagnosis, and survival time. Radiation dose to the contralateral breast was estimated for each patient on the basis of radiation measurements and abstracted treatment information. The anatomical position of each breast cancer was also abstracted from medical records. RESULTS: Radiotherapy had been administered to 82.4% of case patients and controls, and the mean radiation dose to the contralateral breast was estimated to be 2.51 Gy. Radiotherapy did not increase the overall risk of contralateral breast cancer (relative risk = 1.04; 95% confidence interval = 0.74-1.46), and there was no evidence that risk varied with radiation dose, time since exposure, or age at exposure. The second tumors in case patients were evenly distributed in the medial, lateral, and central portions of the breast, a finding that argues against a causal role of radiotherapy in tumorigenesis. CONCLUSIONS: The majority of women in our series were perimenopausal or postmenopausal (53% total versus 38% premenopausal and 9% of unknown status) and received radiotherapy at an age when the breast tissue appears least susceptible to the carcinogenic effects of radiation. Based on a dose of 2.51 Gy and estimates of radiation risk from other studies, a relative risk of only 1.18 would have been expected for a population of women exposed at an average age of 51 years. Thus, our data provide additional evidence that there is little if any risk of radiation-induced breast cancer associated with exposure of breast tissue to low-dose radiation (e.g., from mammographic x rays or adjuvant radiotherapy) in later life.

Prognostic value of steroid hormone receptors: multivariate analysis of systemically untreated patients with node negative primary breast cancer.

The value of estrogen and progesterone receptor (ER and PgR, respectively) determinations in predicting the recurrence-free survival (RFS) has been evaluated in a group of 807 node negative breast cancer patients. All of these patients are enrolled in the Danish Breast Cancer Cooperative Group (DBCG) 77-1a and 82-a protocols for low risk patients, and none of them have received systemic adjuvant therapy. At a median observation time of 50 months and in an evaluation of the total patient population as an entity, ER+ patients had only a marginally significant (P = 0.07) longer RFS than ER- patients while PgR+ patients experienced a significant advantage (P = 0.02). Among patients subgrouped according to menopausal status, both ER and PgR statuses were found to be significant prognostic factors for predicting RFS in the premenopausal women (less than 50 years) but not in peri- or postmenopausal women. Using Cox's multivariate analysis, nuclear pleomorphy was found to be the only significant prognostic variable, while the value of PgR status as a prognostic factor approached significance (P = 0.065). Although knowledge of ER status did not significantly improve distinction between patients with good and poor prognoses in the relatively small subgroup of premenopausal patients (n = 120) when PgR status was known, ER+PgR- patients have a lower risk of recurrence or death than ER-PgR- patients. Using a log-likelihood model, significant and distinct cut-off limits for the definition of receptor positivity were found for premenopausal patients: these were 5 fmol/mg cytosol protein for ER and 10 fmol/mg cytosol protein for PgR. These cut-off levels may reflect the ability of the ligand binding assay method used to discriminate between tissues with and without receptor proteins. Qualitative assessment of receptor status was as valuable as quantitative expression of receptor concentrations in predicting the RFS of the natural course of the disease among node negative premenopausal patients.

The complex between urokinase and its type-1 inhibitor in primary breast cancer: relation to survival.

We examined the relationship between tumor tissue level of the complex formed of urokinase (uPA) and its type-1 inhibitor (PAI-1) and survival of breast cancer patients. The study included 342 axillary lymph node-negative and -positive primary breast cancer patients with a median follow-up of 67 months. Using a newly established ELISA, the levels of preformed uPA-PAI-1 complex were measured in tumor tissue extracts and analyzed with respect to total uPA, total PAI-1, and clinicopathological parameters, including survival. uPA-PAI-1 complex comprised a minor, variable fraction of both total uPA and PAI-1 levels. The complex levels were higher in node-negative tumors than in node-positive tumors and higher in small and low-grade tumors (all, P < or = 0.002). The tumor levels of complex, uPA, and PAI-1 were all associated with survival; high complex levels predicted longer recurrence-free survival (P = 0.03) and overall survival [OS (P = 0.005)], whereas high uPA or PAI-1 levels significantly predicted shorter survival. In multivariate Cox analysis, the only parameters that independently predicted survival were total PAI-1 level and lymph node status for recurrence-free survival and OS and, additionally, steroid hormone receptor status and grade for OS. This is the first demonstration of a relationship between uPA.PAI-1 complex tumor level and patient survival. However, total PAI-1 level showed superior prognostic power. Additional studies are needed to understand the relationship of these parameters to cancer biology and to assess the clinical utility of the uPA PAI-1 complex.

High levels of urokinase-type plasminogen activator and its inhibitor PAI-1 in cytosolic extracts of breast carcinomas are associated with poor prognosis.

The urokinase pathway of plasminogen activation is supposed to be involved in proteolytic degradation of the extracellular matrix during cancer invasion. The prognostic value of urokinase-type plasminogen activator (uPA) and type 1 plasminogen activator inhibitor (PAI-1) levels in cytosolic extracts of ductal breast carcinomas was studied, retrospectively, in 118 premenopausal and 72 postmenopausal high-risk patients entered into the protocol of Danish Breast Cancer Cooperative Group trials for adjuvant treatment of breast cancer. The median observation time was 8.5 years. uPA and PAI-1 levels were determined by sandwich enzyme-linked immunosorbent assays. There is a strong correlation between these levels (P < 0.001; r = 0.57). Univariate analysis showed that a high uPA level is significantly associated with short overall survival in both premenopausal (P < 0.001) and postmenopausal (P = 0.03) patients, while a high PAI-1 content significantly predicts shorter overall survival in premenopausal (P = 0.005) and postmenopausal (P < 0.001) patients and shorter relapse-free survival in postmenopausal patients (P < 0.001). When the levels of uPA and PAI-1 are related to those of other prognostic parameters, both high uPA and high PAI-1 levels are associated with grade of anaplasia in premenopausal patients and with number of tumor-positive lymph nodes in postmenopausal patients. A high PAI-1 level is associated with low estrogen and progesterone receptor levels in both pre- and postmenopausal patients. The prognostic value of uPA and PAI-1 levels was compared with that of established prognostic parameters by multivariate analysis. In premenopausal patients, high uPA is an independent prognostic parameter for shorter overall survival, the relative risk being 2.0 (95% confidence interval, 1.1-3.7). In postmenopausal patients, a high PAI-1 level is a strong and independent factor in predicting shorter overall survival with a relative risk of 2.9 (95% confidence interval, 1.5-5.8). In this group of patients a high PAI-1 level is also an independent predictor of shorter relapse-free survival (relative risk, 2.1; 95% confidence interval, 1.1-3.9). These data together with previous reports indicate that uPA and PAI-1 are potentially important prognostic factors in breast cancer. This is in good agreement with the supposed function of uPA in cancer invasion. It is proposed that PAI-1 plays a role in protecting the tumor against degrading itself. Alternatively, the PAI-1 level may be a biochemical marker of tumor angiogenesis.

Tamoxifen and bone metabolism in postmenopausal low-risk breast cancer patients: a randomized study.

PURPOSE: This trial was undertaken to evaluate the effect of adjuvant tamoxifen on bone metabolism in postmenopausal women undergoing surgery for low-risk breast cancer. PATIENTS AND METHODS: In an open trial, 25 women were randomized to receive tamoxifen 30 mg/d for 2 years, and 25 women constituted the control group. Twenty women treated with tamoxifen and 23 women in the control group provided data for the analysis. Inclusion criteria were operation for low-risk breast cancer and cessation of menstruations for more than 1 year. Exclusion criteria were presence of metastases, disorders of bone metabolism, contraindications against tamoxifen, use of drugs with influence on bone metabolism, ailments that made bone mineral measurements impossible, and age greater than 65 years. Repeated measurements of bone mineral density and content at the lumbar spine and forearms, serum alkaline phosphatase, phosphate, and ionized calcium were performed in all patients. RESULTS: Lumbar spine bone mineral density increased during the first year in women treated with tamoxifen and then stabilized, compared with decreased bone mineral density in the control group (P = .00074). Bone mineral content at the forearms remained almost stable in tamoxifen-treated women compared with a decrease in the control group (P = .024). Serum alkaline phosphatase, phosphate, and ionized calcium decreased in the tamoxifen group (P < .00001, P = .002, and P = .002, respectively). CONCLUSION: Tamoxifen has estrogen-like effects on bone metabolism that result in an increase and stabilization of bone mineral density in the axial skeleton and a stabilization of bone mineral content in the appendicular skeleton.

Evidence of a castration-mediated effect of adjuvant cytotoxic chemotherapy in premenopausal breast cancer.

This prospective randomized trial, conducted by the Danish Breast Cancer Cooperative Group, is the largest study, so far, of adjuvant chemotherapy in premenopausal breast cancer. The trial is unique in that it is nationwide and based on a nonselected population of patients, and is the only adjuvant trial studying the effect of cyclophosphamide monotherapy. After total mastectomy with axillary node sampling, followed by local radiotherapy, 1,032 pre- and perimenopausal women with operable breast cancer were randomized to observation alone, or to adjuvant chemotherapy for 1 year with either cyclophosphamide monotherapy or with a combination of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF). As of January 1987, median follow-up was 68 months. From early on both cyclophosphamide alone and CMF were found to improve recurrence-free survival (RFS) significantly and to a similar degree (P = .0001). However, an overall survival advantage did not become evident until 5 years after the start of treatment. So far, this advantage appears to be more pronounced in CMF (P = .0065) than in cyclophosphamide-only patients (P = .08). Thus, the study confirms the findings of the National Surgical Adjuvant Breast Project (NSABP) and Milan trials that adjuvant chemotherapy prolongs the survival of premenopausal women with early breast cancer. A retrospective analysis revealed that, in contrast with CMF, cyclophosphamide alone did not improve RFS significantly in subsets of patients without amenorrhea, with estrogen-receptor (ER) negative tumors, and with tumors of low histological differentiation. Assuming that cyclophosphamide alone is a less tumoricidal treatment than CMF, these findings suggest that the effect of adjuvant cytotoxic chemotherapy is mediated partly through chemical castration, and partly through a purely cytotoxic effect.

Dose-response relationship of epirubicin in the treatment of postmenopausal patients with metastatic breast cancer: a randomized study of epirubicin at four different dose levels performed by the Danish Breast Cancer Cooperative Group.

PURPOSE: To test for possible correlations between dose of single-drug epirubicin and efficacy/toxicity in postmenopausal women with metastatic breast cancer. The study also included analysis of a correlation between pharmacokinetic and pharmacodynamic parameters. PATIENTS AND METHODS: Two hundred eighty-seven women were randomized to receive either 40, 60, 90, or 135 mg/m2 of epirubicin intravenously (IV) every 3 weeks. Treatment consisted of first-line cytotoxic therapy for metastatic disease. In patients with early progressive disease after either 40 or 60 mg/m2, dose escalation to 135 mg/m2 was performed. A full pharmacokinetic analysis was performed in 78 patients. RESULTS: Among 263 eligible patients, an increase in response rate and time to progression was found with an increase in dose from 40 to 90 mg/m2, while no increase in efficacy was found from 90 to 135 mg/m2. Multivariate analysis, using the Cox proportional hazards model with time to progression as the end point, confirmed that epirubicin dose more than 60 mg/m2 was an independent prognostic covariate. Furthermore, a significant association was established between randomized dose and both hematologic and nonhematologic toxicity. No association between pharmacokinetic parameters and efficacy parameters was demonstrated. On the other hand, a significant correlation between pharmacokinetic parameters and both hematologic and nonhematologic toxicity was found. CONCLUSION: An increase in dose of epirubicin from 40 to 90 mg/m2 is accompanied by increased efficacy. Further increases in dose do not yield increased efficacy. A positive correlation between epirubicin dose and toxicity, as well as a correlation between pharmacokinetic parameters and toxicity, was also established.

Plasminogen activator inhibitor type 1 in cytosolic tumor extracts predicts prognosis in low-risk breast cancer patients.

We have reported previously that both urokinase-type plasminogen activator (uPA) and its type 1 inhibitor (PAI-1) are statistically significant prognostic variables in patients with high-risk breast cancer (Grondahl-Hansen et al., Cancer Res., 53:2513-2521, 1993), and we recently described that the uPA receptor (uPAR) is a prognostic marker in postmenopausal, node-positive breast cancer patients (Grondahl-Hansen et al., Clin. Cancer Res., 1:1079-1087, 1995). The present retrospective study describes the prognostic impact of uPA, its receptor uPAR, and PAI-1 in breast cancer cytosol from 111 low-risk premenopausal patients and 184 low-risk postmenopausal patients with a median follow-up of 6.0 years (range, 3.8-14.9) and 7.4 (range, 3.7-14.0) years, respectively. uPA, uPAR, and PAI-1 levels were determined by sandwich enzyme-linked immunosorbent assays, and data were dichotomized using the median value as the cutoff for calculation of recurrence-free survival and overall survival. A correlation was found between the levels of each of the three molecules. In univariate analysis, high PAI-1 was significantly associated with short overall survival in postmenopausal patients [relative risk (RR), 2.3; 95% confidence interval (CI), 1.3-4.3; P = 0.005] and shorter recurrence-free survival in both premenopausal (RR, 2.5; 95% CI, 1.3-4.7; P = 0.004) and postmenopausal (RR, 1.8; 95% CI, 1.1-2.9; P = 0.02) patients. Neither uPA nor uPAR reached statistical significance in the univariate analyses. The prognostic value of uPA, uPAR, and PAI-1 was then compared with that of other established prognostic variables by multivariate analysis. PAI-1 was an independent prognostic variable for recurrence-free survival in premenopausal patients, with a RR of 2.6 (95% CI, 1.3-5.0). For recurrence-free survival (RR, 1.9; 95% CI, 1.1-3.5) and overall survival (RR, 2.6; 95% CI, 1.2-5.7) in postmenopausal patients, PAI-1 was the only independent variable left in this group of patients. Neither uPA nor uPAR reached significance in the multivariate analysis. These data, together with previously published data on the prognostic significance of components of the urokinase plasminogen activation system in breast cancer cytosols, strongly indicate that PAI-1 is a statistically significant and independent prognostic marker in both low- and high-risk breast cancer patients.

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.

Mitoxantrone as first line cytotoxic therapy in advanced breast cancer: preliminary results of a phase II study.

Mitoxantrone, 14 mg/m2 repeated every 3 weeks was administered to postmenopausal patients with advanced measurable breast cancer previously untreated with cytotoxic agents. Response was achieved in 16 out of 28 (44%) evaluable patients and in four of the patients (with soft tissue disease) the response was complete. The median duration of response was 10+ months with a range from 4-12+ months. At doses which cause significant hematological toxicity other objective and subjective toxicities were remarkably mild.

Classical prognostic factors in node-negative breast cancer: the DBCG experience.

Classical prognostic factors were analyzed in patients with low-risk primary breast cancer, defined as absence of tumor-positive axillary lymph nodes, tumor size less than or equal to 5 cm in diameter, and no invasion into skin or deep fascia. The primary surgical treatment was total mastectomy and lower axillary dissection. None of the patients received adjuvant therapy. Between 1977 and 1990, 7315 patients entered the study, and at the time of this analysis (January 1, 1990), the median follow-up time is 5 years. In univariate analyses, the following variables were significantly related to recurrence-free survival: age in premenopausal patients; tumor size; number of negative nodes removed; histological grade; and in premenopausal patients, estrogen receptor and progesterone (PgR) status. In multivariate analyses, age in premenopausal patients was the most important factor, followed by tumor size and histological grade, whereas PgR status in premenopausal patients was just of borderline significance. These variables should be included in multivariate analyses testing the value of more recently introduced prognostic factors.

Danish randomized trial comparing breast conservation therapy with mastectomy: six years of life-table analysis. Danish Breast Cancer Cooperative Group.

The Danish Breast Cancer Cooperative Group (DBCG) conducted a randomized trial comparing breast conservation with mastectomy in patients with invasive mammary carcinoma. From January 1983 to March 1989, the trial accrued a total of 1153 women. Of this number, 905 patients (79%) were randomly assigned to one of the two treatment options, whereas 248 patients (21%) did not accept randomization. Of the randomly assigned patients, 90% received the surgical option to which they had been originally assigned. In the breast conservation arm the tumor was excised with the intention of obtaining free margins determined at gross examination, and radiotherapy was subsequently administered to residual breast tissue. The axilla was dissected in all instances. Patient and tumor characteristics were similar in the two randomization arms. The median follow-up time was 40 months. At 6 years of life-table analysis the probability of recurrence-free survival was 70% in the breast conservation arm against 66% in the mastectomy arm. Survival figures were 79% against 82%, respectively.

Adjuvant systemic therapy in breast cancer.

Systemic adjuvant therapy has improved the prognosis of patients with primary breast cancer. Meta-analyses have demonstrated that approximately one fourth of deaths can be avoided among younger women treated with multiple cytotoxic drug regimens and among older women treated with tamoxifen. However, with the treatments available today many aspects related to the optimal therapy, taking into account the physical, psychological and socioeconomic consequences, are still open. This review discusses some of the major open questions related to the effectiveness of the adjuvant systemic therapy in terms of its ability to reduce recurrence rate and mortality.

Axillary dissection of level I and II lymph nodes is important in breast cancer classification. The Danish Breast Cancer Cooperative Group (DBCG).

In order to define the term "a node-negative patient", the axillary nodal status at the primary operation for breast cancer was evaluated in 13,851 patients registered by the Danish Breast Cancer Cooperative Group (DBCG). The determinants for node negativity in primary breast cancer were the number of lymph nodes removed and the tumour size. The number of lymph nodes removed should be at least 10 to exclude misclassification of node-positive patients as node negative. There was a strong relationship between tumour size and the percentage of node-negative patients. Another observation was that high rate of node negativity was associated with low histological grade. The age of the patients had no influence on node negativity. Where 10 or more negative lymph nodes were removed, significantly better axillary recurrence-free survival (P less than 0.0001), over-all recurrence-free survival (P less than 0.0001) and survival (P less than 0.005) were found.

Histopathological grade and response to chemotherapy in advanced soft tissue sarcomas.

In a retrospective analysis, we evaluated the possible significance of histopathological grade with regard to response to chemotherapy in advanced soft tissue sarcomas. In three EORTC protocols, the same dose-schedule was used for patients randomised to treatment with doxorubicin as a single agent (75 mg/m2 every third week). The submitted pathological slides from 94 of these patients were reviewed and graded. The following parameters were subjectively graded (+/++/+ + +): nuclear pleomorphism, necrosis, cellularity and vascularity. Mitoses were counted in 20 high-power fields, and a final grade assigned as I, II, IIIA or IIIB. The results were tested both with regard to response (complete response + partial response vs. no change + progressive disease) and survival. However, no statistically significant correlations or trends could be demonstrated. Thus, tumour grade, although a prognostic factor by itself, does not seem to be able to predict response to chemotherapy in the advanced stage.

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.

Medullary carcinoma of the breast. Prevalence and prognostic importance of classical risk factors in breast cancer.

In an earlier study of 235 breast cancers with medullary features, we concluded from a multivariate Cox regression analysis that only four histopathological features contained significantly positive prognostic information. In the present study, continuing our work on the same population base, we used these histological characteristics (predominantly syncytial growth pattern, no tubular component, diffuse stromal infiltration with mononuclear cells and sparse necrosis (< 25%), as diagnostic criteria for medullary carcinoma of the breast (MC). We found a significantly better prognosis for patients with MC than those with non-medullary carcinoma (NMC) or infiltrating ductal carcinoma (IDC). All tumours in the MC group were grade II or III (96% grade III). A significantly different distribution of general risk factors such as lymph node status, invasion, steroid receptor status, and menopausal status, was found between the group of MC and the control group of IDC grades II + III. Further, general risk factors, which are found to be of major prognostic importance in IDC, had little prognostic impact in MC. We found MC to be biologically unique, and patients with MC have a better than average prognosis compared to that of IDC. We propose a new histological definition of MC, but stress that prospective studies have to be performed.