Karin Zedeler

Postoperative Radiotherapy in High-Risk Premenopausal Women with Breast Cancer Who Receive Adjuvant Chemotherapy

BACKGROUND Irradiation after mastectomy can reduce locoregional recurrences in women with breast cancer, but whether it prolongs survival remains controversial. We conducted a randomized trial of radiotherapy after mastectomy in high-risk premenopausal women, all of whom also received adjuvant systemic chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (CMF). METHODS A total of 1708 women who had undergone mastectomy for pathological stage II or III breast cancer were randomly assigned to receive eight cycles of CMF plus irradiation of the chest wall and regional lymph nodes (852 women) or nine cycles of CMF alone (856 women). The median length of follow-up was 114 months. The end points were locoregional recurrence, distant metastases, disease-free survival, and overall survival. RESULTS The frequency of locoregional recurrence alone or with distant metastases was 9 percent among the women who received radiotherapy plus CMF and 32 percent among those who received CMF alone (P<0.001). The probability of survival free of disease after 10 years was 48 percent among the women assigned to radiotherapy plus CMF and 34 percent among those treated only with CMF (P<0.001). Overall survival at 10 years was 54 percent among those given radiotherapy and CMF and 45 percent among those who received CMF alone (P<0.001). Multivariate analysis demonstrated that irradiation after mastectomy significantly improved disease-free survival and overall survival, irrespective of tumor size, the number of positive nodes, or the histopathological grade. CONCLUSIONS The addition of postoperative irradiation to mastectomy and adjuvant chemotherapy reduces locoregional recurrences and prolongs survival in high-risk premenopausal women with breast cancer.

The Nottingham Prognostic Index applied to 9,149 patients from the studies of the Danish Breast Cancer Cooperative Group (DBCG)

SummaryIn primary, operable breast cancer, the Nottingham Prognostic Index (NPI) based on tumour size, lymphnode stage and histological grade can identify three prognostic groups (PGs) with 10-year survival rates of 83%, 52%, and 13%. With the aim of defining a subset of patients having so good prognosis that adjuvant therapy can be withhold, the NPI was applied to a Danish population-based study group comprising 9,149 patients. As opposed to the British study, we used conventional axillary lymph-node staging. Histological grading was in both studies done by means of a similar slight modification of the Bloom and Richardson procedure, but in the Danish study only ductal carcinomas were graded.The 10-year crude survival was 68.1% for 4,791 patients with tumour size ≤ 2 cm and 70.0% for 2,900 patients with grade I tumours. For 4,761 node-negative patients, the 10-year survival was also 70.0%, the expected survival being 89.3%. The relative mortality (observed:expected) was even at 10 years 2.1 demonstrating that more than 10 years observation time is necessary to estimate cumulated mortality. By application of the NPI, the Danish good PG comprising 27.3% of the patients had a 10-year survival of 79.0%. Thus, the index defined a subset with better survival than could be defined individually by each of its three components, but it did not succeed in defining a subset with survival similar to the expected; additional prognostic factors are therefore needed.The somewhat poorer survival of the Danish good PG may be ascribed to the British inclusion of non-ductal carcinomas, to interobserver variation present only in the Danish study, and to poorer expected survival of the Danish patients. The 10-year survival of the Danish moderate PG and poor PG was 56% and 25%, respectively. These improved survival rates are attributed to the administration of adjuvant therapies. There were virtually no node-positive patients in the good PG and no node-negative patients in the poor PG. Patients should therefore still be stratified initially by lymph-node status, but tumour size and histological grade are significant prognostic factors primarily within the node-negative group, and they should be included in future prognostication procedures.

Patient's and Doctor's Delay in Primary Breast Cancer: Prognostic implications

In a study of 7,608 patients with primary breast cancer patients and doctors delay were examined in relation to age, tumour size, grade of anaplasia, and number of positive lymph nodes. The delays were arbitrarily divided into the following intervals: Short (0-14 days), intermediate (15-60 days) and long (> 60 days). The well-established patient and tumour characteristics were shown to have prognostic significance. Similarly the delays showed significant influence on survival. A long patients delay was associated with an unfavourable outcome, as compared with a short delay. On the contrary, the prognosis was superior for patients with a long doctors delay compared to those with a short doctors delay. Overall, when corrected for age, the prognostic value of delay in terms of mortality increased by 24% for a long patients delay compared to a shorter and by 13% for a short doctors delay compared to a longer. This indicates that doctors are capable of distinguishing between more and less aggressive malignancies. The study also suggests that all sources of delays should be kept at a minimum.

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.

Correlation of growth fraction by Ki-67 and proliferating cell nuclear antigen (PCNA) immunohistochemistry with histopathological parameters and prognosis in primary breast carcinomas.

The immunoreactivity for Ki-67 and PCNA was investigated in 487 patients with primary breast carcinomas using MIB-1 (Immunotech, France) and PC-10 (DAKO, Denmark) as primary antibodies. Formalin-fixed and paraffin-embedded tissue sections were used. The immunoreactivity for Ki-67 and PCNA was found to be independent of the length of fixation if the sections were pretreated in a microwave oven in citrate buffer and distilled water, respectively. The immunostaining was evaluated semiquantitatively.High Ki-67 score (more than 1% positive tumour cells) and PCNA over-expression (more than 25% positive tumour cells) were correlated with clinicopathological parameters such as large tumour size, high histological grade (poor differentiation), and absence of steroid hormone receptors, which are parameters of an aggressive phenotype of the tumour.In univariate analysis of survival data, both Ki-67 and PCNA were parameters of a poor overall survival in both lymph node-positive and -negative patients.In multivariate analysis using a Cox model stratified by nodal status, Ki-67 and PCNA failed to be of prognostic significance whereas classical histopathological parameters such as tumour size and histological grade turned out to be of independent prognostic significance in both lymph node-positive and -negative patients, while progesterone receptors were of independent prognostic significance only in lymph node-positive patients.

Inter- and intraobserver variability in the histopathological diagnosis of medullary carcinoma of the breast, and its prognostic implications

SummaryOne hundred thirty-one breast carcinomas with medullary features, registered in the Danish Breast Cancer Cooperative Group from 1977–1982, have been histopathologically reviewed by two senior pathologists and classified as typical medullary carcinoma (TMC), atypical medullary carcinoma (AMC), and non-medullary carcinoma (NMC). Diagnostic criteria were based on those put forward by Ridolfiet al. and Fisheret al. The procedure was repeated with an interval of about one year by both pathologists. The diagnostic interobserver agreement was 72% with a Kappa of 0.55. The intraobserver agreement was 77% and 63% with Kappa values of 0.64 and 0.44, respectively. To see whether the observed inter- and intraobserver variability had any prognostic implications, diagnostic subgroups for both pathologists were analyzed with Kaplan Meier plots for recurrence-free survival (RFS) and with log rank tests. In the first evaluation pathologist 1 segregated a group of TMC with a significantly better RFS than for the NMC group, and pathologist 2 segregated a group of TMC with a corresponding strong trend. These findings could not, however, be reproduced in the second evaluation. The study indicates that the criteria of TMC and AMC as proposed by Ridolfiet al. need to be sharpened and simplified in order to reduce inter-and intraobserver variability. Larger studies with a control group of infiltrating ductal carcinomas are mandatory to elucidate the clinical importance of the diagnoses of Typical and Atypical Medullary Carcinoma of the breast.

The prognostic significance of immunohistochemically detectable metallothionein in primary breast carcinomas

Metallothionein (MT) is a low‐molecular‐weight protein with a high affinity for group II metal ions, especially zinc and copper. MT serves as an intracellular reservoir of these ions, but may also be involved in the detoxification of certain toxic metalions such as cadmium. In addition, high MT contents might protect tumour cells from alkylating agents and irradiation. The aim of this study was to evaluate the prognostic significance of immunohistochemically detected MT overexpression in patients with primary breast carcinoma: 478 patients with primary breast carcinoma diagnosed during the period 1980–1985 were included. Formalin‐fixed and paraffin‐embedded tissue was used. Immuno‐reactivity for MT was found to be independent of the length of formalin fixation if the sections were microwave processed before incubation with the primary antibody. Patients were divided into two groups: those with MT overexpression (more than 10% positive tumour cells) and those with low expression (less than 10% positive tumour cells). MT overexpression was correlated with postmenopausal status, large tumour size, presence of lymph node metastases, high number of mitoses, severe nuclear pleomorphism, high histological grade (poor differentiation), and absence of PgR. In univariate analysis of survival data, MT overexpression was a predictor of poor overall survival in the entire group of patients. In multivariate analysis, MT overexpression failed to be of prognostic significance, whereas classical histopathological parameters such as tumour size, histological grade, and PgR were of independent prognostic significance.

Medullary carcinoma of the breast, prognostic importance of characteristic histopathological features evaluated in a multivariate cox analysis

In this study of 136 breast cancers with medullary features (MC), registered in the Danish Breast Cancer Cooperative Group (DBCG) from 1982 to 1987, we confirmed the prognostic importance of a new definition of medullary carcinoma of the breast (MC newdef) which was recently proposed by us, deduced from a previous study of a corresponding tumour material (DBCG 77-82). However, the individual histological criteria did not have the same prognostic importance as in our previous study, although prognostic trends were the same. To further improve and validate the diagnostic criteria, we combined the two populations and performed a multivariate Cox regression analysis. In the final Cox model, four histological parameters retained positive prognostic importance: (1) predominantly syncytial growth pattern, (2) no tubular component, (3) diffuse stromal infiltration with mononuclear cells and (4) sparse necrosis. We propose that these criteria are emphasized in the histological diagnosis of medullary carcinoma of the breast.

The prognostic importance of syncytial growth pattern in medullary carcinoma of the breast.

The histopathological criteria for medullary carcinoma of the breast (MC) used by most pathologists today were delineated by Ridolfi et al. in 1977. The prime criterion is: “A predominantly syncytial growth pattern”, predominantly being defined as including 75% or more of the tumour. However, no indication has been given as to why this limit was set at 75%. The present study analyzes the prognostic importance of the extent of syncytial growth in a population of 102 breast cancers with medullary features. Generally, we find a positive prognostic influence of an extensive syncytial growth. The prognostic importance of setting the limit for predominantly syncytial growth at 90% and at 75%, respectively, is evaluated. This comparative study provides no basis for changing the definition of predominantly syncytial growth pattern.

650 Medullary carcinoma of the breast, histopathological and clinical characteristics

We characterized 110 medullary breast cancers (MC), diagnosed according to a new definition, recently proposed by us. The criteria are: (1) predominantly syncytial growth pattern and no tubular component, (2) diffuse stremai infiltration with mononuclear cells and (3) sparse ( According to the proposed defenition, MC is biologically unique and the results indicate that the risk factors presently used for selecting breast cancer patients for systemic adjuvant treatment probably should be modified in MC.