Number Of Axillary Nodes Research Articles

Significance of axillary lymph node extranodal soft tissue extension and indications for postmastectomy irradiation.

Extranodal soft tissue extension of axillary lymph node metastases (ETE) has been considered an indication for postmastectomy radiotherapy, including the axilla. However, it is unclear whether patients with ETE are at an increased risk of axillary recurrence. From a single institutional database of 2362 patients with breast carcinoma treated between 1974-1994, a total of 487 patients who underwent mastectomy for lymph node positive, infiltrating (T1-T3) breast carcinoma was found. All the patients had pathologically confirmed axillary lymph node metastases and negative surgical margins; none had received postoperative irradiation. Of these patients, 50 had histologically documented axillary ETE. Forty-three patients had a minimum follow-up of at least 1 year and comprise the study population. The median follow-up time of surviving ETE positive patients was 79 months. Twenty-five patients (58.1%) received adjuvant systemic therapy. Sites of first failure were local or distant. Local failure was categorized further as chest wall failure, axillary failure, supraclavicular lymph node failure, or internal mammary lymph node failure. For the 43 patients with ETE, the median patient age was 59.5 years (range, 38-81 years) and the median tumor size was 3.6 cm (range, 0.5-12.0 cm). The median number of positive axillary lymph nodes was 6 (range, 1-36 lymph nodes) versus 2 (range, 1-30 lymph nodes) for all T1-T3 ETE positive patients compared with ETE negative patients (P < 0. 001). The risk of ETE increased significantly with increasing numbers of axillary lymph node metastases (P < 0.001). Of the patients with ETE, 16 (37.2%) developed recurrent disease. ETE positive patients with disease recurrence had significantly greater numbers of positive axillary lymph nodes (median, 10 lymph nodes) than those patients who were recurrence free (median, 4 lymph nodes) (P = 0.02). The site of first failure was local in 7 patients (16. 3%) and distant in 9 patients (20.9%). All patients with local recurrence had chest wall failures; there were no isolated lymph node recurrences. The only simultaneous local and distant failure was in one patient presenting with supraclavicular and intraabdominal metastases. The risk of axillary recurrence, either as an isolated event or as part of simultaneous failure, is extremely low, even in patients with ETE. These data suggest that patients with ETE frequently have higher numbers of positive axillary lymph nodes and on that basis are at risk for local recurrence and as a rule would be considered for postmastectomy irradiation. However, these data suggest that the presence of ETE is not an indication for routine postmastectomy axillary lymph node irradiation.

Clinical significance of P-glycoprotein expression in breast cancer

To study the clinical significance of P-glycoprotein (P-gp) in breast cancer. Expression of P-gp in 60 cases of breast cancer was examined by immunohistochemistry. P-gp expression and response to chemotherapy were comparatively investigated in 19 patients with metastatic breast cancer. The P-gp was positive in 48.3% of the 60 cases of breast cancer. P-gp expression was not related to patients' age, menstruation status, number of axillary lymph nodes involved, clinical stage, histological type, and hormonal receptor status(P > 0.05). The frequency of metastasis (62.1%) and mortality (51.7%) were higher in P-gp positive cases than those in negative cases (16.1% vs 12.9%, P < 0.005). The 5-year survival rate of P-gp positive cases (48.3%) was significantly lower than that of negative cases (87.1%) (P < 0.05). In patients received adjuvant chemotherapy distant metastasis occurred more frequently in P-gp positive cases (94.7%) than in P-gp negative cases (57.1%) (P = 0.0468). More P-gp negative patients (7/9) than positive patients (1/10) were responsive to chemotherapy (P = 0.0055). Immunohistochemical examination of P-gp expression is useful in predicting response to chemotherapy and prognosis in breast cancer patients. P-gp positivity is associated with poor prognosis.

Significance of axillary lymph node metastasis in primary breast cancer.

Axillary lymph node status is the single most important prognostic variable in the management of patients with primary breast cancer. Yet, it is not known whether metastasis to the axillary nodes is simply a time-dependent variable or also a marker for a more aggressive tumor phenotype. The purpose of this study was to determine whether nodal status at initial diagnosis predicts outcome after relapse and therefore also serves as a marker of breast cancer phenotype. Survival experience after first relapse in 1,696 primary breast cancer cases was analyzed using Cox proportional hazards regression. The following explanatory variables and their first-order interactions were considered: number of axillary lymph nodes involved (zero v one to three v four or more), hormone receptor status (any estrogen receptor [ER] negativity v ER negativity/progesterone receptor positivity v other ER positivity), primary tumor size (< 2 cm v 2 to 5 cm v > 5 cm), site of relapse (locoregional v distant), disease-free interval (< 1.5 years v 1.5 to 3 years v > 3 years), adjuvant endocrine therapy (none v any), adjuvant chemotherapy (none v any), and menopausal status (pre-, peri-, or postmenopausal). Axillary lymph node status, site of relapse, and hormone receptor status were all highly significant as main effects in the model. After adjustment for other variables, disease-free interval alone was only modestly significant but interacted with nodal status. After disease-free interval, hormone receptor status, and site of relapse were accounted for, survival after relapse was poorer in node-positive cases, when compared with node-negative cases. The hazard ratios for patients with one to three and four or more involved nodes were 1.2 (95% confidence interval [CI], 0.8 to 1.9) and 2.5 (95% CI, 1.8 to 3.4), respectively. Patients with four or more involved nodes at initial diagnosis have a significantly worse outcome after relapse than node-negative cases, regardless of the duration of the disease-free interval. We conclude that nodal metastasis is not only a marker of diagnosis at a later point in the natural history of breast cancer but also a marker of an aggressive phenotype.

The sentinel node in breast cancer: implications for adjuvant treatment?

Despite continuous efforts to define more advanced and less invasive prognostic factors, surgical staging of the axilla remains the single most important prognostic factor in localized breast cancer. Axillary lymph node dissection (ALND) of the lymph nodes at levels I and II, and level III when metastatic involvement is suspected, should provide an answer as to whether metastatic spread to the axilla has occurred. In addition to the presence of axillary involvement per se, the number of axillary nodes involved has a supplementary prognostic impact. In general the axillary lymph node status is defined as follows: 0, 1–3, 4–9 or >10 involved lymph nodes, with crude 10-year survival rates of 65%–75%, 45%–60%, 25%–30% and <20% respectively. Besides prognostic implications, the number of involved lymph nodes also has therapeutic importance. Systemic adjuvant chemotherapy is offered to all lymph node-positive patients and, as recently reported by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), produces an absolute improvement of 11% in the 10-year survival of node-positive patients. However, further improvement is clearly warranted and in patients with high-risk primary breast cancer, defined by some authors as having ten or more lymph nodes and by others as having four or more, the value of high-dose chemotherapy with peripheral blood stem cell support is being investigated. Results of the first large randomized trials will be reported in the near future but it is generally not expected that high-dose chemotherapy will have the tremendous impact that was hoped for. In the coming years it is anticipated that the focus of adjuvant treatment will be on further defining the importance of changing the schedule and sequence of relatively standard-dose chemotherapy. In addition, immunotherapy with antibodies against oncogenes, with or without chemotherapy, the development of oncogene/whole cell vaccinations and the importance of interfering with the angiogenesis process will be evaluated. While axillary lymph node invasion is highly indicative for the prognosis, it clearly is not the only important factor since 25%–35% of patients with node-negative disease die of disease within 10 years of diagnosis. High-risk features of the primary tumour such as size, histological grade, nuclear grade, hormone receptor status and vascular and lymphatic invasion, may override the favourable prognosis as determined by the axillary status. In the EBCTCG overview of 69 trials in 36 000 women the proportional reduction in recurrence and mortality due to adjuvant polychemotherapy was independent of nodal status, with a 7% absolute improvement in 10-year survival in the node-negative patients. Does this imply that adjuvant systemic treatment should be given regardless of the axillary nodal status? The International Consensus Panel on the Treatment of Primary Breast Cancer recently published their recommendations on adjuvant treatment, which are as follows: All lymph node-positive patients should be offered some form of chemotherapy and/or tamoxifen. In lymph nodenegative patients it is recommended that patients be categorized into minimal/low risk, intermediate and highrisk groups, where pathological tumour size is considered the most important risk factor. In patients with a tumour size <1 cm, positive oestrogen receptor status, histological and nuclear grade I (the relevance of which is uncertain at this tumour size) and age above 34 years, administration of tamoxifen is optional. If any of these factors are lacking, adjuvant systemic treatment with chemotherapy and/or tamoxifen should be offered. In view of the foregoing information, what will be the role of sentinel node (SN) biopsy with regard to both prognosis and therapy?

Vimentin expression is not associated with poor prognosis in breast cancer

The clinical significance of vimentin intermediate filament (VIF) expression was studied in relation to other established prognostic parameters in primary breast cancer. Archival tumour samples embedded in paraffin were examined by immuno-histochemistry with monoclonal antibodies (MAbs) to VIF, p53 protein and cell proliferation marker MIB-I. The vimentin staining pattern was heterogeneous, but in vimentin-positive areas > 80% of the tumour cells were positive. There was no association between vimentin expression and tumour size or the number of axillary lymph nodes involved. Vimentin expression was significantly associated with high-grade tumours, absence of hormone receptors, increased p53 expression and high tumour proliferation fraction as estimated by MIB-I count. Despite these associations with several recognised features of tumour aggressiveness, vimentin expression was not associated with increase in risk of relapse or death from breast cancer.

Vimentin expression is not associated with poor prognosis in breast cancer

The clinical significance of vimentin intermediate filament (VIF) expression was studied in relation to other established prognostic parameters in primary breast cancer. Archival tumour samples embedded in paraffin were examined by immunohistochemistry with monoclonal antibodies (MAbs) to VIF, p53 protein and cell proliferation marker MIB-1. The vimentin staining pattern was heterogeneous, but in vimentin-positive areas > 80% of the tumour cells were positive. There was no association between vimentin expression and tumour size or the number of axillary lymph nodes involved. Vimentin expression was significantly associated with high-grade tumours, absence of hormone receptors, increased p53 expression and high tumour proliferation fraction as estimated by MIB-1 count. Despite these associations with several recognised features of tumour aggressiveness, vimentin expression was not associated with increases in risk of relapse or death from breast cancer. © 1996 Wiley-Liss, Inc.

Improved Axillary Staging of Breast Cancer with Sentinel Lymphadenectomy

The authors evaluated the effect of intraoperative lymphatic mapping and sentinel lymphadenectomy (SLND) on the axillary staging of patients with carcinoma of the breast. The accurate staging of patients with breast cancer is essential to guide management and determine prognosis. The authors previously reported the feasibility and accuracy of SLND in breast carcinoma. Sentinel lymphadenectomy identifies the first ("sentinel") axillary lymph node draining the site of a primary tumor; because this node is the most likely site of axillary metastasis, histopathologic examination of the sentinel node correlates well with examination of the entire axillary contents. The current study compares SLND with standard axillary lymphadenectomy (ALND) for the staging of breast carcinoma. The incidence of axillary node metastasis and micrometastasis in SLND and ALND specimens from patients undergoing operative treatment of a primary breast carcinoma was compared prospectively. Multiple sections of each sentinel lymph node in SLND specimens were examined by hematoxylin and eosin (H&E) staining and by immunohistochemical techniques using antibodies to cytokeratin. One or two sections of each nonsentinel lymph node in ALND specimens were examined by routine H&E staining. One hundred thirty-four patients underwent ALND (ALND group), and 162 underwent successful SLND followed by completion ALND (SLND group). Both groups were similar with respect to age (median, 55 and 54 years, respectively), palpable primary tumors (54.5% and 59.3%, respectively), palpable axillary nodes (5.2% and 7.4%, respectively), size of primary tumor (median, 1.5 cm in each group), and total number of axillary lymph nodes examined (median, 19 and 21, respectively). The number of patients with axillary metastasis was 39 (29.1%) in the ALND group and 68 (42.0%) in the SLND group (p < 0.03). Of these, 4 of 39 (10.3%) ALND patients (3.0% of all ALND patients) and 26 of 68 (38.2%) SLND patients (16.0% of all SLND patients) had micrometastasis (< or = 2 mm), a highly significant difference (p < 0.0005) Sentinel lymphadenectomy with multiple sectioning and immunohistochemical staining of sentinel nodes increases the accuracy of axillary staging in breast cancer and can identify significantly more patients with lymph nodes metastases, especially micrometastases, than can ALND with routine histopathologic processing of lymph nodes.

ABC of breast diseases. Prognostic factors.

Prognostic factors are of value for three main reasons: FIG Freedom from recurrence of cancer in patients in relation to age when breast cancer first diagnosed. (Proportional hazards model showed age <35 to have relative risk of 1.6 for distant disease.) Prognostic factors can be broadly classified into two groups: chronological factors, which are indicators of how long the cancer has been present and relate to stage of disease at presentation, and biological factors, which relate to the intrinsic or potential behaviour of the tumour. However, recent evidence suggests that age at diagnosis may also be a risk factor: younger women (aged under 35) have a poorer prognosis than older patients with cancer of equivalent stage. ### Chronological factors FIG Survival in relation to size of breast cancer. ### Tumour size The pathological size of a tumour correlates directly with survival; patients with smaller tumours have a better survival rate than those with large tumours. Maximum pathological size should be assessed in fresh specimens, and the size should be subsequently confirmed or amended after histological examination. Status of axillary lymph nodes The single best prognostic factor is the presence or absence of axillary nodal metastases. There is a direct correlation between survival and the number of axillary lymph nodes involved. ### Metastases Patients in whom cancer has spread beyond the axillary or internal mammary nodes (M1 or stage IV disease) have a much worse survival rate than patients whose disease is apparently localised. There are differences in survival between patients depending on the site of the metastatic disease, with patients who have supraclavicular involvement as their only site …

The relative prognostic significance of total cathepsin D and HER‐2/neu oncogene amplification in breast cancer

Total tumor cathepsin D (TCD) levels were determined prospectively by a radioimmunometric assay in tumor cytosol of 858 primary breast cancer patients diagnosed between 1989-1991. In 581 of these patients, tumor HER-2/neu oncogene amplification was simultaneously determined. In a "training-set" of 313 patients, "high" TCD was associated with significantly shorter disease-free survival (DFS). For the whole group, there was no correlation between TCD and pathologic stage, number of axillary nodes with tumor deposits, tumor size, histologic type and grade, or hormone receptor levels. In the node-positive group, high TCD level was associated with HER-2/neu amplification. After a median follow-up duration of 31 months, univariate analysis indicated that high TCD level was significantly associated with shorter DFS only in node-positive patients. The shorter DFS in association with high TCD levels was observed in both estrogen-receptor-positive and -negative patients. Cox multivariate analysis of DFS confirmed that high TCD level was predictive of shorter DFS in node-positive patients only. Because of the short duration of follow-up, the significance of TCD in overall survival was not determined. We conclude that high tumor TCD in node-positive patients is predictive of shorter DFS, and is often associated with HER-2/neu amplification. The possibility exists that high tumor TCD may act in combination with HER-2/neu amplification to promote dissemination of metastases.

Management of early breast cancer in southeast Netherlands since 1984. A population-based study. Regional Breast Cancer Study Group.

We studied changes in staging and treatment of patients with early breast cancer (TNM stage I and II) in eight community hospitals in southeast Netherlands between 1984 and 1991 and related these changes to the guidelines for the management of breast cancer drawn up by the regional Breast Cancer Study Group. Since 1984, the proportion of patients that underwent breast-conserving therapy (local tumour excision, axillary dissection, and irradiation of the breast) increased from 26% to 53%. Although the mean number of axillary lymph nodes examined by the pathologists increased significantly, the proportion of patients with positive lymph nodes remained unchanged. The proportion of patients with involved axillary nodes receiving any form of adjuvant systemic therapy increased from 49% to 82%. Therapeutic policy initially varied significantly from one hospital to another but gradually became more uniform. We conclude that, except for elderly patients, treatment of early breast cancer corresponded increasingly to the guidelines of the regional Breast Cancer Study Group.

Clinical significance of HER-2/neu oncogene amplification in primary breast cancer. The South Australian Breast Cancer Study Group.

To determine prospectively the prognostic significance of HER-2/neu oncogene amplification in the primary tumors of breast cancer patients. HER-2/neu amplification in tumor DNA was determined by the slot-blot technique in 1,056 patients with breast cancer (stage I to III) diagnosed between 1987 and 1990. Parameters such as estrogen receptor (ER) and progesterone receptor (PgR) levels, tumor size, axillary nodal involvement, tumor grade, and time to relapse were prospectively obtained. HER-2/neu oncogene amplification, > or = 2, > or = 3, and > or = 5 copy number, was detected in 21%, 11%, and 7% of patients, respectively. In a test set of 529 patients, Cox multivariate analysis showed HER-2/neu copy number > or = 3 or > or = 5 was associated with shorter disease-free survival (DFS) duration. HER-2/neu copy number > or = 3 correlated significantly with pathologic stage of disease, number of axillary nodes with tumor, histologic type, and absence of ER and PgR. For all patients, after a median follow-up duration of 39 months, Kaplan-Meier univariate analysis indicated that tumor oncogene copy number > or = 3 correlated with shorter DFS in both node-negative and node-positive patients. In Cox multivariate analysis, HER-2/neu copy number > or = 3 was associated with shorter DFS, independent of nodal status, ER level, and tumor size. Although the follow-up duration of this study is relatively short, we conclude that HER-2/neu amplification is an independent predictor of shorter DFS in both node-negative and node-positive patients.

Prognostic factors for bone metastases in breast cancer.

Two hundred and sixty-nine patients with breast cancer were assessed with regard to multiple parameters at the time of initial diagnosis. Over a follow-up period of 6 or 7 years, 84 patients developed skeletal metastases and in 42 they were symptomatic. Symptomatic bone metastases were related to lytic metastases and an elevated sedimentation rate. The significant parameters predisposing to the development of bone metastases were the presence of adenopathies or metastases at the time of initial diagnosis. The number of axillary nodes involved was related to the number of bone metastases, the number of spontaneous abortions, and the gonadal endocrine function. The adherence of axillary nodes was related to the number of bone metastases, an elevated sedimentation rate and the serum calcium level.

Morphometry in predicting survival in breast cancer

To assess the value of morphometry in predicting prognosis of patients with invasive breast cancer (BC) 102 patients with infiltrating ductal and infiltrating lobular cancers were selected for study from the 5 yrs up to 1979. Of these 46 died, 39 from BC and 7 from other causes. Among the cellular and nuclear features measured were mitotic activity index (MAI); cellularity index; N/C ratio; nuclear longest axis, shortest axis, area, perimeter, size, shape factor; and nucleolar area, perimeter and area to perimeter ratio. Two systems for histological grading of invasive BC were compared, the NSABP method and our modification of the WHO system. The number of axillary lymph nodes involved was also noted. The statistically significant χ 2 values for the 3 Cox Regression analyses (CRA) are shown below. VARIABLES CRA 1 CRA 2 CRA 3 Positive nodes >3 8.82 10.20 10.24 MAI (mitoses/10 HPF) 5.61 7.75 4.94 Mitoses/1000 nuclei 6.07 10.14 6.86 Modified WHO histo-grade (3.40) 7.66 6.22 NSABP histo-grade (2.84) 4.93 (0.89) Age >75yrs 4.79 (1.40) (0.46) CRA 1; time to all deaths. CRA 2: time to BC-specific deaths. CRA 3: disease-free interval. ( ) not significant χ 1 2 = 3.84 Of all the morphometric data mitoses/1000 cells achieved the highest statistical significance in separating survivors from non-survivors and was also the single most important feature in both the NSABP grading method and our modified WHO histological grading scores. Of the 3 regressions, the BC-specific death regression (CRA-2) was considered the best χ 2 2 =29.4, p Conclusions : A PI based on mitoses/1000 cells and positive nodes > 3 or ≤ 3 will be useful in identifying and classifying more accurately groups of patients of differing prognosis after the present learning set has been enlarged and tested against a new group of patients (test set) and subjected to statistical evaluation of the accuracy and sensitivity of the classification rule.

Partial mastectomy with axillary lymph node dissection and radiotherapy as a new treatment modality of breast cancer (I).

This is the first preliminary report among two consecutive papers. Partial mastectomy(PM), axillary lymph node dissection(AD) and radiotherapy (RT) were performed on seventeen operable breast cancer patients who had been admitted from April 1991 to March 1992 to the department of surgery, Yongdong Severance Hospital for improved cosmetic appearance and better survival rate. Of seventeen patients, 47% were T1 lesion and 76% were stage I and II. Extensive intraductal component(EIC) within or around the tumor was also analyzed. Twenty nine per cent of the patients were EIC positive. The mean number of axillary lymph nodes was 21.5 after PM with AD and 20.5 after mastectomy. For radiotherapy, 4,500 rad was delivered to the breast parenchyma and 1,600 rad of boost to the primary tumor site using the electron beam method after surgery. All patients have since been living well without any local recurrence and were satisfied with breast preservation for the one-year follow-up period. We concluded that the PM, AD and RT can be another surgical treatment modality of breast cancer. A longer follow-up data will be followed on the second paper.

NODAL INVOLVEMENT IN POORLY DIFFERENTIATED BREAST CANCER

The degree of nodal involvement in a consecutive series of 400 patients with invasive ductal breast cancer is presented. A positive correlation was observed between the number of metastatic nodes identified and the number of axillary nodes examined for poorly but not moderately differentiated tumours. The relevance of this observation to breast cancer trials is discussed.

Characterization of T-lymphocyte subpopulations infiltrating primary breast cancer.

Characterization of T-lymphocyte subpopulations adjacent to and infiltrating the primary tumor of breast cancer was carried out using a direct immunofluorescence procedure with the antibodies anti-(Leu-2a) for suppressor/cytotoxic (CD8+) and anti-(Leu-3a) for helper/inducer (CD4+) T-lymphocytes. Fifty-six primary malignant tumors with lymphoid infiltration were studied. The majority (58.9%) were infiltrating duct carcinoma. There were metastases to axillary lymph nodes in 6.67% of the patients. Massive lymphoid infiltration (greater than 40 lymphocytes per x 400 microscopic field) was found in 19.6% of the tumors and moderate infiltration (20-40 lymphocytes per field) in 51.8%. In all the tumors studied there was a reversed CD4+/CD8+ ratio as compared to that found in normal peripheral blood. In 66.1% the CD4+/CD8+ ratio (helper/suppressor) was less than 1.0. The reversed ratio was due to a significant decrease in the number of helper cells (P less than 0.0005). The most significant drop was in the stroma area (P less than 0.0001) as well as in the tumor tissue (P = 0.001). Of particular interest was the significant positive correlation between the age of the patients and an increased number of CD4+lymphocytes in the stroma (P = 0.02). Significant negative correlations were found between a reduced number of CD4+ lymphocytes or CD4+/CD8+ ratio and several histological parameters: tumor diameter, pleomorphism, nucleus/cytoplasm ratio. There was also a significant positive correlation between the total number of CD8+ lymphocytes infiltrating the tumor tissue and the number of axillary lymph nodes with metastatic disease (P = 0.03). It is suggested that the reversed ratio of CD4+/CD8+ lymphocytes may significantly affect the host/tumor immune surveillance.

Urokinase-plasminogen activator, a marker for aggressive breast carcinomas. Preliminary report.

Plasminogen activator is a serine protease which exists in two forms, known as tissue-type plasminogen activator and urokinase-type plasminogen activator. Here, we show that urokinase-type plasminogen activator activity in primary breast carcinomas correlates with both size of tumor and number of axillary nodes with metastases. Patients with primary carcinomas containing high levels of urokinase-type plasminogen activator activity had a significantly shorter disease-free interval than patients with low levels of activity. It is concluded that urokinase-plasminogen activator may be a new prognostic marker in breast cancer.

Steroid receptors and other prognostic factors in primary breast cancer.

A review and update of published studies on prognostic factors support the following conclusions: The number of axillary lymph nodes involved with tumor remains the most important prognostic factor for women with primary breast cancer. In stage I disease, the lack of estrogen receptor (ER) seems to be the most important factor for predicting earlier recurrence and poorer survival. In stage II breast cancer, progesterone receptor (PgR) content appears to be better than ER content in predicting disease-free and overall survival. Measurement of proliferative activity (S-phase DNA) by thymidine labeling or flow cytometry (FCM) and of aneuploidy by FCM also provides prognostic information. Patients with aneuploid tumors, or with high S-phase diploid tumors, are at increased risk for relapse. Amplification of oncogenes, particularly HER-2/neu, may provide additional prognostic information in combination with other established prognostic factors.

Correlation of morphological criteria with the rate of growth in cancer of the breast

Prognosis of carcinoma of the breast depends on a number of factors. Besides tumour staging, these parameters include the number of axillary lymph nodes with metastatic growths, the status of the hormonal receptors, and the histological type of the tumour, especially the tumour grading and the rate of growth correlated therewith. The first few of these criteria are relatively easy to determine. The tumour duplication time has so far been determined only by means of serial mammographies. Only few studies have been conducted on the correlation of the morphological parameters connected with the dynamics of growth of carcinomas of the breast. In a group of 61 patients with carcinoma of the breast and known tumour duplication time determined by serial mammography, it is shown that broadening of the conventional tumour grading by means of additional histopathological malignancy criteria (frequency of mitosis, incidence of nuclear hyperchromasias, formation of tubules and nuclear irregularities) correlates with the growth dynamics of the tumours. This makes it seem possible to draw prospective conclusions on the growth performance of carcinomas of the breast even without resorting to serial mammographies.

Dose-response effect of adjuvant chemotherapy in breast cancer.

We retrospectively analyzed the role of the dose level of CMF (cyclophosphamide, methotrexate, and fluorouracil) in postoperative adjuvant chemotherapy for breast cancer and in chemotherapy for metastatic breast cancer. There was a clear dose-response effect, indicating that CMF was useful only when given in a full or nearly full dose (greater than or equal to 85 per cent of the planned dose). Those given adjuvant therapy with 12 cycles of CMF at this dose level had a five-year relapse-free survival of 77 per cent, as compared with 45 per cent of patients treated only with radical mastectomy (P = 0.0001). In contrast, a subgroup receiving less than 65 per cent of the planned dose had a five-year survival without relapses of 48 per cent and a five-year survival with relapses of 67 per cent. These results are similar to those observed in a control group. With each dose level, the results at five years were influenced by the number of axillary lymph nodes involved but not by menopausal status. Our findings indicate that it is necessary to administer combination chemotherapy at a full dose to achieve clinical benefit.