The importance of steroid receptors for the prognosis and hormone treatment of breast cancer patients: a retrospective study in Southeastern Netherlands

OBJECTIVE: To assess the effect of oestrogen (ER) and progesterone (PgR) receptors on the prognosis of patients with operable breast cancer and the decision to treat these patients with adjuvant tamoxifen. DESIGN: Retrospective. SETTING: Eight community hospitals in the Southeast Netherlands. METHOD: Using the registry of the Comprehensive Cancer Centre South, 2862 breast cancer patients were identified with stage I, II or IIIA tumours, treated during the period 1984-1992. RESULTS: ER and PgR status were known for 2393 (84%) and 1761 (62%) patients respectively. From 1991, over 80% of the postmenopausal, lymph node positive patients had received tamoxifen, irrespective of the steroid receptor status. Of all lymph node negative patients fewer than 3% received adjuvant systemic treatment. Among the lymph node negative patients the steroid receptor status was not a significant predictor of survival. Among the lymph node positive patients whose tumours were both ER-negative and PgR-negative, a 2.8-fold increased risk of death was found during the first four years after primary treatment. The risk of death was not increased if only the ER or only the PgR status was negative. CONCLUSION: This study shows that ER and PgR receptors are significant prognostic factors for survival in breast cancer patients with involved axillary lymph nodes. The prognostic effect appeared to be restricted to the first four years after primary treatment. Selection of patients for endocrine treatment should be based on the steroid receptor status, considering the importance of the steroid receptors for predicting the response to endocrine treatment.     

Short recurrence-free survival associated with high oestrogen receptor levels in the natural history of postmenopausal, primary breast cancer

The ability of oestrogen and progesterone receptor (ER and PgR, respectively) status to discriminate recurrence-free survival (RFS) among a cohort of consecutively accrued 952 postmenopausal patients has been studied. None of the cohort members investigated were treated with adjuvant therapy. Using a graduated scale of receptor status [low, intermediate and high receptor levels (< 10 vs. 10-107 vs. > or = 108 fmol/mg cytosol protein, respectively)] instead of the more commonly used dichotomous subdivision (positive vs. negative), ER level significantly discriminated between groups of patients with long vs. short RFS. Contrary to our expectations, patients with highest ER levels have as poor a prognosis as ER-negative patients, while patients with intermediate ER levels have longest RFS. The group of patients with ER levels > or = 108 fmol/mg cytosol protein comprises 47% of the cohort. The independent significance of overexpression of ER as a prognostic factor among this patient group is demonstrated in multivariate analysis where ER level is more significant than either grade of anaplasia or tumour size. PgR status did not significantly predict RFS among these patients. While the highest ER levels predispose for poorer prognosis among postmenopausal patients, it is precisely this group that experiences greatest benefit from adjuvant treatment with tamoxifen. Thus, patients who might otherwise go untreated due to their node-negative status can be readily identified and offered adjuvant treatment.     

The prognostic significance of steroid receptor activity in tumor tissues of patients with primary breast cancer

The prognostic significance of steroid-receptor activity is still debatable. Discrepancies in results are probably attributable to few patients, heterogeneous patient populations, and short follow-up. We investigated the prognostic significance of estrogen- and progesterone-receptor (ER and PgR, respectively) activity as a continuous variable in a homogeneous patient population. The prognostic significance of steroid-receptor activity was examined in 329 node-negative and 320 node-positive unselected breast cancer patients. In node-negative patients, ER values of primary tumors between 100 and 400 fmol/mg protein appeared to be a significant predictor for low risk of recurrence, whereas high ER (> 400) revealed an unfavorable prognosis. The classic cutoff level of ER (< 10 fmol/mg proteins) had no prognostic significance, however. In patients receiving adjuvant chemotherapy--the node-positive breast cancer patients--the classic cutoff value of ER (10 fmol/mg protein) predicts significantly distant metastases-free survival and overall survival only in the first 4 years of follow-up after diagnosis. Progesterone receptor is a time-dependent prognosticator in node-negative breast cancer patients (cutoff point for PgR, 80 fmol/mg). In node-positive breast cancer patients treated with chemotherapy or a combination of chemo- and hormonal therapy, PgR values lower than 60 fmol/mg had a worse prognosis. The results show the poor performance of standard cutoff points for ER and PgR positivity in predicting prognosis. Better prognosis is related to higher receptor levels but this relation is predominantly time-dependent. Moreover, patients who have high ER levels have a prognosis that is worse when compared with intermediate ER levels. Standard cutoff points for steroid receptors should not be used to select patients for prognosis.     

Determination of angiogenesis adds information to estrogen receptor status in predicting the efficacy of adjuvant tamoxifen in node-positive breast cancer patients

There is experimental and clinical evidence that angiogenesis is involved in breast cancer progression and metastasis. To investigate whether the determination of angiogenesis adds prognostic information to the estrogen receptor (ER) status, we studied a series of 178 node-positive breast cancer patients, with a median follow-up time exceeding 5 years, treated with adjuvant tamoxifen (TAM). We assessed angiogenesis by the quantification of the intratumoral microvessel density and the determination of the Chalkley score using light microscopy. Microvessels were immunostained using the anti-CD31 antibody. The other features studied were ER status and the conventional clinicopathological prognostic indicators. Results were pooled from two collaborating Centers using Chalkley counts to convert intratumoral microvessel density to a common quantification system. We found that Chalkley score was not associated with any other feature studied. In univariate analysis, Chalkley score was significantly predictive of both relapse-free survival (RFS) and overall survival (OS; P < 0. 00001 and P = 0.00004, respectively). Likewise, ER status, the number of metastatic axillary nodes, histological grading, and tumor size were significantly predictive for RFS and OS. Cox multivariate analysis showed that Chalkley score was the strongest significant independent predictor of outcome. For RFS, ER status, the number of metastatic nodes, and histological grading also retained significance. For OS, the number of metastatic nodes, tumor size, and histological grading were independent prognostic factors. The joint assessment of the above variables had a satisfactory prognostic capability, as found using the Harrel statistics (c = 0. 77). These results suggest the validity of using Chalkley counts to assess and compare angiogenesis for prognostic purposes between different Centers. We found that angiogenesis adds significant prognostic information to ER status in predicting the outcome of breast cancer patients treated with adjuvant TAM. In fact, irrespective of the ER status, the patients with highly angiogenic tumors had a poor outcome, even if treated with TAM. For these patients, the inhibition of angiogenesis with specific angioinhibitory drugs may be a promising new therapeutic strategy.     

Validation of p53 accumulation as a predictor of distant metastasis at 10 years of follow-up in 1400 node-negative breast cancers

Most studies are in favor of a prognostic relevance of p53 accumulation determined by immunohistochemistry in breast cancer, but negative results are not lacking. On a series of 1400 patients with lymph node-negative cancers treated with local-regional therapy alone until relapse and with a median follow-up of 10 years, we validated the prognostic relevance for overall relapse and death of p53 accumulation observed in a pilot study and analyzed its predictivity on different adverse events. p53 protein accumulation was immunocytochemically detected using PAb1801. The case series had also been previously characterized for hormone receptor content [estrogen receptors (ERs) and progesterone receptors (PgRs)] and for cell proliferation [[3H]thymidine labeling index ([3H]dT LI)]. p53 expression, considered as a dichotomous variable with a cutoff value of 5% positive cells, significantly predicted the occurrence of overall relapse, distant metastasis, and death with an interaction with cell proliferation. p53 accumulation, cell proliferation, and their interaction term, along with tumor size and patient age, retained a predictive role for overall relapse, and together with tumor size and PgR, also for overall survival. When considered as continuous variables, we observed that the hazard of metastasis increased linearly with the increase of [3H]dT LI and decreased linearly with the increase of ER and PgR. Conversely, the hazard increased with the increase of p53-positive cells only for tumors with a [3H]dT LI lower than 7.5%. In multivariate analysis, the same prognostic factors for distant metastasis were identified when the biomarkers were considered as continuous or dichotomous variables.     

T1a and T1b breast cancer: a twelve-year experience

To understand the prevalence of axillary node metastasis and survival of patients with T1a and T1b breast cancers, we reviewed the experience at a large community hospital. All patients in the William Beaumont Hospital tumor registry with breast cancer treated between January 1983 and November 1995 were evaluated for tumor size, age, cell type, and the presence or absence of axillary node disease. Long-term survival was evaluated in patients treated between 1983 and 1992. The patients were defined as premenopausal or postmenopausal based on age (49 years or less, premenopausal; 50 years or greater, postmenopausal). Of the 4590 patients treated for breast cancer from 1983 to 1995, 915 had tumors 1.0 cm or less in size. Of 181 patients who had T1a cancer, 27 were premenopausal, and 154 were postmenopausal. Twenty-three premenopausal patients had axillary lymph nodes examined, two (8.7%) had histologically positive lymph nodes. Of 118 postmenopausal patients who had axillary nodes examined, six (5.1%) had positive lymph nodes. In those with T1b tumors, 130 patients were premenopausal; 604 patients were postmenopausal. Of these, 119 premenopausal patients had axillary nodes examined, and 29 (24.4%) had positive lymph nodes. Of 464 postmenopausal patients who had axillary nodes examined, 66 (14.2%) had positive nodes. The overall, disease-free, and tumor-specific survival rates for patients with T1a tumors were 93.8, 87.5, and 93.8 per cent (premenopausal) and 86.2, 95.4, and 95.4 per cent (postmenopausal), respectively. These survival rates for patients with T1b tumors were 87.8, 87.8, and 91.1 per cent (premenopausal) and 82.9, 88.5, and 92.9 per cent (postmenopausal), respectively. Premenopausal T1b patients had a higher rate of nodal involvement than postmenopausal T1b patients (P = 0.011). Postmenopausal T1b patients had a higher nodal metastasis rate than postmenopausal T1a patients (P = 0.01). T1b patients had a higher rate of axillary involvement than did T1a patients (P = 0.0018). Based on the rate of axillary lymph node metastasis and survival statistics, there may be a role for axillary node dissection in select patients with tumors less than 1.0 cm. in size.     

Carcinomatous infiltration into the submucosa as a predictor of lymph node involvement in early gastric cancer

The clinicopathologic features of 114 patients with resectable early gastric cancer (EGC) invading the submucosa were examined retrospectively with respect to lymph node involvement and the possibility of performing a minimally invasive operation. Patients were divided into node-positive (n = 25) and node-negative (n = 81) groups. Among several pathologic factors, the diameter of the tumor and lymphatic involvement were significantly correlated with nodal involvement. Within the submucosal layer the depth of invasion and the horizontal cancerous expansion also correlated with lymph node disease (p < 0.05). The size of the tumor did not correlate with the length of submucosal infiltration (r = 0.12, p = 0.1). Patients with both slight invasion into the submucosa and less than 5 mm of horizontal expansion were often negative for lymph node involvement and thus may benefit from local surgery as an alternative to gastrectomy.     

Axillary node metastasis from T1N0M0 breast cancer: possible avoidance of dissection in a subgroup

BACKGROUND: Axillary lymph node dissection is now no longer considered to be the standard treatment in all patients with invasive breast cancer. We have attempted to identify a sub-group of patients with invasive breast carcinoma who may not need to undergo axillary lymph node dissection. METHODS: Patients (n = 823) with T1 N0M0 invasive breast cancer treated at our hospital between 1970 and 1994 were studied. We investigated the relationship between positive axillary lymph nodes and the following clinico-pathological factors: patient age, menopausal status, contralateral breast cancer (synchronous or asynchronous), tumor location, tumor size (T:cm), histopathology, histological grade, presence or absence of malignant microcalcification or spiculation on mammography and estrogen receptor status. RESULTS: The incidence of axillary lymph node metastases in patients with T1N0M0 invasive breast cancer was 25% (208/823). The node-negative group was significantly older than the node-positive group. Premenopausal patients had a higher rate of lymph node metastases although this was not significant. The frequency of nodal metastases when related to the tumor size was as follows: T< or =1.0 cm, 17%; T< or =1.5 cm, 25%; T< or =2.0 cm, 29%. Mammography revealed that patients with malignant calcification or spiculation had a significantly higher rate of nodal metastases than those without these findings. Certain tumor types (medullary, mucinous and tubular carcinomas) had lower positive rates for lymph node involvement. With regard to the histological grade, lymph node positivity increased significantly with high-grade tumors. No correlation was observed between any other factors and the presence or absence of lymph node metastases. CONCLUSIONS: It may be possible to avoid axillary lymph node dissection in postmenopausal patients (50 years or older) where the histological type is favorable when the tumor diameter is < or =1.0 cm and when microcalcification or spiculation is absent on mammography.     

Clinical significance of cyclin D1 expression in patients with node-positive breast carcinoma treated with adjuvant therapy

BACKGROUND: Experimental and clinical studies suggest that cyclin D1 is involved in transformation and tumour progression. However, there is little and contradictory data on the clinical significance of cyclin D1 in human invasive breast carcinoma. PATIENTS AND METHODS: We investigated whether the determination of cyclin D1 has prognostic value in a series of 180 patients with node-positive breast carcinoma and treated with adjuvant therapy with a median follow-up exceeding 6 years. We assessed cyclin D1 expression using the CDS-6 monoclonal antibody and a highly sensitive immunohistochemical technique. RESULTS: We found that most of the evaluable tumours (117 of 167; 70.1%) presented nuclear cyclin D1 staining and that its expression was significantly associated with both the hormone receptors (P = 0.009 and P = 0.005 for ER and PgR, respectively). Furthermore, 29 (17%) of 167 tumours had a weak (15 cases) or strong (9 cases) cytoplasmic cyclin D1 staining. In a subgroup of cases we also studied the amplification of the cyclin D1 gene and a moderate agreement between cyclin D1 nuclear overexpression assessed immunohistochemically and the gene amplification was found. In univariate analysis, cyclin D1 nuclear positivity was significantly associated with improved 6-year relapse-free survival (RFS) (P = 0.004), but not with overall survival (OS) (P = 0.12). The results of the Cox multivariate analysis (final model) indicate that cyclin D1 expression (P = 0.0049) as well as the number of involved nodes (P < 0.001) and tumour size (P = 0.036) are significant prognostic indicators for RFS. Only the number of involved nodes retained significance (P < 0.001) for OS in our series. The joint assessment of the variables considered in the final model of the multivariate analyses had a moderate prognostic capability as determined using the Harrell c statistic (c = 0.66 and 0.64 for RFS and OS, respectively). CONCLUSIONS: The patients with node-positive breast cancer who have a higher likelihood of gaining benefit from adjuvant therapy are those with tumours with cyclin D1 nuclear expression, small size and less than 3 metastatic nodes. Further studies are needed to verify the prognostic value of cyclin D1 in relation to different adjuvant treatments and to deepen the biological pathways that regulate its activation/ suppression in human breast carcinoma.     

C-erbB-2 overexpression in primary breast cancer: independent prognostic factor in patients at high risk

The prognostic value of c-erbB-2 protein overexpression has been evaluated in 463 patients with operable breast cancer after a median follow-up of 66 months. Overexpression was observed in 99/463 (21%) of the breast tumors. It showed significant positive correlation to histological grade (p < 0.0001) and tumor size (p < 0.02). A relationship of borderline significance was observed between c-erbB-2 protein overexpression and negative or low estrogen receptor (ER) content. No significant correlation was found to lymph node involvement or proliferating tumor cell fraction as determined by the proliferating cell nuclear antigen (PCNA). After a median follow-up of 66 months (range 6 to 109 months), the overall survival of all patients amounted to 63%. Multivariate analysis revealed lymph node involvement, tumor size, histological grade, histological type, c-erbB-2 protein overexpression, progesterone receptor (PR) content, and oral contraceptive use as independent prognostic factors. In an univariate analysis, the overall survival amounted to 72% and 38% of tumor patients with negative and positive c-erbB-2 protein overexpression, respectively. The most significant finding is that c-erbB-2 overexpression has been recognized as an independent predictive factor in subsets of tumor patients who would be expected to have a generally poor prognosis, such as those indicating axillary lymph node involvement, large tumor size (> 2 cm), and PR negativity.     

Relationship of standardized mitotic indices to other prognostic factors in breast cancer

OBJECTIVE: To examine the relationship between mitotic index (MI), calculated from direct microscopic counts, and other prognostic features in breast cancer. DESIGN: Mitotic index was based on direct microscopic observations of mitotic figures in 10 consecutive microscopic fields, and the average cell number was determined by counts of population density in three of those fields. Tumor grade and type were established from tissue sections, whereas metastases were detected in lymph node biopsy, chest roentgenograms, and bone scan. Estrogen receptor (ER) and progesterone receptor (PgR) levels were determined by flow cytometry. RESULTS: The MI for 242 patients ranged from 0.2 to 37.6, with a mean of 5.8 mitoses per 1000 cells. More than 85% of the tumors with an MI below 1.0 were diploid and contained an S-phase fraction of 6.7% or less. In contrast, more than 75% of tumors with an MI above 5.0 were aneuploid with more than 6.7% of cells in S-phase. There was an inverse relationship between ER and PgR status and MI. Eighty percent of tumors with an MI less than 1.0 were both ER and PgR positive while only 25% of those with an MI above 10.0 were both ER and PgR positive. Receptor-positive tumors with high S-phase and MI values had ER and PgR levels below 100 fmol/mg. CONCLUSIONS: Lower MI values calculated from direct cell counts are correlated with negative node status, diploid DNA content, low S-phase fraction, and positive receptor status. Thus, there is a significant relationship between objective MI values and several other factors that predict the probability of breast tumor recurrence.     

Micrometastatic breast cancer cells in bone marrow at primary surgery: prognostic value in comparison with nodal status

BACKGROUND: Approximately 30% of the patients with primary breast cancer who have no axillary lymph node involvement (i.e., lymph node negative) at the time of surgery will relapse within 10 years; 10%-20% of the patients with distant metastases will be lymph node negative at surgery. Axillary lymph node dissection, as a surgical procedure, is associated with frequent complications. A possible alternative to nodal dissection in terms of prognosis may be the immunocytochemical detection of tumor cells in bone marrow. PURPOSE: In a prospective study, the value of tumor cell detection (TCD) in bone marrow was compared with axillary lymph node dissection in the prognosis of primary breast cancer after surgery. METHODS: Data from 727 patients with primary, operable breast cancer were included in the analysis. All patients had surgery, including axillary lymph node dissection, from May 1985 through July 1994 at the Women's Hospital of the University of Heidelberg (Federal Republic of Germany). Bone marrow aspiration at two sites on each anterior iliac crest was performed immediately after surgery while the patients were under general anesthesia. Most patients received some type of systemic adjuvant therapy. The monoclonal antibody 2E11, directed against the polymorphic epithelial mucin TAG12, was used to detect tumor cells in bone marrow samples. The association of TCD with recognized prognostic indicators was evaluated by means of chi-squared tests. Survival without the development of distant metastases (i.e., distant disease-free survival) and overall survival were estimated by use of the Kaplan-Meier method; the logrank test was used to compare survival curves. A multivariate Cox regression analysis with stratification according to adjuvant treatment type was used to assess the independent prognostic value of TCD in bone marrow in relation to other variables. Reported P values are two-sided. RESULTS: Tumor cells were detected in the bone marrow of 203 (55%) of 367 lymph node-positive patients and in 112 (31%) of 360 lymph node-negative patients. TCD was associated with larger tumors (P < .001), lymph node involvement (P = .001), and higher tumor grade (i.e., more undifferentiated) (P = .002). After a median follow-up of 36 months, patients with tumor cells in their bone marrow experienced reduced distant disease-free survival and overall survival (both P values < .001). TCD was an independent prognostic indicator for both distant disease-free survival and overall survival that was superior to axillary lymph node status, tumor stage, and tumor grade. Among patients with tumors less than 2 cm in diameter, TCD was the most powerful predictor of outcome. CONCLUSIONS AND IMPLICATIONS: TCD in the bone marrow of patients with breast cancer is a valuable prognostic tool associated with negligible morbidity. Prospective randomized studies should be performed to determine whether TCD might replace axillary lymph node dissection in a defined subgroup of patients with small tumors.     

Prognostic and predictive value of c-erbB-2 overexpression in primary breast cancer, alone and in combination with other prognostic markers

PURPOSE: To investigate the prognostic and predictive value of c-erbB-2 overexpression in breast cancer in relation to other prognostic markers. PATIENTS AND METHODS: Paraffin-embedded tumors from 315 consecutive primary breast cancer patients were screened for c-erbB-2 protein (p185) overexpression by immunohistochemistry using the monoclonal antibody CB11. RESULTS: c-erbB-2 protein overexpression was detected in 19% of tumors and was associated with shorter 5-year overall survival (OAS) rate compared with c-erbB-2-negative cases in the total patient material (58% and 77%, respectively; P = .004) and in the 96 node-positive patients (31% and 61%, respectively; P = .02), but not in node-negative patients. For 47 node-positive patients treated with adjuvant tamoxifen and radiotherapy, the 5-year OAS was 13% for c-erbB-2 overexpression and 75% for c-erbB-2-negative patients (P = .00004). The frequency of c-erbB-2 overexpression decreased with age at diagnosis. The prognostic value of c-erbB-2 on OAS was independent of age, node status, tumor size, histopathologic grade, hormone receptor status, S phase, p53 status, and adjuvant treatment. c-erbB-2 status added prognostic information to p53-negative and low S-phase cases, but not to p53-positive and high S-phase cases. Correspondingly, these only added information to c-erbB-2-negative cases. CONCLUSION: c-erbB-2 protein overexpression may have a predictive value with regard to adjuvant therapy in node-positive patients, for whom adjuvant tamoxifen with radiotherapy appears insufficient in the presence of c-erbB-2 overexpression. Combination of conventional and newer tumor markers may identify patients with a worse prognosis within groups with a generally favorable prognosis.     

Evaluation of a displacement assay with tamoxifen as prognostic indicator in breast-cancer patients with estrogen-receptor-positive tumors

A displacement assay with tamoxifen, based on the relative binding affinity of tamoxifen and estradiol for the estrogen receptor (ER), was proposed in 1990 as prognostic indicator for breast-cancer patients. Validation of its predictive results in relation to the outcome of 73 patients with ER+ tumors is analyzed. ER, progesterone receptor (PgR) determinations and other conventional prognostic factors in relation to the displacement assay, were considered. Displacement assay results allowed ER+ tumors to be grouped as displaceable (D) or weakly displaceable (WD), with the implication that D tumors should respond better to tamoxifen (Tam) administration. Survival and disease-free interval curves showed highly significant differences between patients with ER+ D and ER+ WD tumors. For survival, including all tumor stages, 73.9% of patients were alive at 9 years after surgery in the group with D tumors and 37.0% in the group with WD tumors (p < 0.005); relative contribution of the different stages is analyzed. Addition of axillary-node number increased the prognostic significance of displacement categories for survival and disease-free interval. PgR determination as another ER functional expression failed to show significant differences for survival and disease-free interval between ER+ PgR+ and ER+ PgR- tumors. Thus, results from the displacement assay and from PgR determinations reflect 2 independent ER functional expressions. Displacement assay data appear as reliable prognostic indicators of breast-cancer outcome, and contribute to more appropriate treatment decisions in this pathology.     

Pathologic correlates of prognosis in lymph node-positive breast carcinomas

BACKGROUND: Many pathologic features of breast carcinomas have been proposed as prognostic correlates; their interrelationships and their relative value as prognostic indicators were studied. METHODS: A series of 399 axillary lymph node-positive infiltrating ductal breast carcinomas was studied histologically and compared with the patient prognosis. RESULTS: Many pathologic findings fit into two groups of closely related features--those related to the extent of local spread and those related to histologic anaplasia and mitotic count. Both groups correlated with the primary tumor size. The best predictors of long-term survival were measures of the extent of axillary metastasis (the number of axillary metastases, the size of the largest metastasis, and lymph node capsular invasion), which are components of the pathologic node stage. The mitotic count, tumor grade, primary tumor stage, smooth tumor border, tumor necrosis, and multifocal primary tumors were weaker but significant survival correlates. The mitotic count and Bloom-Richardson grade best predicted the survival time of patients with node-positive disease who died. Four years after diagnosis, less than 25% of the patients who would die of breast carcinoma in the low mitotic count and Bloom-Richardson Grade 1 (well differentiated) groups already had died; more than 75% of those in the high mitotic count and Bloom-Richardson Grade 3 (poorly differentiated) groups already had died. Among patients with small tumors (< 1.8 cm in diameter), those with one micrometastasis (1-2 mm) had a worse prognosis than those with uninvolved lymph nodes of similar size. CONCLUSION: The extent of axillary metastasis best predicted the long-term prognosis of patients with infiltrating ductal carcinoma and axillary metastases. The mitotic count and tumor grade best predicted the survival time of those who died.     

Distribution of laminin, type IV collagen and fibronectin in the invasive component of breast carcinoma

Laminin, type IV collagen and fibronectin were examined immunohistochemically in the invasive component of breast carcinomas. Laminin was expressed around the invasive carcinoma cell nests in 38 (54%) of 71 cases. Immunoreactivity for type IV collagen was observed around the invasive carcinoma cell nests or the stroma apart from carcinoma cells in 44 (80%) of 55 cases. Fibronectin was strongly expressed in the stroma only in 75 (99%) of 76 cases. The expression of laminin significantly correlated with tubular formation in the invasive carcinoma cell nests and showed a tendency to be correlative to estrogen receptor (ER) and progesterone receptor (PgR) of carcinoma tissue, but no correlation among laminin expression, histological type, the age of patients, tumor size and lymph node metastasis was noted. Type IV collagen and fibronectin did not correlate to any clinicopathological factors such as histological type, grade of differentiation, the age of patients, tumor size, lymph node metastasis, ER and PgR status. No concordant expression of these extracellular matrices was seen.     

Long-term prognostic value of PCNA labeling index in primary operable breast cancer

Cell proliferation was evaluated in 167 tissue specimens obtained from primary breast cancer patients who had undergone radical surgery between 1984 and 1988. Formalin-fixed and paraffin-embedded tissue specimens were used in the immunohistochemical study. The immunohistochemical method was carried out using the avidin-biotin immunoperoxidase technique, and anti-proliferating cell nuclear antigen (PCNA) monoclonal antibody was used for primary antibody. Based upon the PCNA labeling index (LI), the patients were divided into two groups: low PCNA, <25% and high PCNA, >/= 25%. The PCNA LI ranged from 1% to 76% (mean, 23.9%). Patients aged 50 years. There was no relationship between the PCNA LI and tumor size, lymph node involvement and hormone receptors. The survival curves of 146 invasive breast cancer patients showed that the high PCNA group had poor overall survival compared with the low PCNA group. A significant difference in the overall survival between the high and low PCNA groups was observed in lymph node-positive patients, however, no significant difference was found between the two groups in lymph node-negative patients. PCNA LI was identified as an independent predictor in primary breast cancer patients.     

Markers of tumor angiogenesis and proteolysis independently define high- and low-risk subsets of node-negative breast cancer patients

PURPOSE: To compare the prognostic impact of tumor angiogenesis factors (vascular endothelial growth factor [VEGF], angiogenin, and basic fibroblast growth factor [bFGF]), tumor proteolysis factors (urokinase-type plasminogen activator [uPA] and plasminogen activator inhibitor-1 [PAI-1]), and conventional tumor markers (stage, grade, and steroid receptors) in early breast cancer. PATIENTS AND METHODS: In the primary clinical study, tumor angiogenesis and other factors were detected in frozen biopsies from 305 primary breast tumors. VEGF expression was assessed by chemiluminescence immunosorbent assay (ICMA); angiogenin, bFGF, uPA, and PAI-1 by enzyme-linked immunosorbent assay (ELISA); and steroid receptors (estrogen receptor [ER] and progesterone receptor [PgR]) by enzyme immunoassay (EIA). In the validating clinical study, another set of 190 node-negative primary breast tumor samples were collected at a separate institution. RESULTS: Univariate analysis of the primary study showed that VEGF levels were positively correlated with recurrence (P < .001). Angiogenin levels were positively correlated with disease relapse (P < .005) for the overall collective group, but not within the node-negative subset. No significant correlations were found between tumor bFGF levels and patient survival. In multivariate regression analysis, the only independent predictors of relapse-free survival (RFS) were VEGF, uPA, and lymph node status. In the validation set, the distribution of VEGF and uPA values were similar to those in the primary study; low expression of both VEGF and uPA identified patients with a < or = 20% likelihood of recurrence within 7 years. CONCLUSION: Separate primary and validating clinical studies concur that tumor VEGF level is the most important prognostic parameter among several markers of tumor angiogenesis and proteolysis.     

Prognostic significance of Ki-67 and p53 antigen expression in carcinomas of bile duct and gallbladder

Ki-67 and p53 protein expression was evaluated immunohistochemically in 32 patients with intrahepatic, extrahepatic bile duct and gallbladder carcinomas, who underwent surgery at First Department of Surgery, The University of Tokushima School of Medicine. p53 expression was found more in the well differentiated group than poorly differentiated group (p = 0.007). MIB1 labelling index (MIB1 LI) was higher in EHC than in GBC (p = 0.0061). MIB1 LI (T), (MIB1 LI in tumor) was higher in cases with lymph node metastasis than in those without lymph node metastasis (p = 0.0189). Moreover, MIB1 LI (L) (MIB1 LI in metastasized lymph node) was higher in poorly differentiated than in well differentiated carcinoma (p = 0.0404). Prognostically, patients with high MIB1 LI (T) (> 56.93) had a worse prognosis after surgery than those with low MIB1 LI (T) (p < 0.05). There was no association between p53 positive tumors and MIB1 expression. These results suggest that cancer cell proliferative activity was markedly increased in cases with EHC compared to those with GBC and the poorly differentiated and lymph node metastasis group. MIB1 LI in tumor was found to be a good prognostic indicator whereas there was no association of p53 positive tumor with MIB1 expression and prognosis of the patients.     

The benefits of mammography are not limited to women of ages older than 50 years

BACKGROUND: Although the benefits of mammography are established in women age < or = 50 years, its use in women age < 50 years is controversial. It is the purpose of this study to determine whether the better outcome in mammographically detected breast carcinoma compared with clinically detected breast carcinoma observed in women age > or = 50 years also is observed in women age < 50 years. METHODS: The authors analyzed 869 cases of Stage I and II breast carcinoma in women treated with breast-conserving therapy between 1984-1994. The median follow-up was 43 months (range, 3-128 months). Three hundred and eighteen patients (37%) presented with mammographic abnormalities without clinical signs of disease and 551 patients (63%) presented with clinical signs of disease. The median age of the patients was 56 years (range, 22-88 years). Three hundred and four patients (35%) were age < 50 years. RESULTS: Mammographically detected tumors in women age < 50 years were of similar size to those in women age > or = 50 years (median 1.1 cm vs. 1.0 cm). Axillary lymph node involvement and tumor grade were not significantly different between these two groups. However, in women age < 50 years the clinically detected tumors were found to be significantly larger, more likely to be axillary lymph node positive, and of higher grade compared with tumors in older women. Consequently, in patients with mammographically detected tumors, there was no significant difference in recurrence free survival (RFS) between women age < 50 years compared with women age > or = 50 years (90% and 92%, respectively; P=0.4), whereas in patients with clinically detected tumors there was a significant difference in 5-year RFS (77% vs. 87%, respectively; P=0.02). CONCLUSIONS: Mammography results in the diagnosis of smaller and lower grade breast carcinoma. If mammographically detected, there appears to be no difference in RFS between women age < 50 years and those women age > or = 50 but there is a difference if the tumors are clinically detected. If left to grow to the size necessary for clinical detectability, the disease appears to be more aggressive in younger women.