Value of epidermal growth factor receptor status compared with growth fraction and other factors for prognosis in early breast cancer.

The epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein whose expression is important in the regulation of breast cancer cell growth. The relationship between EGFR status (determined by an immunocytochemical assay) and various prognostic factors was investigated in 164 primary breast cancers. Overall 56% of tumours were EGFR-positive and the expression of EGFR was unrelated to axillary node status, tumour size and histological grade; and it was poorly associated with the tumour proliferative activity measured by Ki-67 immuno-cytochemistry. The relapse-free survival (RFS) probability at 3-years was significantly worse for patients with EGFR positive tumours (P = 0.003) and for those whose Ki-67 score was > 7.5% (P = 0.0027), as well as in patients with axillary node involvement (P = 0.01) and with poorly differentiated tumours (P = 0.04). Immunocytochemical determination of EGFR and cell kinetics gave superimposable prognostic information for predicting RFS with odds ratios of 3.51, when evaluated singly. In our series of patients EGFR, Ki-67 and node status retain their prognostic value concerning RFS in multivariate analysis. The 3-year probability of overall survival (OS) was significantly better in node-negative patients (P = 0.04) and was similar in EGFR-positive and negative patients. In conclusion, EGFR status appears to be a significant and independent indicator of recurrence in human breast cancer and the concomitant measurement of the tumour proliferative activity seems to improve the selection of patients with different risks of recurrence.     

c-erbB-3 protein expression in ovarian tumours.

In this study the expression of c-erbB-3 protein was investigated in a range of human ovarian tumours using a monoclonal antibody (RTJ1) raised to a synthetic peptide from the cytoplasmic domain of the human c-erbB-3 protein. A total of 73 samples from 71 patients were graded as negative, weak, moderate or strong according to the intensity of immunohistochemical staining observed, and this was related to tumour characteristics and other clinical parameters. In terms of positivity vs negativity, of the 73 samples examined, 62 (85%) showed positive immunohistochemical staining for c-erbB-3. The majority of all ovarian tumours studied were positive for c-erbB-3 regardless of whether they were malignant (89%), borderline (100%) or benign (61%), however the incidence of positivity was significantly less in the benign group than in overtly malignant tumours (P = 0.03). c-erbB-3 positivity was not significantly associated with either age at diagnosis, tumour stage, differentiation, ploidy, percentage in S-phase or post-operative tumour bulk in malignant tumours. In terms of intensity of staining no significant difference was observed either within the common epithelial group or between this group and tumours of a benign nature. A significantly more intense pattern of c-erbB-3 staining was observed in tumours of borderline malignancy when compared with their overtly malignant counterparts (P = 0.002). Patients presenting with early-stage malignant tumours (I/II) were more likely to display intense tumour staining than those with late-stage disease (III/IV) (P = 0.04). These investigations suggest that c-erbB-3 protein is frequently expressed in both benign and malignant ovarian tumours, and that overexpression is more common in borderline and early invasive lesions.     

C-erbB-3 in human breast carcinoma: expression and relation to prognosis and established prognostic indicators.

A series of 346 patients with primary operable breast cancer and a series of 145 patients with advanced breast cancer were investigated for c-erbB-3 protein expression using the monoclonal antibody RTJ1. Formalin-fixed, paraffin-embedded tumour samples were stained using a standard immunochemical method and staining was assessed on a four-point scale. The study aimed to observe the expression of the c-erbB-3 protein and investigate any relationship between expression and established prognostic indicators and prognosis. In both the primary and advanced series breast tumour tissue was found to stain heterogeneously for c-erbB-3. The staining was observed to be predominantly cytoplasmic and the majority of tumours exhibited moderate positivity. However, 15% and 35% of cases in the primary operable and advanced series respectively displayed strong positive staining. No significant difference was found between the staining in the primary and advanced series. In the primary operable breast cancers, no significant associations were demonstrated with overall survival, disease-free interval, regional recurrence, the presence of distant metastases, age, menopausal status, oestrogen receptor status, histological grade, lymph node stage, vascular invasion and c-erbB-2 protein expression. However, a significant association was seen between the degree of c-erbB-3 immunoreactivity and both tumour size (P < 0.01) and tumour type prognostic group (P = 0.05). No overall association with local recurrence was seen when the four groups of c-erbB-3 expression were analysed (P = 0.12), but when those tumours showing no or weak staining were compared with those showing moderate and strong immunoreactivity it was seen that the latter were significantly more likely to develop local recurrence (P = 0.03). In the series of patients with advanced disease, no significant associations were demonstrated with survival, UICC criteria, age, menopausal status, oestrogen receptor status, histological grade, c-erbB-2 status or the presence of vascular invasion. In conclusion this study found variable expression of c-erbB-3 protein in human breast carcinoma and an association with some recognised prognostic factors in those patients with primary operable breast carcinoma. It seems, however, unlikely that c-erbB-3 protein expression will emerge as a powerful enough prognostic factor to be of value in clinical practice.     

DNA index, S-phase fraction, histological grade and prognosis in breast cancer

DNA index and S-phase fraction (SPF) were measured by flow cytometry on paraffin embedded tissue from 140 primary breast tumours. The results of DNA analysis were compared with the size, degree of axillary node involvement, histological grade and steroid receptor content of the tumours, as well as with the patients' subsequent clinical course. Forty-four (31.4%) of the 140 tumours were diploid. S-phase fraction was evaluable for 134 (95.7%). The median SPF of the whole population was 7.1%, with diploid tumours having a significantly lower median SPF (3.2%) than aneuploid (10.1%, P less than 0.001). Both aneuploidy (P = 0.002) and high SPF (P less than 0.001) were strongly associated with high histological grade. There was no significant association between either DNA ploidy or SPF and tumour size, nodal status or steroid receptor content. An SPF below the median was strongly associated with better relapse-free survival (P = 0.008), overall survival (P = 0.004) and survival after relapse (P less than 0.001). Ploidy did not correlate significantly with clinical course. Multivariate analysis using the Cox model suggested that, while SPF gave prognostic information independent of tumour size or nodal status, this independent significance was lost when histological grade was included in the analysis.     

Is apocrine differentiation in breast carcinoma of prognostic significance?

Apocrine differentiation in human breast cancers has been assessed using immunohistochemistry to detect zinc alpha 2 glycoprotein and the findings related to standard prognostic factors, disease free interval (DFI) and survival in 145 women with early breast cancer. Breast tumour samples from women with a minimum follow-up of 5 years were assessed. Routinely fixed and processed tissue was used throughout. Sixty-six (45%) tumours did not stain with the antibody. Fifty-two (36%) exhibited positive apocrine staining while for 27 (19%) only a few cells were reactive. The presence of apocrine differentiation was unrelated to lymph node status, menstrual status, tumour grade or size, oestrogen receptor (E2R) or progesterone receptor status. However, patients whose tumours exhibited apocrine staining had a shorter disease-free interval (DFI) (P = 0.03) and survival (P = 0.03). A Cox's multiple regression analysis of the data found that the presence of staining added significantly (P = 0.047) to the predictive value of node status (P = 0.0001), menstrual status (P = 0.0001), tumour size (P = 0.0026) and E2R status (P = 0.0014) for patient survival. The other seven prognostic factors tested did not reach significance and were rejected from the model. Apocrine differentiation in breast cancer appears to be an independent predictor of poor prognosis tumours.     

An evaluation of immunoreactivity for c-erbB-2 protein as a marker of poor short-term prognosis in breast cancer

Eighty-five breast carcinomas from the same number of patients have been assessed immunohistochemically using the antiserum 21N for the presence of the c-erbB-2 protein. Twenty-two of the patients had evidence of advanced disease (tumour fixation or distant metastases) at presentation. Follow-up was for a median of 24 months. c-erbB-2 protein was detected in the majority of cells in 14 (16.5%) carcinomas, and to a lesser extent in a further six (7%) tumours. There was no relationship between staining and stage, node status or size but more poorly differentiated carcinomas had evidence of staining (36%) than well (17%) or moderately (14%) differentiated carcinomas (P = 0.02). There was a significant association between staining and mortality (P = 0.009) and recurrence (P = 0.0002). The relative risk of death for staining compared to no staining (after adjusting for node status, stage and grade) was 2.97 (95% confidence interval 1.29, 6.84) and the relative risk of recurrence for staining compared to no staining after similar adjustment was 3.85 (95% confidence interval 1.86-7.97). In this particular group of patients immunoreactivity for c-erbB-2 protein is an independent indicator of poor short-term prognosis.     

The effect of oestrogen and progesterone receptors on recurrence and survival in patients with carcinoma of the breast

Recurrence and survival rates were studied in 175 women with breast cancer who, until the development of recurrent disease, received no treatment other than a modified radical (Patey) mastectomy, and in whom the oestrogen (REc) and progesterone (RPc) receptor content of the primary tumour was measured. At the time of first relapse most patients received endocrine therapy. At a minimum follow-up of 58 months post menopausal patients who possessed REc had an increased relapse-free survival (RFS) (P = 0.02). When examined by node status patients with 1-3 axillary nodes containing tumour also had an improvement in RFS (P = 0.02). There was no benefit for node-negative or premenopausal patients. In 163 patients in whom RPc was measured, RFS was unaffected by the possession of this receptor regardless of the degree of node involvement or menopausal status. Patients with REc had a significantly longer survival following mastectomy than patients without it (P = 0.006). This was most marked in post-menopausal (P = 0.003) and node-positive (P = 0.03) patients. Survival following mastectomy was also increased in patients possessing RPc (P = 0.04) and again was most marked for post-menopausal patients (P = 0.01), although no difference could be identified within node subgroups. There were significant differences in the post-relapse survival of REc and RPc positive and negative patients (REc P = 0.03, RPc P = 0.001). Patients with both receptors survived approximately 37 months longer than their receptor-negative counterparts. This study failed to confirm that the measurement of REc and RPc can reliably predict early relapse in breast cancer. The greater overall survival of receptor-positive patients is mainly due to an increase in survival following relapse. This may reflect the response of receptor-positive tumours to endocrine therapy given for recurrent disease.     

Dual colour flow cytometry of p53 and c-erbB-2 expression related to DNA aneuploidy in primary and metastatic breast cancer.

DNA aneuploidy and p53 or c-erbB-2 expression were simultaneously measured in 29 breast tumours by two-colour flow cytometry. (i) The majority of tumours had some cells expressing either p53 (5-68%) or c-erbB-2 (1-56%). (ii) Expression of p53 and c-erbB-2 was observed mainly in the aneuploid population of mixed aneuploid and diploid tumours but there was no significant correlation with a specific DNA index. Aneuploid tumours contained higher percentages of c-erbB-2 positive cells (average 25%) than purely diploid tumours (average 15%) but this just failed to reach significance (P = 0.074). No relevant trends were noted for p53 expression. (iii) Significantly increased c-erbB-2 expression was observed in stage 2 tumours (26%) compared to stage 1 tumours (12%) (P = 0.001) with no trend evident for p53 expression. (iv) The metastatic tumour in the axillary node contained similar or slightly higher percentages of positive cells than the matched primary tumour.     

The association of cytosol oestrogen and progesterone receptors with histological features of breast cancer and early recurrence of disease.

Two hundred and eighty-eight primary breast tumours were examined for the presence or absence of oestrogen (REc) and progesterone (RPc) receptors. Analysis has shown a relative interdependence between the steroid receptor status of primary breast cancer and other prognostic variables such as histological grade, lymphocytic infiltration and tumour elastosis. There were significant associations between epithelial cellularity, stromal fibrosis and the value of REc in those tumours in which the receptor was present. Cellularity and fibrosis were unrelated to the presence or absence of oestrogen receptor. By contrast, neither the presence or absence nor the value of RPc could be related to cellularity or fibrosis. The value of REc and RPc analysis as an indicator of prognosis was examined in a sub-group of 175 patients receiving no additional treatment following mastectomy. Overall relapse-free survival (RFS) was no different for those patients with receptors compared to those without them (REc P = 0.11, RPc P = 0.7). There was no difference in RFS of receptor positive and negative tumours when the axillary node status was taken into account.     

乳腺癌绝经前后c-erbB-2、ER、PR的表达及与预后的相关性

 目的 探讨乳腺癌绝经前后c-erbB-2、ER、PR受体的表达差异及其与预后的相关性。 方法 回顾性分析432例乳腺癌的病理学资料,其中195例患者随访5年,c-erbB-2、ER、PR的表达采用免疫组化法检测。 结果 （1）绝经前组,c-erbB-2阳性患者的ER阳性率显著低于c-erbB-2阴性患者（P=0.003）;绝经后组,c-erbB-2阳性患者的ER、PR阳性率均显著低于c-erbB-2阴性患者（P＜0.001,P=0.005）。（2）多因素分析显示,绝经前组的独立预后因素为淋巴结转移、c-erbB-2,绝经后组的独立预后因素为淋巴结转移、c-erbB-2和ER。 结论 绝经前与绝经后乳腺癌c-erbB-2、ER、PR受体表达的临床意义有所不同。     

c-erbB-2 oncoprotein overexpression identifies a subgroup of estrogen receptor positive (ER+) breast cancer patients with poor prognosis

Purpose:To investigate the predictive value of c-erbB-2 oncoprotein expression as compared with established histopathological and cytometric indicators of disease evolution in breast carcinoma. Patients and methods:A short-term retrospective study was conducted on a series of 306 breast cancer patients. Classic prognostic factors included tumour size, nodal involvement, histological grading, and hormone receptor status. Flow cytometric DNA ploidy and S-phase fraction (SPF) were also assessed. A Cox proportional hazards regression model was used for multivariate statistical analysis. Results:c-erbB-2 overexpression was present in 43 out of 295 (14.6%) tumours, and showed a statistically significant correlation with high histological grade, DNA aneuploidy, high SPF and lack of estrogen receptors (ER). Univariate analysis revealed its association with worse disease-free survival (DFS) and overall survival (OS). The combined evaluation of c-erbB-2 with ploidy and SPF defines a variable (P + S + c) that showed a significant correlation with disease outcome. By multivariate analysis, only nodal status (P < 0.001) and P + S + c subgrouping (group 2: P = 0.002; group 3: P = 0.001) in relation to DFS, and nodal status (P = 0.001) and DNA ploidy (P = 0.006) in relation to OS, retained independent prognostic significance. Subset analyses showed that cytometric parameters, P + S + c subgrouping and hormone receptors were significantly correlated with disease outcome in node-positive patients, whereas in node-negative subgroup no prognostic indicators were found. c-erbB-2 overexpression exhibited a trend in node-positive breast cancer (DFS: P = 0.068; OS: P = 0.086), and significant correlation with poor clinical evolution in ER positive patients (DFS: P = 0.015; OS: P = 0.004), mostly receiving tamoxifen. Conclusions:c-erbB-2 is an independent prognostic indicator of DFS when evaluated in conjunction with ploidy and SPF. It also seems to predict response to tamoxifen therapy, by identifying a subgroup of ER positive (ER+) breast cancer patients with poor prognosis.     

Relationship between c-erbB-2 protein product expression and response to endocrine therapy in advanced breast cancer.

Of 221 patients with breast cancer of known epidermal growth factor receptor (EGFR) and oestrogen receptor (ER) status, 99 had developed recurrences during the period of follow-up (range 3-60 months, median 24 months). Of these, 72 received endocrine therapy as first-line treatment for relapse. Immunohistochemical assessment of c-erbB-2 protein product expression was made using paraffin-embedded tumour tissue from 65 of these 72 patients. Including patients whose disease remained stable for more than 6 months with those showing an objective response (CR or PR for more than 3 months), only one (7%) of 14 c-erbB-2 positive tumours responded to endocrine manipulation compared with 19 (37%) of 51 c-erbB-2 negative tumours (P less than 0.05). Coexpression of c-erbB-2 reduced the response rate of ER positive patients from 48% to 20% and of ER negative cases from 27% to 0% (P less than 0.01). EGFR and c-erbB-2 protein appeared to have additive effects in reducing the likelihood of response, and none of eight patients with EGFR positive, c-erbB-2 positive tumours derived benefit from endocrine therapy. The results of this study suggest that c-erbB-2 protein overexpression, a marker of poor prognosis in breast cancer, is associated with a lack of response to endocrine therapy on relapse, and particularly in combination with EGFR may be useful in directing therapeutic choices.     

bcl-2 in normal human breast and carcinoma, association with oestrogen receptor-positive, epidermal growth factor receptor-negative tumours and in situ cancer.

The role of bcl-2 expression in solid tumours is as yet undefined. It was, therefore, the purpose of this study to investigate expression of bcl-2 protein in 111 human breast carcinomas using immunohistochemistry and the monoclonal antibody bcl-2 124. Expression was then compared with the established indicators of prognosis and biological behaviour in malignant breast disease. No relationship could be observed between bcl-2 and node status, tumour size, differentiation, type or age at excision. However, a strong positive relationship was seen between bcl-2 and oestrogen receptor (ER), with 70 of 88 (80%) bcl-2-positive tumours being ER positive also, compared with seven of 23 (30%) bcl-2-negative tumours being ER positive (P < 0.0001). The converse was found when bcl-2 was compared with epidermal growth factor receptor (EGFR). A strong negative relationship was observed, with 26 of 88 (30%) bcl-2-positive tumours being EGFR positive, compared with 16 of 23 (70%) bcl-2-negative tumours being EGFR positive (P = 0.001), raising the possibility that bcl-2 is an ER-regulated gene. An inverse relationship was also found between bcl-2 and the oncogenes c-erbB-2 and p53. Thus, loss of bcl-2 expression in breast cancer is associated with a range of molecular markers of poor prognosis and may define part of an ER-negative, EGFR-positive phenotype.     

c-erbB-2 is not a major factor in the development of colorectal cancer

We have investigated c-erbB-2 protein expression in a large cohort of well-characterized colorectal tumours, and in a subset of lymph node metastases. We have also evaluated a Val(655)Ile single nucleotide polymorphism, which is associated with an increased risk of breast cancer, in a subset of the colorectal cancer patients and in healthy control subjects. Immunohistochemical studies revealed that while 81.8% of tumours expressed c-erbB-2, in the majority of cases equivalent levels of c-erb-B2 were seen in adjacent normal mucosa. Colon tumours were significantly more likely to express c-erbB-2 than rectal tumours (P=0.015). Only 52.4% of the metastases displayed staining patterns concordant with their primary tumour, indicating that determination of c-erbB-2 protein in colorectal tumours cannot predict the status of lymph node metastases. PCR--RFLP analysis of the Val(655)Ile single nucleotide polymorphism demonstrated that allele frequencies were identical between colorectal cancer patients and a control group of Caucasian subjects (Ile=0.80 and Val=0.20 in each case), indicating that it is not related to the risk of developing colorectal cancer in this population. Furthermore, there was no relationship between c-erbB-2 protein expression and gene polymorphism (P=0.58). In terms of prognosis, no association was seen between either c-erbB-2 protein expression or the presence of the Val allele and patient survival (P>0.05 in each case), suggesting that c-erbB-2 is not a prognostic marker in colorectal cancer.     

C-erbB-2 Onco-Protein Expression in Breast Cancer: Relationship to Tumour Characterisitcs and Short-Term Survival in Universiti Kebansaan Malaysia Medical Centre

Breast cancer is the commonest cancer affecting females in Malaysia, contributing 31% of all newly diagnosedcases amongst Malaysian women. The present retrospective cohort study evaluated the relationship between cerbB-2 onco-protein overexpression with various tumour characteristics and survival rate of breast cancerpatients treated at the Universiti Kebangsaan Malaysia Medical Centre (UKMMC) between 1996-2000. CerbB-2 oncoprotein overexpression was determined by immunohistochemistry (IHC) and tumors showing 2+positivity were verified by Fluorescence In Situ Hybridization (FISH). One hundred and seventy two patientswere eligible for the study with a short-term follow-up (median) of 5.1 years. C-erbB-2 oncoprotein overexpressioncorrelated with lymph node positivity, oestrogen receptor (ER) and progesterone receptor (PR) negativity.Univariate analyses showed shorter disease free survival (DFS) and overall survival (OS) in patients with cerbB-2 oncoprotein overexpression, Malay ethnicity, higher tumour grade, lymph node positivity, ER and PRnegativity. In a subgroup of patients with c-erbB-2 oncoprotein overexpression, a shorter OS was observed inthose with lymph node positivity, ER and PR negativity. In multivariate prognostic analysis, lymph node status,ER status and tumour grading were the strongest independent prognostic factors for both OS and DFS. However,c-erbB-2 status was not a significantly independent prognostic factor, even in subsets with lymph node positiveor negative group. C-erbB-2 oncoprotein overexpression correlated well with lymph node status, ER and PR.Shorter OS and DFS were significantly observed in patients with c-erbB-2 oncoprotein overexpression. Lymphnode status, ER status and tumour grading were the only three independent prognostic factors for OS and DFSin this study. Although c-erbB-2 expression is obviously important from a biological standpoint, multivariateanalysis showed that it is not an independent prognostic indicator in breast carcinoma in the local population.     

Prognostic significance of Helix pomatia lectin and c-erbB-2 oncoprotein in human breast cancer.

We investigated the prognostic significance of Helix pomatia lectin (HPA) staining on disease-free and overall survival in 120 primary breast carcinomas. HPA staining was present in 58 (48%) of these carcinomas. It was significantly associated with axillary lymph node metastases (P < 0.001) and c-erbB-2 expression (P < 0.01). A univariate study revealed that disease-free and overall survival were significantly correlated with clinical stage, tumour size, axillary lymph node metastases. HPA staining and c-erbB-2 expression. In a multivariate study, all previous prognostic indicators except HPA staining and c-erbB-2 expression were independent factors. However, stratifying the patients on the basis of HPA and c-erbB-2 status suggested that HPA +/c-erbB-2+ status was predictive of a higher incidence of axillary lymph node metastases (P = 0.000001) and a poorer overall (P < 0.0002) and a shorter disease-free (P < 0.000006) survival when compared with the other subgroups, although this combination did not provide any additional prognostic information for overall (P = 0.3544) or disease-free (P = 0.7152) survival by a multivariate analysis. For patients in whom axillary lymph node dissection has not been performed, therefore, HPA and c-erbB-2 status seems to be a powerful tool to discriminate subpopulations with a high recurrence risk and shorter survival who should undergo more aggressive therapy.     

The prognostic significance of DNA flow cytometry in breast cancer: results from 881 patients treated in a single centre.

In this single-centre study of 881 patients, S-phase fraction (SPF) was shown to be a significant prognostic marker in terms of overall survival (OS), relapse-free survival (RFS) and survival after relapse (SAR). Further, SPF had independent prognostic significance when considering a range of other clinicopathological variables, namely tumour grade and stage, nodal status, patient age, tumour size, menstrual status and treatment details. For OS and RFS, SPF was the second strongest predictor of the clinical course of the disease after nodal status, and for SAR it was the strongest prognostic marker. SPF correlated positively with histological grade but was the stronger predictor of survival. The distribution of SPF values was markedly different for the two ploidy classes of tumour, with DNA aneuploid tumours having a significantly higher average SPF. However, SPF retained its independent prognostic ability when DNA diploid and aneuploid tumours were analysed separately, DNA ploidy itself also proved to be an independent prognostic marker but the survival difference between the two ploidy classes was much less than that seen for different levels of SPF. Tumours with several DNA aneuploid populations (multiploid tumours) tended to have a worse prognosis than other aneuploid tumours but this trend did not reach statistical significance. In this and other studies from this centre, SPF has proved to be a robust predictor of clinical outcome in carcinoma of the breast.     

Clinicopathologic study associated with long-term survival in Japanese patients with node-negative breast cancer

This study was undertaken to determine the absolute and relative value of blood vessel invasion (BVI) using both factor VIII-related antigen and elastica van Gieson staining, proliferating cell nuclear antigen (PCNA), p53, c-erbB-2, and conventional prognostic factors in predicting relapse-free survival (RFS) and overall survival (OS) rates associated with long-term survival in Japanese patients with node-negative breast cancer. Two hundred patients with histological node-negative breast cancer were studied. We investigated nine clinicopathological factors, including PCNA, p53, c-erbB-2 using permanent-section immunohistochemistry, clinical tumour size (T), histological grade (HG), mitotic index (MI), tumour necrosis (TN), lymphatic vessel invasion (LVI) and BVI, followed for a median of 10 years (range 1-20). Twenty-one patients (10.5%) had recurrence and 15 patients (7.5%) died of breast cancer. Univariate analysis showed that BVI, PCNA, T, HG, MI, p53, c-erbB-2 and LVI were significantly predictive of 20-year RFS or OS. Multivariate analysis showed that BVI (P = 0.0159, P = 0.0368), proliferating cell nuclear antigen (PCNA) (P = 0.0165, P = 0.0001), and T (P = 0.0190, P = 0.0399) were significantly independent prognostic factors for RFS or OS respectively. BVI, PCNA and T were independent prognostic indicators for RFS or OS in Japanese patients with node-negative breast cancer and are useful in selecting high-risk patients who may be eligible to receive strong adjuvant therapies.     

Prognostic significance of c-erbB-2 and estrogen receptor status in human breast cancer.

Using the 21N polyclonal antibody, we immunohistochemically stained 314 primary breast carcinomas to identify those tumors overexpressing the c-erbB-2 oncoprotein and to ascertain the prognostic significance of this expression on disease-free and overall survival. Positive membrane staining was present in 52 (17%) of these carcinomas of which 7 (13%) were ductal carcinomas in situ. There was no significant relationship between c-erbB-2 positivity and (a) age at diagnosis, (b) menopausal status, (c) tumor size, (d) lymph node status, (e) estrogen receptor status, or (f) whether or not the patient had disseminated disease outside the axillary fields. However, c-erbB-2-positive tumors were significantly associated with poorer grade (P = 0.02). Patients who were positive for this oncoprotein had a shorter disease-free survival (P = 0.002) and reduced overall survival (P = 0.0001). Overexpression of this oncoprotein was predictive of a worse prognosis in lymph node-positive disease (P = 0.003) and in patients presenting with grade II tumors (P = 0.001). Stratifying the patients on the basis of estrogen receptor status suggested that c-erbB-2+/estrogen receptor-negative status was predictive of a poorer prognosis when compared with the other subgroups (P less than 0.001). Primary and recurrent tumor tissues were available from 42 of the 314 patients. Identical patterns of c-erbB-2 expression occurred in 95% of cases, arguing against a direct role for c-erbB-2 expression in the process of tumor dissemination. The high incidence of staining in ductal carcinomas in situ suggests that expression of this oncoprotein is an early event in tumorigenesis. Finally, multivariate analysis indicated that the c-erbB-2 oncoprotein was an independent prognostic indicator for overall survival in breast carcinoma patients.     

Prognosis of breast cancer: Evidence for interaction between c-erbB-2 overexpression and number of involved axillary lymph nodes

The prognostic significance of c-erbB-2 oncogene amplification or overexpression in relation to axillary lymph node metastasis is controversial. We investigated this question in 159 cases of operable breast cancer: 56 patients with node negative disease and 103 patients with pathological involvement of axillary lymph nodes. c-erbB-2 overexpression was assessed by immunohistochemistry using a polyclonal antibody raised against a synthetic peptide fragment of the oncoprotein. The overall incidence of c-erbB-2 overexpression was 35%. c-erbB-2 overexpression was significantly related to survival when all patients were considered (P = 0.0124), and also for patients with positive axillary lymph nodes (P = 0.0026). c-erbB-2 overexpression had no influence on survival of node negative patients (P = 0.7972). A multivariate survival analysis using the Cox proportional hazard model revealed that number of involved lymph nodes, c-erbB-2 overexpression, ER status, and tumour size were independently related to prognosis (P = 0.0000, 0.0012, 0.0112, and 0.0204, respectively). When an interaction term was introduced in the Cox model between c-erbB-2 overexpression and number of involved axillary lymph nodes, a statistically highly significant interaction between these two factors was observed (P = 0.0002), suggesting that the expression of prognostic power of c-erbB-2 overactivity is related to the number of involved axillary lymph nodes. The 159 patients were then subdivided into three groups: node negative (-ve) (56); 1–6 node positive ( + ve) (55); and ≥7 node +ve (48). This cutoff criterion gave the most numerically equitable distribution of the 159 patients into three groups. The relative risk of death increased stepwise from 0.86 (95% CI 0.26–2.78) for node negative patients, to 1.95 (95% CJ 0.82–63) for 1–6 node positive patients, to 2.23 (95% Cl 1.15–4.35) for >7 node positive patients. Our results suggest that the prognostic influence of c-erbB-2 overexpression increases arithmatically with increasing number of involved axillary lymph nodes. © 1995 Wiley-Liss, Inc.