HER-2/neu overexpression and in vitro chemosensitivity to CMF and FEC in primary breast cancer

Available clinical and experimental data on the effect of HER-2/neu overexpression on chemosensitivity are controversial. It was the purpose of this in vitro study to define the association between HER-2/neu overexpression and the sensitivity to the chemotherapeutic drug combinations of cyclophosphamide, methotrexate and 5-fluorouracil (CMF) and 5-fluorouracil, epirubicin and cyclophosphamide (FEC) of breast cancer cells derived from 140 chemotherapy-naïve patients at the time of primary surgery. Both drug combinations were tested at six different concentrations ranging from 6.25–200% peak plasma concentration (PPC). Immunohistochemical detection of HER-2/neu overexpression was performed with the HER-2/neu antibodies, CB11, TAB250 and AO485, in the same tumor specimens. Immunoreactions were determined as negative (0/1+), weakly positive (2+) and strongly positive (3+). However, the antibodies varied in their degrees of sensitivity. Breast cancer samples with strong (3+) HER-2/neu overexpression demonstrated 90% growth inhibition (IC₉₀) at significantly lower PPC values, using the CB11 (p=0.048), TAB250 (p=0.007) and AO485 (p0.01) antibodies, and showed 50% growth inhibition (IC₅₀) at significantly lower PPC values, using the CB11 antibody (p=0.01) compared to their counterparts with lower levels of HER-2/neu expression. When analyzing the group of patients with intermediate and strong HER-2/neu overexpression (2+ and 3+), an association between HER-2/neu overexpression and increased chemosensitivity was seen with the TAB250 (p=0.044) and AO485 (p=0.032) antibodies, but not with the CB11 antibody (p=0.8) at the IC₉₀ level. Differences in chemosensitivity between samples with strong HER-2/neu overexpression and those with lower levels were then analyzed separately for CMF and FEC. Both regimens achieved 90% tumor growth inhibition at lower PPC values in samples with strong HER-2/neu overexpression (3+) compared to their counterparts with lower expression levels (AO485 p=0.011 for CMF, and p=0.09 for FEC). Cumulative concentration-response plots of tumors responding in vitro with 90% tumor cell inhibition showed a stronger dose dependence for both CMF and FEC among tumor samples with strong HER-2/neu overexpression compared to those with lower levels of expression. In conclusion, the data show that HER-2/neu overexpression was not associated with in vitro drug resistance to CMF or FEC. In contrast, tumors with strong HER-2/neu overexpression demonstrated increased dose-dependent in vitro sensitivity to both the FEC and CMF regimens.     

High prevalence of HER-2/neu and p53 overexpression in inflammatory breast cancer

BACKGROUND: Inflammatory breast cancer (IBC) is one of the most aggressive forms of breast cancer. Although the survival of patients with IBC has been greatly improved by the use of combined treatment modalities, women with IBC still have lower survival rates. We have summarized a single-center experience involving IBC patients. Our objectives are to clarify molecular alterations of HER-2/neu and p53 in IBC and to investigate the prognostic factors. METHODS: Between January 1990 and December 2000, 57 patients with IBC were referred to the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. The incidence of IBC among primary breast cancers was 1.0% (57/5,757) in our hospital. Forty-six patients meeting Haagensen's criteria for inflammatory breast carcinoma were evaluated. All patients had biopsy-proven carcinomas but no distant metastases at referral. The median age at diagnosis for IBC was 51.8 (range, 28 to 70). All patients underwent a mastectomy. Chemotherapy was performed pre- or post-operatively. Three-year and 5-year survival rates were 56.5%, and 40.7%, respectively. Expressions of HER-2/neu and the p53 protein were determined retrospectively by immunohistochemical (IHC) staining of thin paraffin-embedded sections of primary tumors. RESULTS: Of 46 patients, 23 (50.0%) with tumors testing positive for HER-2/neu fared somewhat worse than those with negative tumors, but the differences were not significant for either overall survival (OS) or disease-free survival (DFS). Of 46 patients, 19 (41.3%) whose tumors were positive for p53 fared somewhat better than patients with negative tumors, with no significant differences in either OS or DFS. Patients presenting with less than ten pathologically involved axillary lymph nodes showed significantly better OS and DFS. CONCLUSIONS: Overexpression of HER-2/neu and the p53 protein were not significant prognostic factors in inflammatory breast cancer. However, the increased incidence of HER-2/neu and the poor outcome of IBC may be of clinical interest, suggesting the need for clinical trials of antibody therapy targeted to HER-2/neu. Moreover, a high prevalence of p53 may be useful in determining the specific use of chemotherapy.     

HER-2/Neu overexpression does not predict response to neoadjuvant chemotherapy or prognosticate survival in patients with locally advanced breast cancer

Data about the prognostic and predictive value of HER-2/neu overexpression in patients with locally advanced breast cancer (LABC) treated with primary chemotherapy is limited. Therefore, this retrospective study was performed to examine this issue. Fifty-four consecutive patients with LABC were prospectively managed using a uniform multimodality approach. Response to neoadjuvant chemotherapy and survival were examined against HER-2/neu overexpression as determined by an immunohistochemistry method on formalin-fixed, paraffin-embedded samples of breast cancer using the commercially available, United States Food and Drug Administration-approved kit HercepTest (Dako Corp, Carpinteria, CA). The number of patients in each Hercep Test immunostaining group were as follows; 0 in 12 patients (22%), 1+ in 8 (15%), 2+ in 12 (22%), and 3+ in 22 (41%). None of the clinical variables was significantly associated with HER-2/neu expression. After primary therapy, 22% of patients attained clinical complete response and an additional 70% achieved clinical partial response with an overall response rate of 92% (95% confidence interval: 100% to 79%). There was no significant correlation between clinical response and HercepTest positivity (p=0.85). Of 52 patients with complete pathological data, there was no significant difference in HercepTest status between those who attained complete pathological response (46%) and those who did not (38%) (p=0.74). Moreover, there was no significant difference in disease-free survival (75% vs 84%, [p=0.26]) or overall survival (81% vs 84% [p=0.31]) between those who overexpressed HER-2/neu and those with negative HercepTest, respectively. In patients with LABC, HER-2/neu overexpression determined using HercepTest assay and according to the manufacturer’s approved guidelines failed to demonstrate a predictive or a prognostic role.     

Evaluation of HER-2/NEU protein expression in breast cancer by immunohistochemistry: an interlaboratory study assessing the reproducibility of HER-2/NEU testing

This study investigated the degree of interlaboratory agreement when HER-2/neu was evaluated by immunohistochemistry (IHC) on archival primary breast cancer samples. IHC for HER-2/neu was performed on the same archival tissue sections from 394 invasive primary breast cancers in two different laboratories. Both laboratories used the primary antibody NCL-CB11; however, different methods of immunostaining (antigen retrieval procedure and manual processing or no antigen retrieval and autostainer processing) as well as different scoring systems were used. Fluorescence in situ hybridization (FISH), considered as the correlation method for HER-2/neu status determination, was performed using the PathVysion kit and compared to the IHC results. Forty-eight of 394 analyzed tumors (12.2%) were scored as HER-2/neu positive in one laboratory, and 109 (27.7%) in the other laboratory where antigen retrieval was performed. Complete concordance in categorization of HER-2/neu status between the two laboratories was achieved in 333 of 394 cases (84.5%). FISH performed in 248 formalin-fixed samples revealed HER-2/neu gene amplification in 55/248 (22.2%). Concordance of FISH and IHC was found in 211/248 cases (85.1%) and 220/248 cases (88.7%) when the CB11 antibody was used without and with antigen retrieval, respectively. Both IHC methods generated similar rates of false results, but with different positive predictive values. Our data demonstrate that HER-2/neu evaluation by IHC is not a reproducible technique if there is no standardization of the procedure.     

FISH detection of HER-2/neu oncogene amplification in early onset breast cancer

HER-2/neu (c-erbB-2) gene amplification based on Southern blotting or immunohistochemistry has been shown to be predictive of poor outcome in breast cancer occurring in women over 40, but there is little data on the role of HER-2/neu in young women with breast cancer, many of whom may have inherited BRCA1 or other predisposing genes. The present study used fluorescent in situ hybridization (FISH) on archival specimens of breast cancer from 37 women under the age of 40 to evaluate the role of HER-2/neu amplification in this cohort, and to also evaluate the efficacy of FISH for quantifying amplification. The frequency of primary tumors with a greater than fourfold increase in gene copy number was found to be 38%, which is similar to the frequency of amplification reported in Southern blot studies in older women. However, the greater sensitivity of FISH enabled detection of low level amplification (more than 2 but less than 8 gene copies), which was found in an additional 30% of the tumors. Patients with low level amplification demonstrated a 54% recurrence rate, compared to 86% in those with high amplification and 17% in those with no amplification. HER-2/neu amplification appeared to be more prognostic of recurrence than nodal status, with 45% of node negative tumors recurring compared to 62% of those which were node positive, nor was tumor size predictive of recurrence in this cohort since tumors of 2 cm or less recurred in 44% of cases compared to 57% of those larger than 2 cm. Thus, this study demonstrates that FISH is a reproducible and sensitive technique for detecting HER-2/neu amplification, and that amplification of the oncogene is the strongest independent indicator of recurrence of breast cancer in young women.     

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

Summary 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.     

Clinical findings and HER-2/neu gene amplification status of breast carcinoma patients

The study group was derived from the archival materials of 48 invasive intraductal breast cancer patients who had undergone partial mastectomy/ axillary dissection. All patients included in the study had clinically T1-2N0M0 invasive ductal carcinoma. To detect HER-2/neu status, fluorescent in situ hybridization was performed using a HER-2/neu locus-specific probe. Signals were counted and patients were classified in three groups according to signal ratios: signal ratio <2, group 1 (n=31); signal ratio 2-4, group 2 (n=11); signal ratio >4, group 3 (n=6). Ratios of axillary metastatic lymph nodes to dissected total lymph nodes were 17%, 23% and 83% in groups 1, 2 and 3 respectively (P=0.003). The number of metastatic axillary lymph nodes, and the ratio of microscopic metastatic lymph nodes were highest in group 3 (P=0.001 and P=0.008, respectively). No significant difference was observed between groups for distant metastasis in a 5-year follow-up period. Signal ratios decreased with estrogen receptor expression (P=0.03). Histopathologically, an irregular growth pattern of the tumor was observed in 100% of the patients in group 3, and in 54% and 60% in groups 1 and 2, respectively (P=0.04). Lymphovascular invasion of the tumor was significantly higher in group 3 compared to the other two groups (P=0.01). The extensive intraductal component ratio was the highest in group 3 (P=0.04). The appearance of desmoplastic reaction and lymphocyte infiltration did not show significant difference between the groups. Our results show that HER-2/neu signal ratio increases with lymphovascular invasion, an extensive intraductal component, irregular growth pattern and axillary metastasis in clinically T1-2N0M0 invasive ductal carcinoma of the breast.     

Her-2/neu gene amplification compared with HER-2/neu protein overexpression on ultrasound guided core-needle biopsy specimens of breast carcinoma

Genomic amplification and oncoprotein overexpression of Her-2/neu was studied on ultrasound core needle biopsy specimens of the infiltrative ductal carcinomas of the breast. We performed two colour fluorescence in situ hybridization (FISH) for Her-2/neu and chromosome 17 and compared the FISH results with the immunohistochemical overexpression of Her-2/neu protein by 2 antibodies (DAKO HercepTest and the BioGenex monoclonal antibody AM 134-5M). Furthermore, following radical mastectomy with axillary dissection, Her-2/neu status of the patients were compared with the well known histopathological prognostic factors such as histologic grade, tumor stage, lympho/ vascular invasion, surgical margin status and Paget s disease. Amplification was demonstrated 27% of the cases. Her-2/neu protein overexpression was detected in 47% and 80% of the cases with CB11 and HercepTest respectively. We revealed statistically significant association between the tumor, oncoprotein expression and oncogene amplification (p<0.05). The results of our study showed that combination of IHC and FISH methods enhances the evaluation of tumor genetics at both gene and protein level for the analysis of Her-2/neu in breast carcinoma.     

C-erbB-2 protein in the sera of breast cancer patients

Summary The c-erbB-2 protein was measured in sera of patients with breast cancer or benign breast diseases to study the significance of this protein as a tumor marker. The mean value and positive rate for this protein (assuming 20 U/ml as the cut-off value) were 11.8 U/ml (0%) in benign breast disease (n=30), 11.8 U/ml (3.1%) in stage I/II primary breast cancer (n=64), 38.2 U/ml (29.4%) in stage III/IV primary breast cancer (n=17), 17.9 U/ml (33.3%) in locally recurrent breast cancer (n=12), 298.4 U/ml (51.0%) in recurrent breast cancer with distant metastases (n=51), and 12.9 U/ml (0%) in those with no evidence of recurrence (n=57). Thus, the serum c-erbB-2 protein level was significantly higher in the distant metastatic group. In patients with distant metastases, there was a close association between expression of c-erbB-2 protein in the primary tumor and the serum c-erbB-2 protein level. On the basis of these results, serum c-erbB-2 protein was thought to be useful as a tumor marker for postoperative monitoring of breast cancer, especially in patients positive for expression of this protein in primary cancer tissue.     

Breast cancer family history as a risk factor for early onset breast cancer

Summary Since full breast cancer screening is not generally recommended for young women, it is important to identify individuals who are at higher risk for early onset breast cancer. We investigated the relationship between age of onset of breast cancer in 328 probands (consecutively ascertained patients from our oncology clinic) and breast cancer incidence and age of onset in their female relatives. We found that a family history of early onset breast cancer was associated with higher risk of early onset breast cancer. A family history of early onset breast cancer occurred more frequently among young (<40) breast cancer probands than among older (40) breast cancer probands (p<0.001; OR = 23). This relationship was particularly evident when the analysis was restricted to thehereditary breast cancer probands (p<0.001; OR = 44). We also observed a positive family history of breast cancer (any age) more frequently in young breast cancer probands than in older breast cancer probands (p<0.001; OR = 2.8). These observations have important pragmatic implications for surveillance. We recommend intense surveillance for breast cancer, initiated earlier, for women with close relatives diagnosed with early onset breast cancer.     

曲妥珠单抗治疗失败的HER-2阳性乳腺癌患者不同后续治疗方案的疗效及影响因素分析

目的:观察人表皮生长因子受体2（human epidermal growth factor receptor-2,HER-2）阳性乳腺癌患者曲妥珠单抗治疗失败后不同后续治疗方案的疗效,分析影响因素。方法:回顾性分析2014年1月至2016年12月在我院肿瘤科治疗的曲妥珠单抗治疗失败的94例HER-2阳性晚期乳腺癌患者,根据其后续治疗方案不同将其分为A组（接受单纯化疗）、B组（接受曲妥珠单抗+化疗）和C组（接受拉帕替尼+化疗）;比较三组患者治疗效果,并分析可能影响抗HER-2治疗效果的相关因素。结果:94例患者均完成随访,中位随访时间22.3个月。三组患者中位无进展生存期（median progression free survival,mPFS）分别为3个月、4.5个月及6个月,差异有统计学意义（P<0.000 1）;C组PFS较A组及B组均明显延长,B组PFS较A组明显延长。A、B、C三组客观有效率（objective response rate,ORR）分别为8.7%、29.7%、38.2%,三组的临床获益率（clinical benefit rate,CBR）分别为21.7%、54.1%、64.7%,以上差异均有统计学意义（P<0.05）。对可能影响PFS的单因素进行分析,拉帕替尼、一线疗程（曲妥珠单抗）获益时间≥6个月、无内脏转移是PFS的影响因素;而拉帕替尼、一线疗程（曲妥珠单抗）获益时间≥6个月是PFS的独立影响因素。结论:对于曲妥珠单抗治疗失败的HER-2阳性晚期乳腺癌患者,后续治疗方案中含抗HER-2靶向药物可改善患者预后。     

Lack of prognostic significance of HER-2/neu in early epithelial ovarian cancer

A total of 74 patients with apparent early stage epithelial ovarian cancer who underwent exploratory laparotomy at King Chulalongkorn Memorial Hospital or other hospitals and were referred for further treatment, were evaluated. Formalin fixed paraffin-embedded ovarian tissue specimens were collected and immuno-stained with HER-2/neu antibodies for comparison with clinicopathologic data after median follow up of 46 months (range 3 - 83 months). The prevalence of HER-2/neu overexpression in these patients was 10.2%. No significant correlation between HER-2/neu overexpression and clinicopathological parameters (stage, ascites, capsular rupture, capsular adherence, histological subtype and histological grade) was found. Disease free survival and overall survival did not statistically differ between those with lesions positive or negative for HER-2/neu overexpression.     

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.     

Relevance of p185 HER-2/neu oncoprotein quantification in human primary breast carcinoma

The c-erbB-2 proto-oncogene encodes a transmembrane protein tyrosine kinase receptor of 185kDa (p185) and has been associated with several types of human cancers. In human breast cancer, overexpression of p185 occurs in 15–30% of cases, correlates with poor prognostic factors and characterizes breast cancers with a more aggressive behavior. Overexpression of p185 is usually associated with c-erbB-2 amplification, though it may occur independently and thus define subpopulations of breast cancers which might be of clinical interest. p185 expression is usually detected by immunohistochemistry (IHC) and few studies have been carried out to evaluate the p185 content of breast cancers with an ELISA technique. In this context, we showed, in 106 breast cancer samples, that p185 was expressed at high levels in 13.2%, intermediate levels in 55.7% and negative ones in 31.1% of cases. All p185 positive samples showed a c-erbB-2 oncogene amplification while none of the p185 negative samples and only 4% of p185 imtermediate samples had an amplification of c-erbB-2. p185 expression is significantly correlated with the negativity of estrogen and progestrone receptors, with high levels of cathepsin D and in some conditions with axillary nodal involvement. Thus, using the p185 ELISA assay, the c-erbB-2 status of breast cancers can be defined and moreover a subset can be discriminated which is characterized by intermediate levels of p185 and absence of c-erbB-2 amplification. The quantitative approach towards p185 in breast cancers affords the possibility of identifying more appropriately patients with high or low risk and thus permits adaptation of therapeutic regimens.     

Prognostic and Predictive Impact of the HER-2/neu Extracellular Domain (ECD) in the Serum of Patients Treated with Chemotherapy for Metastatic Breast Cancer

BACKGROUND: The extracellular domain of the HER-2/neu -receptor (ECD) is shed from the receptor protein and can be detected in serum. However, the clinical implication of HER-2/neu ECD measurement must be further evaluated. METHODS: In patients with metastatic breast cancer participating in a trial on first-line chemotherapy, the association of serum HER-2/neu ECD with progression-free interval, survival, and response was studied. Blood samples of patients receiving epirubicin and either cyclophosphamide (EC) or paclitaxel (ET) were collected before (n = 103) and in addition, after three courses of therapy (n = 46). RESULTS: HER-2/neu ECD levels correlate with HER-2/neu overexpression of corresponding primary tumors determined by immunohistochemistry (antibody CB11, p = 0.018) with an optimized cut-off at 15 ng/mL. Elevated serum levels of HER-2/neu ECD before chemotherapy were correlated with shorter overall survival (p = 0.0097), but not with reduced progression-free survival and response to chemotherapy. In subgroup analyses, patients with elevated pretherapeutic HER-2/neu ECD levels treated with EC showed shorter overall survival (p = 0.0092); no difference was seen in the ET group. With regard to progression-free survival, patients with elevated HER-2/neu ECD levels tended to benefit from ET (p = 0.0341), in patients with low levels no difference was observed between EC and ET. A decrease of HER-2/neu ECD levels after three courses of therapy was associated with response to therapy (p = 0.006). CONCLUSION: In our group of metastatic breast cancer patients, elevated HER-2/neu ECD levels are associated with decreased overall survival. With regard to progression-free survival, particularly patients with high HER-2/neu ECD levels seem to benefit from taxane-containing chemotherapy.     

HER-2/<Emphasis Type="Italic">neu</Emphasis> expression in primary and metastatic breast cancer

Introduction Trastuzumab is a highly effective therapy for the treatment of HER-2/neu positive breast cancer. To maximize benefit and minimize unnecessary toxicity, patient selection is essential. Currently HER-2/neu analysis is routinely performed only for primary invasive breast cancers, and trastuzumab therapy is recommended based on primary analysis only. Methods Using immunohistochemistry, we performed a retrospective study comparing HER-2/neu expression in original primary to subsequent metastatic breast cancers. Results Tumors from 382 patients with metastatic breast cancer were studied. In 254 cases (66%) both primary and metastatic lesions were concordant. In 90 cases the primary lesion was HER-2/neu positive with the metastatic lesion negative; whereas, in 37 cases the primary lesion was HER-2/neu negative and the metastatic lesion positive. Primary HER-2/neu immunostaining was associated with a negative predictive value of 35.7%. Although all four groups were similar at diagnosis, survival differences were noted with the best survival experienced by patients with initial primary lesions HER-2/neu negative and subsequent metastatic lesions positive. Patients with hormone receptor and HER-2/neu positive primary lesions who received tamoxifen were more likely to have HER-2/neu positive metastasis. Conclusions The significant discordance between HER-2/neu expression in primary and metastatic tumors suggests that determination of HER-2/neu status in metastatic disease should be attempted.     

乳腺癌组织中 PCNA及c-erbB-2 的研究

目的 :探讨PCNA、c erbB 2与乳腺癌发生、发展的关系 ,及其在乳腺癌的临床分期、预后及治疗上的意义。方法 :采用免疫组化ABC法 ,对 52例乳腺癌患者术后病理组织进行检测。结果 :PCNA与临床分期、激素受体及腋淋巴结转移情况呈正相关 ,有淋巴结转移者较无淋巴结转移者阳性表达差异有显著性 (P <0 0 1) ;c erbB 2与临床分期呈正相关 ,与激素受体呈负相关。结论 :PCNA、c erbB 2作为联合指标对乳腺癌的分期、预后的判断有一定的意义 ,并对指导治疗 ,特别是内分泌治疗也起到辅助性作用。     

发病年龄对子宫内膜癌患者预后的影响分析

目的：探讨不同发病年龄对子宫内膜癌患者预后的影响。方法选择380例子宫内膜癌患者作为研究对象,其中年龄≤40岁87例,41~59岁190例,≥60岁103例。通过各类随访方式,观察不同发病年龄患者5年总体生存率及无进展生存率,并对预后影响因素进行多因素分析。结果在发病年龄≤40岁、41~59岁、≥60岁患者的5年总体生存率、5年无进展生存率的观察结果中显示,患者年龄越大,5年总体生存率、5年无进展生存率越低,差异有统计学意义（P﹤0.05）;并且患者分期越高,5年总体生存率、5年无进展生存率越低,差异有统计学意义（P﹤0.05）;Cox回归分析结果显示41~59岁和≥60岁的子宫内膜癌患者死亡风险分别是≤40岁患者的3.465倍和5.142倍,41~59岁和≥60岁的子宫内膜癌患者疾病进展的风险分别是≤40岁患者的2.753倍和4.874倍。结论子宫内膜癌患者发病年龄是影响总生存及无进展生存的独立危险因素,患者年龄越大,病理分期越高,所表现出的预后情况越差。     

Association between HER-2/neu and the progesterone receptor in oestrogen-dependent breast cancer is age-related

Summary In oestrogen receptor-positive (ER⁺) breast cancer, HER-2/neu and the progesterone receptor (PR) are inversely associated. This explains a lower response to anti-oestrogens if ER⁺ breast cancers are HER-2/neu positive. One randomized study however, showed that premenopausal women with an ER⁺ breast cancer respond to anti-oestrogens independent of HER-2/neu. We therefore hypothesized an age-related association between HER-2/neu and PR in ER⁺ breast cancers. Receptors for ER, PR and HER-2/neu were analysed by immunohistochemistry (IHC). A uni- and multivariate analyses was carried out to assess this relationship in 1104 women with an ER⁺ breast cancer. We observed an inverse association between HER-2/neu and PR only after age 45. There were 173 women of age 45 and 931 of age >45 years. In multivariate analysis, only tumour grade (p=0.005) but not PR status was associated with HER-2/neu in women age 45 years. However, in age >45 years group, both PR status (p=0.001) and tumour grade (p = 0.001) were independently associated with HER-2/neu. In ER⁺ breast cancers from women age >45, PR was positive in 76.9% if HER-2/neu negative but in 53.4% if HER-2/neu positive (p<0.001) and the median quantitative PR levels are 150 and 75 respectively in HER-2/neu negative and HER-2/neu positive tumours (p=0.002). This age effect of HER-2/neu on the PR status was not seen in women age 45 years and the median quantitative PR levels are 200 and 220 respectively in HER-2/neu negative and HER-2/neu positive tumours (p = 0.518). The study confirms an age-related inverse relationship between HER-2/neu and PR only in women age >45 years but not in women age 45 years.     

Assessment of intratumoral vascularization (angiogenesis) in breast cancer prognosis

The search for prognostic markers is important both to identify those patients with occult metastases and also to spare chemotherapy in those patients whose tumors have not developed the capacity for distant spread. Angiogenesis, the formation of new blood vessels, is necessary for breast cancer growth and metastasis. Good correlation has been demonstrated between intratumoral vascularization and outcome in patients with breast cancer. Intratumoral vascularization in human breast cancer can be measured by using standard immunohistochemical methods. Strict guidelines for scoring need to be followed. Although attempts are being made to automate the reading, visual scoring remains superior. We studied a population of women with small node-negative breast cancer who received no adjuvant therapy and have a median follow-up of 15 years. We have found intratumoral vascularization, as measured by microvessel count, to be an independent prognostic factor for disease-free survival. Low microvessel count identifies a group of patients with a 20 year disease free survival of 93%. The proportion of women with low microvessel count decreases with increase in tumor size and increases with patient age. But even in mammographically detected nonpalpable breast cancer, that is, the smallest breast cancer we currently detect, the majority already have high microvessel count. Intratumoral vascularization appears to be an early event that is necessary but not sufficient for metastatic progression. Microvessel count seems to be an excellent marker to identify patients with good prognosis because those with low microvessel count have a 93% disease-free survival irrespective of size, grade, or estrogen receptor status, but is less good at predicting those at high risk since the 20-year disease-free survival is still 67-70% in those with high microvessel count. Thus, the higher risk group needs to be further stratified using additional prognostic factors.