Prognostic implication of labeling index versus estrogen receptors and tumor size in node-negative breast cancer

Summary The paper analyzes the relation among tumor size (T), estrogen receptor (ER) status, and labeling index (LI) and their relative merits in predicting the relapse-free (RFS) and overall survival (OS) in 215 node-negative women with primary breast cancer. All patients were subjected to Halsted or modified radical mastectomy; none received postoperative irradiation or systemic adjuvant therapy. The 5-year RFS was 75.3% and OS 89.0%When singly tested, LI and ER were able to significantly predict RFS and OS. In contrast, T influenced only RFS but not OS. The multivariate analysis showed that, in the presence of the two other variables, only LI retained its prognostic significance both for time to relapse (p = 0.0044) and survival (p = 0.035). From the present findings, LI appears to be a new important prognostic variable in the selection of high risk patients for whom adjuvant systemic therapy should perhaps be part of their primary treatment.Presented in part at the Annual Meeting of the American Socicty of Clinical Oncology, May, 1985, Houston, Texas, USA.     

Prognostic and predictive value of thymidine labelling index in breast cancer

In the last few decades, much effort has been directed towards identifying the phenotypic or functional aspect of tumor cells which can contribute to a biofunctional staging for improving the accuracy of pathologic staging used for identifying patients at different risk. Among known biologic factors, the proliferative capacity of the tumor cell population, a feature common to all tumors, has been widely investigated.Several approaches have been used to measure different aspects of the cell cycle. Among these, the thymidine labeling index (TLI) represents the fraction of cells in S-phase cell fraction and is based on the active incorporation of labelled thymidine into DNA. From basic studies conducted on several thousands of patients, the TLI of primary breast cancers appears closely related to steroid receptor status and generally unrelated to pathologic stage. Retrospective analyses performed on large series of patients treated with local regional therapy alone have consistently shown the relevance of TLI value to clinical aggressiveness in terms of relapse-free survival and overall survival. Moreover, TLI is a prognostic indicator which is independent of tumor size, steroid receptors, and p53 and bc12 protein expression, and which, together with patient age and tumor size, is able to identify patients at different risk of loco-regional or distant metastases. Recently, a direct relationship between TLI and response to polychemotherapy has been shown in patients with operable and advanced breast cancers.This finding, derived from retrospective and recently confirmed in prospective clinical studies, has led to the activation of cell kinetics based therapeutic protocols for patients with node-negative and one to three node-positive operable breast cancers.     

Prognostic significance of biologic markers in node-negative breast cancer patients: a prospective study

It is generally thought that future advances in the treatment and cure of breast cancer patients will be made possible through a deeper understanding of tumor biology and an improved capability to define the prognosis of each single patient. This will lead to the formulation of new, more selective, and patient-tailored therapies. It is therefore important, when studying potential prognostic factors, to follow methodologic requirements and guidelines which involve the carrying out of prospective studies as confirmatory steps. Repeatedly or recently investigated prognostic markers (tumor size, menopausal status, ER, PgR, ³H thymidine labeling index, c-erbB-2 and p27 expression) were evaluated on a series of 286 prospectively recruited node negative breast cancer patients who underwent loco-regional treatment alone and were closely followed. The individual and relative prognostic contribution of each variable with respect to other factors, as well as their ability to identify node negative patients at risk, were assessed by univariate and multivariate analysis. At a five-year follow-up, only tumor size (p=0.021) and TLI (p=0.016) individually proved to be significant prognostic indicators of relapse-free survival. Conversely, p27 expression was not related to RFS and c-erbB-2 expression appeared to have only a short-term effect on patient prognosis. TLI and tumor size, tested in multivariate analysis along with ER and menopausal status, maintained their independent prognostic relevance. The study, performed on a large series of node-negative patients given loco-regional treatment alone, for the first time prospectively recruited, showed the prognostic relevance of TLI and its independence from other clinico-pathologic and biologic factors over a five-year period.     

淋巴结阴性乳腺癌患者辅助治疗的研究进展

淋巴结阴性乳腺癌患者中有20%～30%经手术治疗后复发和转移.本文综述了如何选择需要内分泌治疗和/或化疗的淋巴结阴性乳腺癌患者,以及如何选择正确的治疗模式.     

Long-term prognostic significance of HER-2/neu in untreated node-negative breast cancer depends on the method of testing

IntroductionThe prognostic significance of HER-2/neu in breast cancer is a matter of controversy. We have performed a study in 101 node-negative breast cancer patients with long-term follow-up not treated in the adjuvant setting, and analysed the prognostic significance of immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH), both separately and in combination, in comparison with traditional prognostic factors.MethodsOverexpression was classified semiquantitatively according to a score (0 to 3+) (HER-2_SCO). FISH was used to analyse HER2/neu amplification (HER-2_AMP). Patients classified 2+ by IHC were examined with FISH for amplification (HER-2_ALG). Patients with 3+ overexpression as well as amplification of HER-2/neu were positive for the combined variable HER2_COM. These variables were compared with tumour size, histological grade and hormone receptor status.ResultsHER-2_SCO was 3+ in 20% of all tumours. HER-2_ALG was positive in 22% and amplification (HER-2_AMP) was found in 17% of all tumours. Eleven percent of the tumours showed simultaneous 3+ overexpression and amplification. Only histological grade (relative risk [RR] 3.22, 95% confidence interval [CI] 1.73–5.99, P = 0.0002) and HER-2_AMP (RR 2.47, 95% CI 1.12–5.48, P = 0.026) were significant for disease-free survival in multivariate analysis. For overall survival, both histological grade (RR 3.89, 95% CI 1.77–8.55, P = 0.0007) and HER-2_AMP (RR 3.08, 95% CI 1.24–7.66, P = 0.016) retained their independent significance.ConclusionThe prognostic significance of HER-2/neu in node-negative breast cancer depends on the method of testing: only the amplification of HER-2/neu is an independent prognostic factor for the long-term prognosis of untreated node-negative breast cancer.     

淋巴结阴性乳腺癌辅助疗法适应证的分析

目的：探讨淋巴结阴性（N0）乳腺癌辅助疗法的适应证。方法：以233例乳腺癌根治术切取20个以上淋巴结转移阴性的乳腺癌的患者为对象,对N0乳腺癌的复发因素和术后辅助疗法的适应证进行分析。结果：N0乳腺癌的术后复发率为17／233（7．3％）;年龄、月经史、部位、肿瘤直径及病理学因素与预后相关。在有意义的病理学预后因素中将浸润性小叶癌、组织学恶性度Ⅲ级（高度恶性）及淋巴细胞浸润阴性癌3项进行组合分析,其复发率具有3项者为28％,2项者为16％,1项者为7％。结论：对具有高危复发因素的N0乳腺癌需要进行辅助疗法。     

Nuclear pleomorphism,a strong prognostic factor in axillary node-negative small invasive breast cancer

Summary We have evaluated established risk factors (tumor size, menopausal status, receptor status, tumor histology, and grading according to Bloom & Richardson including subfactor analysis) as well as local therapeutic procedures in a series of 121 patients with axillary node-negative (ANN) breast cancer stage T1a and T1b. The patients were operated on at a single institution (Department of Surgery, Hanuschkrankenhaus, Vienna) from 1969 to 1989. After a median observation time of 185 months, a total of 16 patients (13%) had a recurrence; of these, 6 had died of the primary disease by the control date (Dec 1, 1990). Grading (distant recurrence-free survival (DRFS) p=0.01, overall survival (OS) p=0.006, mitosis rate (DRFS p=0.006, OS p=0.02), and particularly nuclear pleomorphism (DRFS p=0.0002, OS p=0.00001) proved to have prognostic impact on distant recurrence-free survival and/or overall survival (Mantel-Cox log rank test; level of significance: p=0.006 after adjustment for multiple testing by Bonferroni correction). Therapeutic procedures had a borderline-significant impact on local recurrence (p=0.09). No other parameters had statistically significant impact. Thus, our long-term analysis confirms the superior prognostic relevance of histologic grading and nuclear pleomorphism in patients with ANN breast cancer stage T1a and T1b.     

淋巴结阴性乳腺癌PAI-Ⅰ表达及预后价值

Objective:To investigate the expressions of plasminogen activator inhibitor type 1(PAI-1),C-erbB-2,VEGF and Ki-67 by immunohistostaining and then to evaluate the prognostic value of PAJ-1 in node-negative breast cancer,Methods:The study included a retrospective series of 62 female patients with axillary lymph node-negative breast cencer.Expressions of PAI-1,C-erbB-2,VEGF and Ki-67 were determined by immunohistostaining on formalin-fixed paraffin-embedded tissue sections from these patients after a median follow-up of 69 months(range 22-117 months).Correlations with well known clinicopathologic factors were assessed and multivariate survival analyses were performed.Results:High PAI-1 level was positively associated with high histologic grade of the tumors.Disease-free survival(DFS)was significantly shorter for the patients with moderate to intensive expression of PAI-1 lban for those with negative(X2=25.46,P＜0.001:X2=23.07,P＜0.001)to mild expression(X2=19.75,P＜0.001:X2=17.40.P＜0.001).Although on univariate analysis of the prognostic factors,tumor size,location of primary tumor and age as well as expressions of PAI-1,VEGF and Ki-67 were all significantly prognostic factors for DFS(P＜0.05),PAI-1 was the only independent prognostic factor on multivariate analysis(P＜0.0001;hazard ratio[HR].4.041:95% confidence intewal[CI],1.928-8.468).Conclusion:These results of the current study indicate that intermediate or high expression of PAI-1 represents a strong and independent unfavorable prognostic factor for the development of recurrence or metastases in axillary node-negative breast cancer.     

Prognosis in node-negative breast cancer

In a selected group of 207 breast cancer patients with tumor-free axillary nodes, clinical and pathological features were evaluated as to their relationship to long-term disease-free survival. No clinical feature was found to be prognostically useful. Of pathologic features studied, four appear to have significance. These are (1) the volume of the primary mass, (2) the histologic or nuclear grade, (3) the presence of invasive lobular carcinoma in the primary mass, and possibly (4) the presence of neoplastic cells in intramammary lymphatic vessels. When two or more of these four features are present, prognosis is less favorable than when there is only one, but the influences are not arithmetically additive.     

Contribution of vascular endothelial growth factor to the Nottingham prognostic index in node-negative breast cancer

The prognostic contribution of intratumour VEGF, the most important factor in tumour-induced angiogenesis, to NPI was evaluated by using flexible modelling in a series of 226 N-primary breast cancer patients in which steroid receptors and cell proliferation were also accounted for. VEGF provided an additional prognostic contribution to NPI mainly within ER-poor tumours.     

The number of tumor-free axillary lymph nodes removed as a prognostic parameter for node-negative breast cancer

Recently, there has been controversy about the relationship between the number of lymph nodes removed and survival of patients diagnosed with lymph node-negative breast cancer. To assess this relationship, 603 cases of lymph node-negative breast cancer with a median of 126 months of follow-up data were studied. Patients were stratified into two groups（Group A, 10 or fewer tumor-free lymph nodes removed; Group B, more than 10 tumor-free lymph nodes removed）. The number of tumor-free lymph nodes in ipsilateral axillary resections as well as 5 other disease parameters were analyzed for prognostic value. Our results revealed that the risk of death from breast cancer was significantly associated with patient age, marital status, histologic grade, tumor size, and adjuvant therapy. The 5- and 10-year survival rates for patients with 10 or fewer tumor-free lymph nodes removed was 88.0% and 66.4%, respectively, compared with 69.2% and 51.1%, respectively, for patients with more than 10 tumor-free lymph nodes removed. For patients with 10 or fewer tumor-free lymph nodes removed, the adjusted hazard ratio（HR） for risk of death from breast cancer was 0.579（95% confidence interval, 0.492-0.687, P 〈 0.001）, independent of patient age, marital status, histologic grade, tumor size, and adjuvant therapy. Our study suggests that the number of tumor-free lymph nodes removed is an independent predictor in cases of lymph node-negative breast cancer.     

The prognostic effect of histological tumor grade in node-negative breast cancer patients

Summary The prognostic effect of histological tumor grade was evaluated in 1036 patients with early breast cancer (pT1 pN0 M0) entered into a trial comparing mastectomy and breast preserving treatment. All analyses were adjusted for the factors treatment, patients' age, and tumor size. Tumor grade was defined according to Bloom and Richardson based on the sum of scores assigned to each of three histological features: 1) degree of differentiation, 2) pleomorphism, and 3) mitotic index. The relative importance of these factors with regard to disease-free survival was evaluated. In univariate as well as in multivariate analyses the pleomorphism was the only factor showing a significant effect (univariate: p=0.0024, multivariate: p=0.015). It was investigated how the factors should be combined to define a histological grading score which yields the best possible classification of the patients with respect to prognosis. A new grading system was defined splitting the patients into three groups: 1) pleomorphism 1; 2) pleomorphism 2 or pleomorphism 3 and mitotic index 1; 3) pleomorphism 3 and mitotic index 2 or 3. This yields a good classification of the patients with respect to prognosis (p=0.0004). The prognostic effect of this score was compared with the effects of the grading systems proposed in the literature. According to Bloom and Richardson and in the modified version by Schauer and Weiss, grading is based on the sum of scores of the various histological factors. Therefore, the strong effect of the pleomorphism was diluted in these grading definitions (Bloom and Richardson: p=0.03, Schauer and Weiss: p=0.028). The grading system proposed by Le Doussalet al. consists only of the scores of pleomorphism and mitotic index (p=0.014). In summary, the factor pleomorphism showed a stronger effect on disease-free survival by itself than the grading systems proposed in the literature.     

Low number of examined lymph nodes in node-negative breast cancer patients is an adverse prognostic factor.

BACKGROUND: The aim of the study was to determine whether the number of lymph nodes removed at axillary dissection is associated with recurrence and survival in node-negative breast cancer (NNBC) patients. PATIENTS AND METHODS: We retrospectively reviewed the medical records of 1606 women with pathologically node-negative T1-T3 invasive breast cancer. Median follow-up was 61 months (range 2-251). Potential prognostic factors assessed included: number of axillary lymph nodes examined, age, menopausal status, tumor size, histological type, tumor grade, estrogen receptor(ER), progesterone receptor (PR) and HER2. RESULTS: At 5 years, relapse-free survival (RFS) rate was 85% and breast cancer-specific survival (BCSS) rate was 94%. In univariate analysis, factors significantly associated with lower RFS and BCSS were: fewer than six lymph nodes examined (RFS, P = 0.01; BCSS, P = 0.007), tumor size >2 cm, grade III, negative ER or PR. Statistically significant factors for lower RFS and BCSS in multivariate analysis were: fewer than six lymph nodes examined [RFS, hazard ratio (HR) 1.36, P = 0.029; BCSS, HR 1.87, P = 0.005], tumor size >2 cm, tumor grade III and negative PR. CONCLUSIONS: Examination of fewer than six lymph nodes is an adverse prognostic factor in NNBC because it could lead to understaging. Six or more nodes need to be examined at axillary dissection to be confident of a node-negative status. This may be useful, in conjunction with other prognostic factors, in the assessment of NNBC patients for adjuvant systemic therapy.     

Urokinase (uPA) and its inhibitor PAI-1 are strong and independent prognostic factors in node-negative breast cancer

Summary Evidence has accumulated that invasion and metastasis in solid tumors require the action of tumor-associated proteases, which promote the dissolution of the surrounding tumor matrix and the basement membranes. The serine protease urokinase-type plasminogen activator (uPA), which is elevated in solid tumors, appears to play a key role in these processes.We used enzyme-linked immunoassays (ELISA) to test for uPA antigen and its inhibitor PAI-1 in tumor tissue extracts of 247 breast cancer patients who were enrolled in a prospective study. The relation of these data to known prognostic factors and to other variables such as DNA analysis and cathepsin D was studied. Disease-free and overall survival were analyzed according to Cox's proportional hazard model.The major new finding is that breast cancer patients with either high uPA (>2.97 ng/mg protein) or high content of the uPA inhibitor PAI-1 (>2.18 ng/mg protein) in their primary tumors have an increased risk of relapse and death. Multivariate analyses revealed uPA to be an independent and strong prognostic factor. The impact of uPA is as high as that of the lymph node status. In node-negative patients the impact of uPA is closely followed by that of PAI-1. Since uPA and PAI-1 are independent prognostic factors, the node-negative patients could be subdivided further by combining these two variables. In this refined analysis, patients whose primary tumors have lower levels of both antigens evidently have a very low risk of relapse (93% disease-free survival at three years) in contrast to patients with high uPA and high PAI-1 (55% disease-free survival at three years).The combination of uPA and PAI-1 in our group of patients with axillary node-negative breast cancer allows us to identify the 45 percent of patients having an increased risk of relapse. Consequently, more than half of the patients had less than a 10% probability of relapse and thus would possibly be candidates for being spared the necessity of adjuvant therapy.Supported by the Deutsche Forschungsgemeinschaft (Sonderforschungsbereich 207, Projects F9 and G10) and the Wilhelm Sander-Stiftung.     

Prognostic factors and natural history in lymph node-negative breast cancer patients

Summary The prognostic significance of clinical and histological factors as well as hormone receptors was analyzed in a population of 3,064 lymph node-negative breast cancer patients operated in the Stockholm region between 1976 and 1988. None of these patients received systemic adjuvant treatment. Multivariate analysis showed that only histological tumor size, number of examined axillary lymph nodes, and progesterone receptors were independent prognostic factors in terms of recurrence-free interval. An individual risk of recurrence was calculated taking into account these three factors to discriminate between three groups of patients with a risk of less than 15%, 15–25%, and more than 25% of recurrence at 5 years. Similar results were obtained taking into account only the first two factors. The prognostic information added by the knowledge of progesterone receptors only changed the recurrence rate in approximately 3%. This study showed that conventional prognostic factors permit the identification of high risk lymph node-negative breast cancer patients. Results obtained by the use of new more sophisticated factors should be compared with those obtained analyzing strong conventional prognostic factors.     

Biological considerations in locally advanced breast cancer treated with anthracycline-based neoadjuvant chemotherapy: thymidine labelling index is an independent indicator of clinical outcome

The present retrospective study aims to determine the clinical value of thymidine labelling index (TLI) together with other established clinical and biological factors in 116 locally advanced breast cancer (LABC) patients treated with anthracycline-based neoadjuvant chemotherapy, surgery, adjuvant chemotherapy and radiotherapy. TLI was determined in 71 LABC patients with a median of 2.62% (0–23.64%) and a mean of 4.71%±5.54. As a result of neoadjuvant chemotherapy, 85 patients (73%) responded to chemotherapy (CT), whereas 31 patients were unresponsive (27%). No relationship has been found between the pretreatment biological variables including TLI, estrogen receptor (ER), progesteron receptor (PgR) status and clinical parameters such as the chemotherapy response rates and axillary lymph node involvement following chemotherapy. Median follow-up was 35 months (18–97 months) and the 3-year overall survival (OS) and disease free survival (DFS) rates were 71.6% and 52.2%, respectively. In univariate analysis, patients with inflammatory breast cancer, high TLI-index (2.62%), lymph node (LN) positivity or >3 positive lymph nodes following neoadjuvant chemotherapy and without any response to neoadjuvant chemotherapy were found to have worse DFS and OS-rates and high local and systemic recurrence rates. In multivariate analysis, TLI was estimated as the most powerful independent factor affecting the OS in LABC patients among the other established clinical and biological parameters (p=0.02). These results suggest that TLI is an important independent indicator of clinical outcome in patients with LABC and these patients with high TLI levels require more effective treatment modalities.     

Vascular endothelial growth factor and prognosis in patients with node-negative breast cancer

Vascular endothelial growth factor (VEGF) has emerged as one of the most important angiogenic growth factors from experimental in vitro and in vivo studies. In the present study, we investigated the relationship between VEGF expression and microvessel density (MVD) and defined their prognostic relevance on a series of 242 patients with node-negative breast cancer, using immunohistochemical methods. In parallel, estrogen and progesterone receptors were quantitatively assessed using the dextran-charcoal technique and cell proliferation was evaluated as S-phase cell fraction according to (3)H-thymidine-labeling index (TLI). The percentage of VEGF-expressing cells varied from 0-95% in the different tumors and was unrelated to menopausal status, tumor size or steroid receptor status. Conversely, a significant inverse relation was observed with patient age or tumor cell proliferation, albeit with very poor correlation coefficients. A significant relation was observed between VEGF expression and MVD (r(s) = 0.55, p < 0.001). Clinical outcome analyzed as a function of high and low VEGF expression showed slight differences in terms of both disease-free survival (DFS) and overall survival (OS) that never reached statistical significance. Moreover, the trend was paradoxically in favor of patients with highly VEGF-expressing tumors. Finally, DFS and OS curves, when analyzed as a function of VEGF expression or MVD, were superimposable. In conclusion, our study did not highlight a prognostic relevance of VEGF expression in patients with node-negative breast cancer, as already observed for MVD.     

全身炎症反应指数(SIRI)在乳腺癌患者中的临床意义和预后价值

目的:探讨乳腺癌患者全身炎症反应指数(systemic inflammatory response index,SIRI)的临床和预后价值.方法:研究对象为1998年01月至2016年12月在我院接受新辅助化疗的乳腺癌患者477例和未接受新辅助化疗的乳腺癌患者308例.ROC曲线(receiver operating ...     

Influence of investigator experience and microscopic field size on microvessel density in node-negative breast carcinoma

In this study on the determination of intratumoralmicrovessel density (MVD) in breast cancer, we haveinvestigated the influence of the observer experience andthe microscopic field size. We have used thesample set reported on earlier in the JNatl Cancer Inst 87: 1797–1798, 1995. This case-controlstudy has shown a positive association of highMVD and unfavorable outcome when comparing node-negative pT1–2breast carcinoma (NNBC) patients with a disease-free periodof over ten years with those with anearly distant relapse.Tumor sections of both outcome groups (favorable: n= 19; unfavorable: n = 19) were immunostainedfor factor VIII related-antigen (FVIII r-Ag). Microvessels werecounted in the areas of most intense vascularization(hot spots), both at magnification × 200 (fieldsize of 0.61 square mm) and × 400(field size of 0.15 square mm), by oneinexperienced and three experienced observers. Microphotographs of individualvascular hot spots were analyzed using overlays resemblingthe two field sizes.The main results obtained are: i) a confirmationof the prognostic value of microvessel density inthe case-control sample set (n = 38) wasestablished by all experienced but not by theunexperienced investigator; ii) both at × 200 and× 400 magnification, angiogenesis quantification in vascular hotspots contained prognostic information.The results of this study indicate that theselection of vascular hot spots in tumor sectionsimmunostained for an antigen expressed on endothelial cellsis more prone to inter-observer variability and moredependent on training than the counting of themicrovessels within predefined hot spots itself. The microscopicmagnification and resulting field size do not influencethe prognostic significance of MVD in NNBC. Thisinformation validates the development of more objective methodsof measuring the amount of angiogenesis within malignanttissue. This will allow more accurate implementation ofthe angiogenesis parameter in multiparametric and prospective prognosticfactor studies in NNBC.