Impact of tumor biological factors on response to pre-operative epirubicin and paclitaxel chemotherapy in primary breast cancer

BACKGROUND: The objective of this study was to determine the predictive impact of several established tumor biological factors (progesterone receptor, estrogene receptor, HER2/neu, and Ki-67) on response to pre-operative combination chemotherapy with epirubicin and paclitaxel in a representative group of primary breast cancer patients. PATIENTS AND METHODS: Thirty-eight primary breast cancer patients (metastasis-negative) received pre-operative chemotherapy with epirubicin and paclitaxel. The response characteristics analyzed included pathological complete response and partial remission determined by 3D ultrasound, as well as down-staging and breast conserving surgery. RESULTS: Pathologically complete response occurred in six patients. Overexpression of HER2/neu, low (negative) hormone receptors and high Ki-67 were all significant positive predictive factors for response to pre-operative chemotherapy. CONCLUSION: HER2/neu overexpression is predictive for response not only to trastuzumab, but also to epirubicin and paclitaxel.     

Perioperative tumor cell dissemination in patients with primary or metastatic colorectal cancer

Introduction

Although there is general correlation between the TNM stage of colorectal cancer (CRC) and its prognosis, there is often significant variability of tumor behaviour and individual patient outcome, which is unaccounted for by pathologic factors alone. Our aim was to estimate perioperative tumor cell dissemination in patients with primary or CRC liver metastases as a possible factor influencing the outcome.

Methods

Forty patients were prospectively enrolled in the study from the year 2007 to 2008. Eighteen patients had histologically proven CRC (50% rectal, 44% colonic, 6% colonic and rectal). Sixteen patients (47%) had CRC liver metastases only. The remaining six patients who underwent colon or liver resection for benign conditions, acted as the control group. All patients with malignant pathologies had R0 resections. Blood samples were taken before the surgical incision (T0), immediately after tumor resection (T1) and at the end of the surgical intervention (T2). Data acquisition was performed using a dual-laser FACSCalibur flow cytometer. Circulating malignant cells were identified as being CD45−/cytokeratin+.

Results

The analysis of patients overall (CRC resection subgroup and hepatectomy subgroup) revealed that there was no statistically significant difference of the tumoral cell count in the blood per million of hematopoietic cells at T0, T1 and T2.

Conclusions

This study demonstrates no differences in the detected circulating numbers of tumor cells at different stages of surgical intervention.     

Relation between primary tumor shape and biological behavior in breast cancer

The aim of this study was to investigate the biological significance of tumor shape in breast cancer by considering the shape not as a casual event but as an expression of the behavior and natural history of the tumor. The shape was studied by an analytical morphometry procedure and was related to axillary metastases, which up to now are the most meaningful prognostic factors in this disease. Fifty cases of infiltrating breast carcinoma (25 N+ and 25 N-) were investigated. The shape, studied on subgross sections of the tumor, was considered as the result of two components: the subtle contour irregularities and the main distortions of the figure. The procedures used allowed us to distinguish and to parametrize these two components in order to submit them to univariate analysis (Student's t test), a principal components analysis and, finally, a multivariate discriminant analysis (Hotelling test). The utilized analytical procedures by work-station S.A.M. (S.A.M. work station is a product of "Metamorphosis") consisted of three steps: 1) Extraction of tumor function curve obtained by Kth order polynominals which gives a smoothing effect to the original curve; 2) Evaluation of contour irregularities by Fourier harmonic analysis; 3) Evaluation of shape asymmetry by SAE (shape asymmetry evaluator). We considered also the roundness factors of the original and function curves and finally the maximum tumor diameter. Three parameters relating to contour irregularities (sum and mean value of Fourier harmonic amplitude and percentage of superimposed points) and parameters relating to main distortions of the figure (mean value of SAE) were highly significant (p less than 0.001). The roundness factor of the original curve was more significant (p less than 0.001) than that of the function curve (p less than 0.01) whereas maximum tumor diameter was not significant when tested by Student's t test. Multivariate discriminant analysis allowed 20% of error to be reached by using 3 parameters relating to the shape analysis and the two roundness factors. By using 8 parameters, including maximum tumor diameter, the percentage error was 16%. The results obtained, while they stress the usefulness of the employed procedure, reveal that shape of the tumor, together with its dimensions, is an important expression of the biological behavior relating to metastatic spread.     

Multiparametric prognostic evaluation of biological factors in primary breast cancer.

BACKGROUND: An array of biological features related to tumor cell differentiation status, growth rate, and invasive potential have been identified as potential prognostic factors in breast cancer. We were interested in determining their relative importance in predicting patient survival. PURPOSE: We evaluated the relative weight of the following four biological factors in predicting survival of patients with breast cancer: tumor cell DNA content (determined by flow cytometry), tumor cell proliferation rate (determined by thymidine kinase activity), expression levels of cathepsin D and urokinase plasminogen activator, and several "classical" clinical and histological factors. METHODS: Selected from a prospectively updated database, the study population consisted of 319 primary breast cancer patients who received treatment and follow-up care (median, 6 years) in the Centre René Huguenin. To determine the profile of biological factors for each patient, we used frozen tumor specimens and (except for the flow cytometric DNA content assay) commercially available assay kits. We determined by Cox multivariate analysis the relationships of the biological factors to each other, to classical prognostic factors, and to disease-free and metastasis-free survival. RESULTS: In the overall population, disease-free survival was best predicted by node status (P = .004), clinical tumor size (P = .02), and cathepsin D expression (P = .01), whereas metastasis-free survival was best predicted by node status (P = .0004), clinical tumor size (P = .009), and urokinase plasminogen activator expression (P = .04). In node-negative patients, thymidine kinase activity was the only factor selected for disease-free (P = .04) and metastasis-free (P = .05) survival. In node-positive patients, the number of positive axillary lymph nodes was the only factor selected for disease-free (P = .0008) and metastasis-free (P = .00017) survival. CONCLUSIONS: Our retrospective analysis has identified protease expression and tumor cell proliferation rate as important biological prognostic factors in breast cancer. Prospective clinical trials should be undertaken to confirm these results.     

Detection and clinical implications of early systemic tumor cell dissemination in breast cancer.

Blood-borne distant metastasis is the leading cause of cancer-related death in breast cancer. The onset of this fundamental process can now be assessed in cancer patients using ultrasensitive immunocytochemical and molecular assays able to detect even single metastatic cells. Analyses of bone marrow (BM) samples show that disseminated cells are present in 20-40% of primary breast cancer patients without any clinical or histopathological signs of metastasis. The common homing of circulating breast cancer cells in BM is indicative for systemic tumor cell spread and predictive for growth of overt metastases in relevant organ sites such as bone, lung, or liver. Recent clinical studies involving more than 3000 breast cancer patients demonstrated that the presence of tumor cells in BM at primary diagnosis is an independent prognostic factor for unfavorable clinical outcome. To date, sampling of BM, however, is not a routine procedure in clinical management of breast cancer patients. Therefore, several research groups have developed sensitive assays for detection of circulating tumor cells in peripheral blood. Studies evaluating the clinical relevance of these blood assays are ongoing. Here, we will review the existing tumor cell assays and discuss their current clinical relevance and perspectives for the clinical management of breast cancer patients.     

Influence of zoledronic acid on disseminated tumor cells in primary breast cancer patients

BackgroundThe presence of disseminated tumor cells (DTCs) in bone marrow of patients with early breast cancer (EBC) has been correlated with increased risk of metastatic disease or locoregional relapse. Zoledronic acid (ZOL) treatment has reduced DTCs in the bone marrow of patients with EBC in several studies. This controlled study sought to confirm these observations.Patients and methodsPatients with EBC and DTC-positive bone marrow were randomized (N = 96) to treatment with ZOL plus adjuvant systemic therapy or adjuvant systemic therapy alone. The change in DTC numbers at 12 months versus baseline was measured.ResultsDTC-positive patients treated with ZOL were more likely to become DTC-negative after 12 months of treatment compared with the controls (67% versus 35%; P = 0.009). At 12 months, DTC counts decreased to a mean of 0.5 ± 0.8 DTCs in the ZOL group and to 0.9 ± 0.8 DTCs in the control group. In addition, ZOL was generally well tolerated.ConclusionsTreatment with ZOL improves elimination of DTCs. Further studies are needed to determine whether the reduction in DTCs by ZOL provides clinical benefit.     

Vascularization in primary breast carcinomas: its prognostic significance and relationship with tumor cell dissemination.

PURPOSE: The interaction between tumor cells, stroma, and endothelial cells is important for the dissemination of tumor cells. The aim of the present study is to examine vascularity in primary breast carcinomas and its prognostic significance and relationship with tumor cell dissemination. EXPERIMENTAL DESIGN: A total of 498 invasive breast carcinomas were analyzed. Representative tumor sections were stained for CD34 and CD105, and vascularity was quantified by the Chalkley method. The relationship between Chalkley counts, vascular invasion, disseminated tumor cells (DTC) in the bone marrow, other clinicopathologic variables, and clinical outcome was evaluated. RESULTS: High vascular grades determined by Chalkley counts were significantly associated with shorter distant disease-free survival and breast cancer-specific survival in all patients (P < 0.001, log-rank) and in node-negative patients not receiving adjuvant systemic therapy (P < 0.05). In multivariate analysis, both CD34 and CD105 Chalkley counts showed prognostic significance for distant disease-free survival (P = 0.014 and P = 0.026), whereas CD34 also showed prognostic significance for breast cancer-specific survival (P = 0.007). Vascular invasion and DTCs in the bone marrow showed independent prognostic significance. DTC did not discriminate survival for CD34 low Chalkley counts, whereas a very poor prognosis was observed for DTC-positive patients with high CD34 counts. In node-negative patients not receiving systemic chemotherapy, high CD34 and high CD105 counts in combination identified patients with unfavorable outcome, as opposed to all other CD34/CD105 combinations. CONCLUSIONS: Improved identification of risk groups could be obtained by adding CD34 and CD105 vascular analysis to DTC, vascular invasion, and other primary tumor factors. This may facilitate the selection of candidates for adjuvant systemic therapy.     

Anthropometric factors in relation to different tumor biological subgroups of postmenopausal breast cancer

Overweight and obesity is associated with an increased risk of postmenopausal breast cancer. However, less is known about the impact of anthropometric factors on tumor pathology and biology. A Swedish population-based prospective cohort study of 9,685 postmenopausal women not using hormonal replacement therapy (HRT) were followed for an average of 10.3 years during which 305 incident breast cancer cases were diagnosed. Invasive and sufficient tumor material was available in 248 cases. Pathological reevaluation of histological type and grade was conducted. Using a tissue microarray (TMA), the tumor expression of Ki67, HER2, ERalpha, ERbeta, PgR, cyclin D1 and p27 was evaluated. Six anthropometric factors: height, weight, body mass index (BMI), waist- and hip circumference and body fat percentage were categorized by quartiles of baseline anthropometric measurements, and relative risks were calculated using multivariate Cox regression models. Invasive breast cancer incidence was increased for women in the higher quartiles of all anthropometric measurements. Height was positively associated with Grade I and ERalpha-positive tumors. Women in the highest quartiles of weight, BMI, waist- and hip circumference and body fat percentage were all associated with tumors of ductal type, Grade II, low Ki67 index, HER2 negativity and low expression of the oncogene cyclin D1. Obesity was further associated with tumors expressing ERalpha and PgR but interestingly not ERbeta. This study confirmed previously described associations between overweight/obesity and increased risk of postmenopausal breast cancer. Furthermore, obesity was associated with tumors expressing several markers corresponding with low malignancy.     

Prognostic factors in primary breast cancer

A review and update of published studies on oestrogen receptor and progesterone receptor as prognostic factors in breast cancer supports the following conclusions. In stage I breast cancer the lack of oestrogen receptor seems to be the most important factor for predicting earlier recurrence and poorer survival. In stage II breast cancer, measurement of progesterone receptor appears to be better than measurement of oestrogen receptor for predicting disease-free survival, and is as important as the oestrogen receptor in predicting overall survival. The benefits of adjuvant endocrine therapy are better predicted by the presence or absence of progesterone receptor rather than by oestrogen receptor. Measurement of proliferative activity (DNA S-phase) by thymidine labelling or flow cytometry, and of aneuploidy by flow cytometry, also provides prognostic information. The strong correlations between tumour receptor content, per cent S-phase and aneuploidy suggest that these measurements in concert might identify a subset of stage I breast cancer patients at increased risk for recurrence, who would thus be potential candidates for adjuvant therapy.     

Influence of tumor location on breast cancer prognosis

Our objective was to investigate the influence of primary tumor location on breast cancer prognosis. We used a population-based registry since 1977 that has collected detailed information regarding clinical and histopathological presentation, postoperative therapy and follow-up status on Danish women with breast cancer. Nodal status and relative risk of dying was estimated according to primary tumor localization in the breast. Overall, 35319 patients with primary breast cancer were included in the study. After adjustment for prognostic factors, the risk of dying increased significantly (up to 21%) with increasing distance of tumor location from the axilla. This trend was seen both among women with and without spread to the axillary lymph nodes. In conclusion, survival is significantly better for women with a tumor in the upper lateral quadrant than tumors located elsewhere in the breast. Our finding of a similar trend according to distance from the axilla among women with positive axillary lymph nodes who all are allocated to systemic therapy suggests that a better lymph node staging procedure alone is unlikely to eliminate these survival differences. Other reasons for the observed differences should be sought to help improve survival for women with breast cancer.     

原发性双侧乳腺癌的预后分析

目的分析影响双侧乳腺癌患者生存率的预后因素.方法对18例经病理组织学证实的原发性双侧乳腺癌患者进行回顾性分析.其中同时发生3例(16.7%);先后发生15例(83.3%),均接受手术、放疗、化疗等综合治疗.分析原发性肿瘤临床T分期、腋下淋巴结的转移、月经情况及两侧乳腺癌发生的间隔时间与患者生存率的关系.结果原发性肿瘤临床T分期、腋下淋巴结的转移及两侧乳腺癌发生的间隔时间为患者的主要预后因素.结论原发性双侧乳腺癌患者的原发灶大小、淋巴结浸润及两侧癌发生的间隔时间与患者的预后有显著关系;第二原发乳腺癌患者的早期发现,早期治疗可提高生存率.     

双侧原发性乳腺癌的分子生物学特征

目的:探讨双侧原发性乳腺癌(bilateral primary breast cancer,BPBC)的分子生物学特征。方法:回顾性分析325例BPBC与650例单侧乳腺癌(unilateral breast cancer,UBC)患者的临床病理资料,应用单因素分析和Logistic回归多因素分析,寻找BPBC发生的相关分子生物学依据。结果:与UBC患者比较,BPBC患者第一癌发病年龄早、有乳腺癌家族史、肿瘤直径>5cm及临床Ⅲ期患者较多(P均<0.05)。在分子生物学特征方面,BPBC第一癌患者雌激素受体(estrogen receptor,ER)和孕激素受体(progesterone receptor,PR)阴性比率、p53阳性率和细胞增殖核抗原Ki67高表达者均高于UBC患者(P<0.05);人表皮生长因子受体2(human epidermal growth factor receptor2,Her-2)表达在二者间的差异无统计学意义(P>0.05)。其中乳腺癌家族史、肿瘤直径>5cm、p53阳性为BPBC发生的独立危险因素,ER(+)或PR(+)者发生BPBC的风险下降。结论:BPBC与UBC在生物学行为上存在一定的差异,对于年轻、有乳腺癌家族史、激素受体阴性,p53阳性及Ki67高表达的乳腺癌患者要注意检查对侧乳腺癌的发生。     

Gamma-heregulin has no biological significance in primary breast cancer

British Journal of Cancer (2002) 86, 1362–1363. DOI: 10.1038/sj/bjc/6600245 www.bjcancer.com© 2002 Cancer Research UK     

乳腺癌生物学预后因子的研究进展

乳腺癌是多步骤发生的疾病，存在多个生物学因子的异常。研究生物学预后因子不仅能发现临床病理学指标不能发现的部分易复发患者，而且有助于实施乳腺癌的个体化治疗。本文综述乳腺癌生物学预后因子，如Her-2/neu、P53、BRCA1、血管生成因子（angiogenesis)杂合性丢失（LOH）等的最新进展。     

Integrins and tumor cell dissemination

The ability of a tumor cell to metastasize is determined, in part, by its adhesive interactions with other cells and with components of the extracellular matrix. An ever-expanding family of cell surface receptors, the integrins, is an essential player in these interactions. Research efforts aimed at understanding the precise role of individual integrins in normal and transformed cells may offer a general framework for future therapeutic approaches. Here we review recent progress toward this goal.     

HLA and prognostic factors in primary breast cancer

A group of 157 women with primary breast cancer (BC) were typed for HLA antigens, and gene frequencies were compared to those of 327 control healthy individuals. Diagnosis of BC was made for all patients on surgical mastectomy specimens; histologic grading, estrogen (ER) and progesterone (PgR) receptors were determined on all primary tumors. Typed antigens included the majority of the specificities controlled by the HLA-A, -B and -C loci, according to the 8th International Histocompatibility Testing Workshop recommendations. No significant discrepancy in their frequencies was found in the undivided sample as compared to controls. The analysis of HLA gene frequency was extended to subsets of patients identified by the following prognostic features: (a) age at tumor diagnosis (pre-menopause vs. post-menopause); (b) receptor status (presence vs. absence of ER and PgR); (c) mammary gland dysplasia (presence vs. absence); (d) histologic grade (grade 3 vs. grades 1 and 2 combined); (e) time to relapse before or after 24 months following mastectomy). A moderate deviation from normal of some genes was found in several subsets, often affecting only one of the antithetical subgroups (feature present vs. feature absent). In the instance of B5, the increase in frequency of the gene in one of the subset pair (ER + subjects) was balanced by a decrease of the same gene in the counterpart (ER-subjects). Increased frequencies were found for the B7 gene in the following prognostic groups: (a) lack of ER (0.08); (b) lack of PgR (0.09); (c) absence of mammary dysplasia (0.075); (d) histologic grade 3 (0.10); and (e) premenopause (0.12), the last two showing significant divergence from normal. When features (d) and (e) on the one hand and (a), (b), (d) and (e) on the other were combined, B7 reached frequencies of 0.18 (p less than 5 X 10(-4] and of 0.29 (p less than 5 X 10(-6], respectively.     

Prediction of lymph node metastases in breast cancer by clinicopathological and biological features of the primary tumor

Background  Although histologically confirmed nodal status continues to be the most important and reliable prognostic factor, preoperative assessment of nodal status has been required in order to avoid unnecessary surgery. Methods  The present review was carried out to elucidate the relationship between nodal status and various histologic/biologic factors of the primary tumor, and to evaluate their nodal predictabilities. Results  The incidence of nodal metastases increases with increasing tumor size. Nodal metastases, however, are quite uncommon in Tla (tumor sized 5 mm or less) cancers and in ductal carcimona in situ (DCIS). The use of various promising biological markers for predicting nodal status, however, seems to be still far from clinical use. Conclusion  The probability of nodal metastases is quite low in patients with Tl a cancer or DCIS. Therefore, routine axillary dissection for these patients has no diagnostic or therapeutic value.