160例乳腺癌术后血行转移患者中医辨证分型的研究

Objective： To discuss the relationship between the postoperative breast cancer with distant metastasis and the TCM syndromes classification. Methods： 160 postoperative 5-year breast cancer patients from 1995 to 2000 were tracked, summed up and analysized TCM syndromes as stagnation of hepatic qi, deficiency of spleen and pathogenic phlegm retention, blood stasis and toxin stagnation, deficiencies of both blood and qi. Results： （1） For blood stasis and toxin stagnation TCM syndrome, the metastatic rate raised to 45% during 5 years. However, the metastatic rates of other three TCM syndromes are 15%, 17.5% and 22.5% respectively. The general distant metastasis rate was 27.5% （P〈0.01）. （2） Lymph node metastasis, tumor size, Her-2 and its receptor have no obvious relation with TCM syndromes classification （P〉0.05）. Conclusion： （1） TCM syndrome classification has close relation with breast cancer distant metastasis. Distant metastasis have close relationship with blood stasis and toxin stagnation syndrome. （2） Lymph node metastasis, tumor size, Her-2 and its receptor have no obvious relation with TCM syndromes classification, which suggested that metastatic ability has been programmed in the early stage of carcinoma initiation. （3） Significantly enlightening for predict the prognosis under the guide of TCM syndrome classification and take right therapeutic strategy： attack pathogen and activate blood circulation against cancer.     

The relationship between the tumour stroma percentage,clinicopathological characteristics and outcome in patients with operable ductal breast cancer

Background:

The percentage of tumour stroma (TSP) has recently been reported to be a novel independent predictor of outcome in patients with a variety of common solid organ tumours. The aim of this study was to examine the relationship between TSP, clinicopathological characteristics and outcome in patients with invasive ductal breast cancer, in particular node negative and triple negative disease.

Methods:

A total of 361 patients with primary operable invasive ductal breast cancer were included in this study. The TSP was assessed visually on the haematoxylin and eosin-stained tissue sections. With a cutoff value of 50% TSP, patients with ⩽50% stroma were classified as the low-TSP group and those with >50% stroma were classified as the high-TSP group.

Results:

A total of 109 (30%) patients had high TSP. Patients with high TSP were old age (P=0.035), had more Her-2-positive tumours (P=0.029), low-grade tumour inflammatory infiltrate (P=0.034), low CD68+macrophage infiltrate (P<0.001), low CD4+ (P=0.023) and low CD8+ T-lymphocytes infiltrate (P=0.017), tumour recurrence (P=0.015) and shorter cancer-specific survival (P<0.001). In node-negative patients (n=207), high TSP was associated with low CD68+macrophage infiltrate (P=0.001), low CD4+ (P=0.040) and low CD8+ T-lymphocytes infiltrate (P=0.016) and shorter cancer-specific survival (P=0.005). In triple negative patients (n=151), high TSP was associated with high tumour grade (P=<0.001), lymph node positivity (P=0.027), low CD68+macrophage infiltrate (P=0.011) and shorter cancer-specific survival (P=0.035). The 15-year cancer-specific survival rate was 79% vs 21% in the low-TSP group vs high-TSP group. In multivariate survival analysis, a high TSP was associated with reduced cancer-specific survival in the whole cohort (P=0.001), node-negative patients (P=0.007) and those who received systemic adjuvant therapy (P=0.021), independent of other pathological characteristics including host inflammatory response. However, TSP was not an independent prognostic factor for triple negative patients (P=0.151).

Conclusions:

A high TSP in primary operable invasive ductal breast cancer was associated with recurrence and poorer long-term survival. The inverse relation with the tumour inflammatory infiltrate highlights the importance of the amount of tumour stroma on immunological response in patients with primary operable ductal breast cancer. Implementing this simple and reproducible parameter in routine pathological examination may help optimise risk stratification in patients with invasive ductal breast cancer.     

The relationship between tumour budding,the tumour microenvironment and survival in patients with invasive ductal breast cancer

Background:

Tumour budding has previously been reported to predict survival in several solid organ tumours, including breast; however, whether this is independent of other aspects of the tumour microenvironment is unknown. In the present study, the relationship between tumour budding, the tumour microenvironment and survival was examined in patients with invasive ductal breast cancer.

Methods:

Patients presenting between 1995 and 1998 were studied (n=474). Using routine pathological sections, tumour budding was measured at the invasive margin and its association with clinicopathological characteristics and cancer-specific survival (CSS) was examined.

Results:

Tumour budding was associated with several adverse pathological characteristics, including lymph node involvement, lymph vessel invasion (LVI), increased tumour stroma percentage (TSP) and weaker local inflammatory infiltrative. Tumour budding was associated with reduced CSS (hazard ratio (HR) 2.08, 95% confidence interval (CI) 1.14–3.09, P=0.004), independent of nodal status, molecular subtypes, tumour necrosis, CD8+, CD138+, LVI, blood vessel invasion and TSP. Further, tumour budding was independently associated with reduced CSS in node-negative patients (HR 2.63, 95% CI 1.16–5.92, P=0.020) and those who have low TSP (HR 1.98, 95% CI 1.09–3.57, P=0.024) and high-grade local inflammatory infiltrative (HR 2.27, 95% CI 1.35–5.36, P=0.014).

Conclusions:

Tumour budding was a significant predictor of survival in patients with invasive ductal breast cancer, independent of adverse pathological characteristics and components of tumour microenvironment. The present study further confirms the clinical utility of both tumour and host-based factors of tumour microenvironment.     

分子分型在早期乳腺癌复发、转移中的预测价值

目的:研究0-Ⅱb期乳腺癌患者分子分型与局部复发、远处转移间的关系,为个体化治疗提供依据。方法:回顾分析2001年-2008年收治的临床分期为0-Ⅱb期乳腺癌患者369例。根据免疫组织化学、荧光原位杂交检测技术结果分为Luminal A、Luminal B、HER-2过表达和Basal-like型,比较局部复发率和远处转移率,并结合临床病理特征对其局部复发和远处转移进行分组分析。Kaplan-Meier法计算局部复发率、远处转移率并Logrank法检验和单因素预后分析。结果:Luminal A、Luminal B、HER-2过表达和Basal-like型分别占30.1%、48.5%、9.2%和12.2%。随访率95.4%,随访时间满5、10年者分别为225、85例。单因素分析显示HER-2过表达型、Basal-like型局部复发、远处转移风险均比Luminal A、Luminal B型高。5年局部复发率和远处转移率分别为23.5%、24.4%、6.3%、6.1%和26.5%、28.9%、2.7%、2.2%（P＜0.001,P＜0.001）。结论:分子分型有助于个体化区别早期乳腺癌患者间局部复发和远处转移的风险。     

Family history and breast cancer tumour characteristics in screened women

Women with a family history of breast cancer have an increased risk of the disease. However, since they tend to experience greater surveillance for the disease, their breast cancers may be detected at an earlier stage, thus making it difficult to assess reliably whether tumour characteristics vary by family history. Information on 9,731 Million Women Study participants with screen-detected breast cancer, diagnosed in 1996-2003, and 37,983 matched controls, who also attended routine screening but were not diagnosed with breast cancer, was used to estimate adjusted relative risks (RRs) of screen-detected breast cancer in women with a family history of the disease. Women with a family history of breast cancer had an increased risk of screen-detected breast cancer (RR 1.57; 95% CI:1.47-1.68) compared with those without such a family history. The RRs were 1.58 (1.46-1.71) and 1.55 (1.34-1.80) for invasive and in situ breast cancer; 1.63 (1.49-1.79) and 1.55 (1.32-1.83) for node-negative and node-positive disease; and 1.56 (1.42-1.70), 1.75 (1.39-2.21) and 1.71 (1.28-2.29) for ductal, lobular and tubular cancers. There was no significant difference in the RR of screen-detected breast cancer associated with a family history of the disease according to invasiveness, size, nodal status, malignancy grade or morphological type of the breast cancer.     

CD44+/CD24-细胞在乳腺癌组织中比例与乳腺癌远处转移关系

目的:旨在探讨CD44+/CD 24-细胞在乳腺癌组织中的比例与乳腺癌远处转移之间关系。方法:随机选取2003年1 月至2004年10月于天津医科大学肿瘤医院确诊的乳腺癌患者60例,并将其分为30例转移组及30例非转移组（对照组）。 免疫组织化学双重染色技术检测60例患者石蜡切片中CD44+/CD 24-细胞在乳腺癌组织中所占比例,分析其与远处转移之间关系。结果:转移组与对照组中CD44+/CD 24-细胞在乳腺癌组织中所占比例具有显著性差异（χ2= 11.334 ,P < 0.05）。 骨转移中CD44+/CD24-细胞在乳腺癌组织中比例有显著性差异（χ2= 9.250 ,P = 0.01）。 CD44+/CD 24-细胞在乳腺癌组织中5 年无瘤生存期比例有显著性差异（χ2= 8.058,P = 0.005）。结论:CD44+/CD 24-细胞在乳腺癌组织中所占比例与乳腺癌远处转移密切相关,特别是骨转移。      

Primary tumour characteristics and axillary lymph node status in breast cancer.

This paper examines the correlation between axillary lymph node status and primary tumour characteristics in breast cancer and whether this can be used to select patients for axillary lymphadenectomy. The results are based on a retrospective analysis of 909 patients who underwent axillary dissection in our unit. Axillary lymph nodes containing metastases were found in 406 patients (44.7%), all with invasive carcinomas, but in none of the 37 carcinomas-in-situ. Nodal status was negative in all T1a tumours, but lymph node metastases were present in 16.3% and 35.7% of T1b and T1c tumours respectively. When histological grade was taken into account, positivity for grade I T1b and T1c tumours fell to 13.6% and 26.7% respectively. Lymph node metastases were found in 85% of patients with lymphovascular invasion in their tumours as compared to only 15.4% of those without and in 45.5% of oestrogen and progesterone receptor-positive tumours. When one or both hormone receptors were absent this figure was much higher. It appears that for T1a breast cancers axillary dissection is not necessary, whereas for T1b, T1c and grade I T2 tumours other histopathological parameters should be taken into consideration in deciding who should undergo axillary lymphadenectomy.     

A preoperative nomogram to predict the risk of synchronous distant metastases at diagnosis of primary breast cancer

Background:

The detection of synchronous metastases at primary diagnosis of breast cancer (BC) affects its initial management. A risk calculator that incorporates many factors to evaluate an individual''s risk of harbouring synchronous metastases would be useful to adapt cancer management.

Patients and Methods:

Patients with primary diagnosis of BC were identified from three institutional databases sharing homogeneous work-up recommendations. A risk score for synchronous metastases was estimated and a nomogram was constructed using the first database. Its performance was assessed by receiver characteristic (ROC) analysis. The nomogram was externally validated in the two independent cohorts.

Results:

A preoperative nomogram based on the clinical tumour size (P<0.001), clinical nodal status (P<0.001), oestrogen (P=0.17) and progesterone receptors (P=0.04) was developed. The nomogram accuracy was 87.3% (95% confidence interval (CI), 84.45–90.2%). Overall, the area under the ROC curve (AUC) was 86.1% for the validation set from the Institut Curie-René Huguenin, and 63.8% for the MD Anderson validation set. The negative predictive value (NPV) was high in the three cohorts (97–99%).

Conclusions:

We developed and validated a strong metastasis risk calculator that can evaluate with high accuracy an individual''s risk of harbouring synchronous metastases at diagnosis of primary BC.

Condensed abstract:

A nomogram to predict synchronous metastases at diagnosis of breast cancer was developed and externally validated. This tool allows avoiding unnecessary expensive work-up.     

CD44 increases the efficiency of distant metastasis of breast cancer

Metastasis is the predominant cause of death from cancer yet we have few biomarkers to predict patients at increased risk of metastasis and are unable to effectively treat disseminated disease. Analysis of 448 primary breast tumors determined that expression of the hylauronan receptor CD44 associated with high grade (p = 0.046), ER- (p = 0.001) and PR-negative tumors (p = 0.029), and correlated with increased distant recurrence and reduced disease-free survival in patients with lymph-node positive or large tumors. To determine its functional role in distant metastasis, CD44 was knocked-down in MDA-MB-231 cells using two independent shRNA sequences. Loss of CD44 attenuated tumor cell adhesion to endothelial cells and reduced cell invasion but did not affect proliferation in vitro. To verify the importance of CD44 to post-intravasation events, tumor formation was assessed by quantitative in vivo imaging and post-mortem tissue analysis following an intra-cardiac injection of transfected cells. CD44 knock-down increased survival and decreased overall tumor burden at multiple sites, including the skeleton in vivo. We conclude that elevated CD44 expression on tumour cells within the systemic circulation increases the efficiency of post-intravasation events and distant metastasis in vivo, consistent with its association with increased distant recurrence and reduced disease-free survival in patients.     

Impact of tumour size on axillary involvement and distant dissemination in breast cancer

Background:

Tumour size and nodal involvement are the two main prognostic factors in breast cancer (BC). Their impact on the natural history of BC is not fully captured by analyses that ignore their quantitative nature.

Method:

Data pertaining to 18 159 patients treated with primary surgery: 3661 at the Institut Gustave-Roussy (IGR, France) between 1954 and 1983, and 14 498 in the breast cancer registry in the Stockholm–Gotland Health Care region (SG, Sweden) between 1976 and 1999, were collected. The risks of distant metastases (DMs) and of nodal involvement were analysed according to tumour size with parametric models.

Results:

Using SG 1976–1990 as the reference group, relative risks (RRs) for DM were equal to 1.42 (95% CI: 1.29–1.56; P<10⁻¹⁰) in IGR and 0.61 (95% CI: 0.55–0.67; P<10⁻¹⁰) in SG 1991–1999. Differences in tumour size explained the increased risk in IGR (RR adjusted for tumour size 1.09; 95% CI: 0.99–1.20; P=0.07), but not the decreased risk in SG 1991–1999 (adjusted RR: 0.63; 95% CI: 0.57–0.69; P<10⁻¹⁰). The relationship between tumour size and DM risk changed significantly during the 1990s.

Conclusion:

Early diagnosis is sufficient to explain differences in the prognosis before 1990. After 1990, the use of adjuvant systemic therapies is the main reason for the reduction in DM.     

TGFBI modulates tumour hypoxia and promotes breast cancer metastasis

Breast cancer metastasis is a complex process that depends not only on intrinsic characteristics of metastatic stem cells, but also on the particular microenvironment that supports their growth and modulates the plasticity of the system. In search for microenvironmental factors supporting cancer stem cell (CSC) growth and tumour progression to metastasis, we here investigated the role of the matricellular protein transforming growth factor beta induced (TGFBI) in breast cancer. We crossed the MMTV‐PyMT model of mammary gland tumorigenesis with a Tgfbi ^Δ/Δ mouse and studied the CSC content of the tumours. We performed RNAseq on wt and ko tumours, and analysed the tumour vasculature and the immune compartment by IHC and FACS. The source of TGFBI expression was determined by qPCR and by bone marrow transplantation experiments. Finally, we performed in silico analyses using the METABRIC cohort to assess the potential prognostic value of TGFBI. We observed that deletion of Tgfbi led to a dramatic decrease in CSC content and lung metastasis. Our results show that lack of TGFBI resulted in tumour vessel normalisation, with improved vessel perfusion and decreased hypoxia, a major factor controlling CSCs and metastasis. Furthermore, human data mining in a cohort of breast cancer patients showed that higher expression of TGFBI correlates with poor prognosis and is associated with the more aggressive subtypes of breast cancer. Overall, these data reveal a novel biological mechanism controlling metastasis that could potentially be exploited to improve the efficacy and delivery of chemotherapeutic agents in breast cancer.

Abbreviations

CSC

cancer stem cell

ECM

extracellular matrix

EMT

epithelial‐to‐mesenchymal transition

FACS

fluorescence‐activated cell sorting

TGFBI

transforming growth factor beta induced

     

乳腺癌术后胸壁转移的外科治疗

目的　探讨乳腺癌术后胸壁转移的外科治疗及方法。方法　 1997年 6月～ 2 0 0 0年 12月手术治疗 30例乳腺癌术后胸壁转移瘤。胸壁肿物切除后行对侧乳腺劈裂瓣修补术 16例 ,行同侧腹直肌瓣修补术 6例 ,行大网膜瓣修补+中厚皮瓣植皮术 8例。术后予以CAF方案化疗 14例 ,NP方案化疗 16例。结果　术后皮瓣部分坏死 2例 ,均为大网膜瓣修补 +中厚皮瓣植皮术治疗病例 ,经清创再植皮而痊愈。全部病例均获得随访。术后肿瘤远处再发转移 5例 ,予以继续化疗获得缓解。结论　外科治疗使乳腺癌术后胸壁转移取得良好效果 ,提高患者的生活质量。     

Genomic instability and proliferative activity as risk factors for distant metastases in breast cancer

The role of genomic instability and proliferative activity for development of distant metastases in breast cancer was analysed, and the relative contribution of these two risk factors was quantified. A detailed quantitative comparison was performed between Ki67 and cyclin A as proliferative markers. The frequency of Ki67 and cyclin A-positive cells was scored in the same microscopic areas in 428 breast tumours. The frequency of Ki67-positive cells was found to be highly correlated with the frequency of cyclin A-positive cells, and both proliferation markers were equally good to predict risk of distant metastases. The relative contribution of degree of aneuploidy and proliferative activity as risk markers for developing distant metastases was studied independently. Although increased proliferative activity in general was associated with an increased risk of developing distant metastases, ploidy level was found to be an independent and even stronger marker when considering the group of small (T1) node negative tumours. By combining proliferative activity and ploidy level, a large group of low risk breast tumours (39%) could be identified in which only a few percentage of the tumours (5%) developed distant metastases during the 9-year follow-up time period.     

Predictors of central nervous system metastasis in patients with metastatic breast cancer. A competing risk analysis of 579 patients treated with epirubicin-based chemotherapy

Summary In order to identify factors predictive of central nervous system (CNS) metastasis, we reviewed the histories of 579 patients treated with epirubicin-based chemotherapy for metastatic breast cancer. Statistical analysis included Kaplan–Meier survival plots, Cox’s regression analysis and competing risk analysis using the cumulative incidence. Median follow-up-time was 137 months (range 0–183+). In this period, one hundred and twenty-four patients (21.4%) developed CNS metastasis. Lung, liver, and lymph node metastases and oestrogen receptor negative or unknown tumor were predictive as well. However, increased pretreatment lactate dehydrogenase (LDH) concentration in serum above the upper normal limits was the strongest single risk factor and should therefore be measured. The risk of CNS metastasis differed considerably among risk groups. Patients without risk factors had a cumulative incidence on 9%, compared to a cumulative incidence of 42%, when the serum LDH concentration was elevated to more than twice the upper normal limits.     

Treatment and outcome of brain metastasis as first site of distant metastasis from breast cancer

Twenty-eight consecutive patients with breast cancer were analyzedwho presented with a single brain metastasis asfirst site of distant metastasis. The response tosurgery with postoperative radiation therapy (RT) (9 patients)and to non-surgical therapy as first-line treatment was100% and 89% respectively with a significant differencein median recurrence-free intervals of 23 months andof 5 months respectively (p=0.033). Retreatmentof a local relapse by surgery (± RT,± chemotherapy) or by non-surgical treatment resulted ina response in 6 of the 7 operatedpatients and in 5 of the 6 non-operatedpatients with a median duration of response of7 months (range 2–20 months) and of 3months (range 2–4 months) respectively. The overall mediansurvival of the 28 patients with a singlebrain metastasis was 16 months (range 2–39 months).The median survival in the primarily operated patientswas 23 months, in the primarily not-operated group10 months, and in the never-operated group 9months. In comparison, the response to non-surgical treatmentin 20 consecutive patients who presented with multiplebrain metastases as first site of distant metastasiswas 55% with a median recurrence free intervalof 4 months. The median survival in thisgroup was 4 months, which was significantly shorterthan survival of patients with single brain metastasis(p=0.0036). These results suggest that breastcancer patients with a single brain metastasis asfirst presentation of relapse constitute a specific subgroupwith a favorable response to treatment and along survival especially if they can be treatedby surgery with postoperative RT.     

Detection and prognostic significance of circulating tumour cells in patients with metastatic breast cancer according to immunohistochemical subtypes

Background:

The enumeration of circulating tumour cells (CTCs) with the EpCAM-based CellSearch system has prognostic significance in patients with metastatic breast cancer (MBC). The aim of this study was to explore potential differences in the detection and prognostic significance of CTCs in MBC according to immunohistochemical subtypes of breast cancer.

Methods:

CellSearch CTC counts were obtained from 154 MBC patients before first-line systemic treatment between November 2007 and August 2012. Patients were categorised in five subgroups according to immunohistochemical surrogate definitions of intrinsic subtypes in breast cancer based on hormone receptor status, HER2/neu status and histological grade. Differences in progression-free (PFS) and overall survival (OS) were assessed relative to the cut-off value of ⩾5 CTCs per 7.5 ml blood.

Results:

No significant differences were observed in the absolute CTC counts (P=0.120) or in CTC positivity rates according to ⩾1 and ⩾5 CTCs per 7.5 ml blood detection thresholds (P=0.165 and P=0.651, respectively) between immunohistochemical subtypes. However, very high CTC counts, defined as ⩾80 CTCs per 7.5 ml, were observed more frequently in patients with Luminal A and triple negative (TN) breast cancer (P=0.024). In the total study population, the presence of ⩾5 CTCs was the single most significant prognostic factor for both PFS and OS in multivariate analysis (P<0.001). A more limited prognostic impact, not reaching statistical significance, was observed in patients with HER2-positive disease as opposed to patients with Luminal A, Luminal B–HER2-negative and TN disease.

Conclusion:

The detection of EpCAM+CTCs was not clearly associated with any of the immunohistochemical subtypes of breast cancer in patients with MBC before first-line treatment. Potentially clinically relevant differences were however observed at very high CTC counts. Furthermore, our data suggest a lower prognostic significance of CTC evaluation in HER2-positive patients with MBC.     

Patterns of metastasis and survival in breast cancer patients: a preliminary study in an Iranian population

Due to lack of sufficient data on characteristics of breast cancer patients and risk factors for developing metastasis in Iran this study was designed to understand clinical aspects impacting on survival. A cross-sectional study on breast cancer patients was conducted in an oncology clinic of the university hospital between 1995 and 2010. Data were retrieved from medical records and included age, menopausal status, tumor diameter, number of involved nodes, histopathological type, estrogen and progesterone receptor expression, c-erbB-2, primary and secondary metastasis sites, overall survival, disease free interval and type of chemotherapy protocol. The results were analyzed with SPSS 13 software.The mean age of the patients was 49.2 (27-89) years. The primary tumors were mainly ER positive (48%) and PR negative (49.3%). The status of lymph nodes dissected and examined in these patients was unknown in 19 patients (25.3%) while 18 patients (24%) had positive lymph nodes with no report on the number of involved nodes. All of the patients had received antracyclin based chemotherapy in an adjuvant or metastatic setting. Adjuvant hormonal therapy was administered to receptor positive patients. In average, overall survival after recurrence was 30 months (95%CI 24.605-35.325) for non-skeletal versus 42 months (95%CI 31.211-52.789) for skeletal metastasis (P= 0.002). The median survival was also greater for receptor positive patients; 39 months (95%CI 33.716-44.284) for PR+ versus 26 months (95%CI 19.210-32.790) for PR- (P=0.047) and 38 months (95%CI 32.908-43.092) for ER+ versus 27 months (95%CI 18.780-35.220) for ER- patients (P=0.016). No relation was found between site of first metastasis and hormone receptor, age, tumor diameter, DFI and menopausal status. Sites of metastasis were independent of age, size of the tumor, menopausal and hormone receptor status in this study. Overall survival provided significant relations with respect to receptor status and bone metastasis.     

咸阳地区女性乳腺癌患者临床特点及预后分析

目的:了解咸阳地区女性乳腺癌患者临床特点和预后情况,为乳腺癌防治及个体化治疗提供依据。方法:本研究纳入472例咸阳市2所三级甲等医院于2008年3月至2015年1月期间收治的乳腺癌患者,入组患者均为女性且行外科手术治疗。收集入组患者的临床特征并分析患者影响复发转移和生存的相关因素。结果:本研究中位随访时间56个月,随访过程中失访9例;肿块大小、是否有淋巴结转移、组织学分级、是否三阴性乳腺癌是预测肿瘤复发转移及预后的独立影响因子。结论:咸阳地区乳腺癌生存情况较国内生活水平高的地区差,复发转移率高,早期诊断能够改善患者预后。