Coexpression analysis of CD133 and CD44 identifies Proneural and Mesenchymal subtypes of glioblastoma multiforme

Accumulating evidence suggests that the stem cell markers CD133 and CD44 indicate molecular subtype in Glioblastoma Multiforme (GBM). Gene coexpression analysis of The Cancer Genome Atlas GBM dataset was undertaken to compare markers of the Glioblastoma Stem-Progenitor Cell (GSPC) phenotype. Pearson correlation identified genes coexpressed with stem cell markers, which were then used to build a gene signature that classifies patients based on a CD133 coexpression module signature (CD133-M) or CD44-M subtype. CD133-M tumors were enriched for the Proneural (PN) GBM subtype compared to Mesenchymal (MES) subtype for CD44-M tumors. Gene set enrichment identified DNA replication/cell cycle genes in the CD133-M and invasion/migration in CD44-M, while functional experiments showed enhanced cellular growth in CD133 expressing cells and enhanced invasion in cells expressing CD44. As with the 4 major molecular subtypes of GBM, there was no long-term survival difference between CD44-M and CD133-M patients, although CD44-M patients responded better to temozolomide while CD133-M patients benefited from radiotherapy. The use of a targeted coexpression approach to predict functional properties of surface marker expressing cells is novel, and in the context of GBM, supports accumulating evidence that CD133 and CD44 protein marker expression correlates with molecular subtype.     

Accumulation of 2-hydroxyglutarate is not a biomarker for malignant progression in IDH-mutated low-grade gliomas

Objectives

To determine whether accumulation of 2-hydroxyglutarate in IDH-mutated low-grade gliomas (LGG; WHO grade II) correlates with their malignant transformation and to evaluate changes in metabolite levels during malignant progression.

Methods

Samples from 54 patients were screened for IDH mutations: 17 patients with LGG without malignant transformation, 18 patients with both LGG and their consecutive secondary glioblastomas (sGBM; n = 36), 2 additional patients with sGBM, 10 patients with primary glioblastomas (pGBM), and 7 patients without gliomas. The cellular tricarboxylic acid cycle metabolites, citrate, isocitrate, 2-hydroxyglutarate, α-ketoglutarate, fumarate, and succinate were profiled by liquid chromatography–tandem mass spectrometry. Ratios of 2-hydroxyglutarate/isocitrate were used to evaluate differences in 2-hydroxyglutarate accumulation in tumors from LGG and sGBM groups, compared with pGBM and nonglioma groups.

Results

IDH1 mutations were detected in 27 (77.1%) of 37 patients with LGG. In addition, in patients with LGG with malignant progression (n = 18), 17 patients were IDH1 mutated with a stable mutation status during their malignant progression. None of the patients with pGBM or nonglioma tumors had an IDH mutation. Increased 2-hydroxyglutarate/isocitrate ratios were seen in patients with IDH1-mutated LGG and sGBM, in comparison with those with IDH1-nonmutated LGG, pGBM, and nonglioma groups. However, no differences in intratumoral 2-hydroxyglutarate/isocitrate ratios were found between patients with LGG with and without malignant transformation. Furthermore, in patients with paired samples of LGG and their consecutive sGBM, the 2-hydroxyglutarate/isocitrate ratios did not differ between both tumor stages.

Conclusion

Although intratumoral 2-hydroxyglutarate accumulation provides a marker for the presence of IDH mutations, the metabolite is not a useful biomarker for identifying malignant transformation or evaluating malignant progression.     

MicroRNA profiling of Chinese primary glioblastoma reveals a temozolomide-chemoresistant subtype

Accumulating evidence demonstrates that defining molecular subtypes based on objective genetic alterations may permit a more rational, patient-specific approach to molecular targeted therapy across various cancers. The objective of this study was to subtype primary glioblastoma (pGBM) based on MicroRNA (miRNA) profiling in Chinese population. Here, miRNA expression profiles from 82 pGBM samples were analyzed and 78 independent pGBM samples were used for qRT-PCR validation. We found that two distinct subgroups with different prognosis and chemosensitivities to temozolomide (TMZ) in Chinese pGBM samples. One subtype is TMZ chemoresistant (termed the TCR subtype) and confers a poor prognosis. The other subtype is TMZ-chemosensitive (termed the TCS subtype) and confers a relatively better prognosis compared with the TCR subtype. A classifier consisting of seven miRNAs was then identified (miR-1280, miR-1238, miR-938 and miR-423-5p (overexpressed in the TCR subtype); and let-7i, miR-151-3p and miR-93 (downregulated in the TCR subtype)), which could be used to assign pGBM samples to the corresponding subtype. The classifier was validated using both internal and external samples. Meanwhile, the genetic alterations of the TCR and TCS subtypes were also analyzed. The TCR subtype was characterized by no IDH1 mutation, and EGFR and Ki-67 overexpression. The TCS subtype displayed the opposite situation. Taken together, the results indicate a distinct subgroup with poor prognosis and TMZ-chemoresistance.     

Different angiogenic phenotypes in primary and secondary glioblastomas

Primary and secondary glioblastomas (pGBM, sGBM) are supposed to evolve through different genetic pathways, including EGF receptor and PDGF and its receptor and thus genes that are involved in tumor-induced angiogenesis. However, whether other angiogenic cytokines are also differentially expressed in these glioblastoma subtypes is not known so far, but this knowledge might be important to optimize an antiangiogenic therapy. Therefore, we studied the expression of several angiogenic cytokines, including VEGF-A, HGF, bFGF, PDGF-AB, PDGF-BB, G-CSF and GM-CSF in pGBMs and sGBMs as well as in gliomas WHO III, the precursor lesions of sGBMs. In tumor tissues, expression of all cytokines was observed albeit with marked differences concerning intensity and distribution pattern. Quantification of the cytokines in the supernatant of 30 tissue-corresponding glioma cultures revealed a predominant expression of VEGF-A in pGBMs and significantly higher expression levels of PDGF-AB in sGBMs. HGF and bFGF were determined in nearly all tumor cultures but with no GBM subtype or malignancy-related differences. Interestingly, GM-CSF and especially G-CSF were produced less frequently by tumor cells. However, GM-CSF secretion occurred together with an increased number of simultaneously secreted cytokines and correlated with a worse patient prognosis and may thus represent a more aggressive angiogenic phenotype. Finally, we confirmed an independent contribution of each tumor-derived cytokine analyzed to tumor-induced vascularization. Our data indicate that an optimal antiangiogenic therapy may require targeting of multiple angiogenic pathways that seem to differ markedly in pGBMs and sGBMs.     

Identification of intrinsic subtype-specific prognostic microRNAs in primary glioblastoma

Background

Glioblastoma multiforme (GBM) is the most malignant type of glioma. Integrated classification based on mRNA expression microarrays and whole–genome methylation subdivides GBM into five subtypes: Classical, Mesenchymal, Neural, Proneural-CpG island methylator phenotype (G-CIMP) and Proneural-non G-CIMP. Biomarkers that can be used to predict prognosis in each subtype have not been systematically investigated.

Methods

In the present study, we used Cox regression and risk-score analysis to construct respective prognostic microRNA (miRNA) signatures in the five intrinsic subtypes of primary glioblastoma in The Cancer Genome Atlas (TCGA) dataset.

Results

Patients who had high-risk scores had poor overall survival compared with patients who had low-risk scores. The prognostic miRNA signature for the Mesenchymal subtype (four risky miRNAs: miR-373, miR-296, miR-191, miR-602; one protective miRNA: miR-223) was further validated in an independent cohort containing 41 samples.

Conclusion

We report novel diagnostic tools for deeper prognostic sub-stratification in GBM intrinsic subtypes based upon miRNA expression profiles and believe that such signature could lead to more individualized therapies to improve survival rates and provide a potential platform for future studies on gene treatment for GBM.     

胶质母细胞瘤经典亚型特征性基因变异的研究进展

目的 胶质母细胞瘤(Glioblastoma,GBM)是颅内最常见的原发恶性肿瘤,其恶性程度高、侵袭能力强、预后差。近年来随着生物学技术的发展,对GBM的理解也从病理学诊断逐步转向分子病理机制的研究。根据基因表达和DNA甲基化的模式将原发性GBM分为经典型、间质型、前神经元型和神经元型四种亚型。这些分子分型与胶质母细胞瘤的生物学特性密切相关。本文简要介绍了原发胶质母细胞瘤的分子分型,重点关注经典型GBM中EGFR、PTEN、PI3K和CDKN2A四种特征性基因的变异情况,并且对经典型胶质母细胞瘤的治疗策略进行了探讨。     

Genome-wide profiling using single-nucleotide polymorphism arrays identifies novel chromosomal imbalances in pediatric glioblastomas

Available data on genetic events in pediatric grade IV astrocytomas (glioblastoma [pGBM]) are scarce. This has traditionally been a major impediment in understanding the pathogenesis of this tumor and in developing ways for more effective management. Our aim is to chart DNA copy number aberrations (CNAs) and get insight into genetic pathways involved in pGBM. Using the Illumina Infinium Human-1 bead-chip-array (100K single-nucleotide polymorphisms [SNPs]), we genotyped 18 pediatric and 6 adult GBMs. Results were compared to BAC-array profiles harvested on 16 of the same pGBM, to an independent data set of 9 pediatric high-grade astrocytomas (HGAs) analyzed on Affymetrix 250K-SNP arrays, and to existing data sets on HGAs. CNAs were additionally validated by real-time qPCR in a set of genes in pGBM. Our results identify with nonrandom clustering of CNAs in several novel, previously not reported, genomic regions, suggesting that alterations in tumor suppressors and genes involved in the regulation of RNA processing and the cell cycle are major events in the pathogenesis of pGBM. Most regions were distinct from CNAs in aGBMs and show an unexpectedly low frequency of genetic amplification and homozygous deletions and a high frequency of loss of heterozygosity for a high-grade I rapidly dividing tumor. This first, complete, high-resolution profiling of the tumor cell genome fills an important gap in studies on pGBM. It ultimately guides the mapping of oncogenic networks unique to pGBM, identification of the related therapeutic predictors and targets, and development of more effective therapies. It further shows that, despite commonalities in a few CNAs, pGBM and aGBMs are two different diseases.     

Genetic alterations defining NSCLC subtypes and their therapeutic implications

Lung cancer is the leading cause of cancer death worldwide, accounting for more deaths than breast, prostate and colon cancer combined. While treatment decisions are determined primarily by stage, therapeutically non small cell lung cancer (NSCLC) has traditionally been treated as a single disease. However, recent findings have led to the recognition of histology and molecular subtypes as important determinants in treatment selection. Identifying the genetic differences that define these molecular and histological subtypes has the potential to impact treatment and as such is currently the focus of much research. Microarray and genomic sequencing efforts have provided unparalleled insight into the genomes of lung cancer subtypes, specifically adenocarcinoma (AC) and squamous cell carcinoma (SqCC), revealing subtype specific genomic alterations and molecular subtypes as well as differences in cell signaling pathways. In this review, we discuss the recurrent genomic alterations characteristic of AC and SqCC (including molecular subtypes), their therapeutic implications and emerging clinical practices aimed at tailoring treatments based on a tumor's molecular alterations with the hope of improving patient response and survival.     

Prognostic value of NUSAP1 in progression and expansion of glioblastoma multiforme

Nucleolar and spindle-associated protein (NUSAP1) is a microtubule and chromatin-binding protein that stabilizes microtubules to prevent depolymerization, maintains spindle integrity. NUSAP1 could cross-link spindles into aster-like structures, networks and fibers. It has also been found to play roles in progression of several cancers. However, the potential correlation between NUSAP1 and clinical outcome in patients with glioblastoma multiforme (GBM) remains largely unknown. In the current study, we demonstrated that NUSAP1 was significantly up-regulated in GBM tissues compared with adult non-tumor brain tissues both in a validated cohort and a TCGA cohort. In addition, Kaplan–Meier analysis indicated that patients with high NUSAP1 expression had significantly lower OS (P?=?0.0027). Additionally, in the TCGA cohort, NUSAP1 expression was relatively lower in GBM patients within the neural and mesenchymal subtypes compared to other subtypes, and associated with the status of several genetic aberrations such as PTEN deletion and wild type IDH1. The present study provides new insights and evidence that NUSAP1 over-expression was significantly correlated with progression and prognosis of GBM. Furthermore, knockdown of NUSAP1 revealed its regulation on G2/M progression and cell proliferation (both in vitro and in vivo). These data demonstrate that NUSAP1 could serve as a novel prognostic biomarker and a potential therapeutic target for GBM.     

Novel insights into vascularization patterns and angiogenic factors in glioblastoma subclasses

Glioblastoma (GBM) is a highly vascularized and aggressive type of primary brain tumor in adults with dismal survival. Molecular subtypes of GBM have been identified that are related to clinical outcome and response to therapy. Although the mesenchymal type has been ascribed higher angiogenic activity, extensive characterization of the vascular component in GBM subtypes has not been performed. Therefore, we aimed to investigate the differential vascular status and angiogenic signaling levels in molecular subtypes. GBM tissue samples representing proneural IDH1 mutant, classical-like and mesenchymal-like subtypes were analyzed by morphometry for the number of vessels, vessel size and vessel maturity. Also the expression levels of factors from multiple angiogenic signaling pathways were determined. We found that necrotic and hypoxic areas were relatively larger in mesenchymal-like tumors and these tumors also had larger vessels. However, the number of vessels, basement membrane deposition and pericyte coverage did not vary between the subtypes. Regarding signaling patterns the majority of factors were expressed at similar levels in the subtypes, and only ANGPT2, MMP2, TIMP1, VEGFA and MMP9/TIMP2 were higher expressed in GBMs of the classical-like subtype. In conclusion, although morphological differences were observed between the subtypes, the angiogenic signaling status of GBM subtypes seemed to be rather similar. These results challenge the concept of mesenchymal GBMs being more angiogenic than other subclasses.     

不同分子亚型乳腺癌的临床病理特征及预后分析

目的 探讨乳腺癌各分子亚型的临床特点及其预后情况.方法 分析1153例可手术乳腺癌患者的临床病理资料,根据雌激素受体(ER)、孕激素受体(PR)和人表皮生长因子受体2(Her-2)的表达情况将乳腺癌分为4种分子亚型,即Luminal A型、Luminal B型、Her-2过表达型和Basal-like型.分析各分子亚型乳腺癌患者在年龄、肿瘤大小、淋巴结转移状况、临床分期和预后的差异及影响预后的因素.结果 1153例患者中,Luminal A型791例(68.6%),Luminal B型50例(4.3%),Her-2过表达型53例(4.6%),Basal-like型259例(22.5%).各分子亚型在年龄、肿瘤大小、淋巴结转移状况、临床分期的差异均无统计学意义(均P>0.05).有完整随访资料的1006例患者中,Her-2过表达型的远处转移率(17.0%)显著高于其他亚型(P=0.005),而各分子亚型间的局部复发率差异无统计学意义(P>0.05).Kaplan-Meier法分析结果显示,Her-2过表达型患者的7年无病生存率和9年总生存率最低(均P<0.05).单因素和多因素分析结果均显示,淋巴结转移状况和分子分型是影响乳腺癌患者无病生存及总生存的独立预后因素.结论 Her-2过表达型乳腺癌患者的预后最差.乳腺癌的分子分型对判断患者预后可能具有重要临床意义,有望成为今后制订乳腺癌个体化治疗方案的重要依据.

Abstract：

Objective To investigate the clinical characteristics and prognosis of different breast cancer molecular subtypes.Methods Clinicopathological and follow-up data of 1153 cases of operable breast cancer were analyzed retrospectively.Their molecular subtypes were categorized as luminal A, luminal B, Her-2 over-expressing and basal-like subtypes, based on detection of ER, PR, Her-2 expression.The correlation of prognosis of different molecular subtypes with age, tumor size, lymph node status and clinical staging was analyzed.Results Among the 1153 cases, 791 cases (68.6%) were of luminal A subtype, 50 cases (4.3%) luminal B subtype, 53 cases (4.6%) Her-2( + )subtype, and 259 cases (22.5%) basallike subtype.There were no statistically significant differences among different molecular subtypes regarding the age, tumor size, lymph node status, and clinical stage.1006 cases had complete follow-up data and the analysis showed that distant metastasis of Her-2 over-expressing subtype was significantly higher than that in other subtypes ( P = 0.005 ), but the differelices of local recurrence rate in different molecular subtypes was not statistically significant (P >0.05).Kaplan-Meier method was used to analyze the survival prognosis of different molecular subtypes, showing both DFS rate and OS rate of Her-2 over-expressing subtype were the lowest, with a statistically significant difference (Log rank test, P < 0.05 ).Univariate and multivariate analyses showed that molecular typing and lymph node status were independent prognostic factors affecting both DFS and OS.Conclusions Her-2 over-expressing subtype has the worst prognosis.Molecular subtypes may provide important information to predict the prognosis of breast cancer and might be an important basis for individualized treatment of breast cancer in future.     

Hypermethylation of the proapoptotic gene <Emphasis Type="Italic">TMS1/ASC</Emphasis>: prognostic importance in glioblastoma multiforme

The identification of clinical subsets of glioblastomas (GBM) associated with different molecular genetic profiles had opened the possibility to design tailored therapies to individual patients. One of the most intrigued subtypes is the long-term survival (LTS) GBM, which responds better to current therapies. The present investigation on GBM from 50 consecutive GBM displaying classic survival and seven LTS GBM is based on molecular epigenetic, clinical and histopathological analyses. Our aim was to recognize biomarkers useful to distinguish LTS from classic GBM. We analyzed the promoter methylation status of key regulator genes implicated in tumor invasion (TIMP2, TIMP3), apoptosis and inflammation (TMS1/ASC, DAPK) as well as overall survival, therapy status and tumor pathological features. For the first purpose a methylation-specific PCR approach was performed to analyze the CpG island promoter methylation status of each gene. The overall TMS1/ASC methylation rate in the 57 analyzed tumors was 21.05%. Hypermethylation of TMS1/ASC was significantly more frequent in LTS GBM (57.1% vs. 16%, P=0.029, Fisher's exact test). DAPK promoter hypermethylation was only observed in the LTS subset (14.3%) whereas TIMP2 and TIMP3 were unmethylated in both GBM collectives. Our results strongly suggest that, compared to classic GBM, LTS GBM display distinct epigenetic characteristics which might provide additional prognostic biomarkers for the assessment of this malignancy.     

A simplified approach for molecular classification of glioblastomas (GBMs): experience from a tertiary care center in India

This study aims to establish a simplified molecular classification of glioblastomas (GBMs) based on molecular genetic alterations. GBM cases (n-114) were evaluated for IDH-1 and TP53 mutation by Sanger sequencing, PDGFRA and EGFR amplification by FISH, NF1 and YKL40 expression by qRT-PCR. Subsequently they were classified into four subgroups: classical like (CL), proneural like (PN), mesenchymal like (MES) and neural like (NEU). CL subtype was most frequent (39 %), followed by PN (32 %) and MES (20 %) subtypes. PN subtype had significantly younger age at presentation and longest survival (median PFS—82.5 weeks; 1 and 2 years OS—90.6 and 71.3 %). Other three subgroups had equally poor prognosis and hence, clubbed together as non-proneural (Non-PN) (median PFS—39 weeks; 1 and 2 years OS—66 and 0 %). Hence, we recommended this relatively easy method of subclassifying GBMs into PN and Non-PN which are statistically different in prognosis (both OS and PFS on uni and multivariate analysis). Although evaluation of six molecular alterations for identifying these two subgroups is still cumbersome, we propose segregation of PN subtype alone based on assessment of IDH1, TP53 and PDGFRA status, which is relatively easy and may be amenable to routine practice.     

IDH1 mutation as a potential novel biomarker for distinguishing pseudoprogression from true progression in patients with glioblastoma treated with temozolomide and radiotherapy

The purpose of this study was to distinguish pseudoprogression (PP) from early true progression in patients with glioblastoma (GBM) based on the presence of a mutation in isocitrate dehydrogenase 1 (IDH1). We retrospectively surveyed 32 patients with GBM or GBM with oligodendroglioma component (GBMO) who underwent biopsy or maximal tumor resection followed by concurrent radiotherapy and temozolomide (TMZ). We then selected patients with early radiological progression in magnetic resonance imaging within 6 months after concurrent radiotherapy and TMZ treatment. DNA was extracted from their tumor blocks. The IDH1 mutation was analyzed in the genomic region by direct sequencing as a biomarker for PP. Twenty-eight patients were diagnosed with GBM and four with GBMO. Eleven patients were discovered to have early radiological progression. PP was detected in two patients (6.3 %) diagnosed with GBMO and one patient with GBM. Both of the GBMO patients with PP had the IDH1 mutation, the one GBM patient with PP and the other eight patients with early true progression with wild type. The sensitivity and specificity of the IDH1 mutation for detecting PP were 66.7 and 100 %, respectively. This study suggests the IDH1 mutation may become a novel molecular biomarker for PP. Analyzing the IDH1 mutation, in the case of recognizing early radiological progression, may enable distinction of PP from early true progression, and we could determine the need for second-look surgery.     

乳腺浸润性导管癌分子分型与临床特征的关系

目的探讨乳腺浸润性导管癌不同分子亚型的分布,并分析各分子亚型与临床特征的关系。方法收集2006年1月-2011年6月明确诊断为乳腺浸润性导管癌病例100例,根据雌激素受体（ER）、孕激素受体（PR）、表皮生长因子受体-2（HER-2）的表达情况划分为四型,进一步分析不同分子亚型与浸润性导管癌临床特征的关系。结果100例中Luminal A型所占比例最大为65%,7%为Luminal B型, Triple Negative型占17%,Her-2(+)型占11%。各分子亚型乳腺浸润性导管癌患者发病年龄主要集中在40~59岁之间,占73%,Luminal A型发病年龄主要集中在40~49岁,而其他三型主要分布于50~59岁,四型在不同年龄组的分布上差异有统计学意义（P＜0.05）;Luminal A型淋巴转移发生率仅为30.1%,而Luminal B型与Her-2(+)型淋巴转移发生率较高,分别为71.4%及63.6%,各分子亚型的腋窝淋巴结转移率有显著差异（P＜0.05）;病理组织学分级Ⅰ级中Luminal A型所占比例最高,而Triple Negative型主要以Ⅲ级为主,差异具有统计学意义（P＜0.05）。结论乳腺浸润性导管癌各分子亚型分布差异具有统计学意义,各分子亚型与其临床特征关系密切。     

Active matrix metalloproteinase 9 expression is associated with primary glioblastoma subtype.

PURPOSE: Glioblastoma multiforme (GBM) is an aggressive cancer characterized by extensive brain invasion. Matrix metalloproteinase (MMP)-9 plays a major role in this process. GBMs can be divided into two subtypes based on distinct clinical and molecular features. Primary GBMs arise de novo and frequently overexpress the epidermal growth factor receptor (EGFR) and its ligand-independent variant, EGFR variant III (EGFRvIII); secondary GBMs progress from a lower grade glioma and commonly harbor p53 mutations. Because EGFR signaling promotes MMP-9 expression and activation in other cancer cell types, we analyzed whether MMP-9 was associated with primary GBM subtype. EXPERIMENTAL DESIGN: Autopsies were performed on 20 GBM patients, and MMP expression was assessed by gelatin zymography in the tumor and the adjacent normal brain. EGFR, EGFRvIII, p53, and activated mitogen-activated protein kinase/extracellular signal-regulated kinase were assessed by immunohistochemistry, and associations between molecular phenotype and MMP-9 expression were analyzed. RESULTS: Latent MMP-9 was detected in 90% of tumors, and active MMP-9 was found in 50% of tumors. MMP-9 was not detected in any of the normal brain samples (P < 0.001). More importantly, primary GBMs were significantly more likely than secondary GBMs to contain active MMP-9 (69% of primary and 14% of secondary GBMs contained active MMP-9; P = 0.027). Active MMP-9 was observed in 73% of EGFR-overexpressing/wild-type p53-staining tumors but in only 20% of EGFR-negative/aberrant p53-staining tumors (P = 0.072). Active MMP-9 expression was even more strongly correlated with EGFRvIII expression, occurring in 83% of the EGFRvIII-immunopositive tumors but in none of the EGFRvIII-negative tumors (P = 0.0004). Extracellular signal-regulated kinase activation was also strongly correlated with EGFRvIII expression (P < 0.0001) and with MMP-9 activation (P = 0.003). CONCLUSIONS: These results identify a novel association between MMP-9 activation and primary GBM subtype and suggest that primary GBM patients, especially those whose tumors express EGFRvIII, may benefit from anti-MMP therapy.     

Breast cancer molecular subtypes and associations with clinicopathological characteristics in Iranian women, 2002- 2011

Breast cancer is a heterogeneous disease that is affected by ethnicity of patients. According to hormone receptor status and gene expression profiling, breast cancers are classified into four molecular subtypes, each showing distinct clinical behavior. Lack of sufficient data on molecular subtypes of breast cancer in Iran, prompted us to investigate the prevalence and the clinicopathological features of each subtype among Iranian women. A total of 428 women diagnosed with breast cancer from 2002 to 2011 were included and categorized into four molecular subtypes using immunohistochemistry. Prevalence of each subtype and its association with patients' demographics and tumor characteristics, such as size, grade, lymph-node involvement and vascular invasion, were investigated using Chi-square, analysis of variance and multivariate logistic regression. Luminal A was the most common molecular subtype (63.8%) followed by Luminal B (8.4%), basal-like (15.9%) and HER-2 (11.9%). Basal-like and HER-2 subtypes were mostly of higher grades while luminal A tumors were more of grade 1 (P<0.001). Vascular invasion was more prevalent in HER-2 subtype, and HER-2 positive tumors were significantly associated with vascular invasion (P=0.013). Using muti-variate analysis, tumor size greater than 5 cm and vascular invasion were significant predictors of 3 or more nodal metastases. Breast cancer was most commonly diagnosed in women around 50 years of age and the majority of patients had lymph node metastasis at the time of diagnosis. This points to the necessity for devising an efficient screening program for breast cancer in Iran. Further, prospective surveys are suggested to evaluate prognosis of different subtypes in Iranian patients.     

不同分子亚型的晚期乳腺癌化疗疗效观察

目的：观察不同分子亚型的晚期乳腺癌对多西紫杉醇联合顺铂化疗方案的反应性、疾病进展时间（TTP）及生存时间,进一步评估不同分子亚型乳腺癌的临床特征及预后。方法：利用免疫组化方法将2000年元月至2006年10月收治的62例晚期乳腺癌分为3种分子亚型,62例多西紫杉醇联合顺铂方案化疗,回顾性分析3种亚型乳腺癌的化疗反应性、疾病进展时间及生存期。结果：62例患者中,Basal—like亚型为14例（22．6％）,HER2＋／ER一亚型（16．1％）,Luminal亚型38例（61．3％）。Basal—like亚型有效率为64．3％,HER2＋／ER一亚型为60．0％,Luminal亚型为47．4％（P=0．551）,3者之间无显著性差异。Basal—like亚型,ITI’P为3．2个月,HER2＋／ER一亚型为5．3个月,Luminal亚型为10．1个（P=0．005）,Basal—like亚型生存时间为7．0个月,HER2-4-／ER-亚型为11．3个月,Luminal亚型为19．8个（P=0．004）,3者在TTP及生存时问存在显著性差异。结论：不同分子亚型的晚期乳腺癌对多西紫杉醇联合顺铂化疗方案的反应性相似,但Basal-like亚型和HER2＋／ER-亚型具有较短的疾病进展时间和生存期,Basal-like亚型的预后最差。原因可能主要与它的生物学特征更具侵袭性有关。