Correlation of human epidermal growth factor receptor 2 expression with clinicopathological characteristics and prognosis in gastric cancer

AIM:To investigate human epidermal growth factor receptor 2(HER2) gene amplification and protein expression in Chinese patients with resectable gastric cancer and the association with clinicopathological characteristics and survival.METHODS:One hundred and ninety-seven gastric cancer patients who underwent curative surgery procedures were enrolled into this study.HER2 gene amplification and protein expression were examined using fluorescence in-situ hybridization(FISH) and immunohistochemistry(IHC) analysis on formalin-fixed paraffinembedded gastric cancer samples from all patients.For scoring,Hofmann's HER2 gastric cancer scoring system was adopted.All cases showing IHC3+ or FISH positiv-ity were defined as HER2 positive.Patient clinicopathological data and survival information were collected.Finally,χ 2 statistical analysis was performed to analyze the HER2 positivity rate amongst the subgroups with different clinicopathological characteristics including;gender,age,tumor location,Lauren classification,differentiation,TNM staging,depth of invasion,lymph node metastases and distant metastasis.The probability of survival for different subgroups with different clinicopathological characteristics was calculated using the Kaplan-Meier method and survival curves plotted using log rank inspection.RESULTS:According to Hofmann's HER2 gastric cancer scoring criteria,31 cases(15.74%) were identified as HER2 gene amplified and 19 cases(9.64%) were scored as strongly positive for HER2 membrane staining(3+),25 cases(12.69%) were moderately positive(2+) and 153 cases(77.66%) were HER2 negative(0/1+).The concordance rate between IHC and FISH analyses was 88.83%(175/197).Thirty-six cases were defined as positive for HER2 gene amplification and/or protein expression,with 24 of these cases being eligible for Herceptin treatment according to United States recommendations,and 29 of these cases eligible according to EU recommendations.Highly consistent results were detected between IHC3+,IHC0/1 and FISH(73.68% and 95.42%),but low consistency was observed between IHC2+ and FISH(40.00%).The positivity rates in intestinal type and well-differentiated gastric cancer were higher than those in diffuse/mixed type and poorly-differentiated gastric cancer respectively(28.57% vs 13.43%,P = 0.0103;37.25% vs 11.64%,P < 0.0001),but were not correlated with gender,age,tumor location or TNM stage,depth of invasion,lymph node metastases and distant metastasis.In poorly-differentiated gastric cancer patients,those without lymph node metastasis showed a higher HER2 positivity rate than those with lymph node metastasis(26.47% vs 7.14%,P = 0.0021).This association was not present in thosepatients with well-differentiated gastric cancer(28.57% vs 43.33%,P = 0.2832).Within our patient cohort,26 cases were lost to follow-up.The median survival time for the remaining 171 patients was 18 mo.The median survival times of the HER2 positive and negative groups were 17 and 18.5 mo respectively.Overall survival was not significantly different between HER2-positive and negative groups(χ 2 = 0.9157,P = 0.3386),but in patients presenting well-differentiated tumors,the overall survival of the HER2-positive group was significantly worse than that of the HER2-negative group(P = 0.0123).In contrast,patients with poorly differentiated and diffuse/mixed subtype gastric cancers showed no significant differences in overall survival associated with HER2.Furthermore,the median survival time of the HER2 positive group did not show any statistically significant differences when compared to the subgroups of gender,age,tumor location,TNM classification,lymph node metastases and distant metastasis.CONCLUSION:Patients with intestinal type gastric cancer(GC),well-differentiated GC and poorly-differentiated GC without lymph node metastasis,may all represent suitable candidates for targeted therapy using Herceptin.

Increased expression of tyrosine phosphatase SHP-2 in Helicobacter pylori-infected gastric cancer

AIM:To explore the alteration of tyrosine phosphatase SHP-2 protein expression in gastric cancer and to assess its prognostic values.METHODS:Three hundred and five consecutive cases of gastric cancer were enrolled into this study.SHP-2 expression was carried out in 305 gastric cancer specimens,of which 83 were paired adjacent normal gastric mucus samples,using a tissue microarray immunohistochemical method.Correlations were analyzed between expression levels of SHP-2 protein and tumor parameters or clinical outcomes.Serum anti-Helicobacter pylori(H.pylori) immunoglobulin G was detected with enzyme-linked immunosorbent assay.Cox proportional hazards model was used to evaluate prognostic values by compassion of the expression levels of SHP-2 and disease-specific survivals in patients.RESULTS:SHP-2 staining was found diffuse mainly in the cytoplasm and the weak staining was also observed in the nucleus in gastric mucosa cells.Thirty-two point five percent of normal epithelial specimen and 62.6% of gastric cancer specimen were identified to stain with SHP-2 antibody positively(P < 0.001).Though SHP-2 staining intensities were stronger in the H.pylori(+) group than in the H.pylori(-) group,no statistically significant difference was found in the expression levels of SHP-2 between H.pylori(+) and H.pylori(-) gastric cancer(P = 0.40).The SHP-2 expression in gastric cancer was not significantly associated with cancer stages,lymph node metastases,and distant metastasis of the tumors(P = 0.34,P = 0.17,P = 0.52).Multivariate analysis demonstrated no correlation between SHP-2 expression and disease-free survival(P = 0.86).CONCLUSION:Increased expression of SHP-2 protein in gastric cancer specimen suggesting the aberrant upregulation of SHP-2 protein might play an important role in the gastric carcinogenesis.

Role of ABCG2 expression driven by cisplatin in platinumcontaining chemotherapy for gastric cancer

AIM:To investigate the relationship between increases in expression time of ABCG2 mRNA driven by cisplatin and efficacy of platinum-containing chemotherapy for gastric cancer.METHODS:Tumor specimens and normal control tissues were collected from 78 patients with gastric cancer treated from January 2008 to December 2011.Fresh tumor tissue obtained from the surgically resected specimens was tested within 6 h.Polymerase chain reaction products were run on 2%agarose gels and analyzed under ultraviolet light after ethidium bromide staining.Increases in ABCG2 mRNA expression time cisplatin,and were divided into terciles and compared in relation to clinical outcomes.RESULTS:Among groups classified by expression time of ABCG2 mRNA,no significant differences in baseline clinical characteristics and pathological findings were detected.The median overall time was 14.2(95%CI:9.7-18.6),11.4(95%CI:6.3-16.5)and 8.1(95%CI:5.4-10.8)in patients with low,intermediate and high increases in ABCG2 mRNA expression times(P<0.05),respectively.Median survival associated with performance status and tumor node metastasis(TNM)stage showed a similar trend,with longer survival and higher risk for mortality associated with lower performance status score and TNM stage.In a multivariate analysis for survival with Cox proportional-hazards model,increased ABCG2 mRNA expression time was an independent predictor for overall survival.Overall survival was longer with increased ABCG2 mRNA expression times≤0.71 than increased ABCG2 mRNA expression times>0.71,with a hazard ratio for death of 0.855(95%CI:0.615-0.962,P=0.038).CONCLUSION:Increased ABCG2 mRNA expression time driven by cisplatin is associated with survival of gastric cancer patients,and this may help modify the therapeutic strategies.

Characterization and strong risk association of TLR2 del-196 to-174 polymorphism and Helicobacter pylori and their influence on mRNA expression in gastric cancer

BACKGROUND Toll-like receptor-2(TLR2) is responsible for recognizing Helicobacter pylori(H.pylori) and activating the immune response. Polymorphisms in TLR2 may modulate gastric carcinogenesis.AIM To evaluate whether the TLR2 19216 T/C(rs3804099) and TLR2-196 to-174 ins/del(rs111200466) polymorphisms contribute to gastric carcinogenesis in the Brazilian population, and to determine the influence of both polymorphisms and H. pylori infection on TLR2 mRNA expression.METHODS DNA was extracted from 854 peripheral blood leukocyte or gastric tissue samples[202 gastric cancer(GC), 269 chronic gastritis(CG), and 383 control/healthy(C)]and genotyped by allele-specific PCR or restriction fragment length polymorphism(RFLP)-PCR. Quantitative polymerase chain reaction by Taq Man■ assay was used to quantify TLR2 mRNA levels in fresh gastric tissues(48 GC, 36 CG, and 14 C).RESULTS Regarding the TLR2-196 to -174 polymorphism, the ins/del and del/del genotypes were associated with a higher risk of GC by comparison with the C in all of the analyzed inheritance models(codominant, dominant, recessive, overdominant and log-additive;P < 0.0001). Similarly, an increased risk was observed when comparing the GC and CG groups [codominant(P < 0.0001), dominant(P <0.0001), recessive(P = 0.0260), overdominant(P < 0.0001) and log-additive(P <0.0001)]. In contrast, TLR2 19216 T/C was associated with a protective effect in the GC group compared to the C group [dominant(P = 0.0420) and log-additive(P =0.0300)]. Regarding the association of polymorphisms with H. pylori infection,individuals infected with H. pylori and harboring the TLR2-196 to-174 ins/del polymorphism had an increased risk of gastric carcinogenesis [codominant(P =0.0120), dominant(P = 0.0051), overdominant(P = 0.0240) and log-additive(P =0.0030)], while TLR2 19216 T/C was associated with a protective effect[codominant(P = 0.0039), dominant(P < 0.0001), overdominant(P = 0.0097) and log-additive(P = 0.0021)]. TLR2 mRNA levels were significantly increased in the GC group(median RQ = 6.95) compared to the CG group(RQ = 0.84, P < 0.0001)and to the normal mucosa group(RQ = 1.0). In addition, both H. pylori infection(P < 0.0001) and the presence of the polymorphic TLR2-196 to -174 del(P = 0.0010)and TLR2 19216 C(P = 0.0004) alleles influenced TLR2 mRNA expression.CONCLUSION The TLR2-196 to-174 ins/del and TLR2 19216 T/C polymorphisms are strongly associated with GC. TLR2 mRNA expression levels are upregulated in neoplastic tissues and influenced by both the presence of H. pylori and variant genotypes.

Quantitative expression of MMP-2 and FN in high metastatic and low metastatic cell lines of breast cancer

To analyze the relation of matrix metalloproteinase-2(MMP-2) and Fibronection (FN) mRNA expression with metastasis of breast cancer and elucidate the role of MMP-2 and FN in breast cancer metastasis.Methods The expression of MMP-2 and FN mRNA in breast cancer cell lines was detected by fluorescence-quantitative RT-PCR.The expression of MMP-2 and FN protein was detected by Western blots.Results The expression of MMP-2 and FN mRNA was down-regulated in high metastatic cell lines MDA-MB-231,MDA-MB-435,but up-regulated in low metastatic cell lines MDA-453,T47D,SK-BR-3 and non-metastatic cell line MCF-7,ZR-75-30.The protein expression of MMP-2 and FN was up-regulated in high mestastic cell lines,and down-regulated in low metastatic cell lines.Conclusion The mRNA and protein expression of MMP-2 and FN was related with breast cancer metastasis.The mRNA expression of MMP-2 and FN is feed-back regulated with protein expression.6 refs,4 figs,2 tabs.

Prognostic value of programmed death.1, programmed death-ligand 1, programmed death-ligand 2 expression, and CD8(+) T cell density in primary tumors and metastatic lymph nodes from patients with stage T1.4N+M0 gastric adenocarcinoma

Background: Anti-programmed death-1/programmed death-ligand 1(PD-1/PD-L1) immunotherapy has been proved to be effective on gastric cancer in ongoing clinical trials. However, the value of PD-L1 in predicting responses of patients with gastric cancer to anti-PD-1/PD-L1 immunotherapy is controversial. Some studies suggested that intra-and inter-tumoral heterogeneity of PD-L1 expression might explain the controversy.This study aimed to analyze the expression of PD-L1, PD-L2, and PD-1 as well as CD8(+) T-cell density in primary tumors and lymph nodes from patients with stage T1-4 N+M0 gastric adenocarcinoma to explore the heterogeneity of PD-1 signaling pathway molecules.Methods: In primary tumors and metastatic as well as non-metastatic lymph nodes from patients with stage T1-4 N+M0 gastric adenocarcinoma, we detected PD-L1 and PD-L2 expression with immunohistochemistry. CD8(+)T-cell density in primary tumors and PD-1 expression on CD8(+)T cells were detected with immunofluorescence. Univariate analysis was used to determine the prognostic values of them. Cox proportional hazard regression model was used to identify independent risk factors that affect patients' overall survival and disease-free survival.Results: Among 119 eligible patients who had undergone surgical resection, the positive rate of PD-L1 was higher in metastatic lymph nodes than in primary tumors(45.4% vs. 38.7%, P = 0.005); the positive rate of PD-1 on CD8(+)T cells was significantly higher in primary tumors and metastatic lymph nodes than in tumor-free lymph nodes(both P < 0.001). The intensity of PD-1 expression on CD8(+) T cells in primary tumors and in metastatic lymph nodes were stronger than that in tumor-free lymph nodes from the same patient. Beside, the positive rate of PD-L2 did not show any differences between primary tumors and metastatic lymph nodes. In multivariate analysis, PD-L1 expression,PD-L2 expression, a low density of CD8(+) T cells in primary tumors, and PD-1 expression on CD8(+) T cells in primary tumors were associated with poor prognosis.Conclusion: The expression of PD-L1 is heterogeneous in primary tumors and in metastatic lymph nodes from patients with stageT1-4 N+M0 gastric adenocarcinoma, which might explain the inconsistent results in assessing the prognostic value of PD-L1 expression in previous studies.

Differential gene expression profiling of gastric intraepithelial neoplasia and early-stage adenocarcinoma

AIM:To investigate the differentiated whole genome expression profiling of gastric high-and low-grade intraepithelial neoplasia and early-stage adenocarcinoma.METHODS:Gastric specimens from an upper magnifying chromoendoscopic targeted biopsy were collected from March 2010 to May 2013.Whole genome expression profiling was performed on 19 low-grade intraepithelial neoplasia(LGIN),20 high-grade intraepithelial neoplasia(HGIN),19 early-stage adenocarcinoma(EGC),and 19 chronic gastritis tissue samples using Agilent 4×44K Whole Human Genome microarrays.Differentially expressed genes between different types of lesions were identified using an unpaired t-test and corrected with the Benjamini and Hochberg false discovery rate algorithm.A gene ontology(GO)enrichment analysis was performed using the Gene Spring software GX 12.6.The differentially expressed gene was verified using a real-time TaqManPCR assay with independent tissue samples,including 26 LGIN,15 HGIN,14 EGC,and 20 chronic gastritis.The expression of G0S2 were further validated by immunohistochemical staining(IHC)in 24 LGIN,40 HGIN,30 EGC and 61 chronic gastritis specimens.RESULTS:The gene expression patterns of LGIN and HGIN tissues were distinct.There were 2521 significantly differentially expressed transcripts in HGIN,with951 upregulated and 1570 downregulated.A GO enrichment analysis demonstrated that the most striking overexpressed transcripts in HGIN compared with LGIN were in the category of metabolism,defense response,and nuclear factorκB(NF-κB)cascade.While the vast majority of transcripts had barely altered expression in HGIN and EGC tissues,only 38 transcripts were upregulated in EGC.A GO enrichment analysis revealed that the alterations of the immune response were most prominent in the progression from HGIN to EGC.It is worth noting that,compared with LGIN,289 transcriptswere expressed at higher levels both in HGIN and EGC.A characteristic gene,G0/G1 switch 2(G0S2)was one of the 289 transcripts and related to metabolism,the immune response,and the NF-κB cascade,and its expression was validated in independent samples through real-time TaqManPCR and immunohistochemical staining.In real-time PCR analysis,the expression of G0S2 was elevated both in HGIN and EGC compared with that in LGIN(P<0.01 and P<0.001,respectively).In IHC analysis,G0S2 immunoreactivity was detected in the cytoplasmic of neoplastic cells,but was undetectable in chronic gastritis cells.The G0S2 expression in HGIN was higher than that of LGIN(P=0.012,χ2=6.28)and EGC(P=0.008,χ2=6.94).CONCLUSION:A clear biological distinction between gastric high-and low-grade intraepithelial neoplasia was identified,and provides molecular evidence for clinical application.

HER2低表达乳腺癌的临床病理特征及预后分析

目的探讨人表皮生长因子受体2(HER2)低表达乳腺癌的临床病理特征、分子分型及生存预后。方法收集2016年1月至2021年9月1,684例原发性乳腺癌患者临床资料,其中浸润性导管癌患者1,023例,纳入805例HER2阴性乳腺癌患者,比较HER2低表达和无表达乳腺癌患者在临床病理特征、分子分型及生存预后方面的差异,采用Kaplan-Meier法绘制两组患者DFS和BCSS的生存曲线,Log-rank检验比较生存差异,单因素和多因素Cox比例风险回归模型分析预后影响因素。结果805例HER2阴性乳腺癌患者中,HER2无表达515例(64.0%),HER2低表达290例(36.0%)。HER2低表达乳腺癌占所有乳腺浸润性导管癌的28.3%,分子分型以Luminal B型为主。与HER2无表达组相比,HER2低表达组中N分期Ⅱ~Ⅲ期(P=0.004)、TNM分期Ⅲ期(P=0.002)、HR阳性患者(P=0.002)的占比更高。805例患者中,HR阳性629例(78.1%),HR阴性176例(21.9%)。629例HR阳性患者中,HER2无表达385例(61.2%),HER2低表达244例(28.8%),HER2低表达较无表达组的确诊年龄小(P=0.031),<45岁(P=0.003)、N分期Ⅱ~Ⅲ期(P=0.001)、TNM分期Ⅲ期(P=0.001)患者的占比更高。176例HR阴性患者中,HER2无表达130例(73.9%),HER2低表达46例(26.1%),与HER2无表达组相比,HER2低表达组患者确诊年龄大(P=0.047),≥45岁占比高(P=0.036),组织学分级(P<0.001)和Ki-67增殖指数(P=0.027)更低。结论HER2低表达乳腺癌占所有乳腺浸润性导管癌的28.3%,具有独特的临床病理特征和分子分型,HR状态可能是其生物学行为的主要驱动因素。HER2低表达和无表达乳腺癌患者的生存预后均无明显差异。

乳腺癌HER2低表达的研究现状及药物治疗进展

随着对于抗人表皮生长因子2(HER2)药物的研究越来越深入,也使新型抗体-药物偶联物(ADC)治疗HER2低表达乳腺癌成为研究热点。HER2低表达不仅可以从抗HER2治疗中获益,其生物学亚型及临床病理学特征也与其他HER2分型表现出明显差异,但对于预后的探讨仍具有争议。新型ADC药物具有靶向选择性,并与化疗的细胞毒性相结合,通过旁观者效应对肿瘤细胞周围散在的HER2低表达细胞进行杀伤。目前有多项研究正在探索多种ADC药物对于乳腺癌HER2低表达的疗效,为乳腺癌HER2低表达患者开辟新的治疗道路。该文对HER2低表达的临床研究现状和ADC药物治疗进展进行概述。

HER2低表达和零表达乳腺癌患者的临床病理特征及其预后风险因素分析

目的分析人表皮生长因子受体2(HER2)低表达和零表达乳腺癌患者的临床病理特征及其预后影响因素。方法收集2018年1月至2021年12月山西医科大学第一医院收治的HER2阴性乳腺癌732例,将其分为HER2低表达组和HER2零表达组,分析两组患者的临床病理特征及预后情况,采用Kaplan-Meier生存曲线进行生存分析,Cox比例风险回归模型分析患者预后影响因素。结果HER2低表达441例(60.25%),HER2零表达291例(39.75%)。与HER2零表达组相比,HER2低表达组组织学类型中非特殊型比例、淋巴结转移率、HR阳性率及AR的阳性率更高(P<0.01),组织学分级更低(P<0.001)。生存分析显示HER2零表达组的总生存期(OS)显著低于HER2低表达组(P=0.016),而两组间无病生存期(DFS)差异无统计学意义(P=0.534);根据激素状态分层,激素阴性和阳性者中两组DFS和OS差异均无统计学意义(P>0.05)。较高的诊断年龄、较高的组织学分级(G3相对于G1-2)、脉管侵犯、淋巴结转移、较高的Ki67增殖指数(≥14%相对于<14%)是影响患者DFS和OS的独立危险因素(P<0.05),HER2零表达相对于HER2低表达也是影响患者OS(HR=0.393,95%CI:0.228~0.679,P=0.001)的独立危险因素。结论HER2低表达患者的激素受体阳性率更高,但患者的生存状态(DFS和OS)与激素状态无关;较高的诊断年龄、组织学分级、Ki67增殖指数及脉管侵犯、淋巴结转移是影响患者DFS和OS的独立危险因素。

HER2/c-erbB-2蛋白在胃癌组织中的表达及临床治疗指导价值

目的探究胃癌患者中HER2/c-erbB-2蛋白表达特征,为治疗和预后的指导价值作进一步研究。方法我院于2020年7月至2021年7月收治的100例胃癌患者被选为受试对象,治疗方案均为手术治疗,术中选择病灶及周围组织(距离病灶直径超于3 cm),采用免疫组化法对组织表达能力作检验;根据患者病理特点及随访资料,比较阳性表达率与胃癌病理特点、生存期之间的关系。采用Cox回归模型进行预后生存影响因素分析,采用Kaplan-Merier进行生存分析。结果淋巴结转移患者的HER2/c-erbB-2阳性率高于未转移者,TNM分期的Ⅲ-Ⅳ期HER2/c-erbB-2阳性率高于Ⅰ-Ⅱ期(P<0.05);病灶组织HER2/c-erbB-2阳性率高于癌旁组织(P<0.05);淋巴结转移、TNM分期和HER2/c-erbB-2为影响胃癌患者预后生存的独立危险因素(P<0.05)。HER2/c-erbB-2蛋白表达阳性患者生存期短于阴性患者(P<0.05)。结论HER2/c-erbB-2蛋白在胃部肿瘤表达程度高,具有缩短生存期的作用,对胃癌的靶向治疗有指导意义。

HER2低表达HR阴性乳腺癌的临床特征及相关新型抗体偶联药物治疗研究进展

乳腺癌是女性最常见的恶性肿瘤,近一半患者为人表皮生长因子受体2(human epidermal growth factor receptor 2,HER2)低表达亚型,对传统抗HER2靶向治疗不敏感。新型抗体偶联药物(antibody-drug conjugates,ADC)通过“旁观者效应”克服HER2表达异质性,为HER2低表达乳腺癌患者提供了新的靶向治疗选择,特别是HER2低表达激素受体(hormone receptor,HR)阴性人群预后不良且既往治疗以化疗为主,新型ADC彻底改变了HER2低表达HR阴性患者的治疗格局及预后。本文将针对HER2低表达HR阴性乳腺癌患者的临床特征以及ADC治疗进展进行综述。

HER2低表达激素受体阳性早期乳腺癌患者临床病理特征及预后分析

目的 分析人表皮生长因子受体2(HER2)低表达激素受体(HR)阳性早期乳腺癌患者的临床病理特征及其预后。方法 收集2014年1月至2021年1月十堰市太和医院收治的498例HR阳性早期乳腺癌患者,根据HER2的表达情况分为HER2阴性组(免疫组化检测HER2为0)和HER2低表达组[免疫组化检测HER2(+)或HER2(++)且荧光原位杂交阴性],比较两组临床病理特征及预后情况。结果 两组患者年龄、肿瘤直径、淋巴结转移、雌激素受体、组织学分级及辅助治疗等比较,差异均无统计学意义(均P>0.05)。与阴性组相比,低表达组雌激素受体阳性表达中位百分比≥80%患者比例、Ki-67低表达患者比例和孕激素受体阳性患者比例更高,而浸润性小叶癌患者比例及脉管癌栓患者比例更低,差异均有统计学意义(均P<0.05)。中位随访65个月,两组无病生存期和总生存期比较,差异均无统计学意义(均P>0.05)。多因素分析显示HER2低表达是HR阳性早期乳腺癌患者无病生存期的独立影响因素(HR=0.698,95%CI:0.493~0.961,P<0.05)。结论 HR阳性乳腺癌中HER2低表达患者与阴性表达患者预后相似,但HER2低表达HR阳性早期乳腺癌具有孕激素受体阳性表达率高、Ki-67表达率低、脉管侵犯少等特点。HER2低表达是HR阳性早期乳腺癌无病生存期的独立保护因素。

HER-2低表达与HER-2阴性早期乳腺癌临床与病理特征及NACT效果对比

目的 探讨人表皮生长因子受体-2(HER-2)低表达与HER-2阴性早期乳腺癌临床与病理特征及新辅助化疗(NACT)效果的差异性。方法 收集2018年1月—2022年7月于我院行NACT及手术治疗的137例早期乳腺癌患者的临床资料行回顾性分析,根据化疗前HER-2状态分为HER-2低表达组(HER2-low组,n=94)和HER-2阴性组(HER2-zero组,n=43),并进一步依据激素受体状态(HR+/-)分为HR+/HER2-low组(n=74)、HR+/HER2-zero组(n=28)、HR-/HER2-low组(n=20)、HR-/HER2-zero组(n=15)四个亚组;对比分析两组及亚组间的年龄、BMI、月经状态、分子亚型、组织学分级,TNM分期、化疗方案和周期、手术方式,NACT前后雌孕激素受体和Ki-67状态,NACT后靶病灶客观缓解率和腋窝淋巴结缩小比例,术后腋窝淋巴结病理状态和病理M&P分级,组间及亚组间pCR率等。结果 HER2-low组患病率显著高于HER2-zero组(P<0.05);HER2-low组与HER2-zero组一般资料差异无统计学意义(P>0.05);HER2-low组雌激素受体阳性率和Ki-67<35%的比例显著高于HER2-zero组,而在靶病灶客观缓解率(ORR)和HR-亚组中的pCR率显著降低,同时对比发现HR-/HER2-low亚组具有较高的组织学分级和较低的Ki-67<35%状态,差异均有统计学意义(P<0.05);HER2-low组与HER2-zero组在腋窝淋巴结缩小比例、术后腋窝淋巴结病理状态及组间pCR率等其他预后指标方面差异无统计学意义(P>0.05)。结论 HER-2低表达较HER-2阴性早期乳腺癌患病率高,且具有较高的雌激素受体阳性率和较低的Ki-67状态,缩瘤效果较差,并在激素受体阴性亚组中的pCR率显著降低,同时发现低pCR率与较高的组织学等级和较低的Ki-67状态相关。

5-aza-2’-deoxycitydine诱导胃癌细胞系TIMP3基因去甲基化和转录上调的实验性探讨

目的:研究人类胃癌细胞系中5-aza-2’-deoxycitydine诱导肿瘤抑制基因TIMP3mRNA和蛋白表达。方法:DNA甲基化抑制剂5-aza-2’-deoxycitydine处理人类胃癌细胞系SGC-7901。应用RT-PCR和Western-Blot方法检测TIMP3基因mRNA和蛋白表达。应用MSP分析TIMP3基因启动子甲基化状态。结果:5-aza-2’-deoxycitydine诱导TIMP3基因启动子去甲基化,上调TIMP3mRNA和蛋白表达。结论:甲基化异常是胃癌细胞TIMP3基因失活的原因之一,并可受去甲基化制剂调控表达。

三阴性乳腺癌中HER-2低表达与HER-2不表达的新辅助化疗疗效评估

目的 探讨三阴性乳腺癌(triple negative breast cancer, TNBC)患者中HER-2低表达和HER-2不表达在新辅助化疗(neoadjuvant chemotherapy, NAC)疗效方面的差异。方法 回顾性收集2018年1月~2020年1月就诊于南阳市中心医院的120例TNBC患者的临床病理资料,初诊行NAC治疗,其中HER-2低表达组57例,HER-2不表达组63例。采用双侧χ^(2)检验分析比较两组患者的临床病理特征。3年术后复发率或转移率。二元Logistic回归分析评价临床病理因素对病理完全缓解(pathological complete response, pCR)的影响。采用生存曲线比较两组患者的无病生存率。结果 相较于HER-2不表达组,HER-2低表达组患者T_(3~4)期的患者比例显著增高(P<0.05),腋窝淋巴结有转移的患者比例也显著增高(P<0.05),而组织学分级显著更低(P<0.05)。腋窝淋巴结状态(P<0.05)和HER-2表达水平(P<0.05)是TNBC患者pCR的独立影响因素,腋窝淋巴结有转移和HER-2低表达的TNBC患者,在NAC治疗后更不容易达到pCR状态,另外,HER-2低表达组相较HER-2不表达组,3年复发率或转移率明显升高(28.1%vs 11.1%,P<0.05),无病生存率显著降低(P<0.05)。结论 在TNBC患者中,相较于HER-2不表达,HER-2低表达患者腋窝淋巴结转移率更高,在NAC后更不容易达到pCR,预后结果也更差。

MRI及临床病理特征对乳腺癌人表皮生长因子受体2表达状态的鉴别诊断价值

目的 探讨MRI联合临床病理特征在乳腺癌人表皮生长因子受体2(human epidermal growth factor receptor 2, HER-2表达状态中的鉴别诊断价值,尤其是在HER-2低表达乳腺癌中的鉴别诊断价值。材料与方法 回顾性分析2018年1月至2019年12月在复旦大学附属肿瘤医院经病理证实为乳腺癌的患者治疗前乳腺MRI图像,205例患者均行双侧乳腺平扫及增强MRI检查。根据免疫组织化学和荧光原位杂交结果将HER-2状态分为HER-2阴性(包括零、低表达)和阳性(过表达)。分析各组临床病理特征及MRI特征,临床病理特征包括年龄、月经状态、雌激素受体(estrogen receptor, ER)、孕激素受体(progesterone receptor, PR)、激素受体(hormone receptor, HR)、分子分型和Ki-67水平。MRI特征包括纤维腺体类型、背景实质强化、多灶或多中心、瘤内T2WI高信号、瘤周水肿、病灶类型、病灶大小、肿块形状、边缘、内部强化模式、非肿块强化分布及内部强化模式。单因素分析中,对于HER-2阴、阳性组间比较,年龄采用独立样本t检验,病灶大小采用Mann-Whitney U检验,其余临床病理特征及MRI特征采用χ^(2)检验;对于HER-2零、低和过表达组的比较,年龄采用单因素方差分析,病灶大小采用Kruskal-Wallis H检验;其余临床病理特征及MRI特征采用χ^(2)检验。多因素分析采用二元logistic回归分析,用受试者工作特征曲线下面积(area under the curve, AUC)、敏感度和特异度评价模型的诊断效能。结果 HER-2阴性中零表达59例、低表达79例,HER-2阳性(过表达) 67例。HER-2阴性与阳性组临床病理特征中,ER、PR、HR和分子分型差异有统计学意义(P均<0.001),MRI特征中肿块边缘差异有统计学意义(P=0.020)。进一步比较HER-2低表达组与零表达组、HER-2低表达组与过表达组,临床病理特征中,ER、PR、HR、分子分型和Ki-67水平(以中位数40%为截断值)组间差异具有统计学意义(ER、PR、HR、分子分型:P均<0.001;Ki-67:P<0.001,P=0.037);MRI特征中,瘤内T2WI高信号与肿块形状组间差异具有统计学意义(瘤内T2WI高信号:P=0.031,P=0.011;肿块形状:P=0.012,P=0.025),且肿块边缘在HER-2低表达与零表达组间差异有统计学意义(P=0.036)。联合临床病理和MRI特征的多因素分析提示,PR状态、Ki-67水平及肿块形状是鉴别乳腺癌HER-2低表达与零表达的独立预测因素,AUC、敏感度和特异度分别为0.772、79.7%和70.9%;PR状态及瘤内T2高信号是鉴别HER-2低表达与过表达的独立预测因素,AUC、敏感度、特异度分别为0.793、69.8%和76.1%。结论 MRI影像特征对乳腺癌HER-2表达状态具有鉴别诊断价值,尤其在HER-2低表达与零表达或过表达乳腺癌鉴别诊断中。联合临床病理特征,PR阳性、Ki-67低于40%、肿块形状不规则和瘤内T2WI高信号可提示HER-2低表达乳腺癌。

抗体药物偶联物在人表皮生长因子受体2低表达胃癌中的应用研究进展

胃癌(GC)是极具异质性和侵袭性的消化系统恶性肿瘤之一,传统化疗药物及曲妥珠单抗等人表皮生长因子受体2(HER2)靶向药物在GC的治疗过程中仍然存在耐药性发生率高、毒副作用大、患者耐受差等缺点。因此,研发更为有效的抗GC药物势在必行。目前针对HER2的新型靶向药层出不穷,但在某些情况下无效或产生耐药,这与HER2在某些GC细胞中低表达有关,HER2低表达(HER2 IHC1+或IHC2+/ISH-)约占全部类型的40%~60%,但在临床实践中,这类患者仍被报告为HER2阴性GC。因此准确检测HER2表达状态对于确定可能受益于曲妥珠单抗治疗的患者至关重要。抗体药物偶联物(ADC)的出现为HER2阳性GC提供了新的治疗选择,凭借其精准高效的抗肿瘤作用,有望在未来替代传统GC化学疗法。近期有研究发现ADC可能在HER2低表达GC中具有潜在抗肿瘤活性,相关临床研究正在评估其在HER2低表达GC治疗中的有效性和安全性。本文就靶向治疗时代ADC在HER2低表达GC患者中的应用和最新研究进展作一综述,并讨论HER2靶向ADC在应用和研发过程中面临的挑战。

5-aza-2'-deoxycitydine induces demethylation and up-regulates transcription of p16^(INK4A) gene in human gastric cancer cell lines

Background To investigate the effects of DNA methylation on the expression of tumor-associated genes and the cell cycle in human gastric cancer cells. Methods Two gastric cancer cell lines (MKN-45 and HGC-27) were treated with DNA methyltransferase (DNMT) inhibitor,5-aza-2’-deoxycytidine (5-aza-dC). The expressions of p16 INK4A,p21 WAF1,p53 , p73 ,c-Ha-ras and c-myc genes mRNA were detected by using reverse transcription PCR (RT-PCR). DNA methylation status of p16 INK4A gene promoter was assayed by bisulfite modification and sequencing. The cell cycle was analyzed by using flow cytometry (FCM). Results 5-aza-dC induced the demethylation of p16 INK4A gene promoter. The expression of p16 INK4A mRNA was obviously up-regulated by treatment with 10 μmol/L (MKN-45 cells) or 5 μmol/L (HGC-27 cells) of 5-aza-dC for 24 hours. However,5-aza-dC treatment failed to regulate the expressions of p21 WAF1,p53 , p73 ,c-Ha-ras and c-myc genes in MKN-45 and HGC-27 cells. Furthermore,5-aza-dC induced the cell cycle arrest in G1 phase in HGC-27 cell,but not in MKN-45 cell. Conclusions DNA methylation regulates the transcription of p16 INK4A but not p21 WAF1 and proto-oncogenes in human gastric cancer cell lines MKN-45 and HGC-27.

人表皮生长因子受体2低表达乳腺癌的临床病理学特征及预后

目的:新型抗人表皮生长因子受体2(human epidermal growth factor receptor 2,HER2)抗体偶联药物临床试验的成功,使HER2低表达乳腺癌是否将成为新的乳腺癌类型而受到关注。本研究分析比较HER2低表达与HER2零表达两组乳腺癌患者间的临床病理特征及生存数据,探讨其临床生物学上的差异性。方法:2014年1月至2017年12月北京大学第一医院乳腺疾病中心收治的1250例女性原发性非转移性乳腺癌中,969例HER2阴性(免疫组织化学染色评分为0、1+、2+,且荧光原位杂交未扩增),分析其中HER2低表达(1+或2+且荧光原位杂交未扩增)和HER2零表达(0分)两组患者间临床病理特征及预后情况。对两组患者进行无病生存期(disease free survival,DFS)和总生存期(overall survival,OS)预后评价,采用Kaplan-Meier曲线计算生存率,Log-rank检验比较生存差异,单因素和多因素Cox回归分析预后影响因素。采用双侧检验,P<0.05为差异有统计学意义。结果:969例HER2阴性乳腺癌中,HER2低表达者606例(62.54%)、HER2零表达者363例(37.46%)。与HER2零表达组相比,HER2低表达组的N分期(P=0.001)和TNM分期更高(P=0.044),非特殊型组织学类型占比(82.7%vs.79.1%,P=0.009)和组织学分级更高(P=0.048),激素受体阳性率偏高(83.2%vs.75.2%,P=0.003),Ki-67增殖指数>30%者的比例偏低(30.4%vs.36.6%,P=0.044)。两组间DFS及OS差异无统计学意义(P>0.05)。969例患者中,激素受体阳性777例,激素受体阴性(即三阴性乳腺癌)192例。激素受体阳性的777例中,HER2低表达504例(64.9%),HER2零表达273例(35.1%),两组比较,HER2低表达组的发病年龄小(P=0.016),未绝经者占比高(P=0.029),淋巴结受累更多(P=0.002),TNM分期更高(P=0.031),小叶癌和黏液癌组织学类型较少见(3.6%vs.7.3%,4.8%vs.10.6%,P<0.001),DFS和OS差异无统计学意义(P>0.05)。192例激素受体阴性(三阴性乳腺癌)中,HER2低表达102例(53.1%),HER2零表达90例(46.9%),两组比较,HER2低表达组的发病年龄大(P=0.001),未绝经所占比例低(P=0.029),组织学分级更低(P<0.001),Ki-67增殖指数更低(P<0.001),雄激素受体阳性率高(58.8%vs.34.4%,P<0.001),DFS比较好(P=0.038),OS差异无统计学意义(P>0.05)。结论:HER2低表达乳腺癌占所有乳腺癌约一半的比例,发病远高于HER2阳性乳腺癌,其临床病理特征存在异质性,激素受体表达状态对HER2低表达乳腺癌的临床生物学有影响。