从2017 ASCO年会看肿瘤代谢及营养支持研究的进展

吴 超(综述) 郑 燕, 杨济萌 鲁 明 董琼珠 钦伦秀,△(审校)

(1复旦大学附属华山医院普外科 上海 200040; 2复旦大学肿瘤转移研究所 上海 200040; 3复旦大学生物医学研究院 上海 200032)

随着发病率和死亡率的不断增长,肿瘤已成为世界范围内居民死亡的主要原因之一[1-2]。传统观念认为,肿瘤是由内部基因变异和外部暴露所致。作为机体内外环境交流桥梁的新陈代谢在肿瘤发生发展中起着重要作用[3]。基于肿瘤与代谢的密切联系,靶向代谢的抗肿瘤药物研制及临床影像新技术近年来不断取得突破。恰逢第53届美国临床肿瘤学会(American Society of Clinical Oncology,ASCO)年会2017年6月在美国芝加哥举行,本文结合目前相关研究进展就年会中有关肿瘤代谢及临床营养方面的内容进行综述。

靶向代谢通路药物的临床研究20世纪20年代,德国科学家发现肿瘤细胞相对正常细胞特有的有氧糖酵解供能表型(Warburg效应),由此揭开肿瘤代谢研究的序幕[4]。2011年,Weinberg综述了癌症的十大表征,失调的细胞供能位列其一[5]。纵观靶向代谢通路药物的演变,可归纳为两个方向,即二甲双胍、他汀类调脂药的老药新用和以突变的异柠檬酸脱氢酶(mutant isocitrate dehydrogenase,mIDH)抑制剂为代表的新药研发。

二甲双胍 二甲双胍用于治疗糖尿病已逾50年。除降糖作用外,该药还能防治多囊卵巢综合征[6]及肿瘤[7]。既往研究显示,使用二甲双胍能够独立地降低丙肝病毒感染所致肝硬化合并2型糖尿病群体的肝癌发生率和肝脏衰竭或肝移植率[8]。伴有糖尿病的肝癌手术患者术后使用二甲双胍能够有更好的总体生存率和无复发生存率[9]。一项系统评价结果表明,对比其他降血糖手段,二甲双胍能够最优效地降低罹患肝癌的风险[10]。该药物的抗肿瘤效应可能通过激活肝癌细胞中的腺苷酸活化蛋白激酶(adenosine monophosphate activated protein kinase,AMPK),下调哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR),从而抑制细胞增殖,降低体内成瘤率[11]。

本次ASCO会议中,二甲双胍被认为在中晚期卵巢癌、输卵管癌、原发腹膜癌、多发性骨髓瘤中有一定程度的抗癌作用[12-14]。相比其他降糖手段,仅二甲双胍能够提升合并糖尿病的肺癌患者生存结局[15]。对P53缺失的Li-Franmeni综合征患者服用二甲双胍后行代谢组学研究显示,干预组患者的三羧酸循环产物增加,同时脂肪酸氧化水平显著提高[16]。此外,一些研究也探索了二甲双胍联合其他干预(如运动和其他通路阻断剂)的临床疗效。一项旨在探索二甲双胍和生活方式干预对子宫内膜癌高危人群(绝经后肥胖女性)作用的初步结果表明,每日服用1 700 mg二甲双胍同时对生活方式干预可减轻体重,并对血清学指标变化(如脱氢表雄酮)有积极效果[17]。一项纳入139例Ⅰ～Ⅲ期结直肠癌或乳腺癌患者的Ⅱ期多中心临床试验表明,运动和服用二甲双胍均能显著改善结直肠癌或乳腺癌生存者的胰岛素、胰岛素样生长因子1(insulin-like growth factor 1,IGF-1)、胰岛素样生长因子结合蛋白1(insulin-like growth factor-binding protein 1,IGFBP1)等水平并潜在协同作用于瘦素水平[18]。二甲双胍联合依维莫司治疗晚期肿瘤患者的生存分析结果显示,尽管不少患者不能耐受两药的联合治疗,但是耐受患者相对不耐受患者生存期更久[19]。体内和体外实验也证明,二甲双胍对血管内皮生长因子(vascular endothelial growth factor,VEGF)阻断剂的抗肿瘤作用有正向调节作用[20]。de Censi等[21]比较了结肠组织和血浆中二甲双胍的浓度,发现二甲双胍在结肠组织中浓度聚集的现象,从药物动力学上阐释了二甲双胍的抗癌作用。该研究组同时发布了一项Ⅰ～Ⅲ期结直肠癌患者使用二甲双胍和阿司匹林独立或协同抗癌作用的临床试验简要方案[22]。

虽然不少研究表明二甲双胍的抗肿瘤效应,但是一项在实体瘤中联合mTOR抑制剂(西罗莫司)和二甲双胍的临床试验因对初期结果分析发现首要终点指标无差异而被中止[23]。此外,意大利的研究团队基于先前研究结论的扩大样本分析(280例)提示,对服用索拉菲尼的伴有糖尿病晚期肝癌患者,使用二甲双胍控制血糖相比胰岛素会促进肿瘤进展和索拉菲尼的耐药[24-25]。作者分析认为,这样的促肿瘤现象可能是由于药效或药物动力学上的转运基因或转录因子的分子改变从而导致联合用药的失败。

总之,目前不少回顾性队列研究和病例对照研究均显示出二甲双胍的抗肿瘤作用,而少数持相反观点的研究结论均来自对中小样本量的回顾性分析。因此,二甲双胍的抗癌作用是否成立仍需严格设计的前瞻性随机对照研究进行检验,同时需明确二甲双胍对非糖尿病癌症患者的作用。

mIDH抑制剂 异柠檬酸脱氢酶(isocitrate dehydrogenase,IDH)是三羧酸循环中的关键酶之一,分为IDH1、IDH2等,可将异柠檬酸转化为α-酮戊二酸。

一项对384例急性髓系白血病(acute myelocytic leukemia,AML)患者的研究发现,其中13例(3.4%)和27例(7%)发生了IDH1/2突变,均低于文献报道[26]。来自美国MD Anderson的科学家对334例多种肿瘤组织二代测序数据的分析结果显示,IDH突变常常伴有TP53、Kras等基因突变[27]。IDH突变可使癌代谢物2-HG的S型构象转换为R型对映异构体的积聚。Sim等[28]研究发现胶质瘤组织中R/S比例能够有效区分是否有IDH突变,此现象可为临床实时决策(如术中切缘)提供帮助。同样在胶质瘤中,经Toca511和Toca FC治疗(Toca511为逆转录病毒复制载体药物,Toca FC为5-Fu的缓释剂型)的患者其IDH1突变情况和客观反应相关[29]。我们既往研究发现IDH1在肝内胆管癌中也存在一定的突变率[30]。AG120是目前正在试验的靶向IDH1突变实体瘤的口服药物。会议摘要编号4015的研究报道了该药物的Ⅰ期临床试验初步结果[31]。截至2016年底,73例患者接受AG120治疗,仅2例患者出现3级不良反应,但无因不良反应而中断治疗的情况发生。这些患者中,4例确认部分缓解,56例患者维持病情稳定,达到6个月无进展生存比例为40%。因此,AG120对IDH1突变的胆管癌患者显示出一定安全性并能延长疾病稳定期。该药物的Ⅲ期临床试验(ClarIDHy)简要方案同期公布[32]。

IDH2抑制剂AG221在复发难治的AML Ⅰ期临床试验中显示出较好的耐受性并能诱导疾病完全缓解[33]。即使产生AG221相关的分化综合征等并发症,系统性激素治疗、密切血流动力学管理及羟基脲的及早使用仍是有效的[34]。

他汀类调脂药 他汀类药物通过抑制内源性胆固醇合成限速酶羟甲基戊二酰辅酶A(hydroxymethylglutaryl-coenzyme A,HMG-CoA)还原酶,减少胞内胆固醇合成并反馈性促进胞膜低密度脂蛋白受体数量和活性增加,从而清除血清胆固醇,达到降脂目的。

针对Framingham队列的一项研究发现,是否达到指南中他汀药物的适应证可筛选出高患癌风险和癌死亡风险人群[35]。另2个队列研究也发现他汀类药物能降低食管腺癌、结肠癌的患癌风险或癌死亡风险[36-37]。Rutledge等对10 868例服用他汀类调脂药的绝经后女性分析发现,服用他汀类药物和晚期结直肠癌诊断率的下降显著相关[38]。此外,阿比特龙治疗去势抵抗前列腺癌患者联合他汀类药物治疗对疾病预后有正向作用[39]。一项纳入197 048例女性的荟萃分析表明乳腺癌患者服用亲脂性他汀类药物有更强的保护作用,但这种作用仅在随访的前4年中可观察到[40]。通过对7 298例姑息治疗的老年非小细胞肺癌患者分析发现,他汀类药物而非二甲双胍使患者获得更好的生存获益[41]。

其他代谢分子抑制剂 除了糖脂代谢通路的明星药物外,本次会议对其他代谢分子抑制剂也有报道。叶酸受体在肺腺癌等众多肿瘤中高表达,而在绝大多数正常组织中表达量低。EC1456为靶向叶酸受体的小分子化合物。一项EC1456的Ⅰ期剂量爬坡临床试验初步结果显示大部分患者对药物耐受良好[42]。通常情况,癌细胞通过糖酵解生成乳酸并排出胞外,而MCT1为乳酸排泄胞外的关键转运酶。英国研究团队报道了靶向MCT1药物AZD3965剂量探索临床试验结果:最大耐受剂量为每天20 mg[43]。SM88是一种选择性增加癌细胞代谢氧化应激的抗癌药物,本次会议上报道了其Ⅱ期临床试验的简要方案[44]。

靶向代谢联合免疫治疗 虽然有关肿瘤免疫检查点抑制剂的研究是当前热点,但临床实践发现,对一些患者使用已批准的免疫检查点抑制剂,其临床效果甚微。联合免疫检查点药物的靶向代谢治疗有望能使部分患者获益。有研究表明,癌细胞能够通过代谢使得肿瘤微环境和免疫调节受体发生改变,从而抑制效应T细胞[45]。Beckermann等[46]致力于阐明肾细胞癌中代谢状态如何抑制T细胞发挥抗肿瘤作用。运用皮下瘤接种模型研究发现,肿瘤浸润CD8淋巴细胞处于失衡的代谢状态,即活性氧和线粒体损伤水平而非糖代谢水平被上调,是免疫治疗的障碍。来自中美两国的联合研究团队同样利用肺腺癌小鼠模型研究程序性细胞死亡1(programmed cell death-1,PD1)抑制剂耐药机制,发现PD1抑制剂耐药组中脂质代谢通路高度富集。脂质代谢网络通过免疫抑制细胞的积聚来驱动PD1抑制剂耐药[47],故联合靶向脂质代谢通路的抑制剂可能是PD1耐药后续治疗的选择之一。

基于代谢原理的肿瘤显像技术目前临床实践中运用最广泛也最成熟的代谢显像技术是氟18标记的脱氧葡萄糖正电子发射计算机断层显像(18F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography,18F-FDG PET/CT)。本次会议中2篇摘要报道了该技术能早期预测纳武单抗治疗非小细胞肺癌患者的效果及预后[48-49]。早期代谢反应评估预测治疗效果同样适用于局部高级别鼻咽癌、弥漫性大B细胞淋巴瘤和HER2阳性的转移性乳腺癌[50-52]。Huang等[53]报道了早期PET扫描用于评估局部晚期食管鳞癌新辅助放化疗一个疗程的预测效果。虽然结果与预期不符,但是作者分析时发现化疗后标准摄取最大值(maximum of standard uptake value,SUVmax)是这些患者无进展生存时间和总体生存时间的独立预测因子。作者进一步分析预测失败的原因可能是选取终点指标不够完善。一项来自日本的研究通过对18例患者分析发现PET/MRI联合检测对妇科肿瘤淋巴结转移有较高的诊断价值[54]。PET结合弥散加权成像(diffusion weighted image,DWI)序列可以提供比这两种方法单独诊断更高的准确率。PET/MRI 最大优势在于 PET 与 MRI 扫描同时进行,较 PET/CT 能缩短时间并简化步骤。

本次大会公布了联合影像学和液体活检技术用于联合诊断的探索研究结果。因目前暂无有效的生物预测指标反映瑞戈非尼治疗转移性结直肠癌患者的预后,Woff等[55]将基线细胞游离DNA(cell free DNA,cfDNA)结合肿瘤代谢体积及体重指数用来预测瑞戈非尼治疗转移性结直肠癌患者的预后,并显示了良好的预测效能。来自西班牙的研究团队通过基因表达芯片技术在71例不同组织类型的转移性肿瘤患者中进行测试,从13例患者中筛选出葡萄糖摄取环节关联基因,结合SUV发现909个探针有意义,基于这909个探针的构建了PLS-3模型,并对比发现其能够准确预测SUV[56]。

代谢分子在肿瘤发生发展中的作用和机制代谢通路及通路涉及的分子纷繁复杂。但正是由于对关键分子的不断探索,二甲双胍、他汀类等药物才有机会在抗癌治疗中得到实践。Millis等[57]回顾分析1 781例前列腺癌患者全基因组数据发现延胡索酸脱氢酶基因变异率为3%,且大部分位于C末端结合区域,对进一步药物研发有提示作用。复旦大学附属肿瘤医院的研究团队报道了FOXC1通过在转录水平调控糖酵解通路中关键酶二磷酸果糖酶(fructose-bisphosphatase 1,FBP1)并形成反馈轴,增强了肿瘤Warburg效应,参与结直肠癌的恶性进展[58]。Trapp等[59]研究发现乳腺癌循环肿瘤细胞可能通过肝激酶B1(liver kinase B1,LKB1)的上调表达,对早期内渗阶段代谢压力进行反馈,从而促进转移。因此,LKB1有望成为捕获循环肿瘤细胞、防止转移的新治疗靶点。Hu等[60]基于先前发现Kras突变的杂合性缺失(loss of heterozygosity,LOH)和Redd1表达上调相关,对比基因工程小鼠来源的Kras突变和Kras-LOH胰腺癌细胞,发现Kras-LOH使得胰腺癌细胞嗜糖酵解并通过Redd1促进增殖和侵袭。

临床营养方案和营养评估癌症患者,特别是癌症晚期患者,因疾病本身或相关治疗易导致恶病质[61],故临床实践中有效的营养方案和恰当的评估很有必要。

Li等[62]公布的食管癌同期放化疗患者行肠内营养的随机对照临床试验结果显示,对存在高营养不良风险的患者群体给予肠内营养能够提升个体营养状态,增加治疗耐受性,其1年和2年的总体生存率明显提高。相似地,头颈部肿瘤行放疗患者口服营养素也能更好地维持体重,获得更优的生存质量和治疗耐受性[63]。992例Ⅲ期结肠癌患者的CALGB 89803研究证明,遵从ASCO肿瘤患者营养及运动指南的结肠癌患者能获得更长的无疾病进展期和总体生存期[64]。该研究还得出另一个有趣的结论:更多坚果的食用可能和结肠癌患者更低的复发和死亡率有关[65]。除了有效的营养方案,恰当的评估也十分重要。Herrera等[66]将包含血清白蛋白水平和总淋巴细胞数的预测营养指数(prognostic nutrition index,PNI)用于91例胃癌术后患者的营养评估,结果发现PNI低于38.7的患者总体生存率更低(46个月vs.25个月,P=0.009)。这种评估方案同样适合乳腺癌患者[67]。

结语肿瘤代谢和营养支持与目前的临床实践密切相关,且在实践中可尝试二甲双胍、他汀类药物及营养素摄入等干预手段。在靶向肿瘤代谢的基础研究中,除mIDH抑制剂外的大多数药物仍停留在Ⅰ或Ⅱ期临床试验阶段。随着新技术和算法的应用,基于肿瘤代谢的肿瘤显像不断取得进展。对于其他传统或新兴治疗耐药的患者,联合靶向代谢治疗初现优势。

参 考 文 献

[1] CHEN W,ZHENG R,BAADE PD,etal.Cancer statistics in China,2015[J].CACancerJClin,2016,66(2):115-132.

[2] SIEGEL RL,MILLER KD,JEMAL A.Cancer statistics,2017 [J].CACancerJClin,2017,67(1):7-30.

[3] VANDER HEIDEN MG,DEBERARDINIS RJ.Understanding the intersections between metabolism and cancer biology[J].Cell,2017,168(4):657-669.

[4] WARBURG O.On the origin of cancer cells[J].Science,1956,123(3191):309-314.

[5] HANAHAN D,WEINBERG RA.Hallmarks of cancer:the next generation[J].Cell,2011,144(5):646-674.

[6] GANGALE MF,MIELE L,LANZONE A,etal.Long-term metformin treatment is able to reduce the prevalence of metabolic syndrome and its hepatic involvement in young hyperinsulinaemic overweight patients with polycystic ovarian syndrome [J].ClinEndocrinol,2011,75(4):520-527.

[7] EVANS JM,DONNELLY LA,EMSLIE-SMITH AM,etal.Metformin and reduced risk of cancer in diabetic patients[J].BMJ,2005,330(7503):1304-1305.

[8] NKONTCHOU G,COSSON E,AOUT M,etal.Impact of metformin on the prognosis of cirrhosis induced by viral hepatitis C in diabetic patients[J].JClinEndocrMetab,2011,96(8):2601-2608.

[9] CHAN KM,KUO CF,HSU JT,etal.Metformin confers risk reduction for developing hepatocellular carcinoma recurrence after liver resection[J].LiverInt,2017,37(3):434-441.

[10] ZHOU YY,ZHU GQ,LIU T,etal.Systematic review with network meta-analysis:antidiabetic medication and risk of hepatocellular carcinoma[J].SciRep,2016,6:33743.

[11] ZHENG L,YANG W,WU F,etal.Prognostic significance of AMPK activation and therapeutic effects of metformin in hepatocellular carcinoma[J].ClinCancerRes,2013,19(19):5372-5380.

[12] BUCKANOVICH RJ,BROWN J,SHANK J,etal.A phase II clinical trial of metformin as a cancer stem cell targeting agent in stage IIc/III/IV ovarian,fallopian tube,and primary peritoneal cancer[J].JClinOncol,2017,35(Suppl):5556.

[13] DUMA N,AGUILERA JV,PALUDO J,etal.Impact of metformin use in the outcomes of multiple myeloma patients post stem cell transplant[J].JClinOncol,2017,35(Suppl):8034.

[14] MANJAPPA S,FIALA M A,VIJ R,etal.Metformin use in diabetic patients with multiple myeloma (MM):A SEER-Medicare study[J].JClinOncol,2017,35(Suppl):e18127.

[15] HUANG P,XIN W,FANG L,etal.Effect of hypoglycemic agents on survival outcomes of patients with lung cancer and diabetes mellitus:A systematic review and meta-analysis[J].JClinOncol,2017,35(Suppl):e21617.

[16] WALCOTT FL,ANNUNZIATA CM,SOTOMAYOR EM,etal.Effect of metformin chemoprevention on metabolomics profiles in Li-Fraumeni Syndrome (LFS)[J].JClinOncol,2017,35(Suppl):1556.

[17] YATES MS,BASEN-ENGQUIST K,ZHANG Q,etal.Prospective randomized biomarker study of metformin and lifestyle intervention for prevention in obese postmenopausal women at increased risk for endometrial cancer[J].JClinOncol,2017,35(Suppl):1551.

[18] MEYERHARDT JA,IRWIN ML,JONES L,etal.Multicenter,randomized phase II trial of physical activity (PA),metformin (Met),or the combination on metabolic biomarkers in stage I-III colorectal (CRC) and breast cancer (BC) survivors[J].JClinOncol,2017,35(Suppl):10059.

[19] MOLENAAR RJ,VENNE TVD,WETERMAN M,etal.Survival analysis of a phase ⅠB/Ⅱ study of everolimus and metformin for patients with advanced cancer[J].JClinOncol,2017,35(Suppl):e14020.

[20] SELMY M,ZULATO E,PASTO A,etal.Modulation of the anti-tumor activity of VEGF blockade by metformin[J].JClinOncol,2017,35(Suppl):e23009.

[21] DE CENSI A,BURHENNE J,HAEFELI WE,etal.High accumulation of metformin in colonic tissue of subjects with diabetes or metabolic syndrome[J].JClinOncol,2017,35(Suppl):1557.

[22] PETRERA M,PALEARI L,PUNTONI M,etal.ASAMET:A randomized,2×2 biomarker prevention trial of low-dose aspirin and metformin in colorectal cancer[J].JClinOncol,2017,35(Suppl):TPS1591.

[23] SEHDEV A,ZHA Y,KARRISON TG,etal.A pharmacodynamic study of sirolimus and metformin in patients with advanced solid tumors[J].JClinOncol,2017,35(Suppl):e11628.

[24] GARDINI AC,FALOPPI L,MATTEIS SD,etal.Metformin effects on clinical outcome in advanced HCC patients receiving sorafenib:validation study[J].JClinOncol,2017,35(Suppl):e15684.

[25] CASADEI GARDINI A,MARISI G,SCARPI E,etal.Effects of metformin on clinical outcome in diabetic patients with advanced HCC receiving sorafenib[J].ExpertOpinPharmaco,2015,16(18):2719-2725.

[26] SANTOS MTD,SMART D,AITA E,etal.Real world patient numbers for AML targeted therapies[J].JClinOncol,2017,35(Suppl):e18510.

[27] JANKU F,GROOT JFD,JAVLE MM,etal.Simultaneous molecular alterations in solid tumors with IDH1 or IDH2 mutations[J].JClinOncol,2017,35(Suppl):e11609.

[28] SIM HW,NEJAD R,ZHANG W,etal.Comparison of 2-hydroxyglutarate (2HG) levels in tissue and serum of isocitrate dehydrogenase (IDH)-mutated (MUT) versus wild-type (WT) gliomas[J].JClinOncol,2017,35(Suppl):2037.

[29] CLOUGHESY TF,OSTERTAG D,LANDOLFI JC,etal.Durable complete responses observed in IDH1 mutated high grade glioma at first recurrence undergoing treatment with Toca 511 and Toca FC[J].JClinOncol,2017,35(Suppl;):e13504.

[30] WANG P,DONG Q,ZHANG C,etal.Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hyper-methylation targets with glioblastomas[J].Oncogene,2013,32(25):3091-3100.

[31] LOWERY MA,ABOU-ALFA GK,BURRIS HA,etal.Phase I study of AG-120,an IDH1 mutant enzyme inhibitor:results from the cholangiocarcinoma dose escalation and expansion cohorts[J].JClinOncol,2017,35(Suppl):4015.

[32] LOWERY MA,ABOU-ALFA GK,VALLE JW,etal.ClarIDHy:a phase 3,multicenter,randomized,double-blind study of AG-120 vs placebo in patients with an advanced cholangiocarcinoma with an IDH1 mutation[J].JClinOncol,2017,35(Suppl):e4142.

[33] STEIN EM,DINARDO CD,POLLYEA DA,etal.Enasidenib in mutant-IDH2 relapsed or refractory acute myeloid leukemia (R/R AML):results of a phase I dose-escalation and expansion study[J].JClinOncol,2017,35(Suppl):7004.

[34] FATHI AT,DINARDO CD,KLINE I,etal.Differentiation syndrome associated with enasidenib,a selective inhibitor of mutant isocitrate dehydrogenase 2 (mIDH2)[J].JClinOncol,2017,35(Suppl):7015.

[35] PURSNANI A,MASSARO JM,D′AGOSTINO RB SR,etal.Guideline-based statin eligibility,cancer events,and noncardiovascular mortality in the framingham heart study[J].JClinOncol,2017,35(25):2927-2933.

[36] ALEXANDRE L,CLARK AB,BHUTTA HY,etal.Association between statin use after diagnosis of esophageal cancer and survival:a population-based cohort study[J].Gastroenterology,2016,150(4):854-865.

[37] VOORNEVELD PW,REIMERS MS,BASTIAANNET E,etal.Statin use after diagnosis of colon cancer and patient survival[J].Gastroenterology,2017,153(2):470-479.

[38] RUTLEDGE B,DESAI PM,ABDEL-RASOUL M,etal.The relationship between statins and colorectal cancer stage in the Women’s Health Initiative[J].JClinOncol,2017,35(Suppl):1540.

[39] BUONERBA C,SONPAVDE G,POND GR,etal.Statin use and survival in patients with metastatic castration-resistant prostate cancer treated with abiraterone acetate or enzalutamide[J].JClinOncol,2017,35(Suppl):e16503.

[40] LIU B,YI Z,GUAN X,etal.The relationship between statins and breast cancer prognosis varies by statin type and exposure time:a meta-analysis[J].JClinOncol,2017,35(Suppl):e21606.

[41] LEE YG,LEE JH,JANG JS,etal.Prognostic benefit of statin with or without metformin in elderly patients with advanced non-small cell lung cancer:a nationwide population-based outcome study [J].JClinOncol,2017,35(Suppl):e20661.

[42] HARB WA,EDELMAN MJ,CHAMBERS SK,etal.Phase 1 dose escalation study of the folate receptor-targeted small molecule drug conjugate EC1456[J].JClinOncol,2017,35(Suppl):2576.

[43] HALFORD SER,JONES P,WEDGE S,etal.A first-in-human first-in-class (FIC) trial of the monocarboxylate transporter 1 (MCT1) inhibitor AZD3965 in patients with advanced solid tumours[J].JClinOncol,2017,35(Suppl):2516.

[44] PRIORE GD,HOFFMAN S,NIXON DW.A phase Ib/II,open-label,dose escalation study to evaluate the safety,pharmacokinetics,and efficacy of SM88 in patients with prostate cancer[J].JClinOncol,2017,35(Suppl):TPS2615.

[45] KISHTON RJ,SUKUMAR M,RESTIFO NP.Metabolic regulation of T cell longevity and function in tumor immunotherapy[J].CellMetab,2017,26(1):94-109.

[46] BECKERMANN K,SISKA P,MASON F,etal.Metabolic barriers to immunotherapy in renal cell carcinoma[J].JClinOncol,2017,35(Suppl):11560.

[47] WELSH JW,NIKNAM S,SCHOENHALS JE,etal.Fatty-acid-binding proteins as a novel target for the treatment of anti-PD-1-resistant tumors[J].JClinOncol,2017,35(Suppl):11562.

[48] KAIRA K,NARUSE I,HIGUCHI T,etal.Metabolic activity by18F-FDG-PET/CT to predict for early response after nivolumab in previously treated NSCLC[J].JClinOncol,2017,35(Suppl):e20615.

[49] GOLDFARB L,DUCHEMANN B,CHOUAHNIA K,etal.FDG-PET in the assessment of metabolic response in patients with NSCLC treated with Nivolumab:preliminary results[J].JClinOncol,2017,35(Suppl):e20554.

[50] KWONG DL W,LEE VH,KHONG PL.Correlation of outcome with early metabolic response on FDG-PET in treatment of locally advanced nasopharyngeal carcinoma [J].JClinOncol,2017,35(Suppl):e17555.

[51] ISLAM P,GOLDSTEIN J,SETHI I,etal.Interim metabolic tumor volume to predict response in diffuse large B-cell lymphoma[J].JClinOncol,2017,35(Suppl):7557.

[52] MORTIMER JE,BADING JR,FRANKEL PH,etal.64Cu-DOTA-trastuzumab PET/CT to predict response to ado-trastuzumab emtansine (TDM1) in HER2-positive metastatic breast cancer[J].JClinOncol,2017,35(Suppl):e12525.

[53] HUANG TC,LIN CC,TZEN KY,etal.A phase Ⅱ study of early FDG-PET evaluation after one-cycle chemotherapy in patients with locally advanced esophageal squamous cell carcinoma treated with neoadjuvant chemoradiotherapy:Final report[J].JClinOncol,2017,35(Suppl):4042.

[54] TSUYOSHI H,TSUJIKAWA T,OKAZAWA H,etal.Diagnostic value of 18F-FDG PET/MRI for the detection of lymph node metastasis in gynecologic cancer[J].JClinOncol,2017,35(Suppl):e17014.

[55] WOFF E,KEHAGIAS P,VANDEPUTTE C,etal.Baseline cell-free DNA (cfDNA) and metabolic tumor volume (MTV) independently predict outcome in metastatic chemorefractory colorectal cancer (mCRC)[J].JClinOncol,2017,35(Suppl):e11569.

[56] SUREDA M,CRESPO-JARA A,MANZANO RG,etal.Contribution of microarrays of gene expression (MAGE) to the definition of PET/CT as a qualified biomarker of early response in metastatic patients[J].JClinOncol,2017,35(Suppl):e11573.

[57] MILLIS SZ,MARSH S,PECCI C,etal.Identification of novel fumarate hydratase gene alterations in prostate cancer[J].JClinOncol,2017,35(Suppl):e11585.

[58] LI D,LI Q,CAI S,etal.The FOXC1/FBP1 signaling axispromotes tumorigenicity by enhancing the Warburg effect in colorectal cancer[J].JClinOncol,2017,35(Suppl):e15123.

[59] TRAPP EK,ANDERGASSEN U,KOCH JG,etal.LKB1 and its importance for survival in EpCAM negative circulating tumor cells (CTC) in metastatic breast cancer[J].JClinOncol,2017,35(Suppl):e23061.

[60] HU M,HUANG P,MA Y,etal.Effect of Redd1 loss on proliferation and metastasis of pancreatic cancer cells with KrasG12D-LOH by inhibiting glycolysis[J].JClinOncol,2017,35(Suppl):e15741.

[61] FEARON K,STRASSER F,ANKER SD,etal.Definition and classification of cancer cachexia:an international consensus[J].LancetOncol,2011,12(5):489-495.

[62] LI T,LV J,ZHU G,etal.Enteral nutrition to improve nutritional status,treatment tolerance,and outcomes in patients with esophageal cancer undergoing concurrent chemoradiotherapy (CCRT):results of a prospective,randomized,controlled,multicenter trial (NCT 02399306)[J].JClinOncol,2017,35(Suppl):4033.

[63] PEDRAZZOLI P,CAPPELLO S,COLOMBO S,etal.Nutritional counseling with or without systematic use of oral nutritional supplements in head and neck cancer patients undergoing radiotherapy[J].JClinOncol,2017,35(Suppl):10098.

[64] VAN BLARIGAN E,NIEDZWIECKI D,XING YE,etal.American Cancer Society (ACS) Nutrition and Physical Activity Guidelines after colon cancer diagnosis and disease-free (DFS),recurrence-free (RFS),and overall survival (OS) in CALGB 89803 (Alliance)[J].JClinOncol,2017,35(Suppl):10006.

[65] FADELU T,ZHANG S,XING YE,etal.Nut consumption and survival in stage Ⅲ colon cancer patients:results from CALGB 89803 (Alliance)[J].JClinOncol,2017,35(Suppl):3517.

[66] HERRERA M,SOBREVILLA-MORENO N,LYRA-GONZALEZ I,etal.Significance of Prognostic Nutritional Index in post-surgical outcomes after surgical management in gastric cancer patients[J].JClinOncol,2017,35(Suppl):e15535.

[67] YAMASHITA N,TANAKA K,SAEKI H,etal.The clinical impact of the prognostic nutritional index (PNI) and controlling nutritional status (CONUT) score on breast cancer patients survival[J].JClinOncol,2017,35(Suppl):1560.