精准医学时代胆囊癌的系统治疗——机遇与挑战并存

张瑞; 耿智敏

doi:10.3969/j.issn.1001-5256.2023.09.005

精准医学时代胆囊癌的系统治疗——机遇与挑战并存

DOI: 10.3969/j.issn.1001-5256.2023.09.005

张瑞,
耿智敏^, ,

西安交通大学第一附属医院肝胆外科，西安 710061

基金项目:

国家自然科学基金 (62076194);

陕西省重点研发计划 (2022SF－606);

陕西省重点研发计划 (2022－YBSF－441)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：张瑞负责收集数据，资料分析，撰写论文，修改论文；耿智敏负责课题设计，拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
耿智敏， gengzhimin@mail.xjtu.edu.cn （ORCID： 0000－0003－2645－9808）

计量
- 文章访问数: 345
- HTML全文浏览量: 179
- PDF下载量: 72
- 被引次数: 0
出版历程
- 收稿日期: 2023-06-12
- 录用日期: 2023-07-15
- 出版日期: 2023-09-19

Systemic therapy for gallbladder cancer in the era of precision medicine： Coexistence of opportunities and challenges

Rui ZHANG,
Zhimin GENG^{,
,}

Department of Hepatobiliary Surgery，The First Affiliated Hospital of Xi’an Jiaotong University，Xi’an 710061，China

Research funding:

National Natural Science Foundation of China (62076194);

Key Research and Development Plan of Shaanxi Province (2022SF－606);

Key Research and Development Plan of Shaanxi Province (2022－YBSF－441)

More Information

Corresponding author: GENG Zhimin， gengzhimin@mail.xjtu.edu.cn （ORCID： 0000－0003－2645－9808）

摘要

摘要: 胆囊癌是胆道系统最常见的恶性肿瘤类型，由于其高度的侵袭性和对传统的放化疗不敏感，极大地制约了临床疗效。近些年随着多种高通量测序技术层出不穷，对胆囊癌分子机制的认识也逐渐加深，一些潜在的治疗靶点逐渐被发现，目前相应的临床试验正在如火如荼地进行。深入探究其异质性的分子分型，对于制订个体化诊疗策略极为重要。近年来结合多组学特征提出了多种分子分型系统，使临床研究者对胆囊癌分子机制及特征有了更加深刻的认识。本文结合胆囊癌最新研究进展，探讨了胆囊癌突变靶点和分子分型等相关问题，分析了靶向治疗和免疫治疗的干预新靶标，提出了胆囊癌精准诊断和个体化治疗的新思路。
- 胆囊肿瘤 /
- 精准医学 /
- 治疗学
Abstract: Gallbladder cancer is the most common malignant tumor of the biliary system， and its treatment outcome is greatly limited by its invasiveness and insensitivity to conventional radiotherapy and chemotherapy. In recent years， the emergence of various high－throughput sequencing techniques has helped to deepen the understanding of the molecular mechanisms of gallbladder cancer， and promising therapeutic targets have been identified and studied in clinical trials at present. A comprehensive exploration of the molecular subtypes of gallbladder cancer is of great importance for developing individualized diagnosis and treatment strategies. Several molecular subtyping systems have been proposed based on multi－omics features， which enhances the comprehension of the molecular mechanisms and features of gallbladder cancer among clinical researchers. With reference to the latest research advances in gallbladder cancer， this article investigates the challenges in the mutation targets and molecular subtyping of gallbladder cancer， analyzes the novel targets for targeted therapy and immunotherapy， and proposes new ideas for the precise diagnosis and individualized treatment of gallbladder cancer.
- Gallbladder Neoplasms /
- Precision Medicine /
- Therapeutics

HTML全文

表 1 纳入GBC靶向治疗的临床试验

Table 1. Clinical trial of targeted therapy including GBC

研究项目	靶向药物	干预的信号通路	纳入人数（例）		试验阶段	客观反应率	中位无进展生存期（月）	中位总生存期（月）	临床试验注册号
研究项目	靶向药物	干预的信号通路	BTC	GBC	试验阶段	客观反应率	中位无进展生存期（月）	中位总生存期（月）	临床试验注册号
Javle等^［31］	曲妥珠单抗+帕妥珠单抗	HER2/neu	39	16	Ⅱa期	23%	4.0	14.2	NCT02091141
Harding等^［37］	来那替尼	HER2和HER3	25	10	Ⅱ期	16.0%	2.8	5.4	NCT01953926
Javle等^［38］	托西酸伐利替尼+卡培他滨	HER1、HER2和HER4	64	18	Ⅱ期	9.4%	2.8	7.8	NCT03093870
Malka等^［39］	吉西他滨+奥沙利铂+西妥昔单抗	EGFR	76	11	Ⅱ期	18%	6.1	11.0	NCT00552149
Demols等^［40］	瑞戈非尼	VEGF和多种其他靶点	33	4	Ⅱ期	NA	3.0	5.3	NCT02162914
Lee等^［41］	吉西他滨+奥沙利铂+厄洛替尼	EGFR	135	35	Ⅲ期	31%	5.8	9.5	NCT01149122
Lowery等^［42］	GC方案+比尼替尼	MEK1/2	41	12	Ⅰ、Ⅱ期	36%	6.0	13.3	NCT01828034
Lee等^［43］	雷莫芦单抗	VEGFR－2	60	13	Ⅱ期	1.7%	3.2	9.5	NA
Valle等^［44］	GC方案+西地尼布	VEGFR	62	20	Ⅲ期	44%	8.0	14.1	NCT00939848
注：GC方案，吉西他滨+顺铂；VEGF，血管内皮生长因子；NA，未提及。

下载: 导出CSV

表 2 纳入GBC免疫治疗的临床试验

Table 2. Clinical trial of immunotherapy including GBC

研究项目	药物	试验阶段	纳入人数（例）		客观反应率	中位无进展生存期（月）	中位总生存期（月）	临床试验注册号
研究项目	药物	试验阶段	BTC	GBC	客观反应率	中位无进展生存期（月）	中位总生存期（月）	临床试验注册号
Piha－Paul等^［46］	帕博利珠单抗	Ⅱ期	104	NA	5.8%	2.0	7.4	NCT02628067
Piha－Paul等^［46］	帕博利珠单抗	Ⅰb期	24	NA	13%	1.8	5.7	NCT02054806
Kim等^［47］	纳武利尤单抗	Ⅱ期	54	17	IR：22%； ICR：11%	3.7	14.2	NCT02829918
Kelley等^［48］	帕博利珠单抗+GM－CSF	Ⅱ期	42	3	12%	2.1	3.1	NCT02703714
Klein等^［49］	纳武利尤单抗+伊匹单抗	Ⅱ期	39	13	23%	2.9	5.7	NCT02923934
Ueno等^［50］	纳武利尤单抗	Ⅰ期	30	10	3%	1.4	5.2	JapicCTI－153098
Ueno等^［50］	纳武利尤单抗+GC方案	Ⅰ期	30	10	37%	4.2	15.4	JapicCTI－153098
Doki等^［51］	度伐利尤单抗	Ⅰ期	42	NA	4.8%	1.5	8.1	NCT01938612
Doki等^［51］	曲美木单抗+度伐利尤单抗	Ⅰ期	65	NA	10.8%	1.6	10.1	NCT01938612
注：GM－CSF，粒细胞－巨噬细胞集落刺激因子；ICR，独立中央评审；IR，研究者评审；NA，未提及。

下载: 导出CSV

表 3 纳入化疗和免疫治疗联合治疗GBC的Ⅲ期临床试验

Table 3. Phase Ⅲ clinical trial of combined chemotherapy and immunotherapy including GBC

研究项目	纳入人数（例）		治疗方案	客观反应率	中位无进展生存期（月）	中位总生存期（月）	临床试验注册号
研究项目	GBC	BTC	治疗方案	客观反应率	中位无进展生存期（月）	中位总生存期（月）	临床试验注册号
Kelley等^［53］	233	1 069	GC方案	29%	5.6	10.9	NCT04003636
Kelley等^［53］	233	1 069	GC方案+帕博利珠单抗	29%	6.5	12.7
Oh等^［52］	171	685	GC方案	18.7%	5.7	11.5	NCT03875235
Oh等^［52］	171	685	GC方案+度伐利尤单抗	26.7%	7.2	12.8
注：NA，未提及。

下载: 导出CSV

参考文献(53)

[1]	ROA JC, GARCÍA P, KAPOOR VK, et al. Gallbladder cancer[J]. Nat Rev Dis Primers, 2022, 8( 1): 69. DOI: 10.1038/s41572－022－00398－y.
[2]	ARE C, AHMAD H, RAVIPATI A, et al. Global epidemiological trends and variations in the burden of gallbladder cancer[J]. J Surg Oncol, 2017, 115( 5): 580－ 590. DOI: 10.1002/jso.24546.
[3]	OKADA K, KIJIMA H, IMAIZUMI T, et al. Wall－invasion pattern correlates with survival of patients with gallbladder adenocarcinoma[J]. Anticancer Res, 2009, 29( 2): 685－ 691.
[4]	SHIMIZU Y, ASHIDA R, SUGIURA T, et al. ASO visual abstract: early recurrence in resected gallbladder carcinoma－clinical impact and its preoperative predictive score[J]. Ann Surg Oncol, 2022, 29( 9): 5460－ 5461. DOI: 10.1245/s10434－022－12018－w.
[5]	SAHARA K, TSILIMIGRAS DI, KIKUCHI Y, et al. Defining and predicting early recurrence after resection for gallbladder cancer[J]. Ann Surg Oncol, 2021, 28( 1): 417－ 425. DOI: 10.1245/s10434－020－09108－y.
[6]	YANG P, JAVLE M, PANG F, et al. Somatic genetic aberrations in gallbladder cancer: comparison between Chinese and US patients[J]. Hepatobiliary Surg Nutr, 2019, 8( 6): 604－ 614. DOI: 10.21037/hbsn.2019.04.11.
[7]	YU C, ZHANG H, LUO J, et al. Abstract 2194: Comparison of molecular profiling between Chinese cholangiocarcinoma and gallbladder cancer through next－generation sequencing[J]. Cancer Res, 2021, 81( 13_Suppl): 2194. DOI: 10.1158/1538－7445.AM2021－2194.
[8]	CHEN X, PANG J, LIU C, et al. Genomic characterization of chinese biliary tract cancers identifies differences between subtypes and therapeutic biomarkers[J]. Cancer Res, 2022, 82( 12_Suppl): 5765.
[9]	MEHROTRA R, TULSYAN S, HUSSAIN S, et al. Genetic landscape of gallbladder cancer: Global overview[J]. Mutat Res Rev Mutat Res, 2018, 778: 61－ 71. DOI: 10.1016/j.mrrev.2018.08.003.
[10]	NEPAL C, ZHU B, O’ROURKE CJ, et al. Integrative molecular characterisation of gallbladder cancer reveals micro－environment－associated subtypes[J]. J Hepatol, 2021, 74( 5): 1132－ 1144. DOI: 10.1016/j.jhep.2020.11.033.
[11]	PANDEY A, STAWISKI EW, DURINCK S, et al. Integrated genomic analysis reveals mutated ELF3 as a potential gallbladder cancer vaccine candidate[J]. Nat Commun, 2020, 11( 1): 4225. DOI: 10.1038/s41467－020－17880－4.
[12]	ALEXANDROV LB, KIM J, HARADHVALA NJ, et al. The repertoire of mutational signatures in human cancer[J]. Nature, 2020, 578( 7793): 94－ 101. DOI: 10.1038/s41586－020－1943－3.
[13]	NAKAMURA H, ARAI Y, TOTOKI Y, et al. Genomic spectra of biliary tract cancer[J]. Nat Genet, 2015, 47( 9): 1003－ 1010. DOI: 10.1038/ng.3375.
[14]	LI M, ZHANG Z, LI X, et al. Whole－exome and targeted gene sequencing of gallbladder carcinoma identifies recurrent mutations in the ErbB pathway[J]. Nat Genet, 2014, 46( 8): 872－ 876. DOI: 10.1038/ng.3030.
[15]	LI M, LIU F, ZHANG F, et al. Genomic ERBB2/ERBB3 mutations promote PD－L1－mediated immune escape in gallbladder cancer: a whole－exome sequencing analysis[J]. Gut, 2019, 68( 6): 1024－ 1033. DOI: 10.1136/gutjnl－2018－316039.
[16]	JAVLE M, RASHID A, CHURI C, et al. Molecular characterization of gallbladder cancer using somatic mutation profiling[J]. Hum Pathol, 2014, 45( 4): 701－ 708. DOI: 10.1016/j.humpath.2013.11.001.
[17]	ABDEL－WAHAB R, YAP TA, MADISON R, et al. Genomic profiling reveals high frequency of DNA repair genetic aberrations in gallbladder cancer[J]. Sci Rep, 2020, 10( 1): 22087. DOI: 10.1038/s41598－020－77939－6.
[18]	XIE F, XU X, XU A, et al. Aberrant activation of Sonic hedgehog signaling in chronic cholecystitis and gallbladder carcinoma[J]. Hum Pathol, 2014, 45( 3): 513－ 521. DOI: 10.1016/j.humpath.2013.10.017.
[19]	JAVLE MM, CATENACCI D, JAIN A, et al. Precision medicine for gallbladder cancer using somatic copy number amplifications(SCNA) and DNA repair pathway gene alterations[J]. J Clin Oncol, 2017, 35( 15_Suppl): 4076. DOI: 10.1200/JCO.2017.35.15_suppl.4076.
[20]	ROA I, DE TORO G, SCHALPER K, et al. Overexpression of the HER2/neu gene: A new therapeutic possibility for patients with advanced gallbladder cancer[J]. Gastrointest Cancer Res, 2014, 7( 2): 42－ 48.
[21]	ZHANG Y, ZUO C, LIU L, et al. Single－cell RNA－sequencing atlas reveals an MDK－dependent immunosuppressive environment in ErbB pathway－mutated gallbladder cancer[J]. J Hepatol, 2021, 75( 5): 1128－ 1141. DOI: 10.1016/j.jhep.2021.06.023.
[22]	IYER P, SHRIKHANDE SV, RANJAN M, et al. ERBB2 and KRAS alterations mediate response to EGFR inhibitors in early stage gallbladder cancer[J]. Int J Cancer, 2019, 144( 8): 2008－ 2019. DOI: 10.1002/ijc.31916.
[23]	GOEPPERT B, ROESSLER S, RENNER M, et al. Low frequency of mismatch repair deficiency in gallbladder cancer[J]. Diagn Pathol, 2019, 14( 1): 36. DOI: 10.1186/s13000－019－0813－5.
[24]	de BITTER T, de REUVER PR, de SAVORNIN LOHMAN E, et al. Comprehensive clinicopathological and genomic profiling of gallbladder cancer reveals actionable targets in half of patients[J]. NPJ Precis Oncol, 2022, 6( 1): 83. DOI: 10.1038/s41698－022－00327－y.
[25]	BIZAMA C, GARCÍA P, ESPINOZA JA, et al. Targeting specific molecular pathways holds promise for advanced gallbladder cancer therapy[J]. Cancer Treat Rev, 2015, 41( 3): 222－ 234. DOI: 10.1016/j.ctrv.2015.01.003.
[26]	MISHRA S, KUMARI S, SRIVASTAVA P, et al. Genomic profiling of gallbladder carcinoma: Targetable mutations and pathways involved[J]. Pathol Res Pract, 2022, 232: 153806. DOI: 10.1016/j.prp.2022.153806.
[27]	EBATA N, FUJITA M, SASAGAWA S, et al. Molecular classification and tumor microenvironment characterization of gallbladder cancer by comprehensive genomic and transcriptomic analysis[J]. Cancers(Basel), 2021, 13( 4): 733. DOI: 10.3390/cancers13040733.
[28]	AGGARWAL V, MONTOYA CA, DONNENBERG VS, et al. Interplay between tumor microenvironment and partial EMT as the driver of tumor progression[J]. iScience, 2021, 24( 2): 102113. DOI: 10.1016/j.isci.2021.102113.
[29]	ROMEO E, CASERTA CA, RUMIO C, et al. The vicious cross－talk between tumor cells with an EMT phenotype and cells of the immune system[J]. Cells, 2019, 8( 5): 460. DOI: 10.3390/cells8050460.
[30]	CHEN P, WANG Y, LI J, et al. Diversity and intratumoral heterogeneity in human gallbladder cancer progression revealed by single－cell RNA sequencing[J]. Clin Transl Med, 2021, 11( 6): e462. DOI: 10.1002/ctm2.462.
[31]	JAVLE M, BORAD MJ, AZAD NS, et al. Pertuzumab and trastuzumab for HER2－positive, metastatic biliary tract cancer(MyPathway): a multicentre, open－label, phase 2a, multiple basket study[J]. Lancet Oncol, 2021, 22( 9): 1290－ 1300. DOI: 10.1016/S1470－2045(21)00336－3.
[32]	MERIC－BERNSTAMF, HANNADL, EL－KHOUEIRYAB, et al. Zanidatamab(ZW25) in HER2－positive biliary tract cancers(BTCs): results from a phase I study[J]. J Clin Oncol, 2021, 39( 3_suppl): 299. DOI: 10.1200/JCO.2021.39.3_suppl.299.
[33]	HARDING JJ, FAN J, OH DY, et al. Zanidatamab for HER2－amplified, unresectable, locally advanced or metastatic biliary tract cancer(HERIZON－BTC－01): a multicentre, single－arm, phase 2b study[J]. Lancet Oncol, 2023, 24( 7): 772－ 782. DOI: 10.1016/S1470－2045(23)00242－5.
[34]	JAVLE M, ZHAO H, ABOU－ALFA GK. Systemic therapy for gallbladder cancer[J]. Chin Clin Oncol, 2019, 8( 4): 44. DOI: 10.21037/cco.2019.08.14.
[35]	OHBA A, MORIZANE C, UENO M, et al. Multicenter phase II trial of trastuzumab deruxtecan for HER2－positive unresectable or recurrent biliary tract cancer: HERB trial[J]. Future Oncol, 2022, 18( 19): 2351－ 2360. DOI: 10.2217/fon－2022－0214.
[36]	Biliary Tract Tumor Committee of China Anti Cancer Association. China Anti Cancer Association guidelines for targeted therapy and immunotherapy of biliary tract malignancies(2022)(summary edition)[J]. Chin J Pract Surg, 2023, 43( 5): 481－ 491. DOI: 10.19538/j.cjps.issn1005－2208.2023.05.01. 中国抗癌协会胆道肿瘤专业委员会. 中国抗癌协会胆道恶性肿瘤靶向及免疫治疗指南(2022)(简要版)[J]. 中国实用外科杂志, 2023, 43( 5): 481－ 491. DOI: 10.19538/j.cjps.issn1005－2208.2023.05.01.
[37]	HARDING J, PIHA－PAUL S, SHAH RH, et al. Targeting HER2 mutation–positive advanced biliary tract cancers with neratinib: Final results from the phase 2 SUMMIT basket trial[J]. J Clin Oncol, 2022, 40( Suppl 16): 4079.
[38]	JAVLE MM, OH DY, IKEDA M, et al. Varlitinib plus capecitabine in second－line advanced biliary tract cancer: A randomized, phase II study(TreeTopp)[J]. ESMO Open, 2022, 7( 1): 100314. DOI: 10.1016/j.esmoop.2021.100314.
[39]	MALKA D, CERVERA P, FOULON S, et al. Gemcitabine and oxaliplatin with or without cetuximab in advanced biliary－tract cancer(BINGO): A randomised, open－label, non－comparative phase 2 trial[J]. Lancet Oncol, 2014, 15( 8): 819－ 828. DOI: 10.1016/S1470－2045(14)70212－8.
[40]	DEMOLS A, BORBATH I, van den EYNDE M, et al. Regorafenib after failure of gemcitabine and platinum－based chemotherapy for locally advanced/metastatic biliary tumors: REACHIN, a randomized, double－blind, phase II trial[J]. Ann Oncol, 2020, 31( 9): 1169－ 1177. DOI: 10.1016/j.annonc.2020.05.018.
[41]	LEE J, PARK SH, CHANG HM, et al. Gemcitabine and oxaliplatin with or without erlotinib in advanced biliary－tract cancer: A multicentre, open－label, randomised, phase 3 study[J]. Lancet Oncol, 2012, 13( 2): 181－ 188. DOI: 10.1016/S1470－2045(11)70301－1.
[42]	LOWERY MA, BRADLEY M, CHOU JF, et al. Binimetinib plus gemcitabine and cisplatin phase I/II trial in patients with advanced biliary cancers[J]. Clin Cancer Res, 2019, 25( 3): 937－ 945. DOI: 10.1158/1078－0432.CCR－18－1927.
[43]	LEE S, SHROFF RT, MAKAWITA S, et al. Phase II study of ramucirumab in advanced biliary tract cancer previously treated by gemcitabine－based chemotherapy[J]. Clin Cancer Res, 2022, 28( 11): 2229－ 2236. DOI: 10.1158/1078－0432.CCR－21－3548.
[44]	VALLE JW, WASAN H, LOPES A, et al. Cediranib or placebo in combination with cisplatin and gemcitabine chemotherapy for patients with advanced biliary tract cancer(ABC－03): A randomised phase 2 trial[J]. Lancet Oncol, 2015, 16( 8): 967－ 978. DOI: 10.1016/S1470－2045(15)00139－4.
[45]	SONG X, HU Y, LI Y, et al. Overview of current targeted therapy in gallbladder cancer[J]. Signal Transduct Target Ther, 2020, 5( 1): 230. DOI: 10.1038/s41392－020－00324－2.
[46]	PIHA－PAUL SA, OH DY, UENO M, et al. Efficacy and safety of pembrolizumab for the treatment of advanced biliary cancer: Results from the KEYNOTE－158 and KEYNOTE－028 studies[J]. Int J Cancer, 2020, 147( 8): 2190－ 2198. DOI: 10.1002/ijc.33013.
[47]	KIM RD, CHUNG V, ALESE OB, et al. A phase 2 multi－institutional study of nivolumab for patients with advanced refractory biliary tract cancer[J]. JAMA Oncol, 2020, 6( 6): 888－ 894. DOI: 10.1001/jamaoncol.2020.0930.
[48]	KELLEY RK, MITCHELL E, BEHR S, et al. Phase II trial of pembrolizumab(PEM) plus granulocyte macrophage colony stimulating factor(GM-CSF) in advanced biliary cancers(ABC)[J]. J Clin Oncol, 2018, 36( Suppl 4): 386.
[49]	KLEIN O, KEE D, NAGRIAL A, et al. Evaluation of combination nivolumab and ipilimumab immunotherapy in patients with advanced biliary tract cancers: Subgroup analysis of a phase 2 nonrandomized clinical trial[J]. JAMA Oncol, 2020, 6( 9): 1405－ 1409. DOI: 10.1001/jamaoncol.2020.2814.
[50]	UENO M, IKEDA M, MORIZANE C, et al. Nivolumab alone or in combination with cisplatin plus gemcitabine in Japanese patients with unresectable or recurrent biliary tract cancer: A non－randomised, multicentre, open－label, phase 1 study[J]. Lancet Gastroenterol Hepatol, 2019, 4( 8): 611－ 621. DOI: 10.1016/S2468－1253(19)30086－X.
[51]	DOKI Y, UENO M, HSU CH, et al. Tolerability and efficacy of durvalumab, either as monotherapy or in combination with tremelimumab, in patients from Asia with advanced biliary tract, esophageal, or head－and－neck cancer[J]. Cancer Med, 2022, 11( 13): 2550－ 2560. DOI: 10.1002/cam4.4593.
[52]	OH DY, RUTH HE A, QIN SK, et al. Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer[J]. NEJM Evid, 2022, 1( 8): a2200015. DOI: 10.1056/evidoa2200015.
[53]	KELLEY RK, UENO M, YOO C, et al. Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer(KEYNOTE－966): A randomised, double－blind, placebo－controlled, phase 3 trial[J]. Lancet, 2023, 401( 10391): 1853－ 1865. DOI: 10.1016/S0140－6736(23)00727－4.