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1、 September 2017CANCER DISCOVERY|OF1 New Horizons for Precision Medicine in Biliary Tract Cancers Juan W.Valle1,2,Angela Lamarca1,Lipika Goyal3,Jorge Barriuso1,4,and Andrew X.Zhu3ReviewabstRactBiliary tract cancers(BTC),including cholangiocarcinoma and gallbladder cancer,are poor-prognosis and low-in

2、cidence cancers,although the incidence of intrahe-patic cholangiocarcinoma is rising.A minority of patients present with resectable disease but relapse rates are high;benefit from adjuvant capecitabine chemotherapy has been demonstrated.Cisplatin/gemcitabine combination chemotherapy has emerged as t

3、he reference first-line treatment regimen;there is no standard second-line therapy.Selected patients may be suitable for liver-directed therapy(e.g.,radioembolization or external beam radiation),pending confirmation of benefit in randomized studies.Initial trials targeting the epithelial growth fact

4、or receptor and angiogenesis pathways have failed to deliver new treatments.Emerging data from next-generation sequencing analyses have iden-tified actionable mutations(e.g.,FGFR fusion rearrangements and IDH1 and IDH2 mutations),with several targeted drugs entering clinical development with encoura

5、ging results.The role of systemic therapies,including targeted therapies and immunotherapy for BTC,is rapidly evolving and is the sub-ject of this review.Significance:The authors address genetic drivers and molecular biology from a translational per-spective,in an intent to offer a clear view of the

6、 recent past,present,and future of BTC.The review describes a state-of-the-art update of the current status and future directions of research and therapy in advanced BTC.Cancer Discov;7(9);120.2017 AACR.1Department of Medical Oncology,The Christie NHS Foundation Trust,Wilmslow Road,Manchester,UK.2In

7、stitute of Cancer Sciences,University of Manchester,Wilmslow Road,Manchester,UK.3Massachusetts General Hospital Cancer Center,Harvard Medical School,Boston,Massachu-setts.4Faculty of Medical,Biological and Human Sciences,University of Manchester,Rumford Street,Manchester,UK.Corresponding Authors:Jua

8、n W.Valle,Department of Medical Oncology,The Christie NHS Foundation Trust,Wilmslow Road,Manchester M20 4BX,UK.Phone:44-161-446-8106;Fax:44-161-446-3468;E-mail:juan.vallechristie.nhs.uk;and Andrew X.Zhu,Massachusetts General Hos-pital Cancer Center,Harvard Medical School,55 Fruit Street,Boston,MA 02

9、114.Phone:617-726-2000;Fax:617-724-1137;E-mail:azhumgh.harvard.edudoi:10.1158/2159-8290.CD-17-02452017 American Association for Cancer Research.iNtRODUctiONBiliary tract cancers(BTC),including cholangiocarcinoma both intrahepatic(ICC)and extrahepatic(ECC)and gall-bladder cancer,are low-incidence can

10、cers carrying a poor prognosis(1).BTCs account for approximately 3%of all adult cancers(2).Incidence and mortality are increasing,largely due to a rise in ICC(35).Most patients(65%)are diagnosed with nonresectable disease(1),and there is a high relapse rate in the minority of patients who undergo po

11、tentially curative surgery(6,7).The five-year survival rate is around 5%to 15%when considering all patients(8,9);estimated five-year sur-vival rate varies with stage:50%for American Joint Commit-tee on Cancer(AJCC)stage I,30%for stage II,10%for stage III,and 0%for stage IV(6,10).It is widely accepte

12、d by the BTC community that BTC malignancies are not one unique disease only,but a group of different diseases with distinct demographics,molecular characteristics,and treatment options(Fig.1).Such differ-ences are worth taking into account at time of treatment planning,research,and clinical trial d

13、esign.BTCs are more frequent in patients between ages 50 and 70 years,with a male preponderance for cholangiocarcinoma and female for gall-bladder cancers(2);90%are adenocarcinomas(1).Several risk factors,mainly associated with chronic gallbladder or bil-iary tract inflammation,have been identified(

14、1113).Opistor-chis viverrini is one of the three major liver trematodes(flukes)that infect humans.It is endemic in Thailand,Vietnam,Cam-bodia,and Laos and accounts for a global“hotspot”of intra-hepatic cholangiocarcinoma in this region.Adult flukes can remain in the bile ducts for years,stimulating

15、a host immune response,leading to chronic biliary tract inflammation.This results in an up to 15-fold increase in the risk of developing intra/extrahepatic cholangiocarcinoma(14).There are also differences in risk factors(1517)and symptoms at presen-tation between the different BTCs gallbladder pati

16、ents(in advanced stages)are less likely to present with jaundice and usually present with abdominal pain;refs.15,18.Research.on August 19,2017.2017 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from Published OnlineFirst August 17,2017;DOI:10.1158/2159-8290.CD-17-0245 Va

17、lle et al.REVIEWOF2|CANCER DISCOVERYSeptember 2017 www.aacrjournals.orgcLiNicaL cONteXtPatients with tumors arising in proximity to the bile ducts present with biliary obstruction,due to local infiltration of the biliary tract.A minority of patients will be diagnosed with early(resectable)disease,in

18、 which case treatment will be surgical with curative intent.For patients diagnosed with advanced disease(often presenting with nonspecific,nonbil-iary obstructive symptoms),treatment options are noncura-tive and mainly chemotherapy-based.Despite potentially curative resection for localized disease,r

19、elapse rates are high(19),highlighting the need to optimize adjuvant strategies.The role of adjuvant treatment for BTC has been unclear for many years(20).A systematic review and meta-analysis found that adjuvant treatment did not improve survival when compared with surgery alone when considering al

20、l patients(21).However,there appeared to be benefit for patients with microscopically involved margins(R1-resection)versus clear resection margins R0-resection;odds ratio(OR),0.36;95%confidence interval(CI),0.190.68 and lymph nodepositive disease(OR,0.49;95%CI,0.300.80).Two randomized phase III clin

21、ical trials explor-ing adjuvant chemotherapy were reported in 2017.First,the results from the PRODIGE-12/ACCORD-18 clinical trial assessing the benefit of adjuvant combination chemotherapy compared with observation alone were reported in January 2017(22).This multicenter phase III trial randomized 1

22、96 patients within 3 months of resection of a localized BTC(intrahepatic,perihilar,or extrahepatic cholangiocarcinoma,or gallbladder cancer),to receive either adjuvant gemcitabine and oxaliplatin or surveillance;there was no significant dif-ference in relapse-free survival between the arms HR of 0.8

23、3(95%CI,0.581.19);P=0.31.Second,the BilCap clinical trial exploring the role of adjuvant capecitabine compared with observation alone was reported at ASCO 2017.A total of 447 patients with BTC were randomized to capecitabine (n=223)or observation(n=224;ref.23).Sensitivity analyses by intention-to-tr

24、eat were adjusted to nodal status,grade of disease,and gender(447 patients).This trial demonstrated benefit from capecitabine in terms of overall survival OS;Figure 1.BTCs are a group of different diseases which includes ICC,ECC,and gallbladder cancer.They differ in many aspects,such as anatomical l

25、ocation,demographics,clinical presentations,and treatment options.Gallbladder cancer Females males Risk factors:gallstones,gallbladder polyps,chronic cholecystitis,Salmonella typhi,obesity,diabetes Typically presents as an incidental finding following cholecystectomy(localized stage)or with abdomina

26、l pain(advanced stage)Biliary tract cancer 90%of cases are adenocarcinoma Level 1 evidence for adjuvant chemotherapy:capecitabine Palliative 1st-line chemotherapy:cisplatin/gemcitabine No 2nd-line palliative chemotherapy with a demonstrated survival benefit over active symptom control Median overall

27、 survival:12 monthsExtrahepatic cholangiocarcinoma Males females Risk factors:primary sclerosing cholangitis,gallstones,Lynch syndrome,Opisthorchis viverrini or Clonorchis sinensis,bile duct morphologic anomalies Typically presents with obstructive jaundiceIntrahepatic cholangiocarcinoma Risk factor

28、s:primary sclerosing cholangitis,cirrhosis,Opisthorchis viverrini or Clonorchis sinensis,obesity,diabetes,chronic hepatitis B and C,hepatolithiasis,Lynch syndrome,biliary papillomatosis,biliary duct morphologic anomalies Typically presents as incidental hepatic lesion(s)Radioembolization or radiatio

29、n can be considered for liver-predominant diseaseResearch.on August 19,2017.2017 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from Published OnlineFirst August 17,2017;DOI:10.1158/2159-8290.CD-17-0245 Precision Medicine in BTCREVIEW September 2017CANCER DISCOVERY|OF3 HR

30、,0.71(95%CI,0.550.92);P 0.01;median OS 51 months(95%CI,3559)and 36 months(95%CI,3045)for capecit-abine and observation arms,respectively.There was also benefit from adjuvant capecitabine in terms of relapse-free survival median 25 months(95%CI,1937)and 18 months(95%CI,1328)for capecitabine and obser

31、vation arms,respectively.Based on these results,adjuvant capecitabine is likely to be considered standard of care following surgery for BTC.Around 60%to 70%of patients will be diagnosed with advanced disease,which is defined as inoperable or metastatic disease.For these patients,palliative treatment

32、,usually in the form of systemic chemotherapy,is the only treatment option.Selected patients with liver-predominant disease may benefit from liver-directed therapies such as external beam radiation(24,25)or radioembolization(26,27).Unfortunately,data suggesting such benefit are based on retrospectiv

33、e series or small phase II trials rather than randomized studies;fur-ther data are awaited to confirm the incremental benefit of approaches involving liver radioembolization.Liver trans-plant has been suggested as a potential treatment option for patients with small perihilar cholangiocarcinoma(28,2

34、9).However,prospective studies are needed to ensure the most suitable patient selection and benefit due to challenges for organ allocation and living donation policies;currently,liver transplant remains controversial in this setting.New options for systemic treatment are an urgent area of unmet need

35、 for this patient population.sYsteMic tHeRaPY OF aDvaNceD DiseaseFirst-Line ChemotherapyThe most active cytotoxic chemotherapy agents in the management of BTCs are gemcitabine and platinum agents(30,31).The first study to suggest that palliative chemother-apy could improve survival and quality of li

36、fe was reported in 1996 and established gemcitabine as a treatment option for patients with advanced disease(32).These results increased the interest in the treatment of BTCs,and over the past 20 years many studies have been performed(30)that have been negative or lacked the statistical power and ri

37、gor to change clinical practice.In 2010 we showed,in the 410-patient,randomized,phase III,ABC-02 study,a benefit from cisplatin/gem-citabine chemotherapy over single-agent gemcitabine;the doublet conferred an advantage in OS over gemcitabine alone(11.7 vs.8.1 months;HR,0.64;95%CI,0.520.80;P 0.05).Ho

38、wever,the study did not meet its primary endpoint(improvement in median PFS),in part due to the relatively poor tolerability of cediranib(139).Forays into VEGF inhibition with other TKIs have been disappointing.Single-arm,phase II studies of sorafenib as monotherapy(140,141)or combined with erlotini

39、b(142)or cisplatin/gemcitabine(143)have all failed to demon-strate sufficient activity in BTC.Most recently,sorafenib failed to improve PFS when added to gemcitabine in a ran-domized phase II,placebo-controlled study(144).A phase II clinical trial of sunitinib including 56 patients with BTC reported

40、 a median time to progression of only 1.7 months,an objective response rate of 8.9%and a disease control rate of 50%(145).In addition,the VanGogh study failed to show an improve-ment in PFS in a 3-arm randomized phase II study explor-ing the role of vandetanib in 173 patients(146).Results of ongoing

41、 studies with pazopanib(NCT01855724),regorafenib(NCT02053376 and NCT02115542),and ramucirumab(NCT02711553)are awaited.HER FamilyEGFR amplifications and mutations have been described in around 6%and 13.6%to 15%of BTCs,respectively.How-ever,the biological implication of these mutations is unclear(1471

42、49).Several phase II clinical trials have combined cetuximab,a monoclonal antibody targeting EGFR,with chemotherapy in the treatment of BTCs,most of them with gemcitabine and oxaliplatin(150153).Initial promising results report-ing high tumor response rates(63%)from a small study (n=30;ref.151)were

43、not confirmed in the randomized phase II BINGO study,in keeping with results from other negative phase II studies combining cetuximab with chem-otherapy(153).KRAS wild-type patients with advanced BTC were treated with panitumumab combined with gemcitabine,capecit-abine,and oxaliplatin(46 patients;re

44、f.154)and with gemcit-abine and oxaliplatin(31 patients;ref.155)in two separate phase II clinical trials.In each study,the primary endpoint was achieved 6-month PFS of 74%(95%CI,5884;ref.154)and response rate of 45%(155),respectively.A third phase II study(panitumumab with gemcitabine and irinotecan

45、 in nonselected patients)also supported further development of this compound in BTC with no difference in OS by KRAS status(7 of 31 patients harbored a KRAS mutation;ref.156).Unfortunately,these signals have not been confirmed in other studies(157,158),including the largest randomized phase II study

46、 combining panitumumab with gemcitabine and oxali-platin(the Vecti-BIL study;ref.158)which showed no differ-ences in survival in 85 randomized patients.Erlotinib,a TKI targeting EGFR,has also shown vary-ing results(159161).In the largest(phase III)study,133 patients were randomized to receive gemcit

47、abine and oxali-platin chemotherapy with or without erlotinib(160);there were no differences in PFS or OS when all patients with BTC were analyzed together.However,the cholangiocarcinoma patient subgroup did appear to derive benefit from adding erlotinib to chemotherapy median PFS 5.9 months(95%CI,4

48、.77.1)vs.3.0 months(95%CI,1.14.9);P=0.049,and further clinical trials are ongoing(NCT00832637 and NCT00987766).HER2(v-ERBB2,erythroblastic leukaemia viral oncogene homolog-2)overexpression and gene amplification are also described in BTCs,with a higher incidence in gallbladder cancer(19%;ref.162).Th

49、e rate of HER2 overexpression was found to be higher in ECC(17.4%)than in ICC(4.8%)in a recent systematic review and meta-analysis published by Galdy and colleagues in 2016(162).Good correlation between overexpression and gene amplification(75%)has been shown(148).Two phase II trials have yielded di

50、sap-pointing results of first-line/second-line lapatinib monother-apy in an unselected population of patients with advanced BTC(163,164).Case reports using trastuzumab in patients with gallbladder carcinoma with HER2 overexpression have suggested activity(165,166),and a phase II clinical trial is un