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23.10.2020 | Original Article

Next-generation sequencing-guided molecular-targeted therapy and immunotherapy for biliary tract cancers

verfasst von: Wei Zhang, Junping Shi, Yingying Wang, Hongyuan Zhou, Zewu Zhang, Zhiqiang Han, Guanghao Li, Bo Yang, Guangtai Cao, Yan Ke, Ti Zhang, Tianqiang Song, QiangLi

Erschienen in: Cancer Immunology, Immunotherapy | Ausgabe 4/2021

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Abstract

Background

Chemotherapy is a standard regimen for advanced or relapsed biliary tract cancer (BTC) with a 5-year overall survival (OS) rate of approximately 5% and a median OS of less than a year. Targeted therapies and immunotherapy aimed at providing more personalized treatments for BTCs have been tested. The objective of this study was to evaluate the effects of targeted therapy and immunotherapy on advanced BTC patients.

Methods

Twenty-four advanced/relapsed BTC patients were enrolled and examined with next-generation sequencing (NGS). Eight of them received NGS-guided targeted or immunotherapy, and the other 16 patients underwent routine chemotherapy. Comparison analysis of OS and objective response rate (ORR) was performed.

Results

IDH1, BRCA2, MAP2K1, and BRAF (V600E) were the major actionable genes mutated in this cohort. Patients who received NGS-guided therapy exhibited higher OS (not achieved vs. 6.5 months, p < 0.001) and ORR (87.5% vs. 25%, p < 0.001) than those without targetable mutations and who received first-line chemotherapy. BTCs harboring mutations in IDH1, ATM/BRCA2, or MAP2K1/BRAF (V600E) received treatment with dasatinib, olaparib, or trametinib, respectively. Three of the patients had high tumor mutation burden (TMB-H) and were treated with immune-checkpoint inhibitors and chemotherapy. All these patients achieved complete response or partial response.

Conclusions

NGS-guided targeted therapy and immunotherapy are promising personalized therapies for advanced or relapsed BTCs. TMB is a useful biomarker for predicting immunotherapy efficacy.

Tella SH, Kommalapati A, Borad MJ, Mahipal A (2020) Second-line therapies in advanced biliary tract cancers. Lancet Oncol 21(1):e29–e41. https://doi.org/10.1016/S1470-2045(19)30733-8CrossRefPubMed

Rizvi S, Khan SA, Hallemeier CL, Kelley RK, Gores GJ (2018) Cholangiocarcinoma - evolving concepts and therapeutic strategies. Nat Rev Clin Oncol 15(2):95–111. https://doi.org/10.1038/nrclinonc.2017.157CrossRefPubMed

Rizvi S, Gores GJ (2013) Pathogenesis, diagnosis, and management of cholangiocarcinoma. Gastroenterology 145(6):1215–1229. https://doi.org/10.1053/j.gastro.2013.10.013CrossRefPubMed

Razumilava N, Gores GJ (2014) Cholangiocarcinoma. Lancet 383(9935):2168–2179. https://doi.org/10.1016/S0140-6736(13)61903-0CrossRefPubMedPubMedCentral

Jarnagin WR, Fong Y, DeMatteo RP, Gonen M, Burke EC, Bodniewicz BJ, Youssef BM, Klimstra D, Blumgart LH (2001) Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma. Ann Surg 234(4):507–517. https://doi.org/10.1097/00000658-200110000-00010CrossRefPubMedPubMedCentral

Morizane C, Okusaka T, Mizusawa J, Katayama H, Ueno M, Ikeda M, Ozaka M, Okano N, Sugimori K, Fukutomi A, Hara H, Mizuno N, Yanagimoto H, Wada K, Tobimatsu K, Yane K, Nakamori S, Yamaguchi H, Asagi A, Yukisawa S, Kojima Y, Kawabe K, Kawamoto Y, Sugimoto R, Iwai T, Nakamura K, Miyakawa H, Yamashita T, Hosokawa A, Ioka T, Kato N, Shioji K, Shimizu K, Nakagohri T, Kamata K, Ishii H, Furuse J (2019) Combination gemcitabine plus S-1 versus gemcitabine plus cisplatin for advanced/recurrent biliary tract cancer: the FUGA-BT (JCOG1113) randomized phase III clinical trial. Ann Oncol J Euro Soc Med Oncol 30(12):1950–1958. https://doi.org/10.1093/annonc/mdz402CrossRef

Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, Madhusudan S, Iveson T, Hughes S, Pereira SP, Roughton M, Bridgewater J (2010) Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. New En J Med 362(14):1273–1281. https://doi.org/10.1056/NEJMoa0908721CrossRef

Nakamura H, Arai Y, Totoki Y, Shirota T, Elzawahry A, Kato M, Hama N, Hosoda F, Urushidate T, Ohashi S, Hiraoka N, Ojima H, Shimada K, Okusaka T, Kosuge T, Miyagawa S, Shibata T (2015) Genomic spectra of biliary tract cancer. Nat Genet 47(9):1003–1010. https://doi.org/10.1038/ng.3375CrossRefPubMed

Kim BH, Kim K, Chie EK, Kwon J, Jang JY, Kim SW, Oh DY, Bang YJ (2017) Risk stratification and prognostic nomogram for post-recurrence overall survival in patients with recurrent extrahepatic cholangiocarcinoma HPB : the official journal of the International Hepato Pancreato. Biliary Ass 19(5):421–428. https://doi.org/10.1016/j.hpb.2016.12.014CrossRef

10.

Doussot A, Gonen M, Wiggers JK, Groot-Koerkamp B, DeMatteo RP, Fuks D, Allen PJ, Farges O, Kingham TP, Regimbeau JM, D’Angelica MI, Azoulay D, Jarnagin WR (2016) Recurrence patterns and disease-free survival after resection of intrahepatic cholangiocarcinoma: preoperative and postoperative prognostic models. J Am College Surg 223(3):493–505. https://doi.org/10.1016/j.jamcollsurg.2016.05.019CrossRef

11.

Saxena A, Chua TC, Chu FC, Morris DL (2011) Improved outcomes after aggressive surgical resection of hilar cholangiocarcinoma: a critical analysis of recurrence and survival. Am J Surg 202(3):310–320. https://doi.org/10.1016/j.amjsurg.2010.08.041CrossRefPubMed

12.

Bernards R, Jaffee E, Joyce JA, Lowe SW, Mardis ER, Morrison SJ, Polyak K, Sears CL, Vousden KH, Zhang Z (2020) A roadmap for the next decade in cancer research. Nature Cancer 1(1):12–17. https://doi.org/10.1038/s43018-019-0015-9CrossRef

13.

Schwartz LH, Litiere S, de Vries E, Ford R, Gwyther S, Mandrekar S, Shankar L, Bogaerts J, Chen A, Dancey J, Hayes W, Hodi FS, Hoekstra OS, Huang EP, Lin N, Liu Y, Therasse P, Wolchok JD, Seymour L (2016) RECIST 1.1-Update and clarification: from the RECIST committee. Eur J Cancer 62:132–137. https://doi.org/10.1016/j.ejca.2016.03.081CrossRefPubMedPubMedCentral

14.

Cao J, Chen L, Li H, Chen H, Yao J, Mu S, Liu W, Zhang P, Cheng Y, Liu B, Hu Z, Chen D, Kang H, Hu J, Wang A, Wang W, Yao M, Chrin G, Wang X, Zhao W, Li L, Xu L, Guo W, Jia J, Chen J, Wang K, Li G, Shi W (2019) An accurate and comprehensive clinical sequencing assay for cancer targeted and immunotherapies. Oncologist 24(12):e1294–e1302. https://doi.org/10.1634/theoncologist.2019-0236CrossRefPubMedPubMedCentral

15.

Kereszturi E, Király O, Sahin-Tóth M (2009) Minigene analysis of intronic variants in common SPINK1 haplotypes associated with chronic pancreatitis. Gut 58(4):545–549. https://doi.org/10.1136/gut.2008.164947CrossRefPubMed

16.

Samstein RM, Lee CH, Shoushtari AN, Hellmann MD, Shen R, Janjigian YY, Barron DA, Zehir A, Jordan EJ, Omuro A, Kaley TJ, Kendall SM, Motzer RJ, Hakimi AA, Voss MH, Russo P, Rosenberg J, Iyer G, Bochner BH, Bajorin DF, Al-Ahmadie HA, Chaft JE, Rudin CM, Riely GJ, Baxi S, Ho AL, Wong RJ, Pfister DG, Wolchok JD, Barker CA, Gutin PH, Brennan CW, Tabar V, Mellinghoff IK, DeAngelis LM, Ariyan CE, Lee N, Tap WD, Gounder MM, D’Angelo SP, Saltz L, Stadler ZK, Scher HI, Baselga J, Razavi P, Klebanoff CA, Yaeger R, Segal NH, Ku GY, DeMatteo RP, Ladanyi M, Rizvi NA, Berger MF, Riaz N, Solit DB, Chan TA, Morris LGT (2019) Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet 51(2):202–206. https://doi.org/10.1038/s41588-018-0312-8CrossRefPubMedPubMedCentral

17.

Zhang W, Shi J, Li R, Han Z, Li L, Li G, Yang B, Yin Q, Wang Y, Ke Y, Li Q (2020) Effectiveness of olaparib treatment in a patient with gallbladder cancer with an ATM-inactivating mutation. Oncologist. https://doi.org/10.1634/theoncologist.2019-0498CrossRefPubMedPubMedCentral

18.

Chen WX, Li GX, Hu ZN, Zhu P, Zhang BX, Ding ZY (2019) Significant response to anti-PD-1 based immunotherapy plus lenvatinib for recurrent intrahepatic cholangiocarcinoma with bone metastasis: A case report and literature review. Medicine 98(45):e17832. https://doi.org/10.1097/MD.0000000000017832CrossRefPubMedPubMedCentral

19.

Alshari OM, Dawaymeh TA, Tashtush NA, Aleshawi AJ, Al Manasra ARA, Obeidat KA (2019) Completely resolved advanced biliary tract cancer after treatment by pembrolizumab: a report of two cases. Onco Targets Ther 12:5293–5298. https://doi.org/10.2147/OTT.S197559CrossRefPubMedPubMedCentral

20.

Liu X, Yao J, Song L, Zhang S, Huang T, Li Y (2019) Local and abscopal responses in advanced intrahepatic cholangiocarcinoma with low TMB, MSS, pMMR and negative PD-L1 expression following combined therapy of SBRT with PD-1 blockade. J Immuno Cancer 7(1):204. https://doi.org/10.1186/s40425-019-0692-zCrossRef

21.

Sui M, Li Y, Wang H, Luo Y, Wan T, Wang X, Hu B, Cheng Y, Lv X, Xin X, Xu Q, Wang G, Lu S (2019) Two cases of intrahepatic cholangiocellular carcinoma with high insertion-deletion ratios that achieved a complete response following chemotherapy combined with PD-1 blockade. J Immuno Cancer 7(1):125. https://doi.org/10.1186/s40425-019-0596-yCrossRef

22.

Mou H, Yu L, Liao Q, Hou X, Wu Y, Cui Q, Yan N, Ma R, Wang L, Yao M, Wang K (2018) Successful response to the combination of immunotherapy and chemotherapy in cholangiocarcinoma with high tumour mutational burden and PD-L1 expression: a case report. BMC cancer 18(1):1105. https://doi.org/10.1186/s12885-018-5021-2CrossRefPubMedPubMedCentral

23.

Filippi R, Lombardi P, Quara V, Fenocchio E, Aimar G, Milanesio M, Leone F, Aglietta M (2019) Pharmacotherapeutic options for biliary tract cancer: current standard of care and new perspectives. Expert Opin Pharmacother 20(17):2121–2137. https://doi.org/10.1080/14656566.2019.1667335CrossRefPubMed

24.

Lombardi P, Marino D, Fenocchio E, Chilà G, Aglietta M, Leone F (2018) Emerging molecular target antagonists for the treatment of biliary tract cancer. Expert Opin Emer Drugs 23(1):63–75. https://doi.org/10.1080/14728214.2018.1444749CrossRef

25.

Luo Q, Zhang L, Luo C, Jiang M (2019) Emerging strategies in cancer therapy combining chemotherapy with immunotherapy. Cancer Lett 454:191–203. https://doi.org/10.1016/j.canlet.2019.04.017CrossRefPubMed

26.

Zhou Y, Chen C, Zhang X, Fu S, Xue C, Ma Y, Fang W, Yang Y, Hou X, Huang Y, Zhao H, Hong S, Zhang L (2018) Immune-checkpoint inhibitor plus chemotherapy versus conventional chemotherapy for first-line treatment in advanced non-small cell lung carcinoma: a systematic review and meta-analysis. J Immuno Cancer 6(1):155. https://doi.org/10.1186/s40425-018-0477-9CrossRef

27.

Garassino MC, Torri V, Colombo MP, Sica A (2018) Choosing the best chemotherapy agent to boost immune checkpoint inhibition activity. Can Res 78(20):5729–5730. https://doi.org/10.1158/0008-5472.CAN-18-2245CrossRef

28.

Saleh K, Daste A, Martin N, Pons-Tostivint E, Auperin A, Herrera-Gomez RG, Baste-Rotllan N, Bidault F, Guigay J, Le Tourneau C, Saada-Bouzid E, Even C (2019) Response to salvage chemotherapy after progression on immune checkpoint inhibitors in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. Eur J Cancer 121:123–129. https://doi.org/10.1016/j.ejca.2019.08.026CrossRefPubMed

29.

Suzuki E, Kapoor V, Jassar AS, Kaiser LR, Albelda SM (2005) Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin Cancer Res J Am Assoc Cancer Res 11(18):6713–6721. https://doi.org/10.1158/1078-0432.CCR-05-0883CrossRef

30.

Vincent J, Mignot G, Chalmin F, Ladoire S, Bruchard M, Chevriaux A, Martin F, Apetoh L, Rebe C, Ghiringhelli F (2010) 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Can Res 70(8):3052–3061. https://doi.org/10.1158/0008-5472.CAN-09-3690CrossRef

31.

Kordbacheh T, Honeychurch J, Blackhall F, Faivre-Finn C, Illidge T (2018) Radiotherapy and anti-PD-1/PD-L1 combinations in lung cancer: building better translational research platforms. Ann Oncol J Eur Soc Med Oncol 29(2):301–310. https://doi.org/10.1093/annonc/mdx790CrossRef

32.

Yoneda K, Kuwata T, Kanayama M, Mori M, Kawanami T, Yatera K, Ohguri T, Hisaoka M, Nakayama T, Tanaka F (2019) Alteration in tumoural PD-L1 expression and stromal CD8-positive tumour-infiltrating lymphocytes after concurrent chemo-radiotherapy for non-small cell lung cancer. Br J Cancer 121(6):490–496. https://doi.org/10.1038/s41416-019-0541-3CrossRefPubMedPubMedCentral

33.

Walshaw RC, Honeychurch J, Illidge TM, Choudhury A (2018) The anti-PD-1 era - an opportunity to enhance radiotherapy for patients with bladder cancer. Nat Rev Urol 15(4):251–259. https://doi.org/10.1038/nrurol.2017.172CrossRefPubMed

Titel: Next-generation sequencing-guided molecular-targeted therapy and immunotherapy for biliary tract cancers
verfasst von: Wei Zhang
Junping Shi
Yingying Wang
Hongyuan Zhou
Zewu Zhang
Zhiqiang Han
Guanghao Li
Bo Yang
Guangtai Cao
Yan Ke
Ti Zhang
Tianqiang Song
QiangLi
Publikationsdatum: 23.10.2020
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Immunology, Immunotherapy / Ausgabe 4/2021
Print ISSN: 0340-7004
Elektronische ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-020-02745-y

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Next-generation sequencing-guided molecular-targeted therapy and immunotherapy for biliary tract cancers