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Metastatic Adenoid Cystic Carcinoma: Genomic Landscape and Emerging Treatments

  • Head and Neck Cancer (PL Swiecicki, Section Editor)
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Opinion statement

Adenoid cystic carcinoma (ACC) is a heterogeneous cancer that commonly develops in the salivary glands. Approximately 40 to 50% of patients with ACC develop recurrence and/or metastasis. Although most patients with ACC have slow-growing disease, a subset experiences aggressive disease with early visceral and/or bone metastasis. Thus far, there is no consensus on the best time to start palliative treatment in patients with indolent disease. The only systemic therapies available for recurrent or metastatic ACC are cytotoxic agents and multikinase inhibitors targeting vascular endothelial growth factor receptor, and both types of therapy have modest activity. Studies integrating proteomics, genomics, and clinical data have revealed distinct molecular ACC subtypes, ACC-I and ACC-II, with ACC-I generally associated with more aggressive disease biology. ACC-I tumors were enriched for NOTCH1-activating mutation and upregulation of MYC and MYC targets, while ACC-II tumors exhibited upregulation of TP63 and receptor tyrosine kinases. These findings highlight the importance of patient selection for surveillance and targeted therapy development in ACC. In recent clinical trials of targeted therapy in ACC, patients are being selected according to tumor molecular profile (e.g., presence of NOTCH-activating mutations), which represents a major advance in the field. Ongoing collaborative research focusing on the development of novel therapeutic strategies for ACC patients based on disease biology will increase the drug armamentarium and improve survival outcomes for these patients in dire need.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Ellington CL, Goodman M, Kono SA, Grist W, Wadsworth T, Chen AY, Owonikoko T, Ramalingam S, Shin DM, Khuri FR, Beitler JJ, Saba NF. Adenoid cystic carcinoma of the head and neck: incidence and survival trends based on 1973-2007 Surveillance, Epidemiology, and End Results Data. Cancer. 2012;118(18):4444–51. https://doi.org/10.1002/cncr.27408.

    Article  PubMed  Google Scholar 

  2. El-Naggar AK, Chan JKC, Grandis JR, Takata T, Slootweg PJ. Pathology and genetics of head and Neck tumours. WHO classification of tumours. 4th ed; 2017.

    Google Scholar 

  3. Moskaluk CA. Adenoid cystic carcinoma: clinical and molecular features. Head Neck Pathol. 2013;7(1):17–22. https://doi.org/10.1007/s12105-013-0426-3.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Szanto PA, Luna MA, Tortoledo ME, White RA. Histologic grading of adenoid cystic carcinoma of the salivary glands. Cancer. 1984;54(6):1062–9. https://doi.org/10.1002/1097-0142(19840915)54:6<1062::aid-cncr2820540622>3.0.co;2-e.

    Article  CAS  PubMed  Google Scholar 

  5. Ciccolallo L, Licitra L, Cantu G, Gatta G, Group EW. Survival from salivary glands adenoid cystic carcinoma in European populations. Oral Oncol. 2009;45(8):669–74. https://doi.org/10.1016/j.oraloncology.2008.10.010.

    Article  PubMed  Google Scholar 

  6. Sung MW, Kim KH, Kim JW, Min YG, Seong WJ, Roh JL, Lee SJ, Kwon TK, Park SW. Clinicopathologic predictors and impact of distant metastasis from adenoid cystic carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg. 2003;129(11):1193–7. https://doi.org/10.1001/archotol.129.11.1193.

    Article  PubMed  Google Scholar 

  7. Lorini L, Ardighieri L, Bozzola A, Romani C, Bignotti E, Buglione M, Guerini A, Lombardi D, Deganello A, Tomasoni M, Bonini SA, Sigala S, Farina D, Ravanelli M, Bossi P. Prognosis and management of recurrent and/or metastatic head and neck adenoid cystic carcinoma. Oral Oncol. 2021;115:105213. https://doi.org/10.1016/j.oraloncology.2021.105213.

    Article  CAS  PubMed  Google Scholar 

  8. Spiro RH, Huvos AG. Stage means more than grade in adenoid cystic carcinoma. Am J Surg. 1992;164(6):623–8. https://doi.org/10.1016/s0002-9610(05)80721-4.

    Article  CAS  PubMed  Google Scholar 

  9. Pfister DG, Spencer S, Adelstein D, Adkins D, Anzai Y, Brizel DM, Bruce JY, Busse PM, Caudell JJ, Cmelak AJ, Colevas AD, Eisele DW, Fenton M, Foote RL, Galloway T, Gillison ML, Haddad RI, Hicks WL, Hitchcock YJ, et al. Head and neck cancers, version 2.2020, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2020;18(7):873–98. https://doi.org/10.6004/jnccn.2020.0031.

    Article  PubMed  Google Scholar 

  10. Spiro RH. Distant metastasis in adenoid cystic carcinoma of salivary origin. Am J Surg. 1997;174(5):495–8. https://doi.org/10.1016/S0002-9610(97)00153-0.

    Article  CAS  PubMed  Google Scholar 

  11. Kokemueller H, Eckardt A, Brachvogel P, Hausamen JE. Adenoid cystic carcinoma of the head and neck--a 20 years experience. Int J Oral Maxillofac Surg. 2004;33(1):25–31. https://doi.org/10.1054/ijom.2003.0448.

    Article  CAS  PubMed  Google Scholar 

  12. Jang S, Patel PN, Kimple RJ, McCulloch TM. Clinical outcomes and prognostic factors of adenoid cystic carcinoma of the head and neck. Anticancer Res. 2017;37(6):3045-52. https://doi.org/10.21873/anticanres.11659.

  13. Terhaard CH, Lubsen H, Van der Tweel I, Hilgers FJ, Eijkenboom WM, Marres HA, et al. Salivary gland carcinoma: independent prognostic factors for locoregional control, distant metastases, and overall survival: results of the Dutch Head and Neck Oncology Cooperative Group. Head Neck. 2004;26(8):681–92; discussion 92-3. https://doi.org/10.1002/hed.10400.

    Article  PubMed  Google Scholar 

  14. Ho AS, Kannan K, Roy DM, Morris LGT, Ganly I, Katabi N, Ramaswami D, Walsh LA, Eng S, Huse JT, Zhang J, Dolgalev I, Huberman K, Heguy A, Viale A, Drobnjak M, Leversha MA, Rice CE, Singh B, et al. The mutational landscape of adenoid cystic carcinoma. Nat Genet. 2013;45(7):791–8. https://doi.org/10.1038/ng.2643.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bell D, Bell AH, Bondaruk J, Hanna EY, Weber RS. In-depth characterization of the salivary adenoid cystic carcinoma transcriptome with emphasis on dominant cell type. Cancer. 2016;122(10):1513–22. https://doi.org/10.1002/cncr.29959.

    Article  CAS  PubMed  Google Scholar 

  16. Frerich CA, Brayer KJ, Painter BM, Kang H, Mitani Y, El-Naggar AK et al. Transcriptomes define distinct subgroups of salivary gland adenoid cystic carcinoma with different driver mutations and outcomes. Oncotarget. 2018;9(7):7341-58. https://doi.org/10.18632/oncotarget.23641.

  17. •• Ferrarotto R, Mitani Y, McGrail DJ, Li K, Karpinets TV, Bell D et al. Proteogenomic analysis of salivary adenoid cystic carcinomas defines molecular subtypes and identifies therapeutic targets. Clin Cancer Res. 2021;27(3):852-64. https://doi.org/10.1158/1078-0432.Ccr-20-1192. Integration of proteogenomic and clinical data suggested two molecular subtypes of ACC tumors, ACC-I and ACC-II, each subtype has distinct prognosis and therapeutic vulnerabilities.

  18. Egal ESA, Scarini JF, de Lima-Souza RA, Lavareze L, Fernandes PM, Emerick C, Gonçalves MT, Helms MN, Altemani A, Mariano FV. Tumor microenvironment in salivary gland carcinomas: an orchestrated state of chaos. Oral Oncol. 2022;127:105777. https://doi.org/10.1016/j.oraloncology.2022.105777.

    Article  CAS  PubMed  Google Scholar 

  19. Andreasen S, Agander TK, Bjorndal K, Erentaite D, Heegaard S, Larsen SR et al. Genetic rearrangements, hotspot mutations, and microRNA expression in the progression of metastatic adenoid cystic carcinoma of the salivary gland. Oncotarget. 2018;9(28):19675-87. https://doi.org/10.18632/oncotarget.24800.

  20. Brill LB, Kanner WA, Fehr A, Andrén Y, Moskaluk CA, Löning T, et al. Analysis of myb expression and myb-nfib gene fusions in adenoid cystic carcinoma and other salivary neoplasms. Mod Pathol. 2011;24(9):1169–76. https://doi.org/10.1038/modpathol.2011.86.

    Article  CAS  PubMed  Google Scholar 

  21. Fujii K, Murase T, Beppu S, Saida K, Takino H, Masaki A, Ijichi K, Kusafuka K, Iida Y, Onitsuka T, Yatabe Y, Hanai N, Hasegawa Y, Inagaki H. Myb, mybl1, mybl2 and nfib gene alterations and myc overexpression in salivary gland adenoid cystic carcinoma. Histopathology. 2017;71(5):823–34. https://doi.org/10.1111/his.13281.

    Article  PubMed  Google Scholar 

  22. Mitani Y, Li J, Rao PH, Zhao YJ, Bell D, Lippman SM, Weber RS, Caulin C, el-Naggar AK. Comprehensive analysis of the myb-nfib gene fusion in salivary adenoid cystic carcinoma: incidence, variability, and clinicopathologic significance. Clin Cancer Res. 2010;16(19):4722–31. https://doi.org/10.1158/1078-0432.CCR-10-0463.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. •• Ho AS, Ochoa A, Jayakumaran G, Zehir A, Mayor CV, Tepe J et al. Genetic hallmarks of recurrent/metastatic adenoid cystic carcinoma. J Clin Invest. 2019;129(10):4276-89. https://doi.org/10.1172/Jci128227. Genomic analysis of 1045 ACCs suggested a molecular classification for ACC based on MYB, NOTCH, and TERT status.

  24. Gragnani L, Lorini S, Marri S, Zignego AL. Role of Notch receptors in hematologic malignancies. Cells. 2020;10(1):16. https://doi.org/10.3390/cells10010016.

    Article  CAS  PubMed Central  Google Scholar 

  25. Doi T, Tajimi M, Mori J, Asou H, Inoue K, Benhadji KA, Naito Y. A phase 1 study of crenigacestat (LY3039478), the Notch inhibitor, in Japanese patients with advanced solid tumors. Invest New Drugs. 2021;39(2):469–76. https://doi.org/10.1007/s10637-020-01001-5.

    Article  CAS  PubMed  Google Scholar 

  26. Zhdanovskaya N, Firrincieli M, Lazzari S, Pace E, Scribani Rossi P, Felli MP, Talora C, Screpanti I, Palermo R. Targeting Notch to maximize chemotherapeutic benefits: rationale, advanced strategies, and future perspectives. Cancers (Basel). 2021;13(20):5106. https://doi.org/10.3390/cancers13205106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Majumder S, Crabtree JS, Golde TE, Minter LM, Osborne BA, Miele L. Targeting Notch in oncology: the path forward. Nat Rev Drug Discov. 2021;20(2):125–44. https://doi.org/10.1038/s41573-020-00091-3.

    Article  CAS  PubMed  Google Scholar 

  28. •• Morris LGT, Chandramohan R, West L, Zehir A, Chakravarty D, Pfister DG et al. The molecular landscape of recurrent and metastatic head and neck cancers: insights from a precision oncology sequencing platform. JAMA Oncol. 2017;3(2):244-55. https://doi.org/10.1001/jamaoncol.2016.1790. This study showed a low tumor mutational burden and activating NOTCH1 mutation in 22% cases of metastatic ACC.

  29. Ferrarotto R, Mitani Y, Diao L, Guijarro I, Wang J, Zweidler-McKay P, Bell D, William WN Jr, Glisson BS, Wick MJ, Kapoun AM, Patnaik A, Eckhardt G, Munster P, Faoro L, Dupont J, Lee JJ, Futreal A, el-Naggar AK, Heymach JV. Activating NOTCH1 mutations define a distinct subgroup of patients with adenoid cystic carcinoma who have poor prognosis, propensity to bone and liver metastasis, and potential responsiveness to Notch1 inhibitors. J Clin Oncol. 2017;35(3):352–60. https://doi.org/10.1200/jco.2016.67.5264.

    Article  CAS  PubMed  Google Scholar 

  30. Stephens PJ, Davies HR, Mitani Y, Van Loo P, Shlien A, Tarpey PS, et al. Whole exome sequencing of adenoid cystic carcinoma. J Clin Invest. 2013;123(7):2965–8. https://doi.org/10.1172/JCI67201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Almeida LO, Guimaraes DM, Martins MD, Martins MAT, Warner KA, Nor JE, et al. Unlocking the chromatin of adenoid cystic carcinomas using HDAC inhibitors sensitize cancer stem cells to cisplatin and induces tumor senescence. Stem Cell Research. 2017;21:94–105. https://doi.org/10.1016/j.scr.2017.04.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Geiger JL, Ismaila N, Beadle B, Caudell JJ, Chau N, Deschler D, Glastonbury C, Kaufman M, Lamarre E, Lau HY, Licitra L, Moore MG, Rodriguez C, Roshal A, Seethala R, Swiecicki P, Ha P. Management of salivary gland malignancy: ASCO guideline. J Clin Oncol. 2021;39(17):1909–41. https://doi.org/10.1200/jco.21.00449.

    Article  PubMed  Google Scholar 

  33. Locati LD, Guzzo M, Bossi P, Massone PPB, Conti B, Fumagalli E, Bareggi C, Cantù G, Licitra L. Lung metastasectomy in adenoid cystic carcinoma (ACC) of salivary gland. Oral Oncol. 2005;41(9):890–4. https://doi.org/10.1016/j.oraloncology.2005.04.014.

    Article  PubMed  Google Scholar 

  34. Bobbio A, Copelli C, Ampollini L, Bianchi B, Carbognani P, Bettati S, Sesenna E, Rusca M. Lung metastasis resection of adenoid cystic carcinoma of salivary glands. Eur J Cardiothorac Surg. 2008;33(5):790–3. https://doi.org/10.1016/j.ejcts.2007.12.057.

    Article  PubMed  Google Scholar 

  35. Girelli L, Locati L, Galeone C, Scanagatta P, Duranti L, Licitra L, Pastorino U. Lung metastasectomy in adenoid cystic cancer: Is it worth it? Oral Oncol. 2017;65:114–8. https://doi.org/10.1016/j.oraloncology.2016.10.018.

    Article  PubMed  Google Scholar 

  36. Park S, Nam SJ, Keam B, Kim TM, Jeon YK, Lee SH, Hah JH, Kwon TK, Kim DW, Sung MW, Heo DS, Bang YJ. VEGF and Ki-67 overexpression in predicting poor overall survival in adenoid cystic carcinoma. Cancer Res Treat. 2016;48(2):518–26. https://doi.org/10.4143/crt.2015.093.

    Article  CAS  PubMed  Google Scholar 

  37. Ho AL, Dunn L, Sherman EJ, Fury MG, Baxi SS, Chandramohan R, Dogan S, Morris LGT, Cullen GD, Haque S, Sima CS, Ni A, Antonescu CR, Katabi N, Pfister DG. A phase II study of axitinib (AG-013736) in patients with incurable adenoid cystic carcinoma. Ann Oncol. 2016;27(10):1902–8. https://doi.org/10.1093/annonc/mdw287.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Locati LD, Cavalieri S, Bergamini C, Resteghini C, Alfieri S, Calareso G, Bossi P, Perrone F, Tamborini E, Quattrone P, Granata R, Galbiati D, Platini F, Orlandi E, Mariani L, Licitra L. Phase II trial with axitinib in recurrent and/or metastatic salivary gland cancers of the upper aerodigestive tract. Head Neck. 2019;41(10):3670–6. https://doi.org/10.1002/hed.25891.

    Article  PubMed  Google Scholar 

  39. •• Kang EJ, Ahn MJ, Ock CY, Lee KW, Kwon JH, Yang Y, et al. Randomized phase II study of axitinib versus observation in patients with recurred or metastatic adenoid cystic carcinoma. Clin Cancer Res. 2021;27(19):5272-9. https://doi.org/10.1158/1078-0432.Ccr-21-1061. This is the only randomized phase II study with a VEGFR inhibitor in patients with ACC. This study showed longer PFS of axitinib than placebo in patients with recurrent or metastatic ACC (N=60) and supports the inclusion of axitinib in the NCCN guideline.

  40. • Tchekmedyian V, Sherman EJ, Dunn L, Tran C, Baxi S, Katabi N et al. Phase II study of lenvatinib in patients with progressive, recurrent or metastatic adenoid cystic carcinoma. J Clin Oncol. 2019;37(18):1529-37. https://doi.org/10.1200/jco.18.01859. This is a phase II study of levantinib in patients with metastatic ACC with promising results in terms of disease control.

  41. • Locati LD, Galbiati D, Calareso G, Alfieri S, Singer S, Cavalieri S et al. Patients with adenoid cystic carcinomas of the salivary glands treated with lenvatinib: activity and quality of life. Cancer. 2020;126(9):1888-94. https://doi.org/10.1002/cncr.32754. This is a phase II study of lenvatinib in patients with metastatic ACC with promising results in terms of disease control.

  42. • Zhu G, Zhang L, Dou S, Li R, Li J, Ye L et al. Apatinib in patients with recurrent or metastatic adenoid cystic carcinoma of the head and neck: a single-arm, phase II prospective study. Ther Adv Med Oncol. 2021;13:17588359211013626-. https://doi.org/10.1177/17588359211013626. This is phase II trial of apatinib for R/M ACC that showed the highest ORR (46.2%) seen in ACC thus far.

  43. • Kang H, Ahn M-J, Muzaffar J, Keam B, Bowles DW, Wong DJL et al. A phase 2 study of the oral vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor, rivoceranib, for recurrent or metastatic (R/M) adenoid cystic carcinoma (ACC). J Clin Oncol. 2022;40(16_suppl):6020-. https://doi.org/10.1200/JCO.2022.40.16_suppl.6020. A phase II trial of apatinib in patients with recurrent or metastatic ACC. Results showed lower ORR than Chinese trial (13.9%).

  44. Schramm VL Jr, Srodes C, Myers EN. Cisplatin therapy for adenoid cystic carcinoma. Arch Otolaryngol. 1981;107(12):739–41. https://doi.org/10.1001/archotol.1981.00790480015004.

    Article  PubMed  Google Scholar 

  45. Licitra L, Marchini S, Spinazze S, Rossi A, Rocca A, Grandi C, et al. Cisplatin in advanced salivary gland carcinoma. A phase II study of 25 patients. Cancer. 1991;68(9):1874–7. https://doi.org/10.1002/1097-0142(19911101)68:9<1874::aid-cncr2820680904>3.0.co;2-s.

    Article  CAS  PubMed  Google Scholar 

  46. de Haan LD, De Mulder PH, Vermorken JB, Schornagel JH, Vermey A, Verweij J. Cisplatin-based chemotherapy in advanced adenoid cystic carcinoma of the head and neck. Head Neck. 1992;14(4):273–7. https://doi.org/10.1002/hed.2880140403.

    Article  PubMed  Google Scholar 

  47. Mattox DE, Von Hoff DD, Balcerzak SP. Southwest Oncology Group study of mitoxantrone for treatment of patients with advanced adenoid cystic carcinoma of the head and neck. Invest New Drugs. 1990;8(1):105–7. https://doi.org/10.1007/BF00216934.

    Article  CAS  PubMed  Google Scholar 

  48. Verweij J, de Mulder PH, de Graeff A, Vermorken JB, Wildiers J, Kerger J, et al. Phase II study on mitoxantrone in adenoid cystic carcinomas of the head and neck. EORTC head and neck cancer cooperative group. Ann Oncol. 1996;7(8):867–9. https://doi.org/10.1093/oxfordjournals.annonc.a010770.

    Article  CAS  PubMed  Google Scholar 

  49. Airoldi M, Pedani F, Succo G, Gabriele AM, Ragona R, Marchionatti S, Bumma C. Phase II randomized trial comparing vinorelbine versus vinorelbine plus cisplatin in patients with recurrent salivary gland malignancies. Cancer. 2001;91(3):541–7. https://doi.org/10.1002/1097-0142(20010201)91:3<541::aid-cncr1032>3.0.co;2-y.

    Article  CAS  PubMed  Google Scholar 

  50. van Herpen CM, Locati LD, Buter J, Thomas J, Bogaerts J, Lacombe D, et al. Phase II study on gemcitabine in recurrent and/or metastatic adenoid cystic carcinoma of the head and neck (EORTC 24982). Eur J Cancer. 2008;44(17):2542–5. https://doi.org/10.1016/j.ejca.2008.08.014.

    Article  CAS  PubMed  Google Scholar 

  51. Tannock IF, Sutherland DJ. Chemotherapy for adenocystic carcinoma. Cancer. 1980;46(3):452–4. https://doi.org/10.1002/1097-0142(19800801)46:3<452::aid-cncr2820460305>3.0.co;2-z.

    Article  CAS  PubMed  Google Scholar 

  52. Vermorken JB, Verweij J, de Mulder PH, Cognetti F, Clavel M, Rodenhuis S, et al. Epirubicin in patients with advanced or recurrent adenoid cystic carcinoma of the head and neck: A phase II study of the EORTC Head and Neck Cancer Cooperative Group. Ann Oncol. 1993;4(9):785–8. https://doi.org/10.1093/oxfordjournals.annonc.a058665.

    Article  CAS  PubMed  Google Scholar 

  53. Sahara S, Herzog AE, Nör JE. Systemic therapies for salivary gland adenoid cystic carcinoma. Am J Cancer Res. 2021;11(9):4092–110.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Licitra L, Cavina R, Grandi C, Palma SD, Guzzo M, Demicheli R, et al. Cisplatin, doxorubicin and cyclophosphamide in advanced salivary gland carcinoma. A phase II trial of 22 patients. Ann Oncol. 1996;7(6):640–2. https://doi.org/10.1093/oxfordjournals.annonc.a010684.

    Article  CAS  PubMed  Google Scholar 

  55. Creagan ET, Woods JE, Rubin J, Schaid DJ. Cisplatin-based chemotherapy for neoplasms arising from salivary glands and contiguous structures in the head and neck. Cancer. 1988;62(11):2313–9. https://doi.org/10.1002/1097-0142(19881201)62:11<2313::aid-cncr2820621110>3.0.co;2-4.

    Article  CAS  PubMed  Google Scholar 

  56. Dreyfuss AI, Clark JR, Fallon BG, Posner MR, Norris CM Jr, Miller D. Cyclophosphamide, doxorubicin, and cisplatin combination chemotherapy for advanced carcinomas of salivary gland origin. Cancer. 1987;60(12):2869–72. https://doi.org/10.1002/1097-0142(19871215)60:12<2869::aid-cncr2820601203>3.0.co;2-y.

    Article  CAS  PubMed  Google Scholar 

  57. Belani CP, Eisenberger MA, Gray WC. Preliminary experience with chemotherapy in advanced salivary gland neoplasms. Med Pediatr Oncol. 1988;16(3):197–202. https://doi.org/10.1002/mpo.2950160309.

    Article  CAS  PubMed  Google Scholar 

  58. Airoldi M, Fornari G, Pedani F, Marchionatti S, Gabriele P, Succo G, Bumma C. Paclitaxel and carboplatin for recurrent salivary gland malignancies. Anticancer Res. 2000;20(5C):3781–3.

    CAS  PubMed  Google Scholar 

  59. Nakano K, Sato Y, Sasaki T, Shimbashi W, Fukushima H, Yonekawa H, Mitani H, Kawabata K, Takahashi S. Combination chemotherapy of carboplatin and paclitaxel for advanced/metastatic salivary gland carcinoma patients: differences in responses by different pathological diagnoses. Acta Otolaryngol. 2016;136(9):948–51. https://doi.org/10.3109/00016489.2016.1170876.

    Article  CAS  PubMed  Google Scholar 

  60. • Airoldi M, Garzaro M, Pedani F, Ostellino O, Succo G, Riva G et al. Cisplatin+vinorelbine treatment of recurrent or metastatic salivary gland malignancies (RMSGM): A final report on 60 cases. Am J Clin Oncol. 2017;40(1):86-90. https://doi.org/10.1097/COC.0000000000000112. This is the largest phase II study of cisplatin and vinorelbine in patients with ACC. Results showed an ORR of 21% and median OS of 10.2 months and supports currently use of this chemotherapy regimen.

  61. Hong MH, Kim CG, Koh YW, Choi EC, Kim J, Yoon SO, Kim HR, Cho BC. Efficacy and safety of vinorelbine plus cisplatin chemotherapy for patients with recurrent and/or metastatic salivary gland cancer of the head and neck. Head Neck. 2018;40(1):55–62. https://doi.org/10.1002/hed.24933.

    Article  CAS  PubMed  Google Scholar 

  62. Ho AL, Bowles DW, Even C, Hao D, Kang H, Metcalf R et al. ACCURACY: A phase II trial of al101, a selective gamma secretase inhibitor, in subjects with recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC) harboring Notch activating mutations (Notchmut): Results of 6-mg cohort. 2021;32:S803-S4 . https://doi.org/10.1016/j.annonc.2021.08.1314.

  63. Miranda EL, Stathis A, Hess D, Racca F, Quon D, Rodon J et al. Phase 1 study of CB-103, a novel first-in-class inhibitor of the CSL-NICD gene transcription factor complex in human cancers. J Clin Oncol. 2021;39(15). https://doi.org/10.1200/JCO.2021.39.15_suppl.3020.

  64. Xu PP, Dan G, Chen B, Zhao Q, Zhou RF, Ouyang J. C-Myc-driven and PRMT5-dependent regulation of multiple myeloma cell proliferation through TNRC6b gene. Blood. 2019;134:5520. https://doi.org/10.1182/blood-2019-125027.

    Article  Google Scholar 

  65. Siu LL, Rasco DW, Vinay SP, Romano PM, Menis J, Opdam FL, Heinhuis KM, Egger JL, Gorman SA, Parasrampuria R, Wang K, Kremer BE, Gounder MM. METEOR-1: A phase I study of GSK3326595, a first-in-class protein arginine methyltransferase 5 (PRMT5) inhibitor, in advanced solid tumours. Ann Oncol. 2019;30(Suppl 5):v159–93.

    Article  Google Scholar 

  66. McKean M, Patel MR, Wesolowski R, Ferrarotto R, Stein EM, Shoushtari AN, Mauro D, Viscusi J, Scherle P, Bhagwat N, Sun W, Chiaverelli R, Mintah E, Jauhari S, Finn L, Palmisiano ND, Baiocchi RA. Abstract P039: a phase 1 dose escalation study of protein arginine methyltransferase 5 (PRMT5) inhibitor PRT543 in patients with advanced solid tumors and lymphoma. Mol Cancer Ther. 2021;20(12 Suppl):P039.

    Article  Google Scholar 

  67. Mitani Y, Liu B, Rao PH, Borra VJ, Zafereo M, Weber RS, Kies M, Lozano G, Futreal PA, Caulin C, el-Naggar AK. Novel MYBL1 gene rearrangements with recurrent MYBL1-NFIB fusions in salivary adenoid cystic carcinomas lacking t(6;9) translocations. Clin Cancer Res. 2016;22(3):725–33. https://doi.org/10.1158/1078-0432.CCR-15-2867-T.

    Article  CAS  PubMed  Google Scholar 

  68. de Sousa LG, Neto FL, Lin J, Ferrarotto R. Treatment of recurrent or metastatic adenoid cystic carcinoma. Curr Oncol Rep. 2022;24:621–31. https://doi.org/10.1007/s11912-022-01233-z.

    Article  CAS  PubMed  Google Scholar 

  69. Mandelbaum J, Shestopalov IA, Henderson RE, Chau NG, Knoechel B, Wick MJ, Zon LI. Zebrafish blastomere screen identifies retinoic acid suppression of MYB in adenoid cystic carcinoma. J Exp Med. 2018;215(10):2673–85. https://doi.org/10.1084/jem.20180939.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Hanna GJ, ONeill A, Cutler JM, Flynn M, Vijaykumar T, Clark JR, Wirth LJ, Lorch JH, Park JC, Mito JK, Lohr JG, Kaufman J, Burr NS, Zon LI, Haddad RI. A phase II trial of all-trans retinoic acid (ATRA) in advanced adenoid cystic carcinoma. Oral Oncol. 2021;119:105366. https://doi.org/10.1016/j.oraloncology.2021.105366.

    Article  CAS  PubMed  Google Scholar 

  71. Kubbutat MHG, Jones SN, Vousden KH. Regulation of p53 stability by Mdm2. Nature. 1997;387(6630):299–303. https://doi.org/10.1038/387299a0.

    Article  CAS  PubMed  Google Scholar 

  72. Carlinfante G, Lazzaretti M, Ferrari S, Bianchi B, Crafta P. P53, bcl-2 and Ki-67 expression in adenoid cystic carcinoma of the palate. A clinico-pathologic study of 21 cases with long-term follow-up. Pathol Res and Pract. 2005;200(11-12):791–9. https://doi.org/10.1016/j.prp.2004.08.008.

    Article  Google Scholar 

  73. Nor F, Warner KA, Zhang Z, Acasigua GA, Pearson AT, Kerk SA, et al. Therapeutic inhibition of the MDM2-p53 interaction prevents recurrence of adenoid cystic carcinomas. Clin Cancer Res. 2017;23(4):1036–48. https://doi.org/10.1158/1078-0432.CCR-16-1235.

    Article  CAS  PubMed  Google Scholar 

  74. Cohen RB, Delord J-P, Doi T, Piha-Paul SA, Liu SV, Gilbert J, Algazi AP, Damian S, Hong RL, le Tourneau C, Day D, Varga A, Elez E, Wallmark J, Saraf S, Thanigaimani P, Cheng J, Keam B. Pembrolizumab for the treatment of advanced salivary gland carcinoma: findings of the phase 1b KEYNOTE-028 study. Am J Clin Oncol. 2018;41(11):1083–8. https://doi.org/10.1097/COC.0000000000000429.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Mahmood U, Bang A, Chen Y-H, Mak RH, Lorch JH, Hanna GJ, Nishino M, Manuszak C, Thrash EM, Severgnini M, Sanborn M, Sridharan V, Margalit DN, Tishler RB, Busse PM, Willers H, Mamon HJ, Yoo HJ, Pai SI, et al. A randomized phase 2 study of pembrolizumab with or without radiation in patients with recurrent or metastatic adenoid cystic carcinoma. Int J Radiat Oncol Biol Phys. 2021;109(1):134–44. https://doi.org/10.1016/j.ijrobp.2020.08.018.

    Article  PubMed  Google Scholar 

  76. Tchekmedyian V, Sherman EJ, Dunn L, Fetten JV, Michel LS, Kriplani A et al. A phase II trial cohort of nivolumab plus ipilimumab in patients (pts) with recurrent/metastatic adenoid cystic carcinoma (R/M ACC). J Clin Oncol. 2019;37(15_suppl):6084-. https://doi.org/10.1200/JCO.2019.37.15_suppl.6084.

  77. Fayette J, Even C, Digue L, Geoffrois L, Rolland F, Cupissol D et al. NISCAHN: A phase II, multicenter nonrandomized trial aiming at evaluating nivolumab (N) in two cohorts of patients (pts) with recurrent/metastatic (R/M) salivary gland carcinoma of the head and neck (SGCHN), on behalf of the Unicancer Head & nNeck group. J Clin Oncol. 2019;37(15_suppl):6083-6083. https://doi.org/10.1200/JCO.2019.37.15_suppl.6083.

  78. Goncalves PH, Heilbrun LK, Barrett MT, Kummar S, Hansen AR, Siu LL et al. A phase 2 study of vorinostat in locally advanced, recurrent, or metastatic adenoid cystic carcinoma. Oncotarget. 2017;8(20):32918-29. https://doi.org/10.18632/oncotarget.16464.

  79. Rodriguez CP, Wu QV, Voutsinas J, Fromm JR, Jiang X, Pillarisetty VG, et al. A phase II trial of pembrolizumab and vorinostat in recurrent metastatic head and neck squamous cell carcinomas and salivary gland cancer. Clin Cancer Res. 2020;26(4):837–45. https://doi.org/10.1158/1078-0432.Ccr-19-2214.

    Article  CAS  PubMed  Google Scholar 

  80. • Ferrarotto R, Bell D, Feng L, Li K, Mott F, Blumenschein GR et al. A phase 2 clinical trial of axitinib and avelumab in patients with recurrent/metastatic adenoid cystic carcinoma (ACC). J Clin Oncol. 2022;40(16_suppl):6019-6019. https://doi.org/10.1200/JCO.2022.40.16_suppl.6019. Phase II trial of a VEGFR inhibitor, axitinib, combined with anti-PD-L1, avelumab. Results showed promising activity of the combination.

  81. Cristescu R, Mogg R, Ayers M, Albright A, Murphy E, Yearley J et al. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade–based immunotherapy. Science. 2018;362(6411):eaar3593.

  82. • Linxweiler M, Kuo F, Katabi N, Lee M, Nadeem Z, Dalin MG et al. The immune microenvironment and neoantigen landscape of aggressive salivary gland carcinomas differ by subtype. Clin Cancer Res. 2020;26(12):2859-70. https://doi.org/10.1158/1078-0432.Ccr-19-3758. This study explored the molecular landscape of salivary gland cancers, including ACC.

  83. Sousa LGd, Neto FL, McGrail DJ, Li K, Marques-Piubelli ML, Borgogno SF et al. Single-cell immune mapping of adenoid cystic carcinoma (ACC) reveals potential therapeutic targets for the aggressive solid subtype. J Clin Oncol. 2022;40(16_suppl):6090-6090. https://doi.org/10.1200/JCO.2022.40.16_suppl.6090.

  84. Wolkow N, Jakobiec FA, Afrogheh AH, Kidd M, Eagle RC, Pai SI, Faquin WC. PD-L1 and PD-L2 expression levels are low in primary and secondary adenoid cystic carcinomas of the orbit: therapeutic implications. Ophthalmic Plast Reconstr Surg. 2020;36(5):444–50. https://doi.org/10.1097/iop.0000000000001585.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Sridharan V, Gjini E, Liao X, Chau NG, Haddad RI, Severgnini M, Hammerman P, el-Naggar A, Freeman GJ, Hodi FS, Rodig SJ, Dranoff G, Schoenfeld JD. Immune profiling of adenoid cystic carcinoma: PD-L2 expression and associations with tumor-infiltrating lymphocytes. Cancer Immunol Res. 2016;4(8):679–87. https://doi.org/10.1158/2326-6066.Cir-16-0031.

    Article  CAS  PubMed  Google Scholar 

  86. Klein Nulent TJW, Valstar MH, Smit LA, Smeele LE, Zuithoff NPA, de Keizer B, de Bree R, van Es RJJ, Willems SM. Prostate-specific membrane antigen (PSMA) expression in adenoid cystic carcinoma of the head and neck. BMC Cancer. 2020;20(1):519. https://doi.org/10.1186/s12885-020-06847-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. van Boxtel W, Lütje S, van Engen-van Grunsven ICH, Verhaegh GW, Schalken JA, Jonker MA, Nagarajah J, Gotthardt M, van Herpen CML. 68Ga-PSMA-HBED-CC PET/CT imaging for adenoid cystic carcinoma and salivary duct carcinoma: a phase 2 imaging study. Theranostics. 2020;10(5):2273–83. https://doi.org/10.7150/thno.38501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. FDA. FDA grants regular approval to sacituzumab govitecan for triple-negative breast cancer. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-sacituzumab-govitecan-triple-negative-breast-cancer. 2021. Accessed 03/14/2022.

  89. Wolber P, Nachtsheim L, Hoffmann F, Klussmann JP, Meyer M, von Eggeling F, et al. Trophoblast cell surface antigen 2 (Trop-2) protein is highly expressed in salivary gland carcinomas and represents a potential therapeutic target. Head Neck Pathol. 2021;15(4):1147–55. https://doi.org/10.1007/s12105-021-01325-5.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Stephanie Deming, scientific editor, Research Medical Library, for editing this article

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  1. Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, PO Box 432, Houston, TX, 77030, USA

    Luana Guimaraes de Sousa, Katarina Jovanovic & Renata Ferrarotto

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  1. Luana Guimaraes de Sousa
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Renata Ferrarotto reports personal fees from Regeneron-Sanofi, Ayala Pharmaceuticals, Prelude Pharmaceuticals, Bicara Therapeutics, Klus Pharma, Medscape, Carevive, Merck, and Guidepoint Global and institutional fees from AstraZeneca, Merck, Genentech, Pfizer, EMD-Serono, Ayala Pharmaceuticals, Prelude Pharmaceuticals, and Rakuten Medical not related to the topic of the submitted work. Luana Guimaraes de Sousa, and Katarina Jovanovic report no conflict of interest.

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de Sousa, L.G., Jovanovic, K. & Ferrarotto, R. Metastatic Adenoid Cystic Carcinoma: Genomic Landscape and Emerging Treatments. Curr. Treat. Options in Oncol. 23, 1135–1150 (2022). https://doi.org/10.1007/s11864-022-01001-y

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