Successful targeted therapy in treatment of non-resectable refractory squamous cell cancer of nasal cavity with mutation in PTCH1 gene

Cancer of the nasal mucosa is a malignant tumor originating from the mucous epithelium of the nasal cavity or paranasal sinuses. Nasal and paranasal sinus cancer accounts for 1.4 % of all malignancies and 3–5 % of head and neck tumors. males are twice as likely to be affected as females, particularly those aged 55 years and older (nearly 80 % of cases). The five-year survival rate is 8 2 % in patients with stage I disease and 43 % in patients with stage Iv disease. Despite the advances in the diagnosis of nasal cancer, over 80 % of new patients are diagnosed with stage III–Iv disease because of nonspecific symptoms in early (I and II) stages. Traditional treatment methods (including surgery, radiation therapy and chemotherapy) often allow us to achieve complete recovery in patients with this disorder. However, in most patients with locally advanced cancer, this approach has a limited effectiveness and is often associated with severe side effects. Considering frequent progression of nasal squamous cell carcinomas on standard regimens, it is necessary to search for new treatment targets to improve outcomes. Extensive molecular testing using multigenic panels based on next-generation sequencing can be helpful in this case. The most common mutations in nasal cancers occur in five genes: TP53 (up to 80 % of cases), EGFR (up to 77 % of cases), IDH2 (approximately 55 % of cases), PIK3CA (14 % of cases), and CDKN2A (9 % of cases). we report a case of successful treatment of a patient with locally advanced, non-resectable, drug-resistant nasal squamous cell carcinoma with a rare driver mutation.

1. Malignant neoplasms in Russia in 2023 (morbidity and mortality). Ed. by A.D. Kaprin, V.V. Starinsky, A.O. Shakhzadova. Moscow: MNIOI im. P.A. Gertsena – filial FGBU “NMITS radiologii” Minzdrava Rossii, 2024. 275 p. (In Russ.).

2. Key statistics about nasal cavity and paranasal sinus cancers. American Cancer Society. Available at: https://www.cancer.org/cancer/types/nasal-cavity-and-paranasal-sinus-cancer/about/keystatistics.html

3. Bray F., Ferlay J., Soerjomataram I. et al. GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68(6):394–424. DOI: 10.3322/caac.21492

4. Pecorari G., Motatto G., Piazza F. et al. Real-life prognosis of sinonasal tumors. J of Pers Med 202;14(5):444. DOI: 10.3390/jpm14050444

5. Brierly J.D. TNM: classification of malignant tumors. Moscow: Logosphere, 2018. 344 p. (In Russ.).

6. Malignant tumors of the sinuses. Medscape. Available at: https:// emedicine.medscape.com/article/847189-overview

7. Treatment of nasal cavity and paranasal sinus cancers, by type and stage. Available at: https://www.cancer.org/cancer/types/nasalcavity-and-paranasal-sinus-cancer/treating/by-stage.html

8. Chalmers Z., Connelly C., Fabrizio D. et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med 2017;9(1):34. DOI: 10.1186/s13073-017-0424-2

9. Martínez J., Pérez-Escuredo J., López F. et al. Microsatellite instability analysis of sinonasal carcinomas. Otolaryngol Head Neck Surg 2009;140(1):55–60. DOI: 10.1016/j.otohns.2008.10.038

10. Park J., Faquin W., Durbeck J. et al. Immune checkpoint inhibitors in sinonasal squamous cell carcinoma. Oral Oncol 2020;109:104776. DOI: 10.1016/j.oraloncology.2020.104776

11. Bracigliano A., Tatangelo F., Perri F. et al. Malignant sinonasal tumors: update on histological and clinical management. Curr Oncol 2021;28(4):2420–38. DOI: 10.3390/curroncol28040222

12. Taverna C., Agaimy A., Franchi A. Towards a molecular classification of sinonasal carcinomas: clinical implications and opportunities. Cancers 2022;14(6):1463. DOI: 10.3390/cancers14061463

13. Jo V., Chau N., Hornick J. et al. Recurrent IDH2 R172X mutations in sinonasal undifferentiated carcinoma. Mod Pathol 2017;30(5):650–9. DOI: 10.1038/modpathol.2016.239

14. Bitar G., Alshaka S., Hsia B. Comprehensive genomic profiling of sinonasal carcinomas: identification of common mutations and potential targets for therapy. J Neurol Surg B Skull Base 2025. DOI: 10.1055/a-2639-5790

15. Speel E. HPV integration in head and neck squamous cell carcinomas: cause and consequence. Recent Results Cancer Res 2017;206:57–72. DOI: 10.1007/978-3-319-43580-0_4

16. Lee D.-H., Lee S., Oh S. Hedgehog signaling pathway as a potential target in the treatment of advanced gastric cancer. Tumor Biol 2017;39(6):1010428317692266. DOI: 10.1177/1010428317692266

17. Cancer Genome Atlas Network. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature 2015;517(7536):576–82. DOI: 10.1038/nature14129

18. Stransky N., Egloff A., Tward A. et al. The mutational landscape of head and neck squamous cell carcinoma. Science 2011;333(6046):1157–60. DOI: 10.1126/science.1208130

19. Agrawal N., Frederick M., Pickering C. et al. Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science 2011;333(6046):1154–7. DOI: 10.1126/science.1206923

20. Leović M., Jakovčević A., Mumlek I. et al. A pilot immunohistochemical study identifies hedgehog pathway expression in sinonasal adenocarcinoma. Int J Mol Sci 2024;25(9):4630. DOI: 10.3390/ijms25094630

21. Hoff D., LoRusso P., Rudin C. et al. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med 2009;361(12):1164–72. DOI: 10.1056/NEJMoa0905360

22. ERIVANCE phase II pivotal trial design. ERIVANCE: The pivotal trial that demonstrated clinically meaningful benefit in advanced BCC. Available at: https://www.erivedge.com/hcp/efficacy/clinicalresults.html

23. Dréno B., Kunstfeld R., Hauschild A. et al. Two intermittent vismodegib dosing regimens in patients with multiple basal-cell carcinomas (MIKIE): a randomised, regimen-controlled, doubleblind, phase 2 trial. Lancet Oncol 2017;18(3):404–12. DOI: 10.1016/S1470-2045(17)30072-4

24. Beatty G., Gladney W. Immune escape mechanisms as a guide for cancer immunotherapy. Clin Cancer Res 2014;21(4):687–92. DOI: 10.1158/1078-0432.CCR-14-1860

25. Migden M., Guminski A., Gutzmer R. et al. Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial. Lancet Oncol 2015;16(6):716–28. DOI: 10.1016/S1470-2045(15)70100-2

26. Basset-Seguin N., Maubec E. Recent advanced in the treatment of advanced SCC tumors. Cancers (Basel) 2022;14(3):550. DOI: 10.3390/cancers14030550

27. Buonamici S., Williams J., Morrissey M. et al. Interfering with resistance to smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma. Scie Transl Med 2010;2(51):51ra70. DOI: 10.1126/scitranslmed.3001599

28. Kim J., Aftab B., Tang J. et al. Itraconazole and arsenic trioxide inhibit hedgehog pathway activation and tumor growth associated with acquired resistance to smoothened antagonists. Cancer Cell 2013;23(1):23–34. DOI: 10.1016/j.ccr.2012.11.017

29. Dorywalska M., Dushin R., Moine L. et al. Molecular basis of valine-citrulline-PABC Linker Instability in Site-Specific ADCs and its mitigation by linker design. Mol Cancer Ther 2016;15(5):958–70. DOI: 10.1158/1535-7163.MCT-15-1004

30. Bakshi A., Chaudhary S., Rana M. et al. Basal cell carcinoma pathogenesis and therapy involving hedgehog signaling and beyond. Mol Carcinog 2017;56(12):2543–57. DOI: 10.1002/mc.22690

31. Pastorino L., Pollio A., Pellacani G. et al. Novel PTCH1 mutations in patients with keratocystic odontogenic tumors screened for nevoid basal cell carcinoma (NBCC) syndrome. PLoS One 2012;7(8):e43827. DOI: 10.1371/journal.pone.0043827