Survival of patients with salivary gland malignancies depending on the molecular profile of the tumor

Introduction. Standard methods of drug or radiation therapy administration for salivary gland cancer is the least successful for now. Therefore, the identification of new markers with morphological features is extremely necessary to improve the effectiveness of treatment and increase the survival rates of patients with this pathology.

The study objective is to assess the prevalence of expression of HER2/neu, PD-L1, and RET mRNA in salivary gland malignancies and assess their impact on overall and disease-free survival.

Materials and methods. Fifty-nine patients with a confirmed diagnosis of salivary gland cancer (stages II–IVA) were examined in the period from 2012 to 2014 at Saint Petersburg City Clinical Oncology Dispensary. All materials were subjected to immunohistochemical research to determine the expression of HER2, PD-L1 in tumor and immune cells, the CPS index was calculated, and the frequency of the mRNA gene RET expression using a real-time polymerase chain reaction was detected.

Results. The overall survival of patients with mild and high HER2 expression was 41 months (95 % confidence interval (CI) 4.50–72.00), which is more than 4 time less than in patients with low or no expression (p = 0.00715). Significant differences were also received in the progression-free survival in the group of patients with negative or insignificant expression of HER2 receptors. The overall survival of patients with CPS >1 was 72 months (95 % CI 19.5–72.00) and significantly differed from the group of patients with CPS <1, where it was not yet achieved (p = 0.0124). mRNA expression of the RET gene was detected in 13 out of 48 cases, which was 27.08 %. The expression level ranged from 0 to 0.205. The progression-free survival in the group of patients with mRNA expression was 168 months (95 % CI 16.00–168.00) and tended to increase in the group of patients who did not have this expression.

Conclusion. When analyzing the obtained data, it was proved that knowledge of the salivary glands malignant tumors receptor status become one of the factors in determining the prognosis of the disease, as well as a predictive factor of targeted drugs effectiveness (after сonducting prospective randomized studies).

1. Van Dijk B.A., Gatta G., Capocaccia R. et al. Rare cancers of the head and neck area in Europe. Eur J Cancer 2012;48(6):783–96. DOI: 10.1016/j.ejca.2011.08.021.

2. Barnes L., Evenson J.W., Reichart P. et al. Salivary glands. In: World Health Organization classification of tumours: pathology & genetics of head and neck tumours. Lyon, France: IARC Press; 2005. Pp. 209–281.

3. Storey M.R., Garden A.S., Morrison W.H. et al. Postoperative radiotherapy for malignant tumors of the submandibular gland. Int J Radiat Oncol Biol Phys 2001;51(4):952–8. DOI: 10.1016/s0360-3016(01)01724-2.

4. Holmes T., Das R., Low D. et al. IMRT Documentation Working Group. American Society of Radiation Oncology recommendation for documenting intensity-modulated radiation therapy treatments. Int J Radiat Oncol Biol Phys 2009;74(5):1311–8. DOI: 10.1016/j.ijrobp.2009.04.037.

5. Lee N.Y., O’Meara W., Chan K. et al. Concurrent chemotherapy and intensitymodulated radiotherapy for locoregionally advanced laryngeal and hypopharyngeal cancers. Int J Radiat Oncol Biol Phys 2007;69(2):459–68. DOI: 10.1016/j.ijrobp.2007.03.013.

6. NCCN Clinical practice guidelines in oncology. Salivary gland tumors. Head and Neck Cancer. 2019. Version 1. P. 1.

7. Laurie S.A., Ho A.L., Fury M.G. et al. Systemic therapy in the management of metastatic or locally recurrent adenoid cystic carcinoma of the salivary glands: a systematic review. Lancet Oncol 2011;12:8152–4. DOI: 10.1016/S1470-2045(10)70245-X.

8. Eneroth C.M. Salivary gland tumors in the parotid gland, submandibular gland, and the palate region. Cancer 1971;27:1415–8. DOI: 10.1002/1097-0142(197106)27:63.0.co;2-x.

9. Alotaibi A.M., Alqarni M.A., Alnobi A. et al. Human epidermal growth factor receptor 2 (HER2/neu) in salivary gland carcinomas: a review of literature. J Clin Diagn Res 2015;9(2):ZE04–8. DOI: 10.7860/JCDR/2015/11289.5572.

10. Bradley P.J. Classification of salivary gland neoplasm. Adv Otorhinolaryngol 2016;78:1–8. DOI: 10.1159/000442119.

11. Seethala R.R. An update on grading of salivary gland carcinoma. Head Neck Pathol 2009;3(1):69–77. DOI: 10.1007/s12105-009-0102-9.

12. Szewczyk M., Marszalek A., Sygut J. et al. Prognostic markers in salivary gland cancer and their impact on survival. Head Neck 2019;41(9):3338–47. DOI: 10.1002/hed.25857.

13. Skálová A., Vanecek T., Sima R. et al. Mammary analogue secretory carcinoma of salivary glands, containing the ETV6-NTRK3 fusion gene: a hitherto undescribed salivary gland tumor entity. Am J Surg Pathol 2010;34(5):599–8. DOI: 10.1097/PAS.0b013e3181d9efcc.

14. Krings G., Joseph N.M., Bean G.R. et al. Genomic profiling of breast secretory secretory carcinomas. Mod Pathol 2017;30(8):1086–99. DOI: 10.1038/modpathol.2017.32.

15. Bunone G., Uggeri M., Mondellini P. et al. RET receptor expression in thyroid follicular epithelial cell-derived tumors. Cancer Res 2000;60(11):2845–9.

16. Locati L.D., Perrone F., Cortelazzi B. et al. A phase II study of sorafenib in recurrent and/or metastatic salivary gland carcinomas: translational analyses and clinical impact. Eur J Cancer 2016;69:158–65. DOI: 10.1016/j.ejca.2016.09.022.

17. Van Boxtel W., Verhaegh G.W., van Engen-van Grunsven I.A. et al. Prediction of clinical benefit from androgen deprivation therapy in salivary duct carcinoma patients. Int J Cancer 2020;146(11):3196–206. DOI: 10.1002/ijc.32795.

18. Mukaigawa T., Hayashi R., Hashimoto K. et al. Programmed death ligand-1 expression is associated disease free survival in salivary gland carcinomas. J Surg Oncol 2016;114(1):36–43. DOI: 10.1002/jso.24266.

19. Masconi C., Arantes D.A.C., Goncalves A.S. et al. Immunohistochemical investigations on the expression of programmed cell death ligand 1, human leukocyte antigens G and E, and granzyme B in intraoral mucoepidermoid carcinoma. Arch Oral Biol 2017;83:55–62. DOI: 10.1016/j.archoralbio.2017.07.004.

20. Sridharan V., Gjini E., Liao X. et al. Immune profiling of adenoid cystic carcinoma: PD-L2 expression and associations with tumor-infiltrating lymphocytes. Cancer Immunol Res 2016;4(8):679–87. DOI: 10.1158/2326-6066.CIR-16-0031.