Biomarkers for Immunotherapy in Poorly Differentiated Sinonasal Tumors

Abstract

The sinonasal cavities harbor a wide variety of rare cancer types. Histopathological classification can be challenging, especially for poorly differentiated tumors. Despite advances in surgery and radio-chemotherapy, the 5-year survival rate is still very low. Thus, there is an unmet clinical need for new therapeutic options. We retrospectively evaluated poorly differentiated tumors of 9 different histological subtypes from 69 patients who had received conventional treatments for the presence of CD8+ tumor-infiltrating lymphocytes (TILs), as well as the expression of PD-L1 and microsatellite instability (MSI) markers MLH1, MSH2, MSH6 and PMS2, as biomarkers for immunotherapy. CD8+ TILs were present in 23/69 (33%) cases, PD-L1 expression was observed in 23/69 (33%), and markers for MSI positivity in 5/69 (7%) cases. CD8+ TILs correlated with PD-L1 positivity, while both were mutually exclusive with MSI markers. None of the biomarkers were associated with clinical features as age, gender or tumor stage. Cases with CD8+ TILs and PD-L1 positivity showed a tendency toward worse disease-specific survival. Immune checkpoint inhibitors are emerging as new options for treatment of many tumor types. Our results indicate that also a substantial subset of patients with poorly differentiated sinonasal tumors may be a candidate to be treated with this promising new therapy.

Progress and emerging strategies to preserve function in the treatment of sinonasal cancer

“…Moreover, several studies on tumor-infiltrating lymphocytes and aspects of the PD-L1/PD1 checkpoint have indicated a role for immunotherapy in several sinonasal tumor subtypes. [60][61][62] Limited information is available regarding the effectiveness and ad hoc use of targeted agents for treating SNCs. In a multicenter, retrospective study in Japanese patients with recurrent or metastatic head and neck cancer who received nivolumab for the first time between July and December 2017, overall, 256 patients were enrolled in this study.…”

“…Candidate therapies include PI3K/mTOR inhibitors for intestinal‐type adenocarcinomas, EGFR and CDK4/6 inhibitors for SCC, MEK inhibitors for mucosal melanomas, IDH2 inhibitors for neuroendocrine and SNUC 48 and ONB, 52 and EZH2 inhibitors for SNUC, 48 while DNA repair and FGFR inhibitors may be considered for many of the SNC subtypes. Moreover, several studies on tumor‐infiltrating lymphocytes and aspects of the PD‐L1/PD1 checkpoint have indicated a role for immunotherapy in several sinonasal tumor subtypes 60–62 …”

Sox2 and βIII-Tubulin as Biomarkers of Drug Resistance in Poorly Differentiated Sinonasal Carcinomas

“…Another candidate treatment option for PDC is immunotherapy, although few studies have studied immune checkpoint inhibitors in these tumors. Recent immunotherapeutic biomarker studies have reported CD8+ TILs in up to 20% of ONBs, which were associated with a more favorable prognosis [71][72][73]. PD-L1 expression occurred in 14-20% of ONBs.…”

“…PD-L1 expression occurred in 14-20% of ONBs. CD8+ TILs and PD-L1 expression have also been observed in 17% and 33% of SNECs, respectively, and in 33% and 16% of SNUCs, respectively [73]. Other biomarkers include the tumor mutation burden and microsatellite instability, but few data on PDC are available.…”

Sinonasal Cancer: Improving Classification, Stratification and Therapeutic Options

“…Genetic analysis also allows for the identification of molecular targets for modern targeted therapies. Several studies on tumor-infiltrating lymphocytes and aspects of the PD-L1/PD1 checkpoint have indicated a role for immunotherapy in several sinonasal tumor subtypes [ 10 , 11 , 12 , 13 , 14 , 15 , 16 ], and we strongly encourage research into the clinical response to treatment with immune checkpoint inhibitors in sinonasal cancers such as recently reported on MMM [ 17 ]. Next-generation sequencing identified recurrent subtype-unique mutations including: APC , CTNNB1 , PIK3CA and KRAS in ITAC, EGFR and CDKN2A in SNSCC, NRAS and NF1 in MMM, IDH2 in SNUC, and ARID1A , SMARCB1 and SMARCA4 in SNEC, SNUC and TCS [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ].…”