Multimodal treatment and immune checkpoint inhibition in sinonasal mucosal melanoma: real-world data of a retrospective, single-center study.

PURPOSE: Local failure and distant metastases occur frequently in sinonasal mucosal melanoma (SNMM). Response rates to chemotherapy are low and targetable mutations are rarely detected. However, there is increasing data indicating efficacy of immune checkpoint inhibition (ICI). The aim of this retrospective monocenter study was to assess the mutational landscape and to evaluate the outcome of surgical treatment and ICI in SNMM in a real-world setting. METHODS: Thirty-eight SNMM patients being treated between 1999 and 2020 at our institution were retrospectively reviewed. Survival curves were generated according to Kaplan-Meier and compared by the log-rank test. RESULTS: Local failure was seen in 60% of patients treated in a curative intent. Overall, 24% of all patients suffered from regional and 66% from distant metastases. Next generation sequencing revealed mutations of BRAF, NRAS and KRAS. One out of three patients treated with a primary ICI showed a complete response (CR) and two showed progressive disease. Eleven patients received ICI as a palliative treatment. CR could be observed in three patients and stable disease in one patient. In the whole study population, the 5-year overall survival rate (OS) was 26%. OS was better for patients who received ICI during the course of disease. CONCLUSIONS: Recurrences and distant metastases are frequent in SNMM. Durable CR could be observed after primary and palliative ICI. Therefore, ICI in a palliative, adjuvant or even neoadjuvant setting might play a promising role in SNMM therapy while targetable mutations are rarely detected.

MAGE-A9 in head and neck cancer: Prognostic value and preclinical findings in the context of irradiation.

Radiotherapy alone, or as an addition to surgery is important for the treatment of head and neck squamous cell carcinoma (HNSCC). In addition to their expression in germ cells, melanoma associated antigens-A (MAGE-A) are only expressed in malignant tissue. Notably, there is a known correlation between MAGE-A9 expression and poor prognosis in HNSCC patients. However, current knowledge regarding the function of MAGE-A9 expression, particularly in the context of irradiation, is limited. MAGE-A9 expression in 37 oral squamous cell carcinoma patents was immunohistochemically determined and analyzed for overall survival by the Kaplan-Meier log-rank test. Next, the expression of MAGE-A9 was determined by reverse transcription-quantitative polymerase chain reaction in HNSCC cell lines prior to and following irradiation with 2 Gray. The radiosensitivity of each cell line was determined using a clonogenic survival assay. There was a significantly (P=0.0468) longer overall survival in patients with a low level of MAGE-A9 expression. The median overall survival in patients with high MAGE-A9 expression was 47% compared to 73% in the group with low MAGE-A9 expression. The cell lines revealed a distinct expression pattern of MAGE-A9. Following irradiation of the cell lines, a significant enhancement of MAGE-A9 mRNA expression levels was observed. The most prominent alteration in MAGE-A9 expression was observed in the most radioresistant cell line. A high MAGE-A9 expression level correlates significantly with lower overall survival in HNSCC patients. Additionally, irradiation increased the MAGE-A9 mRNA levels in all five HNSCC cell lines, and the most resistant cell line demonstrated the greatest increase in MAGE-A9 expression following irradiation.

MAGE-A expression clusters and antineoplastic treatment in head and neck cancer.

The nonsurgical treatment of head and neck squamous cell carcinoma (HNSCC) usually consists of radiation and chemotherapy. In general, the treatment efficacy of chemotherapy in head and neck cancer is limited. Apart from the placenta, testis and fetal keratinocytes, melanoma-associated antigens-A (MAGE-A) are only found in malignancies. Even though their molecular role remains unclear, several subgroups have been found to contribute to resistance to different chemotherapeutic agents. In the present study, established human squamous cell carcinoma cell lines were incubated with various concentrations of cisplatin, 5-fluorouracil, paclitaxel, docetaxel, cetuximab and panitumumab for 5, 10, 20 and 40 h. The treatment efficacy was measured dynamically by real-time cell analysis (RTCA). In addition, we determined the expression of all known MAGE-A subgroups (MAGE-A1 to MAGE-A12, excluding pseudogene MAGE-A7) by reverse transcription quantitative polymerase chain reaction. Of note, one cell line showed only a marginal expression of MAGE-A antigens, whereas another cell line showed a distinct expression of almost all the MAGE-A subgroups. The expression pattern varied in the other cell lines. MAGE-A4 was the most highly expressed of all the subgroups, and MAGE-A8 could not be detected. With the exception of MAGE-A6, -A8, -A9 and -A10, the expression levels differed significantly between the cell lines. Factor analysis suggested simplifying the MAGE-A expression level into two groups. Spearman's rank correlation revealed a significant association between MAGE-A expression and treatment efficacy for 20.8% (25/120) of the experiments. In 100% of these cases (25/25), Spearman's Rho revealed a positive correlation between clustered MAGE-A expression and poor treatment efficacy. Our data highlight the fact that higher a MAGE-A expression correlates with a poorer outcome of antineoplastic treatment. Clustered MAGE-A expression analysis may help to identify patients who are at a higher risk of antineoplastic treatment failure.