No abstract

Oral squamous cell carcinoma (OSCC) is a very aggressive cancer, representing one of the most common malignancies worldwide. Oral potentially malignant disorders (OPMDs) regroup a variegate set of different histological lesions, characterized by the potential capacity to transform in OSCC. Most of the risk factors associated with OSCC are present also in OPMDs’ development; however, the molecular mechanisms and steps of malignant transformation are still unknown. Treatment of OSCC, including surgery, systemic therapy and radiotherapy (alone or in combination), has suffered a dramatic change in last years, especially with the introduction of immunotherapy. However, most cases are diagnosed during the advanced stage of the disease, decreasing drastically the survival rate of the patients. Hence, early diagnosis of premalignant conditions (OPMDs) is a priority in oral cancer, as well as a massive education about risk factors, the understanding of mechanisms involved in malignant progression and the development of specific and more efficient therapies. The aim of this article is to review epidemiological, clinical, morphological and molecular features of OPMDs, with the purpose to lay the foundation for an exhaustive comprehension of these lesions and their ability of malignant transformation and for the development of more effective and personalized treatments.

Despite the progress of surgery, radiotherapy, and neoadjuvant chemotherapy, the prognosis for advanced sinonasal cancers (SNCs) remains poor. In the era of precision medicine, more research has been conducted on the molecular pathways and recurrent mutations of SNCs, with the aim of understanding carcinogenesis, helping with diagnosis, identifying prognostic factors, and finding potentially targetable mutations. In the treatment of SNC, immunotherapy is rarely used, and no targeted therapies have been approved, partly because these tumors are usually excluded from major clinical trials. Data on the efficacy of targeted agents and immune checkpoint inhibitors are scarce. Despite those issues, a tumor-agnostic treatment approach based on targeted drugs against a detected genetic mutation is growing in several settings and cancer subtypes, and could also be proposed for SNCs. Our work aims to provide an overview of the main molecular pathways altered in the different epithelial subtypes of sinonasal and skull base tumors, focusing on the possible actionable mutations for which potential target therapies are already approved in other cancer types.

Olfactory neuroblastoma (ONB) is a rare sinonasal neoplasm with a peculiar behavior, for which limited prognostic factors are available. Herein, we investigate the transcriptional pathways altered in ONB and correlate them with pathological features and clinical outcomes. We analyze 32 ONB patients treated with curative intent at two independent institutions from 2001 to 2019 for whom there is available pathologic and clinical data. We perform gene expression profiling on primary ONB samples and carry out functional enrichment analysis to investigate the key pathways associated with disease-free survival (DFS). The median age is 53.5 years; all patients undergo surgery and a pure endoscopic approach is adopted in the majority of cases (81.2%). Most patients have advanced disease (stages III–IV, 81.2%) and 84.4% undergo adjuvant (chemo)radiotherapy. The median follow-up is 35 months; 11 (26.8%) patients relapse. Clinical characteristics (gender, stage and Hyams’ grade) are not associated with the outcomes. In contrast, TGF-beta binding, EMT, IFN-alpha response, angiogenesis, IL2-STAT5 and IL6-JAK-STAT3 signaling pathways are enriched in patients experiencing recurrence, and significantly associated with shorter DFS. Clustering of transcriptional profiles according to pathological features indicates two distinct molecular groups, defined by either cytokeratin-positive or -negative immunostaining. Definition of the characterizing ONB transcriptomic pathways may pave the way towards tailored treatment approaches.

9520 Background: In LA/M cSCC patients (pts), immunotherapy with pembrolizumab (P) and cemiplimab showed an overall response rate (ORR) of 34-49%, with durable antitumor activity. However, primary and acquired resistance represents a therapeutic challenge. In cSCC, monotherapy with cetuximab (C) showed promising signs of activity (ORR 28%), but with limited duration of response. This study aims at reverting P resistance by adding C, leveraging on its mechanism of action in reducing immune escape process. Methods: I-TACKLE is an open-label, nonrandomized, phase II trial in pts with LA/M cSCC conducted in 3 Italian centers. Eligible pts had LA/M cSCC not manageable with surgery or radiation and with ECOG PS= 0 or 1. They received intravenous P 200 mg every 3 weeks. In case of partial (PR) or complete response (CR), pts continued to receive P alone. In case of stable disease (SD) or progression (PD), pts received C (400 mg/sm loading dose, then weekly 250 mg/sm) in addition to P until progression. The primary endpoint was cumulative ORR by single agent or by combination strategy; safety, PFS (since start of P and P+C), OS and duration of response (DOR) were secondary endpoints. Results: Between May 2019 and April 2021, 43 pts were enrolled and treated with P. Table 1 depicts population baseline features. The median follow up was 24 (range 7-30) months. Twenty-three pts underwent the combination treatment (17/23 due to PD and 6/23 due to SD); 21 of them due to primary resistance and 2 because of acquired resistance. Median treatment exposure was 3 and 4 months to P and combination therapy, respectively. Cumulative ORR was 63% [95% confidence interval 48-77], including 19/43 (44%) pts with response to P and 8/21 (38%) with response to combination strategy after primary resistance to P. Both pts experiencing an acquired resistance to P obtained PR when C was introduced. Overall, 10/23 pts (44%) obtained a response to combination therapy. Median DOR and OS were not reached both with P alone and with P+ C. One-year PFS was 51% with P alone and 42% with P+C. Overall, grade 3-4 treatment-related adverse events occurred in 7/43 (16%) pts during treatment with P and 8/23 (35%) pts during P+C, mostly dermatitis 7/23 (30%). Three out of 43 (7%) pts discontinued treatment because of toxicity, one pancreatitis, one impaired renal function and one for worsening of clinical condition, all during treatment with P. Four patients died during treatment, due to PD. Conclusions: In LA/M cSCC, the addition of C to P reverts primary and acquired resistance, with manageable toxicities. The sequential approach deserves to be studied in future clinical trials. Clinical trial information: NCT03666325. [Table: see text]