High-Frequency Targetable EGFR Mutations in Sinonasal Squamous Cell Carcinomas Arising from Inverted Sinonasal Papilloma

Abstract

Inverted sinonasal papilloma (ISP) is a locally aggressive neoplasm associated with sinonasal squamous cell carcinoma (SNSCC) in 10-25% of cases. To date, no recurrent mutations have been identified in ISP or SNSCC. Using targeted next generation sequencing and Sanger sequencing, we identified activating EGFR mutations in 88% of ISP and 77% of ISP-associated SNSCC. Identical EGFR genotypes were found in matched pairs of ISP and associated SNSCC, providing the first genetic evidence of a biological link between these tumors. EGFR mutations were not identified in exophytic or oncocytic papillomas or non-ISP-associated SNSCC suggesting that the ISP/SNSCC spectrum is biologically distinct among sinonasal squamous tumors. Patients with ISP harboring EGFR mutations also exhibited an increased progression-free survival compared to those with wild-type EGFR. Finally, treatment of ISP-associated carcinoma cells with irreversible EGFR inhibitors resulted in inactivation of EGFR signaling and growth inhibition. These findings implicate a prominent role for activating EGFR mutations in the pathogenesis of ISP and associated SNSCC and rationalize consideration of irreversible EGFR inhibitors in the therapy of these tumors.

Sinonasal squamous cell carcinoma and EGFR mutations: a molecular footprint of a benign lesion

“…This finding in NSCLC raises the question of whether the frequency of EGFR mutations in SNSCC may differ among ethnic groups. However, the distribution of EGFR mutations is different between SNSCC and NSCLC; most EGFR mutations are exon 20 insertion mutations in SNSCC but are exon 19 deletion mutations or L858R point mutations in NSCLC . No differences in the frequency of NSCLC with EGFR exon 20 insertion mutations have been observed between Asian and Caucasian patients .…”

Malignant transformation of sinonasal inverted papilloma and related genetic alterations: a systematic review

“…Fibroblast growth factor receptor-1 (FGFR1) amplification is a recently described common and tractable event in squamous cell lung cancer and adenocarcinoma of the breast [8,9,43]. Functional studies have shown that inhibition of FGFR1 with a molecule inhibitor leads to a significant reduction of tumor cell numbers in FGFR1-amplified SCC cell line of the lung [43].…”

“…Functional studies have shown that inhibition of FGFR1 with a molecule inhibitor leads to a significant reduction of tumor cell numbers in FGFR1-amplified SCC cell line of the lung [43]. Patients with FGFR1-amplified cancers are currently being treated with FGFR-inhibitors, in phase 1 clinical trials.…”

“…An important study about epidermal growth factor receptor-1 (EGFR) mutations was recently published by Udager et al [43]. The authors identified activating EGFR mutations in 88% of SNIPs and 77% of SNIP-associated sinonasal SCCs.…”

The role of systemic therapy in the management of sinonasal cancer: A critical review

“…Next-generation sequencing recently suggested that EGFR mutations is detectable in the majority of patients with sinonasal SCC related to Inverted Sinonasal Papilloma (ISP). Since identical genotypes were found in matched pairs of ISP and their associated SNSCC, these findings strongly pointed to a biologic link between these tumors [12]. Clinically relevant activating genomic mutations in selected genes were not identified in a series of SNUC, underlining the importance and complexity of a more comprehensive evaluation in such a disease [13].…”