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<p>Recently, the first case of a novel <i>DEK</i>-<i>AFF2</i> fusion has been identified in nonkeratinizing squamous cell carcinoma (SCC) of the sinonasal tract with an exceptional response to pembrolizumab. Here we present the case of a 71-year-old female with metastatic poorly differentiated SCC of the sinonasal cavity with a <i>DEK</i>-<i>AFF2</i> fusion. She initially received pembrolizumab monotherapy as first-line treatment, but the disease progressed after two months. Subsequent treatment with paclitaxel plus cetuximab also led to disease progression after two months. She was enrolled in the SCRUM-Japan MONSTAR-SCREEN-2, a nationwide molecular profiling project. Tumor tissue samples were analyzed using whole exome and transcriptome sequencing (WETS). WETS of a pretreatment tissue specimen revealed <i>DEK</i>-<i>AFF2</i> fusion and <i>APC</i> pathogenic variant (p.G1677fs), and HLA genotype HLA-A*02:06/24:02, HLA-B*39:04/54:01, and HLA-C*01:02/07:02. Third-line therapy with 5-FU, carboplatin, and pembrolizumab achieved a partial response, but disease progression occurred after nine months. In tissues obtained from pancreatic metastases, acquired amplification of <i>MYC</i> (copy number 8.7) was detected in addition to <i>DEK</i>-<i>AFF2</i> fusion and <i>APC</i> mutation. These findings suggest that the lack of benefit from pembrolizumab despite the presence of <i>DEK</i>-<i>AFF2</i> fusion may be due to the HLA haplotype being different from one reported to be associated with efficacy. Additionally, acquired <i>MYC</i> amplification may contribute to resistance to chemotherapy and pembrolizumab. These findings underscore the importance of personalized treatment strategies in SCC patients with specific genomic alterations.</p>

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Resistance mechanism to pembrolizumab in DEK-AFF2 fusion-associated sinonasal squamous cell carcinoma

  • 期刊论文

  • 发表日期：

    2025年8月20日

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  • Shogen Boku,
  • Takao Fujisawa,
  • Shigenori Kadowaki,
  • Hironaga Satake,
  • Hisateru Yasui,
  • Koushiro Ohtsubo,
  • Yasushi Shimizu,
  • Tomoyuki Otsuka,
  • Bunya Kuze,
  • Riu Yamashita,
  • Taro Shibuki,
  • Yoshiaki Nakamura,
  • Hideaki Bando,
  • Takayuki Yoshino,
  • Milan Radovich,
  • Susumu Okano

摘要

Recently, the first case of a novel DEK-AFF2 fusion has been identified in nonkeratinizing squamous cell carcinoma (SCC) of the sinonasal tract with an exceptional response to pembrolizumab. Here we present the case of a 71-year-old female with metastatic poorly differentiated SCC of the sinonasal cavity with a DEK-AFF2 fusion. She initially received pembrolizumab monotherapy as first-line treatment, but the disease progressed after two months. Subsequent treatment with paclitaxel plus cetuximab also led to disease progression after two months. She was enrolled in the SCRUM-Japan MONSTAR-SCREEN-2, a nationwide molecular profiling project. Tumor tissue samples were analyzed using whole exome and transcriptome sequencing (WETS). WETS of a pretreatment tissue specimen revealed DEK-AFF2 fusion and APC pathogenic variant (p.G1677fs), and HLA genotype HLA-A*02:06/24:02, HLA-B*39:04/54:01, and HLA-C*01:02/07:02. Third-line therapy with 5-FU, carboplatin, and pembrolizumab achieved a partial response, but disease progression occurred after nine months. In tissues obtained from pancreatic metastases, acquired amplification of MYC (copy number 8.7) was detected in addition to DEK-AFF2 fusion and APC mutation. These findings suggest that the lack of benefit from pembrolizumab despite the presence of DEK-AFF2 fusion may be due to the HLA haplotype being different from one reported to be associated with efficacy. Additionally, acquired MYC amplification may contribute to resistance to chemotherapy and pembrolizumab. These findings underscore the importance of personalized treatment strategies in SCC patients with specific genomic alterations.