Exceptional response to neoadjuvant capecitabine and temozolomide in TSC2-mutant pancreatic neuroendocrine tumor

Abstract

Tuberous Sclerosis 1/2 (TSC1/2) functions as a negative regulator of the mammalian target of rapamycin (mTOR) pathway, one of the key oncogenic pathways described in neuroendocrine neoplasm (NEN) carcinogenesis. While loss-of-function mutations in TSC1/2 lead to disinhibition of mTOR and uncontrolled cellular growth and proliferation, they concomitantly result in p53 sensitivity which manifests functionally as sensitivity to DNA damage. Here we report a case of a 57-year old male patient with a well-differentiated pancreatic NEN (PanNEN) who underwent neoadjuvant chemotherapy with capecitabine and temozolomide and achieved a near-complete pathologic response. The unusual response prompted further tumor characterization with next-generation sequencing which demonstrated a previously uncharacterized mutation in TSC2. We hypothesize that the TSC2 mutation may have contributed towards the exceptional response to the DNA damaging alkylating agent-based chemotherapy regimen. Furthermore, this case warrants the evaluation of alkylating agent-based chemotherapy regimens in NENs harboring mutations in mTOR pathway negative regulators such as TSC1/2.

Keywords

• Neuroendocrine neoplasm
• Alkylating agent
• Temozolomide
• Tuberous sclerosis-1/2
• Mammalian target of rapamycin