Molecular characterization of gastro-entero-pancreatic advanced mixed adeno-neuroendocrine carcinomas: NIRVANA sub-study

Gastro-entero-pancreatic (GEP) mixed adeno-neuroendocrine carcinomas (MANECs) are rare and aggressive neoplasms with a very poor prognosis and their molecular features are still not properly addressed. Our aim is to evaluate clinical, pathological, and biomolecular data of patients with GEP-MANEC in order to identify prognostic and predictive factors which could potentially correlate with clinical outcomes. This cohort of patients is derived from a larger retrospective - prospective observational dataset of patients with pure or mixed extra-pulmonary (EP) high grade neuroendocrine neoplasms. We reviewed clinical and pathological data of advanced GEP-MANECs managed at our Institute between 2015 and 2021 with available surgical/biopsy specimens. All the tumor tissues were tested for 26 genes by next-generation sequencing (NGS) using a targeted multi-genes NGS panel both in neuroendocrine and non-neuroendocrine component. Descriptive analyses will be performed. Primary and secondary endpoints are descriptive in nature, therefore no formal statistical hypotheses were pre-specified. The study is approved by IEO Ethical Committee. Among 55 high grade neuroendocrine neoplasms, 7 patients with GEP-MANEC resulted eligible. The primary sites were: 2 rectum, 1 appendix, 1 caecum, 1 stomach, 1 gallbladder. Almost all cases showed at least one somatic mutation in > 5% of the tissue. The most frequently mutated genes were KRAS and TP53 (4/7 patients) in both components. Other genes, including PI3K and RB1 were mutated, only in one case and only in the NEC component. All MANECs showed TP53 mutation in NEC and non-NEC component. Five out of seven (71%) received at least one line of chemotherapy, mostly represented by cis/carbo-platinum-based regimens. Among them, 4 patients (80%) received a second-line therapy, mainly irinotecan-containing, and then a 3-line therapy (2 capecitabine/temozolomide). Although low numbers, these preliminary data seem to suggest that the carcinogenesis of the MANECs of the GEP tract relies on its biomolecular features and site of origin. Specific targetable alterations indicate a high potential for personalized treatments. The study is ongoing.