3666 Background: Neuroendocrine carcinoma (NEC) is a rare and aggressive subtype of colorectal cancer (CRC), often arising in association with poorly differentiated adenocarcinoma. Two histologic subtypes, small cell NEC (SCNEC), and large cell NEC (LCNEC), have been described; however, how these subtypes differ, and whether they share molecular origins with the adenocarcinoma component in mixed adenocarcinoma and neuroendocrine carcinoma (MANEC) tumors, remain unclear. Better characterization of the genomic alterations driving NECs is needed to clarify disease biology and improve outcomes. Methods: We identified 125 patients with NEC of the colon and rectum who received care at Memorial Sloan Kettering Cancer Center. All patients underwent tumor profiling using the institutional targeted sequencing platform MSK-IMPACT. For 11 patients with MANEC, the adenocarcinoma and NEC components were sequenced separately. Results: Among 125 patients, 33 had SCNEC, 50 had LCNEC, and 42 had histologic features intermediate between SCNEC and LCNEC. 62% of patients presented with stage IV disease, and NEC was enriched at metastatic sites in MANEC cases. Clinical outcomes were poor across all groups, with a median survival of 11 months for stage IV patients (9.5m for SCNEC, 11m for LCNEC). SCNEC was more commonly observed in the rectum and genomically characterized by frequent RB1 loss (70%), with a smaller subset harboring PTEN loss (24%). Notably, TP53 mutations were identified in 58% of the cases, lower than the frequency observed in sporadic advanced CRC. In contrast, LCNEC was more often right sided, associated with an adenocarcinoma component and genomically enriched for MYC amplification (28%) and BRAF mutations (38%). We found that MYC amplification frequently occurred on extrachromosomal DNA, as confirmed by both FISH and shallow whole genome sequencing. Based on genomic alterations, 21of the 42 (50%) unclassified cases could be assigned a histologic subtype. A subset of NECs lacked known neuroendocrine associated genomic alterations and are being investigated further. In 11 MANEC cases with separately sequenced components, RB1 loss and MYC amplification were restricted to the neuroendocrine component, supporting a causal role in neuroendocrine differentiation and clonal evolution from adenocarcinoma. Across the cohort, PIK3CA (6%) and SMAD4 (9%) mutations were less frequent than expected and were absent in the NEC component of MANEC cases. DLL3 expression was evaluated in a small subset and was positive in some SCNECs but not in LCNEC. Conclusions: SCNEC and LCNEC represent clinically and genomically distinct subtypes of colorectal NEC. For NECs that cannot be classified based on histology alone, genomic profiling should be used to aid classification. Ongoing studies aim to validate our genomic findings above and to model the biology of NEC to identify more effective therapeutic strategies.
Xue et al. (Wed,) studied this question.