Organotropic and genomic characterization of pancreatic neuroendocrine carcinoma.

Abstract

4172 Background: Pancreatic neuroendocrine carcinoma (PNEC) is a rare, aggressive malignancy. Neuroendocrine carcinomas (NEC) of other primary sites, such as small cell lung cancer (SCLC), have a propensity to metastasize to the brain. Incidence of brain metastases in PNEC is poorly characterized, and most staging recommendations for extrapulmonary NEC do not include routine brain imaging. We evaluated the incidence of brain metastases in PNEC, identified factors associated with brain metastases, and characterized the genomic profile of PNEC. Methods: We reviewed the genomic profile of patients with PNEC, pancreatic ductal adenocarcinoma (PDAC), SCLC, and pulmonary large cell neuroendocrine carcinoma (LCNEC), who underwent next generation sequencing (NGS) at Memorial Sloan Kettering Cancer Center (MSKCC). We queried the Surveillance, Epidemiology, and End Results (SEER) database to identify all cases of metastatic PDAC and small cell or large cell PNEC diagnosed 2010-2022. We performed multivariable logistic regression to identify demographic and clinical factors associated with brain metastases. We used chi-squared testing to compare metastatic site frequency between tumor types. Results: The SEER query identified 412 cases of metastatic PNEC and 60,668 cases of metastatic PDAC with documented site of metastasis at diagnosis. Compared to PDAC, PNEC had higher rates of metastasis to the brain (8% vs 0.8%, p<0.001), bone (16% vs 9%, p<0.001), and distant lymph nodes (15% vs 8%, p<0.001) but lower rates to the lung (19% vs 25%, p=0.03). The incidence of liver metastases was similar in both tumor types (88% vs 87%). Within the PNEC cohort, lung metastasis was positively associated with brain metastasis (odds ratio [OR] 5.4, 95% confidence interval [CI] 2.4-12.5, p<0.001), but liver metastasis was negatively associated with brain metastasis (OR 0.2, 95% CI 0.1-0.5, p<0.001). The presence of brain metastases did not impact overall survival. Twenty eight patients with PNEC underwent NGS at MSKCC, including 12 with mixed ductal-neuroendocrine carcinoma or mixed acinar-neuroendocrine carcinoma. TP53 alterations were common (>50%) in all tumor types. RB1 alterations were seen frequently in SCLC (78%), PNEC (54%), and LCNEC (24%), but not in PDAC (2%). KRAS alterations were highly prevalent in PDAC (84%), uncommon in SCLC (3%), and with intermediate frequency in PNEC (36%). Conclusions: We found a high incidence of brain metastasis in PNEC, especially in patients with lung metastases, supporting neuroimaging in many patients with this disease. The strong association between lung and brain metastases is also noted in breast cancer, possibly explained by sequential seeding or shared features driving organotropism to these organs. PNEC demonstrated genomic features of both PDAC and SCLC. More research is needed to determine how these genomic features can inform management practices in individual patients.