MOHAMED, AMR

The classification and management of neuroendocrine neoplasms (NENs) arising in the tubular gastrointestinal (GI) tract and pancreas have significantly evolved over the last decades. In the latest WHO classification published in 2022, NEN are separated regardless of their primary origin into two main groups: well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). The substantial changes in grading system changed the definition of grade 3 to include high grade well differentiated NETs (G3-NETs), and poorly differentiated NECs (-NECs). Although, these two subgroups are considered high grades with Ki-67 >20%, they have different genomic profiles, prognosis and clinical behavior which critically influence their treatment strategies. The available clinical trial data to guide therapy of these high-grade subgroups are extremely limited which impact their management. In this review, we will summarize the current advances in the multidisciplinary approach for management of high grade GEP-NENs including G3-NETs and NECs.

759 Background: BRAF V600E mutations are present in 5-10% of patients with advanced colorectal cancer (CRC) and associated with poor prognosis. Recently, there was tumor agnostic FDA approval of dabrafenib + trametinib for BRAF V600E mutated solid tumors. However, the frequency of BRAF alterations ( BRAF alt), especially non-V600E, in other gastrointestinal (GI) cancers are not well described. This study characterizes BRAF alt in CRC vs other GI cancers (non-CRC). Methods: De-identified records from 51,560 patients diagnosed with GI cancers were retrospectively analyzed from the Tempus database. The molecular landscape including presence of pathogenic/likely pathogenic BRAF alt was evaluated by panel-based tissue DNA, RNA or ctDNA NGS sequencing (Tempus Labs, Inc.). The frequency of BRAF alt, co-mutations, MSI, TMB and MMR were compared between CRC and (non-CRC) by Chi-squared/Fisher’s Exact or Wilcoxon rank-sum tests. False-discovery rate correction was used for multiple testing. Results: BRAF alt were identified in 8.9% of CRC and 2.2% of non-CRC cohort. BRAF alt frequency varied by tumor type with the highest observed in colon (11%), jejunum (9.6%), intrahepatic bile duct (5.3%), rectal (4.5%), and ampulla of vater (4.5%) and lower in esophageal (0.9%) and gastric (1.6%). BRAF alt CRC had higher frequency of females (57% vs 45%, p <0.001) and older age at diagnosis (67 vs 66 yrs, p=0.029) compared to non-CRC group. Race was also significantly different, with white patients being more predominant in both groups (85% CRC,77% non-CRC). Among the BRAF alt, fusions (12% vs 2.2%, p <0.001) and amplifications (3.1% vs 0.3%, p <0.001) were higher in non-CRC vs CRC (Table). BRAF V600E was most common in all GI tumors, but higher in CRC vs non-CRC (75% vs 27%, q<0.001). Mutations higher in non-CRC vs CRC (q<0.009) included class II (G469A, K601E, BRAF-SND1, and BRAF amplification) and class III (D594N & N581S) BRAF alt. BRAF co-occurring mutations in CRC were TP53 (70%), APC (42%), RNF43 (30%), SMAD4 (22%), and PIK3CA (21%), and in non-CRC: TP53 (52%), CDKN2A (32%), CDKN2B (20%) SMAD4 (17%) and MTAP (16%). Among tissue samples, MSI-H (30% vs 4.%, p <0.001) and TMB-H ≥10 mut/MB (32% vs 6.7%, p <0.001) were more frequent in BRAF alt CRC vs non-CRC. Conclusions: Meaningful differences were found between the groups in terms of demographics, frequency, and type of BRAF alt and co-occurring mutations. In particular, certain BRAF fusions were present in a higher proportion of other GI cancers and could be an important therapeutic target for this patient population.[Table: see text]

736 Background: Patients with dMMR/MSI-H gastrointestinal (GI) cancer occasionally receive neoadjuvant immunotherapy (NIT) due to various clinical considerations. To systematically evaluate the outcome of these patients, we initiated the DREAM-GI national database, intending to harness real-world data to provide crucial insights into the outcomes, safety profile, and response patterns of dMMR/MSI-H GI cancer patients undergoing NIT. Herein, we present the initial findings. Methods: We developed a centralized database to collect de-identified clinical data from patients with dMMR/MSI-H GI cancers receiving NIT. We collected data retrospectively and prospectively through September 15, 2023. Results: The current report includes 50 patients with a median age of 67 years (range 32 to 90); 21 (42%) were female, 9 (18%) were Black, and the remaining were White. The cohort included the following tumor types- 31 (62%) colorectal, 7 (14%) gastroesophageal, and 12 (24 %) pancreaticobiliary. Most patients had localized disease (34, 68%), while the rest had oligometastatic disease. NIT consisted of pembrolizumab monotherapy in 40 (80%) patients, ipilimumab plus nivolumab in 8 (16%), and nivolumab plus chemotherapy in 2 (4%) patients. Most patients, 33 (66%), were treatment-naive. The median duration of NIT was 6 months (range: 1.5 to 55), with a time to best response of 3 months (range: 1.5 to 12). Among 47 evaluable patients, the best responses were as follows: an overall response rate of 75% (35/47), consisting of radiologic complete response (CR) in 20 (43%), pathologic CR in 4 (9%), and partial response in 11 (24%). The median progression-free survival and overall survival were not reached after a median follow-up of 14 months (range: 2-80), calculated from the date of the first immunotherapy dose to the last follow-up or death. Among 24 patients achieving CR, all remained progression-free after a median follow-up of 25.5 months (range: 3-80). Stable and progressive diseases were observed in 7 (15%) and 5 (10%) patients, respectively. Only 5 (10%) patients underwent surgery following NIT, with 4 (80%) achieving pathologic CR. The reasons for not proceeding with surgery were comorbidities in 40 (80%) patients, disease extent in 4 (8%), and patient refusal in 1 (2%). Out of the 12 patients who expired at the data cut-off, 1 was due to immunotherapy-related pneumonitis, 6 due to disease progression, and the remainder from underlying comorbidities. Conclusions: Our study underscores the remarkable response rates and durability of responses achieved with NIT in patients with dMMR/MSI-H GI cancers. Progression on NIT was infrequent. These real-world data support further investigation into non-operative approaches for patients with dMMR/MSI-H GI cancers.