Khan, Abdul H.

431 Background: Patients (pts) with localized PC do not routinely undergo comprehensive genomic profiling (CGP) unless they develop recurrent or metastatic disease. KRAS is the most frequently mutated gene in PC, however, the impact of different KRAS mutations in localized PC has not been well characterized. We interrogated our genomic database to analyze the KRAS status in PC pts who presented with localized disease at diagnosis (Dx). Methods: We identified PC pts at our institution who underwent CGP utilizing the Foundation One CDx assay and had localized disease at initial Dx; these pts were categorized into resectable/borderline resectable PC (LPC) and locally advanced PC (LAPC). All pts with LPC and LAPC underwent neoadjuvant chemotherapy and chemoradiation prior to possible surgery (all intended therapy - AIT). Tissue from metastatic sites was used for CGP in pts who developed recurrent/metastatic disease before or after completion of AIT. The primary tumor was used for CGP in pts who completed AIT without subsequent relapse or in the absence of adequate metastatic tissue. Effect of each gene on response and survival outcomes was estimated using proportional odds and Cox regression analysis, respectively, adjusting for stage. Results: 75 pts were identified, median age at Dx was 65 years, 59% were male, 65% had a primary tumor in the pancreatic head. 38 (86%) pts with LPC completed AIT compared to 21 (68%) pts with LAPC (p<0.001). KRAS mutation was detected in 95% (71/75) of pts– 94% (67/71) in codon 12 and 6% (4/71) in codon 61. The various KRAS mutations and their association with completion of AIT is summarized in the table. The likelihood of completing AIT did not differ based on KRAS wildtype (WT) vs mutated status (p =1.00), the mutated codon (codon 12 vs. codon 61; p =1.00) or the individual KRAS point mutations (p = 0.7); however, all patients with G12A (N= 1), G12C (N=1), G12L (N=1) and G12R (N=11) mutations completed AIT. KRAS status (mutated vs. WT) and the individual KRAS mutations were not associated with overall survival (OS) after adjusting for stage (p= 0.13 and p = 0.26 respectively). Median OS for patients with LPC and LAPC, was 39 months (mos) and 29 mos respectively. Conclusions: KRAS status and individual KRAS mutations did not have an impact on completing AIT or mOS; however, these findings need to be interpreted with caution due to the inherent biases involved in such analyses. The clinical significance and functional relevance of KRAS G12A, G12C, G12L and G12R mutations, though relatively rare, needs further characterization as well as mechanistic elucidation. [Table: see text]

231 Background: Both peri-operative chemotherapy and neoadjuvant chemoradiation have been shown to improve outcomes in patients (pts) with LA-GEJ CA compared to surgery alone. Rates of post-operative chemotherapy delivery remain suboptimal. Total neo-adjuvant therapy (TNT) in LA-GEJ CA - induction chemotherapy (IC) followed by concurrent chemoradiation (CRT) - may improve systematic delivery of neoadjuvant therapy and result in favorable clinical outcomes. Methods: We retrospectively reviewed medical records of 135 pts with LA-GEJ CA at our institution between 2/2007 and 11/2019; pertinent clinical data were abstracted with Institutional Review Board approval. Patients treated with IC and curative-intent CRT with ≥40 Gy dose of radiation for adenocarcinoma were included in this analysis (N = 59). Doublet or triplet IC regimens utilizing 5-Flurouracil(5-FU), Cisplatin/Oxaliplatin and Docetaxel were commonly administered while combinations of Carboplatin +Paclitaxel or 5-FU + Oxaliplatin were used in CRT. Clinical complete response (CCR) was defined as metabolic imaging and endoscopic biopsies negative for residual malignancy after completion of TNT. Patients were followed from diagnosis to recurrence and overall survival. Survival probabilities were estimated using the Kaplan-Meier method and compared between groups using a log-rank test. Results: Out of 59 evaluable pts, 69% were clinical stage T3, 71% were node positive. 37 pts (63%) underwent surgery, R0 resection rate was 89% (33/37), pathologic complete response (pCR) rate was 19% (7/37). Among the pts who did not undergo surgery, 41% (9/22) opted to forego surgery since they attained a CCR. For the entire cohort, median Disease-Free Survival (mDFS), median Overall Survival (mOS), and 3-yr OS were 2.4 yrs, 4.7 yrs, and 67% respectively. Pts who did not undergo surgery had a mDFS, mOS, and 3-yr OS of 1.5 yrs, 4.2 yrs, and 59% respectively. Median DFS, mOS, and 3-yr OS of patients who underwent surgery were 3.5 yrs, 5.8 yrs and 72% respectively. Patients who achieved a CCR and opted to forego surgery (N = 9) had a 3 -yr DFS of 42% vs 83% for pts (N = 7) who demonstrated a pCR after curative intent tri-modality therapy. (P = 0.0099) Interestingly, the same group that achieved CCR and opted out of surgery had 3yr OS of 89% vs 83% of those who demonstrated a pCR (p = 0.0042). Conclusions: TNT for pts with LA-GEJ CA is associated with high rates of R0 resection as well as excellent DFS and OS compared to historical controls, warranting prospective evaluation. The remarkable DFS and OS in patients who opted to forego surgery due to achieving CCR is reflective of the local and systemic control rendered by this approach. Careful characterization and close longitudinal follow-up of patients who achieve CCR may help identify a subgroup of LA-GEJ CA pts who may benefit from surgery sparing approaches.