Chakrabarti, Sakti

656 Background: Non-neutropenic enterocolitis (NNEC), a potentially fatal toxicity of capecitabine (CAPE), is under-reported in the literature. An institutional review was performed to determine the incidence, clinical course, and outcome of patients developing CAPE-induced NNEC. Methods: After the institutional review board approval, a database search identified patients requiring inpatient care for CAPE-induced diarrhea over a period of 6 years (between 01/2015 and 12/2020). Among the patients requiring hospital admission, patients with radiologic features of enterocolitis were included in the analysis. Data on patient characteristics, imaging study results, clinical course, and outcomes were gathered by electronic chart review. Results: Among the 789 patients treated with CAPE, 25 patients (3%) developed grade 3 or higher diarrhea requiring hospital admission, and 13 out of these 25 patients (1.6 % of patients treated with CAPE) had evidence of enterocolitis on CT scan: ileitis in 7/13 (54%), colitis in 1/13 (8%), and both in 5/13 (38%) patients. The median age of the patient cohort was 64 years (range, 31-81), 8/13 (62%) were female, and all patients were Caucasian. CAPE was administered for the following indications: breast cancer in 6 patients, colorectal cancer in 4 patients, cholangiocarcinoma in 2 patients, and neuroendocrine tumor in 1 patient. ECOG performance status at the time of CAPE initiation was 0 in 7 patients and 1 in 6 patients. Most patients (7/13, 54%) received single-agent CAPE, and the majority (10/13, 77%) developed diarrhea with the first cycle after a median of 21 days (range, 10-50). Patients were hospitalized after a median of 27 days (range, 13-51), and the median hospital stay was 12 days (range, 4-25). None of the 13 patients demonstrated neutropenia at the time of hospital admission. The associated adverse effects at the time of admission included grade 3 abdominal pain in 8 (62%) patients, grade 3 nausea in 7 (54%) patients, and grade 3 vomiting in 3 (23%) patients. Hypokalemia and oral mucositis were present at admission in 6 (46%) and 2 (15%) patients, respectively. Stool studies performed in 11 (85%) patients ruled out infection. Testing for dihydropyrimidine dehydrogenase deficiency performed in 4 (31%) patients was negative. All patients were treated with supportive measures, and 2 (15%) patients required total parenteral nutrition. All but 1 patient recovered fully; 1 patient died due to a condition unrelated to CAPE. Intravenous infusional 5-fluorouracil (5-FU) administration in 3 patients after the recovery was tolerated well. Conclusions: CAPE-induced NNEC is uncommon and generally occurs after the first cycle of therapy. Most patients developing CAPE-induced NNEC recover fully with appropriate supportive measures. Infusional 5-FU-based regimens appear to be safe in this patient group.

607 Background: Immunotherapy (IO) is known to have robust anti-tumor activity in patients with MSI-H solid tumors. However, clinical trials investigating IO activity have used tissue-based testing to determine MSI-H status. Pancreatic tumor biopsy often does not provide sufficient tumor tissue for MSI testing. We investigated if the MSI-H status detected by plasma-based circulating tumor DNA (ctDNA) testing predicts robust response to IO in patients with PC. Methods: Genomic results from a well-validated plasma-based ctDNA assay (Guardant360[G360]) performed as part of routine clinical care between October 1, 2018 and September 7, 2021 in patients with PC were queried to identify patients with MSI-H tumors. Patient characteristics, tumor characteristics, treatment details, and outcomes were reported by ordering clinicians where available. The data cut-off date was September 1, 2021. Results: A total of 52 patients with PC who had MSI-H tumors on G360 were identified. Clinical outcomes data were available for 10/52 (19%) patients who were included for analysis. This patient cohort had a median age of 68 years (range: 56-82); 80% were male and 80% of patients had metastatic disease. 9/10 patients received IO: 3 in the first-line, 3 in the second-line, 3 in the third-line setting; most received pembrolizumab (8/9) while 1 received ipilimumab plus nivolumab. The median duration of IO was 8 months (range: 1-24). The overall response rate was 77% (7/9) and 6 of the 7 responders continue to show response at the time of data cut-off after a median follow-up of 21 months (range:11-33). The median progression-free survival and overall survival were not reached in the IO-treated cohort. Tissue-based MSI testing results were concordant with plasma-based G360 results in 5 of 6 patients (83%) who had tissue-based test results available. The patient with the discordant result was MSI-H by G360 but had intact mismatch repair protein expression by immunohistochemistry. This patient received neoadjuvant IO followed by surgery and the resected specimen confirmed pathological complete response. Conclusions: The detection of MSI-H status by plasma-based ctDNA testing is highly concordant to tissue-based testing and predicts robust and durable response to IO in patients with PC. The use of a well-validated plasma-based ctDNA analysis may expand the identification of MSI-H tumors in patients with PC and enable treatment with IO resulting in improved outcomes.

596 Background: Genomic alterations (GA) that drive cancer development and predict therapeutic response remain elusive in patients (pts) with KRAS WT PDAC. We interrogated our institutional database to identify actionable GAs in pts with metastatic, KRAS WT PDAC and analyzed the therapeutic impact of matched TT. Methods: We reviewed electronic medical records of KRAS WT PDAC pts (n=24) who underwent comprehensive genomic profiling (CGP) utilizing Foundation One CDx (25.0%) or Tempus (75.0%) between 2015-2021. Duration of response (DOR) was calculated from date of treatment (Tx) initiation to Tx discontinuation. Overall survival (OS) was measured from the date of the diagnosis (Dx) of advanced disease (AD) to death or last follow-up. OS was estimated using the Kaplan-Meier method, with at-risk periods left-truncated at the time of CGP. The effect of covariates on survival was evaluated using Cox proportional hazards regression. Results: Of the 24 KRAS WT pts, 14 (58%) had AD: 8 (57%) pts had metastatic disease at or shortly after Dx, 6 (43%) pts developed metachronous recurrence. Median age at Dx for pts with AD was 65, and 57% were female. Seven of 14 pts with AD (50%) had highly actionable GA (HAGA), (Table). Pts with HAGA demonstrated durable responses to TT (Table) with manageable toxicities. Pts with HAGA had a median OS of 28 mo compared to 5.9 mo for those without (Hazard Ratio = 0.47, p = 0.33). Conclusions: The sustained therapeutic benefit noted with TT matched to HAGA in pts with KRAS WT PDAC underscores the need for systematic interrogation of the somatic genome in PDAC pts. Optimal sequencing of cytotoxic therapy with TT and its impact on modulating clonal selection pressure in pts with KRAS WT PDAC merits prospective evaluation.[Table: see text]

474 Background: FLO is a rare variant of liver cancer that disproportionately affects young adults and is frequently progressive and fatal as it is often detected in a clinically advanced stage. It is seldom associated with cirrhosis of liver, viral hepatitis or other risk factors associated with conventional HCC. Treatment options are largely limited to surgical resection, and there is dearth of effective targeted therapies for FLO. Methods: Comprehensive genomic profiling (CGP) was performed using the Foundation Medicine Inc. (FMI) data base on 63 FLO and 1,793 HCC clinically advanced cases between 6/2013-12/2020 using a hybrid capture-based assay of up to 324 genes a to detect genomic alterations (GA), tumor mutational burden (TMB) and microsatellite instability (MSI). PD-L1 expression in tumor cells (Dako 22C3) was measured by IHC and scored using the tumor proportion score (TPS) method. Results: The FLO patients (pts) were significantly younger than HCC pts (median age 20 vs. 64, respectively) and the male preponderance was similar. The HCC group featured significantly more GA/tumor than FLO group (3.74 vs 1.31 p<.0001). In the currently untargetable GA group, CTNNB1, TERT and TP53 GA were significantly more frequent in HCC than FLO. GA in potentially targetable genes were extremely uncommon in both FLO and HCC with HCC featuring slightly more MTOR pathway targets ( PTEN, TSC2, NF1). GA in DNA damage and repair (DDR) pathway including BRCA2 were infrequent in both groups. GA in targetable kinases including EGFR, ERBB2, ALK, RET and PIK3CA were extremely uncommon in both groups. GA associated with intrahepatic cholangiocarcinoma (IDH1, FGFR2) were extremely uncommon in these tumors. Although the mean TMB was significantly higher in HCC than FLO, overall TMB was low with very few cases having TMB > 10 mutations/Mb. PD-L1 expression was relatively low in both groups. GA in genes associated with immune checkpoint inhibitors (ICPI) drug response like PBRM1, CD274, MDM2, STK11 were rarely identified in both groups. Additional details are illustrated in the table. Conclusions: Comparison of CGP of FLO with HCC illustrates the multifarious nature of these cancers. In HCC, there is a high prevalence of GA in TERT, CTNNB1 and TP53. CGP identified certain targetable GA in the MTOR and DDR pathways and TMB was higher in HCC. These findings warrant further evaluation of clinically advanced FLO and HCC pts by CGP to identify possible targetable genomic pathways. [Table: see text]

248 Background: Esophageal carcinoma is the 6th most common cause of death worldwide. While squamous cell carcinoma (SCC) was the most common among the histologic subtypes in the 20th century, recent reports have demonstrated an increased incidence of adenocarcinoma in both Eastern and Western world. With this changing paradigm of esophageal carcinoma, it is important to estimate the future burden of esophageal carcinoma by histology, age, sex, and race, that could help plan prevention, control, and treatment strategies for this cancer. Methods: We used Surveillance, Epidemiology, and End Results (SEER) 14 registries to obtain incidence data from 2000 to 2016. We applied age-period-cohort models to estimate future esophageal carcinoma incidence rates and the estimated disease burden by multiplying incidence forecasts by corresponding US Census population projections. Results: Our estimate suggests that the incidence (per 100,000 persons) of esophageal adenocarcinoma is increasing in people within the age group of 40-65 years. Our prediction showed that the incidence will increase from 2.12 in 2021 to 2.82 in 2030 (3.2% per year, 95% CI –2.3% to 9.1%, p=0.26). Notably, we noticed a similar marginal increase in incidence among Asians, Black, and Whites in the 40-65 years age group (3.1%, 3.2%, and 4.2%, per year, respectively). White males aged >65 years had the highest incidence of esophageal adenocarcinoma (17.34 in 2021), and incidence decreased 1.3% per year. We noticed a marginally decreased incidence in Black male (-1.1% per year, p=0.71) and Asian male (-3.9% per year, p=0.17) population aged >65 years. Interestingly, we found a decrease in the incidence of SCC in the current age groups 40-65 (-2.7% per year, p=0.31) and >65 years (-4.6% per year, p=0.081). We observed that Asians had the greatest decrease in incidence (-4.3% per year) as compared to that of Blacks (-4.2% per year) and Whites (-2.9% per year), although there was no statistically significant difference in the annual decrease among races. Conclusions: In our study of esophageal cancer, we predict an increased incidence of adenocarcinoma histology subtype in the younger age group (40-65 years) while the SCC subtype will have a decreased trend. Strategies to prevention esophageal adenocarcinoma, including dietary changes, should preferentially target patients <65 years of age.[Table: see text]

191 Background: Somatic alterations in KRAS and BRAF have prognostic as well as predictive impact in pts with mCRC; however, the differential impact of various somatic alterations in these genes need further characterization. We analyzed the prognostic impact of specific somatic mutations in K RAS and BRAF in mCRC pts. Methods: We retrospectively reviewed the electronic medical records of pts with mCRC at our institution who underwent comprehensive genomic profiling (CGP) utilizing the Foundation One assay. Prevalence of genetic alterations was estimated using proportions and compared between groups using a chi-squared test. Patients were followed for survival from metastatic diagnosis until death or last follow-up, with left truncation at the time of CGP. Kaplan-Meier estimates were used to estimate overall survival, and groups were compared using a Cox-regression based likelihood ratio test. Results: 192 pts were identified - median age at diagnosis was 55 years, 62% (119/192) presented with metachronous metastatic disease, and 28% (54/192) had a rectal primary. Somatic mutations in KRAS were found in 49% (95/192) pts, and 53% (50/95) had a left sided primary (p = 0.3). Majority of the KRAS mutations localized to codon 12 (72/95 -76%), KRAS G12C comprised 12% (11/95). Median Overall Survival (mOS) of KRAS mutated pts was 3.0 years compared to 3.5 years for KRAS wild type (WT) pts (p = 0.5). Median OS of pts with different KRAS mutations were as follows: codon 12 mutations (excluding G12C) - 2.7 years; KRAS G12C – 5.2 years; non-codon 12 KRAS mutations - 4.8 years. BRAF mutations were identified in 7.8% (15/192) pts, and 67% (10/15) had a right sided primary (p = 0.062). BRAF V600E represented the most common alteration in BRAF – 87% (13/15). Patients with BRAF mutation had a mOS of 1.8 years compared to 3.1 years for BRAF WT pts (p = 0.2). Median OS of pts with different BRAF mutations were as follows: BRAF V600E – 1.8 years and BRAF non V600E - 2.1 years (p = 0.4). Conclusions: The numerically higher mOS in pts with KRAS G12C and non-codon 12 KRAS mutations merit further biologic characterization with functional assays. Individualized therapeutic strategies must be conceptualized for mCRC pts with specific RAS/BRAF mutations, considering their widely disparate prognosis and putative downstream signaling mechanisms. Dynamic molecular simulation to understand conformational changes in proteins associated with specific mutations will be pivotal to optimizing precision therapeutic strategies.

44 Background: Despite an alarming rise in incidence, data on survival outcome and treatment response of young-onset (age < 50 years) locally advanced rectal cancer (YO-LARC) patients receiving total neoadjuvant therapy (TNT) are sparse. We retrospectively compared the outcome between YO-LARC and later-onset (aged 50 years or older) LARC (LO-LARC) patients treated with TNT. Methods: After the institutional review board approval, electronic medical records of the LARC (T3/T4 or node-positive) patients treated with TNT at a tertiary care cancer center between January 1, 2015, and June 30, 2020, were reviewed for data collection. TNT consisted of systemic chemotherapy with oxaliplatin-based regimens for 16 weeks followed by long-course radiation with concurrent capecitabine or 5-fluorouracil (CRT). Patients receiving only preoperative CRT were excluded. Most patients underwent surgical resection following the TNT. Non-operative management was offered to patients if TNT resulted in clinical complete response (cCR). The following comparisons between the YO-LARC and the LO-LARC patients were performed: patient characteristics, pathological complete response (pCR) rate, combined pCR + cCR rate, disease-free survival (DFS), and overall survival (OS). Results: Of 72 patients included in the analysis, 44(61%) were male, 49 (68%) were Caucasian, and 62 (86%) had clinical stage III disease. The study included 26 (36%) patients with YO-LARC (median age, 43 years) and 46 (64%) patients with LO-LARC (median age, 64 years). The comparison of patient characteristics that included gender, clinical stage, baseline carcinoembryonic antigen level, the distance of the tumor from the anal verge, presence of high-risk features, and histologic grade did not differ significantly between the groups. There were no statistically significant differences in pCR and combined pCR+cCR rates (p = 0.16) between the groups: YO-LARC, 12 % (3/26) and 15 % (4/26), respectively; LO-LARC, 22% (10/46) and 30% (14/46), respectively. Either group did not reach median DFS and OS after a median follow-up of 38 months for survivors. The estimated 5-year OS rates in patients with YO-LARC and LO-LARC were 86 % (95% confidence interval [CI], 69% to 100%) and 84% (95% CI, 68% to 100%), respectively (p = 0.92). The estimated 3-year DFS rates in patients with YO-LARC and LO-LARC were 67 % (95% CI, 50% to 89%) and 83% (95% CI, 72% to 95%), respectively (p = 0.19). Conclusions: The current retrospective analysis did not demonstrate significant differences in the pCR rates, combined pCR +cCR rates, DFS, or OS between the YO-LARC and LO-LARC patients treated with TNT.

4136 Background: The genomic alterations which characterize PDAC holds great promise for novel therapeutic interventions. Constitutive signaling via mutated KRAS is considered the signature pathognomonic alteration in PDAC, less than 10% of patients (pts) have tumors which are KRAS wild type (WT). We retrospectively reviewed our institutional genomic database to characterize PDAC pts with KRAS WT tumors. Methods: We reviewed electronic medical records of PDAC pts who underwent comprehensive genomic profiling (CPG) utilizing Foundation One CDx (50.6%) or TEMPUS (49.4%) between 2015-2020. Demographic and disease characteristics were compared between cohorts using Wilcoxon rank-sum test or chi-square tests. Left truncation at the time of CGP was used to account for the time of entry into the study cohort. Kaplan-Meier method was used for survival curve estimation, and log-rank test was used for between-group comparison. Cox regression was used to adjust for confounders. Results: We identified 235 patients: median age at diagnosis was 65 years and 52% were male. Clinical stages at diagnosis were localized (resectable/borderline resectable), locally advanced, or metastatic in 105 (44.7%), 61 (26.0%), and 69 (29.4%) patients, respectively. KRAS status was mutated in 212 (90%) patients: the most common alterations being G12D (48%), G12V (28%) and G12R (14%). KRAS WT status was noted in 23 (9.8%) pts, actionable genomic alterations in this subgroup are summarized in the table. Baseline demographic and treatment characteristics were similar between patients with KRAS mutated and WT tumors. Of the 23 patients with KRAS WT tumors, 16 (69.6%) completed all planned curative intent therapy compared to 121 (57.3%) of the 212 KRAS mutated pts (p=0.26). Median Overall Survival of patients with KRAS mutated tumors was 18.6 months compared to 44.1 months for WT pts (p=0.03). Adjusting for stage, WT vs. mutated status was associated with a 62% decreased hazard of death (HR 0.38 [0.18-0.83]; p=0.016). Conclusions: Patients with KRAS WT PDAC appear to have a distinct biology compared to those with KRAS mutations, meriting exploration in larger data sets. Further, comprehensive whole genome or transcriptomic characterization of KRAS WT tumors is necessary to identify putative driver alterations as well as actionable therapeutic targets.[Table: see text]

AbstractThrough our involvement in KEYNOTE‐059, we unexpectedly observed durable responses in two patients with metastatic gastroesophageal adenocarcinoma (mGEA) who received ramucirumab (anti‐VEGFR‐2)/paclitaxel after immune checkpoint inhibition (ICI). To assess the reproducibility of this observation, we piloted an approach to administer ramucirumab/paclitaxel after ICI in more patients, and explored changes in the immune microenvironment. Nineteen consecutive patients with mGEA received ICI followed by ramucirumab/paclitaxel. Most (95%) did not respond to ICI, yet after irRECIST‐defined progression on ICI, all patients experienced tumor size reduction on ramucirumab/paclitaxel. The objective response rate (ORR) and progression‐free survival (PFS) on ramucirumab/paclitaxel after ICI were higher than on the last chemotherapy before ICI in the same group of patients (ORR, 58.8% vs 11.8%; PFS 12.2 vs 3.0 months; respectively). Paired tumor biopsies examined by imaging mass cytometry showed a median 5.5‐fold (range 4‐121) lower frequency of immunosuppressive forkhead box P3+ regulatory T cells with relatively preserved CD8+ T cells, post‐treatment versus pre‐treatment (n = 5 pairs). We then compared the outcomes of these 19 patients with a separate group who received ramucirumab/paclitaxel without preceding ICI (n = 68). Median overall survival on ramucirumab/paclitaxel was longer with (vs without) immediately preceding ICI (14.8 vs 7.4 months) including after multivariate analysis, as was PFS. In our small clinical series, outcomes appeared improved on anti‐VEGFR‐2/paclitaxel treatment when preceded by ICI, in association with alterations in the immune microenvironment. However, further investigation is needed to determine the generalizability of these data. Prospective clinical trials to evaluate sequential treatment with ICI followed by anti‐VEGF(R)/taxane are underway.

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]