Tsai, Susan

Importance Neoadjuvant therapy (NT) is an increasingly used treatment strategy for patients with localized pancreatic ductal adenocarcinoma (PDAC). Little research has been conducted on cancer care delivery during NT, and the standards for optimal delivery of NT have not been defined. Objective To develop consensus best practices for delivering NT to patients with localized PDAC. Design, Setting, and Participants This study used a modified Delphi approach consisting of 2 rounds of voting, and a series of virtual conferences (from October to December 2023) to reach expert consensus on candidate best practice statements generated from a systematic review of the literature and expert opinion. An interdisciplinary panel was formed including 47 North American experts from surgical, medical, and radiation oncology, radiology, pathology, gastroenterology, integrative oncology, anesthesia, pharmacy, nursing, cancer care delivery research, and nutrition as well as patient and caregiver stakeholders. Main Outcome and Measures Statements that reached 75% agreement or greater were included in final consensus statements. Results Of the 47 participating panel members, 27 (57.64%) were male, and the mean (SD) age was 47.6 (8.2) years. Physicians reported completing training a mean (SD) 14.6 (8.6) years prior and seeing a mean (SD) 110.6 (38.4) patients with PDAC annually; 35 (77.7%) were in academic practice. Final consensus was reached on 82 best practices for delivering NT. Of these, 38 statements focused on pre-NT practices, including diagnosis and staging (n = 15), evaluation and optimization (n = 20), and decision-making (n = 3); 29 statements defined best practices during NT, including initiation (n = 3), delivery of therapy (n = 8), restaging practices (n = 12), and management of complications during NT (n = 6); and 15 best practices were identified to guide treatment post-NT, focusing on surgery (n = 7), pathology (n = 4), and follow-up (n = 3). Conclusions Using a modified Delphi consensus technique, best practice guidelines were developed focusing on the optimal standards for delivering NT to patients with localized PDAC. Given the prognostic importance of completing multimodality therapy, efforts to standardize and optimize the delivery of NT represent an immediate opportunity to decrease care variation and improve outcomes for patients with PDAC. Future research should focus on validating and implementing best practice standards into clinical practice.

3053 Background: Recently, early studies have identified circulating stromal cells (CStCs), i.e. Cancer Associated Macrophage-Like cells (CAMLs), in patients (pts) with newly diagnosed invasive cancers, which are phagocytic myeloid immune cells emanating from primary tumors. However, no study has evaluated CAMLs as a pan solid tumor screening tool nor their clinical impact on pt outcomes. We analyzed the blood of untreated newly diagnosed cancer pts (n=441), or in non-malignant conditions (i.e. pancreatic cysts, n=77), or healthy controls (n=100). We found that CAMLs are prevalent (82%) in cancer pt blood, absent in healthy controls (0%) and less common in non-malignant conditions (36%), with correlations to worse clinical outcomes. Methods: Anonymized peripheral blood was taken from n=441 pts before or after confirmation of invasive malignancy [stage I (n=105), stage II (n=125), stage III (n=114), stage IV (n=97) with pathologically confirmed lung (n=84), pancreas (n=61), breast (n=73), prostate (n=65), esophageal (n=34), Renal Cell (n=29), Sarcoma (n=27), or Other (n=68). In addition, anonymized blood was taken from pts with untreated non-malignant conditions including benign breast masses (n=19), Lupus (n=11), liver Cirrhosis (n=6), rising PSA (n=24), or other benign mass (n=17); and from healthy control volunteers (n=100). CAMLs were isolated by CellSieve microfiltration, defined as enlarged polyploid cells with cytokeratin+ and/or CD45/CD14+. Pts were monitored for 0-8 years (median=2.6) for progression free survival (PFS) and overall survival (OS). Results: CAMLs were found in 82% of all cancer pts averaging 5.4 CAMLs, specifically, in 66% of Stage I, 85% Stage II, 84% Stage III, and 92% Stage IV. No CAMLs were found in any healthy controls, but were in 36% of non-malignant pts. CAML sensitivity in cancer vs healthy was 82% (CI95% 78-85%), specificity=100% (CI95% 96-100%), PPV=100% (CI95% 99-100%), NPV=55% (CI95% 50-60%). CAML sensitivity in cancer vs benign was 82% (CI95% 78-85%), specificity=64% (CI95% 32-44%), PPV=93% (CI95% 90-95%), NPV=38% (CI95% 32-44%). CAML presence was significantly associated with worse PFS (HR=2.0, 95%CI 1.4-2.9, p<0.0001) & OS (HR=2.2, 95%CI 1.4-3.3, p=0.0004), with engorged phagocytic CAMLs (>50um), highly significant for worse PFS (HR=3.3, 95%CI 2.5-4.5, p<0.0001) & OS (HR=3.0, 95%CI 2.1-4.3, p<0.0001). Further, in benign pts positive for CAMLs, 2 pts were in situ, 16 had histologies with increased cancer risk (i.e. IPMN, atypical hyperplasia), and 5 pts died within 3 years. Conclusions: CAMLs appear to be a highly sensitive blood based biomarker that can identify invasive carcinoma in all stages of cancer regardless of subtype, but are not found in healthy controls & rare in non-malignant conditions. Further, enlarged phagocytic CAMLs appeared to correlate with shorter PFS and OS prior to treatment induction.

e16260 Background: Therapeutic inhibition of constitutive signaling mediated by mutated KRAS in PDAC remains a challenge except for modest success reported with KRAS G12C inhibition. A combinatorial strategy utilizing simultaneous MEK and autophagy inhibition holds therapeutic promise based on mechanism of action and preclinical data. We described characteristics and outcomes of patients (pts) treated with MEK-inh and HCQ at our institution. Methods: Ten KRAS-mutated advanced PDAC pts were treated with trametinib-HCQ (n = 9) or cobimetinib-HCQ (n = 1) off label due to lack of standard treatment options or toxicity concerns with cytotoxic systemic therapy. Trametinib dose was 2 mg once daily orally, Cobimetinib dose was 20 mg BID orally for 3/4 weeks cycles. HCQ was started at 200 mg BID and up-titrated weekly to 600 mg BID. Description of baseline and treatment (tx) characteristics, safety and efficacy is provided. Results: Median age at diagnosis was 61.3 years, and 7 pts were female. The number of prior lines of tx were 0/1/2/3/4 in 3/2/1/2/2 pts, respectively. KRAS mutations were: G12R/G12D/G12V/Q61H in 6/2/1/1 pts. Median overall survival was 6.6 months (m) in all pts, and 6.6/1.7 m in KRAS G12R/other KRAS (p = 0.31). Median progression-free survival was 5.7/6.2/1.5 m in all/ KRAS G12R/other KRAS (p = 0.16). Among 8 pts with evaluable response, 1 (12%) had partial response ( KRAS G12R) and 4 (50%) stable disease (3/4 KRAS G12R) as best response with disease control rate of 63%/80%/33% in total/ KRAS G12R/other KRAS (p = 0.29). Toxicity data are summarized in table 1. Conclusions: MEK-inh-HCQ demonstrated modest efficacy and manageable toxicities among KRAS G12R PDAC pts. Unlike G12D and G12V mutations in the KRAS gene, G12R is defective of conductive interactions for both PI3Ka and NF1. This ultimately results in a weakened signal being shunted through MAPK cascade and provides a unique opportunity where MEK inh can ablate signaling without the alternate pathways and WT-RAS isoforms compensating. Furthermore, as activation of PI3Ka is known to suppress autophagy, its lack of activation by KRAS G12R further sensitizes cells to HCQ. The combination therapy MEK-inh-HCQ is therefore mechanistically-rationale and warrants the further investigation of KRAS G12R as an actionable biomarker.[Table: see text]

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]

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]

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]

3535 Background: Peripheral blood allows for a simple non-invasive method for isolating various cancer associated circulating stromal cells (CStCs) which may predict for cancer presence. Cancer Associated Macrophage-Like cells (CAMLs), a specific CStC, are phagocytic myeloid cells that derive from an immunological response to cancer and emanate from primary tumors. Using a filtration platform we screened the peripheral blood of untreated newly diagnosed cancer patients (n = 308) for CAMLs. In parallel, we screened patients with newly diagnosed non-malignant diseases, i.e. lupus, benign cysts, etc. (n = 39), and healthy control samples (n = 76). We found that CAMLs are highly prevalent (87%) in the blood of cancer patients, but uncommon in non-malignant conditions (20%) & absent in healthy individuals (0%). Methods: Anonymized peripheral blood were taken from 308 cancer patients after confirmation of invasive malignancy [stage I (n = 76), stage II (n = 73), stage III (n = 72), stage IV (n = 65) and unstaged non-metastatic (n = 22)] with pathologically confirmed lung (n = 65), pancreas (n = 53), breast (n = 52), prostate (n = 40), esophageal (n = 30), renal cell (n = 18), hepatocellular (n = 15), neuroblastoma (n = 10), melanoma (n = 8), and other (n = 17). Further, anonymized blood was taken from patients with untreated non-malignant conditions including benign breast masses (n = 19), lupus (n = 11), liver cirrhosis (n = 5), benign prostatic hyperplasia (BPH) (n = 3), and viral infection (n = 1); or from healthy control volunteers (n = 76). CAMLs were isolated from whole peripheral blood by the CellSieve™ microfiltration technique and defined as enlarged, multinuclear cells with cytokeratin and/or CD45/CD14 positive. Results: CAMLs were found in 87% of all cancer patients regardless of stage, ~5.4 CAMLs/7.5mL blood. Specifically, CAMLs were found in 80% of Stage I, 90% Stage II, 89% Stage III, and 97% Stage IV patients. No CAMLs were found in any healthy controls, but were found in 26% of benign breast masses, 18% of lupus, 0% of BPH and 0% of cirrhosis. In total, CAML sensitivity in cancer vs healthy was 87% (CI95% 82-90%), specificity = 100% (CI95% 95-100%), PPV = 100% (CI95% 100%), NPV = 67% (CI95% 58-71%). CAML sensitivity in cancer vs benign was 87% (CI95% 82-90%), specificity = 80% (CI95% 64-91%), PPV = 97% (CI95% 95-98%), NPV = 43% (CI95% 35-51%). Conclusions: CAMLs, a Circulating Stromal Cell subtype, is a sensitive blood based biomarker found in all stages of cancer that is rare in non-malignant conditions and absent in healthy individuals.

11503 Background: Cancer Associated Macrophage-Like cells (CAMLs) are a recently described circulating stromal cell subtype commonly found in the peripheral blood of patients in all stages of solid malignancies and in a variety of cancer subtypes. However, while their biological association to cancer is being studied, their clinical utilization as it relates to cancer prognosis has not been evaluated. Methods: A two year prospective study was undertaken to evaluate the relationship of CAMLs and overall survival (OS) in 6 solid tumor types. The single blind multi-institutional study consisted of 269 stage I-IV patients; breast (n = 57), esophageal (n = 21), prostate (n = 43), pancreatic (n = 59), lung (n = 54), and renal cell (n = 35), in treatment (n = 134) and untreated baseline (n = 135). 7.5mL of whole blood was filtered by CellSieve microfiltration assay and CAMLs enumerated, as previously described. Patients were grouped by CAML number ( < 6 or ≥6) and by size ( < 49 or ≥50 µm) to evaluate hazard ratios (HR) by censored univariate & multivariate analysis. Results: CAMLs were identified in 93% of samples, averaging 8.2 CAMLs/7.5mL blood sample, and found in all 6 cancers at baseline and during treatment. Average CAML number was associated with disease stage and CAML positivity was 4.4 & 80% (Stage I), 4.7 & 93% (Stage II), 9.3 & 98% (Stage 3), 12.1 & 97% (Stage IV). Univariate analysis of patients (n = 269) stratified by ≥6 CAMLs had reduced OS (HR = 1.8, 95%CI 1.1-2.9, p = 0.03). Further, CAML size also had reduced OS in patients with ≥50 µm CAMLs (HR = 2.7, 95%CI 1.8-4.0, p < 0.0001). Conclusions: Our data suggests that in solid malignancies, CAML number and size appear to clinically correlate with OS in early and late stage disease. Given these results relating CAMLs with OS, further analysis is warranted to determine if CAMLs can serve as a clinically-relevant blood-based marker.