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Recent advances in small cell lung cancer (SCLC) treatments necessitate a better understanding of real-world health utility scores (HUS) in patients treated under current standards to facilitate robust pharmaco-economic assessments.In this single institution cohort observational study, HUS were evaluated in patients with SCLC through EQ-5D questionnaires at outpatient visits (encounters). In addition, patients completed questionnaires relating to treatment toxicities and cancer symptoms. Clinical and pathological variables were abstracted from electronic medical records and disease status at each patient visit was documented. The impact of these variables on HUS were explored.There were 282 clinical encounters (12% newly diagnosed; 37% stable on treatment; 22% progressing on treatment; 29% stable off therapy/other) in 111 SCLC patients (58% male; 64% extensive stage (ES) SCLC). At the first encounter 29% of patients had an ECOG performance status (PS) ≥ 2. ES-SCLC, bone metastases, female sex, progressive disease and/or PS were each significantly associated with decreased HUS in multivariable analyses. Patients clinically stable on first line therapy had generally steady HUS longitudinally, with differences in HUS between limited disease (LD) and ES patients emerging as treatment progressed. Decreased HUS were associated with increased severity of the majority of measured symptoms (fatigue/tiredness, loss of appetite, pain, drowsiness, shortness of breath, anxiety, depression, and overall well-being; each p0.001), supporting the value of EQ-5D-derived HUS in assessing health utility.Our HUS values in chemotherapy-treated SCLC are clinically relevant and are associated with specific clinico-demographic, symptom and toxicity factors.

Points cles L’incidence de l’adenocarcinome canalaire pancreatique (ACCP) est en hausse et selon les projections, il pourrait devenir la troisieme cause de deces par cancer au Canada[1][1]. Meme si on connait les facteurs de risque d’ACCP, la raison de cette incidence croissante est

Aims The aims of the study were to identify predictors of locoregional failure (LRF) following surgery for pancreatic adenocarcinoma, develop a prediction risk score model of LRF and evaluate the impact of postoperative radiation therapy (PORT) on LRF. Materials and methods A retrospective review was conducted on patients with stages I–III pancreatic adenocarcinoma who underwent surgery at our institution (2005–2016). Univariable and then multivariable analyses were used to evaluate clinicopathological factors associated with LRF for patients who did not receive PORT. The risk score of LRF was calculated based on the sum of coefficients of the predictors of LRF. The model was applied to the entire cohort to evaluate the impact of PORT on the high- and low-risk groups for LRF. Results In total, 467 patients were identified (median follow-up 22 months). Among patients who did not receive PORT (n = 440), predictors of LRF were pN+, involved or close ≤1 mm margin(s), moderately and poorly differentiated tumour grade and lymphovascular invasion. After adding patients who received PORT, the 2-year LRF in the high-risk group was 57% for patients who did not receive PORT (n = 242) and 32% among patients who received PORT (n = 22), with an absolute benefit to LRF of 25% (95% confidence interval 5–52%, P = 0.07). The 2-year overall survival for the high-versus the low-risk group was 36% versus 67% (P Conclusion This risk group classification could be used to identify pancreatic adenocarcinoma patients with higher risk of LRF who may benefit from PORT. However, validation and prospective evaluation are warranted.

While adjuvant treatment of colon cancers that penetrate the serosa (T4) have been well-established, neoadjuvant strategies have yet to be formally evaluated. Our objective was to perform a scoping review of eligibility criteria, treatment regimens, and primary outcomes for neoadjuvant approaches to T4 colon cancer. A librarian-led, systematic search of MEDLINE, Embase, Cochrane Library, Web of Science, and CINAHL up to 11 February 2020 was performed. Primary research evaluating neoadjuvant treatment in T4 colon cancer were included. Screening and data abstraction were performed in duplicate; analyses were descriptive or thematic. A total of twenty studies were included, most of which were single-arm, single-center, and retrospective. The primary objectives of the literature to date has been to evaluate treatment feasibility, tumor response, disease-free survival, and overall survival in healthy patients. Conventional XELOX and FOLFOX chemotherapy were the most commonly administered interventions. Rationale for selecting a specific regimen and for treatment eligibility criteria were poorly documented across studies. The current literature on neoadjuvant strategies for T4 colon cancer is overrepresented by single-center, retrospective studies that evaluate treatment feasibility and efficacy in healthy patients. Future studies should prioritize evaluating clear selection criteria and rationale for specific neoadjuvant strategies. Validation of outcomes in multi-center, randomized trials for XELOX and FOLFOX have the most to contribute to the growing evidence for this poorly managed disease.

Skeletal muscle mass is a prognostic factor in pancreatic ductal adenocarcinoma (PDAC). However, it remains unclear whether changes in body composition provide an incremental prognostic value to established risk factors, especially the Response Evaluation Criteria in Solid Tumors version 1.1 (RECISTv1.1). The aim of this study was to determine the prognostic value of CT-quantified body composition changes in patients with unresectable PDAC starting chemotherapy. We retrospectively evaluated 105 patients with unresectable (locally advanced or metastatic) PDAC treated with FOLFIRINOX (n = 64) or gemcitabine-based (n = 41) first-line chemotherapy within a multicenter prospective trial. Changes (Δ) in skeletal muscle index (SMI), subcutaneous (SATI), and visceral adipose tissue index (VATI) between pre-chemotherapy and first follow-up CT were assessed. Cox regression models and covariate-adjusted survival curves were used to identify predictors of overall survival (OS). At multivariable analysis, adjusting for RECISTv1.1-response at first follow-up, ΔSMI was prognostic for OS with a hazard ratio (HR) of 1.2 (95% CI: 1.08–1.33, p = 0.001). No significant association with OS was observed for ΔSATI (HR: 1, 95% CI: 0.97–1.04, p = 0.88) and ΔVATI (HR: 1.01, 95% CI: 0.99–1.04, p = 0.33). At an optimal cutoff of 2.8 cm2/m2 per 30 days, the median survival of patients with high versus low ΔSMI was 143 versus 233 days (p < 0.001). Patients with a lower rate of skeletal muscle loss at first follow-up demonstrated improved survival for unresectable PDAC, regardless of their RECISTv1.1-category. Assessing ΔSMI at the first follow-up CT may be useful for prognostication, in addition to routine radiological assessment. • In patients with unresectable pancreatic ductal adenocarcinoma, change of skeletal muscle index (ΔSMI) in the early phase of chemotherapy is prognostic for overall survival, even after adjusting for Response Evaluation Criteria in Solid Tumors version 1.1 (RECISTv1.1) assessment at first follow-up. • Changes in adipose tissue compartments at first follow-up demonstrated no significant association with overall survival. • Integrating ΔSMI into routine radiological assessment may improve prognostic stratification and impact treatment decision-making at the first follow-up.

Transcriptional classifiers (Bailey, Moffitt and Collison) are key prognostic factors of pancreatic ductal adenocarcinoma (PDAC). Among these classifiers, the squamous, basal-like, and quasimesenchymal subtypes overlap and have inferior survival. Currently, only an invasive biopsy can determine these subtypes, possibly resulting in treatment delay. This study aimed to investigate the association between transcriptional subtypes and an externally validated preoperative CT-based radiomic prognostic score (Rad-score).We retrospectively evaluated 122 patients who underwent resection for PDAC. All treatment decisions were determined at multidisciplinary tumor boards. Tumor Rad-score values from preoperative CT were dichotomized into high or llow categories. The primary endpoint was the correlation between the transcriptional subtypes and the Rad-score using multivariable linear regression, adjusting for clinical and histopathological variables (i.e., tumor size). Prediction of overall survival (OS) was secondary endpoint.The Bailey transcriptional classifier significantly associated with the Rad-score (coefficient = 0.31, 95% confidence interval [CI]: 0.13-0.44, p = 0.001). Squamous subtype was associated with high Rad-scores while non-squamous subtype was associated with low Rad-scores (adjusted p = 0.03). Squamous subtype and high Rad-score were both prognostic for OS at multivariable analysis with hazard ratios (HR) of 2.79 (95% CI: 1.12-6.92, p = 0.03) and 4.03 (95% CI: 1.42-11.39, p = 0.01), respectively.In patients with resectable PDAC, an externally validated prognostic radiomic model derived from preoperative CT is associated with the Bailey transcriptional classifier. Higher Rad-scores were correlated with the squamous subtype, while lower Rad-scores were associated with the less lethal subtypes (immunogenic, ADEX, pancreatic progenitor).• The transcriptional subtypes of PDAC have been shown to have prognostic importance but they require invasive biopsy to be assessed. • The Rad-score radiomic biomarker, which is obtained non-invasively from preoperative CT, correlates with the Bailey squamous transcriptional subtype and both are negative prognostic biomarkers. • The Rad-score is a promising non-invasive imaging biomarker for personalizing neoadjuvant approaches in patients undergoing resection for PDAC, although additional validation studies are required.

472 Background: The rates of gastric (GC) and esophageal adenocarcinoma (EA) among individuals younger than age 50 years have increased by 30% and 50%, respectively, over the past three decades in the US. There is limited information on incidence and demographics for EO esophageal and gastric cancer in Europe. Methods: We conducted a retrospective review of the prospectively maintained upper gastrointestinal (UGI) cancer database in St James’s Hospital (SJH), the National Centre for Oesophageal and Gastric Cancer in Ireland. We reviewed all cases diagnosed with esophageal cancer (EC) and gastric cancer (GC) less than or equal to 50 years of age from 2000 to 2021. Results: From 2000 to 2021, 374 EO EA & GC cases were identified, 8% of the 4663 total EC & GC cases. The results are presented in the table. Conclusions: The major presenting symptoms for EO-UGI cancer were dysphagia, weight loss and dyspepsia, further investigation is warranted in young patients presenting with these symptoms, even in the absence of elevated BMI or other known risk factors for malignancy. A high proportion have advanced disease at diagnosis despite good PS and clinical outcomes are poor. There is a critical need to understand the pathogenesis of EO-UGI cancers to determine optimal strategies for prevention and management.[Table: see text]

587 Background: Oncogenic driver mutations in KRAS represent a hallmark genomic event in approximately 90% of pancreatic adenocarcinoma (PDAC). For the remaining 10% of patients with KRAS wildtype (wt) PDAC, distinct driver mutations have been described, but their transcriptional landscape has not been reported. Here, we leverage sequencing data from the PanGen trial to provide a comprehensive characterization of advanced KRASwt PDAC. Methods: 63 patients with advanced PDAC received whole genome and transcriptome sequencing prior to treatment for metastatic disease as part of the PanGen trial (NCT02869802). Clinical features, somatic mutation data and gene expression patterns were compared between KRASwt and mutant groups. PDAC samples were contrasted with 77 other metastatic carcinoma (colorectal and cholangiocarcinoma) samples from the Personalized OncoGenomics trial (NCT0215562). KRAS wt-associated genes were further investigated using 3 additional PDAC cohorts (COMPASS NCT02750657, TCGA, and ICGC). Results: 9 of 63 (14%) samples were KRASwt, with an earlier median age at diagnosis (51.4 vs. 60.9 years; p=0.03). Clinical features, including diabetes, family history of malignancy, and location of primary tumor, were comparable. CA 19-9 at baseline was lower in the KRASwt group, with median 58 vs. 4900 U/mL in the KRAS-mutant group ( p=0.03). Patients with KRASwt PDAC showed increased overall survival in univariable ( p=0.0024) and multivariable ( p=0.0089) analyses. 6 of 9 (67%) KRASwt tumors had fusions involving NRG1 (n = 3), FGFR2 (n = 1), BRAF (n = 1) or NTRK2 (n = 1), while known actionable fusions were not observed in KRAS mutant patients. KRASwt tumors showed increased expression of genes associated with cholangiocytes and grouped with cholangiocarcinoma samples in unsupervised clustering analysis. Validation using three independent PDAC cohorts revealed a core set of 70 KRAS wt-associated genes that converge on keratinization, ion transport, and hormone metabolism pathways. Conclusions: Patients with KRASwt PDAC show potentially targetable molecular traits with actionable fusions. We also highlight novel mutation and expression-based similarities between KRASwt PDAC and cholangiocarcinoma samples. Recurrent dysregulation of genes involved in cellular structure and metastasis provide impetus for further investigation into the developmental trajectory and potential therapeutic vulnerabilities of KRASwt PDAC.

The aryl hydrocarbon receptor (AhR) is a sensor of products of tryptophan metabolism and a potent modulator of immunity. Here, we examined the impact of AhR in tumor-associated macrophage (TAM) function in pancreatic ductal adenocarcinoma (PDAC). TAMs exhibited high AhR activity and Ahr-deficient macrophages developed an inflammatory phenotype. Deletion of Ahr in myeloid cells or pharmacologic inhibition of AhR reduced PDAC growth, improved efficacy of immune checkpoint blockade, and increased intra-tumoral frequencies of IFNγ(+)CD8(+) T cells. Macrophage tryptophan metabolism was not required for this effect. Rather, macrophage AhR activity was dependent on Lactobacillus metabolization of dietary tryptophan to indoles. Removal of dietary tryptophan reduced TAM AhR activity and promoted intra-tumoral accumulation of TNFα(+)IFNγ(+)CD8(+) T cells; provision of dietary indoles blocked this effect. In patients with PDAC, high AHR expression associated with rapid disease progression and mortality, as well as with an immune-suppressive TAM phenotype, suggesting conservation of this regulatory axis in human disease.

TPS635 Background: Over 70% of patients with pancreatic ductal adenocarcinoma (PDAC) present with metastatic disease where the mainstay of treatment is combination chemotherapy. Two pivotal phase III trials showed survival benefit of mFOLFIRINOX (mFFX) and gemcitabine/nab-paclitaxel (GnP), respectively, compared to gemcitabine alone. Both are considered standard 1st line treatment options but have not been compared prospectively. Other than the BRCA phenotype there are no predictive molecular markers to identify which patients will benefit from mFFX versus GnP. Growing data suggests that RNA signatures and GATA6 expression may predict response to chemotherapy. Genomic platforms do identify small subsets of patients who may benefit from a targeted approach however, impact has been small. Patient-derived organoids (PDOs) are now feasible to passage for drug pharmacotyping that could inform drug therapy approaches. Combining all molecular strategies in real time including genomics, RNA signatures and adding PDO drug sensitivities could enable better precision choices for more patients with metastatic PDAC. Methods: PASS-01 is a multi-institutional randomized phase II trial evaluating the benefit of 1st line mFFX vs GnP in de novo metastatic PDAC patients with good PS who have undergone baseline tumor biopsies with tissue prepared for whole genome (WGS) and RNA sequencing and PDO generation/pharmacotyping using standard and novel drugs. The 10 objective is to determine the PFS benefit of mFFX compared to GnP as 1st line treatment with 80% power to detect a median PFS of 7 vs 5 months, favoring mFFX. 27 of a planned 150 patients have been accrued to date. Secondary endpoints include ORR (RECIST), DOR, OS by chemotherapy and biomarkers of therapy response including GATA-6 as a surrogate biomarker for the Moffit RNA classifier. Exploratory objectives include: to evaluate if each PDO DNA/RNA signature matches the patient and if the PDO chemotherapy sensitivities correlate to the patient’s 1st line response; to evaluate the benefit in switching patients to 2nd line treatment based on PDO drug sensitivity; to evaluate novel agents derived from PDO pharmacotyping and potential findings from profiling in 2nd/3rd line treatment; to explore retrospectively whether serial cell-free circulating tumor DNA analysis, circulating tumor cells and CA19.9 could reflect potential early predictors of emerging or de novo resistance and explore biomarkers of immune-oncologic sensitivity with multiplex immunohistochemistry. Each patient’s WGS and PDO data is discussed at a combined tumor board with study investigators immediately following their 1st 8-week CT and ongoing as data develops with the goal of recommending precision treatment choices back to their treating investigator. References: Conroy T et al. NEJM, 2011.; Von Hoff DD et al. NEJM,2013; Aung KL et al. CCR 2017; O’Kane G et al. CCR 2019; Tiriac H et al. Can Discov, 2018. Clinical trial information: NCT04469556.

469 Background: The Gustave Roussy Immune Score (GRIm-S) considers a composite of neutrophil to lymphocyte ratio (> 6 = 1), albumin (< 35 = 1) and LDH (> ULN = 1) and has been established as a prognostic score and may in aid in the selection of patients for phase 1 trials of immune checkpoint inhibitors. Methods: We explored the prognostic impact of the GRIm-S (high > 1) in patients enrolled on the COMPASS trial and correlated the score with genomic and clinical characteristics. Patients in this trial had biopsies for whole genomic and RNA sequencing prior to standard chemotherapy regimens in the advanced setting. Results: 252 patients were included in the analyses with a median follow-up time of 28 months. 16% of patients had a high GRIm-S with significantly shorter median overall survival (OS) of 4.1 months versus 10.0 months in those with a low score (HR 2.18, 95% CI 1.4-3.4, p < 0.0001). In the GRIm-S-high cohort, early progression with non-evaluable disease and disease progression were more common than in the GRIm-S low cohort (56% vs 31%, p = 0.003). In a multivariable analysis, a high GRIm-S was poorly prognostic (HR 1.6 95% CI 1.3-1.9, p < 0.001), whereas the classical RNA subtype (vs. basal-like) (HR 0.41, 95% CI 0.3-0.6, p < 0.001) and a high HRDetect score (HR 0.47 95% CI 0.3-0.7, p < 0.001) associated with superior OS. The GRIm-S did not correlate with RNA subtypes or with specific KRAS mutations. There were no differences in structural variant load or tumour mutational burden between groups. However those with a high GRIm-S did have a higher total target lesion diameter at baseline (p < 0.001). Conclusions: The GRIm-S identifies a subset of patients who have aggressive pancreas cancer and short life expectancy. This information may help clinicians in treatment decision making and selection for clinical trials.

Pancreatic adenocarcinoma (PDAC) remains a highly fatal disease that is increasing in incidence. PDAC can be classified according to resectability status with 3 nonmetastatic groups defined: resectable, borderline resectable, and locally advanced PDAC (LAPC). Delineating these subtypes is important with the optimal treatment approach dictated by high-quality CT imaging and multidisciplinary team discussion. Patients with LAPC are thought unresectable and are therefore rarely cured. In these patients, chemotherapy remains the mainstay of treatment. Aggressive approaches in this cohort are increasingly employed. Local therapies after induction chemotherapy including standard fractionation radiation, stereotactic body radiotherapy (SBRT), and irreversible electroporation (IRE) are being investigated in an attempt to improve long-term control. In some cases, responses to neoadjuvant therapy may facilitate surgical resection. Biomarkers that can select patients most likely to benefit from these options are urgently needed. This review aims to highlight the emerging treatment of patients with LAPC and to discuss current trials.

Intratumoral heterogeneity is a critical frontier in understanding how the tumor microenvironment (TME) propels malignant progression. Here, we deconvolute the human pancreatic TME through large-scale integration of histology-guided regional multiOMICs with clinical data and patient-derived preclinical models. We discover "subTMEs," histologically definable tissue states anchored in fibroblast plasticity, with regional relationships to tumor immunity, subtypes, differentiation, and treatment response. "Reactive" subTMEs rich in complex but functionally coordinated fibroblast communities were immune hot and inhabited by aggressive tumor cell phenotypes. The matrix-rich "deserted" subTMEs harbored fewer activated fibroblasts and tumor-suppressive features yet were markedly chemoprotective and enriched upon chemotherapy. SubTMEs originated in fibroblast differentiation trajectories, and transitory states were notable both in single-cell transcriptomics and in situ. The intratumoral co-occurrence of subTMEs produced patient-specific phenotypic and computationally predictable heterogeneity tightly linked to malignant biology. Therefore, heterogeneity within the plentiful, notorious pancreatic TME is not random but marks fundamental tissue organizational units.

Investigations of carcinogenesis have evolved from the identification of clonal driver mutations in candidate genes to the integration of large volumes of genomic and transcriptomic data revealing recurrently altered pathways and signatures of mutational processes. Inactivation of BRCA1, BRCA2, or PALB2 impairs efficient double-strand break repair (DSBR), giving rise to a spectrum of homologous recombination deficiency (HRD) cancer phenotypes. Harnessing HRD therapeutically has been promising in a number of tumors; these approaches include leveraging synthetic lethality by targeting alternative repair pathways via PARP inhibition, inducing HRD to modulate potential tumor vulnerabilities, and preventing mechanisms of drug resistance. It is therefore crucial to develop assays for accurate HRD detection and to broaden the patient population who can avail of novel treatment options.

Molecular profiling in advanced non-small cell lung cancer (NSCLC) has allowed for the detection of actionable mutations, which has revolutionized the treatment paradigm in this highly fatal disease. Mutations involving the epidermal growth factor receptor (EGFR) gene are most common and the 'classical mutations', exon 19 deletions and the point mutation L858R at exon 21, predict response to EGFR tyrosine kinase inhibitors (TKIs). The 'uncommon' EGFR mutations account for 10-18% of all EGFR mutations and primarily consist of exon 20 insertions, exon 18 point mutations and complex mutations. Improved detection techniques have broadened the spectrum of reported aberrations within the 'uncommon group' but response to TKIs is variable and not fully elucidated. This review provides an overview of the biology and incidence of uncommon EGFR mutations and summarizes reported outcomes when treated with EGFR-TKIs.

Reflex immunohistochemistry (rIHC) for mismatch repair (MMR) protein expression can be used as a screening tool to detect Lynch Syndrome (LS). Increasingly the mismatch repair‐deficient (dMMR) phenotype has therapeutic implications. We investigated the pattern and consequence of testing for dMMR in three Irish Cancer Centres (CCs). CRC databases were analyzed from January 2005–December 2013. CC1 performs IHC upon physician request, CC2 implemented rIHC in November 2008, and CC3 has been performing rIHC since 2004. The number of eligible patients referred to clinical genetic services (CGS), and the number of LS patients per center was determined. 3906 patients were included over a 9‐year period. dMMR CRCs were found in 32/153 (21%) of patients at CC1 and 55/536 (10%) at CC2, accounting for 3% and 5% of the CRC population, respectively. At CC3, 182/1737 patients (10%) had dMMR CRCs (P

396 Background: BRCA1/2 and PALB2 are genes critical to the faithful repair of double strand breaks through the homologous recombination repair (HRR) pathway. Alterations in these genes serve as predictive biomarkers to both platinum and PARP inhibitors. Ataxia-telangiectasia mutated ( ATM) is also indirectly involved in HRR; however, its role as a predictive biomarker to DNA damage response agents is debated. Herein we evaluated the genomic characteristics and clinical outcomes of patients with ATM alterations on the Comprehensive Molecular Characterization of Advanced Ductal Pancreas Adenocarcinoma for Better Treatment Selection (COMPASS) trial. Methods: Patients on this study undergo a biopsy for whole genome sequencing (WGS) and RNA sequencing prior to chemotherapy; those with germline variants in ATM were reviewed by a genetics counsellor and defined as pathogenic, likely pathogenic, variant of unknown significance (VUS) or benign/likely benign. Genomic characteristics were reviewed and published classifiers of homologous recombination deficiency (HRD) were applied to all cases and included the percentage of substitution base signature (SBS) 3, the HRDetect score, the computed algorithm of large scale transitions, telomeric allelic imbalances and loss of heterozygosity (LOH), otherwise known as the genomic instability score (GIS). Results: As of January 2020, 304 patients were enrolled and 245 patients had both WGS and clinical data available. 86 germline variants in ATM were present in 70 patients. The majority of these (80%) were classified as benign or likely benign. 10 VUS were detected and 4 patients (2%) had pathogenic/likely pathogenic variants (PV). Of these 4 patients, LOH or a second somatic hit was evident in 1 case. Upon review of the PVs and VUS, SBS were consistent with typical PDAC and tumour mutational burden was low. HRDetect scores were low ( < 0.1) for 13/14 cases with either a VUS or PV; one VUS without biallelic loss, had a high HRDetect score, with presence of SBS 3 and a high GIS. This particular case was also found to have a tandem duplicator phenotype. None of the 4 cases with PV had evidence of HRD. Furthermore all four were treated with platinum based regimens without evidence of response. Conclusions: In a large series of sequenced pancreatic cancers, the presence of pathogenic germline variants in ATM was rare, with none of the cases demonstrating evidence of HRD. This suggests that this population is unlikely to benefit from PARP inhibition.

430 Background: Familial pancreatic cancer (FPC) is broadly defined as kindreds with at least a pair of first-degree relatives with pancreatic ductal adenocarcinoma (PDA). The role of DNA damage response agents, including platinum has not been well studied in this patient population. Methods: In this retrospective analysis, treatment details and clinical outcomes were analyzed in pts with FPC with advanced, unresectable or recurrent disease enrolled in the Ontario Pancreatic Cancer Study database. The primary outcome, overall survival (OS) was calculated from the initial diagnosis of advanced disease until death. 179 non-FPC patients from the COMPASS trial [NCT02750657] served as a control cohort all of whom had full molecular profiling and family history documented. OS between pts that received platinum-based therapy, and those that did not was compared using multivariable Cox proportional hazards model adjusting for age, sex, diagnosis year and FPC status. Interaction between FPC status and platinum was evaluated. Results: A total of 205 FPC pts were identified, 71% of pts had full germline testing and 16 (8%) had germline pathogenic variants in BRCA1/2. 104 (51%) were female and 101 (49%) male. Median age was 63 years (20-93) and 58 (28%) received platinum-based chemotherapy. Within the control arm (n=179), 71 (40%) were female, and 108 (60%) male; the median age was 64 years (29-84) and 106 (59%) received platinum-based therapy. In univariable analysis, median OS in pts with FPC was 16.9 months compared to 9.6 months (HR 0.46 [95% CI 0.37-0.58]). FPC patients receiving platinum had a superior median OS of 19 months compared to 15.5 months without platinum. In a multivariable analysis, both FPC (HR 0.33 [95% CI 0.21-0.51]) and receipt of platinum HR 0.53 [95% CI 0.38-0.73]) were prognostic. No interaction was seen with FPC and receipt of platinum (p=0.15). Conclusions: FPC status is prognostic but not predictive of platinum response in this study. Further molecular profiling of this unique cohort of patients will provide insights into putative predisposing germline alterations, and novel treatment strategies.

340 Background: Cholangiocarcinoma (CCA) is a lethal malignancy with limited treatment options. Molecular profiling of these tumours has revealed a number of actionable mutations and four clusters have been defined through integrative genomic analysis. We sought to explore whole genome sequencing (WGS) data in 20 patients enriched for CCA arising in the setting of cirrhosis or inflammatory disorders. Methods: A previously established Biliary Tract Cancer (BTC) database at the Princess Margaret Cancer Centre (PMCC)/University Health Network (UHN) was used to identify patients of clinical interest including long-term survivors, those with germ-line mutations, and those with chronic inflammatory disorders. WGS and bioinformatic analyses were performed at the Ontario Institute for Cancer Research. Results: The 20 resected samples included 12 patients (pts) with intrahepatic CCA, 7 perihilar CCA, and 1 distal CCA. 8 pts were alive > 8 years post resection and one patient harboured a germline MLH1 pathogenic variant (MLH1 G67R). 3 pts had documented cirrhosis (hepatitis B n = 2, haemochromatosis n = 1); other inflammatory disorders (n = 4) included ulcerative colitis (UC) without documented PSC (n = 1), PSC alone (n = 1), UC with PSC (n = 1), and ankylosing spondylitis (n = 1). The remaining cases were randomly selected. The predominant COSMIC single base substitution (SBS) mutational signatures were 1, 8 and 5, and the median TMB was 1.75 mutations per MB (0.73-33.23). The pt with an MLH1 mutation exhibited a TMB of 33.23 with predominance of SBS26. Actionable variants were enriched in the 8 pts who are alive and disease free including 2 predicted FGFR fusions and mutations in IDH1 (n = 1), BRAF V600E (n = 1), and BAP1 (n = 1). TP53 mutations (n = 7) were present exclusively in patients with cirrhosis or inflammatory disorders and the median survival in the group was 12 months (3 -21 months). Although SBS signatures were similar in this group, in the two cases of UC, SBS17 (unknown etiology) was evident. SBS17 was also dominant in one case where the TMB was 13 mutations per MB and the patient died within 3 months of diagnosis. A somatic case of homologous recombination deficiency, with no causative genetic alteration identified, was evident in a further patient receiving maintenance rituximab for a coexisting stage 4 mantle cell lymphoma. Conclusions: WGS may provide additional biological information in CCA particularly in patients with underlying inflammatory disorders, where TP53 mutations are prevalent and mutational signatures are distinct.

TPS145 Background: Although most cancers are initially susceptible to existing anticancer therapies, over time cancer cells develop resistance. BOLD-100 is a first-in-class therapy that targets the GRP78 pathway, a major regulator of cellular stress and resistance. This therapy suppresses drug resistance, survival and proliferation by restraining stress-induced upregulation of GRP78 in tumor cells, leading to inhibition of the cell survival response. BOLD-100 successfully completed a Phase 1 monotherapy trial, with a manageable safety profile; it has demonstrated synergy in established preclinical models in combination with a wide variety of anticancer therapies and shown to restore sensitivity of drug-resistant cell lines. Methods: BOLD-100-001 is a multicenter, prospective, two-stage, non-randomized Phase 1b dose escalation and expansion study of BOLD-100 in combination with FOLFOX chemotherapy for selected advanced solid gastrointestinal (GI) tumors: colorectal (CRC), pancreatic (PANC), gastric (GC) and bile duct cancers (BDC). Each patient will receive BOLD-100 along with FOLFOX chemotherapy on Day 1 of each 14-day cycle. In the dose-escalation phase (Part A), patients will be enrolled to determine the combination recommended dose using a standard 3+3 design. In the dose-expansion phase (Part B), up to 80 patients with selected GI tumors will be enrolled in 5 cohorts (comprising the 4 GI cancers referred) and treated with BOLD-100 at the recommended dose and FOLFOX, until progressive disease or unacceptable toxicity. In Part A dose-escalation, the primary objective is to assess the safety, tolerability and maximum tolerated dose. The Part B dose-expansion will assess the efficacy (progression free survival, overall survival and response rate), of FOLFOX chemotherapy plus BOLD-100. Secondary objectives in Part A and B include the assessment of pharmacokinetic and pharmacodynamic parameters and potential biomarkers predictive of efficacy. Eligible patients will have previously treated histologically/cytologically confirmed metastatic/unresectable GI tumor (CRC, PANC, GC or BDC), measurable disease per RECIST criteria, an ECOG performance score of 0 or 1, and adequate organ function. In Part A, no formal statistical hypotheses will be tested; analysis of the data will focus on comparisons of safety and dose-limiting toxicities between cohorts and only descriptive methods will be used. In Part B, Bayesian modelling will be used to continually reassess the efficacy endpoints: progression free survival, overall survival and objective response rates. The study was opened for enrollment in August 2020; approximately 25-30 patients will be screened to achieve up to 20 patients in Part A and up to 80 patients will be enrolled in Part B with a maximum of 25 patients per arm. Clinical trial information: NCT04421820.

Keywords: pancreatic cancer, patient-derived organoids, transcriptomic signatures, PASS-01 Background: Patients with advanced pancreatic ductal adenocarcinoma (PDAC) continue to have a dire prognosis and only a minority of patients is fit enough to receive second-line treatment. Using patient-derived organoids (PDOs), we have identified transcriptomic signatures of chemotherapy sensitivity that may be able to stratify patients such that they receive maximal benefit from the currently approved, first-line chemotherapy regimens [1-3]. We will now test this hypothesis in the Pancreatic Adenocarcinoma Signature Stratification for treatment (PASS) – 01 trial, which is a multi-institutional randomized phase II trial between FOLFIRINOX (mFFX) and gemcitabine/nab-paclitaxel (GA). Methods: The overall aim of PASS-01 is to evaluate biomarkers and gene signatures that may predict response to mFFX and GA. The primary objective is to determine the progression free survival (PFS) benefit of mFFX compared to GA. Using 1:1 randomization, 131 evaluable patients with untreated metastatic PDAC will be recruited to provide 80% power to detect a 2-month improvement in PFS with mFFX (one-sided alpha 0.2). Secondary and exploratory objectives include determine the objective response rate, duration of response and overall survival associated with mFFX or GA, whether the chemotherapy sensitivity signature predictions correlate with responders, if PDO transcriptomic profiles parallel those obtained from patient samples, whether GATA6 expression can serve as a biomarker of response [4], the use of serial cell free circulating tumor DNA and circulating tumour cell analysis to identify emerging or de novo resistance and evaluate biomarkers of immune-oncologic sensitivity. The main inclusion and exclusion criteria are similar to major efficacy trials, with the mandatory requirement that a minimum of 4 x 18G good quality tumour core biopsies can be safely obtainable under CT or US guidance. At progression, as per RECIST 1.1 criteria, chemotherapy sensitivity signatures (RNA) and/or PDO pharmacotyping and WGS data will be used where possible to guide second-line therapy in an effort to continually provide the most active therapeutic regimens to each patient. The trial is anticipated to open Q4 2020. Conclusions: PASS-01 will provide candidate biomarkers and gene signatures that predict response to mFFX and GA, which will be further investigated in a subsequent adaptive, stratified trial.

Background: Ipilimumab has been shown to improve overall survival in patients with metastatic melanoma; however, complete responses (CRs) are uncommon. Immune-related side effects usually involve the skin or gastrointestinal tract. Neurologic events occur less frequently but are well described. Case Report: We report the case of a 58-year-old man with metastatic melanoma who commenced ipilimumab post spinal decompression and radiation. He developed a colitis post cycle 2 and ipilimumab was discontinued. Imaging, however, documented a radiological CR. 8 weeks later, he developed paraplegia and a myelitis despite an ongoing radiological CR. Steroid use resulted in some improvement radiologically, without clinical improvement. Conclusion: We report myelitis with consequent paraplegia as a potential neurological immune-related side effect of ipilimumab. We further describe a patient with a CR after 2 cycles of ipilimumab in the setting of radiation.

We integrated clinical, genomic, and transcriptomic data from 224 primaries and 95 metastases from 289 patients to characterize progression of pancreatic ductal adenocarcinoma (PDAC). Driver gene alterations and mutational and expression-based signatures were preserved, with truncations, inversions, and translocations most conserved. Cell cycle progression (CCP) increased with sequential inactivation of tumor suppressors, yet remained higher in metastases, perhaps driven by cell cycle regulatory gene variants. Half of the cases were hypoxic by expression markers, overlapping with molecular subtypes. Paired tumor heterogeneity showed cancer cell migration by Halstedian progression. Multiple PDACs arising synchronously and metachronously in the same pancreas were actually intra-parenchymal metastases, not independent primary tumors. Established clinical co-variates dominated survival analyses, although CCP and hypoxia may inform clinical practice.