bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic and predictive value of circulating tumour DNA (ctDNA) by amplicon-based next generation sequencing (NGS) of advanced pancreatic cancer (APC) in a phase I trial of oxaliplatin capecitabine and irinotecan (OXIRI) triplet chemotherapy.
Authors: Seet Amanda Oon Lim , Choo Su Pin , Tai David Wai-Meng , Lam Justina Yick Ching , Tan Tira Jing Ying , Tan Daniel Shao-Weng , Tan Aaron C. , Chang Yvonne , Chowbay Balram , Ng Matthew C.H.
Published: February 2020

730

Background: Tumoral KRAS mutations (KRAS mt) are detected in ~80% of APC and associated with a negative prognosis. Digital droplet PCR (ddPCR) has high sensitivity for circulating KRASmtbut narrower gene coverage. NGS using hybrid-capture methods has reported ctDNA KRASmtin ~30% of patients (pt). We previously presented clinical results of the Phase I trial of OXIRI (GI ASCO 18 #411). We now present the first prospective evaluation of ctDNA in APC by an amplicon-based NGS approach in this Phase I trial. Methods: Paired ctDNA and CA19-9 samples were taken at baseline, C2D1, C3D1 and end of trial. A targeted panel with error-correction (Lucence Diagnostics) was used to detect for mtin KRAS, TP53, SMAD4, CDKN2A, CTNNB1, GNAS, APC and MYC. CT scans were performed every 2 cycles. Survival curves by Kaplan Meier were compared by mutational status, ctDNA and CA19-9 response using the log-rank test. Spearman correlation of ctDNA and CA19-9 changes was performed. Results: ctDNA mtwas detected at baseline in 19/23 (83%) samples, comprising KRAS 17/23 (73%), TP53 (61%), SMAD4 (48%) and CDKN2A (30%). KRAS mtand SMAD4 mt conferred a negative prognosis for overall survival with a hazard ratio of 4.2 (CI: 1.6-10.4; p = 0.01) and 2.8 (CI: 0.9-8.65; p = 0.01) respectively. Drop in ctDNA and CA19-9 was associated with a trend for longer progression free survival at C2D1 (both) and C3D1 (ctDNA only). Radiological partial response (PR) was associated with lower ctDNA in 5/5 pt and CA 19-9 in 4/5 pt. Decrease in ctDNA and CA19-9 was associated with disease control (PR/SD) at C2D1 in 11/14 pt and 10/10 pt; at C3D1 in 11/12 pt and 6/7 respectively. No significant correlation between the amplitude of CA19-9 and ctDNA changes was found. Conclusions: ctDNA could be detected in 83% of pts of whom KRAS mtrates were similar to reports using tissue NGS. Determination of RAS mtand SMAD4 mtin ctDNA may aid in the prognostication of pts and decrease in ctDNA levels may predict for treatment benefit, similar in extent to CA 19-9. This may be particularly useful in non-CA19-9 secreting APC as an adjunct to imaging. Clinical trial information: NCT02368860.
Loss of Rnf43 to accelerate KRAS-mediated neoplasia in a clinically relevant genetically engineered mouse model of pancreatic adenocarcinoma.
Authors: Hosein Abdel Nasser , Dangol Gita , Okumura Takashi , Abou-Elkacem Lotfi , Maitra Anirban
Published: February 2020

733

Background: The genetic heterogeneity of pancreatic ductal adenocarcinoma (PDAC) demands a personalized molecular-targeted treatment approach. While activating KRAS mutations are a near ubiquitous event in PDAC pathogenesis, 5-10% of cases display deleterious driver mutations in the Wnt-signaling negative regulator, ring finger 43 (RNF43). Despite this characterization there are no personalized treatment options for this subset of patients. Methods: We have developed a genetically engineered mouse model (GEMM) of PDAC, driven by an activating mutation in Kras and deletion of Rnf43 under control of a pancreas specific promoter (KRC). Mice were followed for survival outcomes and histological changes which were compared to a Kras driven PDAC GEMM (KC). Mice underwent serial magnetic resonance imaging (MRI), with and without dynamic contrast enhanced (DCE) imaging, to evaluate cystic tumor morphology and contrast enhancement during tumor progression. Single cell RNA sequencing (scRNAseq) was also performed to assess changes in single cell populations during tumor progression. Lastly, we established ex vivo cultures from KRC and KC tumors and performed bulk RNA-sequencing (RNAseq) and in vitro pharmacology studies. Results: KRC mice displayed a decrease in overall survival and higher incidence of both high grade pre-neoplastic lesions and invasive PDAC compared to KC mice. Serial MRI revealed increased cystic morphology of KRC mice during tumor progression with increasing DCE intensity. scRNAseq of KRC tumors from moribund mice displayed two distinct populations of both macrophages and fibroblasts, similar to our previous report of Kras/Tp53 and Kras/Ink4a driven GEMMs. Lastly, primary cultures from KRC tumors demonstrated increased expression of Wnt-related genes by RNAseq and increased sensitivity to small molecule porcupine inhibition relative to KC cell lines, demonstrating functional Wnt dependence of the KRC system. Conclusions: Rnf43 is a bona fide tumor suppressor gene in PDAC. This GEMM is a novel platform for drug discovery in RNF43-mutated PDAC with the eventual goal of implementing a precision oncology approach in these patients.
Early progression (progr) in patients (pts) with metastatic pancreatic cancer (mPaC) and a germline BRCA mutation (gBRCAm): Phase III POLO trial of olaparib (O) versus placebo (P).
Authors: Macarulla Teresa , Kindler Hedy L. , Hammel Pascal , Reni Michele , Van Cutsem Eric , Hall Michael J. , Park Joon Oh , Hochhauser Daniel , Arnold Dirk , Oh Do-Youn , Reinacher-Schick Anke C. , Tortora Giampaolo , Algül Hana , O'Reilly Eileen Mary , McGuinness David , Cui Karen , Schlienger Katia , Locker Gershon Y. , Golan Talia
Published: February 2020

750

Background: In POLO (NCT02184195), maintenance O was associated with significant progr-free survival benefit vs P in pts with a gBRCAm and mPaC (Golan NEJM 2019). Early progr or death (within 4 months [m]) occurs in ~35−45% of pts on standard-of-care first-line (1L) chemotherapy for mPaC (Conroy NEJM 2011; von Hoff NEJM 2013); however, predictive factors are currently unknown and early progr has not been addressed in the maintenance setting. We examined factors potentially associated with early progr in POLO. Methods: Following ≥16 weeks of 1L platinum-based chemotherapy (PBC) without progr, pts were randomized to maintenance O (tablets; 300 mg bd) or P until progr or unacceptable toxicity. Early progr was defined as progr (by blinded independent central review) or death within 4 m of randomization. A stepwise logistic regression model included baseline (BL) factors age, albumin, lactate dehydrogenase (LDH), global health status (GHS) and physical functioning (PhysF) as continuous variables, and discrete variables listed in the Table. Results: 62/154 randomized pts (40%) were defined as early progressors (EP; Table). Due to missing BL data, the multivariate analysis included 127 pts (56 EPs [44%]). Lower BL PhysF score (continuous) was significantly associated with early progr ( P= 0.02); no difference for partial/complete response (PR/CR) vs stable disease (SD). Conclusions: While small sample size limited analysis power, PhysF score was the only BL factor significantly associated with early progr in pts with a gBRCAm and mPaC in the POLO trial of maintenance O vs P. Clinical trial information: NCT02184195 . [Table: see text]
Evaluation of the ratio of plasma fibrinogen to platelet in resectable pancreatic cancer.
Authors: Arakawa Yusuke , Shimada Mitsuo , Morine Yuji , Imura Satoru , Ikemoto Tetsuya , Saito Yu , Yamada Shinichiro , Yoshikawa Masato , Miyazaki Katsuki
Published: February 2020

756

Background: Several prognostic factors were reported in pancreatic cancer such as neutrophil lymphocyte ratio (NLR), platelet lymphocyte ration (PLR) modified GPS. Fibrinogen platelet ratio (FPR) was reported as one of the prognostic factor of resectable gastric cancer (Surgery today 2019). In this report, the FPR was evaluated in patients with resectable pancreatic cancer. Methods: Between 2004 and 2019, one hundred and sixty-three patients in our institution with curative resection for pancreatic cancer were enrolled in this retrospective study. The cases of non-curative resection were excluded. The FPR was calculated with the preoperative plasma fibrinogen and the platelet counts. Cut-off value was decided with ROC curve. The patients were divided into high and low FPR group according to cut-off value. Results: The cut-off value of FPR was 25.51. In age, gender, BMI, operative factors including operative type, amount of blood loss and operative time, there was no significant difference between these two groups. Patients in low FPR group had significantly better overall survival (OS) rates and relapse-free survival (RFS) rates compared with high FPR group (p < 0.05). On multivariate analysis, the high FPR, CA19-9 > 300 U/ml and receipt of adjuvant chemotherapy were independent risk factor of post-operative recurrence. Conclusions: The FPR might be a prognostic factor of patients with resectable pancreatic cancer.
Impact of CDKN2A/b status in pancreatic cancer (PC).
Authors: Annunzio Kaitlin , Griffiths Claire , Arapi Igli , Lasowski Matthew , Singavi Arun K. , Dua Kulwinder , Khan Abdul H. , Ritch Paul S. , Kamgar Mandana , Thomas James P. , Hall William Adrian , Erickson Beth , Tsai Susan , Christians Kathleen K. , Evans Douglas B. , Urrutia Raul , Szabo Aniko , George Ben
Published: February 2020

759

Background: PC is a lethal disease with limited treatment options. We utilized Comprehensive Genomic Profiling (CGP) to identify putative prognostic and/or predictive biomarkers. Methods: We retrospectively reviewed PC patients (pts) at our institution who underwent CGP utilizing the Foundation One assay. CGP was performed on hybrid-capture, adaptor ligation-based libraries for up to 315 genes plus 47 introns from 19 genes frequently rearranged in cancer. PC pts were categorized by clinical stage – localized (resectable and borderline resectable PC; LPC), locally advanced (LAPC) and metastatic (mPC). Effect of gene alterations (GAs) with at least 10% prevalence were analyzed. The marginal effect of each gene on radiographic response and survival outcomes was estimated using proportional odds and multivariate Cox regression analysis, respectively, adjusting for stage. Results: Ninety-three pts were identified - median age was 63, 55% were male, and 50% were smokers. Clinical stage at diagnosis was LPC, LAPC and mPC in 42 (45%), 23 (25%) and 28 (30%) pts, respectively. The most commonly altered genes were KRAS (94%), TP53 (75%), CDKN2A (41.2%) and SMAD4 (32.9%). All patients were microsatellite stable and the median tumor mutational burden was 1.7. 5-FU (52%) or Gemcitabine (46%) based chemotherapy combinations were utilized as the first systemic therapy. Median overall survival for patients with LPC, LAPC and mPC were 30.7, 28.8 and 9.6 months respectively. Thirty-eight (91%) pts with LPC underwent curative intent surgery compared to 15 (65%) pts with LAPC (p = 0.019). Thirty-five (95%) pts with wild type (WT) CDKN2A and 47 (94%) pts with WT CDKN2B underwent curative intent surgery compared to 13 (65%) and 1(14%) pt(s) with GAs in CDKN2A and CDKN2B respectively (p = 0.003 and p < 0.0001 respectively). The response to chemotherapy was statistically significantly higher in pts with WT CDKN2A (53%) and CDKN2B (48%) compared to pts with GAs in CDKN2A (19%) and CDKN2B (12%) (p = 0.03 and p = 0.05, respectively). Conclusions: GAs in CDKN2A/B may have a predictive and possibly a prognostic impact. The clinical validity and biological relevance of these findings need to be further explored in larger studies.
Analysis of associations of CXCR3 ligands with immune microenvironment and aggressiveness in murine and human pancreatic ductal adenocarcinoma.
Authors: Cannon Andrew , Thompson Christopher M , Atri Pranita , Bhatia Rakesh , Kumar Sushil , Batra Surinder
Published: February 2020

762

Background: The complex milieu of cytokines within pancreatic ductal adenocarcinoma (PDAC) promotes tumor progression and immune suppression thereby contributing to the dismal prognosis of patients with PDAC. However, the roles of many cytokines, including CXCR3 ligands, in PDAC have not been thoroughly investigated. Methods: Bioinformatics analyses of PDAC microarray and TCGA datasets were used to identify cytokines overexpressed in PDAC, their association with patient survival as well as the expression of cognate cytokine receptors. Comparative analysis of cytokine expression in KrasLSL-G12D-P53LSL-R172H-Pdx1-Cre (KPC) and KrasLSL-G12D-Pdx1-Cre (KC) murine PDAC models were used to validate these findings. Pathway and CIBERSORT analyses were employed to determine mechanistic basis of altered survival associated with cytokines of interest. Results: Of the 149 cytokines analyzed, CXCR3 ligands CXCL9 and CXCL10 were highly and consistently overexpressed in PDAC datasets. Concurrently, CXCL9, CXCL10 and PF4 were overexpressed in the aggressive KPC murine model compared to the indolent KC model. CXCR3 showed robust expression in PDAC in microarray, TCGA and IHC analyses. Interestingly, high expression of CXCR3 ligands was associated with shorter overall survival (p = 0.04 for CXCL9, 10 and 11 and p = 0.02 for PF4) while high expression of CXCR3 was associated with increased overall survival (p = 0.03). Pathway analysis of genes correlated with CXCR3 and/or its ligands showed that CXCR3 ligands may promote T-cell exhaustion (p < 0.001). Finally, CIBERSORT analysis of TCGA data demonstrated that high CXCR3 expression was associated with increased CD8 T-cell and naïve B-cell signatures and loss of plasma cells signatures. High CXCR3 ligand expression was associated with increased CD8 T-cell, and M1 macrophage, and loss of NK-cell signatures(p < 0.05). Conclusions: CXCR3 ligands are overexpressed in PDAC and are associated with poor survival, likely related to alterations in tumor immune infiltrate/activity and may represent targets to augment anti-tumor immunity.
Association of neutrophil, platelet, and lymphocyte ratios with prognosis in metastatic pancreatic cancer.
Authors: Allen Jessica , Cernik Colin , Bajwa Suhaib , Saeed Anwaar , Kasi Anup
Published: February 2020

767

Background: High mortality associated with pancreatic ductal adenocarcinoma (PDA) warrants research into prognostic factors. We examined the relationship between the daily rate of change of CA19-9 over the first 90 days of treatment (DRC90) and pretreatment levels of neutrophils, lymphocytes, and platelets with overall survival (OS) and progression free survival (PFS) in patients with stage IV PDA that received chemotherapy. Methods: We retrospectively evaluated 102 locally advanced and metastatic PDA patients treated at KU Cancer Center between Jan 2011 and Sep 2019. We compared the ratio of pretreatment absolute neutrophil count to pretreatment absolute lymphocyte count (NLR) and the ratio between pretreatment platelet count to pretreatment absolute lymphocyte count (PLR) with OS and PFS. We also compared DRC90 to OS and PFS. Log-rank trend test using the mean of NLR, PLR, and DRC90 as the threshold for two groups within each variable. Results: Baseline demographics are shown in the table. Pts with ≥ mean NLR (4.6) had significantly lower OS [p = 0.0444] and PFS [p = 0.0483] than Pts below the mean. Pts with PLR ≥ mean (3.9) did not have significantly different OS [p = 0.507] or PFS [p = 0.643] than Pts below the mean. Pts with DRC90 ≥ mean (-1%) did not have significantly different OS [p = 0.342] or PFS [p = 0.313] than Pts below the mean. Conclusions: Pts with NLR ≥ mean (4.6) had significantly lower OS and PFS than Pts with NLR below the mean. This implies the possibility of NLR as a prognostic marker in PDA that could guide treatment approach but needs validation in a larger cohort. [Table: see text]
Clinical outcomes of first-line FOLFIRINOX versus gemcitabine plus nab-paclitaxel in metastatic pancreatic cancer at the Yale Smilow Healthcare System.
Authors: Patel Timil , Srikumar Thejal , Miccio Joseph Anthony , Lacy Jill , Stein Stacey , Kortmansky Jeremy S. , Staugaard Carol , Gambaccini Melissa , Axtmayer Alfredo , Cecchini Michael
Published: February 2020

769

Background: FOLFIRINOX (FFX) and Gemcitabine plus nab-paclitaxel (GN) are established first line (1L) therapies for metastatic pancreatic cancer (MPC) but real-world data on their comparative effectiveness is limited. Methods: All cases of MPC treated with 1L FFX or GN at Yale Smilow Cancer Hospital and the affiliated community care centers (CCC) from January 2011 – April 2019 were reviewed. Patient (pt) demographics, prior therapy, initial and subsequent dose reductions (DR), time to treatment discontinuation (TTD), overall survival (OS), and second line (2L) treatment data were manually abstracted from the electronic medical record. Categorical and continuous variables were compared between 1L FFX and GN cohorts via the Chi-squared and Wilcoxon rank-sum tests. Median OS was calculated by the Kaplan-Meier method. Results: We identified 363 MPC pts treated with 1L FFX or GN; 269 (74%) pts were treated with FFX and 94 (26%) with GN as 1L therapy. 204 (56%) pts were treated at the main campus and 159 (44%) at a CCC. Demographics and baseline characteristics (FFX/GN) were as follows: gender (male) 55% / 41%; race (white) 82% / 77%; age < 76 90% / 71% ( P < 0.001). 332 (91%) of pts received no prior therapy; 21 (6%) had prior surgery plus adjuvant gemcitabine and 10 (3%) had surgery alone. 98% of FFX-treated pts were treated with upfront DR, compared to 78% of GN-treated pts ( P= 0.003). 78% and 53% of FFX-treated and GN-treated pts, respectively, had subsequent DR ( P< 0.001). Median TTD was 4.8 months with FFX and 3.4 months with GN ( P= 0.0029) and the median OS was 11.3 months with FFX versus 7.2 months with GN ( P < 0.0001). After 1L, 33% and 61% of FFX- and GN-treated pts, respectively, received no further chemotherapy ( P< 0.001). Conclusions: In the largest manually abstracted retrospective analysis to date, MPC pts treated with 1L FFX were younger, more likely to receive 2L therapy, and had increased survival compared to pts treated with GN. The OS of pts treated with FFX was similar to the OS reported by Conroy et al despite upfront dose attenuations in 98% of pts. A randomized trial is needed to confirm optimal sequencing of chemotherapy in MPC.
Feasibility of pharmacist co-management for patients prescribed oral anticancer therapy for gastrointestinal cancers.
Authors: Cao Cathy , Cleary James M. , Patel Anuj K. , Yurgelun Matthew B. , Ng Kimmie , Perez Kimberly , Rubinson Douglas Adam , Wolpin Brian M. , Meyerhardt Jeffrey A. , McCleary Nadine Jackson
Published: February 2020

77

Background: There is an increased use of oral anti-cancer therapies (OACTs) for treatment of gastrointestinal (GI) cancers. While OACTs provide convenience compared to IV agents, they carry similar risks for drug-drug interactions (DDI), toxicities, and unique challenges like adherence and drug access. Patients on OACTs have fewer touch-points with clinicians, requiring more patient ownership of treatment. Pharmacist co-management of pts has been shown to be successful in teaching and monitoring of IV therapy. We sought to assess feasibility of pharmacist co-management for pts prescribed OACTs for treatment of GI cancers. Methods: In 2019, the Dana-Farber GI Cancer Center (GCC) had an embedded pharmacist 8 hrs/week to help with co-management of pts on OACTs. The pharmacist provided (1) in-person and telephone teaching; (2) comprehensive medication reconciliation; (3) DDI review; and (4) supportive care recommendations. Patients were identified by reviewing provider schedules and through provider referrals. The initial teach visit was one-on-one with each patient before initiation, with joint visits with providers thereafter for monitoring and adherence checks. Data were collected to quantify the types of support/recommendation provided by pharmacist and the impact on clinical workflow. Results: After 4 months in the GCC clinic, the pharmacist has co-managed 26 new pts, 61% seen in-person. In initial visits, the pharmacist identified 3 DDI, updated 15 medication lists, and assisted 11 pts/or providers with drug access and drug information. The pharmacist saw 10 of 26 pts for follow up, totaling 21 encounters. The pharmacist assisted in 17 of the 21 encounters with drug access and drug information. Pharmacist spent 20 min/pt on teaching. For follow-up visits, the pharmacist did not additional incur clinic resources as patients were seen with providers. Conclusions: Pharmacist co-management of patients on OACTs is feasible and offers an added safety resource to pts and providers from initial teaching to monitoring. Future research will focus on the impacts of co-management on clinical outcomes, such as the use of emergency/hospital visits, the duration of therapy, and adherence.
Is adjuvant chemotherapy beneficial for stage II-III goblet cell tumors of the appendix?
Authors: Zakka Katerina Mary , Williamson Shayla , Jiang Renjian , Alese Olatunji B. , Shaib Walid Labib , Wu Christina , Behera Madhusmita , El-Rayes Bassel F. , Akce Mehmet
Published: February 2020

796

Background: Goblet cell tumors (GCT) of the appendix are very rare tumors constituting 2.5%-5% of all primary appendiceal neoplasms. Role of adjuvant chemotherapy (AC) is not established for GCT. This study aims to evaluate the impact of AC in stage II-III appendiceal GCT. Methods: Patients with pathological stage II and III GCT who underwent surgical resection between 2006 and 2015 were identified from the National Cancer Database (NCDB) using ICD-O-3 morphology and topography codes: 8243/3, 8245/3 and C18.1. Patients treated with neoadjuvant systemic and/or radiation therapy and adjuvant radiation were excluded. Univariate and multivariable analyses were conducted, and Kaplan-Meier Curves were used to compare overall survival (OS) based on treatment received with Log-rank test. Results: A total of 1,046 patients were identified. 53.7% males and 89.0% Caucasian; median age 56 (range, 20-90) years. Distribution across pathological stages II-III was 83.6% (N = 874) and 16.4% (N = 172) consecutively. 8.3% (N = 73) of stage II and 50.6% (N = 87) of stage III patients received AC. In the total cohort, AC was not associated with better OS compared to no AC in univariate analysis (HR 1.84; 95% CI 1.26-2.67; p = 0.001) or multivariable analysis (HR 0.94; 95% CI 0.57-1.52; p = 0.790). For stage II patients, AC was not associated with better OS in univariate (HR 1.24; 95% CI 0.60-2.57; p = 0.562) or multivariable analyses (HR 1.67; 95% CI 0.76-3.64; p = 0.199). Similarly, in stage III patients, AC was not associated with better OS in univariate (HR 0.78; 95% CI 0.48-1.29; p = 0.340) or multivariable analyses (HR 0.55; 95% CI 0.28-1.04; p = 0.067). In the entire cohort 5-year OS for patients that received AC was 83.9% (80.3%, 86.9%) versus 70.7% (60.9%, 78.5%) (p = 0.001) with no AC. For stage II patients, 5-year OS was 77.3% with AC vs. 87.7% with no AC (p = 0.562). For stage III patients, 5-year OS was 64.8% with AC vs. 54.4% with no AC (p = 0.340). Conclusions: AC was not associated with improved 5-year OS in patients with pathological stage II and III GCT compared to no AC.
Nationwide large-scale investigation of microsatellite instability status in more than 18,000 patients with various advanced solid cancers.
Authors: Akagi Kiwamu , Oki Eiji , Taniguchi Hiroya , Nakatani Kaname , Aoki Daisuke , Kuwata Takeshi , Yoshino Takayuki
Published: February 2020

803

Background: The recent success of immunotherapy in high-frequency microsatellite instability (MSI-H) and/or mismatch repair protein deficient (MMR-D) tumors now supports testing for MSI in all advanced solid tumors. We previously reported using the quasi-monomorphic variation range (QMVR), the MSI status can be determined without matched normal DNA (Bando H, et al. Cancer Sci. 2018). Here, we investigate the proportion of the MSI status across various advanced solid tumors by this method. Methods: The MSI analysis was performed centrally by CLIA-certified, CAP-accredited, the single laboratory using tumor DNA from formalin-fixed paraffin embedded (FFPE) tissues with the MSI test kit (FALCO), which includes fluorescent-labelled primers for co-amplification of five mononucleotide markers (NR-21, BAT-25, MONO-27, NR-24 and BAT-26). The MSI-H was defined as positive if 2 or more makers showed instable. Results: A total of 18,250 patients with advanced solid tumors were registered from Dec 2018 to Aug 2019, and the MSI status was confirmed in 18,088 patients (99%). Among them, 51.9% were male, with median of 62.0 y/o. Overall prevalence of the MSI-H was3.3% (2.3% in male and 4.5% in female); the highest was 16.2% (149/916) in endometrial cancer, followed by 13% (13/100) in small intestinal cancer, 5.9% (74/1277) in gastric cancer, 3.3% (236/7190) in colorectal cancer, 2.6% (4/154) in prostate cancer, 2.5% (20/806) in ovarian cancer, 2.1% (9/426) in cervical cancer, 1.6% (13/831) in biliary tract cancer, 1.5% (4/271) in hepatocellular carcinoma, 0.9% (16/1852) in pancreas cancer. Interestingly, among biliary tract cancers, all MSI-H cases were arising from gall bladder (13/152) but no other sites. High prevalence was observed in cancer of teens or twenties (7.9%) and over 80y/o (5.6%), compare with others (3.0%) in this study (p < 0.001, both). Conclusions: These data show the MSI-H advanced solid tumors are distributed across a much broader tumor spectrum, and confirm the clinical relevance of the screening in patients with most advanced solid tumors, which can select patients sensitive to immune checkpoint blockade, regardless of the cancers' tissue of origin.
Female representation in clinical trials leading to FDA cancer drug approvals for gastrointestinal (GI) cancers between 2008 to 2018.
Authors: Mendis Shehara Ramyalini , Anand Seerat , Dasari Arvind , Unger Joseph M. , Gothwal Anirudh , Ellis Lee M. , Varadhachary Gauri Rajani , Kopetz Scott , Overman Michael J. , Raghav Kanwal Pratap Singh , Loree Jonathan M.
Published: February 2020

809

Background: Proportionate representation of women in health research is an area for improvement. This study aims to assess the representation of women in gastrointestinal (GI) cancer clinical trials leading to FDA cancer drug approvals over the past 10 years. Methods: FDA cancer drug approvals between 07/2008-06/2018 were identified and trial reports supporting approvals sourced. The ratio of female to male (F:M) enrollment was compared with F:M cancer incidence in the U.S., and U.S. cancer prevalence and mortality. Results: Although F:M enrollment for all 229 trials leading to FDA cancer drug approvals in this period was similar to overall F:M cancer incidence in the U.S. (0.89 vs 0.86; Odds Ratio for female enrollment (OR) 1.05, 95% Confidence Interval (CI) 1.03-1.06, P<0.0001), in 17 trials that led to drug approvals in GI cancers there was lower F:M trial enrollment compared to cumulative U.S. incidence at those tumor sites (0.55 vs 0.79, OR 0.71, 95% CI 0.68-0.74, P<0.0001). F:M enrollment and U.S. incidence by the main GI tumor sites where approvals occurred is shown in Table. Female enrollment rates were also lower than U.S. female cancer mortality and prevalence rates in these tumor sites (P<0.0001 for all). Female enrollment in GI trials fell between 2008-2013 and 2014-2018 (38 vs 33%, OR 0.80, 95% CI 0.74-0.87, P<0.0001). Conclusions: Although disparity in female enrollment may be improving across combined FDA cancer drug approval trials, underrepresentation of females has persisted in GI cancer trials when compared to F:M cancer incidence, prevalence and mortality in the U.S. More work is required to determine the drivers of this disparity, in order to mitigate it. [Table: see text]
The relationship between naldemedine administration and the maximum dose of oral opioids.
Authors: Kajiura Shinya , Chikaoka Shingo , Kadota Ayaka , Fukai Sakie , Matsushita Takako , Hayashi Naomi , Ryu Nobukazu , Yagi Yuta , Takaki Akiyoshi , Horikawa Hideyo , Takemura Yoshinori , Sakamoto Kazunori , Furuichi Astushi , Shima Tomoko , Motoo Iori , Ando Takayuki , Yasuda Ichiro , Hayashi Ryuji
Published: February 2020

818

Background: Opioid-induced constipation (OIC) is the most common side effect of opioid therapy. Laxatives are usually used as a first-line treatment for OIC. Treatment options for OIC are switching to other opioids associated with less frequent OIC, such as Fentanyl. Naldemedine is an orally active peripherally acting µ-opioid receptor antagonists that was approved in Japan from 2017 for management of cancer-related OIC. The aim of this study is to investigate the relationship between Naldemedine administration and the maximum dose of oral Oxycodone which is the most frequently used oral opioids at our hospital. Methods: During June 2017 and December 2018, a total of 217 patients with cancer-related pain received Oxycodone at our institution. The first group of the patients concurrently received Naldemedine 0.2 mg daily (group A, n = 101), and the second group didn’t receive it (group B, n = 116) for cancer-related OIC reduction. We compared the maximum Oxycodone dose between two groups by medical record retrospectively. Results: The median age of group A was 69 y.o. (range 20-87 y.o.), and the median age of group B was 67 y.o. (range 27-88y.o.). There was no significant difference in common patient background between group A and B. The median dose of maximum Oxycodone dose of group A was 40 mg/day (range 10-480 mg/day), and that of group B was 20 mg/day (range 10-320 mg/day). There was a significant difference in the median dose of maximum Oxycodone between group A and B (Mann-Whitney U test, P < 0.0001). In Group A, the administration was started in 31 patient Naldemedine and Oxycodone at the same time. As for 70 remaining patients, the administration was started when they had constipation after oxycodone was administrated. In those patients, the median days was 19 days from the Oxycodone administration starting date to the Naldemedine administration starting date. Conclusions: Naldemedine administration in patients with cancer-related OIC may increase the maximum dose of oral Oxycodone.
Stereotactic radiotherapy in oligometastatic (OM) gastrointestinal (GI) tumors: A single institution retrospective analysis.
Authors: Figueiredo Renata Reis , Palhares Daniel Moore Freitas , Fernandes Gustavo Dos Santos , Pereira Allan Andresson Lima , Marchetti Katia Regina , Gumz Brenda Pires , Faria Luiza Dib , Alves Teixeira Marcela , Gadia Rafael
Published: February 2020

825

Background: Metastatic GI cancers are mainly treated with systemic treatment (ST), in selected patients (pts), surgery is considered depending on pts characteristics and institutional preferences. Stereotactic Radiotherapy (SRT) is a growing treatment option in such landscape aiming to improve local disease control and maximize ST results for oligometastatic pts. Methods: This is a single center retrospective study. Data were collected from sequential pts with GI tumors who underwent SRT for OM-GI cancers from May 2014 to July 2019. Information was collected on pts characteristics, primary site, clinical staging at diagnosis, sites undergoing SRT, whether there was progression after the first SRT, time between the first SRT and progression and the last follow-up date. Results: 381 pts underwent SRT in our center, of these, 75 pts had OM-GI tumors and underwent 120 courses of SRT. 50,7% were women, the median age at diagnosis was 60 years and the median follow-up was 36 months. 76% had colorectal cancer (CRC) being 26% from the right, 26% from the left colon and 30% were from the rectum, in 18% of the patients we could not determine sidedness. 35% already had metastatic disease at diagnosis. The lung was the site with largest number of lesions treated with SRT (50), followed by central nervous system (CNS) (42), bones (32), liver (29) and lymph nodes (16). After a median follow up of 15.3 months, 11% of patients were progression-free and only 24% had progressed on treated lesions. The median progression free survival following SRT was 4.5 months (0.6-45.8 range) for distant metastasis and was not achieved for treated sites. Conclusions: This retrospective study adds to the previous body of evidence supporting the use of SRT to improve GI cancer management. Detailed information on pts characteristics, pathology, toxicity and previous treatments will be presented.
Clinical outcome for gastrointestinal cancers with polymerase epsilon mutations treated with immunotherapy.
Authors: Zhu Limin , Meric-Bernstam Funda , Holla Vijaykumar , Kim Taebeom , Shaw Kenna Rael , Chen Ken , Routbort Mark , Kopetz Scott , Overman Michael J.
Published: February 2020

828

Background: Predictive factors for immunotherapy benefit across gastrointestinal (GI) cancers are limited to those with deficient mismatch repair (dMMR). Mutations in DNA polymerase E (POLE) can cause a hypermutated phenotype irrespective of MMR status and may serve as a predictor factor for immunotherapy. Methods: All POLE-mutant GI cancers with tumor mutation burden (TMB) measured at MD Anderson Cancer Center were identified (N = 58) from 2014 to 2019 and those that had received immunotherapy (N = 18) were studied. TMB was measured by genomic profiling assays FoundationOne or STGA 2018. Samples were analyzed using Kaplan-Meier method and compared using log rank test, with a predefined high TMB threshold of 20 muts/mb. Results: Of the 58 POLE-mutant GI tumors a high TMB was present in 50% of the cases. 18 patients (median age 64, female gender 16.7%, median prior lines of therapy 2) with locally advanced (N = 4) or metastatic (N = 14) POLE-mutant GI cancers (13 colorectal, 1 small intestine, 1 esophageal, 1 pancreatic, and 2 gallbladder) were identified. Immunotherapy agents were PD-1/PD-L1 based in 17 and CTLA-4 based in 1. High TMB was present in 11 patients. dMMR was present in 7 patients, all with high TMB. Treatment response was seen in 3 patients (2 CR and 1 PR), all TMB high and dMMR. Progression-free survival (PFS) was significantly longer in those with high TMB (median: 10.1 months vs. 3 months, p = 0.048). Of the 11 pMMR patients median PFS was 9.3 months in high TMB and 3 months in low TMB (p = 0.246). Conclusions: POLE mutations in GI cancers were associated with a high TMB ( > 20muts/mb) in 50% of patients. Within POLE mutant GI cancers a high TMB may identify patients who benefit from immunotherapy irrespective of mismatch repair status.
Platinum-based therapy of patients with gastrointestinal cancers that harbor homologous recombination DNA damage response (HR-DDR) mutations: A single institutional retrospective analysis.
Authors: Singh Bhavana Pendurthi , Ballman Madison , Drake Evan , Khanchandani Ashish , Prins Petra , Weinberg Benjamin Adam
Published: February 2020

836

Background: HR-DDR deficiencies have been described across cancer types and associated with response to specific therapies, including platinum (Pt)-based drugs and poly ADP-ribose polymerase (PARP) inhibitors. We sought to estimate the frequency of HR-DDR gene mutations in gastrointestinal (GI) cancers and determine if these patients (pts) benefit from Pt-based therapy. Methods: A retrospective chart review was performed on 421 pts with GI cancers treated at our institution. Tumors were categorized as colorectal (CRC), gastroesophageal (GE), pancreatic (PDA), hepatobiliary (HB), or other. All had next-generation sequencing with mutations in one or more of the following HR-DDR genes: BRCA1, BRCA2, PALB2, CHEK2, ATM, ARID1A, MRE11A, NBN, BARD1, and BL M. Overall survival (OS) of pts was analyzed using Log-rank test. Results: Of those analyzed, 127 pts (84 women and 43 men) met the inclusion criteria. Forty-eight percent had primary CRC tumors, and the remainder had primary GE (17%), PDA (14%), HB (10%), and other GI (11%) tumors. Fifty-four percent had stage IV disease. Sixty-five percent received Pt-based therapy at some point during their disease course. HR-DDR analysis revealed the following mutation rates: 34% ARID1A; 16% ATM; 19% BRCA2; and 9% BRCA1. OS analysis showed no significant survival advantage based on stage or mutation type for any of the disease-specific cohorts. There was no significant OS benefit in pts who received Pt-based therapy vs. those who did not, although pts with ARID1A-mutated tumors did show a trend towards improved OS (P = 0.09). Conclusions: Despite our limited cohort, our data suggest that pts with GI tumors harboring certain HR-DDR gene mutations might benefit from Pt-based therapy, supporting the development of mutation-specific Pt-based clinical trials.
Travel distance and time to adjuvant chemotherapy in veterans with colorectal cancer.
Authors: Martin Richard Lewis , Edwards Gretchen C. , Samuels Lauren R. , Roumie Christianne L.
Published: February 2020

84

Background: Patients from rural areas have well described disparities in quality cancer care. We hypothesized that longer travel distance is associated with less chemotherapy acceptance and less timely treatment. Methods: We reviewed 705 electronic medical records of patients with colorectal surgeries from January 1, 2000 to December 31, 2015 at the Veterans Health Administration Tennessee Valley Healthcare System. Two trained abstractors reviewed standard elements (k = 0.79 – 0.92). The study sample included patients with pathological stage high risk II or III CRC and excluded those with metastatic disease or documented National Comprehensive Cancer Network (NCCN) defined medical exclusions from chemotherapy. Primary exposure was distance to care calculated from central zip code of residence to Nashville infusion center. Primary outcomes were receipt of any chemotherapy, and days from surgery to first treatment (truncated at 120 days). We analyzed 2 populations; chemotherapy received and a second sensitivity population who were eligible for, but did not receive, chemotherapy (no documentation of NCCN ineligibility or declined). Results: Of 705 colorectal resections, we excluded 262 for non-cancer, 220 for stage I or low risk stage II, and 46 for NCCN exclusion criteria, yielding 177 cases: 120 colon and 57 rectal. Most patients were male (98%) and white (85%); median age was 64 [Interquartile Range 60, 70]. Distribution by travel distance was 60/177 [33.9%] < 50 miles, 61/177 [34.5%] 50-99 miles, and 56/177 [31.6%] > 100 miles. Of all eligible patients, 123/177 [69.5%] patients received chemotherapy and 54/177 [30.5%] did not receive chemotherapy. Among receivers, median times to treatment were 52 days [40, 61] < 50 miles; 48.5 [40,61] 50-99 miles; and 54 [43,77] > 100 miles, p = 0.3. Patients not receiving chemotherapy varied by distance: 15/60 (25%) < 50 miles; 18/61 (30%) 50-99 miles; 21/56 (38%) > 100 miles, p = 0.3. Including non-receivers, median times to treatment were 58 days [43, 120] < 50 miles; 58.5 [46.5, 120] 50-99 miles; and 80 [48.5, 120] > 100 miles, p = 0.1. Conclusions: Distance to care may influence acceptability of chemotherapy. Understanding patient/provider reasons for omission merits exploration.
Racial disparity of stage III rectal cancer among young adults: A combined NCDB/SEER analysis.
Authors: Quinn Thomas J. , Kabolizadeh Peyman
Published: February 2020

85

Background: With the advent of screening colonoscopy in 1997, there has been an overall decreasing incidence in rectal cancer. Recently, the ACS updated guidelines to started screening patients at 45 years old. The purpose of this study was to further investigate incidence and overall survival trends for rectal cancer among young white and African-American (AA) patients using the SEER and NCDB databases. Methods: Rectal cancer incidence trends in SEER-9/SEER-18 were analyzed for patients < 50 years old. Treatment and survival outcomes were also evaluated using the NCDB (2004-2014). White and AA patients were matched using propensity score analysis and inverse probability of treatment weighting (IPTW). Baseline characteristics were compared with Pearson Chi Square, before and after matching. Univariate and multivariable analyses were performed with Kaplan-Meier and Cox proportional hazard modeling, incorporating the IPTW-adjusted population. Results: 6,144 (SEER) and 17,819 (NCDB) young, white or AA patients were identified. There was an overall increase in incidence of stage III (APC 5.57, P < 0.05) and IV (APC 4.66, P < 0.05) rectal cancer among young white patients. For the entire population, there was improved overall survival for white patients compared to AA patients, even after adjusting for confounding factors. Subset analysis of both the SEER and NCDB databases revealed that the largest disparity was between AAn and white rectal cancer patients, is among the Stage III subset with HR of 1.6 (P < 0.001) and HR of 1.4 (P < 0.001), respectively. Conclusions: There is an alarming increase in younger patients being diagnosed with rectal cancer. Specifically, there appears to be more locally advanced rectal cancer among younger patients and a racial disparity favoring whites for survival outcomes was identified. This research further supports the utility of earlier screening and to identify the factors involved in this rise in rectal cancer incidence.
Evaluation of adjuvant chemotherapy-associated steatosis in colorectal cancer.
Authors: Lee Michelle (Chae Min) , Taqi Ayesha , Malik Aftab , Dzulynsky Raissa , Di Tomaso Amy , Brezden-Masley Christine
Published: February 2020

94

Background: Chemotherapy-associated steatosis (CAS) is poorly understood in context of colorectal cancer (CRC). It has been anecdotally observed that CRC patients undergoing chemotherapy appeared to develop steatosis at a higher rate than expected, and that statin therapy may have protective effects against CAS. Here, we sought to evaluate 1) the frequency of CAS in Stage II-III CRC patients; and 2) whether patients on statins throughout adjuvant chemotherapy develop CAS at a lower frequency. Methods: This study retrospectively examined medical records of 267 Stage II-III CRC patients who received adjuvant chemotherapy and were followed up at St. Michael’s Hospital, Toronto, Canada between January 1, 2006 and January 1, 2017. Patient information, relevant co-morbid conditions, statin use, and adjuvant chemotherapy were collected. Baseline and incident steatosis for up to one year from chemotherapy start date was assessed based on imaging reports (CT, ultrasound, MR). Results: Of 267 patients, 78 (29.2%) had steatosis at baseline radiology, prior to treatment with adjuvant chemotherapy. Of the remaining 189 cases, the incidence of steatosis within one year of adjuvant chemotherapy start date was significantly greater in patients who received adjuvant treatment (n = 132) compared to those who did not (n = 57), (39% vs. 23%, p = 0.03). Among patients who underwent chemotherapy, statin use for preexisting hyperlipidemia, a known risk factor for steatosis (n = 39), was associated with a lower incidence of steatosis compared to no statin administration (n = 93), although this result was not significant (31% vs. 42%, p = 0.243). Among statin users, 42.9% of patients treated using oxaliplatin-containing FOLFOX regimen (n = 21) developed steatosis, compared to 20% in patients on a capecitabine regimen (n = 15). There was a trend towards significance, with p = 0.151. Conclusions: Chemotherapeutic treatment of Stage II-III CRC is associated with an increased incidence of steatosis. Statins may protect against acute development of CAS within one year following chemotherapy, particularly with single agent capecitabine. Prospective clinical trials should be considered to assess protective use of statin in this curative patient population.
A phase II study of capecitabine plus concomitant radiation therapy followed by durvalumab (MEDI4736) as preoperative treatment in rectal cancer (PANDORA).
Authors: Tamberi Stefano , Grassi Elisa , Barbera Maria aurelia , Corbelli Jody , Papiani Giorgio , Montroni Isacco , Di Bartolomeo Maria , Cascinu Stefano , Marzola Marina , Bonetti Andrea , Frassineti Giovanni , Pinto Carmine , Zingaretti Chiara , Nanni Oriana , Carli Moretti Chiara , Panzini Ilaria , Rossi Giulio , Ugolini Giampaolo
Published: February 2020

TPS259

Background: The standard treatment for cT3-4 N0-1 rectal cancer is preoperative chemo-radiation therapy (CT/RT). The combination of capecitabine plus long course radiotherapy (RT) is standard therapy in this setting. Pathologic Complete remission (pCR) can be considered as surrogate end point of efficacy of treatment in terms of disease free survival (DFS). Clinical complete remission (cCR) is an important endpoint for “wait and see” strategy. In the PACIFIC trial in non-small cell lung cancer the patients were treated with durvalumab maintenance after CT/RT with advantage in progression free survival. Preclinical data points heavily toward a strong synergy between RT and immune treatments. Furthermore, a systemic effect of RT is possible when enhanced by targeted immune treatments. Methods: This is a prospective phase II, open label, single arm, multi-centre study to evaluate the activity of an innovative sequence in operable rectal cancer: standard concomitant CT/RT therapy with 825 mg/m2 twice daily capecitabine every day and 5040 cGy radiotherapy for 5 days per week for 5 weeks followed by 1500 mg Q4W durvalumab for 3 administration. After 9-10 weeks from neoadjuvant therapy will be performed re-staging with CT and MRI scan. Surgery will be performed at week 10-12 from the end of CT/RT. Primary Objective: pCR rate, defined as a TRG 3-4 according to DWORAK criteria. Secondary Objectives: Safety of treatment with durvalumab; cCR rate after durvalumab treatment before surgery and DFS. cCR will be evaluated with clinical, endoscopic and radiological assessment to look for evidence of residual disease. DFS will be evaluated during a follow up of 5 years. Exploratory Objective: Biological translational analysis of tumor biomarkers will be performed on the endoscopy biopsy done at the diagnosis and on the biopsy performed after the CT/RT prior to treatment with durvavalumab. We hypothesize that the addition of durvalumab after standard CT/RT for the treatment of locally advanced rectal cancer may improve the pathological response rate and we have planned to enlist 60 patients in 7 centers with an enrollment period of 12 months, already underway. Clinical trial information: NCT04083365.