bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II study of copanlisib in combination with gemcitabine and cisplatin in advanced cholangiocarcinoma.
Authors: Tan Elaine , Kim Dae Won , Mehta Rutika , Cao Biwei , Kim Jongphil , Meroni Angel , Centeno Barbara , Kim Richard D.
Published: February 2020

556

Background: First line therapy for advanced cholangiocarcinoma (CCA) is currently gemcitabine and cisplatin. However, survival rarely exceeds one year with this regimen. PI3K/AKT activation has been shown to increase resistance to chemotherapy in CCA; therefore, inhibiting this pathway may improve chemotherapy’s efficacy. This phase II study evaluated the safety and efficacy of copanlisib, a potent and reversible pan-class I PI3K inhibitor, with gemcitabine and cisplatin in advanced CCA. Methods: Between July 2016 and April 2019, pts with histologically confirmed advanced/unresectable CCA received cisplatin (25 mg/m2), gemcitabine (1000mg/m2), and copanlisib 60mg on day 1 and 8, every 21 days as first line treatment. The primary endpoint was PFS at 6 months. Secondary endpoints were RR, median OS and PFS, and safety profile. A single-arm Simon’s two-stage minimax design with one-sided 10% type I error and 80% power was used. Based on ABC-01 and ABC-02 studies, PFS6 for gemcitabine and cisplatin were 57.1% and 59.3%, respectively. Therefore, PFS6 of 57% was considered not to warrant further study and ≥72% to warrant further investigation. Results: Twenty-four pts received at least one dose of the study drug (62.5% female, median age 64 years), with 70.8% intrahepatic, 16.7% extrahepatic, and 12.5% gallbladder cancer. For all pts, median OS was 13.9 months (95% CI: 6.8-17.9) and median PFS was 6.2 months (95% CI: 1.3-11.1). PFS at 6 and 12 months was 57.0% and 42.2%, and 6 and 12-month OS was 73.9% and 53.2%, respectively. Only 19 pts were considered evaluable for RR. Five pts were either lost to follow up, withdrew consent, or died before a second scan was done. Six pts achieved PR (31.5%) and 11 (57.9%) had SD. Grade 3 or higher adverse events (AE) occurred in 75% of pts. The most common grade 3/4 AEs were decreased neutrophil count (40%) and increased lipase (20%). Treated related AEs led to drug discontinuation for 3 pts (12.5%) and dose modification for 7 pts (29.2%). Conclusions: Gemcitabine, cisplatin, and copanlisib in combination did not meet the primary endpoint of 6-month PFS. However, additional correlative work is ongoing to identify a possible biomarker for copanlisib. Clinical trial information: NCT02631590.
Apurinic/apyrimidinic endonuclease-1 and hepatocellular carcinoma.
Authors: Skill Nicholas James , Maluccio Mary Alice
Published: February 2020

563

Background: The enzyme apurinic/apyrimidinic endonuclease-1 (APE1) is associated with protection against DNA damage and oxidative damage congruent with cancer. The purpose of this study is to investigate hepatic APE1 levels in association with hepatocellular carcinoma (HCC) in order to better stratify patients with underlying liver disease for the development of HCC and identify novel targets for therapy. Methods: Hepatic APE1 levels were determined by immunohistochemistry staining and ELISA within liver and tumor samples from patients with HepC±HCC. Hepatic APE1 staining was semi-quantitated using a scale of 0-100. Serum APE1 levels were determined by ELISA. In addition, APE1 staining was quantified in hepatic paraffin embedded sections from MDR2−/− mice with HCC and within MDR2−/+ mice controls that do not develop HCC. Results: Hepatocyte APE1 staining was lower in livers from patients with HepC and HCC when compared to patients with HepC without HCC. In a similar manner, hepatic APE1 levels were significantly lower in patients with HepC and HCC patients when compared to HepC controls. In contrast, serum APE1 level was greater in patients with HepC and HCC when compared to patients with HepC and no HCC. Moreover, APE1 levels were greater in HCC tumors when compared to non-malignant liver tissue. Hepatocyte APE1 staining in MDR−/− mice with HCC was lower when compared to MDR2−/+ mice that do not develop HCC. In addition, cytosolic APE1 staining was increased in HCC tumor of MDR2−/− mice when compared to controls. Conclusions: Increased APE1 is a potential biomarker of HCC risk in patients with underlying liver disease and is a novel target for therapy in patients with underlying liver disease whom have a higher risk of developing HCC. Consequently, targeted APE1 inhibition may increase chemotherapy response by reducing tolerance to DNA damage. Additional studies are required to better understand the role of APE1 inhibition in HCC in the face of reduced background hepatic APE1 levels.
Therapeutic targeting of extracellular FGFR2 activating deletions in intrahepatic cholangiocarcinoma.
Authors: Cleary James M. , Raghavan Srivatsan , Li Yvonne Y. , Spurr Liam , Wu Qibiao , Shi Lei , Brais Lauren K. , Odhiambo Zunelly , Goyal Lipika , Patel Anuj K. , Shinagare Atul B. , Clancy Thomas E. , Shapiro Geoffrey , Cerami Ethan , Sellers William R. , Hahn William C. , Cherniack Andrew D. , Bardeesy Nabeel , Meyerson Matthew , Wolpin Brian M.
Published: February 2020

567

Background: Fibroblast growth factor receptor (FGFR) pathway alterations have been identified in approximately 20% of patients (pts) with intrahepatic cholangiocarcinoma (IHCC), most commonly by FGFR2 fusions. Early phase clinical trials have demonstrated encouraging efficacy of FGFR inhibitors in pts with FGFR2-translocated cholangiocarcinoma, but efficacy in pts with other FGFR2 activating alterations is less clear. Methods: Pts with cholangiocarcinoma underwent CLIA-certified next generation DNA sequencing (NGS) to identify actionable alterations. FGFR2 fusions and other FGFR2 genomic events were assessed, with genomic characterization performed before and after treatment with FGFR inhibitors in appropriate pts. Novel extracellular domain in-frame deletions (INDELs) of FGFR2 and apparent resistance mutations were investigated for oncogenic activity and inhibitor resistance in vitro and in vivo. Results: Cholangiocarcinomas from 284 pts (136 male, 148 female; median age, 64 [20-89], including 139 IHCCs, were sequenced. Among the IHCCs, 16 (11.5%) had FGFR2 fusions, with 9 different gene partners. Surprisingly, 5 (3.6%) IHCCs harbored extracellular domain FGFR2 INDELs. Two of these IHCCs harbored an exon 5 deletion FGFR2 p.H167_N173del. Expression of FGFR2 p.H167_N173del in 3T3 cells resulted in oncogenic transformation. In the clinic, two pts with FGFR2 p.H167_N173del were treated with Debio1347, an oral FGFR-1/2/3 inhibitor. Both patients achieved a durable partial response (PR) of 11 months, with one of the pts still on active treatment with Debio-1347. The patient who developed acquired resistance underwent repeat biopsy, and NGS identified a secondary mutation ( FGFR2 p. L617F) in the kinase domain. In vitro studies demonstrated that this mutation confers resistance to Debio1347. This patient was subsequently treated with another FGFR inhibitor and again experienced a PR lasting 17 months. A third biopsy after disease progression demonstrated a previously undetected L597Q BRAF mutation. Conclusions: Extracellular domain FGFR2 in-frame deletions are a novel genomic alteration in IHCC that are transforming and predict clinical sensitivity to FGFR inhibitors.
Total skeletal, psoas, and rectus abdominis muscle mass as prognostic factors for patients with advanced hepatocellular carcinoma.
Authors: Shao Yu Yun , Wu Chih-Horng , Liang Po-Chin , Hsu Chih-Hung , Shih Tiffany Ting-Fang
Published: February 2020

568

Background: We investigated whether low skeletal muscle mass (LSMM) defined according to different muscle groups on computed tomography (CT) scans could predict prognosis of advanced hepatocellular carcinoma (HCC). Methods: We analyzed patients who received first-line sorafenib treatment for advanced HCC in a prospective patient cohort between 2007 and 2012. The muscels areas of total skeletal muscle (TSM), paraspinal muscle (PS), psoas muscle (PM), rectus abdominis (RA), and abdominal wall (AW) were evaluated using a single CT slice at the third lumbar vertebra before treatment. LSMM was determined according to the TSM, PS, PM, RA and AW indices, which was calculated as the parameters divided by the square of the body height. Results: We enrolled 137 patients, with a mean age of 57.5 years; 120 were male and 17 were female. Liver disease etiology was hepatitis B virus in 94 (68.6%) patients and hepatitis C virus in 28 (20.4%) patients. All patients had Child–Pugh class A liver reserve. Women had significantly lower TSM index than men did ( p < .001). Among men, the optimal cut points of the TSM, PM and RA indices for LSMM diagnosis were 39.1, 8.3 and 2.9 cm2/m2, respectively. Patients with LSMM exhibited poorer overall survival than patients without LSMM, whether LSMM was defined by TSM index (median 5.1 vs. 8.0 months, p = 0.007), PM index (median 5.8 vs. 11.8 months, p < 0.001), or RA index (median 7.2 vs. 8.1 months, p = 0.003). After adjusting for clinical variables including underweight, age, tumor extent, and performance status, LSMM defined by TSM index (hazard ratio [HR]: 2.123, 95% confidence interval [CI]: 1.124-4.010, p = 0.020), PM index (HR: 1.855, 95% CI: 1.163-2.959, p = 0.009), or RA index (HR: 1.650, 95% CI: 1.004-2.710, p = 0.048) remained independent predictors for poor OS. Conclusions: LSMM defined by TSM, PM and RA indices are independent predictors for poor prognosis of advanced HCC, even after adjusted for body weight.
Impact of baseline hepatitis B viremia and management on outcomes in patients (Pts) with advanced hepatocellular carcinoma (HCC) and elevated alpha-fetoprotein (AFP): Outcomes from REACH-2.
Authors: Galle Peter R. , Kudo Masatoshi , Llovet Josep M. , Finn Richard S. , Karwal Mark , Pezet Denis , Kim Tae-You , Yang Tsai-Sheng , Zagonel Vittorina , Tomasek Jiri , Phelip Jean Marc , Touchefeu Yann , Koh Su-Jin , Stirnimann Guido , Wang Chunxiao , Ogburn Kenyon , Abada Paolo , Widau Ryan C. , Zhu Andrew X.
Published: February 2020

569

Background: REACH (NCT01140347) and REACH-2 (NCT02435433) were global, randomized, blinded, placebo (PL)-controlled phase 3 trials of ramucirumab (RAM) in pts with advanced HCC following sorafenib. REACH-2 limited enrollment to pts with AFP ≥400 ng/mL, and met its primary OS endpoint, consistent with the prespecified REACH subgroup with baseline AFP ≥400 ng/mL. Analysis of pooled individual pt data from REACH (AFP ≥400 ng/mL) and REACH-2 showed improved OS with RAM vs PL for pts with hepatitis B virus (HBV) etiology (7.7 vs 4.5 mos; HR 0.74, 95% CI 0.55, 0.99). Here we investigate survival and liver function in REACH-2 pts with HBV etiology tested for serum HBV DNA. Methods: Pts had advanced HCC, Child-Pugh A, ECOG PS 0/1, AFP ≥400 ng/mL, prior sorafenib treatment, and were randomized (2:1) to receive RAM 8 mg/kg or PL Q2W. Pretreatment serum HBV DNA was quantified by HBV-specific PCR (Roche) by a central lab. HBV DNA > 15 IU/mL were detectable (HBV DNA+), < 15 IU/mL were undetectable (HBV DNA-). OS in pooled treatment arms was evaluated using Kaplan-Meier method and Cox proportional hazards model. Liver function was assessed at baseline and before each cycle with the ALBI linear predictor. Outcomes were assessed by concomitant antiviral therapy. Adverse events (AEs) were graded by NCI-CTCAE v4.0. Results: Of 107 REACH-2 pts with HBV etiology, 106 had available PCR samples and were included in a pooled analysis (70 RAM and 36 PL pts). 48 pts were HBV DNA+ and 58 pts were HBV DNA-. HBV DNA+ pts had poorer median OS vs HBV DNA- pts (5.3 vs 10.1 mos, unstratified HR 1.45 95% CI 0.93, 2.28). HBV DNA+ pts taking concomitant antiviral therapy (n = 36) had numerically improved OS compared with those without (n = 12) (5.8 vs 4.0 mos). No difference in OS was noted for HBV DNA- pts by antiviral therapy use (n = 39 antiviral; n = 19 no antiviral) (10.2 vs 9.7 mos for yes vs no antiviral). In pts taking antiviral therapy, regardless of HBV DNA serology, liver function was improved and liver injury/failure related AEs were less frequent. Conclusions: Our data reinforce the use of antiviral therapy to improve outcomes in pts with advanced HBV-associated HCC and elevated AFP. Clinical trial information: NCT02435433.
Oncology precision medicine for hepatobiliary and pancreatic cancer: Insights and updates upon an institutional review.
Authors: Bellini Geoffrey , Sich Nicholas , Godden Jennifer Jo , Weese James L. , Papenfuss Wesley Allan , Chevinsky Aaron , Ruggeri Antony , Thompson Michael A.
Published: February 2020

570

Background: Hepatobiliary cancers - hepatocellular carcinoma (HCC), intra or extrahepatic cholangiocarcinoma (I/EC), and gallbladder carcinoma (GB) - and pancreatic adenocarcinoma (PC) do have actionable alterations (AA). The importance of testing early in a patient’s (pts) course to identify oncology precision medicine (OPM) options could be paramount for progression free survival (PFS). Methods: We identified pts with HCC, IC, EC, GB or PC in our OPM database since the centralization of our system. Pts who underwent molecular panel testing had AA’s identified and stratified by cancer type. Treatment course was analyzed using swimmers plots. Results: 456pts were diagnosed with HCC, IC, EC, GB or PC. 104/456pts (23%) were ordered for molecular testing and 88/456pts (19.3%) completed testing: 18/88pts (20.4%) I/EC, 2/88pts (2.3%) HCC, 5/88pts (5.7%) GB, and 63/88pts (71.6%) PC. Of the PC pts, 3/63 (4.8%) had a BRCA mutation. These pts did not receive targeted therapy. Overall, 5/88pts (5.7%) had a BRAF mutation (2 PC, 2 I/EC, 1GB). Thus, 8/88 (9.1%) of tested pts became eligible for some form of targeted therapy over their treatment course. Of those with a BRAF mutation, only 2/5 pts had OPM testing sent with initial diagnostic workup, and 2/5 eventually began targeted therapy. One had a progression free survival (PFS) of 2.5months while the other discontinued secondary to toxicity. Conclusions: Our data showed that we are testing a minority of pts with pancreas and hepatobiliary cancers. Of those tested, it may have occurred too late in the course of illness to improve outcomes. Given the potential utility of uncovering potential germline alterations like BRCA1/2 as well as pragmatic AAs including somatic BRCA and BRAF, we are moving to a more systematic evaluation of pts to capture and respond to these issues.

[Table: see text]
Primary versus metastatic intrahepatic cholangiocarcinoma: A comparative comprehensive genomic profiling (CGP) study.
Authors: Ross Jeffrey S. , Sokol Ethan , Vergilio Jo-Anne , Killian Keith , Lin Douglas I. , Williams Erik , Danziger Natalie , Ramkissoon Shakti H. , Severson Eric Allan , Hemmerich Amanda , Edgerly Claire I. , Huang Richard , Ali Siraj Mahamed , Madison Russell , Alexander Brian M , Venstrom Jeffrey Michael , Reddy Venkataprasanth P. , McGregor Kimberly , Elvin Julia Andrea , Schrock Alexa Betzig
Published: February 2020

578

Background: Genomic alterations (GA) characteristic of IHCC are well known. We queried whether the GA of IHCC from primary tumor biopsies (p-bx) would differ from IHCC metastasis biopsies (m-bx). Methods: CGP was performed on 1,268 cases of advanced stage IHCC using p-bx in 1,048 cases and m-bx from 220 cases. Tumor mutational burden (TMB) was determined on 0.8-1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression in tumor cells (Dako 22C3) was measured by IHC. Results: M-bx sites included: lymph nodes (63), soft tissues (47), peritoneum (34), lung/pleura (27), omentum (15), bone (10), GYN tract (5), brain (2), Upper GI (2), colon (2), bladder (1), abdomen (1) and adrenal (1). The GA per sample were similar as were biomarkers of immuno-oncology (IO) drug response. The KRAS mutation frequency was doubled in the m-bx compared to the p-bx (p < 0.001), and enrichment of the potentially targetable KRAS G12C was also observed. Frequencies of untargetable GA were similar overall. IDH1 (p < 0.001) and FGFR2 GA known to be enriched in IHCC were less frequent in the m-bx cohort. GA in STK11 were more frequently identified in m-bx. Conclusions: GA found in p-bx vs m-bx in IHCC are significantly different; the m-bx cohort featuring greater KRAS and lower IDH1 and FGFR2 GA. This suggests that the m-bx group may contain a significant number of non-IHCC cases whose metastatic lesions were actually derived from other primary sites incorrectly assigned the diagnosis of IHCC.

[Table: see text]
Progression-free survival in patients with cholangiocarcinoma with FGFR2 fusions or rearrangements: An exploration of response to systemic therapy.
Authors: Bibeau Kristen , Féliz Luis , Barrett Scott , Na Ling , Lihou Christine Francis , Asatiani Ekatherine
Published: February 2020

588

Background: Most cholangiocarcinoma (CCA) patients (pts) are diagnosed with advanced disease and are ineligible for surgery. FGFR2 fusions or rearrangements are present in 10–16% of pts with intrahepatic CCA (iCCA) and are reported to be oncogenic drivers. However, little data are available on the role of FGFR2 genetic alterations in the response to systemic cancer therapy. FIGHT-202 is a phase 2 study of pemigatinib (a selective, potent, oral FGFR1–3 inhibitor) in pts with previously treated advanced/metastatic CCA (NCT02924376); primary results were reported at ESMO 2019. FIGHT-202 enrolled pts who progressed on ≥1 prior therapy, allowing the examination of the role of FGFR2 alterations on the response to prior therapy. The objective of this post hoc analysis was to evaluate progression free survival (PFS) on standard systemic therapy received prior to study enrollment among pts with CCA harboring FGFR2 fusions or rearrangements ( FGFR2+). Methods: Case report forms were reviewed to determine disease history and exposure to prior lines of systemic cancer therapies (LOSCT) in the advanced setting before receiving pemigatinib. Only pts with sufficient data on prior LOSCT were included in this analysis. Median PFS was calculated using the Kaplan-Meier method. Results: 102 pts were included in this analysis (median age 54.5, 61.8% female). Median PFS on first-line therapy was 5.5 (95% CI: 4.0, 8.0) months. Among the 38 pts (37.3%) with ≥2 prior LOSCT, median PFS on second-line therapy was 4.4 (95% CI: 3.0, 5.3) months. Conclusions: This analysis provides data about PFS on standard systemic therapies for pts with FGFR2+ CCA. Median PFS on first-line therapy was lower than historical published data, and median PFS on second-line therapy was slightly longer than previously reported, in unselected CCA populations. Limitations of this analysis include retrospective examination of investigator reported data, and that clinical trial participants may not truly reflect a general CCA patient population. The short PFS on standard therapies in pts with FGFR2+ CCA highlights the need for development of other options including targeted therapies to improve outcomes.
Preventive effects of gender and metabolic syndrome in 40s on colorectal cancer by colonoscopy.
Authors: KIM Hyun-Soo , Kim Su Young , Lee Jung Kuk
Published: February 2020

59

Background: This study was aimed at measuring the preventive effect of colonoscopy for CRC development depending on age of index colonoscopy, gender and metabolic syndrome among persons aged 40 to 59 years. Methods: Between January 2005 and December 2006, data for the population aged from 40 to 59 who underwent colonoscopy (CSP cohort) claimed were collected from National Health Insurance Service (NHIS). Non-CSP (N-CSP) subjects were also collected by 1:5 propensity score matching with parameters of age, sex, and metabolic profiles, smoking, alcohol and past history of cancer. After one year of washout period, the risk of developing CRC was estimated by the occurrence of new case from January 2009 to December 2014 using the link of National CRC Registry to NHIS database. Compared with N-CSP cohort, hazard ratios (HRs) were obtained via conditional logistic regression analysis to estimate the risk of CRC in CSP cohort by age groups. Results: A total of 2,339,359 subjects were included (CSP cohort: 395,738 and matched N-CSP cohort: 1,943,621). The HRs for developing CRC by ages of 40-44, 45-49, 50-54, and 55-59 years in a CSP cohort were 0.864 ( P = NS), 0.591 ( P < 0.001), 0.599 ( P < 0.001), and 0.524 ( P < 0.001) in men, and 0.774 ( P = NS), 0.841 ( P = NS), 0.598 ( P < 0.001), and 0.605 ( P < 0.001) in women, respectively. Interestingly, when confined to patients with metabolic syndrome in their 40s, HRs for CRC in the colonoscopy cohort were statistically significantly lowered to 0.372 in early 40’s and 0.386 in men of late 40s, respectively, but not in women of 40s. Conclusions: The CRC prevention effect of colonoscopy is expected from late 40s in men and early 50s in women. Furthermore, in cases with metabolic syndrome, the preventive effect of colonoscopy is expected in men of early forties.
Colorectal cancer prevalence and risk factors among the uninsured of Tampa Bay: A free clinic study.
Authors: Song Ethan , Patel Artish , Swanson Justin , Aponte Alexandra , MacDonald Madeline , Segarra Daniel , Shah Nirav , Ayoubi Noura , Mirza Abu-Sayeef
Published: February 2020

61

Background: Uninsured patients with low socioeconomic status are at higher risk for developing colorectal cancer. There is limited quantifiable data regarding risk factors and prevalence of colorectal cancer in this vulnerable population. The purpose of this study is to assess the risk factors for colorectal cancer in the low income and uninsured patient population across nine free clinics around Tampa Bay, Florida. Methods: An IRB-approved manually extracted retrospective query of several medical record systems from nine free clinics in the Tampa Bay area in 2017 revealed 1,836 (36.1%) of 5,076 total patients who are over 50 years old. Patient demographics, weight, smoking status, alcohol use, type 2 diabetes status, inflammatory bowel disease and colorectal cancer prevalence were also extracted and analyzed. Results: Among patients over 50, the majority of patients were female (n = 1073, 58.4%) and of Hispanic ethnicity (n = 752, 41.0%). Of the 1,349 patients who reported their smoking status, 213 (15.8%) were active smokers and 218 (16.2%) were past smokers, with a mean 16.3 (SD = 15.5) pack year history. Of the 1,124 patients who reported their history of alcohol consumption, 217 (19.3%) were current consumers and 40 (3.6%) were past consumers. The average BMI of patients over 50 years was 30.2 (SD = 6.9), with 558 (30.4%) cases of diabetes. Eleven patients (0.6%) had a history of inflammatory bowel disease. The prevalence of documented colorectal cancer in this sample was 0.6% (n = 11) in our sample population. Conclusions: There is a high prevalence of risk factors for colorectal cancer in this sample of uninsured patients but a lower reported prevalence of colorectal cancer compared to the general population. Additionally, many known risk factors for colorectal cancer, such as diet, physical activity, or family history, are not routinely documented by free clinics. As these clinics provide opportune points of primary care, this baseline data should prompt more attention to colorectal screening and risk factor modification in this vulnerable population.
The antidiarrheal efficacy of a proprietary amino acid mixture (enterade) in neuroendocrine tumor (NET) patients: Updated data.
Authors: Chauhan Aman , Miller Rachel C. , Luque Laura , Weiss Heidi , Anthony Lowell Brian
Published: February 2020

614

Background: Diarrhea is a common quality of life limiting symptom seen in neuroendocrine tumor patient. Diarrhea in these patients could be due to excessive serotonin production, secondary to post-operative short gut syndrome, steatorrhea from somatostatin analogs, bile acid colitis or intestinal bacterial overgrowth. In this study we summarize our single center experience with enterade. Methods: Medical records of all the NET patients treated with enterade for symptomatic diarrhea were retrospectively reviewed after appropriate IRB approval. Patients were treated at Markey cancer center between May 2017-June 2019. Results: Total 98 patients were offered enterade. enterade was instructed to be taken as one 8 Oz bottle BID for 1 week. Antidiarrheal efficacy data was available on 49 patients at the time of abstract submission. 37 (75%) patients had GEPNETs, 8 had bronchial NETs, 1 gynecological NET and 3 patients had unknown primary. 28 (57%) patients had history of prior bowel resection either for primary neuroendocrine tumor resection or debulking. 28 (57%) patients were on somatostatin analog at the time of initiation of enterade. 42 (85%) out of 49 patients reported subjective improvement in diarrheal symptoms. 27 (64%) out of these 42 responders reported at least 50 percent reduction in diarrhea frequency. Conclusions: 85% (42/49) neuroendocrine tumor patients reported improvement in diarrhea with enterade. 64% (27/42) reported more than 50% reduction in diarrhea frequency. A prospective Phase II study of enterade in neuroendocrine tumor patients with quality of life limiting diarrhea is currently being conducted (NCT03722511).
Phase I dose-escalation trial of trifluridine/tipiracil (TAS-102) and temozolomide in the treatment of advanced neuroendocrine tumors.
Authors: Uboha Nataliya Volodymyrivna , Lubner Sam Joseph , LoConte Noelle K. , Mulkerin Daniel , Eickhoff Jens C. , Deming Dustin A.
Published: February 2020

615

Background: Systemic chemotherapy plays a role in treating neuroendocrine tumors. Trifluridine/tipiracil (FTD/TPI), known as TAS-102, is an antineoplastic agent that is non-cross resistant with 5-fluorouracil and capecitabine and that has a different toxicity profile. We are presenting results from a phase 1 portion of the study evaluating safety of FTD/TPI in combination with TMZ in patients in neuroendocrine tumors. Methods: Phase 1 portion to the study utilized “3+3” design to determine maximum tolerated doses (MTD) of FTD/TPI and TMZ when administered in combination. Patients with advanced NETs of any grade were eligible for participation. FTD/TPI was taken twice a day on days 1-5 and 8-12 and TMZ was taken daily on days 8-12 of a 28 day cycle. 3 dose levels (Lv) were evaluated. FTD/TPI was started at a goal dose of 35 mg/m2 twice daily. Three doses of TMZ were studied: 100, 150 and 200 mg/m2. Growth factor support was required during DLT evaluation period for all patients starting with the fourth subject on study. Results: Sixteen evaluable subjects (6 females, median age 64) enrolled in the phase 1 portion of the study (4 on Lv1, 6 on Lv2, 6 on Lv3). 3/16 had high-grade tumors, 8/16 had non-GI or unknown primary. No DLTs were observed on Lv1. One DLT was observed on Lv2 (grade 3 fatigue and inability to resume treatment) and 1 DLT on Lv3 (grade 4 thrombocytopenia). Overall the treatment was well tolerated. 7 subjects had grade ≥3 AEs at least possibly related to treatment, with neutropenia and lymphopenia being the most common. 4 subjects required dose reductions. 7 subjects remain on active treatment. 4 subjects discontinued treatment due to AEs and 1 due to clinical disease progression. Efficacy data is being collected and will be presented at the meeting. Conclusions: This study established MTD of FTD/TPI (35mg/m2 twice daily) and TMZ (200 mg/m2). This regimen is well tolerated. Enrollment into expansion cohort for patients with advanced Grade 1-2 pancreatic NETs is ongoing (NCT02943733). Clinical trial information: NCT02943733.
Single institution experience with peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumors (NET).
Authors: Duan Heying , Ninatti Gaia , Girod Bradley , Ferri Valentina , Kunz Pamela L. , Fisher George A. , Moradi Farshad , Davidzon Guido Alejandro , Franc Benjamin Lewis , Iagaru Andrei , Mari Carina
Published: February 2020

623

Background: Neuroendocrine tumors (NETs) are rare but increasing in incidence. The only curative treatment is surgery, which in many cases is not an option due to metastatic disease at diagnosis. The NETTER-1 study showed high efficacy and low toxicity of peptide receptor radionuclide therapy (PRRT) for midgut NETs. Here, we present our initial experience with PRRT in the treatment of patients with NET. Methods: Fifty-two patients (27 males and 25 females; 37 - 81 yo, mean ± SD: 61.8 ± 10.6 years) with documented progressive NET (25 pancreas, 17 small intestine, 1 coecum, 4 unknown primary, 3 paragangliomas, and 2 pheochromocytomas) were referred to undergo PRRT at our institution from July 2018 to September 2019. Laboratory tests were obtained at baseline, 1 week before each cycle and every 3 months following treatment. Progression-free survival (PFS), objective response rate (ORR) and toxicity were assessed. An interim overall survival (OS) analysis was performed. Results, when possible, were compared with the NETTER-1 trial. Lines of therapy were documented. Results: 22/52 (42%) patients completed all 4 cycles of PRRT. 18/52 (34%) patients are currently being treated. 12/52 (23%) patients had to discontinue treatment. Hematotoxicity was the only side effect which can be related to PRRT. The 6-month and 9-month PFS rate was 82.4% and 66.8% respectively vs. 89% and 84% in the NETTER-1 trial. The ORR was 36% vs. 18% in the NETTER-1 trial. In the interim OS analysis, 6 deaths occurred. In contrast to the NETTER-1 study, PRRT in our patient cohort was performed later in the course of treatment (median lines of therapy before PRRT = 4 ±1.3 (range 1-6)). Conclusions: Our preliminary data show overall good results of PRRT in patients with NETs. However, compared to the NETTER-1 trial, PFS is shorter which is most likely due to the extensive pretreatment, but ORR was higher. [Table: see text]
Validating enhancer signature classifications (ESCs) in pancreatic neuroendocrine tumors (PNETs).
Authors: Trinh Vincent Quoc-Huy , Shi Chanjuan , Berlin Jordan , Das Satya
Published: February 2020

627

Background: Predicting recurrence risk (RR) for resected (res) PNET patients (pts) is challenging using existing pathologic criteria. Better predictive models to tailor surveillance for individual pts are needed. A recent study suggests expression patterns of the transcriptomic/epigenomic enhancers ARX and PDX1 may predict RR. In this study, distant metastases occurred almost exclusively in ARX+/PDX1- tumors. Our primary objective was to validate ESCs within our institutional cohort. Methods: We used a tissue microarray generated from res localized PNETs at Vanderbilt University Medical Center (VUMC) between 2002-2012. Clinical, pathological, and outcomes data were extracted from records. Immunohistochemistry was performed with PDX1 by Novus and ARX by Sigma. Patients were grouped as double-positives (DP), ARX+/PDX1-, ARX-/PDX1+ and double-negatives (DN). Time-dependent ROC analysis was performed in R (v3.6.1; survivalROC v1.0.3) to determine ARX and PDX1 positivity. Comparative analyses were performed in SPSS v23.0 (Kruskal-Wallis, Freeman-Halton exact test, Log-rank). Primary outcomes were progression-free survival (PFS) and cancer-specific survival (CSS). Results: 61 PNET specimens had adequate tissue for analysis. Table shows PFS plus CSS data by ESC distribution. Pts with ARX+ (DP & ARX+/PDX1-) tumors were younger (P=0.015) and possessed larger tumors (P=0.065). Pts with ARX+ tumors demonstrated shorter PFS (log-rank P=0.006) and a trend toward lower CSS (log-rank P=0.09). Notably, pts with ARX-/PDX1+ and DN tumors had no deaths and only 1 progression event over a median follow-up period of 91 months (m). Conclusions: Building upon earlier data that ARX+ res PNETs are more likely to relapse, we demonstrate that pts with such tumors have diminished PFS and a trend toward diminished CSS. ESCs need prospective validation but carry the potential to guide surveillance for res PNET patients. [Table: see text]
HALO 109-301: A randomized, double-blind, placebo-controlled, phase 3 study of pegvorhyaluronidase alfa (PEGPH20) + nab-paclitaxel/gemcitabine (AG) in patients (pts) with previously untreated hyaluronan (HA)-high metastatic pancreatic ductal adenocarcinoma (mPDA).
Authors: Tempero Margaret A. , Van Cutsem Eric , Sigal Darren , Oh Do-Youn , Fazio Nicola , Macarulla Teresa , Hitre Erika , Hammel Pascal , Hendifar Andrew Eugene , Bates Susan Elaine , Li Chung-Pin , De La Fouchardiere Christelle , Heinemann Volker , Maraveyas Anthony , Bahary Nathan , Layos Laura , Sahai Vaibhav , Zheng Lei , Lacy Jill , Bullock Andrea J. ,   HALO 109-301 Investigators
Published: February 2020

638

Background: HA is a major component of the tumor microenvironment (TME) in PDA. PEGPH20 degrades tumor HA, remodeling the TME. In PDA models, PEGPH20 has shown antitumor activity and increased TME delivery of anticancer agents to improve efficacy. A randomized phase 2 study showed promising results for PEGPH20+AG (PAG) in mPDA and identified HA accumulation as a biomarker. We present results from a phase 3 study (NCT02715804) of PAG for pts with HA-high mPDA. Methods: Pts ≥18 years with untreated HA-high mPDA were randomized (stratified by geographic region) 2:1 to PAG or placebo+AG (AG). HA status was prospectively determined with VENTANA HA RxDx Assay, with HA-high defined as ≥50% staining of a tumor sample. Treatment was administered IV in 4-wk cycles (3 wks on, 1 wk off) until progression or intolerable adverse events (AEs): PEGPH20 3.0 µg/kg twice wkly for Cycle 1 and once wkly (QW) thereafter, A 125 mg/m2 QW and G 1000 mg/m2 QW. Prophylactic enoxaparin 1 mg/kg was given daily for thromboembolism (TE) risk. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), objective response rate (ORR) and safety. Response was independently assessed per RECIST v1.1. The estimated sample size was ~500 pts to detect a hazard ratio (HR) for OS of 0.67 (93% power, 2-sided α = 0.05) after 330 deaths. Results: As of 20 May 2019, 494 pts were randomized with 492 (327 for PAG and 165 for AG) included in ITT analyses (2 pts excluded due to site violations). Baseline characteristics were balanced for PAG vs AG. After 330 deaths, median OS for PAG vs AG was 11.2 vs 11.5 mo (HR 1.00, 95% CI 0.80–1.27; P = 0.97); median PFS was 7.1 vs 7.1 mo (HR 0.97, 95% CI 0.75–1.26); confirmed ORR was 34% vs 27%. Grade (G) 3+ AEs (PAG vs AG) included neutropenia (44% vs 47%), thrombocytopenia (21% vs 16%) and fatigue (16% vs 10%); G3+ rates were 6% vs 7% for TE events, 5% vs 2% for bleeding events and 13% vs 5% for musculoskeletal events. Conclusions: PAG did not improve clinical outcomes vs AG. The PAG safety profile was consistent with that of previous studies. Clinical trial information: NCT02715804.
Impact of biliary metal and plastic stents on preoperative staging for pancreatic cancer.
Authors: Hachem Hachem , Reddy Sanjay S. , Tokar Jeffrey , O'Halloran Eileen , Higa Jennifer , Sapp Abby , Civitarese Albert , Bartel Michael
Published: February 2020

646

Background: Multiple studies have shown the superiority of biliary metal compared with plastic stents for pre-operative (preop) biliary drainage in pancreatic cancer (PDAC). Despite the importance of preop cross-sectional imaging, particularly in the era of neoadjuvant treatment, there is no data on the impact of such stents on the quality of preop cross-sectional imaging. We hypothesis, that biliary metal stents negatively impact the accuracy of preop cross-sectional imaging in pancreatic cancer, with unknown impact for the adequacy of surgical candidacy. Methods: Data of all patients undergoing pancreatic resection for PDAC between 1/1/2012 and 1/1/2018 was retrospectively abstracted. Clinical staging based on preop cross-sectional imaging following biliary stent placement (within 2 months prior surgical resection) was compared with the surgical pathology (staging gold standard). Accuracy of clinical and surgical pathology staging was compared. Logistic regression was performed to control for biliary stent type, neoadjuvant treatment and patient baseline characteristics including BMI and type of imaging. Results: 312 patients underwent pancreatic resections. 118 patients required preop biliary drainage in setting of PDAC, including 92 ERCPs of which 83 were successful (46 plastic and 37 metal stents). 76 patients underwent neoadjuvant chemoradiation therapy. Surgical pathology revealed following stages: 0 n = 4, 1A n = 5, 1B n = 8, 2A n = 20, 2B n = 24, 3 n = 1, 4 n = 14. 96% underwent preop CT and 4% MRI pancreas protocol imaging. Exact correlation between clinical and surgical pathology was present in only 48% of cases (57% plastic, 46% metal stent), with 28% of clinical T overstaging, 4% clinical T understaging, 16% clinical N understaging and 4% unable to stage due to artefacts. More importantly, 8% patients were incorrectly staged to be surgical candidates (14% plastic, 6% metal). Controlling for stent type, neoadjuvant treatment and BMI did not impact preop cross-sectional imaging accuracy. Conclusions: Despite their impact on preop cross-imaging biliary metal stents did not negatively impact the accuracy and patient selection for surgical candidacy compared with biliary plastic stents in PDAC.
A colorectal cancer screening initiative to assist the healthcare for the homeless program within the Harris Health Safety-net Health Care System.
Authors: Rosen Allison , Escobar Betsy , Datar Gandhar , Chenier Roshanda , Montealegre Jane , Jibaja-Weiss Maria
Published: February 2020

65

Background: The homeless population presents unique challenges for Colorectal Cancer (CRC) screening and follow-up, due to difficulty completing at home procedures such as stool-based screening and prepping for a colonoscopy. Harris Health System’s Healthcare for the Homeless Program (HHS-HHP) screens patients for CRC using strategies such as on-site stool collection to promote completion of fecal immunochemical tests (FIT). According to the HHS screening algorithm, there are currently no targeted interventions at HHS-HHP to address diagnostic follow-up of FIT-positive patients who require colonoscopy Homeless patients face barriers to colonoscopy, notably the structure of shelters, which makes it difficult to prep for a colonoscopy; and the lack of a companion to accompany patients to and from their procedures. Methods: We reviewed data regarding FIT screening and colonoscopy completion from Harris Health for the 2016-2017 fiscal year. We convened meetings with administrators of the Star of Hope Cornerstone Community and HHS-HHP to examine barriers faced by this population and identify potential interventions to address them. Results: For the 2016-17, fiscal year the average FIT completion rate for the entire population was 72% versus the homeless population was 38%. In the colonoscopy database, 173 homeless patients had positive FITs, but only 43 got their colonoscopy (25%). Reasons for not getting the colonoscopy were poor prep, not being able to reach the patient, and no-shows. There is an obvious need for an intervention to assist homeless patients in completing a colonoscopy after a positive FIT. Conclusions: Our project will assist with the care coordination for the homeless patients requiring a colonoscopy. We plan to coordinate care with the homeless shelters to schedule the use of a private, subacute care room (respite unit), if available, to ensure the patients appropriately prep the night before their procedure. In addition, medical student volunteers will be serving as companions for this project; thus, we plan to work with the patient and shelters to provide volunteers accompany patients to and from their procedures.
Safety and efficacy of chemotherapy in older adults with locally advanced and metastatic pancreatic ductal adenocarcinoma (PDAC).
Authors: Ostios-Garcia Lorena , Saade Patricia , Grossman Joseph Elan , Lanniello Leanne , Bullock Andrea J.
Published: February 2020

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Background: PDAC is often diagnosed in patients (pts) ≥75yrs. However, older adults comprise a small proportion of subjects in prospective trials, and there is little reported on the safety and efficacy of chemotherapy in this population. Methods: Records were reviewed on all pts ≥75yrs treated with chemotherapy for locally advanced and metastatic PDAC at a single institution from April 2010 - March 2018. Response rate (RR), progression free survival (PFS), overall survival (OS) and toxicities were compared among the different regimens, and among pts < or ≥80yrs. Survival was estimated with the Kaplan-Meier method and compared by log-rank test. Univariate analyses were performed by Fisher’s exact test and multivariate analyses by a Cox-regression model to identify factors associated with PFS and OS in this population. Results: 67 pts were treated, median age 81yrs (range: 75-90), stage III (34, 51%) and IV (33, 49%). Chemotherapy regimens included: gemcitabine alone (39), gemcitabine/nab-paclitaxel (17), gemcitabine/vinorebine (1), FOLFOX (8) and FOLFIRINOX (2). 59 (88%) pts required dose adjustments due to toxicity; no differences by age or regimen. RR, PFS, and OS did not differ by age or regimen (Table), although sample size was small. Age >80yrs was associated with reduced PFS (p 0.03). On univariate analyses liver metastases and performance status (PS)>1 were associated with reduced OS; PS>1 was associated with reduced OS on multivariate analysis. Conclusions: Among pts with locally advanced and metastatic PDAC ≥75yrs, there were no differences in RR, PFS or OS by chemotherapy regimen. PS was the only variable associated with reduced OS. Older adults with PS 0-1 are likely to benefit from chemotherapy for non-resectable PDAC.[Table: see text]
Comparison of clinicopathological characteristics and prognosis of borderline resectable pancreatic cancer according to the location of the primary tumor.
Authors: Takeda Tsuyoshi , Sasaki Takashi , Mie Takafumi , Furukawa Takaaki , Kanata Ryo , Kasuga Akiyoshi , Matsuyama Masato , Ozaka Masato , Sasahira Naoki
Published: February 2020

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Background: Little is known about the clinicopathological and prognostic differences between borderline resectable (BR) pancreatic head (Ph) and pancreatic body/tail (Pbt) cancer. Therefore, we conducted this study to compare the clinicopathological features and prognosis of BR pancreatic cancer (PC) according to the location of the primary tumor. Methods: We retrospectively investigated consecutive patients with BR PC who initiated neoadjuvant chemotherapy (NAC) between March 2015 and April 2019. We compared clinicopathological characteristics and prognosis between Ph and Pbt cancer. Furthermore, multivariate survival analysis was performed using cox proportional hazard model. Results: A total of 104 patients with BR PC (median age 68, male 49%) were included in this study. The location of the tumor was Ph 72 and Pbt 32, respectively. The initial regimen of NAC was nab-paclitaxel/gemcitabine in 102 and gemcitabine in 2, respectively. The median cycle of NAC was 4. Median age, sex, primary tumor size, performance status, neutrophil to lymphocyte ratio, and serum level of carbohydrate antigen 19-9 at the time of the initiation of NAC were not significantly different between Ph and Pbt cancer, while the modified glasgow prognostic score (mGPS) was lower in Pbt cancer (mGPS = 0; 78% vs. 94%, p = 0.05). R0/R1 resection rate (81% vs. 69%, p = 0.21) and median survival time (928 days vs. NA, p = 0.13) were also not different between Ph and Pbt cancer. Multivariate survival analysis revealed that R0/R1 resection (HR, 0.11; p < 0.01) and Ph (HR, 2.29; p = 0.03) were independent prognostic factors for survival in patients with BR PC. Conclusions: Although R0/R1 resection rate was similar between BR Ph and Pbt cancer, Pbt cancer had a higher rate of mGPS score of 0 compared to Ph cancer. Furthermore, R0/R1 resection (HR, 0.11) and Ph (HR, 2.29) were independent prognostic factors for survival in patients with BR PC.
Impact of dose reductions on clinical outcomes among patients (pts) with metastatic pancreatic cancer (mPC) treated with liposomal irinotecan (nal-IRI) in oncology clinics in the United States.
Authors: Cockrum Paul , Surinach Andy , Kim George P. , Mercer Daniel , Koeller Jim M. , Miksad Rebecca A.
Published: February 2020

665

Background: The recommended starting dose for nal-IRI is 70mg/m2 (free base, equivalent to 80 mg/m2 salt-based dosing). This study evaluates the impact of nal-IRI dose reductions on clinical outcomes. Methods: Using the nationwide Flatiron Health electronic health record-derived database, de-identified data were extracted and analyzed for adult mPC pts treated with nal-IRI Jan 2014-Jan 2019 and who initiated treatment at approximately the recommended dose (RD), 70mg/m2 +/- 5mg. Initial dose was derived from structured medication records, prioritizing administrations. The cumulative dose (CD) of nal-IRI over the first six weeks of treatment, the presence of dose reductions (DR) – (a decrease ≥ 7mg/m2), overall survival (OS) from treatment initiation, and duration of treatment (DoT) were assessed. Results: 257 mPC pts treated with nal-IRI (median age: 68y, IQR: 61 - 73) were identified initiating therapy at approximately the RD. 26.5% (N = 68) of pts experienced a DR during treatment. Mean 6-week CD was 175.8 mg/m2 (SD: 77.9) among pts with no DR. For pts with DR, mean CD was 191.8 mg/m2 (53.2). Median DoT was 6.1 wks (IQR: 2.1 – 15.3). Pts that experienced a DR had a longer median DoT: 15.1 wks (7.1 – 23.0) vs 4.3. wks (2.1 – 12.1) for pts with no DR. Overall Median OS (mOS) was 4.2 months (95% CI: 3.7 – 5.4). mOS for DR pts was 7.2 mos (95% CI: 5.5 – 9.7) and 3.7 mos (3.0 – 4.1) for pts who did not experience a DR. Conclusions: This real-world analysis suggests that reducing the dose of subsequent administrations of nal-IRI during treatment is associated with pts remaining on therapy longer, experiencing a larger CD, and a with longer OS. Additional real-world prospective studies are necessary to characterize the impact of nal-IRI dosing on clinical outcomes.
Real-world patterns of care among patients with metastatic pancreatic cancer (mPC).
Authors: O'Reilly Eileen Mary , Surinach Andy , Wu Zheng , Cockrum Paul
Published: February 2020

666

Background: Pancreatic cancer is the third deadliest cancer in the US and mPC has a 2.9% 5-year survival. The analyses herein describe treatment patterns, trends in usage, and overall survival (OS) in mPC. Methods: Using the Flatiron Health EHR-derived database, data were extracted and analyzed for patients with mPC (pts) between Jan 1, 2014 and Jun 30, 2019. The database includes de-identified data from over 280 cancer clinics (~800 sites of care) representing more than 2.2 million U.S. cancer patients available for analysis, with 80% of pts from community centers and 20% from academic centers. Lines of therapy in the metastatic setting are derived from structured medication records. OS from metastatic diagnosis was reported using the Kaplan-Meier method. Results: 7,666 pts with mPC were identified. 5,687 (74.2%) received therapy in the metastatic setting. Pts who didn’t receive therapy in the metastatic setting were more likely to be older (p < 0.0001) and less likely to have been diagnosed initially with stage IV disease (p < 0.0001) than pts who were treated. The frequency of (1L) regimens were gemcitabine plus nab-paclitaxel (GnP) 46.8%, FOLFIRINOX (FFX) 24.1%, gemcitabine monotherapy 9.3%, and FOLFOX 3.8%. Gemcitabine monotherapy use was 12.9% in 2014 and 7.3% in 2018. GnP (31.4%), FFX (12.3%), FOLFOX (11.4%), and liposomal irinotecan (nal-IRI) + 5-FU/LV (10.2%) were the most frequent second line (2L) regimens. Between 2015 and 2018 nal-IRI based regimens increased from 6% to 17.6% in 2L. In the third line (3L) setting nal-IRI + 5FU/LV (19.3%), GnP (12.1%), FOLFOX (11.4%), and FFX (9.1%) were the most common treatments. Aggregate median OS (mOS) for treated pts was 8.1 mos (95% CI 7.8 – 8.4), and mOS for untreated pts was 2.8 mos (2.6 – 3.0), p < 0.0001. Conclusions: Survival for mPC is improving and practice patterns are changing. GnP is the most commonly used 1L regimen, followed increasingly by nal-IRI + 5-FU/LV in 2L and 3L. Further studies are necessary to understand the treatment gaps for pts with mPC. [Table: see text]