bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploration of patients with gastric cancer who benefit from apatinib: An updated real-world study.
Authors: Sun Guo-ping , Li Dongliang , Ning Zhongliang , He Yifu , Zhang Fenglin , Chang Jiacong , Cheng Yunsheng , Yu Changjun , Peng Wanren , Hu Bin , Xia Liming , Jiang Congqiao , Wang Zi'an , Zhao Yong , Du Yingying , Wang Guihe , Zhang Nianqing , Liang Hui , Wang Daoqin , Hu Wenjun
Published: January 2019

161

Background: A real-world study to observe the efficacy and safety of apatinib treatment in clinical practice, and explored patients (pts) who could benefit from apatinib. Methods: This is an open-label, prospective, observational study, pts (age ≥ 18 yrs) with pathologically or histologically diagnosed GC who were given apatinib treatment met the inclusion criteria. Results: From September 1, 2017 to September 1, 2018. 954 pts were enrolled. 679 pts received palliative treatment were included in the analysis. 499 (73.6%) were males. The age of the pts was (63.1 ± 10.8) yrs. Pts with ECOG PS 0/1 accounted for 78.1%. Pts received first-line treatment, second-line treatment, third-line treatment or above , respectively were 42.2%, 30.5%, 27.3%. 509 (75.1%) pts were treated with apatinib at dose of 500 mg. There were 375 pts available for efficiency evaluation. Among them, 1 achieved CR, 35 achieved PR, 198 had SD, and 57 had PD, resulting in an ORR of 11.9% and a DCR of 77.4%. The mPFS is 4.2 m (95% CI: 3.5-4.8), OS data was still in follow-up. This study showed its efficacy for pts with monotherapy compared with combined chemotherapy (3.3 m vs. 5.0 m, P = 0.003). The mPFS for patients with hypertension were longer than without hypertension (7.1m vs. 3.7m, P = 0.038). And pts also had longer mPFS with good ECOG PS (0-1) compared to those with poor ECOG PS (2-4) (4.7 m vs. 2.9 m, P = 0.003). The incidence of AEs was 402 (88.2%) and the grade 3/4 treatment-related AEs was 14.7%. The most common treatment-related AEs were debilitation (31.2%), hand-foot syndrome (27.5%), hypertension (25.3%), anorexia (11.5%), diarrhea (10.3%), albumin decreased (38.5%), uric acid elevated (31.6%), and total bilirubin increased (29.1%). Conclusions: In the real world, apatinib is confirmed to be effective and safe for GC pts. Factors associated with better prognosis were apatinib combined chemotherapy, ECOG PS 0/1 and occurrence of hypertension. Further analysis is needed to identify pts who benefit from apatinib treatment. Preliminary results of the study were released in ESMO 2018 Congress (683P). Clinical trial information: NCT 03333967.
Analysis of survival and objective response (OR) in patients with hepatocellular carcinoma in a phase III study of lenvatinib (REFLECT).
Authors: Kudo Masatoshi , Finn Richard S. , Qin Shukui , Han Kwang-Hyub , Ikeda Kenji , Cheng Ann-Lii , Piscaglia Fabio , Ueshima Kazuomi , Aikata Hiroshi , Vogel Arndt , Lopez Carlos , Pracht Marc , Meng Zhiqiang , Daniele Bruno , Park Joong-Won , Palmer Daniel H. , Dutcus Corina E. , Tamai Toshiyuki , Saito Kenichi , Lencioni Riccardo
Published: January 2019

186

Background: In REFLECT, Lenvatinib (LEN) demonstrated treatment effect on overall survival (OS) by statistical confirmation of noninferiority to sorafenib (SOR). OR rates for LEN versus SOR were: 24% versus 9% by investigator review and 41% versus 12% by independent review (Kudo et al 2018). Since the relationship between OR and OS in phase III HCC studies is unclear, we explored the relationship between OR and OS in REFLECT. Methods: OR assessed by investigators per mRECIST were used to analyze the association between OR and OS of pts treated with LEN or SOR. The median OS of responders (CR or PR) was compared to that of nonresponders (SD, PD, or UNK/NE) irrespective of treatment. Landmark analyses were performed by OR status at several fixed time points as sensitivity analyses, and the effect on OS was evaluated by Cox regression with OR as a time-dependent covariate, with other prognostic factors. Results: Median OS was 22.4 months for responders and 11.4 months for nonresponders. Hazard ratios (HR) of landmark analyses at 2, 4, and 6 months were 0.75 (95% CI, 0.57–0.98), 0.72 (95% CI, 0.56–0.92), and 0.73 (95% CI, 0.57–0.93). Independent predictors of OS based on unstratified Cox regression are in the table. Conclusions: In REFLECT, OR was an independent predictor of OS in pts with HCC regardless of treatment. The results indicate this correlation is worth further investigation. Clinical trial information: NCT01761266. [Table: see text]
Determination of O-6-methylguanine-DNA methyltransferase by immunochemistry and pyrosequencing as a predictive factor of response to temozolomide in pancreatic neuroendocrine tumors.
Authors: Escala Roberto , Navarro L Miguel , Del Carmen Martínez Sofía , Malmierca Gonzalez Sandra I , Ayuso Martín-Romo Julia , Cigarral García Belén , García Muñoz María , Casado Elía Diego , Barrios Collado Beatriz , Claros Ampuero Juncal , Escalera Martín Elena , Cruz-Hernández Juan J.
Published: January 2019

195

Background: Temozolomide (TMZ) is an alkylating agent that has shown good results in the treatment of neuroendocrine and central nervous system (CNS) tumors. The loss of O-6-methylguanine-DNA methyltransferase (MGMT) expression by pyrosequencing (PSQ) is a predictive factor of response to treatment with TMZ in high-grade gliomas. However, its predictive value in pancreatic neuroendocrine tumors (pNET) is controversial, and there is no consensus on how to best assess MGMT. The aim was to evaluate the objective response rate in pNET according to the state of MGMT, assessed by PSQ for evaluation of promoter methylation and immunohistochemistry (IHC). Methods: Patients with pNET who were treated with TMZ at the center between 2008 and 2017 were studied retrospectively. Ten patients were included in the study. A deficiency of MGMT was determined by IHC and MGMT promoter methylation by PSQ. For IHC, the cut-off was 10%, defined as negative < 10% of tumor cells positive in the tumor tissue. For the PSQ, the cut-off was 8%, defined as methylated who presented > 8%. Results: A deficiency of MGMT was detected in five patients (50%) by IHC. An MGMT promoter methylation by PSQ was observed in three patients (30%). The IHC results were consistent with PSQ results in only six patients (60%); one patient with methylated MGMT had positive IHC, and three patients had unmethylated MGMT by PSQ unmethylated, IHC negative. PSQ had a high positive predictive value of response because the three patients with MGMT promoter methylation by PSQ presented objective responses (OR). Nevertheless, a low negative predictive power (57%) was observed because three of seven patients with unmethylated MGMT presented OR. Of the five patients with MGMT deficiency by IHC, four (80%) presented OR, suggesting positive predictive value of 80%; however, it also presented a low negative predictive power of 60%. Conclusions: Despite having 100% of the patients with MGMT promoter methylation showing OR in this series, the low negative predictive power suggests that the absence of MGMT deficiency by IHC or MGMT unmethylated by PSQ does not contraindicate the use of TMZ in pNET treatment.
Baseline and longitudinal quantification of lean muscle mass using routine CT measurements prior to resection for pancreatic adenocarcinoma.
Authors: Oberstein Paul Eliezer , Rosario Vilma , Guo Xiaotao , Zhao Binsheng , Genkinger Jeanine M , Kluger Michael D. , Chabot John A.
Published: January 2019

198

Background: When compared to healthy populations subjects are defined as sarcopenic if they have severe loss of lean muscle mass (LMM). Sarcopenia is associated with poor outcomes in some studies of pancreatic cancer (PDA) but the prevelance remains uncertain in resected patients and there is little data about changes in LMM during neoadjuvant chemotherapy. Muscle mass can be reliably quantified in cancer patients using routine imaging. We analyzed a large cohort of patients undergoing surgery at a high-volume center to quantify LMM at baseline and with treatment, and to determine the association of sarcopenia with tumor histology and outcomes. Methods: We analyzed subjects undergoing surgery for PDA at the Pancreas Center at Columbia University from 2011-2014. We utilized CT scans to measure cross sectional area of muscle at the L3 vertebral body (LMM in cm2) and used height to define a smooth muscle index (SMI-cm/m). Sarcopenia was determined based on SMI < 38.9 for females and < 55.4 for males. In subjects undergoing neoadjuvant chemotherapy, SMI was also calculated on post therapy scans. We collected information on clinical and pathological variables and performed statistical analyses utilizing SAS 9.4 software. Results: Among subjects with available imaging (n = 106) sarcopenia rates at initial staging were high whether they were immediately resectable (52%) or locally advanced (63%). Rates of sarcopenia were higher in males than females (77 vs 38%, p < 0.001). Sarcopenic status was not correlated with survival, tumor stage or grade but was associated with age, gender, and BMI. Among locally advanced subjects who proceeded to surgery after neoadjuvant chemotherapy (n = 40) there was no change in SMI or incidence of sarcopenia following treatment (median 171 days). Conclusions: Sarcopenia is highly prevalent at diagnosis in subjects undergoing surgery for PDA but was not associated with survival, tumor grade or stage in this cohort. Subjects who successfully completed neoadjuvant treatment did not experience significant loss in LMM despite extensive treatment suggesting that lack of change in LMM may assist in predicting favorable response to neoadjuvant therapy in PDA.
Enhancements in pancreatic protocol CT as a prognostic indicator in pancreatic cancer.
Authors: Park Jaewon , Cho In Kuk , Lee Jong-Chan , Lee Jongchan , Kim Young Hoon , Kim Jaihwan , Hwang Jin-Hyeok
Published: January 2019

216

Background: Pancreatic protocol CT (pCT) is widely used to evaluate stage and resectability of pancreatic ductal adenocarcinoma (PDAC). Recent studies show that CT enhancement patterns are related to the patient’s prognosis in several cancers, however it is not well described that pCT enhancement has prognostic effect in resectable PDAC so far. We aimed to show correlaton between pCT enhancements and prognosis in resectable PDAC. Methods: We retrospectively enrolled 159 patients (median age, 67.8 years) who underwent pCT before curative resection in Seoul National University Bundang Hospital between January 2010 and December 2015, with final pathological diagnosis of PDAC. CT enhancement ratio (CTER) of each primary lesion was calculated as proportional difference between maximum Houndsfield Unit (HU) of pancreatic phase (PP) image and maximum HU of non-contrast image; [(max HU of PP) - (max HU of non-contrast)] / (max HU of non-contrast). Patients were classified into two groups, based on CTER. Kaplan–Meier analysis and Cox proportional hazards models were used to correlate CTER with overall survival (OS) and recurrence free survival (RFS). Results: Median overall survival was 22.0 months during a median follow-up period of 18.5 months. Based on CTER with cut-off value of 1.8, higher (CTER ≥ 1.8) group (N = 43) was compared with lower (CTER < 1.8) group (N = 116) in terms of OS and RFS. Lower group showed significantly shorter median OS (18.5 months versus 39.3 months, P < 0.001) and median RFS (9.9 months versus 21.5 months, P = 0.006) than those of higher group. Multivariate regression analysis showed that lower group had shorter OS (HR 1.70; CI 1.01-2.85, P = 0.044) and RFS (HR 1.84; CI 1.10-3.06, P = 0.019). Conclusions: Our study suggests that lower enhancement in pancreatic phase of pCT is related to poor prognosis in PDAC. Therefore, active surveillance would be required in resected PDAC patients with CTER less than 1.8.
Comparison of biomarkers among 34855 GI cancer samples shows heterogeneity of tumor types.
Authors: Dawood Shaheenah S.
Published: January 2019

217

Background: Recent data indicate that biomarker driven use of targeted therapy and I/O-therapy among patients with GI cancer is associated with improved outcome. The presence of biomarkers varies broadly between different GI tumor types, highlighting the importance of comprehensive molecular profiling. To analyze the presence of various alterations in GI cancer samples of a large database, comparing congruency between various tumor types. Methods: A retrospective data analysis of 34855 GI cancer patients profiled at CARIS Life Sciences obtained from Jan 1, 2010 till Sep 14, 2018 was performed. GI tumors were classified as CRC, esophageal/gastric/GIST, small intestine, pancreatic/hepatobiliary/liver. Technologies used to analyze the biomarkers: IHC for PD-L1, MMR and Her2, and DNA-NGS for EGFR, BRAF, KRAS, NRAS, MET-CNV, TMB, MSI, POLE and BRCA1/2. Results: Median age was 61 range (18-89 years). 51.5% was CRC (n=18047), 15.5 % was esophageal/Gastric/GIST (n=5470), 3% was small intestinal cancer (n=886) and 30% was pancreatic/hepatobiliary/liver cancer (n=10452). Information on biomarkers was available from 2931 cases for MET amplification to 28536 for RAS mutation. Overall, the most common finding was a pathogenic RAS-mutation in 7650 cases (26.81%), the rarest one was a mutation in EGFR in 12 cases (0.06%). Higher rate of HER2 amplification was observed among pts with esophageal/gastric/GIST tumors (6.5%) in comparison to tumors at other GI sites ( ~1.5%). High TMB was seen among patient with CRC and small intestine tumors (~7%) while it was lowest among pancreatic cancer (1.8%). Compared to other GI sites lower MSI /MMR deficiency rates were observed in pancreatic /hepatobiliary tumors, significantly higher PD-L1 positivity was observed in gastrooesophageal cancer types, increased MET-amplifications in gastrooesophageal and small intestinal cancer types and lower RAS-mutation rate in gastrooesophageal cancer. Conclusions: Molecular profiling analyzing druggable biomarkers can help identify patients with increased likelihood for benefit from immune-checkpoint-inhibitors and targeted therapies. Further investigations are needed to evaluate the different findings in various GI cancer types.
Circulating calprotectin, innate inflammatory protein, was decreased under disease control during first-line chemotherapy for advanced pancreatic cancer.
Authors: Shibuki Taro , Mitsunaga Shuichi , Kan Motoyasu , Kimura Gen , Umemoto Kumiko , Watanabe Kazuo , Sasaki Mitsuhito , Takahashi Hideaki , Hashimoto Yusuke , Imaoka Hiroshi , Ohno Izumi , Ikeda Masafumi
Published: January 2019

218

Background: There is increasing evidence of a close link between inflammation and disease control in pancreatic ductal adenocarcinoma (PDAC). Damaged-associated molecular patterns (DAMPs) were inducers of inflammation in the innate immune system and were detected in PDAC tissue in recent reports. Calprotectin, one of DAMPs, is recognized as a potential mediator of the process of disease control in various tumors. In this study, circulating calprotectin is characterized on disease control in patients with 1st line chemotherapy for advanced PDAC. Methods: Patients with treatment-naïve advanced PDAC were enrolled in this study. Patients with obvious infectious conditions were excluded. Serum levels of calprotectin and pro-inflammatory cytokines including interleukin-6 (IL-6) were measured at baseline and at one or two months later after the start of 1st line chemotherapy. Disease control rate (DCR) was evaluated on the Response Evaluation Criteria in Solid Tumors ver. 1.1. Results: A total of 73 patients were evaluated. DCRs of gemcitabine group (GEM) (n = 57) and the patients with modified FOLFIRINOX or GEM + nab-paclitaxel (mFFX/GN) (n = 16) were 52.6% and 75.0%,respectively. In comparison of baseline-and-after data, circulating calprotectin levels were significantly decreased under disease control in GEM (baseline vs. after: 2.9 vs. 2.3 ng/ml in median, p = 0.084) and GN/mFFX (2.7 vs. 0.5 ng/ml, p = 0.024. IL-6 was decreased in GN/mFFX (9.1 vs. 5.9 pg/ml; p= 0.095) but not in GEM (4.3 vs. 3.1　pg/ml; p = 0.303). There were no obvious changes under non-disease control in calprotectin (baseline vs. after: 6.2 vs. 5.9 ng/ml in GEM, 5.1 vs. 4.5 ng/ml in mFFX/GN) and IL-6 (16.5 vs. 25.6 pg/ml in GEM, 3.1 vs. 4.7 pg/ml in mFFX/GN). Conclusions: DCR relateda decrease of circulating calprotectin levelduring 1st line chemotherapy for advanced PDAC. Innate immune system plays a role in the chemotherapeutic efficacy in advanced PDAC.
Gastric cancer staging in the era of neoadjuvant therapy and its prognostic implications.
Authors: Kim Gina , Friedmann Patricia , Muscarella Peter , McAuliffe John Christopher , In Haejin
Published: January 2019

22

Background: Increasingly patients are undergoing neoadjuvant therapy for gastric cancer. The relationship between stage-based prognostic information available prior to treatment (cStage), after surgery (ypStage), and difference between cStage and ypStage (delta) remains unclear. We aim to describe the relationship between cStage and ypStage as relates to survival for gastric cancer patients. Methods: Data from the National Cancer Data Base (NCDB) from 2004-2015 was used for the analysis. Patients with gastric adenocarcinoma who received neoadjuvant therapy then underwent surgery were included. Kaplan Meier curves were used to model survival. Harrell’s C-statistics obtained from Cox Regression models were reported. Results: 9,959 patients met our inclusion criteria. Increases in cStage, ypStage and delta (ypStage-cStage) were associated with worse survival. Median overall survivals for cStages 1-4 were: 53.8, 39.5, 29.2, 20.9 months (logrank test, p<0.0001). Median survivals for ypStage 0-4 were: 95.4, 89.7, 36.9, 23.4, 16.0 months (logrank test, p<0.0001). Survival was further stratified by delta. A representative table comparing cStage 2 and ypStage 2 is shown below. A cox regression model with cStage as predictor of survival yielded a Harrell’s C-statistic of 0.555; when delta was added to the model, the C-statistic increased to 0.638. Separately, a Cox-regression model with ypStage as predictor yielded a C-statistic of 0.632; when delta was added to this model, the C-statistic increased negligibly to 0.638. Conclusions: Prognostic accuracy using cStage prior to treatment improved when tumor responsiveness was considered while this was not the case for ypStage. Pre-surgical prognostic information should be provided with a caveat that treatment response will influence survival. Post-surgery, the clinical stage is less relevant and ypStage can be used alone in providing prognostic information. [Table: see text]
The gastric cancer survivorship experience: A global perspective.
Authors: Raymond Martha Ann , Lustig Craig
Published: January 2019

24

Background: The World Health Organization estimates 1.03 million new gastric cancer cases will be diagnosed in 2018. Globally, gastric cancer is the 5th most common cancer and the 3rd most common cause of cancer death. Our study explores the gastric cancer survivorship experience throughout the care continuum. Methods: The Ruesch Center for the Cure of Gastrointestinal Cancers and the GI Cancers Alliance developed a global gastric cancer advocacy initiative (December 2017) to better understand the patient experience. As convener, we facilitated numerous meetings with international advocacy organizations; healthcare professionals; patients and caregivers to gain a global perspective. Based on our goal to help improve patient outcomes, our initiative included analysis to support: efforts to increase earlier detection; provide access to best treatment protocols including clinical trials; enhanced patient education and patient-centered communication. A key element of our research began with a global patient survey, focus groups and interviews. Results: 521 gastric cancer patients (54% female 46% male) participated in the international survey (April-May 2018). 49% indicated a ‘poor’ quality of life; 91% indicated survivorship care gaps; 42% were Stage 4. North and South America, Europe, Asia, and Australia were represented. Follow-up interviews and focus groups (July-September 2018) provided valuable insight and a greater understanding of the patient profile. Conclusions: Additional educational and supportive services are needed to meet patient unmet needs. We will continue providing key stakeholder platforms to address patient concerns; create meaningful and relevant patient education; continue outreach leading to increased patient empowerment; convene and work with global partners improving patient quality of life to ultimately achieve better patient outcomes.
Incidence patterns of neuroendocrine neoplasms in California.
Authors: Paciorek Alan , Shih Brandon , McKinley Meg , Cheng Iona , Zhang Li , Mulvey Claire , Griffin Ann , Van Loon Katherine , Bergsland Emily K.
Published: January 2019

242

Background: Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors that typically account for < 5% of tumors arising in any organ site. Both the low incidence and heterogeneity contribute to the paucity of epidemiologic data regarding risk factors. However, evidence suggests that incidence rates in the U.S. are rising. We aimed to further characterize the burden of NENs in California. Methods: Using data from the California Cancer Registry (CCR), we identified all newly diagnosed NENs arising from pulmonary (including SCLC) and gastrointestinal (GI) sites from 1992-2015. We estimated age-adjusted incidence rates (AIR) standardized to the 2000 U.S. census population. We calculated annual percent change (APC) in AIRs using Joinpoint regression and compared AIRs by sex, race-ethnicity, primary tumor site, and county of residence categorized as urban, suburban or rural using SEER∗Stat. Results: From 1992-2015, 97,398 NENs were reported, with 40,099 GI (not lung or bronchus). Overall AIR was 12.5 per 100,000 person-years. Most NENs were of pulmonary (AIR 7.6) or colorectal (AIR 1.3) origin. Females had lower AIR with IR ratio (IRR) vs. males (0.80 95% CI 0.79-0.81). However, females had higher rates of gastric (IRR 1.22 95% CI 1.12-1.32) and appendiceal (IRR 1.19 95% CI 1.07-1.33) primaries vs. males. Compared to non-Hispanic (NH) whites, NH blacks had an IRR of 1.06 (95% CI 1.03-1.09), Asian/Pacific Islanders had an IRR of 0.46 (95% CI 0.45-0.48), and Hispanics had an IRR of 0.57 (95% CI 0.56-0.58). For all NEN subtypes, we estimated lower rates for residents of urban counties (IRR 0.83 95% CI 0.80-0.86) and suburban counties (IRR 0.94 95% CI 0.90-0.97) vs. rural counties. However for GI NENs, we estimated higher rates for residents of suburban counties (IRR 1.11 95% CI 1.03-1.18) and urban counties (IRR 1.10 95% CI 1.03-1.18) vs. rural counties. We found that rates of pulmonary NENs decreased since 1992 (APC -2.6), but rates increased in colorectal (APC 3.9) and all other GI primaries (all APCs ≥ 2.8). Conclusions: Based on these results we conclude that incidence rates for GI NENs reported to CCR steadily increased from 1992-2015. Residence in a suburban or urban county was associated with increased incidence of GI NENs. Additional analyses are ongoing.
A systematic review and network meta-analysis of adjuvant therapy for curatively resected biliary tract cancers.
Authors: Kish Maxine , Chan Kelvin K. , Perry Kaitlyn , Ko Yoo-Joung
Published: January 2019

247

Background: Although recently completed randomized controlled trials (RCTs) have added high-quality data regarding adjuvant therapy in curatively resected biliary tract cancer (BTC), there is still no standard approach to manage these patients. We conducted a systematic review and network meta-analysis to compare the efficacy of adjuvant therapy regimens in curatively resected BTC to help guide clinical decision making and the design of future prospective trials. Methods: We conducted a systematic review of published studies and abstracts up to and including June 2018. Studies were included if they were phase III RCTs on patients with histologically proven BTC receiving adjuvant chemotherapy after a complete surgical resection (R0 or R1). BTCs included gallbladder cancer, intrahepatic and extrahepatic cholangiocarcinoma. The endpoints of interest were overall survival (OS) and relapse-free survival (RFS). Network meta-analysis methods were used for indirect comparison between adjuvant therapy regimens. Results: Five RCTs were included in the qualitative synthesis and three RCTs (BILCAP, PRODIGE 12-ACCORD 18 and BCAT) included sufficient data to be included in the meta-analysis. Results from the indirect comparison demonstrated no significant difference in OS between any of the adjuvant therapy regimens, however there was a trend that favoured adjuvant therapy with capecitabine over gemcitabine or gemcitabine plus oxaliplatin (GEMOX), with hazard ratios (HRs) of 0.82 (95% CI, 0.53-1.27) and 0.86 (95% CI, 0.56-1.34), respectively. Similarly there was no significant improvement in RFS with capecitabine compared to gemcitabine or GEMOX with HRs of 0.82 (95% CI, 0.53-1.27) and 0.86 (95% CI, 0.56-1.34), respectively. Conclusions: Although capecitabine is considered to be standard of care in the adjuvant setting based on a single randomized phase III study, in this indirect comparison, we did not find a statistically significant improvement in OS or RFS with capecitabine compared to GEMOX or gemcitabine. Further prospective trials comparing adjuvant therapies to capecitabine are warranted.
Enhancement of the efficacy of radiofrequency ablation by neoadjuvant oncolytic virus therapy via antitumor immunity and the booster effect of immune checkpoint inhibitors.
Authors: Yamada Tomoharu , Inou Yasushi , Iwai Miwako , Tateishi Ryosuke , Koike Kazuhiko , Todo Tomoki
Published: January 2019

253

Background: A third generation oncolytic herpes simplex virus type 1, G47Δ, destroys tumor cells selectively and induces antitumor immune responses. Radiofrequency ablation (RFA) is a standard local therapy for hepatocellular carcinoma (HCC). Here, we examined the efficacy of G47Δ used in combination with RFA and evaluated the antitumor immune responses. Methods: In A/J mice harboring bilateral poorly immunogenic Neuro2a subcutaneous tumors, tumors on one side were treated with intratumoral injections with G47Δ (2×106 pfu) on days 0, 2 and 4 followed by RFA treatment on day 6, which results in complete regression of the treated tumors. We further treated with an immune checkpoint inhibitor (ICI) in combination. Tumor infiltrating lymphocytes in contralateral tumors were analyzed with flow cytometric analysis. To examine the contribution of CD8+ T cells, CD8+ T cells were depleted by treatment with anti-CD8 monoclonal antibody. To mimic a remote recurrence, unilateral subcutaneous tumors were treated with G47Δ and RFA, and Neuro2a cells were implanted on the same day of RFA. In a separate experiment without rechallenge, antitumor immunity was evaluated using ELISpot assay on day 20. Results: The G47Δ+RFA treatment caused smaller volumes of contralateral tumors and increased infiltration of CD8+/CD45+ T cells within the tumor, compared with RFA or G47Δ monotherapy. Without CD8+ T cells, the antitumor effect on the contralateral tumors was completely abolished. When mice were rechallenged, those cured by G47Δ+RFA rejected the Neuro2a more frequently than those cured by RFA alone. ELISpot assay revealed that the number of Neuro2a reactive splenocytes was significantly greater in the G47Δ+RFA group than the RFA group. The G47Δ+RFA+anti-PD-L1 treatment caused smaller volumes of contralateral tumors compared with G47Δ+RFA treatment, whereas anti-PD-L1 alone showed no effect. Conclusions: Intratumoral administration of G47Δ prior to RFA would enhance systemic antitumor immunity that is further enhanced by ICI.
An open-label phase Ib/2 trial of TRC105 plus sorafenib in patients with advanced/metastatic hepatocellular carcinoma (HCC) (NCT01806064).
Authors: Raghav Kanwal Pratap Singh , Lee Richard T. , Paluri Ravi Kumar , Mody Kabir , Simpson Brian , Adams Bonne J. , Theuer Charles P. , Kaseb Ahmed Omar
Published: January 2019

268

Background: TRC105, an endoglin antibody, potentiates the activity of sorafenib (S) in preclinical HCC models, and TRC105 + S demonstrated a 33% partial response rate (5/15 pts) by RECIST, at RP2D doses of TRC105 in HCC pts ( Clin Can Res 2017). Adverse events characteristic of each drug were not increased in frequency or severity when the two drugs were administered concurrently. Methods: P1: Compare wkly TRC105 dosing vs four wkly doses followed by every other wkly dosing + S 800 mg daily. P2: Four objective responses are required in 21 pts to reject the null hypothesis that the true response rate probability is < 5% with an alpha level of 0.1 and 80% power. Key inclusion criteria: disease not amendable to surgical or local therapies, ECOG ≤ 1; Child-Pugh A or B (7 points) classification. Results: Thirteen pts were enrolled in phase 1b at TRC105 10 mg/kg wkly for four doses and 15 mg/kg every other week thereafter + S. Mean serum levels of TRC105 exceeded the target conc. following 4 wkly doses of TRC105 at 10 mg/kg (mean = 34 µg/ml, range BLOQ-80). Mean trough conc. decreased following every other week dosing (mean = 13 µg/ml, range BLOQ-31), resulting in infusion reactions or a continued requirement for premedication. Therefore, wkly dosing of TRC105 at 10 mg/kg is the recommended Phase 2 dose. ADA were detected in 10 of 14 pts and correlated with lower than expected PK conc. Common TRC105 related AEs included ≤ G2 epistaxis, ≤ G2 fatigue and ≤ G2 headache. Common S related AEs included ≤ G3 fatigue, ≤ G3 hand foot syndrome and ≤G2 epistaxis. A total of 3 out of 14 evaluable patients (21%) enrolled in phase 1 and 2 achieved durable PR, 2 of these ongoing at week 45 and 17. Conclusions: TRC105 dosed at 10 mg/kg wkly was required to achieve target conc. due to higher clearance in HCC pts, which may have been influenced by a higher rate of ADA compared to studies of TRC105 in other tumor types. The combination of TRC105 + S demonstrated encouraging signs of activity, including durable PR in 2/9 evaluable pts in Phase 1b and 1/5 pts thus far in Phase 2. An additional 16 pts will be enrolled at the RP2D to assess the primary endpoint of ORR by RECIST. Clinical trial information: NCT01806064.
KRAS and TP53 status as a predictor of survival in patients with resected pancreatic ductal adenocarcinoma.
Authors: McIntyre Caitlin A , Lawrence Sharon Anita , Wong Winston , Chou Joanne F. , Capanu Marinela , Berger Michael F. , Allen Peter , O'Reilly Eileen Mary
Published: January 2019

276

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. KRAS, TP53, CDKN2A and SMAD4 are established driver genes in PDAC. We aimed to determine if the mutational status of these 4 driver genes, and other frequently altered genes, are predictive of clinical outcomes in patients who undergo resection. Methods: Patients who underwent resection of PDAC and consented to targeted sequencing of their primary tumor using MSK-IMPACT, were included. Genomic alterations were determined based on MSK-IMPACT sequencing results of formalin-fixed, paraffin-embedded tumor. A prospectively maintained database and electronic medical record were queried for clinical and pathologic variables. Gene mutation status was compared with overall survival (OS) and recurrence free survival (RFS) using the log-rank test, and with pathologic variables using Wilcoxon rank-sum and Fishers exact tests. Results: Targeted genomic sequencing was performed on N = 285 primary tumors resected between 2004-2017. N = 55 (19%) patients received neoadjuvant therapy prior to sequencing and N = 220 (77%) received adjuvant therapy. Median OS was 39 months with a median follow up of 22 months. Frequency of genomic alterations and their association with OS and RFS are shown in Table 1. Alterations in both KRAS and TP53 were associated with worse OS, but not RFS, as compared to wildtype. Mutant KRAS was also associated with larger tumor size (median, 3.0 vs 2.2cm, p = 0.009). Conclusions: Alterations in KRAS and TP53 were associated with worse OS in patients with resected PDAC. Further analysis will include the association of driver gene variants, as well as other gene alterations, with clinical and pathologic outcomes. [Table: see text]
Comprehensive genomic profiling in metastatic pancreatic adenocarcinoma, correlation with early death versus prolonged survival.
Authors: Kamgar Mandana , Dyson Gregory , Shields Anthony Frank , Tesfaye Anteneh A. , Philip Philip Agop , Al Hallak Mohammed Najeeb
Published: January 2019

282

Background: PDAC has a very poor prognosis and around 50% of the patients die within two months of their diagnosis and around 10% live beyond one year. In this study we sought to find biomarkers differentiating patients with early death from those with more prolonged survival. Methods: Tumors from our patients with PDAC were examined using NexGen sequencing (evaluating somatic mutations in 592 genes), immunohistochemistry, and in-situ hybridization (Caris Life Sciences). Tumor mutational burden, microsatellite instability, copy number variation, and gene fusion assessment were done in a subset of samples. Extremes in clinical outcome were defined as death in < 4 months and > 12 months from metastasis diagnosis. Fischer’s exact tests were used to associate the categorical clinical data and genomic factors with the extremes of clinical outcome. A t-test was used to associate the continuous clinical factors with the extreme outcomes. Hierarchical clustering using the Ward amalgamation and binary distance metric was used to define cluster based upon the genomic factors. Results: From October 2014 to August 2018, we evaluated 115 patients. 15 patients with PDAC died < 4 months and 39 died > 12 month from the time of metastasis diagnosis. Compared to the patients with prolonged survival, patients with an early death were significantly older (Average 67.5 vs. 60.5 years old, P = 0.03) and had significantly higher neutrophil counts (average 9.6 vs. 5.1, P = 0.001) and monocyte counts (average 1 vs. 0.6, P = 0.01). No genomic alteration differentiated the groups with extreme outcomes. None of the clusters defined upon the genomic factors differentiated the two outcome groups. Using classification model to predict early death vs prolonged survival, no factor evaluated by the genomic profiling was discriminatory between the groups. Conclusions: We did not find a pattern of genomic alteration difference in PDAC patients between the short-term versus the long-term survivals using Next Generation Sequencing. The short-term survivals were older and had higher neutrophil and monocyte counts at the time of metastatic disease diagnosis.
Defining DNA damage repair deficiency and replication stress in pancreatic cancer.
Authors: Dreyer Stephan , Paulus-Hock Viola , Upstill-Goddard Rosie , Lampraki Eirini , Jamieson Nigel , Cooke Susie , Bailey Peter , Biankin Andrew , Chang David Kuang-Fu
Published: January 2019

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Background: Integrated multi-omic analyses revealed 24% of pancreatic cancer (PC) harbor defects in DNA damage response (DDR) and a subgroup demonstrate upregulation in replication stress pathways. DDR defective tumors preferentially respond to DNA damaging agents, and clinical responses to cell cycle inhibitors are seen in undefined subgroups, representing novel therapeutic strategies for PC. The aim of this study is to define and refine therapeutic segments for agents targeting DDR and replication stress in PC. Methods: We performed whole genome and RNA sequencing (RNAseq) on 48 patient-derived cell lines (PDCL) generated and characterized as part of the International Cancer Genome Initiative (ICGC). This identified increased replication stress in a sub-group of tumours, correlating with previously defined molecular subtypes of PC, irrespective of DDR status. Cytotoxic viability assays were performed using agents targeting the DDR pathway and cell cycle checkpoints, including Cisplatin, and inhibitors of PARP, ATR, WEE1, CHK1, CDK4/6 and PLK4. Subcutaneous patient derived xenografts (PDX) were generated to test therapeutic regimens in vivo. Results: DDR defective models, as defined by signatures of homologous recombination deficiency (HRD) were highly sensitive to Cisplatin and PARP inhibitors. Replication stress predicted differential responses to cell cycle inhibitors of WEE1, CHK1, CDK4/6 and PLK4. A novel mRNA signature of ATR inhibitor sensitivity was generated and correlated with response. Response to cell cycle checkpoint inhibitors were independent of DDR status, but strongly associated with replication stress. Conclusions: This proof of concept data demonstrates DDR deficiency and increased Replication Stress to be attractive targets in PC. Therapeutic vulnerabilities extend beyond platinum chemotherapy and can be targeted with novel small molecule inhibitors, with independent biomarkers predicting response to agents targeting either DDR or cell cycle checkpoints. This has led to the design and development of several personalized medicine trials via the Precision Panc platform targeting DDR and Replication stress, and will allow clinical testing of signatures of HRD and replication stress.
Impact of obesity upon the survival of cholangiocarcinoma patients.
Authors: Surapaneni Phani Keerthi , Li Zhuo , Vemireddy Lalitha Padmanabha , Kasi Pashtoon Murtaza , Starr Jason Scott , Ritter Ashton , McMillan Jessica , Wylie Natasha , Mody Kabir
Published: January 2019

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Background: Obesity is a risk factor for developing cholangiocarcinoma (CCA). However, the effect of obesity on survival of CCA is unclear. The primary aim of this study was to analyze the impact of obesity upon overall survival of CCA patients. Secondary aims were to analyze impact of obesity upon other disease characteristics such as tumor site, stage, age, sex, BMI and Ca 19-9. Methods: A total of 411 unique pts diagnosed with CCA at Mayo Clinic Florida between 2000 and 2018 were retrieved from our collective SDMS database. Variables evaluated included:demographics, Body Mass Index (BMI), AJCC stage, tumor location and Ca 19-9.A total of 185 pts had all data available pertaining to these variables. We further restricted the analysis to pts with intrahepatic CCA classified BMI as per CDC criteria normal (18.5-25kg/m2), overweight (25-29.9kg/m2) and obese (≥30 kg/m2), thus leaving a total of 152 pts. Continuous and categorical variables were compared across BMI groups using Chi-squared or Fisher’s exact test. Overall survival rates after diagnosis at 1, 2 and 3 years were estimated using Kaplan-Meier method. Results: Among 152 pts included in the study, 28% were normal weight, 40% were overweight and 32% were obese. The overall survival rate at 1, 2 and 3 years for normal weight pts with all stages combined was 54.1%, 35%, and 30.7%, respectively. The overall survival rate at 1, 2 and 3 years for overweight pts with all stages combined was 59.7 %, 32.6%, and 25.4%, respectively. The overall survival rate at 1, 2 and 3 years for obese pts with all stages combined was 63.9%, 37.6%, and 26.7%, respectively(p = 0.8766). Multivariate analysis demonstrated is no significant difference in overall survival for obese pts compared to normal or overweight pts.(Table to be shown) However it showed, gender and Ca19-9 were statistically significant predictors of overall survival, with males and pts with Ca19-9≥100 doing worse (HR1.65 (CI = 1.05, 2.61, p = 0.031) and HR 2.31 (CI = 1.49, 3.59, p = < 0.01), respectively). Conclusions: BMI did not make a significant impact on the overall survival, though there may be a trend toward worse OS for ptswith higher BMI. A larger, stage focused evaluation is warranted for further exploration of this trend.
Landscape of circulating tumor DNA and tissue-based profiling in advanced cholangiocarcinoma.
Authors: Mody Kabir , Kasi Pashtoon Murtaza , Surapaneni Phani Keerthi , Bekaii-Saab Tanios S. , Ramanathan Ramesh K. , Ahn Daniel H. , Mahipal Amit , Starr Jason Scott , Ritter Ashton , McMillan Jessica , Wylie Natasha , Roberts Ali , Nagy Rebecca J , Borad Mitesh J.
Published: January 2019

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Background: Cholangiocarcinoma (CCA) has limited treatment options. Genomic analyses have led to development of targeted therapies now in clinical trials, and may enable discovery of new treatment options. However, biopsy often yields limited tissue, thus hampering tissue-based profiling opportunities. Comparative data regarding circulating tumor DNA (ctDNA) analysis and tissue based profiling in CCA are limited. Methods: We performed ctDNA NGS analysis along with tissue based profiling in pts with advanced CCA (January 2015- February 2018). ctDNA analysis was performed using Guardant 360 (Guardant Health, CA) which detects single nucleotide variants, amplifications, fusions, and specific insertion/deletion mutations in up to 73 different genes and the majority of tissue based profiling using Foundation One. The mutant allele fraction (MAF) for detected alterations was calculated relative to wild type in ctDNA. Therapeutic relevance was defined as alterations within OncoKB levels 1-3B and R1. The study was conducted in accordance with Mayo Clinic IRB requirements. Results: Among 124 pts and 139 total samples, ctDNA NGS revealed at least one genomic alteration (excluding variants of uncertain significance and synonymous mutations) in 89% of pts. Median number of alterations per pt was 3 [range, 1-15], with a median MAF of 0.42% (range, 0.1% - 94.2%). The total number of unique alterations was 321. The most commonly altered genes: TP53 (31%), KRAS (11%), FGFR2 (7%), APC and PIK3CA (each 5%) and ARID1A (3%). Amplifications were noted in 14 genes: BRAF, CCND1, CCND2, CCNE1, CDK4, CDK6, EGFR, ERBB2, FGFR1, FGFR2, MET, MYC, PDGFRA, and PIK3CA. Tissue-based profiling was available in 57 (46%) pts, with a median of 63 days between liquid and tissue biopsy. IDH1, FGFR2, TP53 and KRAS were most common gene mutations found in pts who had both liquid and tissue biopsy done. (Comparative results to be shown). Conclusions: ctDNA plasma profiling of pts with advanced CCA is a feasible alternative method to gather comprehensive genomic data. Further larger cohort studies comparing landscape of alterations seen on ctDNA versus tissue-based assays are needed.
Symptom burden at the end of life for neuroendocrine tumors: A population-based analysis of patient-reported outcomes.
Authors: Hallet Julie I. , Davis Laura , Mahar Alyson L. , Law Calvin , Bubis Lev , Isenberg-Grzeda Elie , Singh Simron , Myrehaug Sten , Zhao Haoyu , Beyfuss Kaitlyn , Moody Lesley , Coburn Natalie G.
Published: January 2019

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Background: How to best support neuroendocrine tumor (NET) patients remains unclear. While the peri-diagnostic period has been investigated, there is no data regarding symptoms at the end of life, when suboptimal symptom control may be particularly burdensome. This study examined symptom trajectories and factors associated with high symptom burden in NET at the end of life. Methods: We conducted a population-based retrospective cohort study of NET diagnosed from 2004-2015, who died between 2007-2016. Prospectively collected patient-reported Edmonton Symptom Assessment System scores were linked to provincial administrative datasets. Moderate-to-severe symptom scores in the 6 months prior to death were presented by 2-week intervals. Multivariable Poisson regression identified factors associated with moderate-to-severe symptoms scores. Results: Among 677 decedents, 2,579 symptom assessments prior to death were analyzed. Overall, moderate-to-severe scores were most commonly reported for tiredness (86%), wellbeing (81%), lack of appetite (75%), and drowsiness (68%) at any time. This proportion changed over time, progressively increasing closer to death: 56.8% to 83.9% tiredness, 50.5% to 73.1% wellbeing, 40.9% to 80.6% lack of appetite, and 41.5% to 68.8% drowsiness. The increase was steeper in the 8 weeks before death for lack of appetite, drowsiness, and shortness of breath. On multivariate analyses, the risk of moderate-to-severe symptoms was significantly higher in the last 2 months prior to death and with shorter survival from diagnosis (< 6 months). Women reported a higher burden of anxiety, nausea, and pain than men. There was no association between symptom burden and age or primary tumor site. Conclusions: NET patients suffer a high symptom burden at the end of life, not previously described. The proportion of moderate-to-severe symptoms increases steeply as death nears, highlighting an opportunity for improved management. Combined with identified factors associated with moderate-to-severe symptom, this information is important to improve patient-centred and personalized supportive care for NET at the end of life.
Efficacy and safety of trifluridine/tipiracil (FTD/TPI) in patients (pts) with metastatic gastric cancer (mGC) with or without prior gastrectomy: Results from a phase III study (TAGS).
Authors: Ilson David H. , Prokharau Aliaksandr , Arkenau Hendrik-Tobias , Ghidini Michele , Fujitani Kazumasa , Van Cutsem Eric , Thuss-Patience Peter C. , Beretta Giordano D. , Mansoor Wasat , Zhavrid Edvard , Alsina Maria , George Ben , Catenacci Daniel V.T. , Winkler Robert E. , Makris Lukas , Doi Toshihiko , Shitara Kohei
Published: January 2019

3

Background: The phase 3 study TAGS demonstrated that the novel oral therapy FTD/TPI (TAS-102) represents an effective treatment option with a manageable safety profile for pts with heavily pretreated mGC. In an earlier single-arm Japanese phase 2 trial in mGC, no differences were found in the pharmacokinetics of either FTD or TPI in pts with or without prior gastrectomy. We evaluated the efficacy and safety of FTD/TPI in pts with or without prior gastrectomy within the TAGS study. Methods: In this global phase 3 study of adult pts with mGC who had received ≥ 2 prior regimens of chemotherapy, pts were randomized 2:1 to receive FTD/TPI (35 mg/m2 BID on days 1–5 and 8–12 of each 28-day cycle) or placebo, plus best supportive care. We performed a preplanned analysis of efficacy and safety endpoints in pt subgroups with or without prior gastrectomy. Results: Of 507 randomized pts, 221 (44%) had a prior gastrectomy (FTD/TPI, 147/337; placebo, 74/170). Baseline pt characteristics were balanced across pt subgroups. FTD/TPI prolonged survival versus placebo regardless of gastrectomy (table). The frequency of neutropenia/leukopenia appeared to be higher among FTD/TPI-treated pts with vs without gastrectomy, but this did not result in more treatment discontinuations (table). Conclusions: In the TAGS study, subgroup analysis demonstrated that FTD/TPI is an effective treatment option with a manageable safety profile for pts with heavily pretreated mGC, regardless of prior gastrectomy. Clinical trial information: NCT02500043. [Table: see text]