bluuebunny/crossref_metadata_2025 huggingface dataset:
In vitro and in vivo efficacy and safety of tumor treating fields (TTFields) and sorafenib combination in hepatocellular carcinoma.
Authors: Davidi Shiri , Tempel-Brami Catherine , Munster Mijal , Gotlib Karnit , Zeevi Einav , Schneiderman Rosa S , Voloshin Tali , Giladi Moshe , Kinzel Adrian , Kirson Eilon D. , Weinberg Uri , Palti Yoram
Published: February 2020

551

Background: Hepatocellular carcinoma (HCC) is a leading global cause of cancer-related mortality. Sorafenib (oral multikinase inhibitor) is approved in patients with advanced HCC, yet survival benefit is limited. Tumor Treating Fields (TTFields) are an effective, anti-neoplastic treatment modality delivered via noninvasive, low intensity (1-3 V/cm), intermediate frequency (100-500 kHz), alternating electric fields. The study aim was to explore in vitro and in vivo effects of TTFields alone and combined with sorafenib for HCC treatment. Methods: HCC (HepG2 and Huh-7D12) cells were TTFields treated with at frequencies of 100-400 kHz for 72 hr using the inovitro system. Efficacy of TTFields and sorafenib combined treatment was tested at optimal frequency with various sorafenib concentrations. Cell counts, apoptosis induction, and clonogenic potential were determined. Healthy rats were used to assess safety of TTFields applied to the abdomen. N1S1 HCC cells were injected into the left hepatic lobe of Sprague Dawley rat; after 1 week, TTFields (1.2 V/cm) and sorafenib (10 mg/kg) were applied for 6 days. Tumor growth was evaluated using MRI. Results: The optimal TTFields frequency was 150 kHz in HepG2 and Huh-7D12 HCC cells. TTFields 150 kHz treatment (1.0 - 1.7 V/cm, 72 hr) led to cell count reductions (53-55%) and further decreases in clonogenic potential (65-69%). TTFields and sorafenib combination treatment led to a significant reduction in cell count (2-way ANOVA, P < 0.05) vs either treatment alone. Also, tumor growth was significantly reduced in the combined treatment group vs the control group (student t test, P < 0.01). Tumor volume (fold increase) in the combination treatment group (1.6) was significantly lower vs control (5.9, P < 0.0001), TTFields alone (3.3, P < 0.01), and sorafenib alone (2.3, P < 0.05) groups. Safety studies did not reveal any TTFields related adverse events with delivery to the rat abdomen. Conclusions: In vitro and in vivo data demonstrated efficacy and safety of TTFields in HCC; and improved efficacy in combination with sorafenib. A phase 2 study (HEPANOVA; NCT03606590) will explore the clinical potential of TTFields 150 kHz plus sorafenib.
Clinical characteristics and outcomes of patients with advanced hepatocellular carcinoma treated with immunotherapy: A real-world retrospective study.
Authors: Chergui Adel , Gadde Eswar , Tolu Seda Serra , Acuna-Villaorduna Ana , Kabarriti Rafi , Goel Sanjay , Kaubisch Andreas
Published: February 2020

557

Background: Advanced HCC is an aggressive malignancy with dismal prognosis. Newer agents, including immunotherapy (IT), have been granted accelerated approval. Information outside clinical trials is scarce. This study is aimed to describe the clinical characteristics and outcomes of HCC patients treated with IT. Methods: Patients with HCC treated with IT were identified using the institutional data-mining software, Clinical Looking Glass. Patient demographics, clinical, and treatment characteristics were collected. Progression-free survival (PFS) was defined as time from treatment initiation to disease progression or death, and overall-survival (OS) as time from diagnosis of advanced disease to death. PFS and OS were plotted using Kaplan-Meier curves. Results: A total of 52 patients; median age 64 years; male predominance (38, 73.1%) were identified. There were 24 (54.5%) Hispanics, 9 (20.5%) Non-Hispanic Blacks, 7 (15.9%) Non-Hispanic White and 4 (9.1%) Asians. Cirrhosis was seen in 41 (83.7%), and median MELD score was 8 (IQ: 7-10). Hepatitis B and C infection were encountered in 12 (24.5%) and 22 (44%) patients, respectively. Imaging evidence of intravascular invasion was seen in 16 (34.8%) and extrahepatic metastases in 7 (14.9%) cases. Local treatment was provided to 29 (59.2%) and radiation treatment to 14 (28.6%) patients. Nivolumab was used in all the cases, as first-line treatment in 17 (32.7%) and as ≥ second line in 35(67.3%). The median PFS was 6.2 (3.1-10.6) months and was similar in first-line and ≥ second line treatment (8 vs 5.9 months, p=0.90). The median OS was 24.2 (18-28) months; there was a tendency towards higher survival rates in patients that were treated in ≥ second line (16.8 vs 25.2 months, 0=0.07). Conclusions: In this multiethnic cohort, the “real world” experience of the benefit of IT in HCC is encouraging, with a median OS exceeding two years. Expanded data may elucidate the differences if any, between use of IT as front vs. second line therapy, in PFS and OS.
Intensity-modulated proton therapy using dose-painting pencil beam scanning for high-risk hepatocellular carcinoma.
Authors: Schaub Stephanie K. , Bowen Stephen R. , Nyflot Matthew J. , Apisarnthanarax Smith
Published: February 2020

558

Background: High rates of local control are achievable with hypofractionated proton therapy with passive techniques for hepatocellular carcinoma (HCC), but may have limitations when tumors are adjacent to organs-at-risk (OARs), which may result in tumor underdosage and lead to inferior local control. We present the first reported series of HCC patients treated with pencil beam scanning (PBS) intensity-modulated proton therapy (IMPT) using a simultaneous-integrated boost and protection (SIB/SIP) technique to escalate tumor dose while protecting adjacent OARs. Methods: Twenty-five HCC patients were treated between 2015-2019 with a 15-fraction regimen using IMPT SIB/SIP. SIB/SIP dose levels generally ranged from 36.0-67.5 GyRBE to minimize dose to OARs at their respective dose-limiting thresholds (e.g. luminal gastrointestinal organs, chest wall). Radiation-induced liver disease (RILD) was defined by a Child-Pugh (CP) score increase of 2 or greater and/or any RTOG grade 3 enzyme elevation. Other toxicities were graded by CTCAEv5.0. Overall survival (OS), progression-free survival (PFS), and local control were calculated using the Kaplan-Meier method. Results: Patients most commonly had BCLC stage B or C disease (84%) and CP-A (80%) and ALBI grade 2 (60%) liver function. Median gross tumor volume (GTV) size and volume were 12.3 cm (range 2.17-20.57) and 461 cc (range 4.68-2439), and 32% had gross vascular invasion. Median mean and minimum dose delivered to the gross tumor volume (GTV) was 64.0 GyRBE (EQD2 76.1, BED 91.3, range 54.3-69.6) and 45.1 GyRBE (EQD2 48.9, BED 58.7, range 33.4-67.7), respectively. Median mean dose to liver minus GTV was 15.0 GyRBE (range, 8.2-19.6). 1-year OS, PFS, and local control were 66%, 32%, and 84%, respectively. No isolated local failures occurred. Two patients experienced RILD with no RILD-related deaths. Two grade 3 non-GI toxicities occurred: 1 rib fracture and 1 pneumonitis. No acute or late GI grade ≥2 occurred. Conclusions: In our series of HCC patients with large tumors near OARs, IMPT SIB/SIP allows for tumor dose escalation while sparing of OARs and results in favorable local control and acceptable toxicities.
Phase Ib study of regorafenib (REG) plus pembrolizumab (PEMBRO) for first-line treatment of advanced hepatocellular carcinoma (HCC).
Authors: El-Khoueiry Anthony B. , Kim Richard D. , Harris William P. , Sung Max W. , Waldschmidt Dirk , Iqbal Syma , Zhang Xiaojing (Amily) , Nakajima Keiko , Galle Peter R.
Published: February 2020

564

Background: REG is a multikinase inhibitor with immunomodulatory activity and PEMBRO is an anti-PD-1 monoclonal antibody. Both are approved as monotherapy for patients (pts) with HCC previously treated with sorafenib. Based on their potential synergistic effects, we conducted a phase 1b study of REG plus PEMBRO for first-line treatment of advanced HCC. Methods: This is an ongoing, open-label, dose-escalation study in pts with advanced HCC who had no prior systemic therapy. In the first cohort, pts received REG 120 mg/day PO for 3 weeks on/1 week off plus PEMBRO 200 mg IV q 3 weeks. In later cohorts, the REG dose could be escalated (160 mg) or reduced (80 mg) based on the modified toxicity probability interval design; the PEMBRO dose is fixed. The primary objective is safety and tolerability. Secondary objectives are to define the maximum tolerated dose (MTD) and recommended phase 2 dose, and to assess antitumor activity. Results: As of August 23, 2019, 29 pts have been treated at the REG 120 mg level. Median age is 65 years (range 32–81); 41%/55% of pts are BCLC stage B/C; 100% are Child–Pugh A; ECOG status 0/1 is 72%/28%. Dose-limiting toxicities occurred in 4/18 evaluable pts: grade (Gr) 3 increased ALT/AST with Gr 2 increased bilirubin (n = 2); Gr 3 rash (n = 2). The MTD of REG in the combination was 120 mg. Most common Gr 3 or 4 treatment-emergent adverse events (TEAEs) are shown (n = 29). There were no Gr 5 TEAEs. 59%/31% of pts had REG/PEMRO-related Gr 3 or 4 TEAEs. Dose modifications (reductions or interruptions) of REG/PEMBRO for drug-related TEAEs occurred in 59%/31% of pts. Of 23 evaluable pts, 7 (30%) had a partial response (PR) and 14 (61%) had stable disease (RECIST v1.1); 1 additional pt had PR by mRECIST. Conclusions: The combination of REG plus PEMBRO for first-line treatment of advanced HCC showed no unexpected safety signals and encouraging antitumor activity. Accrual is continuing at REG 120 mg dose and an expansion cohort evaluating REG 80 mg plus PEMBRO is planned. Clinical trial information: NCT03347292.

[Table: see text]
Circulating levels of soluble urokinase plasminogen activator receptor (suPAR) to predict outcome after resection of biliary tract cancer.
Authors: Loosen Sven H , Breuer Annemarie , Tacke Frank , Alizai Patrick Hamid , Ulmer Tom Florian , Trautwein Christian , Longerich Thomas , Roderburg Christoph , Neumann Ulf Peter , Luedde Tom
Published: February 2020

572

Background: Surgical resection is the only curatively intended therapy for patients with biliary tract cancer (BTC), but 5-year survival rates after tumor resection have remained below 30%, corroborating the need for better preoperative stratification tools to identify the ideal surgical candidates. The soluble urokinase plasminogen activator receptor (suPAR) represents a mediator of inflammation and has recently been associated with cancer. In this study, we evaluated a potential role of suPAR as a novel biomarker in patients undergoing resection of BTC. Methods: Tumor expression of uPAR, the membrane bound source of suPAR, was analyzed by IHC in 108 BTC samples. Serum levels of suPAR were analyzed by ELISA in a training and validation cohort comprising a total of 117 BTC patients and 76 healthy controls. Results: A high tumoral uPAR expression was associated with an adverse outcome after BTC resection. In line, circulating levels of suPAR were significantly elevated in BTC patients compared to healthy controls and patients with primary sclerosing cholangitis (PSC). Using a small training set, we established an optimal prognostic suPAR cut-off value of 3.72ng/ml for BTC patients. Importantly, preoperative suPAR serum levels above this cut-off value were associated with significantly impaired overall survival in both the training and validation cohort. Multivariate Cox-regression analysis including clinicopathological parameters such as the tumor stage, markers of systemic inflammation or organ dysfunction and established tumor markers revealed suPAR as an independent prognostic marker following BTC resection. Finally, high preoperative suPAR levels were indicative for acute kidney injury after tumor resection. Conclusions: Circulating suPAR represents a previously unrecognized biomarker in patients with resectable BTC, which might be useful to preoperatively identify the ideal candidates for tumor resection.
NTRK gene fusions in biliary tract cancers.
Authors: Demols Anne , Rocq Laureen , Charry Manon , De Nève Nancy , Verrellen Audrey , Ramadhan Ali , Van Campenhout Claude , De Clercq Sarah , Salmon Isabelle , D'Haene Nicky
Published: February 2020

574

Background: Gene fusions involving one of the 3 neurotrophic tyrosine receptor kinases ( NTRK) have been identified in approximately 1% of solid tumors and inhibitors of TRK (e.g. larotrectinib) have been shown to have anti-tumor activity regardless of tumor type. NTRK gene fusions have been previously reported in bilio-pancreatic cancers. It is of interest therefore to determine the incidence and molecular characteristics of NTRK gene fusions in patients with bilio-pancreatic cancers. Methods: Formalin-fixed paraffin-embedded archival blocks from surgical resections, biopsies or cytological samples of biliary tract tumors including intra-hepatic cholangiocarcinoma (IH), extra-hepatic cholangiocarcinoma (EH), perihilar cholangiocarcinoma (PH) and gallbladder tumors (G) were selected/retrieved from the tumor bank of the CUB Hôpital Erasme between January 2010 and July 2019. A two-step diagnostic method incorporating immunohistochemistry (IHC) screening followed by NGS analysis was used. Pan–TRK IHC (monoclonal antibody clone EPR17341 [AbCam, Cambridge, MA]) was used for the screening method. Staining intensity (negative, weak, moderate or strong) and localization (cytoplasmic or nuclear) were evaluated. The presence of at least weak staining tumor cells led to testing by a RNA-based NGS panel (Oncomine Focus Assay, ThermoFisher scientific). Results: 145 archival tumors samples (81 surgical resections, 48 biopsies and 16 cytology) have been selected, including 61 IH, 32 PH, 26 EH and 26 G (67 female and 78 male). 134 samples were suitable to perform IHC. 17 samples were IHC positive. Intensity of staining was weak in 16 samples and moderate in one. Staining location was cytoplasmic (14/17), nuclear (2/17), and nuclear+cytoplasmic (1/17). NGS testing of the 17 IHC positive samples revealed a single NTRK3 gene fusion ( ETV6(4)- NTRK3(14)). In this case (female patient with a poorly differentiated PH, deceased), IHC had a weak focal cytoplasmic and nuclear staining. Overall in the patients screened by IHC and confirmed by NGS, the percentage of NTRK fusions was 0.75%. Conclusions: NTRK gene fusions are rare in biliary cancers but testing is of high interest due to the emergence of possible treatment with specific TRK inhibitors.
Beta-catenin mutations in hepatocellular cancer, tumor cell metabolism, and the response of these tumors to mTOR inhibition.
Authors: Monga Satdarshan , Borad Mitesh J. , Tao Junyan
Published: February 2020

583

Background: Hepatocellular cancer (HCC) continues to grow in incidence despite approval of many new therapies including immune checkpoint inhibitors (ICIs) and TKIs. Genomic landscape of HCC is becoming increasing apparent through WGS and WES. One major driver of HCC is the Wnt/b-catenin pathway. Mutations in CTNNB1, which encodes for b-catenin, are evident in 26-37% of all human HCCs. However, expression of mutant-b-catenin in liver in mice is insufficient for HCC development. Indeed, analysis of HCC cases has revealed CTNNB1 mutations to significantly co-exist with other aberrations including activation/overexpression of Met and Myc and mutations in TERT promoter or mutations in NFE2L2/KEAP1, APOB and ARID2. Methods: Using sleeping beauty transposon/transposase and hydrodynamic tail vein injection, we co-expressed mutant-CTNNB1 (S45Y, S33Y or T41A) and one other clinically relevant co-occurrence to study significance and biology of HCC. Any novel findings in the preclinical model were validated in HCC patient cohorts. Results: Co-expression of mutant-CTNNB1 and one relevant co-occurrence led to development of HCC in mice in 6-10 weeks. All HCC in these models showed a dramatic increase in glutamine synthetase (GS), encoded by Glul, a known target of the Wnt/b-catenin signaling pathway in the liver. This led to an increase in glutamine levels in the tumor-bearing livers. Increased glutamine in the tumors in turn led to increased levels of phospho-mTOR-S2448, a marker of mTORC1 activation. In fact, examination of ~400 patient HCCs showed a significant correlation between positive GS and p-mTOR-S2448 staining. Treatment of Met-b-catenin model with Rapamycin led to notable and significant decrease in HCC burden. Conclusions: Our studydemonstrates b-catenin-mutated HCC to be positive for both GS and in turn mTORC1 active. This provides a novel opportunity for personalized medicine in HCC and CTNNB1-mutated HCCs may be vulnerable to therapeutic targeting by mTOR and more specially, mTORC1 inhibitors.
Neuroendocrine and carcinoid tumors of the gastrointestinal tract: Epidemiology and outcomes from the National Cancer Database.
Authors: Uhlig Johannes , Nie James , Stein Stacey , Cecchini Michael , Lacy Jill , Kim Hyun S.
Published: February 2020

609

Background: While carcinoid and neuroendocrine tumors (NET) can manifest throughout the human body, approximately 2/3 of these tumors arise in the gastrointestinal (GI) tract. Methods: The 2019 version of the National Cancer Database was searched for adult patients with carcinoid or neuroendocrine tumors of the GI tract. Tumor incidence, patient demographics, treatment and cancer variables of GI carcinoid/NETs were compared to other GI cancers. Cox proportional hazards models were used to evaluate overall survival (OS). Results: A total of 101,744 patients were included. Carcinoid/NET incidence varied with primary location, with highest proportion in the small intestine (55.7% of all small intestinal cancers). Compared to other histologies, carcinoid/NETs were more common in younger patients (median age 60 vs. 68years, p < 0.001) and African Americans (18 vs 12%, p < 0.001). Median carcinoid/NET diameter 15mm vs. 40mm for other cancers (p < 0.001). Carcinoid/NETs were diagnosed at lower stages than other histologies (AJCC stage 3/4, 30% vs. 47%, p < 0.001), with most metastases in the liver (8.9%). Stage 1/2 carcinoid/NETs were most often treated by surgical resection with or without concurrent chemotherapy (65%; 22%), whereas stage 3/4 patients received chemotherapy alone or in combination with surgical resection more commonly (39%; 25%). After multivariable adjustment, primary cancer site emerged as an independent prognosticator: longest OS was observed in patients with carcinoid/NET of the small intestines (vs. colonic frame HR = 0.40, 95% CI: 0.37-0.44, p < 0.001). Comparable results were evident in patients with hepatic metastases (small intestines vs. colonic frame carcinoid/NETs; HR = 0.20, 95% CI: 0.17-0.24, p < 0.001). Other independent OS prognosticators were patient age, gender, race and comorbidities, as well as tumor size, stage and treatment. Conclusions: Compared to other GI-associated tumors, carcinoid/NETs are more common in younger patients, African Americans, diagnosed with smaller diameter at low stage. Carcinoid/NETs of the small intestines are associated with improved overall survival compared to other primary disease sites.
The benefits of upfront primary tumor resection for metastatic small bowel neuroendocrine tumors: A population-based analysis.
Authors: Bennett Sean , Coburn Natalie , Law Calvin , Zuk Victoria , Mahar Alyson , Singh Simron , Myrehaug Sten , Zhao Haoyu , Davis Laura E , Gupta Vaibhav , Hallet Julie
Published: February 2020

620

Background: Early resection of the primary tumor in metastatic small bowel neuroendocrine (SB-NET) remains controversial. Conflicting data exist regarding its clinical and survival benefits. We compared the long-term outcomes of upfront small bowel resection (USBR) and non-operative management (NOM) for metastatic SB-NETs. Methods: A population-based analysis of patients with SB-NET metastatic at diagnosis between 2001-2017 was conducted by linking administrative datasets. USBR was defined as resection within 6 months of diagnosis. Primary outcomes were subsequent unplanned acute care admissions and small bowel related surgery. Secondary outcome was overall survival (OS). USBR and NOM patients were matched 2:1 using a propensity-score including age, sex, year of diagnosis, socioeconomic status, institution academic status, and functional status. We used time-to-event analyses with cumulative incidence functions and univariate Andersen-Gill regression for primary outcomes, and Kaplan-Meier methods and univariate Cox regression for OS. E-value methods assessed the potential for residual confounding. Results: Of 1000 patients identified, 785 (78.5%) had USBR. The matched cohort included 348 patients with USBR and 174 with NOM. Matched groups were well balanced with standardized mean differences <10% for matched variables. Patients with USBR had lower 3-year risk of subsequent admissions (72.6% vs 86.4%, p<0.001) than those with NOM, with hazard ratio (HR) 0.72 (95%CI 0.57-0.91). USBR was associated with lower risk of subsequent small bowel related surgery (15.4% vs 40.3%, p<0.001), with HR 0.41 (95%CI 0.30-0.56). OS was superior for USBR patients compared to NOM (HR 0.55, 95%CI 0.41-0.74). E-values indicated it was unlikely that the observed risk estimates could be explained by an unmeasured confounder. Sensitivity analysis excluding emergent resections to define USBR did not alter the results. Conclusions: USBR for metastatic SB-NETs was associated with clinical benefits over NOM, in terms of decreased subsequent admissions and interventions, and improved survival. USBR should be considered for metastatic SB-NETs to improve patient outcomes.
PRRT neuroendocrine tumor response assessment using blood transcript analysis: The NETest.
Authors: Bodei Lisa , Kidd Mark A. , Singh Aviral , van der Zwan Wouter A , Severi Stefano , Drozdov Ignat A. , Malczewska Anna , Baum Richard P. , Kwekkeboom Dik J. , Paganelli Giovanni , Krenning Eric , Modlin Irvin Mark
Published: February 2020

625

Background: Peptide receptor radionuclide therapy (PRRT) is effective for metastatic/inoperable neuroendocrine tumors (NETs). Imaging response assessment is most effective after treatment completion. Blood biomarkers such as PRRT Predictive Quotient (PPQ) and NETest are effective in real-time. PPQ predicts PRRT efficacy, NETest monitors disease. We prospectively evaluated: 1) NETest as a surrogate biomarker for RECIST; 2) Correlation of NETest levels, PPQ prediction and treatment efficacy. Methods: Three independent 177Lu-PRRT-treated GEP-NET and BPNEN cohorts (Rotterdam, Netherlands: n=41; Bad-Berka, Germany: n=44; Meldola, Italy: n=72). Treatment response: RECIST1.1 [Responder (stable, partial/complete response) vs Non-Responder]. Blood sampling: pre-PRRT, prior to each cycle and 6 months (median) after completion of all cycles. PPQ (positive/negative) and NETest (0-100 score) by PCR. Stable<40; progressive >40). CgA (ELISA) as comparator. Samples deidentified, measurement and analyses blinded. Kaplan-Meier survival and Mann-Whitney analyses. Results: 122 of 157 were evaluable. RECIST stabilization or response in 67%; 33% progressed. NETest significantly ( p<0.0001) decreased in RECIST-“responders” (-47±3%); in “non-responders” it elevated (+79±19%, p<0.0005). NETest monitoring accuracy 98% (119/122). Follow-up levels >40 (progressive) vs stable (<40) significantly correlated with mPFS (not reached vs. 10 months; HR 0.04, 95%CI: 0.02-0.07). PPQ response prediction was accurate in 118 (97%); 99% accurate positive and 93% accurate negative prediction. NETest significantly ( p<0.0001) decreased in PPQ-predicted responders (-46±3%) and remained increased in PPQ-predicted non-responders (+75±19%). Follow-up NETest categories stable vs progressive significantly correlated with PPQ prediction and mPFS (not reached vs. 10 months; HR 0.06, 95%CI: 0.03-0.12). CgA failed to identify response to PRRT ( p=NS). Conclusions: NETest accurately (98%) monitors PRRT response and is an effective surrogate marker for radiological response (image concordance 98%). A NETest decrease identified responders and correlated (>97%) with the pretreatment PPQ response predictor.
Allele frequencies of two MUTYH variants, Y179C, and G396D, in a direct-to-consumer genetic database.
Authors: Nhan Hoang , Zhan Jianan , Kosinski Cindy , Hampel Heather , Wu Shirley ,   23andMe Health Team
Published: February 2020

63

Background: MUTYH-associated polyposis (MAP) is an autosomal recessive condition that accounts for about 0.3-0.7% of all colorectal cancer (CRC) cases. The two most common variants among people of Northern European descent are MUTYH Y179C (rs34612342) and G396D (rs36053993), with a carrier frequency of 1-2%. However, understanding the frequency of these variants in other populations can better inform population health approaches for CRC screening and prevention. This study assessed the frequency of these two variants in a generally unselected group of genotyped individuals who have used direct-to-consumer (DTC) genetic testing (23andMe, Inc. Sunnyvale, CA). Methods: Study participants were genotyped on Illumina genotyping arrays, which included the Y179C and G396D variants. Eligible subjects were 23andMe customers who were at least 18 years of age and who consented to participate in research. IRB approval was obtained from Ethical and Independent Review Services. Results: Out of the 3,617,279 eligible participants included in this study, the overall allele frequencies of Y179C and G396D were 0.18% and 0.51%, respectively. People of European descent had the highest frequencies (0.22% and 0.59%), while people of Ashkenazi Jewish, East Asian, and South Asian descent had the lowest frequencies ( < 0.015% for both variants). The allele frequencies for people of Hispanic/Latino descent were 0.15% and 0.51%. Conclusions: This is the first description of an unselected cohort of individuals with MUTYH Y179C and G396D variants identified through DTC genetic testing. While these two variants were most common among people of European descent, they were also observed at relatively high frequency among people of Hispanic/Latino descent. These results may help guide CRC screening and prevention strategies in different ethnicities.
Implementation of systematic genetic counseling (GC) and multigene germline testing (MGT) for pancreatic cancer (PC) patients (pts).
Authors: Yurgelun Matthew B. , Chittenden Anu B. , Ukaegbu Chinedu I. , Perez Kimberly , Madigan Audrey P. , Gaonkar Shraddha , Cleary James M. , Aguirre Andrew , Wolpin Brian M. , Syngal Sapna
Published: February 2020

678

Background: MGT identifies cancer susceptibility gene variants in 4-10% of unselected PC pts. Such data have prompted national guidelines to recommend GC and MGT of all PC pts, but the benefits and barriers to implementing systematic testing are unknown. This study’s aim was to study the implementation of universal GC for all PC pts seen in an academic oncology practice. Methods: In 12/2016, all Dana-Farber Cancer Institute (DFCI) gastrointestinal oncologists were recommended to refer all PC pts for GC and MGT. In 10/2018, workflows were changed such that PC patients were automatically scheduled for GC consultation on the same day as their initial oncologic evaluation (unless patients opted out), rather than relying on provider referral. Clinical and germline data were collected on a consecutive cohort of PC pts undergoing GC and MGT from 3/1/2017-3/31/2019. Two additional months (4/1/2019-5/31/2019) were collected for clinical quality assessment purposes. Results: 1305 (48.3/month) PC pts were seen for oncologic new patient visits, 318 (25.1%; 12.1/month) of whom underwent GC. Rates of GC/MGT increased significantly after the 10/2018 workflow change (8.2 PC pts/month [17.2% of all new PC pts seen] versus 20.3 PC pts/month, [40.9% of all new PC pts seen]; p<0.01). Of the 318 PC pts who underwent GC, 29 (9.1%; 95% CI 6.4-11.9%; 2.2% of all PC pts seen) were found to carry germline PC susceptibility gene mutations on MGT. Rates of mutation carrier identification increased after the clinical workflow change from 0.79 mutation carriers/month (1.6% of all new PC pts seen) to 1.75 mutation carriers/month (3.5% of all new PC pts seen). The majority of identified mutation carriers have either received therapy targeted towards their germline mutation or are undergoing first-line palliative systemic therapy with potential for future targeted therapy. Conclusions: Clinical implementation of routine GC/MGT in PC pts is feasible and results in the detection of mutations that are actionable for PC pts and at-risk family members. Systematized workflows for GC evaluation not reliant on active referral result in markedly higher uptake of MGT and mutation carrier identification. Clinical trial information: NCT03060720.
Efficacy and safety of second-line nab-paclitaxel plus gemcitabine (nab-P+GEM) after progression on first-line FOLFIRINOX in advanced pancreatic ductal adenocarcinoma (PDAC): Multicenter retrospective analysis.
Authors: Yoo Changhoon , Jeong Hyehyun , Chae Heejung , Cheon Jaekyung , Chon Hong Jae , Ryu Hyewon , Kim Il-Hwan , Jeong Jae Ho , Kim Kyu-Pyo , Ryoo Baek-Yeol
Published: February 2020

689

Background: FOLFIRINOX is one of standard 1st-line regimens for patients (pts) with advanced PDAC. However, there is no globally established 2nd-line regimen after failure of FOLFIRINOX. Although gemcitabine-based regimens are recommended by multiple guidelines and widely used in daily practice, further analysis is needed to reveal the magnitude of clinical benefit with these regimens. Nab-P+Gem is another standard 1st-line regimen for PDAC, but there are limited data as 2nd-line therapy in PDAC. Therefore, we conducted multicenter retrospective analysis of 2nd-line nab-P+Gem after progression on FOLFIRINOX in pts with advanced PDAC. Methods: Between Feb 2016 and Feb 2019, a total of 103 pts with histologically documented PDAC who received nab-P+GEM after progression on 1st-line FOLFIRINOX were identified among 5 referral cancer centers in South Korea. Results: Median age was 60 years and 50 pts (49%) were male. All but one pts had ECOG performance status of 0-1 at the time of nab-P+GEM. At the time of nab-P+GEM, 25 (24%) and 78 (76%) patients had locally advanced and metastatic disease, respectively. Median overall survival (OS) and progression-free survival (PFS) with nab-P+GEM was 9.8 months (95% CI: 8.9-10.6) and 4.6 months (95% CI: 3.7-5.5), respectively. Among pts with measurable disease (n = 95), partial response and stable disease were achieved in 8 (8%) and 56 (54%), respectively. Median OS from the start of 1st-line FOLFIRINOX was 20.9 months (95% CI: 15.2-26.6). Most common adverse event of all grade was anemia (77%), followed by neutropenia (60%), fatigue (52%), thrombocytopenia (45%), and peripheral neuropathy (30%). Most common grade 3-4 adverse events were neutropenia (36%), anemia (9%), and peripheral neuropathy (8%). Conclusions: In medically fit pts with advanced PDAC who failed on 1st-line FOLFIRINOX, nab-P+GEM was effective and well tolerated as 2nd-line therapy.
A pilot clinical trial of p53/p16-independent epigenetic therapy for pancreatic ductal adenocarcinoma (PDA).
Authors: Sohal Davendra , Krishnamurthi Smitha S. , Tohme Rita , Shepard Dale Randall , Khorana Alok A. , Saunthararajah Yogen
Published: February 2020

699

Background: PDA treatment is limited to cytotoxic drugs. A key factor limiting their efficacy is TP53 mutations, omnipresent in PDA, which counter apoptosis-mediated cell kill. We evaluated a novel epigenetic approach using decitabine (Dec) to inhibit DNA methyltransferase 1 (DNMT1) and effect cancer cell cycle exits by epithelial-differentiation, combined with tetrahydrouridine (THU) to inhibit cytidine deaminase (CDA) and thereby permit oral bioavailability and solid-tissue distribution of Dec. Methods: Open-label single-arm, IRB-approved clinical trial at Cleveland Clinic and University Hospitals for patients with metastatic PDA that had progressed on prior chemotherapy, ECOG PS of 0-2. Treatment was oral, weight-based, with Dec 10-20 mg, and THU 500-1000 mg daily, 5 days/week. Primary endpoint was DNMT1 protein levels at 16-week vs baseline biopsies. Results: From Apr to Aug 2017, we enrolled 13 patients. Median age was 65 (range 44-74) years; 7 (54%) males; 11 (85%) Caucasians. Median time from diagnosis was 13 (3.9-53.5) months, with a median of 2 (1-3) prior lines of therapy. Baseline ECOG PS was 0/1 in 12 (92%) patients. All patients started study drugs; median time on treatment was 35 (4-63) days, and on study 72 (25-105) days. The most frequent adverse events attributable to the study drugs were anemia (n=5), and anorexia, dehydration, nausea, fatigue, febrile neutropenia and decreased lymphocyte count, in 3 patients each; no deaths. Eight (62%) patients underwent evaluation scans at 8 weeks, showing stable disease in 1 patient and progression in 7. Common reasons for coming off of study drugs were progression (n=6), physician discretion (n=3), and adverse events (n=2). Overall, 6 patients died; median survival was 3.1 months, and patients did not reach the 16-week biopsy. Shifts in blood counts, a sensitive indicator of Dec systemic activity, were unexpectedly mild, and plasma CDA enzyme activity was increased versus other cancer and normal controls. Conclusions: This first-of-its-kind study demonstrated feasibility and safety of the novel oral epigenetic therapy. Systemically elevated CDA in these patients requires higher doses of THU; a trial accordingly refined is planned. Clinical trial information: NCT02847000.
A phase I study of olaparib in combination with capecitabine-based chemoradiation (CRT) in patients (pts) with locally advanced pancreatic cancer (LAPC).
Authors: Evans T.R. Jeffry , Eatock Martin McKinlay , Lewsley Liz-Anne , Kelly Caroline , McCartney Elaine , Duffton Aileen , Houston Peter , Harrison Claire , Purcell Colin , Ashton Miranda , Morton Alanna , Graham Jill , Chalmers Anthony J. , Thomson Fiona , Pou Chantevy , Bilsland Alan , Cooke Susie , McIntosh David , Grose Derek B.
Published: February 2020

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Background: Olaparib is a potent inhibitor of PARP-1, which has a critical role in signalling DNA single strand breaks (SSB) as part of the base excision repair pathway, and may have radio-sensitizing effects due to impaired resolution of radiation induced SSB. We hypothesize that O may potentiate the effects of X-CRT in pts with LAPC. Methods: Eligible pts with LAPC, ECOG < 1, tumor diameter < 6cm, with stable disease (SD) or response after 12 weeks’ induction chemotherapy, were treated with 1 of 4 escalating doses of O given bid po starting on day -3, and then in combination with X (830 mg/m2 bid) and radiation (50·4 Gy in 28 fractions) all administered Mon-Fri. Dose limiting toxicities (DLT) were determined on clinical and lab toxicity assessments (NCI-CTC AE v4.03) performed weekly from the start of O until completion of O plus X-CRT (i.e. 6 weeks). Dose escalation continued with a rolling-six design until the Maximum Tolerated Dose (MTD) was reached. Blood samples for PK analyses of O and PD measurement (inhibition of PARP activity) were collected on day -3 (O monotherapy) and during week 1 of O + X-CRT. Results: 18 pts, (9 m, 9 f, ECOG 0/1 [n=6/12]), age range 49-81 (median=70) years, with histologic (14) or cytologic (4) proven LAPC, had received induction chemotherapy with gemcitabine [GEM] (n=2), GEM + X (12), or FOLFIRINOX (3) with partial response (n=4) or stable disease (14). Pts received 50 (3), 100 (4), 150 (6), or 200 (5) mgs bid of O with X+CRT. DLTs were observed in 2 pts (both at 200mgs bid): 1 pt with grade 3 nausea (on optimal anti-emetics) and grade 3 fatigue, 1 pt with grade 3 anorexia. 6 pts were subsequently recruited at 150mgs bid with no DLTs. No pts had complete response, 2 pts had partial response (1 pt each at 100 and 150 mgs bid) and 1 pt (at 100 mgs bid) had progressive disease; the remaining 14 pts had SD. Conclusions: The recommended dose (RP2) of O is 150mgs bid when given in combination with X + CRT in LAPC. Recruitment of up to 12 pts with borderline operable LAPC at the RP2 is ongoing. PK analyses of O, PD studies (PARP inhibition – PBMCs; cytokeratin 18 – serum; γH2AX foci – hair follicles), and exploratory predictive marker studies (tumor – NGS; RNA exome sequencing) are ongoing. Clinical trial information: ISRCTN10361292.
Phase Ia, first-in-human study of AbGn-107, a novel antibody-drug conjugate (ADC), in patients with gastric, colorectal, pancreatic, or biliary cancers.
Authors: Ko Andrew H. , Coveler Andrew L. , Schlechter Benjamin L. , Bekaii-Saab Tanios S. , Wolpin Brian M. , Clark Jeffrey William , Cheng Yi-Lin , Cheng Ting-Ying , Langecker Peter J. , Lin Shih-Yao
Published: February 2020

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Background: AbGn-107 is an ADC directed against AG-7 antigen, a Lewis A-like glycol-epitope expressed in 24-61% of gastric (G), colorectal (CRC), pancreatic (PDA), and biliary (BIL) cancers. Based on promising antitumor activity of AbGn-107 in both in vitro and in vivo preclinical studies, we performed a Phase Ia trial in pts with the aforementioned GI malignancies. Methods: Standard 3+3 dose escalation was used. Key eligibility criteria: locally adv or metastatic G, CRC, PDA, or BIL cancer, previously treated, ECOG PS 0-1; positive AG-7 expression was not required. Two dosing intervals were tested: AbGn-107 administered i.v. Q4 weeks (at doses ranging from 0.1-1.2 mg/kg) and Q2 weeks (at doses from 0.8-1.0 mg/kg). DLTs were based on grade 3/4 hematologic and non-heme AEs occurring during the initial 4-week rx window. Pts were treated until dz progression or unacceptable toxicity, with tumor assessments Q8 weeks. 1o objectives: safety and MTD; 2o objectives: PK, immunogenicity, and efficacy defined by ORR (RECIST 1.1). Results: 35 patients were enrolled across 6 dose levels (median age 61.5 yo (range 40 – 81); G (0)/CRC (12)/PDA (20)/BIL (3); median # lines of prior rx = 3 (range 1-7). Safety: 5 pts experienced Grade 3 or 4 neutropenia, all at higher dose levels, with 1 episode of febrile neutropenia. Other frequent drug-related AEs, mostly grade 1/2, inc. fatigue (29%), nausea (20%), and diarrhea (14%). DLTs include grade 4 CK elevation (n = 1) at 0.8 mg/kg Q4W and grade 3 arthralgias (n = 1) at 1.2 mg/kg Q4W. MTD was not reached at either 1.2 mg/kg Q4W or 0.8 mg/kg Q2W; the 1.0 mg/kg Q2W cohort will complete enrollment in Oct 2019. Efficacy: Median duration of treatment = 56 days (range, 8 – 225 days); best response observed to date is stable dz lasting > 6 months at 0.8 mg/kg Q4W and Q2W cohorts (n = 1 each). Conclusions: Overall, AbGn-107 appears well-tolerated with encouraging prelim signs of efficacy (prolonged dz control) in non-biomarker selected pts with advanced GI cancers. Pre-screening for high AG-7 expression is underway for subjects with G, CRC, PDA, and BIL cancers for the cohort expansion phase of this study, which will be open across multiple sites in U.S. and Taiwan. Clinical trial information: NCT02908451.
Homologous recombination deficiency (HRD) by BROCA-HR and survival outcomes after surgery for patients (pts) with pancreatic adenocarcinoma (PC): A single institution experience.
Authors: Chang Amy E. , Zhen David Bing , Radke Marc , Baker Kelsey K. , Coveler Andrew L. , Wong Kit Man , Pillarisetty Venu Gopal , Redman Mary Weber , Swisher Elizabeth , Chiorean E. Gabriela
Published: February 2020

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Background: 5-7% of PC pts exhibit deleterious germline mutations (MUT) in HR tumor suppressor genes BRCA1 and BRCA2. BROCA-HR is a targeted capture and massively parallel sequencing assay designed to detect all mutation classes including gene rearrangements, copy number variations, and gene aberrations within the Fanconi Anemia-BRCA HR, non-homologous end joining (NHEJ) DNA repair, and DNA mismatch repair pathways. BROCA-HR has been successfully used in breast and ovarian cancer pts for overall prognosis and prediction of response to platinum-based therapies. While BRCA1/2 MUT may confer survival advantage for PC pts if treated with platinum-chemotherapy, the survival impact of HRD is less well defined. Methods: We retrospectively identified 100 consecutive pts who underwent surgical resection for suspected PC at University of Washington Medical Center between 1999 and 2008. Formalin-fixed paraffin embedded resected tumors were sequenced using BROCA-HR. HRD was grouped based on the following deleterious genetic mutations: 1) BRCA1, BRCA2; 2) core HRD: BARD1, BRIP1, RAD51C, RAD51D, PALB2, CDK12, NBN; 3) non-core HRD: ATM, ATR, ATRX, BAP1, BLM, CHEK1/2, ERCC, FANC A/C/D2/E /F/G/L, MRE11, RAD50/51/51B, RIF1, SLX4; 4) HR proficient. Overall survival (OS) was measured from diagnosis until death or last follow-up. Results: 95 pts had histologically confirmed PC, and 81 pts had adequate tumor DNA for analysis. Six pts (7%) had BRCA1/2 MUT (n = 5), or BRCA1 methylation (n = 1), 1 pt (1%) had non-BRCA core HRD ( PALB2 MUT), 7 pts (9%) had non-core HRD: ERCC (2), CHEK2 (2), ATR, RAD51D, and FANCA MUT (1 each). Median OS was: all pts 1.93 yrs (95% C.I. 1.53, 2.16), BRCA1/2 pts 3.09 yrs (95% CI 0.41, 12.21), all core HRD pts 1.21 yrs (95% CI 0.41, 12.21), all core and non-core HRD pts 1.89 yrs (95% CI 0.57, 4.96), HR proficient pts 1.93 yrs (95% CI 1.51, 2.15). There were no OS differences between pts with HRD vs those HR proficient. Conclusions: HRD is common (17%) but does not affect OS for pts with resected PC. Prospective clinical trials should test neo/adjuvant therapies including platinum chemotherapy and PARP inhibitors for pts with HRD.
Tumor infiltration and cytokine biomarkers of prostate stem cell antigen (PSCA)-directed GOCAR-T cells in patients with advanced pancreatic tumors.
Authors: Shaw Joanne , Ballard Brandon , Yi Xiaohui , Malankar Aditya , Collinson-Pautz Matthew R. , Becerra Carlos Roberto , Woodard Joseph Paul , Foster Aaron E.
Published: February 2020

734

Background: PSCA is a cell surface protein overexpressed in approximately 60% of pancreatic cancers. BPX-601 is an autologous GOCAR-T cell therapy engineered to express a PSCA-CD3ζ CAR and the MyD88/CD40 (iMC) costimulatory domain activated by rimiducid (Rim), designed to boost CAR-T performance in solid tumors. The safety and activity of BPX-601 activated with Rim in PSCA+ metastatic pancreatic cancer is being assessed in a Phase 1/2 clinical trial, BP-012 (NCT02744287). Methods: Phase 1 of BP-012 is a 3+3 dose escalation of BPX-601 (1.25-5 x106/kg) administered on Day 0 with a single, fixed-dose of Rim (0.4 mg/kg) on Day 7 in subjects with previously treated PSCA+ metastatic pancreatic cancer. All 5 subjects in cohort 5B received Flu/Cy lymphodepletion followed by BPX-601 (5 x106/kg) and Rim. BPX-601 kinetics, PBMC phenotype, and serum cytokines were assayed by qPCR, flow cytometry, and cytokine multiplex, respectively. Baseline and on-treatment biopsies were evaluated by RNAscope in situ hybridization. Results: BPX-601 cells expanded in all subjects and persisted up to 9 months (median 42 days). Transient reduction in BPX-601 vector copy number and total T cell count concurrent with Rim infusion, supports margination of activated BPX-601 cells. Increased serum cytokines, such as IFN-γ and GM-CSF, were observed following BPX-601 infusion with further elevation after Rim activation. All subjects with evaluable on-treatment biopsies had infiltration of BPX-601 cells (n = 3) proximal to tumor cells 7-15 days after Rim, but not in an end of treatment biopsy > 200 days after Rim (n = 1). Stratification by best response (RECIST 1.1) revealed stable disease in 3 subjects and progressive disease in 2 subjects was potentially associated with distinct cytokine signatures. Conclusions: BPX-601 GOCAR-T cells expand and persist in patients with PSCA+ metastatic pancreatic cancer and infiltrate metastatic lesions. A peripheral cytokine signature was observed following BPX-601 infusion. Select cytokines were enhanced after GOCAR-T cell activation and may correlate with clinical response. A cohort of subjects exploring serial administration of Rim is open for enrollment. Clinical trial information: NCT02744287.
Comparison of gemcitabine delivery and tumor response in a pressurized pancreatic retrograde venous infusion versus systemic infusion in an orthotopic murine model.
Authors: Vicente Diego , Shankara Narayanan Jayanth , Ray Partha , Chai Louis F. , Erdem Suna , Carr Matthew , Capacio Benedict , Cox Bryan , Jaroch David , Katz Steven C. , White Rebekah Ruth
Published: February 2020

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Background: Pancreatic ductal adenocarcinoma (PDAC) is associated with limited response to systemic therapy (ST). Elevated tumor interstitial fluid pressures (IFP) inhibit penetration of ST. Regional Pressure Enabled Drug Delivery has recently demonstrated improved response for liver tumors in a clinical trial. However, this delivery method has not been evaluated in PDAC. We compared gemcitabine (Gem) by systemic delivery vs. a novel pressurized Pancreatic Retrograde Venous Infusion (PRVI) method in an orthotopic PDAC mouse model. Methods: PDAC murine cell line (KPC4580P) tumors were transplanted onto the pancreatic tail of C57BL/6J mice. Groups of 15 mice were randomly assigned to PRVI Gem, PRVI saline (Control), or intraperitoneal Gem (Systemic) groups. Five mice from the PRVI and Systemic groups were randomly selected after one hour post infusion to evaluate Gem tumor concentrations by liquid chromatography - tandem mass spectrometry (ng/mg), and the remainder of mice were euthanized after 7 days to evaluate treatment response. Results: Tumor concentrations of Gem were significantly higher following PRVI compared to Systemic (128 vs. 19, p < 0.01) at one hour after treatment. Seven days after treatment, PRVI Gem mice demonstrated lower mean tumor volume (mm3) than Systemic Gem and Control mice (274 vs. 857 vs. 629, p < 0.01), respectively. Histologic evaluation of tumors demonstrated decreased cellularity in the PRVI Gem mice compared to Systemic and Control mice (35 vs. 78 vs. 71%, p = 0.01), respectively. No differences were seen in Ki67% or immune cell infiltrate between groups. Conclusions: PRVI delivery resulted in increased PDAC Gem concentrations and improved treatment responses with decreased tumor burden and cellularity. These findings suggest that pressurized regional chemotherapy infusion overcomes the elevated PDAC IFP and justifies additional translational pre-clinical studies with other chemotherapeutics (including immunomodulating antibodies) with different physicochemical properties.