bluuebunny/crossref_metadata_2025 huggingface dataset:
Morphologic and molecular analysis of early-onset gastroesophageal adenocarcinomas.
Authors: Setia Namrata , Wang Cindy , Lager Angela , Maron Steven Brad , Peterson Bryan , Arndt Nicole , Misdraji Joseph , Ma Changqing , Kupfer Sonia , Hart John , Catenacci Daniel V.T.
Published: May 2020

4547

Background: The incidence of early-onset gastroesophageal adenocarcinomas (EO-GEA) is increasing, and these tumors now constitute > 30% of all gastroesophageal cancers. Besides hereditary gastric cancer syndromes, which form ~3% of EO-GEA, the morphologic and molecular spectrum of these tumors is not well-studied. Methods: Next-generation sequencing (NGS) data obtained from routine clinical care from patients with EO-GEA, defined as age ≤50 years, from 3 tertiary care centers was evaluated and compared with tumor profiles of 2,081 patients with GEA from cBioPortal for Cancer Genomics. Available histologic slides were reviewed, and the tumors were classified into Lauren and WHO subtypes. Tumor-detected pathogenic variants of potential germline origin were identified from the NGS data. Results: The study cohort was formed by 79 patients with gastroesophageal (42%) and gastric (58%) adenocarcinoma. The most commonly mutated genes included TP53 (28.5%), CDH1 (10%), ARID1A (5%), KRAS (3.9%) and PIK3CA (3.9%). EO-GEA were less likely to harbor TP53 (28.5% vs. 57.5%, p 0.003) and ARID1A (5% vs. 20.6%, p 0.002) mutations when compared with cBioPortal data. Based on the Lauren scheme, the tumors were classified into intestinal (40%), diffuse (24%), mixed (12%), and indeterminate (15%) subtypes. Driver mutations in CDH1, TP53, FBXW7, BAP1 genes were seen in diffuse/mixed subtype, and TP53, ARID1A, KRAS, PIK3CA, APC, ATM, NBN, MUTYH genes in intestinal subtype. The indeterminate subtype showed TP53 mutations and additional alterations, including SMARCB1/ SMARCA4 loss leading to rhabdoid/undifferentiated morphology. ERBB2 amplification was more likely to be present in intestinal and indeterminate subtypes (p = 0.003). CD274 amplification/PD-L1 expression was more likely to be present in indeterminate subtype (p < 0.0001). Potential germline variants included mutations in gastric cancer susceptibility genes such as CDH1 (2.5%) and APC (1%), and other cancer susceptibility genes such as ATM (4%), NBN (1%), MUTYH (1%) and POLD1 (1%). Conclusions: The molecular profile of EO-GEA is distinct from traditional gastric cancers. Histologic subtypes of EO-GEA correlate with distinct genomic alterations. Our findings also support multigene germline panel testing in parallel for patients with EO-GEA.
Prediction of esophageal fistula from esophageal cancer CT images using multi-view multi-scale attentional convolutional neural network (MM-Atten-CNN).
Authors: Xu Yiyue , Cui Hui , Fan Bingjie , Zou Bing , Sun Xindong , Yu Jinming , Wang Linlin
Published: May 2020

4553

Background: We aimed to propose a risk model based on MM-Atten-CNN for predicting esophageal fistula in patients with esophageal cancer (EC) from computerized tomography (CT) -based radiomics. Methods: EC patients who didn’t received esophageal surgery between July 2014 and August 2019 were collected. Of these, 186 patients (cases) who developed esophageal fistula were enrolled and compared with 372 controls (1:2 matched with the diagnosis time of EC, sex, marriage, and race). All 558 patients were divided into training set (n = 390) and validation set (n = 168) randomly. The MM-Atten-CNN risk model was trained over 2D slices from nine views of planes, where there were three patches of contextual CT, segmented tumor and neighbouring information in each view. In the training set (130 cases and 260 controls), data augmentation was performed including pixel shifting [-10, -5, +5, +10] and rotation [-10, +10]. In total, there were (130+260) *16*2 = 12480 subjects used for training. Finally, the risk model was validated in the validation set (56 cases and 112 controls) and measured by accuracy (acc), sensitivity (sen), and specificity (spe). Results: The developed risk model achieved (acc, sen, spe) of (0.839, 0.807, 0.926), which were more predictive for the occurrence of esophageal fistula when compared to CNN models using single coronal view (acc 0.763, sen 0.581, spe 0.837), multi-view 2D contextual CT slices (acc 0.779, sen 0.656, spe 0.896), and 3D CNN using contextual CT volumes (acc 0.781, sen 0.689, spe 0.852). Conclusions: MM-Atten-CNN CT-based model improved the performance of esophageal fistula risk prediction, which has the potential to assist individualized stratification and treatment planning in EC patients.
PET-directed chemoradiation (CRT) with induction FOLFOX compared to induction carboplatin/paclitaxel (CP) in patients with locally advanced esophageal adenocarcinoma (EA).
Authors: Carr Rebecca , Hsu Meier , Tan Kay See , Bains Manjit S. , Bott Matthew , Ilson David H. , Isbell James M. , Janjigian Yelena Yuriy , Maron Steven Brad , Park Bernard , Rusch Valerie W. , Sihag Smita , Wu Abraham Jing-Ching , Jones David Randolph , Ku Geoffrey Yuyat , Molena Daniela
Published: May 2020

4554

Background: Induction chemotherapy with PET-directed CRT and surgery is the standard treatment for locally advanced EA at our institution. Following results of the CALGB 80803 trial, FOLFOX has recently replaced CP as the preferred induction regimen. Methods: We retrospectively evaluated patients with locally advanced EA treated with induction CP vs FOLFOX, followed by trimodality therapy between January 2010 and June 2019. Patients treated with CP with RT followed by surgery without induction chemo were also included. We compared pathological complete response (pCR) and near pCR (ypN0 with ≥90% response) rates in the induction FOLFOX group to the induction CP and no-induction groups. Univariable and multivariable analyses were used to adjust for confounding factors. Disease-free survival (DFS) was estimated by the Kaplan-Meier method and compared between groups using max-combo weighted log rank test. Results: 445 patients were included. Patients in the induction FOLFOX group had significantly higher pCR and near pCR rates vs induction CP patients. Notably, pCR rate was 38% among FOLFOX PET responders vs 19% in non-responders. In multivariable analysis, compared to induction CP, induction FOLFOX administration was an independent predictor of near pCR (OR: 2.22, 95%CI: 1.20-4.20, p = 0.012). Compared to 24% pCR rate among no-induction patients, induction FOLFOX pCR rate was slightly higher at 32%. DFS by 2-years was higher in induction FOLFOX compared to no-induction-treated patients (62% vs. 42%, p = 0.05). Postoperative complication rates were similar among the three groups. Conclusions: PET-directed CRT with FOLFOX instead of CP improves pCR and near pCR rates. Improved DFS was observed in the FOLFOX vs no-induction patients. Longer follow-up is needed to confirm any survival benefits. [Table: see text]
A phase II study of efficacy and safety of RC48-ADC in patients with locally advanced or metastatic HER2-overexpressing gastric or gastroesophageal junction cancers.
Authors: Peng Zhi , Liu Tianshu , Wei Jia , Wang Airong , He Yifu , Yang Liuzhong , Zhang Xizhi , Fan Nan-Feng , Luo Suxia , Gong Jifang , Li Zhen , Gu Kangsheng , LU Jin Wei , Xu Jianming , Fan Qingxia , Xu Rui-hua , Zhang Liangming , Fang Jianmin , Ba Yi , Shen Lin
Published: May 2020

4560

Background: RC48-ADC is an antibody-drug conjugate (ADC) drug comprised of a novel humanized anti-HER2 IgG1, a linker, and a microtubule inhibitor, MMAE. The MoA included inhibition of HER2 signal pathway and cytotoxicity of MMAE. RC48-ADC has demonstrated promising anti-tumor activity in pre-clinical and early clinical studies. The current study is designed to evaluate the efficacy and safety of RC48-ADC in heavily treated patients with HER2-overexpressing (IHC 2+ or 3+) gastric or gastro-esophageal junction cancers. Methods: This is an open-label, multicenter, single-arm, phase II study. Eligibility criteria include: histologically confirmed gastric or gastro-esophageal junction cancers, HER2-overexpression (IHC 2+ or 3+), ECOG PS 0-1, post-to ≥2 prior systemic treatment. The patients received RC48-ADC, 2.5 mg/kg, q2w until disease progression, unacceptable toxicity, withdrawal, or study termination. The primary endpoint was ORR. PFS, OS, and safety were also evaluated. Results: Patient enrollment started in July 2017, and completed in November 2019. By the data cut-off date on 17-Dec-2019, 127 patients were enrolled. The median age was 58 years. At baseline, 59 patients (46.5%) had received ≥ 3 lines prior treatment. For the overall 127 patients, the investigator-assessed confirmed ORR was 18.1% (95% CI: 11.8%, 25.9%). Sub-group ORR was 19.4% and 16.9% for the patients post to 2 lines and ≥ 3 lines, respectively. For the 111 patients who were monitored for ≥ 2 cycles of efficacy assessments (i.e. 12 weeks), the ORR was 20.7% (95% CI: 13.6%, 29.5%). For the 127 patients, the mPFS was 3.8 months (95% CI: 2.7, 4.0, 89 events [70.1%]) and the mOS was 7.6 months (95% CI: 6.6, 9.2, 52 events [40.9%]). The most commonly reported treatment-related AEs were leukopenia (52.0%), alopecia (51.2%), neutropenia (48.0%), and fatigue (42.5%). Conclusions: RC48-ADC demonstrated a clinically meaningful response and survival benefit in the heavily treated patients with HER2-overexpressing gastric or gastro-esophageal junction cancers. The safety profile was in line with the previously reported data of RC48-ADC. RC48-ADC showed positive benefit/risk ratio for the target population. Clinical trial information: NCT03556345 .
Cabozantinib (cabo) combined with durvalumab (durva) in gastroesophageal (GE) cancer and other gastrointestinal (GI) malignancies: Preliminary phase Ib CAMILLA study results.
Authors: Saeed Anwaar , Phadnis Milind , Park Robin , Sun Weijing , Al-Rajabi Raed Moh'd Taiseer , Baranda Joaquina Celebre , Williamson Stephen K. , Collins Zachary , Firth-Braun Jeanette , Saeed Azhar , Foster Carolyn , Roberts Benjamin , Subramaniam Dharmalingam , Kasi Anup , Anant Shrikant
Published: May 2020

4563

Background: Cabo targets multiple tyrosine kinases, including VEGFR, MET, and AXL, and has been reported to show immunomodulatory properties that may counteract tumor-induced immunosuppression, providing a rationale for combining it with PD-L1 inhibitors like durva. We conducted a phase Ib GI basket trial to evaluate the safety & efficacy of this regimen in advanced GE adenocarcinoma (GEA), colorectal cancer (CRC), & hepatocellular carcinoma (HCC). Methods: Patients received cabo and durva in 3+3 dose escalation then expansion to determine the dose limiting toxicity (DLT), Recommended Phase 2 Dose (RP2D), ORR, PFS & OS. Cabo was dosed at 20mg QD, 40mg QD, and 60mg QD in the first, second, and third cohorts respectively. Durva was dosed at 1500mg IV Q4W in all cohorts. DLT window was 28 days. Scans were obtained every 8 wks. Treatment beyond progression was allowed. Results: 23 Pts (16 M, 7 F), median age 60 yrs (range 33-79) were currently enrolled. 12 in the dose escalation cohort with cabo 20mg (6 pts), or 40mg (3 pts), or 60mg (3 pts). 11 pts enrolled in the dose expansion cohort with cabo 60mg. 8 pts had GEA, 13 pts had CRC, and 2 pts had HCC. Median number of prior chemotherapies was 3 (range 1-3). 3 pts were not evaluable for DLT due to missing ≥30% of DLT window doses, not related to DLT. No DLTs were observed. Drug-related Grade (G) 1&2 AEs included fatigue (83%), abnormal LFTs (39%), anorexia (26%), diarrhea (26%), nausea (13%), & hand foot syndrome (13%). One pt each developed drug related G3 hypertension, hyperthyroidism, thrombocytopenia, & thromboembolic event, all occurring outside the DLT window. 19 pts were evaluable for response: 4 PR (2 GEA & 2 CRC), 12 SD, 3 PD; ORR 21%; clinical benefit rate 84%; median time to PD 16 wks (range 8-40+). Conclusions: RP2D was determined to be Cabo 60mg QD and Durva 1500mg Q4W. Enrollment to phase I dose expansion is ongoing. RP2D may be adjusted based on additional experience & long-term tolerability. Early efficacy data was encouraging. This is an investigator-initiated trial funded by Exelixis & Astrazeneca. Clinical trial information: NCT03539822 .
HER2 heterogeneity in adenocarcinoma of the distal esophagus and stomach.
Authors: Butter Rogier , Hooijer Gerrit , van der Wel Myrtle , Bart Jos , ter Borg Susan , van Velthuysen Loes , van de Vijver Marc J.
Published: May 2020

4567

Background: Patients with HER2 positive adenocarcinoma of the esophagus or stomach are eligible for HER2 targeted therapy, which can improve survival in selected patients. Previous research shows that HER2 gene amplification and HER2 overexpression is frequently heterogeneous within these tumors. Biopsies taken from heterogeneous tumors for predictive testing may therefore result in false-negative outcomes. The objective of this study was to assess HER2 amplification and expression in biopsies and paired resection specimens with adenocarcinoma of the esophagus or stomach, from patients who did not receive neoadjuvant systemic therapy. Methods: Paired biopsies and resection specimens of patients with adenocarcinomas of the esophagus or stomach were retrospectively selected. Immunostaining was performed on all samples using antibody 4B5 (Ventana Medical Systems) and Silver-In-Situ-Hybridization was performed in selected cases. Scoring for HER2 was performed according to the method described by Hofmann et al. (2008). Results: We included 378 cases for analysis. In both biopsies and resection specimens 14% of the cases were HER2 positive. Intratumor heterogeneity in HER2 positive tumors was present in 45% ( n= 24/53) in biopsies and 75% ( n= 39/52) in resection specimens. In HER2 positive resection specimens, 65% ( n= 34/52) of paired biopsies were also positive. In the 18 remaining discordant tumors (resection HER2 positive, biopsy negative), intratumor heterogeneity was present in 16/18 cases. For HER2 negative resection specimens all paired biopsies were also HER2 negative. SISH was performed in 110 tumors. Agreement of HER2 gene amplification between biopsy and resection specimens was observed in 86% (n = 95/110). Five HER2 negative biopsies were positive in the resection specimen. Conclusions: The results of this study indicate that predictive HER2 assessment in adenocarcinoma of the esophagus or stomach can lead to false negative results based on biopsies. As a result, patients with HER2 positive tumors can unintentionally be denied neoadjuvant HER2 targeted therapy. The set of patients investigated in this present study is unique because of the absence of any systemic and/or radiation therapy between the biopsy and the resection of the tumor. Hopefully these results can help in developing methods for improved patient selection for HER2 targeted therapy.
Identification of SLX4 as the most frequently mutated gene in homologous recombination deficiency in Asian gastric cancer.
Authors: Zhang Shi , Mu Tianhao , Dang Shiying , Huang Tanxiao , Duan Jingxian , Chen Shifu , Wang Guoqiang
Published: May 2020

4570

Background: Gastric cancer is the third most common malignancy worldwide. Homologous recombination (HR) is a type of genetic recombination, and homologous recombination deficiency (HRD) is highly involved in multiple types of cancers and can predict response to anticancer therapies. However, homologous recombination deficiency is not well characterized in patients with Asian gastric cancer. Methods: 196 Asian patients with gastric cancer were analyzed in this study. A list of 102 genes related to HRD was compiled based on previous literature. Haplox 605-gene panel was used to capture the sequencing library. Mutations related to HRD were analyzed following next-generation sequencing. In addition, tumor mutational burden (TMB) was calculated by dividing the total number of mutations by the size of the coding region. The correlation analysis between HRD and TMB was also conducted. Results: In total, 43 (21.94%) of 196 Asian patients with gastric cancer harbored at least one HRD gene. The top 10 mutant HRD genes included SLX4 (3.57%), ATR (2.04%), RECQL (1.53%), NBN (1.53%), ERCC4 (1.53%), BAP1 (1.53%), ATM (1.53%), RAD54L (1.02%), BRCA1 (1.02%) and PARP1 (1.02%). In addition, the occurrence of HRD mutations was significantly correlated with a higher TMB. The median TMB of HRD group (8.28 muts/Mb) was significantly higher than that of the Non-HRD group (3.07 muts/Mb) (p < 0.01). The overall upper quantile value (4.80 muts/Mb) was used to screen patients with high TMB (TMB-H). The TMB-H in HRD group was significantly higher than the Non-HRD group (44.19% VS 17.92%, p < 0.01). Conclusions: Our study described that SLX4 was the most frequently mutated HR-related gene in Asian gastric cancer. Moreover, the positive correlation with homologous recombination deficiency (HRD) and tumor mutational burden (TMB) was observed in these patients.
A novel gene signature for predicting response to chemoradiotherapy in locally advanced esophageal adenocarcinoma.
Authors: Sahu Divya , Omstead Ashten N. , Gorbunova Anastasia , O’Meally Dennis , Salvitti Madison , Lam Vincent K. , Jobe Blair A , Kelly Ronan Joseph , Goel Ajay , Zaidi Ali Hussainy
Published: May 2020

4571

Background: While neoadjuvant chemoradiotherapy (CRT) has emerged as an important treatment modality in patients with locally advanced esophageal adenocarcinoma (EAC), ~60%-70% of patients do not respond to such treatments; but are exposed to their toxicity nonetheless. This highlights the clinical need for the development of biomarkers that can robustly predict response to CRT and spare others from the toxicity and expense associated with these treatments. Herein, we systematically and comprehensively identified a biomarker signature that predicts response to neoadjuvant therapy in EAC patients. Methods: A cohort of 31 EAC patients treated with chemotherapy or chemoradiotherapy was assembled, with a majority of patients receiving carboplatin, paclitaxel and concurrent radiotherapy. Specifically, we performed a capture based targeted sequencing in paired biopsy specimens obtained at baseline and 3-6 weeks post-treatment. In addition, we also analyzed the predictive potential of a panel of immune-related genes (TIM3, LAG3, IDO1 and CXCL9) in these matched pre- and post-treatment tissues. Results: In our cohort, based upon pathologic response to neoadjuvant CRT, 8 EAC patients were categorized as non-responders, while 23 were deemed as responders to CRT. Among responders, the most frequently mutated genes were MKI67, SYNE1, PCLO, RECQL4, MSH3, NOTCH2, ILR7, CIITA, LRRK2 and EML4, and the overall tumor mutation burden (TMB) was significantly reduced for these genes in post-treatment samples ( P=5.73E-03). Similarly, in non-responders NLRP1, MAP3K1, ASMTL, and ALK harbored frequent mutations, and the TMB was significantly reduced for these genes in post-treatment samples ( P=5.57E-03). We compared responders and non-responders from the pre-treatment samples and identified differentially mutated genes including EPHA5, ZNF217, RELN, PALB2 and MYO18A. Similarly, responders had all four immune-related genes significantly up-regulated in post-treatment samples than pre-treatment samples. We constructed a risk-stratification model that comprised of mutational score from 5 differentially mutated genes, together with 4 immune-related genes, which achieved an AUC of 0.96 in predicting response to CRT in EAC patients ( P=1.03E-04). Conclusions: Using a systematic biomarker discovery approach, we have developed a novel biomarker signature that robustly predicts response to CRT in EAC patients and has a significant potential for personalized management of locally advanced EAC patients.
Algorithm for blood-based panel of methylated DNA and protein markers to detect early-stage hepatocellular carcinoma with high specificity.
Authors: Chalasani Naga P. , Bhattacharya Abhik , Book Adam , Neis Brenda , Xiong Kong , Ramasubramanian T , Johnson Scott , Lidgard Graham P. , Roberts Lewis R. , Kisiel John B. , Reddy K Rajender , Singal Amit G , Olson Marilyn , Bruinsma Janelle J
Published: May 2020

4577

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. Though biannual ultrasound surveillance with or without alpha-fetoprotein (AFP) testing is recommended for at-risk patients, its sensitivity for early-stage HCC detection is suboptimal. We therefore evaluated performance of a biomarker panel incorporating methylated DNA markers (MDMs) and proteins for early HCC detection in at-risk patients with chronic liver disease. Methods: In an international, multicenter, case-control study, blood specimens were collected from patients with HCC per AASLD criteria and controls matched for age and liver disease etiology. All patients had underlying cirrhosis or chronic HBV infection. Whole blood was collected in cell-free DNA stabilizing and serum-separation tubes and shipped to a central laboratory for processing. The levels of 5 MDMs, AFP, and AFP-L3 were assessed along with age and sex. We used 537 samples in a 5-fold validation for developing a LASSO regression algorithm to classify samples as HCC positive or negative. Model robustness was tested by perturbing the data in silico and analyzing results with the predictive algorithm. Algorithm performance was compared to AFP alone and the GALAD score (Gender, Age, AFP-L3, AFP, and DCP). Results: The study included 136 HCC cases (81 early-stage—BCLC stage 0/A) and 401 controls. With specificity set at 89%, we developed a model using sex, AFP, and 3 MDMs (HOXA1, TSPYL5, B3GALT6) with higher sensitivity (70%) for early-stage HCC compared to GALAD (54%) or AFP (31% at 20 ng/mL or 52% at ≥7.7 ng/mL) (Table). The AUC for the HCC marker panel was 0.91 (95% CI 0.89 – 0.94) compared to GALAD (0.88; 95% CI 0.85 – 0.91) or AFP (0.84; 95% CI 0.81 – 0.87). The panel performed similarly in viral (AUC = 0.94) and non-viral (AUC = 0.89) etiologies. Conclusions: The robust algorithm based on novel blood-based biomarkers presented here provides higher sensitivity for early-stage HCC compared to other available blood-based biomarkers and, therefore, could significantly impact HCC clinical management and patient outcomes. Further clinical studies to validate the algorithm are ongoing. Clinical trial information: NCT03628651 . [Table: see text]
A multicenter randomized phase II study of nivolumab in combination with gemcitabine/cisplatin or ipilimumab as first-line therapy for patients with advanced unresectable biliary tract cancer (BilT-01).
Authors: Sahai Vaibhav , Griffith Kent A. , Beg Muhammad Shaalan , Shaib Walid Labib , Mahalingam Devalingam , Zhen David Bing , Deming Dustin A. , Dey Sumi , Mendiratta-Lala Mishal , Zalupski Mark
Published: May 2020

4582

Background: Patients (pts) with advanced biliary tract cancers (BTC) have poor prognosis with a median overall survival (OS) less than 12 months (mos). This randomized phase 2, multi-institutional, study was designed to investigate the role of combinational immunotherapy, using nivolumab (nivo) with gemcitabine (gem)/cisplatin (cis), or nivo with ipilimumab (ipi) in pts with untreated advanced BTC. Methods: Key eligibility criteria include histologically confirmed unresectable or metastatic BTC without prior systemic therapy, measurable disease per RECISTv1.1, ECOG PS 0-1, and absence of autoimmune disease or chronic steroid use. Arm A included gem 1000 mg/m2 and cis 25 mg/m2 d1, 8 Q3w + nivo 360 mg d1 Q3w for 6 mos followed by nivo 240 mg Q2w monotherapy for a total duration of 2 yrs; Arm B included nivo 240 mg Q2w and ipi 1 mg/kg Q6w for 2 yrs, in absence of disease progression. Primary endpoint is progression-free survival (PFS) rate at 6 mos with an alternative hypothesis of 80% (null hypothesis of 59%, one-sided alpha 0.05, power 80%) for each non-comparative arm. Secondary endpoints include overall response rate (ORR) per immune related (ir)RECIST, median PFS and OS and safety. Exploratory objectives include biomarker analysis using include sequential whole exome/transcriptome and immune cell subsets in tissue and blood. Results: 71 eligible pts (49% male, 83% Caucasian) with 35 in Arm and 36 in Arm B with a median age of 62 (range 20-80) yrs, and majority with metastatic disease (90%) were enrolled across 6 US sites. PFS rate at 6 mos was 70% in Arm A and 18.6% in Arm B. The median PFS was 8.8 mos (95% CI, 6.1 to 11.3) in Arm A and 4.1 mos (95% CI, 2.4-5.2) in Arm B. Ten patients on Arm A and 2 on Arm B remain on active treatment; additional 7 are in follow-up for OS. ORR, safety data and median OS evaluation are underway and will be presented at the meeting. Exploratory analyses are pending. Conclusions: The observed PFS rates at 6 mos in either arm are insufficient to reject the null hypothesis of 59% PFS at 6 months. While Arm B is inferior, Arm A appears to be as effective as standard of care although OS estimates are pending maturity. Clinical trial information: NCT03101566 .
Genomics and translational precision oncology for 803 patients with biliary tract cancer.
Authors: Lin Jianzhen , Yang Xu , Cao Yinghao , Li Guangyu , Zhao Songhui , Shi Junping , Pan Jie , Hu Ke , Zhao Lin , Guan Mei , Sang Xinting , Javle Milind M. , Wang Kai , Wang Xiaoyue , Zhao Hai-Tao
Published: May 2020

4589

Background: Both incidence and mortality of biliary tract cancer (BTC) are increasing, and BTCs are characterized by poor prognosis and limited antitumoral treatments. There is no well-received regimen as the non-first-line treatment in patients with advanced BTCs, leading to the urgency of umbrella-setting personalized therapies according to genomic alterations. Methods: We performed genomic sequencing in a total of 803 BTCs, including 160 patients with whole-exome sequencing and 643 patients with hybrid capture–based comprehensive genomic profiling. Our molecular tumor board developed precise targeted therapies for patients with actionable targets. Results: Overall, the median tumor mutation burden was 3.0 (IQR: 0.8-6.1) Mut/Mb, with 10.5% patients of hypermutated BTCs. The most frequently mutated genes included TP53 (51%), KRAS (23%), ARID1A (16%) and SMAD4 (11%). The most common genes with significantly amplified oncogenes were CCND1 (6.97%), MET (6.72%) and MDM2 (6.6%), while the frequently deleted tumor-suppressor genes are CDKN2A (5.73%) and CDKN2B (5.35%). The mutational map of BTCs highlighted pathways of receptor-tyrosine kinase (RTK)/RAS and p53 signaling were frequently altered. Somatic truncating mutations of mismatch repair genes were identified in 6.1% (49/803) of patients, and germline pathogenic mutations in DNA damage response genes occurred in 8% (64/803) of BTCs. In addition, we demonstrate the amplified chromosomal focal at 7q31.2 was an oncogenic factor and it independently predicts both disease-free survival and overall survival of BTC patients. When molecular screening was linked to targeted therapies, 25.4% (204/803) of patients could match biomarker-assigned drug treatment (BADT). The frequent actionable biomarkers included amplifications of ERBB2 and MET, FGFR2/3 fusions and IDH1 mutations. For 46 patients with refractory BTCs received BADT, the objective response rate was 26.1%, with a median progression-free survival (mPFS) of 5.0 (95%CI: 3.5-6.5) months, and 56.8% patients achieved a ≥1.3 ratio of PFS2/PFS1. 4 of 6 (67%) patients with high microsatellite instability (MSI-H) BTCs had a responsive status after immunotherapy of PD1 inhibitor, confirming that MSI-H status was a robust biomarker of anti-PD1 treatments. Conclusions: Our study established the largest cohort in Chinese BTC patients to investigate the tumor mutational profiling and its translational clinical applications. Clinical trial information: NCT02715089 .
A phase II open-label, single-center, nonrandomized trial of Y90-radioembolization in combination with nivolumab in Asian patients with advanced hepatocellular carcinoma: CA 209-678.
Authors: Tai Wai Meng David , Loke Kelvin Siu Hoong , Gogna Apoorva , Tan Sze Huey , Ng David Chee Eng , Hennedige Tiffany Priyanthi , Irani Farah , Lee Joycelyn Jie Xin , Too Chow Wei , Ng Matthew C.H. , Tham Chee Kian , Lam Justina Yick Ching , Koo Si-Lin , Chung Alexander , Toh Han Chong , Thng Choon Hua , Lim Kiat Hon , Yeong Joe Poh Sheng , Chan Chung Yip , Choo Su Pin
Published: May 2020

4590

Background: Nivolumab (N) and Y90-radioembolization (RE) are both therapeutic options in advanced hepatocellular carcinoma (aHCC). Increasing evidence suggests that radiotherapy synergizes with immune checkpoint inhibitors to augment anti-tumour effects. Methods: Eligible Child-Pugh A aHCC patients (pts) were treated with Y90-RE followed by N 240mg, 21 days after Y90-RE and every 2 weeks thereafter. Pre- and on-treatment tumor biopsies together with circulating biomarkers were obtained. Primary end-point was overall response rate (ORR) (per RECIST v 1.1). Overall response was defined as the composite overall response observed for the lesions within Y90-RE field and outside Y90-RE field. Key secondary end points included disease control rate (DCR), progression free survival (PFS), overall survival (OS), and safety. 36 evaluable pts were needed to assess whether the addition of N improved the ORR of Y90-RE from 21% to 41% as determined by Simon two-stage optimal design with 80% power and one sided significance level of 0.05. Results: Forty pts were enrolled of which 36 were evaluable. At baseline: 63.9% were HepB in aetiology; 63.9% BCLC stage C; 47.2% had AFP > 400ng/mL; number of liver lesions – median 5 (range 1- 20); size of largest liver lesion – median 80mm (range 14-177mm); 27.8% had prior TACE; and 13.9% had prior systemic therapy. ORR was 31% (95% CI 16.4 - 48.1%). Eight out of 11 responders had not progressed at study cut-off. DCR was 58.3%. 81% of target lesions within Y90-RE field regressed. With a median follow up of 16.4 months, median PFS and OS were 4.6 months (95% CI 2.3m - 8.4m) and 15.1 months (95% CI 7.8m - NE) respectively. Six- and 12-month PFS rates were 44.2% (95% CI 27.3% - 59.9%) and 26.1% (95% CI 11.2% - 43.8%) respectively. Overall, N+ Y90-RE was well tolerated and safe; only 11% had grade 3/4 treatment related adverse events (AEs). Responders demonstrated significant alterations of LIF, MIG and Eotaxin3 levels in the pre-treatment cytokine analyses. Conclusions: Combination N+Y90-RE resulted in an encouraging ORR of 31% (95% CI 16.4 - 48.1%) in aHCC. 81% of target lesions within Y90-RE field regressed suggesting synergy in combining Y90-RE with nivolumab. This combination is safe and tolerable with low G3/4 treatment related AEs of 11%. Further biomarker analyses will be presented at the meeting. Clinical trial information: NCT03033446 .
Perioperative circulating tumor DNA analysis to predict patient prognosis in liver cancer.
Authors: Zhou Ledu , Xu Ying , Wang Dong , Ye Ke , Xiao Liang , Long Guo , Chen Rongrong , Xia Xuefeng
Published: May 2020

4593

Background: Resection is a major method for early-stage liver cancer patients. Unfortunately, there still a few patients with post-operation recurrences. Circulating tumor DNA (ctDNA) had been reported as a biomarker in reflecting tumor load and treatment efficacy in some cancer species. Here, we report an application of ctDNA in the perioperative period of liver cancer using targeted sequencing with a 1021-gene panel. Methods: 97 patients diagnosed with liver cancer were enrolled in this study. Postoperative peripheral blood samples were collected within 7 days after surgery and analyzed using hybridization capture based NGS ERSeq method from all patients. Whether a mutant gene was detected in the peripheral blood was defined as ctDNA(+) and ctDNA(-), respectively. Results: Multivariate Cox analysis showed that the post-operation ctDNA was an independent poor prognostic predictor (AFP, RR: 1.0002, 95% Cl: 1.0001-1.0002; ctDNA, RR: 3.738, Cl: 1.872-7.691). 21 patients were ctDNA(+), and all of them had recurrenced (21/21, 100%), while 76 patients were ctDNA(-), and only 12 (12/76, 15.8%) patients had recurrenced. The median disease-free survival time was 5.0 months in ctDNA(+) group and the ctDNA(-) group had not reach the median time (Log-rank test, P < 0.0001). ctDNA combined with AFP would effectively predict the prognosis of patients after surgery. AFP(H) ( > = 400 ng/mL) and ctDNA(+) patients have the worst prognosis and all of the patients had relapsed, while AFP(L) ( < 400 ng/mL) and ctDNA(-) patients had the best prognosis, with less than 20% of patients had relapsed (Log-rank test, P < 0.0001). The median disease-free survival time was 2.0, 6.0 and 7.0 months in ctDNA(+)-AFP(H) (n = 8), ctDNA(-)-AFP(H) (n = 30) and ctDNA(+)-AFP(L) (n = 13) groups, respectively, while ctDNA(-)-AFP(L) group (n = 46) had not reach the median time statistically (Log-rank test, P = 0.0364). Conclusions: In summary, Perioperative ctDNA detection has great potential value clinically, and it also suggests that patients with positive ctDNA after surgery should receive some adjuvant treatments as soon as possible to improve the survival time.
Australasian Gastrointestinal Trials Group (AGITG) CONTROL NET Study: Phase II study evaluating the activity of 177Lu-Octreotate peptide receptor radionuclide therapy (LuTate PRRT) and capecitabine, temozolomide CAPTEM)—First results for pancreas and updated midgut neuroendocrine tumors (pNETS, mNETS).
Authors: Pavlakis Nick , Ransom David Turner , Wyld David , Sjoquist Katrin Marie , Asher Rebecca , Gebski Val , Wilson Kate , Kiberu Andrew Ddembe , Burge Matthew E. , Macdonald William , Roach Paul , Pattison David A. , Butler Patrick , Price Timothy Jay , Michael Michael , Lawrence Benjamin James , Bailey Dale L. , Leyden Simone , Zalcberg John Raymond , Turner J. Harvey
Published: May 2020

4608

Background: CAPTEM is an accepted regimen for patients (pts) with advanced pNETs. Single agent 177Lu-Octreotate PRRT is now a standard of care for progressive WHO Grade (G) 1/2 mNETs. High activity was seen with LuTate/CAPTEM in a single arm Phase I/II trial. This study was undertaken to determine the relative activity of adding CAPTEM to LuTate PRRT in pts with mNETs and pNETs. Methods: Non-comparative randomised open label parallel group phase II trial with 2:1 randomisation to PRRT/CAPTEM (experimental arm) vs. PRRT (mNETs control) and CAPTEM (pNETS control). PRRT/CAPTEM: 7.8GBq LuTate day(D) 10, 8 weekly (wkly) x 4, with b.i.d. oral CAP 750mg/m2 D1-14 & TEM 75mg/m2D10-14, 8 wkly x 4; PRRT: 8 wkly x 4; CAPTEM 8 wkly x 4. Primary endpoint: Progression free survival (PFS). mNETS- at 15 months (mo) assuming 15mo PFS 66.4% in control arm, aiming for PFS ³ 80%; pNETS- at 12mo assuming 12mo PFS 60% in control arm, aiming for PFS ³ 75%. Secondary endpoints: Objective tumour response rate (complete or partial) (OTRR), clinical benefit rate (OTRR, stable disease) (CBR), toxicity, quality of life. Results: 75 pts enrolled (Dec 2015 – Nov 2018): mNETs 33 PRRT/CAPTEM and 14 PRRT; pNETS 19 PRRT/CAPTEM and 9 CAPTEM. mNETS: Median follow-up 35mo; 15mo PFS was 90% (95% CI: 73-97%) v 92% (95% CI: 57-99%); OTRR 31% vs 15%; and CBR 97% vs 92% for PRRT/CAPTEM v PRRT respectively. Treatment related adverse events (AEs): 24/32 PRRT/CAPTEM pts had at least one G3 event (75%) vs 5/13 (38%, PRRT); and 4/32 pts at least one G4 event (13%) v 1/13 (8%) respectively, mostly haematologic (haem). Only one patient failed to complete therapy (PRRT/CAPTEM). pNETS: Median follow-up 34mo; 12mo PFS was 76% (95% CI: 48-90%) v 67% (95% CI: 28-88%); OTRR 68% vs 33%; and CBR 100% vs 100% for PRRT/CAPTEM v CAPTEM respectively. Treatment related AEs: 5/18 PRRT/CAPTEM pts had at least one G3 event (28%) vs 3/9 (33%) CAPTEM; 3/18 pts at least one G4 event (17%) v 1/9 (11%) respectively. Conclusions: CAPTEM/PRRT is active, meeting its target landmark PFS for CAPTEM/PRRT (12mo pNETs; 15mo mNETs) with numerically greater OTRR in both pNETs and mNETs, but with more haem toxicity in mNETs. As activity was high in both control arms longer follow up is required to determine if the relative activity of PRRT/CAPTEM is sufficient to warrant Phase III evaluation. Clinical trial information: ACTRN12615000909527 .
Pretherapeutic 68Ga-DOTATATE PET SUV predictors of survival of radionuclide therapy for metastatic neuroendocrine tumors.
Authors: Ladwa Rahul , Pattison David A. , Smith Jye , Goodman Steven , Burge Matthew E. , Rose Stephen , Dowson Nicholas , Wyld David
Published: May 2020

4609

Background: Peptide receptor radionuclide therapy (PRRT) is an effective treatment option in patients with advanced neuroendocrine tumours (NETs). Patients are pre-selected based on 68Gallium-DOTA-(0-Tyr3)-octreotate Positron Emission Tomography (68Ga-DOTATATE PET) uptake. The level of uptake in tumour on the baseline 68Ga-DOTATATE PET scan has been explored as a predictor of response in NETs with inconclusive evidence. The aim of this study is to determine the correlation between 68Ga-DOTATATE PET SUV parameters to survival outcomes. Methods: We retrospectively analysed 142 lesions (up to five lesions per patient) in 73 patients with NET undergoing PRRT with 177Lutetium octreotate (8.0-8.3GBq) and pretherapeutic 68Ga-DOTATATE PET/CT in a single institution. Standardised uptake values (SUVs) max and mean were correlated with progression-free survival (PFS) and overall survival (OS). Results: A total of 73 patients were included in the analysis. The median age was 63 (28-89) years. NET origin was gastroenteric (49%), pancreatic [pNET] (38%), bronchial (10%) and other (3%). Ki-67 proliferation index ( < 3%: 36%, 3-20%: 36%, > 20%- < 50%: 8%, unknown: 21%) was seen. Pretherapeutic SUV max but not SUV mean was higher in pNETs (P = 0.04). No difference was seen with Ki-67 index. The median PFS was 32 (95%CI: 26-38) months. Median PFS was reduced with increasing ECOG performance status [PS] (P= 0.029), increasing tumour grade (P = 0.003), increasing Ki-67 proliferation index (P = 0.013), reduced SUV max (P= 0.003), reduced SUV mean (P= 0.001). Multivariate analysis confirmed SUV mean (HR =-1.71 [95%CI: -2.66- -0.80]; P<0.01) and Ki-67 index (HR = 1.11 [1.06-1.17]; P < 0.01) as maintaining significance when incorporating ECOG PS (HR = 1.96 [0.68-5.47]; P = 0.22). The mean OS was 40 [37-44] months. A higher SUV max (SUV max < 30: 34 [30-40] months vs SUV max > 30: 48 [44-51]; P<0.01) and higher SUV mean (SUV mean < 20: 33 [28-39] months vs SUV mean > 20: 47 [43-51]; P<0.01) were associated with improved mean OS. Mean OS was not affected by ECOG performance status (P = 0.896), primary site of origin (P = 0.567) and Ki-67 index (P = 0.110). Conclusions: 68Ga-DOTATATE PET SUV measures correlated with an improved PFS on multivariate analysis as well as improved OS in this select group of patients suitable for PRRT. Those patients with lower SUV mean may benefit from escalation of therapy such as increasing administered therapeutic activity.
Toxicity analysis of capecitabine/temozolomide in NETs.
Authors: Al-Toubah Taymeyah E. , Pelle Eleonora , Haider Mintallah , Strosberg Jonathan R.
Published: May 2020

4614

Background: The capecitabine/temozolomide regimen has significant activity in advanced NETs. Concerns exist regarding risk of opportunistic infections and long-term myelotoxicity. Analysis of large patient cohorts is needed for evaluation of rare toxicities and for assessment of risk factors. Methods: Retrospective study of all patients with advanced neuroendocrine neoplasms seen at the Moffitt Cancer Center between 1/2008 and 6/2019 who received treatment with CAPTEM. Patients who initiated treatment at outside institutions were included if they were prescribed treatment at appropriate doses and if complete records were available. Results: 462 patients met eligibility criteria for evaluation: 210 (45%) females and 252 (55%) males with a median age of 59. Median starting doses of CAP and TEM were 658mg/m2 and 180mg/m2 respectively. Median duration on treatment was 8 months. 25% of patients required a dose reduction and 16% discontinued due to toxicity of any grade. Incidence of grade 4 thrombocytopenia was 7%: 10% in females and 5% in males (p = 0.02). 4 cases were complicated by bleeding (0.8%). Incidence of grade 4 neutropenia was 3%: 5% in females and 1% in males (p = 0.004). Incidence of grade 4 lymphopenia was 2%. Only one case (0.2%) of suspected PCP was observed in a patient taking corticosteroids. There were 5 cases of herpes zoster and no other opportunistic infections. 3 patients developed myelodysplastic or myeloproliferative disease, all of whom had also received prior PRRT with Lutetium-Dotatate. There were no acute treatment related deaths, although one patient died 2 months after a thrombocytopenic bleed. Conclusions: Severe myelotoxicity is rare, but risks of grade 4 thrombocytopenia and neutropenia are significantly increased in females compared to males. Gender-based dosing should be considered. While alkylating agents are often associated with MDS, there were no cases except among patients who also had received PRRT, a known risk factor. PCP is not a significant risk with this regimen in patients not concurrently on corticosteroids.
Olaparib sensitivity observed in metastatic pancreatic cancer (mPaC) with a wide spectrum of germline BRCA1 and BRCA2 mutations (gBRCAm).
Authors: Golan Talia , Kindler Hedy L. , Schatz Philipp , Goranova Teodora , Locker Gershon Y. , Cui Karen , Schlienger Katia , McGuinness David , Williams J. Andrew , Orr Maria , Gutjahr Thorsten , Liu Yu-Zhen
Published: May 2020

4621

Background: The POLO study (NCT02184195) showed that mPaC patients (pts) with a deleterious or suspected deleterious gBRCAm, and whose disease had not progressed during ≥16 weeks of first-line platinum-based chemotherapy, had significantly longer progression-free survival (PFS, primary endpoint) with maintenance olaparib vs placebo: median 7.4 vs 3.8 months, hazard ratio (HR) 0.53; P=0.004. PFS benefit was observed in pts with g BRCA1m (HR 0.40) and g BRCA2m (HR 0.63). The POLO study represents the largest BRCAm prevalence study in pancreatic cancer. We report additional exploratory analysis to further characterize patient gBRCAm profiles, including the relationship with efficacy. Methods: Pts were enrolled based on either a previously identified gBRCAm status from a local test result and subsequently confirmed by central testing, or a prospectively identified gBRCAm. Pts received maintenance olaparib 300 mg twice daily (tablet) or placebo. PFS was assessed by blinded independent central review (modified RECIST v1.1). Results: Of 3194 prospectively screened pts, a valid BRCA test result was obtained for 3175 (99%) from 12 countries; gBRCAm prevalence was 6.2% in pts not previously known to harbor a gBRCAm (196/3175; 1.6% g BRCA1m, 4.5% g BRCA2m). In countries (n=8) with >100 pts prospectively tested, highest gBRCAm prevalence was 9.2% (USA) and lowest 4.0% (Spain). Prevalence by race (>100 pts); 6.4% Caucasian, 4.6% Asian. In total, 154 pts with a gBRCAm satisfied all eligibility criteria and were randomized (106 prospectively tested and 48 by local test [44/48 subsequently confirmed by Myriad testing]). 37/154 (24%) randomized pts carried a common Ashkenazi Jewish founder mutation, the majority being from Israel (21 pts). From a total of 151 variants, frameshift mutations were most frequent (g BRCA1m 69.6%, g BRCA2m 71.4%) followed by nonsense mutations (g BRCA1m 6.5%, g BRCA2m 17.1%). The efficacy (PFS) of olaparib vs placebo in the different subgroups are shown in the table. Conclusions: In pts with mPaC enrolled in POLO, g BRCA2m were more prevalent than g BRCA1m and mutation type was predominantly frameshift. PFS benefit was consistent across a heterogenous spectrum of gBRCAm and with the previously reported full analysis set. Clinical trial information: NCT02184195 . [Table: see text]
A phase I trial targeting advanced or metastatic pancreatic cancer using a combination of standard chemotherapy and adoptively transferred nonengineered, multiantigen specific T cells in the first-line setting (TACTOPS).
Authors: Smaglo Brandon George , Musher Benjamin Leon , Vasileiou Spyridoula , Kuvalekar Manik , Watanabe Ayumi , Robertson Catherine , Wang Tao , Francois Monica , Ramos Carlos Almeida , Hill LaQuisa , Van Buren George , Fisher William , Armaghany Tannaz , Sada Yvonne , Vera Valdes Juan Fernando , Grilley Bambi , Gee Adrian P , Heslop Helen E. , Lulla Premal D. , Leen Ann M.
Published: May 2020

4622

Background: Immunotherapy is emerging as a potent therapy for a range of hematologic malignancies and solid tumors. To target pancreatic carcinoma we have developed an autologous, non-engineered T cell therapy using T cell lines that simultaneously target the tumor-associated antigens (TAAs) PRAME, SSX2, MAGEA4, NY-ESO-1 and Survivin. These multiTAA-specific T-cell lines could be consistently prepared by culturing PBMCs in the presence of a Th1-polarizing/pro-proliferative cytokine cocktail, and adding autologous pepmix-loaded DCs as APCs. Methods: Patients with locally advanced or metastatic pancreatic adenocarcinoma who achieved cancer control with three months of standard chemotherapy were eligible to receive up to 6 infusions of multiTAA T-cells (fixed dose - 1x107 cells/m2). While also continuing the same chemotherapy, T-cells were given at monthly intervals from month four, onwards. The primary study endpoints were safety and feasibility of completing all 6 planned infusions, with secondary and tertiary endpoints including anti-tumor effects, patient survival, in vivo expansion and T cell persistence of the infused cells as well as recruitment of the endogenous immune system. Results: Between June 2018 and December 2019, we treated 13 patients with multiTAA T-cells. For 12/13 patients, we generated sufficient cells for all 6 planned doses; 2 doses were available for the remaining patient. Of the 13 patients, 8 maintained cancer control for a longer than expected duration, compared to historical controls. With administration of T-cells, 3 of these 8 patients had partial responses and 1 patient had a radiographic complete response (per RECIST). These responses were seen in patients with metastatic cancer. Notably, no patient had infusion-related systemic- or neuro-toxicity. Thus, infusion of autologous multiTAA-targeted T cells directed to PRAME, SSX2, MAGEA4, NY-ESO-1 and Survivin has been safe and provided durable clinical benefit to patients with pancreatic adenocarcinoma. Conclusions: Autologous, TAA cytotoxic T-cells can reliably be generated and safely administered to patients in conjunction with standard of care chemotherapy. In some patients, addition of T-cells may extend duration of first line therapy cancer control and induce additional tumor responses, and activation of the endogenous immune system has been documented in all patients. Exploration in a higher phase study is warranted. Clinical trial information: NCT03192462 .