bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic profiles of BRAF inhibitor resistance mechanisms in metastatic colorectal cancer.
Authors: Xu Ting , Wang Xicheng , Changsong Qi , Wang Zhenghang , Li Jian , Shen Lin , Wang Jia , Lin Xuan , Zhang Lu , Lin Jing , Li Xi
Published: June 2021

e15527

Background: BRAF mutations are present in 5-10% of metastatic colorectal cancers (mCRCs). Patients with mCRC whose tumors harbor BRAF V600 mutation generally respond poorly to standard chemotherapy. Treatment with BRAF inhibitors has been shown to improve outcomes, whereas the resistance develops through undefined mechanisms. Therefore, it is imperative to accurately comprehend the genomic profiling of resistance mechanisms to BRAF inhibitors in mCRC for exploring its clinical treatment strategies. Methods: We analyzed next-generation sequencing results in 520 cancer-associated genes for 22 patients who had BRAF V600E mutant mCRC in order to characterize genomic predictors of treatment outcome and track the acquired resistance (AR) mechanisms during the vemurafenib/dabrafenib/encorafenib treatment in combination with cetuximab +/- trametinib. The median age of the patients was 61 years old, 54.5% were male, 54.5% had right-sided mCRC, and 81.8% received one or more prior chemotherapy lines. Tissue and/or plasma samples were collected at baseline (prior to anti-BRAF treatment) and upon disease progression (PD). Objective tumor responses were radiologically assessed every 6 weeks according to RECIST v1. 1. Results: By Feb 2021, treatment had been discontinued in 15 (63.2%) of the patients due to disease progression, while the other 7 cases were still under treatment. The median PFS (mPFS) for all patients was 4.5 months. The overall response rate was 32%, and the disease control rate was 86%. In addition to BRAF V600E, the most common concomitant mutations were identified in TP53 (20/22), RNF43 (8/22), LRP18 (7/22), APC (7/22) and PIK3CA (5/22). Patients with baseline alterations in RNF43 (n = 8; p = 0.0466), or RECQL4 (n = 4; p = 0.0406) had significantly longer PFS than their respective wild type counterparts. In contrast, baseline alterations in PPP2R2A (n = 3; p = 0.0131), RUNX1T1 (n = 3; p = 0.0147), and receptor tyrosine kinase (RTK) signaling pathway genes (n = 6; p = 0.0057) were each significantly associated with shorter PFS. Among the 15 patients whose disease progressed, 9 were identified with newly developed AR mutations in PD tumor or plasma samples. MET amplification was the most common AR mechanism (n = 4) followed by BRAF amplification, KRAS, NRAS mutations (n = 3 each), and MAP2K1, PIK3R1 mutations (n = 1 each). Q61 substitution was the most dominant form for both KRAS and NRAS AR mutations (83%, 5/6). In terms of signaling pathway, MAPK (67%, 6/9) and RTK (44%, 4/9) pathway alterations were most frequently observed. Conclusions: Our study illustrated the landscape of genetic alterations in patients with BRAF V600E mutant mCRC upon BRAF inhibitor treatment, which could be critical to predict responses to BRAF inhibitors and guide personalized clinical decision-making after disease progression.
Prevalence of NTRK1/3 fusions in mismatch repair-deficient (dMMR)/microsatellite instable (MSI) tumors of patients with metastatic colorectal cancer (mCRC).
Authors: Svrcek Magali , Colle Raphael , Cayre Anne , Bourgoin Pierre , Cohen Romain , Andre Thierry , Penault-Llorca Frederique Madeleine , Radosevic-Robin Nina
Published: June 2021

e15537

Background: Inhibitors of tropomyosin receptor kinase (TRK) have shown promising activity against neurotrophic TRK ( NTRK) fusion-driven cancers, regardless of tumor histotype or cell of origin. NTRK gene fusions are observed in less than 1% of colorectal cancers (CRCs). CRCs harboring wild-type BRAF and KRAS and MisMatch Repair deficiency (dMMR)/MicroSatellite Instability (MSI) due to MLH1 hypermethylation have been associated with NTRK fusions in small cohorts of non-metastatic tumors. We aimed at evaluating the incidence of NTRK fusions among dMMR/MSI metastatic CRCs (mCRC) for which there is a need for innovative therapies, as well as the associated clinical characteristics of these patients (pts) carrying NTRK fusion-positive tumors. Methods: Tumor samples of dMMR/MSI mCRC pts, paired primary and metastasis or primary alone, were obtained from a French multicenter retrospective cohort and from a single-center cohort of patients treated by immune checkpoint inhibitors (ICI) (Saint-Antoine Hospital, Paris). Clinico-pathological data including KRAS and BRAFV600E status, MMR proteins and MLH1 methylation status were available for all pts. All samples were screened for TRK expression by immunohistochemistry (IHC) using a pan-TRK antibody (clone EPR17341, Abcam; positivity: 1% of labeled tumor cells)) and for NTRK1 and NTRK3 gene rearrangements, by fluorescent in situ hybridation (FISH). A threshold of 15% nuclei positive for a break apart signal was considered positive for gene rearrangement. Results: A total of 158 pts with dMMR/MSI mCRCs (paired samples: n=39; primary only: n=119) were screened. Tumor samples of 10 patients (6.3%) harbored NTRK fusion genes by FISH ( NTRK1=8; NTRK3=2). Only four of these 10 patients had TRK immunoreactivity. One patient showed a discordance between metastasis harboring NTRK1 fusion (+) and primary tumor being negative. Eight tumors were sporadic with MLH1 hypermethylation. The remaining 2 cases were related to a MMR gene germline mutation (Lynch syndrome) with concurrent loss of MSH2 and MSH6 expression and isolated loss of MSH6 respectively. One Lynch-related tumor was KRAS mutated, one sporadic MLH1-negative tumor was BRAF V600E mutated. Four patients out of 91 treated by ICI had tumors with NTRK fusions. Three have shown radiological response according to iRECIST criteria (two complete responses, one partial response with 25 to 54 months of follow up) and one had primary resistance to ICI. Conclusions: Frequency of NTRK1/3 fusions is 6.3% in our dMMR/MSI mCRCs population. These fusions are not restricted to sporadic cases. The diagnostic accuracy of pan-TRK IHC is low. Optimal testing algorithms for theragnostics remain to be defined in this setting.
Effectiveness and tolerability of FOLFOXIRI regimen in the third- and subsequent lines of therapy in patients with metastatic colorectal cancer.
Authors: Yakimovich Kseniya , Alaniya Mariya , Shilo Polina , Mochalova Anastasia , Ledin Evgeny
Published: June 2021

e15584

Background: Options of therapy are limited for patients with colorectal cancer who developed disease progression during standard 5-FU-, oxaliplatin-, and irinotecan-contained regimens. There is straight information about synergy of irinotecan (SN-38) and oxaliplatin gained from fundamental and early clinical trials. We aimed to analyze effectiveness and safety of triple drug-combination of 5-FU, oxaliplatin and irinotecan (FOLFOXIRI) in heavily pretreated patients with metastatic colorectal cancer. Methods: Patients with a metastatic colorectal cancer who received more than 2 lines of standard 5-FU-, oxaliplatin- and irinotecan-based doublet regimens with or without targeted therapy were included. Reinduction of chemotherapy in previous lines was allowed. The retrospective analysis of medical histories was done. Eligible patients had to receive number of cycles that were sufficient for response rate estimation. Disease response was evaluated according to RECIST 1.1 criteria. Survival analysis was performed using the Kaplan-Meier method. Tolerability was estimated by CTCAE v. 5.0. Results: Forty-six patients were included in retrospective per protocol analysis. The median follow-up was 19 months. The median number of previous lines of chemotherapy was 2 (2-6). Primary resistance to oxaliplatin- and irinotecan-based chemo during previous lines was noted in 20 patients (43%) and 16 patients (35%), respectively, while seven patients (15%) developed the primary resistance to both agents given in a sequential order. All patients were treated with targeted therapy during previous treatment lines. The median of FOLFOXIRI cycles was 8 (range, 2-19). Two patients (4%) were treated with FOLFOXIRI without any targeted agents. The objective response rate was 33% (n = 15). The disease stabilization was reached in 43% (n = 20). The disease control rate was 76% (n = 35). Eleven patients (24%) had the progression of disease at the first follow-up. The median progression free survival and median overall survival were 6 months and 11 months, respectively. Toxicity was evaluated in 35 patients. The most common severe adverse events (grade 3 and 4) were neutropenia (46%) and fatigue (26%). Treatment was delayed in 20 patients (57%), and 13 patients (37%) required dose reduction. One patient had to discontinue treatment due to unacceptable toxicity. Conclusions: According to our study FOLFOXIRI provides the objective response and increased life expectancy in heavily pretreated patients. The further assessment of FOLFOXIRI regimen for refractory colorectal cancer in the prospective trials is needed.
Neoadjuvant chemotherapy for locally advanced colon cancer patients: Long-term results from a single institutional experience.
Authors: Ceniceros Lucia , Pastor Carlos , Sanchez-Justicia Carlos , Arean Carolina , Baixauli Jorge , Chopitea Ana , Granero Lucia , Arredondo Jorge , Martinez Patricia , Hernandez-Lizoain Jose Luis , Rodriguez Javier
Published: June 2021

e15598

Background: Neoadjuvant chemotherapy (NAC) is an emerging alternative in the management of patients with locally advanced colorectal cancer (LACRC), with promising results in terms of R0 resection rates, compliance, postoperative morbidity and a trend towards reduced risk of relapse. However, more mature data are required. We evaluated the long-term outcome of this strategy in our institution. Methods: We retrospectively analysed LACRC patients treated preoperatively with either biweekly FOLFOX or XELOX at standard doses as a follow-up of our previous experience with this neoadjuvant approach. Patients were identified from a prospectively collected tumor registry database from our institution. Clinical staging was based on colonoscopy and CT-scan. Only patients with radiological signs of lymph node involvement and/or extramural invasion > 5 mm were included. The uracil/dihidrouracil ratio was calculated at baseline as a surrogate marker of DPD deficiency. Pathological tumor regression was graded according to the MSKCC and toxicity with the NCI-CTCAE 4.0. Results: From February 2006 to November 2019 91 pts with MSS LACRC (M/F: 62/29; median age 66. Clinical stage; T3: 60.4%, T4: 37.4%, N+: 75.8%; Sideness: 82.4% left located were analysed. Preoperative chemo was FOLFOX in 46 pts and CAPOX in 45 pts. Median number of preoperative cycles was 4 (range 1-10). Side effects profile included G3-4 diarrhea (3.3%), G2 sensitive neuropathy (12.1%) and G2 neutropenia (4.4%). 9 pts had a treatment delay due to haematological toxicity. No progressive disease was noted during neoadjuvant chemotherapy. All patients underwent surgery, most of them (63.7%) by a laparoscopic approach. pCR was found in 11 pts (12.1%). Grade 3, 3+ and 4 tumor regression according to MSKCC score was reached in 50.5% of the patients (Median number of harvested nodes was 17 (range 7-51), with 75.8% being ypN0. Lymphovascular and perineural invasion were found in 7.7% and 6.6% of the patients, respectively. The median hospital stay was 7 days (3-36) and 13 pts develop any surgical complication. 37.4% received adjuvant treatment. After a median follow-up of 63 months, median progression-free (PFS) and overall survival (OS) have not been reached. 5-year actuarial PFS for right and left LACRC was 77 and 87%, respectively. Conclusions: Our data add to the growing evidence suggesting that NAC may play a meaningful role in LACRC patients
Effects of prognostic nutrition index on side effects and prognosis of radiotherapy and chemotherapy after radical gastrectomy.
Authors: Liu Jiyu , Dong Hongmin , Wang Wenling , Wang Gang , Pan Huan , Chen Weiwei , Wang Qian , Wang Ze-Jun
Published: June 2021

e16002

Background: To investigate the impact of preoperative prognostic nutritional index (PNI) on the severity of radiotherapy and chemotherapy toxicity and survival prognosis in patients with gastric cancer through retrospective analysis and research in order to guide clinical nutritional support treatment for patients with gastric cancer. Methods: Through a retrospective cohort study，we analyzed the data of 191 patients with gastric cancer in the Department of Gastrointestinal Surgery of the Affiliated Hospital of Guizhou Medical University and Guizhou Cancer Hospital from January 2008 to December 2018. According to the cut-off value, the patients were divided into high PNI group (PNI≥47.7) and low PNI group (PNI < 47.7). We Compared the incidences of severe radiotherapy and chemotherapy toxicities and overall survival in high PNI group and low PNI group. and make Analysis of prognostic factors. Results: The low PNI group was more prone to severe radiochemotherapy hematological side effects than the high PNI group, and the postoperative survival time was shorter. Multivariate analysis showed that: TNM stage (P = 0.000) and PNI (P = 0.001) were Independent risk factors in predicting overall survival rate. Conclusions: The preoperative prognostic nutrition index is a useful factor for predicting the incidence of radiotherapy and chemotherapy toxicities in patients after gastric cancer surgery.It is one of the important factors affecting the prognosis of gastric cancer and helps to guide the nutritional support treatment of gastric cancer patients.
A real-world clinical study of camrelizumab in the treatment of esophageal cancer.
Authors: Sun Guoping , Qian Dong , Zhao Dong , Liang Hui , Cheng Huaidong , Wang Genhe , Wang Fan , Jiang Hao , Xu Tengyun , Wu Qibing , Zhu ShaoJin , Xu Dong
Published: June 2021

e16008

Background: Camrelizumab, a fully humanized monoclonal antibody against PD-1, has been approved in the treatment of advanced esophageal squamous carcinoma in China. The purpose of this study was to observe the efficacy and safety of Camrelizumab in the treatment of esophageal cancer in the real world. Methods: This is an open-label, prospective, multicenter, observational study. Eligible patients (pts) who received Camrelizumab had esophageal cancer; age≥18, ECOG PS of 0-2; and measurable disease. Results: As of November 30, 2020, a total of 229 patients were enrolled, of which 192 were male (83.8%). The ECOG PS score was 0 in 48 cases (21.0%), 1 in 149 cases (65.0%), and 2 in 32 cases (14.0%). Among the 134 patients of stage IV patients (58.5%), 174 patients had metastases (76.0%), and 99% of patients did not undergo PD-L1 testing. A history of radiotherapy accounted for 57.6%, and a history of surgery on the primary lesion accounted for 42%. Camrelizumab accounted for 26.2% of the first-line treatment, 33.6% of the second-line treatment, and 35.4% of the third-line and above. Camrelizumab combined with chemotherapy accounted for 40%, combined with anti-angiogenesis therapy accounted for 38.0%, combined with anti-angiogenesis + chemotherapy accounted for 9.0%, and combined radiotherapy accounted for 6.2%. Among 145 patients with evaluable efficacy, 5 cases of CR, 14 cases of PR, 97 cases of SD, and 29 cases of PD. The ORR reached 13.1% and the DCR reached 80.0%. The overall adverse event rate was 42.8%, the major adverse event RCCEP rate was 11.7%, pneumonia was 8.3%, and fatigue was 4.1%. Adverse events greater than or equal to grade 3 included 1 case of RCCEP, 3 cases of bleeding, 1 case of diarrhea, and 1 case of fever. Conclusions: In this real-world study of esophageal cancer, most of the patients enrolled were patients with poor PS score and late stage, but the efficacy and safety of Camrelizumab in patients with advanced esophageal cancer were still confirmed. The dominant population and combination therapy are still under study. Clinical trial information: ChiCTR1900027275.
Camrelizumab in combination with preoperative chemotherapy for locally advanced esophageal squamous cell carcinoma: A single-arm, open-label, phase II study.
Authors: Wang Feng , Qi Yu , Meng Xiangrui , Fan Qingxia
Published: June 2021

e16072

Background: At present, ESCC has a dismal prognosis with huge unmet clinical needs. With the potential benefit of combining PD-1 inhibitor with nCT, we conducted a phase II trial to assess the efficacy and safety of Camrelizumab plus nCT for locally advanced ESCC. Methods: 43 patients (pts) with histologically confirmed stage II/III/IVa(cT2-4aN0-3M0) ESCC were enrolled from February 2020 to February 2021.The study was divided into two stages, stage 1: we administered 1 cycle of camrelizumab for induction therapy (200 mg q2 weeks); stage2: pts received 2 cycle of camrelizumab (200 mg every 3 weeks) plus docetaxel and nedaplatin, followed by surgery within 4̃6 weeks after neoadjuvant therapy completion. Primary endpoint was major pathologic response (MPR). Secondary endpoints included pathologic complete response (pCR), R0 resection rate, disease-free survival (DFS) and overall survival (OS). Results: At the cutoff date of Feb 5, 2021, 43 eligible pts were enrolled (63% males, median age 66), neoadjuvant treatment was completed in 33 pts and is ongoing in 3 pts. Thus far 27 out of 33 pts were resected, 6 pts are planned to undergo surgery, 3 pts were not suitable for operation after evaluation,1 pt had interval metastases preoperatively, 1 pt declined surgery, 1 pt was allergic to camrelizumab, 1 pt died due to unknown reasons. All patients underwent an R0 resection. Postoperative pathology showed that TNM stage decreased in 23 pts with 85.19% reduction rate. 17 pts (62.96%) reached major pathologic response, 8 pts (29.63%) reached pathologic complete response (no surgery related mortality). The most common AEs (all grade, grade≥3) were reduced hemoglobin (53%, 0%), hypoproteinemia (26%, 0%), neutrophil (21%, 12%), TSH reduction (21%, 0%), increased blood lactate dehydrogenase (16%, 0%), hyperthyroidism (16%, 0%), elevated alanine aminotransferase (9%, 0%), fatigue (7%, 0%), rash (5%, 2%). Date for median DFS and OS were not matured. Conclusions: Camrelizumab in combination with preoperative chemotherapy followed by surgery for locally advanced ESCC showed promising downstaging effect and MPR with good tolerance, and its efficacy and safety could be further studied in later trials. Clinical trial information: NCT03917966. Clinical trial information: NCT03917966.
Analysis of DNA damage response gene signature for prognosis prediction of esophageal squamous cell carcinoma.
Authors: Zhuang Weitao , Ben Xiao-song , Tian Dan , Zhou Zihao , Chen Gang , Deng Cheng , Liao Yuchen , Zhao Jing , Wang Guoqiang , Cai Shangli , Tang Jiming , Shi Ruiqing , Xie Liang , Zhang Dongkun , Zhou Haiyu , Qiao Gui-Bin
Published: June 2021

e16073

Background: Esophageal squamous cell cancer (ESCC) is a malignant tumor with a poor 5-year relative survival. A prognosis prediction signature associated with DNA Damage Response (DDR) genes in ESCC was explored in this study. Methods: The clinical and gene expression profiles of ESCC patients were downloaded from the GEO and TCGA database. Univariate Cox regression and 1000 iterations of 10-fold cross-validation of LASSO Cox regression with binomial deviance minimization criteria were used to identify DDR genes as potential object and a prognostic signature for ESCC survival prediction, followed by validation of the signature via TCGA cohort and identification of independent prognostic predictors. A nomogram for prognosis prediction was built and Gene Set Enrichment Analysis (GSEA) was performed to further understand the underlying molecular mechanisms. Results: A signature of 8 DDR genes were constructed as being significantly associated with overall survival (OS) among patients with esophageal squamous cell carcinoma. The pronostic signature stratified ESCC patients into low- vs high-risk groups in terms of OS in the training set, testing set and the validation cohorts, and remained as an independent prognostic factor in multivariate analyses (hazard ratio (HR) in training set, 0.17 [95% CI, 0.09-0.35; P < 0 .001], HR in testing set, 0.38 [95% CI, 0.16-0.93; P = 0.029], HR in discovery cohort, 0.171 [95% CI, 0.03-0.48; P < 0 .001]) after adjusting for clinicopathological factors. The 8-DDR gene signature achieved a higher accuracy (C-index, 0.69; AUCs for 1-, 3- and 5-year OS, 0.74, 0.77 and 0.76, respectively) than 7 previously reported multigene signatures (C-index range, 0.53 to 0.60; AUCs range, 0.55to 0.66, 0.54 to 0.64 and 0.62 to 0.66, respectively) for estimation of survival in comparable cohorts. A nomogram incorporating tumor location, grade, adjuvant therapy and signature-based risk group showed better predictive performance for 1- and 3- year survival than for 5 year survival. Moreover, GSEA revealed that the DNA repair was more prominently enriched in the high-risk group while the low-risk group had not enrichment of any process (P > 0.05 for all). Conclusions: Taken together, our study identified 8 DDR genes related to the prognosis of ESCC patients, and constructed a robust prognostic signature to effectively stratify ESCC patients with different survival rates, which may help recognize high-risk patients potentially benefiting from more aggressive treatment.
Income-inequality and rate of doctors per inhabitant and their influence on esophageal cancer mortality in Brazil.
Authors: Schoueri Jean Henri , Werneck De Carvalho Luis Eduardo , Portugal Isabella Batista Martins , de Almeida Roediger Manuela , de Sousa Santos Edige Felipe , Paiva Laercio da Silva , de Abreu Luiz Carlos , Fonseca Fernando Luiz Affonso , Barbosa do Nascimento Vânia , Adami Fernando
Published: June 2021

e16089

Background: There are substantial disparities in esophageal cancer mortality across different social groups, including sex, race/ethnicity, geographical location and socio-economic status. Methods: This is an ecological study with secondary data from 2016 to 2018 that evaluated the effects of income-inequality and number of doctors per inhabitant on esophageal cancer mortality in Brazil and its Federative Units. The amount of deaths and the overall number of doctors were obtained from the Department of Informatics of the Unified Health System. Mortality was estimated per 100,000 individuals and age-standardized through the World Health Organization’s population, whereas the rate of doctor per inhabitant was calculated per 1,000 inhabitants. Income-Inequality was measured by the Gini index, obtained from the United Nations Development Programme. Linear regression was performed by the stepwise backward method. Results: Sex, Gini index values and oncology surgeons were all related to lower mortality rates (p < 0.05), whereas clinical oncologists and general surgeons were both associated with higher mortality (p < 0.05). Conclusions: Esophageal cancer mortality rates were influenced by both the type and amount of doctors per inhabitant of any given administrative region in Brazil, however there was no association found with regards to income inequality.[Table: see text]
Prolonged overall survival observed in patients with locally advanced gastric cancer receiving prophylactic simplified heated intraperitoneal chemotherapy after D2 surgery.
Authors: Cheng Junchi , Yang Yunshan , Zhong Haijun
Published: June 2021

e16110

Background: Despite advances in surgery and adjuvant chemotherapy, intraperitoneal recurrence is highly frequent in gastric cancer (GC) with a dismal prognosis. In this retrospective study, we aimed to evaluate the effectiveness of adding simplified prophylactic heated intraperitoneal chemotherapy (sp-HIPEC) between surgery and systemic chemotherapy. Methods: Clinical data of 170 patients diagnosed as having locally advanced GC and receiving D2 surgery were retrospectively reviewed. Of the patients, 99 received sp-HIPEC, followed by systemic postoperative chemotherapy, and 71 received only systemic postoperative chemotherapy. Overall survival and recurrence rates between the groups were compared. Results: The median survival was 30.3 and 17.2 months for the sp-HIPEC and systemic groups, respectively (hazard ratio, 0.56; 95% CI, 0.10-0.97). The 3- and 5-year survival rates were 48.2% vs 41.4% and 22.9% vs 14.4%, respectively. Moreover, adding sp-HIPEC significantly reduced peritoneal relapse rate.Both regimens were well tolerated. Conclusions: Adding sp-HIPEC between surgery and systemic chemotherapy may benefit the overall survival without causing additional treatment toxicity.
Camrelizumab in combination with TACE for the treatment of unresectable hepatocellular carcinoma (HCC): A multicenter, single-arm, prospective real-world study.
Authors: You Ran , Yin Guowen , Xu Hao , Zhu Xiaoli , Zhang Qingqiao , Wang Qi , Cao Chi , Lu You , Jiang Hao , Liu Jun , Yu Hui , Xu Qingyu
Published: June 2021

e16114

Background: Transcatheter arterial chemoembolization (TACE) is considered to be the first-line topical therapy for unresectable hepatocellular carcinoma (HCC). However, the long-term efficacy of single TACE treatment is poor, with a five-year survival rate of 8%-43%. This study aims to investigate the efficacy and safety of TACE combined with camrelizumab in the treatment of unresectable HCC. Methods: This is a single-arm, prospective real-word study conducted in 14 hospitals in Jiangsu, China. Patients diagnosed with HCC received Camrelizumab (200mg, i.v. Q2W or Q3W) with or without antiangiogenic therapy (apatinib, lenvatinib, sorafenib, or regorafenib) at any stage of the TACE treatment. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Kaplan-Meier method was used for survival analysis. This study was registered with ChiCTR.org.cn, number ChiCTR1900026163. Results: From September 2019 to January 2021, 151 patients were enrolled, of whom most were males and younger than 65 years, 92 (60.93%) had extrahepatic metastasis and 120 (79.47%) suffered from HBV infection, 59 (39.07%) had an AFP concentration of 400 ng/mL or higher, 150 (99.34) had an ECOG PS of 0 or 1, a Child-Puph score of A or B, and were classified as BCLC Stage B or C. In addition to TACE, 52 patients received camrelizumab alone, while the others also received antiangiogenic therapy. Most (139, 92.06%) of the patients received camrelizumab 200mg every 3 weeks. Of the 112 patients who were available for efficacy evaluation, 4 patients achieved CR, 25 achieved PR, and 53 achieved SD, resulting in an ORR of 25.89% and DCR of 73.21%. The median PFS was 4.27 months (95% CI, 3.45 to 7.36 months) and the median OS was 14.0 months (95% CI, 10.6 to NE months). The safety data were obtained from 140 patients. Treatment-related adverse events (TRAEs) occurred in 130 (92.86%) patients, with the commonest types including increased alanine and aspartate aminotransferases (65%), thrombocytopenia (57.86%), hypoalbuminemia (54.29%), hyperbilirubinemia (48.57%), anemia (42.86%), leukopenia (42.14%), neutropenia (37.14%) and proteinuria (20.71%). Severe AEs occurred in 52 (37.14%) patients, with the commonest types including thrombocytopenia (17.14%), increased alanine and aspartate aminotransferases (13.57%), neutropenia (8.57%) and hyperbilirubinemia (7.14%). Conclusions: The treatment strategy of TACE in combination with camrelizumab with or without antiangiogenic therapy showed encouraging clinical efficacy and manageable toxicity profile in treating unresectable HCC, which provided a new treatment option for HCC. Clinical trial information: ChiCTR1900026163.
Impact of bodyweight (BW)-based starting doses on safety and efficacy of lenvatinib (LEN) in patients (pts) with hepatocellular carcinoma (HCC).
Authors: Okusaka Takuji , Kudo Masatoshi , Ikeda Kenji , Ikeda Masafumi , Okita Kiwamu , Tamai Toshiyuki , Ren Min , Saito Kenichi , Kumada Hiromitsu
Published: June 2021

e16119

Background: In Study 202, pts received LEN 12 mg/d for treatment of unresectable (u)HCC, irrespective of BW. Correlations between early dose adjustments and BW in Study 202 led to BW-adjusted dosing in the phase 3 REFLECT study of LEN in uHCC. In REFLECT, pts <60 kg received LEN 8 mg/d and pts ≥60 kg received LEN 12 mg/d. While improvements in safety were expected by reducing the LEN starting dose to 8 mg/d in pts <60 kg, any differences in safety and efficacy of BW-adjusted dosing vs standard dosing among pts with lower BW have yet to be determined. Herein, we compare safety and efficacy of LEN based on pts’ BW (<60 kg vs ≥60 kg) in Study 202 (LEN 12 mg/d irrespective of BW) and in Japanese pts in REFLECT (dose adjusted by BW). Methods: This ad hoc analysis included all pts from Study 202 (n=46; all Asian, 43 Japanese) and Japanese pts from REFLECT (n=81). Safety and efficacy were assessed in Study 202 and REFLECT according to pt BW (<60 kg vs ≥60 kg). Tumors were assessed using mRECIST, by independent radiologic review. Results: In Study 202, pts in the <60 kg group had a median treatment duration of 5.8 mos and received 57% of the LEN planned starting dose (PSD); pts in the ≥60 kg group had a median treatment duration of 9.4 mos and received 78.6% of the LEN PSD. Among Japanese pts in REFLECT, median treatment duration was 5.7 mos in both treatment groups; pts in the LEN 8 mg group received 79.1% of the PSD and pts in the LEN 12 mg group received 70.7% of the PSD. In Study 202, treatment-related adverse events (TRAEs) led to dose reduction in 80.8% of pts in the <60 kg group and 55% of pts in the ≥60 kg group. In REFLECT, TRAEs led to dose reductions in 52.5% of pts in the LEN 8 mg group and 70.7% of pts in the LEN 12 mg group. Serious TRAEs occurred at incidences of 46.2% and 10.0% in Study 202 in the <60 kg and ≥60 kg groups, and 15.0% and 22.0% in REFLECT in the LEN 8 mg and LEN 12 mg groups, respectively. Efficacy results are in the Table. Conclusions: Despite the small sample size, this comparison of Study 202 pts and Japanese pts from REFLECT indicates that BW-adjusted LEN dosing in pts with uHCC yielded comparable efficacy between pts <60 kg who received LEN 8 mg and pts ≥60 kg who received LEN 12 mg. The safety profile was favorable in pts <60 kg who received LEN 8 mg in REFLECT vs those who received LEN 12 mg in Study 202. Fewer serious TRAEs and dose reductions due to TRAEs were observed in pts with lower BW who received the LEN 8 mg starting dose in REFLECT. These data suggest that by reducing the starting dose from LEN 12 mg to 8 mg in pts with uHCC and lower BW (<60 kg), safety is improved without compromising efficacy. Clinical trial information: NCT00946153; NCT01761266. [Table: see text]
A pilot study of the combination of checkpoint inhibition with ablation in subjects with biliary tract cancer.
Authors: Wetzel Rebecca , Monge B. M. Cecilia , Xie Changqing , Mabry-Hrones Donna , Webb Santhana , Akoth Elizabeth , Redd Bernadette , Levy Elliot B , Wood Bradford , Greten Tim F.
Published: June 2021

e16150

Background: Immune checkpoint inhibition has demonstrated modest activity in biliary tract carcinoma (BTC). Augmentation of the immune response by ablative procedures to improve efficacy of immune checkpoint inhibition has been previously demonstrated in hepatocellular carcinoma, however the outcome of the combination of immune checkpoint inhibition with tremelimumab (anti-CTLA4) and durvalumab (anti-PD1) with ablation in advanced biliary tract carcinoma is unclear. The primary objective of this study was to establish the efficacy via 6-month progression-free survival (PFS) of combining tremelimumab and durvalumab in patients with advanced BTC either alone or with tumor ablation. Secondary objectives were safety and feasibility of combination treatment. An exploratory objective was overall survival (OS). Methods: Eligible patients had histologically confirmed advanced or unresectable BTC (intra- or extrahepatic cholangiocarcinoma, gallbladder cancer, or ampullary cancer) who had progressed on, been intolerant to, or refused prior chemotherapy. Disease had to be technically amenable to cryoablation with at least two measurable lesions. Adequate organ function and an ECOG of 0 or 1 were required. Patients were treated with tremelimumab and durvalumab with or without tumor ablation. Tremelimumab and durvalumab were administered intravenously every 28 days for four cycles followed by durvalumab every 28 days until disease progression. Cryoablation was performed on day 36. Patients were imaged every 8 weeks and response was defined per RECIST v 1.1 criteria. Results: In total, 22 patients have been enrolled into the BTC cohort. Half underwent ablation and half received immunotherapy alone. The median age was 59 years (range 21-80). All patients had received prior systemic chemotherapy, locally advanced disease was present in 68% of patients. Median PFS was 2.1m and median OS was 5.6 m. DCR was 45% (SD). Median OS and PFS was similar in the group that received ablation vs immunotherapy alone with a median OS of 6.8 m vs 6.7 m and 2.0 m vs 2.7 m respectively. The most common grade 3- 4 adverse events were lymphopenia (27%), increased AST (41%), increased alkaline phosphatase (32%) and elevated bilirubin (27%). Conclusions: Combination checkpoint inhibition combined with tumor ablative procedures is a safe and effective treatment strategy for patients with advanced BTC, however the addition of ablative therapy may not enhance efficacy in this small cohort of patients. Results illustrate the poor prognosis of advanced BTC and may represent a non-chemotherapeutic approach to treatment in this patient population. Further studies are warranted to identify patient populations most likely to respond to these interventions. Clinical trial information: NCT02821754.
Analysis of DNA damage repair pathway genes as a predictive biomarker for HAIC in hepatocellular carcinoma.
Authors: Mai Qicong , Mo Zhiqiang , He Jian , Chen Tingting , Huang Mengli , Chen Xiaoming
Published: June 2021

e16159

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide.Hepatic arterial infusion chemotherapy (HAIC) with oxaliplatin, fluorouracil, and leucovorin (FOLFOX) is one of the effective treatment for advanced HCC patients. DNA damage repaired (DDR) pathway has been widely researched in many cancers recent years, which was a promising predictive biomarker for the response to platinum-based chemotherapy and Immunotherapy. But the DDR characteristics of different subset pathways in HCC, and its correlation with HAIC efficacy were unknown. Methods: Whole exome sequencing (WES) data of 366 HCC patients was obtained from the Cancer Genome Altas (TCGA). Next generation sequencing (NGS, panel on 381/733-gene) was performed on FFPE tumor samples from 2092 Chinese HCC patients (Chinese cohort). Germ-line or somatic mutations of 32 DDR pathway genes (including Mismatch Repair and Homologous Recombination) were classified as DDR gene mutations. TMB was defined as total number of somatic non-synonymous mutations in coding region. Whole exome sequencing (WES) data and clinical data of 21 HCC advanced patients treated with HAIC were obtained to survival analysis. Results: In total, 59.84% (219/366) of HCC patients in TCGA harboring DDR mutation and 67.38% (1316/2092) in Chinese cohort. In Chinese HCC cohort, the mean TMB level of DDR mutant group was significant higher than wild-type group (mean TMB, mutation vs wild-type = 8.12 vs 6.42 Muts/Mb, P < 0.0001). The top three mutation frequency DDR genes were BRCA2 (17%), ATM (13%) and BARD1 (12%), respectively. The highest mutation frequency DDR subset pathways were Fanconi anemia (FA, 44.14%, 862/2092), homologous recombination repair (HRR, 38.71%, 756/2092) and check point factors (CHP, 17.31%, 338/2092) come in second and third, respectively. Next we compared the TMB level between different DDR subset pathways, the mutant of nucleotide excision repair (NER) pathway harbored the highest medium TMB level (7.26 Muts/Mb). The survival analysis was performed on HCC patients treated with HAIC with FOLFOX. There was no difference in clinical baseline information between DDR mutation group (n = 6) and wild-type group (n = 15). The progression-free survival (PFS) of DDR mutation group were significantly longer than wild-type group (median PFS, mutation vs. wild-type = 8.9 vs. 4.5 months; HR 0.34[95% CI 0.13-0.85]; P = 0.0349), and an extending trend on overall survival (OS) without significant difference (median OS, 15.7 vs 8.9 months; HR 0.37[95% CI 0.13-1.00]; P = 0.0921). Conclusions: The DDR pathways was associated with higher TMB level. Preliminary data from clinical cohorts suggested better treatment outcomes of HAIC with FOLFOX in DDR mutation HCC patients.
A phase Ⅰ open-label dose-escalation study of AL2846 in combination with gemcitabine in patients with locally advanced or metastatic pancreatic adenocarcinoma.
Authors: Liu Rui , Deng Ting , Bai Ming , Zhang Le , Ning Tao , Wang Xia , Ji Zhi , Yang Yuchong , Ge Shaohua , Li Hongli , Duan Jingjing , Ba Yi
Published: June 2021

e16210

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a 5-year survival rate of 10%. Overexpression of c-Met is associated with the poor prognosis in patients with PDAC and it was noted that phosphorylation of c-Met is increased in gemcitabine-resistant PDAC. AL2846 is an oral c-Met inhibitor, which targets multiple receptor tyrosine kinases (RTK’s) primarily including c-Met, VEGFR1, KIT, Axl and RET. The combination of AL2846 with chemotherapy may improve the clinical efficacy of PDAC. Based on these consideration, a phase Ⅰ clinical trial was initiated to determine the maximum tolerated dose (MTD) of AL2846 in combination with gemcitabine in patients with advanced PDAC and to clarify the potential anti-tumor activity. Methods: Patients with untreated locally advanced or metastatic PDAC were enrolled to receive oral AL2846 once daily in a fasted state in combination with gemcitabine intravenous infusion over 30 min on days 1, 8, and 15 every 28 days. The starting dose level is AL2846 40 mg and gemcitabine 1000 mg/m2. Primary endpoint was the maximum tolerated dose (MTD), defined as the highest dose level at which ≤33 % of patients incurred a dose-limiting toxicity (DLT), and RP2D. Secondary endpoints included response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results: As of January 1, 2021, a total of 15 patients with PDAC were enrolled and received 4 dose-levels of AL2846 (40 mg: n = 1; 60 mg: n = 6; 90 mg: n = 3; 120 mg: n = 5) treatment. DLTs occurred in 1 patient who experienced grade 3 abnormal liver function. The most common grade 3 or above drug-related adverse events were neutropenia (n = 7, 46.7%), thrombocytopenia (n = 5, 33.3%), leukopenia (n = 4, 26.7%), GGT increased (n = 4, 26.7%), hyperbilirubinemia (n = 3, 20.0%) and alkaline phosphatase increased (n = 3, 20.0%). Among the 15 patients available for efficacy evaluation, 1 patient (6.6%) achieved partial response who was at the dose levels of 90mg. There were 4 patients whose PFS was more than 5 months. Although there were no more than 2 DLT events, we chose 90 and 120 mg as the target dose for RP2D according to the dose reduction and proportion of gemcitabine. Conclusions: The RP2D of AL2846 in combination with standard dose of gemcitabine were 90 and 120 mg QD continuously. The results demonstrated that AL2846 in combination with gemcitabine was well tolerated at doses up to 120 mg. Further clinical studies about the efficacy of AL2846 in pancreatic cancer are in progress. Clinical trial information: CTR20201021.
Association of TP53 mutation status and GATA6 amplification with clinical outcome of pancreatic cancer.
Authors: Yang Jung-In , Ha Taehoon , Zhou Edward , Tzanavaris Chris , Devoe Craig E. , Zhu Xinhua , Boyd Jeff
Published: June 2021

e16224

Background: Recent advances in pancreatic adenocarcinoma (PDAC) research unveiled that molecular subtypes reflect cancer prognosis and chemosensitivity. Here, we examined the possible use of genomic profiling of PDAC in the clinic by assessing retrospective clinical outcomes and treatment responsiveness based on genetic alterations. Methods: All patients treated for PDAC with Next-Generation Sequencing (NGS) data available between 2014 to 2020 at Northwell Health Cancer Institute were included in a retrospective analysis. Patients were subdivided into resectable and unresectable cancer. Genetic findings frequently reported in NGS were used to compare progression-free survival (PFS) and overall survival (OS) within subgroups. Survival probability was compared using Peto-Peto’s modified survival estimate followed by pairwise comparisons using Peto-Peto’s modified survival estimate. Family-wise error rate was adjusted using Benjamini & Hochberg method. Results: A total 115 patients were qualified for the evaluation. In all cases of PDAC, TP53 mutation (n = 89) was associated with poor OS compared to the wild-type TP53 gene (n = 19) (median OS 20.2 months, 95% CI 10.2 to 39.7, vs. 41.1 months, 95% CI 20.9 to 81.0, HR 1.98, p = 0.028). In unresectable PDAC, tumors with GATA6 amplification (n = 11) were associated with a significantly better OS over patients whose tumors harbored a TP53 mutation (n = 57) (median OS 22.9 months, 95% CI 9.6 to 54.5, vs. 10.0 months, 95% CI 4.2 to 23.8, HR 0.48, p = 0.048) . Within the TP53 mutation group, FOLFIRINOX (n = 21) did not show improved OS compare to Gem/NabP (n = 30) (mean OS 13.8 months, 95% CI 6.8 to 28.2, vs. 8.5 months, 95% CI 4.17 to 17.4, HR 0.84, p = 0.25). Other genetic alterations were not associated with OS. There was no difference in PFS in all PDACs. Conclusions: Our retrospective analysis showed that genetic changes in TP53 and GATA6 were significantly associated with the clinical outcome for PDAC. Mutation of TP53 was associated with poor OS in general. However, in unresectable PDAC, GATA6 amplification was associated with better clinical outcome than tumors with TP53 mutation. In contrary to general belief, FOLFIRINOX did not result in better OS than Gem/NabP.
The impact of first-line chemotherapy in elderly patients (pts) with advanced pancreatic cancer (APC): A mono-institutional retrospective study.
Authors: Chiaravalli Marta , Maratta Maria Grazia , Bensi Maria , Di Stefano Brunella , Ribelli Marta , Barone Diletta , Gurreri Enrico , Monaca Federico , Cutigni Claudia , Bagalà Cinzia , Tortora Giampaolo , Salvatore Lisa
Published: June 2021

e16229

Background: Pancreatic cancer median age at diagnosis is 70 years old. However, elderly pts are underrepresented in randomized clinical trials (RCTs) and chemotherapy efficacy and safety data in this population are limited. Herein, we present a retrospective analysis of an elderly population treated at our Institution, investigating the role of baseline clinical factors in guiding treatment decision making. Methods: Pts aged ≥70 years old receiving a first-line chemotherapy for APC were included in the analysis. The primary end-points were progression-free survival (PFS) and overall survival (OS). The following variables were collected: gender; age (≥ 70 and < 75 years vs ≥ 75 years); baseline ECOG PS (0-1 vs 2-3); site of primary tumor (head/uncinate process vs body/tail); disease stage (locally advanced vs metastatic); baseline CA 19.9 ( < vs ≥ 200); chemotherapy regimen; comorbidities (yes vs no); number of comorbidities (0-1 vs ≥ 2). Univariate and multivariate analysis for PFS and OS were performed. Results: A total of 169 APC pts aged ≥70 years old, receiving first-line chemotherapy between March 2015 and August 2020, were included in the analysis. The median age was 76 years (70-89), ECOG PS was 0-1 in 77% of pts; 70% were metastatic; 70% of pts had a head/uncinate process primary tumor; 25% had baseline CA 19.9 ≥ 200; 9.4% of pts had no comorbidities and 50% had ≥2 comorbidities. The majority of pts received gemcitabine nab-paclitaxel (60%), other regimes included gemcitabine (28%), FOLFIRINOX (5%), capecitabine (4%), FOLFOX (2%) and FOLFIRI (1%). The overall population median PFS and OS were 6.5 (median follow-up 19.1 months) and 11 months (median follow-up 21.8 months), respectively. Out of 164 pts evaluable, 38 (23%) pts achieved a partial response and 58 (35%) a stable disease, with a disease control rate of 58%. At the multivariate analysis, ECOG PS 0-1 resulted independently associated both with improved PFS (p 0.005) and OS (p 0.0084). At the multivariate analysis for PFS, also locally advanced stage resulted significantly associated with better PFS (p = 0.036). In pts with ECOG PS 0-1 vs 3-4 the median PFS was 6.7 vs 3.3 months (p 0.0004) and median OS was 11.3 vs 5.5 moths (p 0.003), respectively. Conclusions: Despite the retrospective nature of the analysis and the limited sample size, we observed that elderly APC pts can benefit from a first-line treatment achieving survival outcomes comparable to the one reported for younger pts in RCTs. On the basis of our results, the baseline ECOG PS can be considered a prognostic factor for both PFS and OS. In conclusion, elderly pts should not be precluded from an active treatment and careful patient selection, mainly according to baseline ECOG PS, should guide treatment indication.
Patient's characteristics and outcome of small bowel adenocarcinoma in Saudi Arabia.
Authors: Alshamsan Bader I , Badran Ahmed ali , Aseafan Mohamed , Shaheen Amgad , Elshenawy Mahmoud Abdelsatar , Aljubran Ali H
Published: June 2021

e16277

Background: Small bowel adenocarcinoma (SBA) is a rare disease. We aim to describe patient's characteristics and clinical outcomes among Saudi patients. Methods: All patients with SBA diagnosed between 2007 - 2020 were reviewed. Logistic regression was used to assess variables associated with metastasis at diagnosis, and a log-rank test was used to compare factors associated with survival. Results: Forty-three patients were eligible for analysis, and (76.7%) were males. The median age at diagnosis was 53 years. History was significant for colon cancer in two patients, celiac disease in three patients, Lynch syndrome, Familial adenomatous polyposis (FAP), Non-APC in one patient, and cholecystectomy in seven patients. The common initial presenting symptoms were abdominal pain (58.8%), bowel obstruction (30.2%), Overt gastrointestinal bleeding (9.3%). Tumor markers were elevated in 21 patients. EGD was used for diagnosis in 60.5%, while CT scan in 23.3%. The most common primary site was duodenum 60.5%, jejunum 27.9%, ilium 7%. Stage IV was (41.9%). The most common site for metastases was the liver in 10 patients. Patients' ECOG performance status was 0/1 in 51% at diagnosis. Univariate analysis did not reveal that patients with high Neutrophil-lymphocyte Ratio (NLR) (≥0.85) are more likely to be metastatic; P = 009. There was no association of sex, presenting complaints, tumor markers with the stage at diagnosis. Surgery was performed for 53.4% of patients (RO, 73%), and the median DFS was 49 vs. 8 months in R0 vs. R1 group, respectively (p = 0.01). FOLFOX Chemotherapy regimen was given for 10 patients as adjuvant treatment and for 8 patients for metastatic sitting. The median duration of follow-up was 12 months. The median overall survival (OS) for localized stages was not reached, and for the metastatic stage was 10 months. The 3 years OS based on stages were 100% (I), 85% (II), 53% (III) and 35% for (IV), p = 0.001. Other factors associated with survival were ECOG Performance status (p < 0.001), NLR ( < 0.001), CA19-9 (p = 0.04), and receiving chemotherapy in a metastatic setting (p = 0.02). Conclusions: SBA is diagnosed at a younger age in Saudi patients and more in males. The advanced stage, lower performance status score, high CA19-9, and high NLR at diagnosis are associated with poor OS. NLR could be a prognostic factor for a metastatic stage at diagnosis.