bluuebunny/crossref_metadata_2025 huggingface dataset:
Apatinib plus paclitaxel versus placebo plus paclitaxel as second-line therapy in patients with gastric cancer with peritoneal carcinomatosis: A double-blind, randomized phase II trial.
Authors: Wang Fenghua , Ren Chao , Xu Jianying , Wang Zhiqiang , He Ming-ming , Qiu Miaozhen , Jin Ying , Luo Huiyan , Wang Feng , Li Yuhong , Tan Qiong , Zhang Rong , Xu Ruihua
Published: June 2021

e16022

Background: Individuals with gastric cancer who present with peritoneal metastasis (PM) have poor prognosis. VEGF and VEGFR-2-mediated angiogenesis can increase vascular permeability, mesothelial cell permeability and promote peritoneal metastasis and ascites formation. This study assessed whether apatinib, a small-molecule VEGFR-2 tyrosine kinase inhibitor, in combination with paclitaxel would improve survival in patients with gastric cancer with PM as second-line therapy. Methods: This was a randomized, placebo-controlled, double-blind phase 2 trial. Recruitment of the trial was stopped after 44 patients due to poor accrual. Patients aged 18 years or older with gastric adenocarcinoma with PM and disease progression after first-line chemotherapy (platinum plus fluoropyrimidine) were randomly assigned in a 1:1 ratio to receive apatinib or placebo 500 mg oral once daily plus paclitaxel 80 mg/m2 intravenously on days 1, 8, and 15 of a 28-day cycle. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR), disease control rate (DCR) and safety profiles. Results: Between January 2017 and January 2019, 44 patients were randomly assigned to treatment (21 in Paclitaxel/apatinib group while 23 in Paclitaxel/placebo group). Median PFS was significantly longer in apatinib plus paclitaxel group than in placebo plus paclitaxel group (4.67 months [95% CI, 3.90 to 9.13 months] vs 4.07 months [95% CI, 1.93 to 5.00 months]; hazard ratio 0.46 [95% CI, 0.22 to 0.97]; P=0.037). There was no significant difference between the two groups in median OS (8.57 months vs. 9.03 months; P=0.85), ORR (19.0% vs. 4.3%; P=0.290) and DCR (76.2% vs. 52.2%, P=0.098). Apatinib group showed a higher incidence of proteinuria (38.1% vs. 4.3%; P=0.016), while no significant difference was found in the incidence of grade 3 or higher drug-related adverse events. Conclusions: Compared with placebo plus paclitaxel, the combination of apatinib with paclitaxel as second-line therapy significantly improved median PFS with an acceptable safety profile in patients with gastric cancer with peritoneal metastasis. Clinical trial information: NCT03144843. [Table: see text]
A nutritional management algorithm in older patients with locally advanced esophageal cancer.
Authors: Moy Ryan H. , Sabwa Shalom , Maron Steven Brad , Shcherba Marina , Apollo Arlyn J. , Janjigian Yelena Y. , Ku Geoffrey Yuyat , Tew William P. , Ilson David H. , Won Elizabeth
Published: June 2021

e16038

Background: Esophageal cancer primarily affects older adults, who are at highest risk for poor nutritional status due to medical comorbidities, physiological changes of aging and geriatric issues such as altered cognition and mobility. Malnutrition is correlated with poor outcomes in patients with esophageal cancer; however, standardized nutritional interventions are not commonly utilized. Therefore, we performed a feasibility study of a nutritional management algorithm with risk-based guidelines for older patients with esophageal cancer receiving chemoradiation (CRT). Methods: Elderly patients (age ≥ 65 years old) with locally advanced esophageal or gastroesophageal junction (GEJ) cancer receiving induction chemotherapy and preoperative or definitive CRT were eligible for enrollment on this single center study. Patients completed baseline nutritional assessment using the Mini Nutritional Assessment (MNA) screening scale, and patients who were at risk for malnutrition or malnourished were referred to a clinical dietician for evaluation and counseling. Nutritional status was reassessed after induction chemotherapy, and patients with severe malnutrition were to be referred for enteral feeding tube placement prior to CRT. The primary objective was to determine the feasibility of the nutritional management algorithm based on completion rates of nutritional assessment, clinical dietician referral and enteral feeding. Secondary endpoints included toxicity, functional status and quality of life assessment. Results: Twenty elderly patients with locally advanced esophageal cancer were enrolled, and fourteen patients met criteria for clinical dietitian referral based on poor baseline nutritional status. Induction chemotherapy was associated with improved dysphagia, with 92% of patients reporting improvement or resolution of symptoms. There were no patients who met criteria for enteral feeding prior to CRT based on the guidelines, and only one patient (5%) required feeding tube placement during CRT. In total, 17 patients (85%) completed the nutritional management algorithm and finished the planned treatment course. Rates of hospitalization, grade ≥2 esophagitis, grade ≥3 toxicity and early CRT discontinuation were similar between patients with normal and abnormal baseline nutrition. Conclusions: This study demonstrates that a risk-based nutritional management algorithm is feasible in elderly patients with esophageal cancer. The induction chemotherapy approach may ameliorate dysphagia, reduce the need for enteral feeding and facilitate CRT completion in this nutritionally vulnerable population. Clinical trial information: NCT02027948.
The efficacy and safety of toripalimab combined with definitive chemoradiotherapy for patients with locally advanced esophageal squamous cell carcinoma.
Authors: Xi Mian , Zhu Yujia , Li Qiao-Qiao , Zhao Lei , Yang Yadi , Hu Yonghong , Liu Mengzhong
Published: June 2021

e16043

Background: Definitive chemoradiotherapy (CRT) is the standard treatment option for unresectable locally advanced esophageal cancer. However, the loco-regional and distant recurrences after definitive CRT were as high as 50%. Immunotherapy targeting the PD-1/PD-L1 axis has demonstrated antitumor activity in advanced esophageal cancer. With the potential benefit of combining PD-1 blockade to CRT, we performed a phase II trial to evaluate the efficacy and safety of the combination of toripalimab (an anti-PD-1 antibody) and definitive CRT in locally advanced esophageal squamous cell carcinoma (ESCC). Methods: Patients with previously untreated, unresectable, stage II–IVA ESCC were enrolled. Patients received concurrent radiotherapy (50.4 Gy in 28 fractions), chemotherapy (weekly paclitaxel 50 mg/m2 and cisplatin 25 mg/m2 for 5 cycles), and toripalimab (240 mg, every 3 weeks until 12 months or disease progression). The primary endpoint was clinical complete response (cCR) rate at 3 months after CRT according to PET-CT scan and esophagogastroduodenoscopy with biopsies. Second endpoints were overall survival (OS), progression-free survival (PFS), adverse events (AEs). Exploratory endpoints included PD-L1 expression, tumor mutational burden, and genetic biomarkers as potential efficacy predictors. Results: Between November 2019 and December 2020, 42 eligible patients (2 stage II, 19 stage III, and 21 stage IVA) were included. Of them, 39 completed CRT and 3 remained under treatment. Twenty-eight patients were included for efficacy analysis (median follow-up: 7.2 months) and 42 for safety analysis (median follow-up: 5.8 months). The cCR rate was 60.7% (17/28) and the median OS and PFS were not reached. Thirty-nine patients (92.9%) had AEs, 20 patients (47.6%) experienced grade ≥3 AEs, and 1 patient (2.4%) suffered grade 5 esophageal fistula. The most common grade ≥3 AEs were lymphopenia (45.2%), neutropenia (33.3%), and anemia (28.6%), respectively. Conclusions: The addition of toripalimab to definitive CRT for locally advanced ESCC demonstrated encouraging efficacy and acceptable toxicity. The exploratory endpoints including PD-L1 expression and genetic biomarkers analyses are ongoing. Clinical trial information: NCT04005170.
Irradiated esophageal squamous cell carcinoma cells induced the increase of Treg by TGF-beta.
Authors: Wang Yuan , Li Tao , Lv Jiahua , Xiao Ling
Published: June 2021

e16092

Background: The infiltration of CD4+CD25+Foxp3+ regulatory T cells (Treg) in the tumor microenvironment is one of the main reasons for radiation resistance and tumor recurrence after radiotherapy. It has been established that Treg is more resistant to radiation than other T cells, but the proliferation of immune cells after radiotherapy is affected by other factors, including tumor cells. Treg frequency in the tumor microenvironment after radiotherapy has not been defined. We studied the effect and mechanism of esophageal squamous cell carcinoma on Treg cells after radiation. Methods: After 2Gy irradiation, TE-1 cells were co-cultured with normal peripheral blood lymphocytes for 48 hours. Flow cytometry was used to detect Treg/CD4+T cell frequency. The mRNA expression of TGF-β1/2 in TE-1 was detected by qPCR, and the protein content of TGF-β1/2 in the medium was detected by ELISA. Results: Compared with non-irradiation group, the expression of TGF-β1 and TGF-β2 in TE-1 cells of irradiation group increased, and the protein content of TGF-β1 and TGF-β2 in culture medium increased, the difference was statistically significant(P < 0.001). Flow cytometry showed that CD4+CD25+/CD4+Tcell and CD4+CD25+Foxp3+/CD4+Tcell were increased in the radiotherapy group after co-culture, and the difference was statistically significant(P < 0.001). Conclusions: The expression of TGF-β1 and TGF-β1 in esophageal squamous cell carcinoma cells increased after irradiation, and the frequency of Treg induced by co-culture increased, suggesting that esophageal squamous cell carcinoma cells after radiotherapy can induce the increase of Treg cells, which may be achieved mainly through the mechanism of increasing the secretion of TGF-β1/2.
Sensitive and dynamic CTCs measurement for prediction and monitoring of PD-1 therapy in GC/EGJC patients: Results from a pilot phase 2 study.
Authors: Wei Qing , Qi Xu , Chen Lei , Yang Yanlian , Li Yankun , Hu Zhiyuan , Ying Jieer , Luo Cong , Jingjing Li
Published: June 2021

e16094

Background: Programmed death-ligand 1 (PD-L1) expression is currently being explored as a predictive biomarker for anti-PD-1antibody treatment in patients with advanced gastric or esophagogastric junction cancer (GC/EGJC) patients. Circulating tumor cells (CTCs) can be collected non-invasively and sequentially, and may allow real-time monitoring of immune activation in tumor. The aim of this study was to investigate whether PD-L1 expression on CTCs can accurately represent tumor PD-L1 expression and the potential of CTCs as a companion diagnosis (CDx) biomarker. Methods: We evaluated the CTCs counts and PD-L1 status on CTCs during treatment in a phase 2 clinical trial, where patients with previously treated gastric cancer received JS001 in combination with Apatinib. The multi-center trial was registered with ClinicalTrials.gov, number NCT04190745. Blood samples were collected from patients. Sixteen patients with GC were analyzed to investigate the association between clinical outcome and changes of CTC counts pre and post JS001 plus Apatinib. The correlation between the binary clinical outcome (SD/PR/CR vs. PD) and the change in CTCs counts pre and post treatment was analyzed using a logistic regression adjusting for baseline CTCs counts. PD-L1 expression on CTCs were analyzed to determine whether they were in accordance with tissue biopsy. Results: CTCs were detected in all the patients (16/16，100%) ranging from 1 to 33 CTCs/ml. PD-L1+ CTCs were detected in 12 of 16 patients (75%) ranging from 1 to 5 PD-L1 + CTCs/ml. PD-L1 expression in tumor tissue was positive in 11 of 13 patients (84.6%, positive means CPS > = 1), the sensitivity of PD-L1+ CTCs is 90.9% (10/11) if using biopsy as gold standard. The only false negative patient though with CPS 40%, got no benefit from immunotherapy. The specificity of PD-L1+ CTCs detection is 100%, and the accuracy is 90.9%. Overall response rate of this regimen is 26.6% (4/15). Disease control rate is 53.3% (8/15). Progression free survival (PFS) was 2.43 months in all the evaluable patients. However, patients with PD-L1+ CTCs had a longer PFS compared to patients without PD-L1+ CTC (3.30months vs 1.37months, p = 0.001). Overall Survival is not reached. Change of CTCs counts after treatment was significantly correlated with clinical response (p = 0.024). The logistic model McFadden goodness of fit score was 0.435, which is a strong correlation value. Notably, one of the patients who had pseudo-progression shows remarked decreased CTCs count. Conclusions: Our results reveal the potential of CTCs as a noninvasive CDx biomarker in patients with advanced GC/EGJC.
Genomic profiling of Chinese esophageal squamous cell carcinoma patients and difference of genomic mutation between Chinese and American cohorts.
Authors: Li Lin , Wang Kefeng , Tan Binghua , Lyu Yingcheng , He Xiaotian , Wang Wenjian , Hu Xueting , Wu Duoguang , Lin Huayue , Wang Minghui
Published: June 2021

e16108

Background: Esophageal squamous cell carcinoma (ESCC) remains an aggressive malignancy and most patients are diagnosed at advantage stage with limited treatments. Large amount of evidence has demonstrated that immune biomarkers such as PD-l/PD-L1 and tumor mutational burden (TMB) are associated with clinical outcomes and disease prognosis. Methods: A total of 475 ECSS patients enrolled in this study. Deep sequencing of 450 cancer genes performed on formalin-fixed paraffin-embedded tumor tissues and matched blood. Results: Genomic mutation landscape indicated the top five mutated genes are TP53 (95.0%), CCND1 (42%), FGF3 (42%), FGF19 (41%), FGF4（41%. We found that CCHD2, FOXL2 and PIK3CA were tumor-driver genes in 475 ECSS patients. BCL6 ( p< 0.02), CCND1 ( p< 0.03), FGF12 ( p< 0.04), FGF19 ( p< 0.04), FGF3 ( p< 0.02) and FGF4 ( p< 0.05) mutations are significantly associated with high expression of PD-L1 Moreover, we found that BCL6 ( p< 0.04), BRD4 ( p< 0.03), EP300 ( p< 0.03), HGF ( p< 0.02), KMT2C ( p< 0.005), KMT2D ( p< 0.04), MET ( p< 0.006), NSD1 ( p< 0.04), PBRM1 ( p< 0.003), PTCH1 ( p< 0.01), SPEN ( p< 0.006), SPTA ( p< 0.02), ZHF750 ( p< 0.004), TP53 ( p< 0.01) mutation are significantly associated with high TMB as well. The cutoff for TMB is set for 6.9 mut/Mb. The target gene analysis indicated that over half of Chinese ECSS patient might benefit from gene target therapy. By comparison between Chinese and TCGA cohorts, EBFR ( p< 0.05), FGRF1 ( p< 0.05) and CDKN2A ( p< 0.001) have significantly mutated frequency, which indicated the gene mutated profiling is significantly different between Chinese and American ECSS patients. Conclusions: This study identified certain gene alteration associated with PD-L1 and TMB status. It is necessary to conduct large clinical study to identify biomarker for evaluation the efficacy of novel adjunct immunochemotherapy.
Novel systemic therapies in the treatment of fibrolamellar carcinoma.
Authors: Gottlieb Sara , Gliksberg Ariel , Schadde Erik , Kent Paul
Published: June 2021

e16161

Background: Fibrolamellar carcinoma (FLC) is an exceedingly rare liver cancer affecting children and young adults without underlying liver disease. Complete surgical resection is the primary treatment option, but recurrence is common. There are currently no established systemic therapies. We have treated patients in both the neoadjuvant and adjuvant setting with three novel combination therapies: 5-fluorouracil/interferon/nivolumab (“Triple Therapy” or TT), gemcitabine/oxaliplatin/lenvatinib (GOL), and nivolumab/lenvatinib/quercetin (NLQ). The purpose of this study was to evaluate objective responses and tolerability of three multi-agent systemic therapies in the treatment of FLC. Methods: Data from all patients with FLC who received TT, GOL, or NLQ between May 2018 and February 2021 were reviewed. Patients who received a minimum of six cycles of systemic therapy with follow up scans at least two months after initiation were assessed based on objective response, survival, and toxicity. Results: Twenty-nine patients with FLC who were treated with novel multi-agent systemic therapy were evaluable based on the above criteria. Median age at start of treatment was 20 (7-52; 16F, 12M, 1 non-disclosed). Twenty-three patients received one combination therapy (13 TT, 8 GOL, 2 NLQ), five received two different lines (3 TT/NLQ, 2 TT/GOL), and one patient received all three novel combinations. Between our 29 patients, they had relapsed 36 total times, and 11 had already tried 2+ systemic therapies. Best RECIST 1.1 objective response (clinical remission + partial response) and tumor control rate (clinical remission + partial response + stable disease) were 58%/95%, 55%/100%, and 33%/83% for TT, GOL, and NLQ respectively. The median longest Progression Free Survival (PFS) on any novel multi-agent regimen was 9 months (2-29; 9.5 for TT, 7 for GOL, 6.5 for NLQ), with 18 patients still receiving the therapy extending their PFS. Of those with previous relapses, 56% have a PFS longer than their previous longest remission and 69% have a PFS longer than their previous shortest time to relapse. Half of patients with previous relapses are still receiving the treatment responsible for their longest PFS. Fever, chills, and nausea were the most common adverse effects experienced throughout all three regimens. Seven patients experienced 1+ grade 3 adverse event. There were no toxic deaths or organ failure. Two patients died as a result of disease; their longest PFS (1 on GOL, 1 on TT) were nine and 10 months. Conclusions: FLC is a devastating cancer with patients often relapsing even after successful surgical remission. There is a strong need for effective and tolerable systemic therapies for those with unresectable, relapsed, progressive, or metastatic disease. We have had promising results in treating FLC and prolonging survival with minimal toxicities using novel multi-agent regimens.
Toripalimab with chemotherapy as first-line treatment for advanced biliary tract tumors: Update analytic results of an open-label phase II clinical study (JS001-ZS-BC001).
Authors: Li Wei , Yu Yiyi , Xu Xiaojing , Guo Xi , Wang Yueqi , Li Qian , Wang Yan , Cui Yuehong , Liu Houbao , Hao Qing , Qu Yueting , Huang Lujia , Liu Tianshu
Published: June 2021

e16170

Background: A phase II clinical study was conducted to evaluate the safety and efficacy of toripalimab, a novel PD-1 inhibitor, combined with chemotherapy in patients with advanced biliary tract cancers (aBTCs) (NCT03796429). The preliminary results indicated the combination treatment is well tolerable and effective. Methods: Treatment naive patients with aBTCs received toripalimab (240mg intravenously every three weeks) combined with chemotherapy (gemcitabine 1000 mg/m2 d1, d8 + S-1 40-60mg bid D1-14, Q21d). The treatment continued until the disease progress or having intolerable effects. The primary endpoints of the study were progression free survival (PFS) and overall survival (OS). The secondary endpoints were objective response rate (ORR), safety and treatment biomarkers. Results: At data cutoff (January 24, 2021), fifty aBTC patients were enrolled at Shanghai Zhongshan Hospital. Among these patients, 56% are males. The median age of the study participants was 62 years of age. The median follow-up time was 10 months (ranged from 4 to 19 months). The primary tumor type was intrahepatic cholangiocarcinoma (ICC) accounting for 48% of total cases, followed by gallbladder cancer (GBC) (40.0%), and extrahepatic cholangiocarcinoma (ECC) (12.0%). At the time of data collection, 48 eligible patients were included for data analysis. The median PFS was 7.0 months（95%CI, 5.5-9.1 months）and median OS was 16.0 months (95%CI, 12.1 to unreachable). The ORR was 27.1 % and disease control rate was 87.5% including 13 partial response (PR) and 29 stable disease (SD) cases. The most treatment related AEs (TRAE) were leukopenia (92.0%), anemia (86.0%) and rash (52.0%). Grade III/IV non-hematological TRAEs were seen in 12 patients (24.0%), including rash (n = 3), infection (n = 6), immune-related colitis (n = 1), immune-related pneumonitis (n = 1) and mucositis (n = 1). Grade III/IV hematological TRAEs were seen in 62% patients. 6 patients discontinued the study drug due to TRAE. Serious adverse events (SAE) were seen in 8 patients and 2 patients died of biliary obstruction complicated with infection. Forty-nine patients were included in biomarker analysis. The most mutated genes were TP53 (51%), KRAS (20%), CDKN2A (18%) and SMAD4 (16%). Patients with activated PI3K signaling pathway had significantly shorter PFS (P = 0.026). Tumor mutational burden (TMB) could not serve as a predictor for the efficacy of immunotherapy combined with chemotherapy. Conclusions: The clinical study of toripalimab combined with chemotherapy continued to show tolerance and efficacy in patients with aBTCs. Gene mutation profiling by NGS suggested mutated PI3K pathway might assocate with shorter PFS. Clinical trial information: NCT03796429.
Association between antibiotic exposure and survival in patients with hepatocellular carcinoma treated with nivolumab.
Authors: Alshammari Kanan , Alsugheir Futoon , Aldawoud Mohammad , Alolayan Ashwaq , Algarni Mohammad Ahmad , Sabatin Fouad , Mohammad Mohammad F. , Alosaimi Abdulaziz , Sanai Faisal , Odah Hassan , Alshehry Ahmed , Aldibasi Omar , Al Saleh Abdullah S , Jazieh Abdul-Rahman
Published: June 2021

e16186

Background: Nivolumab, an immune checkpoint inhibitor, has improved the outcomes of patients with hepatocellular carcinoma (HCC). It is approved for HCC patients previously treated with sorafenib. Outcomes have been reported in previous studies, in malignancies other than HCC, to be worse when patients have been exposed to antibiotics while receiving immune checkpoint inhibitors. We aimed to evaluate the effects of antibiotics on survival in HCC patients treated with nivolumab. Methods: We performed a retrospective review of 59 patients with advanced HCC that have been treated with nivolumab in two academic centers in Saudi Arabia. Patient characteristics, tumor data, antibiotic use (2 weeks prior, during, and 4 weeks after nivolumab therapy), survival data, and other factors were collected. Log-rank test analysis was performed to test the difference in overall survival (OS) time with and without antibiotics use. Results: The majority of patients were males (n=51, 85%), and 38 were Child-Pugh A (64%). A large number of patients had Barcelona Clinic Liver Cancer (BCLC) stage C tumors (n=42, 71%), and 20 patients (34%) used antibiotics. Most patients received nivolumab as second-line therapy after exposure to sorafenib (n=49, 83%). In patients who received nivolumab as first- or second-line therapy (n=57) and did not receive antibiotics, the median OS was double that of patients who received antibiotics (10 vs. 4.5 months, P=0.04). In child A patients who received nivolumab as second-line therapy (n=32), those who were exposed to antibiotics had a statistically significant shorter median OS compared to those who did not (5.5 vs. 20 months, P=0.04). More patients achieved partial response, or complete response (as per modified RECIST criteria) in the cohort that did not receive antibiotics compared to patients who received antibiotics (21% vs. 15%) but that was not statistically significant (P=0.6). Conclusions: This study shows that HCC patients receiving nivolumab have worse survival if they received antibiotics. Antibiotic mediated alteration of the gut microbiome may impact nivolumab response and shorten patient survival. Although this finding may warrant a prospective larger study but it is consistent with other previous studies. Antibiotics should be used very cautiously when treatment with checkpoint inhibitors is considered.
Molecular profiling of pancreatic neuroendocrine neoplasms (panNENs): A single-institution experience.
Authors: Azar Ibrahim , Yazdanpanah Omid , Bongu Shiva Swaroop , Al Hallak Mohammed Najeeb , Korn W. Michael , Shields Anthony Frank , Philip Philip Agop
Published: June 2021

e16207

Background: PanNENs are rare with a heterogeneous pathophysiology and widely differing clinical course. Despite a recent update of the grading system, prognostication and prediction of response to therapy remain challenging. Somatostatin receptor aside, there are currently no predictive biomarkers or targeted agents for panNENs. Molecular profiling offers an opportunity to develop new drugs and personalize treatments. Methods: We compiled data from patients diagnosed with panNENs from Karmanos Cancer Institute between 2014 and 2020. Of the 35 patients with panNENs, 33 underwent Next Generation Sequencing (Caris Molecular Intelligence). Two tumor biopsies were insufficient for molecular analysis. Results: Of the 35 tumors analyzed, 11 were grade 1, 18 were G2, 2 were well-differentiated G3 and 4 were poorly differentiated pancreatic neuroendocrine carcinomas (panNEC). Median age at diagnosis was 61. 21 patients identified as White, 6 as Black and 8 as other. 21 were men. 28 patients were metastatic at diagnosis. The most frequently detected molecular alteration was MEN1 mutations (11 G1, 1 G1 and 1 G3). 3 G2 and 2 G3 tumors expressed PTEN mutations. All 3 p53 mutations were G3, 2 of them panNEC. An FGFR3 amplification was detected in a single G1 panNEN. Her2/Neu amplification was detected in a G2 tumor. Other frequent alterations were MGMT (4), TOP2A (4), ARID1A (3), TUBB3 (3) and TSC2 (3). 3 tumors were PD-L1 positive. All tumors were TMB non-high and MMR-proficient. Conclusions: Molecular profiling of panNEN can detect targetable alterations with currently validated commercial agents. panNENs are immunologically cold. Further genomic and epigenomic profiling studies can help understand the molecular underpinnings of pathophysiology and aid in the development of biology-driven targeted therapies.
Clinical performance of blood-based RNA signatures (GemciTest) for the gemcitabine response in advanced pancreatic cancer.
Authors: Piquemal David , Bruno Roman , Noguier Florian , Pierrat Fabien , Gamez Amelia , Cros Jerome , LoConte Noelle K. ,   BACAP and GemciPANC Consortia
Published: June 2021

e16238

Background: Pancreatic ductal adenocarcinoma (PDAC) is highly lethal often presents at a later stage. Gemcitabine is still an important component in PDAC treatment however there is no routine biomarker to predict its efficacy. We had previously performed a discovery cohort of two separate RNA-blood signatures in 60 patients (NCT00789633) showing an association with PFS and OS. Called GemciTest, this CE-IVD molecular test requires 2.5ml whole blood sample before starting the patient's 1st line chemotherapy. From this liquid biopsy, IVD measures the expression levels of nine genes using real-time PCR processes. This abstract presents the clinical validation of GemciTest. Methods: In this study, clinical validations were done on 214 patients (mean 68.7-year-old; 37-88) from 3 distinct cohorts with the University of Wisconsin Biobank, GemciPANC trial (NCT03599154), and BACAP (NCT02818829). These cohorts included first-line treatment,with either a gemcitabine or fluoropyrimidine based regimen. Results: Patients with a clinical benefit response identified by GemciTest (31.5%) had a significantly longer progression free survival (PFS) (5.4 months vs. 3.1 months p = 0.0032) and a longer overall survival (OS) (13.1 months vs. 5.4, p < 0.0003). In multivariate analyses including tumor localization and performance status, this signature continued to be associated with PFS (HR = 0.52 (0.34–0.81) p = 0.003) and OS (HR = 0.44 (0.28 – 0.69) p = 0.0002).Conclusions: GemciTest validation was performed, showing a strong association with PFS and OS.[Table: see text]
Real-world treatment and outcomes of frontline chemotherapy in patients with metastatic pancreatic cancer.
Authors: Al Mutar Salwan , Beg Muhammad Shaalan , Hansen Eric , Belli Andrew J. , Vaz Maegan , Velamoor Sudhakar , He Ming , Wang Ching-Kun
Published: June 2021

e16249

Background: The difference between the FOLFIRINOX and gemcitabine/nab-paclitaxel (GnP) regimens’ clinical trial designs limit the ability to generate cross-study comparisons. Therefore, there is a significant need to understand the impact of various demographic and clinical characteristics on the effectiveness of these systemic therapies in the real-world treatment setting. This study seeks to compare the real-world outcomes of patients with metastatic pancreatic cancer treated with frontline FOLFIRINOX or GnP. Methods: Patients with primary metastatic pancreatic cancer who received first-line (1L) FOLFIRINOX or GnP were identified in the COTA real-world database. The COTA database is a de-identified database of real-world data (RWD) derived from the electronic health records of healthcare providers in the United States. Real-world overall response rate (rwORR) was calculated as the proportion of patients achieving complete response (CR) or partial response (PR). Overall survival (OS) was calculated using the Kaplan-Meier method and multivariate analyses utilized Cox proportional hazards. Results: The overall qualified cohort (n=236) was stratified by 1L FOLFIRINOX (n=109) or GnP (n=127). Select patient characteristics are shown in table. Patients treated with 1L FOLFIRINOX showed greater rwORR as compared to those treated with GnP (68.8% vs. 55.9%, p=0.04). Additionally, patients treated with 1L FOLFIRINOX had longer median OS (14.4 vs 11.4 mos, respectively). In univariate analysis, patients treated with GnP had a greater chance of mortality (HR: 1.3, 95% CI: 1.0, 1.8, p=0.05). This relationship strengthened in multivariate analysis (GnP treated HR: 1.6, 95% CI: 1.1, 2.1, p=0.01). Conclusions: Due to lack of enrollment of representative patients in clinical trials and in the absence of a comparative clinical trial, real-world experience with chemotherapy regimens provide critical insights on the outcome of treatments. In our cohort, patients treated with frontline GnP had a significantly greater chance of mortality as compared to patients treated with frontline FOLFIRINOX. The FOLFIRINOX cohort also showed greater rwORR. Future research will continue to expand on treatment patterns in subsequent lines of therapy, as well as emerging therapy types, in order to better understand the optimal treatment sequence in metastatic pancreatic cancer.[Table: see text]
Gasdermin C as a potential prognostic biomarker and its correlation with immune infiltration in pancreatic ductal adenocarcinoma.
Authors: Xia Xianghou , Yu Yang , Yang Hongjian , Zou Dehong , Wang Canming , Hu Jiejie , Mao Jiefei , Cai Xixi , Yin Wenjuan
Published: June 2021

e16256

Background: Although pyroptosis is critical for macrophages against pathogen infection, its role in cancer cells remains elusive. GSDMC is a pyroptosis executioner newly identified in cancer cells and have been shown to facilitate inflammatory tumor death. However, the expression of GSDMC in Pancreatic Ductal Adenocarcinoma (PDAC), its prognostic significance and possible impact on reshaping tumor immune microenviroment in PDAC is still unknown. Methods: We investigated the expression level of GSDMC using TNM plotter with TCGA and GTEx databases, the prognostic value of GSDMC in PDAC using Kaplan-Meier plotter with TCGA, GTEx and TCGA databases. The correlations between GSDMC and immune infiltration in PDAC were calculated using TIMER2.0 and TIDE with TCGA database. We further validated the prognostic value of GSDMC with immunohistochemistry(IHC) staining on a tissue microarray of 172 cases of PDAC patients receiving treatment in our institution. Correlations between expression of GSDMC and tumor infiltration lymphacytes(TILs) cells were also analyzed on tissue samples of those 172 PDAC patients. Results: TNM plotter analysis shows that the expression of GSDMC in PDAC tumor tissue is 10.49 folds higher than it is in pancreatic normal tissues (p = 8.86*e-56). Results from Kaplan-Meier plotter analysis shows high expression of GSDMC is significantly correlated with poorer overall survival(OS), HR = 1.8(1.19−2.71) logrank P = 0.004 and shorter relapse free survival (RFS), HR = 4.6(1.94−10.88), Logrank P = 0.00014 in PDAC. Analysis with TIMER2.0 and TIDE platform shows that expression of GSDMC is positively correlated with immunosuppressive cells, Cancer Associated Fiberblast (CAF) and Meyloid Derived Tumor Suprresso Cells(MDTSC). IHC staining analysis results is also consistent with aformentioned bioinformatic analysis, showing that high GSDMC expression correlated with shorter OS and reduced Tils infiltration. Conclusions: Our findings suggest that high expression of GSDMC is related to poor prognosis and compromised immune cell infiltration in PDAC. GSDMC holds promise for serving as a valuable prognostic marker and therapeutic target in PDAC.
Association of FGFR alterations with FGFR 1-4 gene expression in TUR biopsies and matched NMP22 urine levels in early bladder cancer of the prospective real world clinico-pathological register trial: BRIDGister.
Authors: Wirtz Ralph M. , Friedersdorff Frank , Veltrup Elke , Kilic Ergin , Watts Richard , Kellner Ronny , Hake Roland , Eidt Sebastian , Roggisch Jenny , Koch Stefan , Ecke Thorsten
Published: June 2021

e16533

Background: The objective of the present study was to identify molecular charactersitics associated with FGFR positive tumors in matched urine and TUR biopsy samples from patients being suspicious of bladder cancer and undergoing first TURB at the pilot center of the multicentric BRIDGister Real World Experience trial that are helpful for patient management and prognosis. Methods: For this pilot study paraffin fixed pretreatment tissue samples from the first TURB of 28 pts participating in the BRIDGister trial and matched urine samples were prospectively collected and analyzed. RNA from FFPE tissues were extracted by commercial kits and analyzed by Therascreen FGFR IVD kit (Qiagen GmbH, Hilden). Relative gene expression of subtyping markers (KRT5, KRT0) as well as FGFR1, FGFR2, FGFR3, FGFR4, ERBB2 was centrally tested by standardized test systems (STRATIFYER Molecular Pathology GmbH, Cologne). In addition urine samples were analyzed by commercially available urine tests (UBC Rapid, BTA stat, NMP22). Spearman correlation, Kruskal-Wallis, MannWhitney and Sensitivity/Specificity tests were done by JMP 9.0.0 (SAS software). Results: The pilot cohort of the BRIDGister trial consisted of 28 patients (median age: 73, male 71% vs female 29%) of diverse clinical stages (Benign lesions/no tumor 21%, pTa 32%, pT1 21%, pT2 21%) and WHO 1973 grade (G1 7%, G2 43%, G3 21%). Based on FFPE tissue testing using Therascreen FGFR IVD kit 9 out of 28 patients exhibited FGFR alterations (32%). FGFR positive tumors were associated with high expression of FGFR3 mRNA (r = 5.951, p = 0.0011) but low FGFR1 mRNA as well as FGFR4 mRNA (r = -0.3882, p = 0.0412 and r = -0.6305, p = 0.0004, respectively). Interestingly, FGFR alteration was positively associated with the basal marker KRT5 (r = 0.3929, p = 0.0386), but not with luminal KRT20 mRNA expression (r = -0.0208, p = 0.9179). Moreover FGFR3 altered bladder cancer was associated with elevated NMP22 levels in pretreatment urine (r = 0.3978, p = 0.0361). Conclusions: In early bladder cancer FGFR3 alterations are tightly associated with a characteristic FGFR mRNA signature. Mutation/Fusion of FGFR3 results in high FGFR3 but low FGFR1 and FGFR4 mRNA expression, which might be i.a. relevant for the response to FGFR inhibition and important to predict outcome of FGFR inhibitors. Morever FGFR alteration was associated with elevated NMP22 urine levels, which might be helpful for detecting and monitoring FGFR altered bladder cancer in a non invasive fashion. These results warrant further investigation and its impact on outcome prediction (BCG responsiveness, recurrence, proegression, etc) will be prospectively analyzed in the framework of the ongoing multicenter BRIDGister Real World Experience trial.
Comparative effectiveness of combination first-line therapies for metastatic renal cell carcinoma (mRCC).
Authors: Shay Rebecca C. , Nicklawsky Andrew , Lam Elaine Tat
Published: June 2021

e16549

Background: Numerous immunotherapy (IO) and vascular endothelial growth factor receptor inhibitors (VEGFI) options are approved for first-line (1L) treatment of mRCC. We performed a systematic review and meta-analysis to compare the oncologic outcomes and adverse events of these therapies. Methods: We searched databases for randomized controlled trials (RCT) evaluating agents that are currently FDA-approved or on the NCCN compendium for 1L mRCC, with sunitinib (S) as a comparator. Primary outcomes were overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and grade 3 and 4 (G3/G4) adverse events (AEs). We attempted network meta-analysis (NMA) to estimate relative effects of the comparative treatments. Survival outcomes were summarized using hazard ratios (HR). In the case that the HR was not reported but a Kaplan-Meier curve was available, the curve was digitized using Engauge Digitizer software. A frequentist fixed-effects NMA model was applied to each outcome. Results: 798 articles were identified, of which 47 were eligible for full text screening, and 8 were included for evidence synthesis. Eight RCTs recruiting a total of 5,565 pts with advanced or metastatic treatment-naïve RCC were included. The summary of all included studies is reported in Table 1. Ordered from the most to least effective, treatments with greatest mOS benefit include Nivolumab plus Cabozantinib (NC), Pembrolizumab plus Axitinib (PA), and Nivolumab plus Ipilimumab (NI); treatments with greatest mPFS benefit include Cabozantinib (C), NC, and Avelumab plus Axitinib (AA); treatments with the highest ORR include C, NC, and AA. Ordered from least to most toxic, treatments with G3/G4 AEs less frequent than sunitinib include Pazopanib (P), NI, and AA. Conclusions: OS generally favored IO-IO or IO-VEGFI combinations, while PFS and ORR favored single agent C or IO-VEGFI. The lowest risks of G3/G4 AE were seen with P or IO-IO. IO-VEGFI combinations had similar risks for G3/G4 AE. Longer real-world follow-up is needed. We recognize the limitations of cross-trial comparisons, but sought a summative view of the current data.[Table: see text]
Baseline neutrophil-to-eosinophil ratio (NER) and its association with clinical outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (CPI).
Authors: Ravindranathan Deepak , Liu Yuan , Martini Dylan J. , Brown Jacqueline T , Nazha Bassel , Russler Greta , Yantorni Lauren Beth , Caulfield Sarah , Carthon Bradley Curtis , Kucuk Omer , Master Viraj A. , Bilen Mehmet Asim
Published: June 2021

e16569

Background: Inflammatory markers have been studied as prognostic markers in patients with mRCC treated with CPIs. Recently, eosinophilia has been found to be associated with improved survival of patients with melanoma treated with CPIs. We reported baseline NER in patients with mRCC treated with CPIs and its association with clinical outcomes. Methods: We conducted a retrospective analysis of patients with mRCC treated with CPIs at Winship Cancer Institute from 2015-2018. Clinical outcomes were measured as overall survival (OS), progression-free survival (PFS), and clinical benefit (CB). OS and PFS were calculated from CPI-initiation to date of death and radiographic or clinical progression, respectively. Patients with baseline NER were categorized into high or low; high defined as NER > 49.2 and low defined as NER < 49.2. Univariate (UVA) and multivariate (MVA) analyses were carried out for OS and PFS using Cox proportional hazard model. Results: A total of 184 patients were studied with a median follow up of 25.4 months. Median age was 63 years old with 72% male and 20% black. About 25% were in high NER group. The high NER patients had significantly shorter OS in both UVA (HR: 0.58, p-value=0.017) and MVA (HR: 0.62, p-value=0.046) (Table). There was no significant difference between groups for PFS. Clinical benefit was seen in 47.3% of patients with low baseline NER and 40% with high NER. Conclusions: High baseline NER was associated with worse OS in patients with mRCC treated with CPIs. Larger, prospective studies are warranted to validate this hypothesis generating data.[Table: see text]
Value of cabozantinib in the treatment of advanced metastatic clear cell renal cell carcinoma (ccRCC): Real-world data from a single Korean institution.
Authors: Lee Seoyoung , Kim Seul-Gi , Park Sejung , Lee Jeehyun , Beom Seung-Hoon , Shin Sang Joon , Rha Sun Young
Published: June 2021

e16578

Background: Cabozantinib is a multitarget tyrosine kinase inhibitor and getting attention in these days through its combination with immune checkpoint inhibitors. In this article, we analyze the efficacy of cabozantinib in patients with metastatic ccRCC in Korean who had progression after 1 or more VEGFR TKI therapies. Methods: Seventy-five patients from Jan.2019 to Dec. 2021 at Yonsei Cancer Center who had received cabozantinib treatment in second to fourth line of therapy were retrospectively reviewed. The primary endpoint was PFS. The secondary outcomes were the response rate, disease control rate (DCR), and OS. The evaluable subjects for efficacy were those who had at least one response evaluation. Results: Among 75 patients, 57 (76.0%) were male and median age was 59 years (range 33-81). Median follow up time was 12.1 months. There were 22 (29.3%) patients of second line, 38 (50.7%) of third line and 15 (20.0%) of fourth line of treatment. Median PFS was 5.6 months (95% CI, 4.6-6.6). Median OS was 13.6 months (95% CI, 5.0-22.2). The PFS based on the line of treatment was 4.7 months for second line, 5.6 months for third line and 12.0 months for 4th line. Proportion of patients who were previously treated with ICI was different between treatment line groups and showed increasing trend toward later line; 13.6% of second line, 31.6% of third line, and 66.7% of fourth line, respectively. The objective response rate was 8.0% with 6 patients of partial response. The DCR was 69.3%. The major toxicities were similar with the western population and most of them were less than CTCAE grade 3. Most common grade 3 or 4 AEs were anemia, hand-foot syndrome, fatigue, and stomatitis. There were no grade 5 AEs. Conclusions: Our results demonstrate that cabozantinib is an effective treatment option after first line TKI in Korean ccRCC patients with manageable toxicities. Notably, its tolerability in the advanced line of treatment and synergy with ICIs are suggested in this study despite heterogeneous patients of real world setting. This is the first real world data with cabozantinib in Asian patients.
Clonal hematopoiesis in prostate cancer inferred from somatic tumor profiling.
Authors: Marshall Catherine Handy , Holler Albert E , Tsai Hua-Ling , Gondek Lukasz , Luo Jun , Antonarakis Emmanuel S.
Published: June 2021

e17001

Background: Clonal hematopoiesis (CH) is a process associated with normal aging and may complicate the interpretation of liquid-biopsy genomic testing in oncology. Little is known about the prevalence of CH in prostate cancer as detected on somatic tumor profiling, or its association with clinical parameters and outcomes in prostate cancer. We sought to estimate the prevalence and clinical characteristics of patients with CH identified from tissue-based prostate cancer specimens. Methods: This was a retrospective study of men with prostate adenocarcinoma who underwent clinical somatic tissue-based next-generation sequencing using commercial platforms (n = 364). Patients with known hematologic malignancies (n = 7), and those with only liquid biopsies were excluded (n = 34), leaving 323 cases. Classical CH mutations were defined as those in DNMT3A, TET2 or ASXL1. Additional CH mutations included were defined as those in BCORL1, GNAS, SF3B1, JAK2 or PPM1D. Chi-squared tests were used to compare prevalence by categorical variables, Kruskal-Wallis tests to compare means across groups, and Cox proportional hazards were used for time-to-event analyses. Results: The prevalence of CH mutations in prostate cancer was 9% (30/323), and the prevalence of classical CH mutations was 7% (22/323)(Table). The most common mutations were in DNMT3A (n = 9), TET2 (n = 8) and ASXL1 (n = 5); other less common CH alterations were in GNAS and SF3B1 (n = 3 each), followed by CBL and JAK2 (n = 1 each). The most common site of tumor biopsy was the prostate (N = 266) followed by visceral (n = 19) and lymph node (N = 19) metastases. Men with any CH mutation were not significantly older at age of prostate cancer diagnosis (64 vs 62 years; p = 0.19) than those without; however, men with classical CH mutations were statistically older at diagnosis than those without (66 vs 62 years; p = 0.04). There was no difference in prevalence of CH mutations by Gleason sum (P = 0.67). Among men with localized disease at diagnosis, the median metastasis-free survival was 3.9 years in those with overall CH mutations and 6.6 years in those without CH mutations (HR [adjusted for age and Gleason] 1.3; 95% CI 0.7-2.3; p = 0.4). OS from the time of diagnosis to death was also numerically shorter in those with any CH mutation (median 9.7 years in those with and 14.2 years in those without CH mutations; HR 1.2, 95% CI 0.6-2.5; p = 0.6). Conclusions: CH can be detected in about 7-9% of prostate cancer patients from tissue-based tumor samples, is associated with older age, and may be linked to adverse oncological outcomes. The prognostic impact of CH in the context of specific systemic therapies (hormonal, chemotherapeutic) remains to be elucidated.[Table: see text]
Phase II study of gemcitabine, carboplatin and veliparib in multiple relapsed/refractory germ cell tumors (GCTs).
Authors: Mego Michal , Svetlovska Daniela , Reckova Maria , Kalavska Katarina , Obertova Jana , Palacka Patrik , Rejlekova Katarina , De Angelis Valentina , Sycova-Mila Zuzana , Chovanec Michal , Mardiak Jozef
Published: June 2021

e17009

Background: GCTs represent a model for the cure of cancer. Nonetheless, a small proportion of patients develop disease recurrence. PARP is overexpressed in GCTs compared to normal testis and PARP overexpression is early event in GCTs development. Gemcitabine and carboplatin showed activity in refractory GCTs. This study aimed to determine the efficacy and toxicity of gemcitabine, carboplatin and PARP inhibitor, veliparib, in patients with multiple relapsed/refractory GCTs. Methods: Fifteen patients with multiple relapsed/refractory GCTs were enrolled in the phase II study from October 2016 to October 2020. All patients were pretreated with at least 2 cisplatin-based therapies (median 2, range 2 – 4); 3 tumors (20.0%) were absolutely refractory to cisplatin and 5 patients (33.3%) had visceral non-pulmonary metastases. Gemcitabine was administered at a dose 800mg/m2 day 1 and 8 every 3 weeks; carboplatin AUC = 4, day 1, every 3 weeks and veliparib 250mg bid day continuously. The primary end point was 12-months progression-free survival (PFS), if < 8 patients experienced 12-months PFS, the treatment will be considered ineffective. Results: Median age was 31 years (range: 22 – 48 months). Median number of treatment cycles was 4 (range 2 – 8). During a median follow-up period of 9.2 months (range: 1.9 – 23.8), all (100%) patients experienced disease progression and 14 patients (93.3%) died. Twelve-months PFS was achieved in 1 (6.7%) patient. Median PFS was 3.1 months, 95%CI (2.2 – 3.9) and median OS was 10.5 months, 95% CI (8.9 – 11.1). Partial remission was observed in 4 (26.7%) and disease stabilization in 5 (33.3%) of patients. Favorable response (complete or partial remission with negative serum tumor markers) experienced 3 (20%) patients. Treatment was well tolerated, however, 12 (80%) of patients experienced grade 3/4 neutropenia, 9 (60%) anemia, 14 (93.3%) thrombocytopenia and 2 (13.3%) febrile neutropenia. Conclusions: This study failed to achieve its primary end point and our data suggest limited efficacy of gemcitabine, carboplatin and veliparib in multiple relapsed/refractory germ cell tumors. Clinical trial information: NCT02860819.