bluuebunny/crossref_metadata_2025 huggingface dataset:
Predictors of lymph node metastasis in T1 colorectal cancer in young patients: Results from a national cancer registry.
Authors: Singh Jameel Kenneth , Ramai Daryl , Bhandari Peter , Kani Tarik , MD Mohamed Barakat , Tai Waqqas , Chandan Saurabh , Facciorusso Antonio
Published: June 2021

e15590

Background: The incidence of colorectal cancer in young adults ( < 44 years) is on the rise. Identifying young patients at risk of regional lymph node metastasis (LNM) is crucial for long-term survival. Prior studies have examined rates of LMN in average risk patients. The objective of this study is to fill the knowledge gap by examining predictors of LMN in young patients using a national cancer registry. Methods: Patients diagnosed with T1 colorectal cancer were identified in the Surveillance, Epidemiology, and End Results register 2000-2017. Potential predictors of LNM and its impact on cancer-specific survival were assessed in logistic and Cox regression with and without multivariable adjustment. Results: In total, 692 patients with T1 colorectal cancer were identified. Most tumors occurred in White race (77.7%), between 40-44 years of age (49.4%), grade III tumor differentiation (59.8%), 1 to 1.9 cm in size (32.2%), and were left sided tumors (61.1%). The overall LNM rate was 22.5 % (n = 149). Using multivariate analysis, LMN was associated with tumor grade IV (undifferentiated) (odds ratio (OR) 2.94, CL: 1.06-8.12; p = 0.038), and increasing tumor size (1 cm – 1.9 cm: OR 2.92, CL: 1.71-4.97, p < 0.001; 2.0 cm – 2.9 cm: OR 2.00, CI: 1.05-3.77, p = 0.034; and ≥ 3.0 cm: OR 2.68, CI: 1.43-5.01, p = 0.002). Five-year cancer-specific survival for patients with LNM was 91% and for patients without LNM 98%. Adjusted cox proportion models showed that LMN was associated with four times higher rate of mortality (hazard ratio (HR) 4.43, CI: 1.27-15.52, p = 0.020). Conclusions: In conclusion, the overall LNM rate is approximately 22% for T1 CRC in young patients (less than 45 years). Tumor size and tumor grade are significant predictors for LNM in patients with T1 CRC cancer. Moreover, positive lymph node involvement is a significant prognostic factor for cancer specific survival. Thus, careful preoperative assessment of lymph node status is essential in clinical decision making, to achieve better long-term outcomes
“No problem” health-related quality of life (HRQoL) in patients treated with regorafenib (Reg) for relapsed metastatic colorectal cancer (mCRC).
Authors: Su Yun , Ostojic Helene , Jaeger Savina
Published: June 2021

e15593

Background: REG has been shown to improve survival and delay time to quality of life deterioration over placebo (PBO) in two large randomized, double-blind, placebo-controlled multi-center phase III trials CORRECT and CONCUR for the treatment of relapsed mCRC. We report on findings of the five-dimensions of HRQoL in the two trials. Methods: The five key dimensions of HRQoL were captured in the CORRECT and CONCUR trials using EuroQol 5-Dimension questionnaire 3-level version (EQ-5D-3L). The 5 dimensions are mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 3 levels: no problems, some problems, severe problems. We calculated the proportion of intent-to-treat (ITT) patients reporting “no problems” (NP) in each of the 5 dimensions by cycle and arm of treatment in the two trials. Results: Detailed descriptions of the trials have been reported previously. Due to space, data below focuses on CORRECT. ITT patients included 760 total in the CORRECT trial, 2:1 randomized to receive REG (N=505) and PBO (N=255). At baseline (BL), 95% of the ITT patients completed the questionnaire (Table), and patients reported the highest percentage of NP in self-care (87%) and lowest in pain/discomfort (35%). EQ-5D completion rates decline with each cycle of treatment, as are the percentages reporting NP in each dimension. The declines however appeared much more rapid for PBO than for REG. Both completion rate and percentages of NP were somewhat higher for PBO than for REG at BL, this continued until only cycle 2 and reversed completely from cycle 3 onward showing increasingly diminished proportion of those on PBO able to complete the questionnaire and reporting NP in each dimension. The differences between arms became larger with each cycle beginning cycle 3. Findings were similar for CONCUR (not shown). Conclusions: REG appeared to enable patients to maintain their mobility, self-care, usual activity, being pain-free and anxiety-free as well as their ability to complete the EQ-5D questionnaire, at much higher rates than PBO. Those whose EQ-5D were no longer available were likely poor performers that discontinued due to progression, death, toxicity or other unfavorable factors associated with their treatments. For PBO, toxicity was unlikely the reason. These findings suggest REG has a positive impact on quality of survival, as well as on length of survival. Further confirmatory analyses are needed.[Table: see text]
Effect of prolonged exposition to growth factors differently on proliferation of CRC cell cultures encapsulated in alginate.
Authors: Filippova Svetlana Yu. , Sitkovskaya Anastasia O. , Mezhevova Irina V. , Timofeeva Sofia V. , Shamova Tatiana V. , Novikova Inna A. , Kolesnikov Vladimir E. , Kolesnikov Valeriy V. , Sidorenko Maria , Panchenko Pavel , Kit Oleg I.
Published: June 2021

e15610

Background: Cancer stem cells (CSCs) are promising targets in modern oncology. A lot of CSCs enrichment and cultivation techniques are being currently developed. Most of the approaches deploy high doses of growth factors in culture media, - EGF and FGF2 above all, - without prior testing. Since prolonged exposition to growth factors may cause paradoxical growth inhibition it is worth developing test systems to evaluate culturing conditions before establishing the main experiment. Encapsulation in alginate may serve as a promising approach to develop such test-systems due to alginate reduced ability to adsorb proteins and maintain proper attachment to the ECM of non-stem cell even in the presence of serum. It is important to notice that serum addition may be crucial during initial stages of primary CSCs culture establishment. The aim of the study was to test EGF and FGF2 effects on anoikis resistant cells growth in permanent colorectal cancer cell lines. Methods: The cells of Caco-2, HT-29, and HCT 116 cultures were encapsulated in 1% alginate beads at a concentration of 100 000 cells/ml. Subsequently encapsulated cells were kept in 2 variants of culture media: DMEM/F12 + 10%FBS with and without addition of growth factors (EGF 20 ng/ml, FGF2 10 ng/ml). The cultivation was carried out for 10 days, after that the colonies area (A) was measured. Data are given as: Mean ± 95% confidence interval. Results: The average area of Caco-2 culture colonies increased significantly with the addition of growth factors (FBS only A = 1755.16±195.87 μm2, with additional growth factors Af = 3270.57±274.91 μm2), the difference was significant (t = 8.83, n = 300, p < 0,05). The area of HCT116 colonies after growth factors addition increased only slightly (A = 2844.89±461.57 μm2, Af = 3530.31±503.85 μm2), the difference nevertheless did not reach significant values (t = 1.94, n = 300, p > 0.05). At the same time, the area of HT-29 colonies significantly decreased in the culture medium containing additional growth factors (A = 4605.10±324.02 μm2, Af = 3167.85±249.07 μm2), the difference was significant (t = 6.92, n = 300, p < 0.05). Conclusions: Combining alginate encapsulation and colonies size measurement enabled us to evaluate culturing conditions of anoikis resistant cells in permanent CRC cultures and proved growth factors addition to be an ambiguous practice in CSCs research. This tactics can be applied in a broad spectrum of tasks concerning more effective CSCs medium formulations development.
Association of genomic characterization with clinical benefits of anti-PD-1 antibody combined with FOLFOX as neoadjuvant therapy on locally advanced gastric or gastroesophageal junction adenocarcinoma.
Authors: Liu Ying , Han Guangsen , Li Hongle , Zhao Yuzhou , Li Zhi , Liu Zhentian , Zhuang Jing , Wang Gangcheng , Li Baodong , Wang Jinbang , Li Zhimeng , Xia Qingxin , Zhang Chengjuan , Yu Juan , Gao Xuan , Li Ke , Xu Shuning , Qiao Lei , Kuang Gaizhen , Li Danyang
Published: June 2021

e16025

Background: Anti-PD-1 antibody combined with chemotherapy showed promising efficacy in gastric adenocarcinoma. However, little is known about biomarkers that identify clinical response. Here, we focus on genomic alteration patterns to predict response of neoadjuvant immunotherapy in patients with locally advanced gastric or gastroesophageal junction adenocarcinoma (GC/GEJC). Methods: Patients with locally advanced GC/GEJC were received 4 cycles of FOLFOX plus anti-PD-1 antibody (camrelizumab) as neoadjuvant therapy in the study. We prospectively conducted whole exome sequencing (WES) in paired biopsy specimens from enrolled patients at baseline. According to Tumor Regression Grading (TRG) assessment by postoperative pathology, patients were classified into group A (TRG0 & TRG1) and group B (TRG2 & TRG3). Results: We eventually performed WES in 23 patients who had adequate available tumor tissues. The clinical characterizations were not significantly different between two groups. All 23 cases were microsatellite stable (MSS). Alterations of AHNAK2 (50.0%/6.67%), TG (50.0%/6.67%), CTNNB1 (37.5%/0.0%) and ZFHX2 (37.5%/0.0%) significantly enriched in group A (n = 8) compared to group B (n = 15).Furthermore, we inspecting 10 hallmark oncogenic pathways, alterations of WNT pathway also occurred more frequently in group A than those of group B. Genomic alterations in WNT pathway were identified in 5 of 23 cases (21.74%), of which the most frequently mutated genes were CTNNB1 (13.04%), LRP5 (8.69%) and RNF43 (8.69%). Tumor mutation burden (TMB, p = 0.357), whole genome duplication (WGD) status (p = 0.667), copy number variant burden (p = 0.825), fraction of loss of heterozygosity (LOH) in chromosome level (p: 0.07-1), tumor neoantigen burden (TNB) (p = 0.65), HLA type (p: 0.49-1) and HLA LOH status (p: 0.37-1) were not significantly associated with neoadjuvant therapy response. Conclusions: Aberrant activation of WNT pathway was reported to be associated with immune evasion. Our study demonstrated that CTNNB1/WNT-pathway-mut may be a promising predictor for clinical response of neoadjuvant immutherapy in GC/GEJC. Clinical trial information: NCT03939962.
Detection of genes related to peritoneal metastasis of primary gastric cancer based on large-panel Next Generation Sequencing.
Authors: Tao Si , Liu Xin , Jin Chunhui , Chen Rongrong
Published: June 2021

e16026

Background: Peritoneum is a common site of recurrence and metastasis of gastric cancer. The traditional clinical methods have poor sensitivity for the diagnosis of peritoneal metastasis, and there is no effective marker for predicting peritoneal metastasis of gastric cancer. In this study, the genetic profiles of primary tumors in gastric cancer patients with and without peritoneal metastasis, as well as the genetic alterations before and after metastasis in the same patient were analyzed to explore the genetic alterations associated with peritoneal metastasis. Methods: 232 patients with stage Ⅳ gastric cancer were divided into PM group and non-PM group according to whether there was peritoneal metastasis, DNA based Next Generation Sequencing (NGS) with a 1021 gene panel was performed on their samples. Clinical information was obtained synchronously from physicians and surgeons. Results: There was no significant difference in baseline clinical characteristics between patients in PM and non-PM groups. Molecular analysis revealed that in the PM group, the incidence of CDH1, CDH23, HDAC1, IDH1, KRAS, MED12, RHOA, NOTCH2, TGFBR1 mutations was significantly higher in PM group than that in non-PM group, and these mutated genes were mostly located in wnt/β- catenin and MAPK signaling pathway. On the contrary, the incidence of ERBB2 and CCNE1 amplification was significantly higher in non-PM group than in the other group. Further analysis of samples before and after peritoneal metastasis of 13 patients did not find significant differences in genetic alterations. Conclusions: Compared with other sites, the primary tumor of gastric cancer patients with peritoneal metastasis seems to have its unique molecular characteristics, and large-panel NGS can help us identify this part of patients. Future research may need to clarify whether more radical treatment strategies are needed for these patients.
Correlation of E- and N-cadherin expressions as a prognostic factor in metastatic and nonmetastatic gastric tumors.
Authors: Ulianova Elena P. , Sagakyants Aleksandr B. , Novikova Inna A. , Nepomnyashchaya Evgeniya M. , Chernikova Elena N. , Bakulina Svetlana M. , Pushkareva Tatiana F. , Dzhenkova Elena A. , Shaposhnikov Aleksandr V. , Kolesnikov Evgeniy N.
Published: June 2021

e16028

Background: Over the past 10 years, gastric cancer has been in the top five most common malignant tumors with a high mortality rate. Its poor prognosis is determined by the aggressive disease course with the development of distant metastases. Additional markers of tumor progression are required, and a special role in tumor progression is assigned to the epithelial-mesenchymal transition (EMT). E- and N-cadherins are among the key EMT regulators. Our purpose was to reveal possible prognostic value of EMT markers in different forms of gastric cancer. Methods: The study included patients (aged 30-80 years) with gastric cancer: control group (n = 20, 58.9±9.7 years) – non-metastatic gastric cancer T3-4аN0-3M0 (G2); main group (n = 20, 53.4±11.9 years) – gastric cancer T3-4аN0-3M1 (G2) with peritoneal metastases. IHC analysis was performed on sections from paraffin tumor blocks using mouse monoclonal antibodies to E-cadherin (SMP471, Diagnostic BioSystems) and N-cadherin (SP90, Spring Bioscience) diluted 1:30, and the Reveal Polyvalent HRP-DAB Detection System. Expression of E- and N-cadherins was analyzed semi-quantitatively according to the percentage of cells showing membrane positivity and the intensity of staining: 0 (from 0 to 10%); 1+ (from 11 to 30%); 2+ (from 31 to 70%); 3+ ( > 70%). Expression was considered positive in ≥2. Statistical analysis of results was performed in the Statistica 13.0 program (StatSoftInc., USA) using the Pearson's chi-square test and the Spearman's correlation. Results: Maximal staining for E-cadherin was observed in the control group (in 90%), staining for N-cadherin – in the main group (in 70%). Average expressions of E- and N-cadherins were: in controls – 34.5±4.5 and 24.1±5.7; in the main group – 24.6±5.8 and 28.3±4.3. The Pearson's test showed the statistically significant prevalence of patients with E-cadherin+ tumors in the control group (7.619, p = 0.006), and the prevalence of patients with N-cadherin+ tumors in the main group (4.912, p = 0.027). However, when considering the correlation between E-cadherin and N-cadherin in the groups, the Spearman's correlation was not statistically significant (rs = -0.342 in the control group and rs = -0.430 in the main group at p > 0.05). Conclusions: The study revealed only a tendency towards the loss of E-cadherin and increased expression of N-cadherin, which is often associated with a poor prognosis. However, a more extensive study is required to assess the possible prognostic value of these EMT markers in metastatic and non-metastatic gastric cancer.
Efficacy and safety of PD-1 inhibitors as first- and second- line treatments for advanced gastroesophageal cancers: A network meta-analysis of phase III clinical trials.
Authors: Lopes Da Silva Laercio , Park Robin , Aguiar Pedro Nazareth , Edleman Saul Eduardo , Haaland Benjamin , Lopes Gilberto
Published: June 2021

e16032

Background: Advanced gastroesophageal tumors are among the most prevalent and burdensome cancers worldwide. They have a poor prognosis and limited treatment options. Recent studies show that PD-1/PD-L1 inhibitors can improve outcomes, but the results are inconsistent across trials. Herein, we compare the effectiveness and safety of PD-1/PD-L1 inhibitors with chemotherapy in patients with ERBB2 negative advanced/metastatic gastric and esophageal cancers. Methods: We searched bibliographic databases (PubMed, Embase, Cochrane Central, Web of Science, Medline, Scopus) and ClinicalTrials.gov from January 1, 2010, to November 23, 2020. We included phase III randomized clinical trials comparing anti-PD-1/PD-L1 single-agent or in combination with chemotherapy (chemoimmunotherapy) for advanced gastric or esophageal cancers in the first- or second-line settings. We performed a network meta-analysis with a frequentist approach and a random-effects model using the package ‘netmeta’ for R statistical software. A prospective protocol was uploaded to PROSPERO (CRD42020221822). Results: The final analysis included a total of 8 trials that compared different anti-PD-1 agents; none of them involved anti-PD-L1 agents. The four first-line studies involved 3817 patients. Chemoimmunotherapy improved OS and PFS with no significant safety difference: Nivolumab + chemotherapy, OS (HR, 0.83; 95% CI, 0.75-0.92), PFS (HR, 0.68; 95% CI, 0.57-0.81), SAE (OR 0.54; 0;95% CI, 0.1-2.92); Pembrolizumab + chemotherapy: OS (HR, 0.77; 95% CI, 0.67-0.88), PFS (HR, 0.72; 95% CI, 0.60-0.85), SAE (OR, 1.31; 0;95% CI, 0.23-7.35). Pembrolizumab monotherapy was the safest first-line treatment, SAE (OR, 0.02; 95% CI, 0.00-0.2), but did not improve survival, OS (HR, 0.91; 95% CI, 0.71-1.16), PFS (HR, 1.62; 95% CI, 1.23-2.14). The four second-line studies totalized 2087 individuals. Anti-PD-1 drugs were significantly safer but did not significantly improve survival: camrelizumab, OS (HR 0.71; 95% CI, 0.54-0.93), PFS (HR 0.69; 95% CI, 0.45-1.06), SAE (OR, 0.37; 95% CI, 0.24-0.56); nivolumab, OS (HR 0.77; 95% CI, 0.58-1.02), PFS (HR 1.08; 95% CI, 0.77-1.66), SAE (OR, 0.13; 95% CI, 0.08-0.2) pembrolizumab, OS (HR 0.86; 95% CI, 0.72-1.04), PFS (HR 1.28; 95% CI, 0.96-1.71), SAE (OR, 0.4; 95% CI, 0.30-0.53). Conclusions: the combination of PD-1 inhibitors with chemotherapy improves OS and PFS in previously untreated gastroesophageal cancers. Single-agent anti-PD-1 drugs improve safety in refractory disease, with no significant change in OS and PFS.
The association of renal function with safety and efficacy of cisplatin plus S-1 (CS) therapy and docetaxel plus cisplatin plus S-1 (DCS) therapy in patients with advanced gastric cancer (AGC): An additional analysis of JCOG1013.
Authors: Hironaka Shuichi , Sadachi Ryo , Machida Nozomu , Iwasa Satoru , Yamada Yasuhide , Sasako Mitsuru , Yoshikawa Takaki , Boku Narikazu , Terashima Masanori
Published: June 2021

e16035

Background: A phase III study, JCOG1013, did not show the superiority of docetaxel plus cisplatin plus S-1 (DCS) to cisplatin plus S-1 (CS) in overall survival (OS) (Yamada Y, Lancet GH 2019). It is known that cisplatin and gimeracil (an inhibitor of dihydropyrimidine dehydrogenase contained in S-1) are excreted in urine. We previously reported (abstr 197, ASCO-GI 2021) exploratory analysis of JCOG1013 which showed creatinine clearance (CrCl) was associated with safety (Grade [G]4 hematological toxicity for CS, and G3-4 non-hematological toxicity for CS and DCS), but not with efficacy in either group. Here, we report the additional detail results of this exploratory analysis. Methods: Among 741 participants in JCOG1013, patients with serum creatinine level < 1.2 mg/dL were included in this analysis and categorized by CrCl and treatment into A1 (CrCl ≥ 80 mL/min, CS), A2 (60 < CrCl < 80, CS), A3 (CrCl < 60, CS), B1 (CrCl > 80, DCS), B2 (60 < CrCl < 80, DCS), and B3 (CrCl < 60, DCS). The dose (mg/m2) of C/S was 60/80 regardless renal function in group A (A1, A2 and A3), and that of D/C/S was adjusted in group B as follows: 40/60/80 in B1, 40/50/80 in B2, and 40/40/65 in B3. Adverse events, OS, progression-free survival (PFS), and objective response rate (ORR) were compared by CrCl in group A (A1 vs. A2 vs. A3) and group B (B1 vs B2 vs B3), respectively. Results: Of 723 pts (169/136/57 in A1/A2/A3 and 170/138/53 in B1/B2/B3), the median CrCl (mL/min) was 94.1/71.9/53.4 in A1/A2/A3 and 98.2/70.0/55.6 in B1/B2/B3. The relative dose intensity of C/S was 90.4/75.3%, 87.8/74.9% and 85.7/72.8% in A1, A2 and A3, and that of D/C/S was 87.5/77.7/74.9%, 85.8/61.2/72.7% and 87.8/49.4/58.3% in B1, B2 and B3. The incidence of G4 white blood cell decreased, G4 neutrophil count decreased, and G3-4 anorexia were 1.2/4.4/9.3% (P < 0.01), 4.8/11.1/18.5% (P < 0.01), 14.4/28.1/28.6% (P < 0.01) in A1/A2/A3, and 1.8/3.0/4.0% (P = 0.36), 27.3/24.8/20.0% (P = 0.28), 22.4/29.3/32.0% (P = 0.11) in B1/B2/B3, respectively. No significant association between CrCl and other adverse events was observed either in CS or in DCS group. The median OS was 15.4/15.5/15.4 months in A1/A2/A3 (P = 0.89) and 15.3/13.7/13.7 months in B1/B2/B3 (P = 0.72). The median PFS was comparable among A1/A2/A3 (7.1/6.8/6.2 months, P = 0.88) and B1/B2/B3 groups (7.5/7.2/7.8 months, P = 0.85). ORR showed no significant difference in A1/A2/A3 (58.9/57.8/46.9%, P = 0.31) and B1/B2/B3 groups (62.0/61.5/51.5%, P = 0.36). Conclusions: Dose modification according to renal function in the DCS arm could control the increase of severe toxicities, which were observed frequently in patients with low renal function in patients receiving fixed dose of CS. Clinical trial information: 000007652.
Phase II trial of surufatinib plus toripalimab for disease progression after first-line chemotherapy with platinum and fluoropyrimidine in advanced gastric or gastroesophageal junction adenocarcinoma.
Authors: Shen Lin , Lu Ming , Chen Zhendong , Ye Feng , Zhang Yanqiao , Li Zhiping , Zhang Xing , Yin Fei , Chen Wei , Sheng Wang , Ma Yue , Zhao Yaqin , Weng Desheng , Yin Xiaolei , Zhou Jinghong , Shi Haiyan , Tan Panfeng , Su Weiguo
Published: June 2021

e16040

Background: Surufatinib is a novel small-molecule kinase inhibitor targeting VEGFRs, FGFR and CSF-1R, simultaneous targeting of angiogenesis through VEGFRs/FGFR1 and modulating tumor immune microenvironment through CSF-1R may be a uniquely potent strategy to enhance antitumor activity. Toripalimab is a monoclonal humanized IgG4 PD-1 antibody. Encouraging efficacy of surufatinib plus toripalimab treating patients with advanced solid tumors was reported at 2020 AACR. This is an ongoing, multicenter, open-label, single-arm, phase II study to evaluate the efficacy and safety of surufatinib in combination with toripalimab in various solid tumors. Here we report the results of patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. Methods: Patients with histologically confirmed gastric or GEJ adenocarcinoma who have failed first-line of systemic chemotherapy were enrolled. Surufatinib 250 mg once a day (QD) will be orally administrated and toripalimab 240 mg will be intravenously administered every 3 weeks. Primary endpoint was the objective response rate (ORR) per RECIST v1.1. Results: As of Dec 31, 2020, a total of 21 gastric or GEJ adenocarcinoma patients were enrolled. The median age was 58 years old, and 81% of the patients were male. Median duration of treatment was 3 months (surufatinib, 3 months; toripalimab, 3 months). Among 15 patients with at least one post-baseline efficacy evaluation, 2 patients achieved confirmed partial response (PR), with 3 additional unconfirmed PR. And there were 6 in stable disease (SD), 3 in progressive disease (PD) and one not evaluable per RECIST v1.1. There were 5 in PR, 7 in SD and 2 in PD per irRECIST, respectively. The confirmed and unconfirmed ORR were 13.3% (95% CI: 1.7%-40.5%) and 33.3% (95% CI: 11.8%-61.6%), respectively. The disease control rate (DCR) was 73.3% (95% CI: 44.9%-92.2%) per RECIST v1.1. Median PFS was 3.71 months (95% CI: 1.41-unknown). 14.3% (3/21) of patients had treatment-related adverse events (TRAEs) of ≥ Grade 3. The most common TRAEs of ≥ Grade 3 were herpes zoster (4.8%), lymphopenia (4.8%), lymphocyte count decreased (4.8%), white blood cell count decreased (4.8%), liver injury (4.8%) and anaemia (4.8%). 4.8% (1/21) of patients had serious TRAEs. One patient died due to unknown reasons. Conclusions: Surufatinib plus toripalimab appeared to show encouraging activity in advanced gastric or GEJ adenocarcinoma with manageable safety profile. Such combination could be a promising strategy for advanced gastric or GEJ adenocarcinoma in the future. Clinical trial information: NCT04169672.
Association between timely targeted therapy initiation and clinical outcomes in patients with advanced HER2+ gastroesophageal adenocarcinoma.
Authors: Lau-Min Kelsey S. , Li Yimei , Eads Jennifer Rachel , Mamtani Ronac , Getz Kelly D.
Published: June 2021

e16048

Background: Delayed treatment initiation is associated with increased mortality in early-stage cancers. Few studies have examined the impact of timely initiation in advanced cancers. Timely targeted therapy initiation can be especially challenging due to the additional biomarker testing required to identify patients eligible for these treatments. We examined the impact of timely targeted therapy initiation on survival among patients with metastatic HER2+ gastroesophageal adenocarcinoma (GEA). Methods: We performed a retrospective cohort study of patients with metastatic HER2+ GEA treated with first line systemic therapy between 1/2011 and 12/2017 using the nationwide Flatiron Health EHR-derived deidentified database. Timely targeted therapy, defined as initiation of the anti-HER2 monoclonal antibody trastuzumab up to 14 days after first line chemotherapy initiation, was entered as a time-varying exposure on the day of initiation. Patients who initiated trastuzumab after the 14-day cut point or who lacked documentation of having received trastuzumab were classified as having non-timely targeted therapy initiation. Extended Cox regression models were used to compare progression-free (PFS) and overall survival (OS) from the date of first line treatment initiation, adjusted for potential confounders. Pre-planned sensitivity analyses assessed alternative “timeliness” definitions as well as the impact of any trastuzumab administration, regardless of the timing of initiation. Results: We included 459 patients with metastatic HER2+ GEA; 293 (63.8%) received trastuzumab, of whom 223 (76.1%) initiated in a timely manner. The median age was 65.0 years, and patients were predominantly male (82.4%) and non-Hispanic White (78.2%) with an ECOG performance status of 0-1 (85.9%). Relative to non-timely initiation, timely targeted therapy was associated with significantly higher OS (2-year OS 29.6% vs 14.6%; adjusted HR 0.72, 95% CI 0.57-0.91, p = 0.006) and PFS (2-year PFS 8.3% vs 3.9%; adjusted HR 0.78, 95% CI 0.62-0.98, p = 0.030). Results remained similar in sensitivity analyses 1) using alternative “timeliness” definitions (up to 70 days after chemotherapy initiation), and 2) comparing any trastuzumab administration, regardless of the timing of initiation, to no trastuzumab administration (OS - adjusted HR 0.75, 95% CI 0.60-0.95, p = 0.018; PFS - adjusted HR 0.81, 95% CI 0.64-1.02, p = 0.069). Conclusions: OS and PFS were higher among patients with metastatic HER2+ GEA treated with trastuzumab, regardless of the timing of targeted therapy initiation. Although our results provide reassurance to clinicians that delays in targeted therapy may not be detrimental to patient outcomes, efforts should still be made to ensure that all patients with metastatic HER2+ GEA receive first line trastuzumab.
Investigation of prognostic factors for second-line treatment with nivolumab for unresectable or recurrent esophageal cancer.
Authors: Ogata Takashi , Machida Nozomu , Takahashi Kosuke , Kano Kazuki , Koumori Keisuke , Watanabe Hayato , Fujikawa Hirohito , Yamada Takanobu , Inokuchi Yasuhiro , Furuta Mitsuhiro , Kaneta Yoshihiro , Hayashi Kei , Ishida Ayaka , Oshima Takashi
Published: June 2021

e16055

Background: Nivolumab, an immune-checkpoint inhibitor for unresectable or recurrent esophageal cancer is used as second-line treatment. On the other hand, the relationship between indicators of cancer immunity (GPS, NLR, PLR), indicators of nutritional status (PNI, BMI), and prognosis of patients treated with nivolumab is unclear. Methods: We investigated the prognostic factors of nivolumab for unresectable or recurrent esophageal cancer. The subjects were 62 patients who received nivolumab as a second-line or later treatment for unresectable or recurrent esophageal cancer before January 2021. Of these 13 patients had previously been treated with taxan. We used GPS (Glasgow prognostic score), NLR (Neutrophil-Lymphocyte Ratio: cutoff value is 3.5), PLR (Platelet-Lymphocyte Ratio: cutoff value is 200), PNI (Prognostic nutrition index: cutoff value is 40), BMI (Body mass index: cutoff value is 18.5 for under 70 years old, and 20 for over 70 years old defined by Asian GLIM standard) as prognostic indicators. We examined the association between age, gender, PS, GPS, NLR, PLR, PNI, BMI and prognosis in patients treated with nivolumab. And we also examined the relationship between the history of taxan administration, the presence of adverse events and the prognosis. Results: Of the 62 cases, 48 cases were male and 14 cases were female. The median age was 70 years. Median OS was 359 days, and median PFS was 97 days. OS in patients with no prior taxan treatment group was significantly longer (P<0.05). AE appeared in 49 cases (79%), and irAE appeared in 22 cases (35.5%). OS in patients with irAE was significantly longer (P<0.01). PS (0/1/2) was 27 cases/33 cases/2 cases, and GPS (0 point/1 point/2 point) was 41 cases/11 cases/10 cases. NLR high was 35 cases, and NLR low was 27 cases. PLR high was 31 cases and PLR low was 31 cases. PNI high was 46 cases and PNI low was 16 cases. BMI normal or high was 27 cases and BMI low was 35 cases. In univariate analysis of OS, GPS (P<0.001), NLR (P<0.01), PS (P<0.05), PNI (P<0.001) showed a significant difference in survival, and in multivariate analysis, PS (p<0.05) and PNI (P<0.05) were significant prognostic factors. Conclusions: PS and PNI were good prognostic factors with nivolumab after second or later treatment for unresectable or recurrent esophageal cancer.
TRG as indicator of efficacy of FLOT versus FOLFOX in perioperative chemotherapy for resectable gastric cancer patients (single institution experience).
Authors: Beliak Natalia P. , Orlova Rashida , Kutukova Svetlana , Zhukova Natalia V. , Balashov Pavel , Usmanov Nazif
Published: June 2021

e16061

Background: Based on results German FLOT-4 study, the FLOT regimen could be considered the new standard chemotherapy regimen for perioperative strategy of resectable GC. Since more and more patients have received neoadjuvant treatment,the efficacy and side effect must be weighted before performing NACT. Two-drug regimens were preferred according to the NCCN guidelines in principle because of their lower toxicity. And three-drug regimens may be applied in medically fit patients with access to frequent evaluation during treatment, to ensure that they can still tolerate surgery after NACT. Methods: We analyzed the data of 79 patients with resectable locally advanced gastric cancer who received the FLOT or FOLFOX regimen as NACT. The group of patients with NAСT FLOT included 44 patients, including 32 men, 12 women. Age in the first group varied from 28 to 80 years, the median age was 59.0 (95% CI 54.1-62.0) The group of patients with the FOLFOX chemotherapy regimen included 35: 17 (48.6%) men and 18 women (51.4%). Age in the second group varied from 60 to 75 years, the median age in the second group was 67.5 (95% CI 62.2-71.0). The second group included significantly older patients U = 137.0; p = 0.0001. Results: The severity of drug pathomorphosis was assessed in a standard way according to the Mandard system, in the first group there were 5 patients - TRG1 (11.4%), 7 patients - TRG2 (15.9%), 9 patients - TRG3 (20.5%), 15 patients TRG4 (34.0%), 5 patients - TRG5 (11.4%), 3 patients it was not evaluated (6.8%). In the second group, 6 patients - TRG1 (17.1%), 2 patients - TRG2 (5.7%), 2 patients - TRG3 (5.7%), 16 patients - TRG4 (45.8 %), 7 patients - TRG5 (20.0%), for 2 patients it was not evaluated (5.7%). Complete pathomorphosis was not statistically different in both groups (p = 0.47). TRG 2 was not statistically different (p = 0.16). The number of registered cases of TRG3 in the first group exceeded (p = 0.06). The frequency of TRG4 and TRG 5 did not differ (p = 0.29). Major pathological regression (TRG1 + TRG2) was 27.3% in the first group and 22.8% (p = 0.65). A decrease in the stage in the first group occurred in 22 patients (50.0%), and in the second group - in 19 patients (54.3%), p = 0.70. yp≤ T2 was diagnosed in 21 out of 79 patients (26.6%), in the first group in 11 patients (25%), in the second group in 10 (28.6%), p = 0.72. Conclusions: the FOLFOX regimen showed similar efficacy in the tumor response grade rate compared to the FLOT regimen, therefore, these two regimes are interchangeable, especially among patients of the older age group or in patients with high risks of a four-component regimen.
Profiling genomic characteristics related to immunotherapy for gastric cancer with amplified MET.
Authors: Yu Yiyi , Li Wei , Yu Shan , Wang Yan , Zhu Mengxuan , Yi Zhao , Liu Tianshu
Published: June 2021

e16066

Background: Gastric cancer (GCA) is one of the most deadly cancers all over the world, with an estimate of 26,560 new cases and 11,180 deaths in United States according to the cancer statistics of 2021. As immunotherapy has become available for GCA, it is necessary to distinguish patients who might be resistant to it. Methods: We identified 41 patients with amplified MET from a large Chinese cohort including 934 GCA (4.4% out of them) according to the ratio of purity adjusted copy number of MET and chromosome 7. Then, we comprehensively profiled genomic characteristics related to immunotherapy for GCA with amplified MET and compared them with other GCA. Results: First, mutated RNF43 and AXIN1 were much more prevalent in GCA with amplified MET. These two genes are components of Wnt pathway, whose aberrance is associated with resistance to immunotherapy. Second, carrier ratios of amplified CDK6 and CCND1 were much higher in GCA with amplified MET. These two genes play important roles in cell cycle pathway, while amplification of CCND1 has been recognized as a negatively predictive biomarker for immunotherapy. Third, we calculated mutational load of immunotherapy-related positively (mutated ATM, BRCA1, BRCA2, CHEK2, ERCC2, ERCC4, FANCA, KRAS, MLH1, MSH2, MSH6, NRAS, PALB2, PBRM1, PMS2, POLD1, POLE, RAD50 and TP53; deleted POLE) and negatively (mutated B2M, CTNNB1, DNMT3A, EGFR, JAK1, JAK2 and STK11; amplified CCND1, EGFR, FGF19, FGF3, FGF4, MDM2 and MDM4; deleted B2M, JAK2, PTEN and STK11) predictive biomarkers for GCA with amplified MET. We defined the mutational load as mean carrier ratio of point mutations or copy number variations (CNVs) appeared in a gene set. As is expected, the mutational load of point mutations in 19 positively predictive biomarkers in GCA with amplified MET was much lower than that in other GCA, whereas the mutational load of CNV in 11 negatively predictive biomarkers in GCA with amplified MET was much higher than that in other GCA. Finally, we found GCA with amplified MET possessed lower tumor mutational burden (TMB) and microsatellite instability (MSI), depleted somatic signature of defective DNA mismatch repair and higher copy number instability (CNI). Conclusions: Genomic characteristics of GCA with amplified MET are associated with adverse response to immunotherapy and thus it should be carefully evaluated when these patients are treated with immunotherapy.
Optimizing the program of sequential chemotherapy for advanced gastric cancer based on gene-level CNVs called from ctDNA.
Authors: Xi Wenqi , Zhou Chenfei , Zhang Shouwei , Yi Zhao , Chen Yawei , Ji Jun , Ma Tao , Wu Junwei , Shangguan Chengfang , Zhu Zhenggang , Zhang Jun
Published: June 2021

e16068

Background: Tumor evolutionary trade-offs under treatment pressure can be utilized to optimize therapy. We aimed to profile the dynamic pattern of gene-level copy number variations (CNVs) for advance gastric cancer (GCA) patients who underwent sequential chemotherapy and optimized the therapy program. Methods: 27 chemo-naive advanced GCA patients with distant metastasis were enrolled. Peripheral blood samples were collected at different time points, including pre-therapy and disease progression on a specific regimen. Gene-level CNVs were called from ctDNA of blood samples and drug modified score (DMS) was defined as the ratio of CNV value between samples of pre- and post-treatment for each gene. Positive and negative DMS of a gene represented its resistance and sensitivity to a selected regimen, respectively. Then, the best initial regimen was selected and the optimal program of sequential chemotherapy was designed for each patient. Results: DMS of gene was calculated for four chemotherapy regimens, including platinum-based doublet regimen (Pt-2d), oral-fluorouracil prodrug (O-FP), paclitaxel-based regimen (PTX) and irinotecan-based regimen (CPT-11). Based on DMS distribution, resistant and sensitive genes were determined for each regimen through a heuristic method. Functional enrichment analysis showed that resistant genes mainly involved in cellular response to oxygen-containing compound and regulation of cell proliferation, while sensitive genes mainly involved in positive regulation of macromolecule biosynthetic process and regulation of apoptotic process. Then, drug resistant score (DRS, defined as DMS weighted sum of CNV values of resistant genes) was calculated and the regimen with the lowest DRS was selected as the best initial treatment for each patient. The best initial treatment of 16 patients was CPT-11, of 8 patients was O-FP, of 2 patients was Pt-2d and of 1 patient was PTX. Following that, the optimal program of sequential chemotherapy was designed according to the percentage of shared resistant genes between regimens for each patient, where two regimens with the lowest percentage were recommended to use one by one. Finally, prognostic analysis showed that differences between the optimal and practical program of sequential chemotherapy were negatively correlated to overall survival of patients. Conclusions: Based on gene-level CNVs called from ctDNA of blood samples, we determined the best initial treatment and designed the optimal program of sequential chemotherapy for advanced GCA patients, pacing a key step toward precision medicine in GCA field.
Effect of ethnicity and chemotherapy (mFOLFOX6) on zolbetuximab pharmacokinetics in patients with claudin 18.2-positive locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma (G/GEJ).
Authors: Lee Keun-Wook , Klempner Samuel J , Yang Jianning , Desai Amit , Yamada Akihiro , Ueno Yoko , Wojtkowski Tomasz , Park Jung Wook , Pavese Janet , Loupakis Fotios , Bang Yung-Jue , Shitara Kohei
Published: June 2021

e16078

Background: Zolbetuximab is a chimeric IgG1 monoclonal antibody that targets Claudin 18.2 (CLDN18.2), a tight junction protein that is normally confined to gastric mucosa but is retained in G/GEJ. A phase 2 (NCT01630083, FAST) trial demonstrated significantly prolonged survival with zolbetuximab + EOX (epirubicin, oxaliplatin, capecitabine) vs EOX in G/GEJ. Two global phase 3 studies are ongoing, comparing zolbetuximab + chemotherapy vs chemotherapy as first-line treatment in CLDN18.2-positive G/GEJ. This study assessed the influence of ethnic differences and chemotherapy on the pharmacokinetics (PK) of zolbetuximab in patients (pts) with G/GEJ and the potential effect of zolbetuximab on chemotherapy PK. Methods: In the Japanese phase 1 and global phase 2 studies, adult pts with CLDN18.2-postitive G/GEJ received zolbetuximab 800 mg/m2 IV on Cycle 1 Day 1 (Cycle 1 Day 3 in Cohort 2 of phase 2) then 600 mg/m2 Q3W. Phase 1 and Cohort 1A of the phase 2 study assessed zolbetuximab monotherapy in 21-day cycles. Cohort 2 of the phase 2 study assessed zolbetuximab + mFOLFOX (5-FU, folinic acid, oxaliplatin; 4 cycles) in 42-day cycles (Q2W from Cycle 1 Day 1). Blood samples for zolbetuximab PK following single and multiple doses, and for chemotherapy (5-FU and oxaliplatin) PK alone or with zolbetuximab were collected. Maximum serum drug concentration (Cmax) and area under the concentration-time curve from 0-21 days (AUC0-21) were assessed. Potential ethnic differences in zolbetuximab exposures across Japanese, other Asian (Korean and Taiwanese), and Western pts, and the potential drug-drug interaction between zolbetuximab and chemotherapy were evaluated. Results: Zolbetuximab concentration profiles and PK parameters were generally comparable across Japanese, other Asian, and Western populations (Table). Zolbetuximab PK properties were similar between monotherapy and combination therapy cohorts (Table). Chemotherapy PK was comparable with and without zolbetuximab. Conclusions: The analyses suggest no apparent ethnic differences in zolbetuximab PK across Japanese/Asian and Western pts and no PK interactions between zolbetuximab and mFOLFOX6. These results support the use of zolbetuximab and mFOLFOX without the need for dose adjustment in global phase 3 trials. Clinical trial information: NCT03505320, NCT03528629. [Table: see text]
Role of adjuvant therapy in esophageal cancer patients after neoadjuvant therapy and curative esophagectomy: A systematic review and meta-analysis.
Authors: Lee Yung , Samarasinghe Yasith , Lee Michael H , Thiru Luxury , Shargall Yaron , Finley Christian , Hanna Wael , Levine Oren Hannun , Juergens Rosalyn A. , Agzarian John
Published: June 2021

e16083

Background: While neoadjuvant therapy followed by esophagectomy is the standard of care for locally advanced esophageal cancer, the role of adjuvant therapy is uncertain. As such, this review aims to analyze esophageal cancer patients who previously underwent neoadjuvant therapy followed by a curative resection (negative margins) to determine whether additional adjuvant therapy is associated with improved survival outcomes. Methods: MEDLINE, EMBASE, and CENTRAL databases were searched up to August 2020 for studies comparing patients with esophageal cancer who underwent neoadjuvant therapy and curative resection with and without adjuvant therapy. Primary outcome was overall survival (OS), and secondary outcomes were disease-free survival (DFS), locoregional recurrence, and distant recurrence at 1 and 5-years. Random effects meta-analysis was conducted where appropriate. Grading of recommendations, assessment, development, and evaluation (GRADE) was used to assess the certainty of evidence. Results: Ten studies involving 6,462 patients were included. 6,162 (95.36%) patients from 7 studies received adjuvant chemotherapy, whereas 296 (4.58%) patients from 3 studies underwent either adjuvant radiotherapy or chemoradiotherapy. When compared to patients who received neoadjuvant therapy and esophagectomy alone, adjuvant therapy groups experienced a significant overall survival benefit by 48% at 1-year (RR 0.52, 95%CI 0.41-0.65, P < 0.001, moderate certainty). This reduction in mortality was consistent at long-term 5-year follow-up (RR 0.91, 95%CI 0.87-0.96, P < 0.001, moderate certainty). Subgroup analysis on pathologic node positive patients demonstrated a consistent survival benefit at 1-year (RR 0.57, 95% CI 0.42-0.77, P < 0.001, moderate certainty) and 5-year (RR 0.89 95%CI 0.84-0.95, P < 0.001, moderate certainty). While adjuvant therapy presented no benefit for the T0-2 stage subgroup, patients with T3-4 disease experienced a significant reduction in mortality with the addition of adjuvant therapy at both 1-year (RR 0.51, 95% CI 0.41-0.63, P < 0.001, moderate certainty), and 5-years (RR 0.91, 95% CI 0.85-0.97, P = 0.005, moderate certainty). Due to incomplete reporting, the added benefit of adjuvant therapy was uncertain regarding DFS, locoregional recurrence, and distant recurrence. Conclusions: Adjuvant therapy after neoadjuvant treatment and curative esophagectomy provides improved OS at 1 and 5 years, but the benefit for DFS and locoregional/distant recurrence was uncertain due to limited reporting of these outcomes.
The epidemiological trend of esophageal cancer in Mumbai, India over the past two decades.
Authors: Sekar Anbarasan , Rajendra Akhil , Noronha Vanita , Mokal Smruti , Patil Vijay Maruti , Menon Nandini , Chopade Sunil , Dikshit Rajesh , Banavali Shripad Dinanath , Prabhash Kumar
Published: June 2021

e16095

Background: There has been a definite histopathological shift in esophageal cancer in the West over the past few decades, with adenocarcinoma overtaking squamous cell carcinoma as the commonest type. Asian countries with a high human development index like China have also reported an increased incidence of esophageal adenocarcinoma. Data on the epidemiology of esophageal cancer in India are limited. Methods: We retrospectively evaluated the data of all patients with histologically proven esophageal cancer at Tata Memorial Hospital, from 2003 to 2018. We excluded non-squamous and non-adenocarcinoma histologies. Results: Of a total of 7,874 patients with esophageal cancer, 5,092 (64.7%) were men, for a male to female ratio of 2.5:1. The median age was 57 years (IQR, 50-65); 4,465 (56.7%) were below 60 years old. Of the 4912 patients in whom a history of tobacco or alcohol use had been elicited, there were 1,360 (27.7%) patients with no history of substance use. The site of the primary was the upper third in 906 (12.8%), middle third esophagus in 2,942 (41.5%), lower third in 2,331 (32.8%) and gastroesophageal junction in 917 (12.9%) patients. The predominant histology was squamous cell carcinoma in 6,413 (81.4%) patients and adenocarcinoma in 1461 (18.6%). There was no change in the histologic pattern over the period of the study; squamous cell carcinoma constituted 78.5% of the cases in 2003, and 85.5% in 2018; Chi square test for the year wise trend in histologic patterns was not significant, p=0.143. Evaluation of the histologic subtype according to sex revealed that in the male patients, there were 3890 (76.4%) squamous and 1202 (23.6%) adenocarcinoma cases, while in female patients, there were 2523 (90.7%) squamous and 259 (9.3%) adenocarcinoma cases. On a uni variate analysis, male sex (p<0.001), a history of tobacco or alcohol use (p<0.001), and the presence of comorbidity (p<0.007) were associated with an increased risk of squamous cell carcinoma. Multivariate analysis by logistic regression model revealed that female sex and use of tobacco or alcohol were positively associated with squamous cell carcinoma, while the presence of comorbities and primary in lower esophagus/GEJ were positively associated with adenocarcinoma. Conclusions: Squamous cell carcinoma continues to be the commonest esophageal cancer histologic subtype in over 80% Indian patients. The mid esophagus is the most common site (42%). There is no evidence of an epidemiological shift or an increase in the occurrence of adenocarcinoma or of lower esophageal/GEJ malignancy over the past two decades.