bluuebunny/crossref_metadata_2025 huggingface dataset:
Side effects of extended interval dosing of checkpoint inhibitors among patients during COVID-19 pandemic at the Moncton and the Miramichi hospitals.
Authors: Abdelsalam Mahmoud , Sughayar Rana , Myers Glenn , Avileli Mrudula , Salem Maged
Published: June 2021

e14550

Background: Since the COVID-19 pandemic started, managing cancer patients who are more vulnerable than the rest of the population has been a concern. One of the strategies to decrease cancer patient visits to the Oncology Clinic was by the use of an extended dosing schedule of immune checkpoint inhibitors. The goal of the present study is to record and describe patients’ experiences with irAEs on the modified treatment schedules. Methods: The study included cancer patients getting their treatment at the cancer care clinics at The Moncton Hospital and the Miramichi Hospital, and who switched to receiving either a modified dose of Pembrolizumab or Durvalumab. These participants were asked to complete a short survey that covered important data in their diagnosis and treatment, as well as the type of cancer diagnosed and which drug they were prescribed for treatment. Participants were also asked about the presence of any possible immune-related symptoms from a list of possible AEs since their last treatment visit, and to indicate (A) how often the symptom was experienced, and (B) how severe the symptom was. Results: Twenty-one patients filled out the questionnaire half of whom were females. Most of the patients had lung cancer and were on pembrolizumab. All the patients interviewed developed at least one new symptom after the change in the dose was introduced. The most frequent symptoms reported were itchy skin and fatigue and they were severely experienced. However, very few of the symptoms experienced required a physician consult or hospitalization. Most of the participants welcomed the change in the dose to protect them from COVID-19 and were mainly indifferent as to whether they get the low dose more frequently or the higher dose less frequently. Conclusions: This study has highlighted the frequency and severity of irAEs with the use of extended dosing schedule of immune checkpoint inhibitors. Future research should have more patients to validate this outcome and look for the causes behind the increased incidence and severity of irAEs with higher dose less frequent intervals of these immunotherapies.[Table: see text]
The mechanism of the growth inhibitory effect of paclitaxel on gefitinib-resistant non-small cell lung cancer (NSCLC) cells during the COVID-19 pandemic.
Authors: Mohiuddin Md , Kimura Hideharu , Watanabe Satoshi , Abo Miki , Sone Takashi , Saeki Keigo , Terada Nanao , Tanimura Kota , Kasahara Kazuo
Published: June 2021

e15007

Background: Coronavirus disease 2019 (COVID-19) poses a great challenge for the treatment of cancer patients. It presents as a severe respiratory infection in aging individuals, including lung cancer patients. COVID-19 may be linked to the progression of aggressive lung cancer. In addition, the side effects of chemotherapy, such as chemotherapy resistance and the acceleration of cellular senescence, can worsen COVID-19. Given this situation, we investigated the role of paclitaxel (a chemotherapy drug) in the cell proliferation, apoptosis, and cellular senescence of gefitinib-resistant non-small-cell lung cancer (NSCLC) cells (PC9-MET) to clarify the underlying mechanisms. Methods: PC9-MET cells were treated with paclitaxel for 72 h and then evaluated by a cell viability assay, DAPI staining, Giemsa staining, apoptosis assay, a reactive oxygen species (ROS) assay, SA-β-Gal staining, a terminal deoxynucleotidyl transferase dUTP nick-end labeling assay and Western blotting. Results: Our results revealed that paclitaxel significantly reduced the viability of PC9-MET cells and induced morphological signs of apoptosis. The apoptotic effects of paclitaxel were observed by increased levels of cleaved caspase-3 (Asp 175), cleaved caspase-9 (Asp 330) and cleaved PARP (Asp 214). In addition, paclitaxel increased ROS production, leading to DNA damage. Inhibition of ROS production by N-acetylcysteine attenuates paclitaxel-induced DNA damage. Importantly, paclitaxel eliminated cellular senescence, as observed by SA-β-Gal staining. Cellular senescence elimination was associated with p53/p21 and p16/pRb signaling inactivation. Conclusions: Given these findings, paclitaxel may be a promising anticancer drug and offer a new therapeutic strategy for managing gefitinib-resistant NSCLC during the COVID-19 pandemic.
Transcriptome (RNA next generation sequencing) for personalizing of cancer treatment: A correlation with previous clinical resistance.
Authors: Sureda Manuel , Rebollo Joseba , González-Manzano Ramón , Martínez Elena Ma , Rostagno Roman , Mata Juan José , Monedero Elena , Ortega Jose , Brugarolas Antonio
Published: June 2021

e15046

Background: RNA Next Generation Sequencing (transcriptome) is a potential useful tool to predict chemoresistance to available anticancer drug therapy. A correlation between previous clinical resistance and drug resistance profiling according to RNA NGS results has been studied. Methods: Since March 2018, whole transcriptome RNA NGS has been performed using Ion-Torrent GeneStudio S5 System in fresh-frozen biopsies obtained from tru-cut or surgical excision procedures from patients with resistant metastatic cancer. We have selected patients with clinically unequivocal drug resistance to previous therapies (tumor progressing to ongoing therapies or less than six months of stopped therapy). Drugs evaluated includes anthracyclines, alkylating agents (temozolomide), platinum derivatives, taxanes, TOPO 1 inhibitors (irinotecan and topotecan), antimetabolites (fluoropyrimidines, gemcitabine, methotrexate and pemetrexed), and more recently, immune checkpoint inhibitors. Results: A total of 111 procedures have been performed. In 64 patients an unequivocal clinical resistance to previous therapies could not be demonstrated, so the analyses has been performed in 47 patients with a number of different tumor histologies: colorectal cancer (13 patients), ovary/peritoneum (8), pancreas (4), NSCLC (4), breast (3), prostate (3), sarcoma (3), head and neck (2), uterus (2), kidney, bladder, cholangiocarcinoma, stomach and cervix (1 patient each). One hundred and fifty two drugs have been used in these patients (Median 3, Range 1 to 8) previous to the RNA NGS procedure. Resistance profile has been found in 120 out of 152 (78.9% of coincidence), and a favourable profile has been found in 32 (21%) previously used drugs, that could be re-used again in these patients. RNA NGS procedure gives additional information about drugs not previously used that helps in the treatment selection for the patients. Conclusions: Transcriptome provide drug resistance information that correlates in 78.9% of drugs with the previous clinical information. However, in 21% of the previously used drugs transcriptome informs as potentially active and could be tried again in subsequent therapies. Transcriptome (RNA sequencing) provides useful clinical information for treatment decision in the vast majority of pretreated cancer patients.
A phase 1 study evaluating preliminary safety, pharmacokinetic and pharmacodynamic of pemigatinib in Chinese patients with advanced malignancy.
Authors: Ba Yi , Deng Ting , Shi Yehui , Zhang Le , Bai Guiying , Pan Yueyin , Shen Aizong , Han Xinghua , Yang Zhaoyi , Cao Lian , Luo Yang , Wang Yan , Zhou Hui
Published: June 2021

e15051

Background: Dysregulation of fibroblast growth factor receptor (FGFR) is strongly associated with establishment and progression of cancer. Pemigatinib is a selective FGFR1–3 inhibitor that are active in a targeted manner against cancers with activated FGFR pathway. The study was aimed at evaluating the tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) of pemigatinib in Chinese patients (pts) with advanced malignancy. Moreover, potential efficacy of pemigatinib was explored in a broad spectrum of FGFR alteration in variety of cancer types. Methods: In this phase 1 study, Chinese patients with advanced, recurrent or metastatic malignancy that were histologically or cytologically confirmed and harboring FGF/ FGFR 1-3 variation were enrolled. Pemigatinib was self-administered orally at 13.5 mg QD on a 3-week cycle (2-weeks-on/1-week-off schedule). Adverse events and other safety factors were monitored throughout the study. Blood samples were obtained at prespecified time points for PK and PD analysis and efficacy was assessed every 9 weeks per RECIST v1.1 guideline. Results: As of Jan 31, 2021, 12 patients with 5 different cancer types (colorectal cancer (4 pts), gastric and gastroesophageal junction carcinoma (3 pts), cholangiocarcinoma (2 pts), esophageal carcinoma (2 pts) and breast cancer (1pts)) were enrolled. Documented FGF/ FGFR1-3 alterations were FGFR amplification (6), FGFR point mutation (5), FGFR2 fusion (2) and FGF alteration (4) with 2 subjects had more than one alteration types. All the subjects were failed to at least 1 line of prior standard therapy. All patients had at least 1 treatment related adverse events (TRAE) and the most common ones were hyperphosphatemia (100%), decreased appetite (50%) and diarrhea (33.3%). Two patients (16.7%) reported ≥ grade 3 TRAEs, which were hyponatremia (8.3%) and proteinuria (8.3%). There were no TEAEs leading to death or treatment discontinuation. Among 11 efficacy evaluable patients, 2 of them had partial responses (PR) as evaluated by investigators with 1 cholagiocarcinoma harboring FGFR2 point mutation (p.F276C) and the other esophageal carcinoma carrying FGFR1 mutation (p.A354V). 3 patients had a best overall response of stable disease (SD). The objective response rate (ORR) was 16.7% (95%CI: 2–48%) and disease control rate was 41.7% (95%CI: 15–72%). Conclusions: Pemigatinib had an acceptable and manageable toxicity and demonstrated a possible anti-cancer benefit in Chinese patients with advanced malignancy that accompanied with FGF/FGFR1-3 aberrance. A significant implication of the data is that it extended the population that potentially benefit from pemigatinib other than FGFR2 fusion/rearrangement. Clinical trial information: NCT04258527.
Sequential usage of imidazole followed by tamoxifen to enhance the anticancer effect of tamoxifen in estrogen receptor-positive breast cancer cell lines.
Authors: Inci Tarik , Kahraman Erkan , Goker Erdem
Published: June 2021

e15057

Background: In women, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death worldwide. Tamoxifen is the most commonly used drug for the endocrine treatment of breast cancer. It reduces the risk of recurrence and death from breast cancer when given to estrogen-receptor-positive breast cancer patients. It has recently been shown that imidazoles, an antifungal drug, possess anticancer potentials, and it can be a novel therapeutic in cancer treatment. However, the effects of combined treatment with imidazole and tamoxifen are unknown in estrogen receptor-positive breast cancer cell lines. Our study aimed to investigate the effects of imidazole and tamoxifen combination in estrogen receptor-positive breast cancer cell lines. Methods: MCF7 cell line, an estrogen receptor-positive breast cancer cell line, was used in this study. Following 24 hours 50 mM imidazole (molecular grade) treatment, 15µM tamoxifen was treated to MCF-7 cells by 72 hours. As control groups, following for 24-hour imidazole alone treated, only medium treated cells for 72 hours were used. MTT assay was performed for the determination of cell viability. Apoptosis was shown using acridine orange/ethidium bromide staining. The cellular morphological alterations were observed on bright-field microscopy using Giemsa staining. Cell migration status was determined using by in vitro scratch assay. Results: MTT assay results showed that tamoxifen alone treatment for 72 hours decreased cell viability by 18 percent (p < 0.001). On the other hand, cell viability is not affected by imidazole alone treatment for 24 hours compared with the control group (p > 0.05). However, it was calculated that 24 hours of imidazole followed by tamoxifen for 72 hours decreased cell viability up to 42 percent (p < 0.001). Tamoxifen alone group, compared with combined treatment with tamoxifen and imidazole, observed an increase of apoptotic cell numbers in combined treatment with tamoxifen and imidazole group, statistically significantly (p < 0.01). It was observed that cellular morphology was affected by combined treatment with tamoxifen and imidazole. Giemsa staining results showed that MCF 7 cells changed their cellular morphology, lost cell-cell contact, differentiated from parental morphology and cellular morphology, and appeared unhealthy. Parallel to these findings, a decrease in cell migration was observed in the combined-treated group compared to the tamoxifen alone group (p < 0.01). Conclusions: Our results showed that sequential usage of imidazole followed by tamoxifen has an enhanced anticancer effect of tamoxifen in estrogen receptor-positive breast cancer cell lines. These results allow us to establish a new hormonal treatment for patients with breast cancer.
Neoadjuvant PD-1 blockade combined with chemotherapy followed by concurrent immunoradiotherapy for locally advanced anal canal squamous carcinoma patients: Antitumor efficacy, safety and biomarker.
Authors: Xiao Weiwei , Yuan Yan , Wang SuiHai , Cai Peiqiang , Chen BaoQing , Zhang Rong , Zeng ZhiFan , Gao Yuanhong
Published: June 2021

e15500

Background: Efficacy and safety of PD-1 inhibitors have been approved for the treatment of metastatic anal squamous cancer patients, but the efficacy of neoadjuvant treatment with PD-1 in anal squamous cancer patients has not yet been defined. We report results for the cohort of patients with locally advanced anal canal squamous carcinoma treated with neoadjuvant PD-1 inhibitor toripalimab and chemotherapy followed by concurrent immunoradiotherapy. Methods: Five locally advanced anal canal squamous carcinoma patients received 4 cycles of neoadjuvant PD-1 inhibitor toripalimab and Docetaxol and Cisplatin chemotherapy followed by concurrent immunoradiotherapy. Whole exome sequencing (WES) and mIHC were performed with the pretreatment tumor tissue for biomarker analysis. Results: Complete clinical response (cCR) was achieved in 4 patients after neoadjuvant treatment before radiotherapy while the other patient achieved near cCR. cCR was achieved in all the 5 patients 3 months after definitive immunoradiotherapy. Grade 3 toxicity was noted in 1 patient. Molecular testing revealed that PD-L1 expression (≥1%) in tumor and CD4/CD163 expression in tumor and paracancerous tissue were positively correlated with tumor shrinkage in the neoadjuvant treatment phase while TMB didn’t appear to significantly impact the response. Conclusions: PD-1 inhibitor combined with chemoradiotherapy has quite promising effect in locally advanced anal canal squamous carcinoma patients, with very mild toxicity. Pretreatment PD-L1 expression is positively correlated with tumor response to PD-1 inhibitor toripalimab and chemotherapy. It is worthy of further investigation in prospective clinical trial.
LDL receptor related protein 2 to promote colorectal cancer metastasis via enhancing GSK3β/β-catenin signaling.
Authors: Zheng Xiaobin , Liu Huashan , Zhong Xiaoli , Liu Xuanhui , Cai Zerong , Chen Yufeng , He Xiaosheng , Lan Ping , Wu Xiaojian
Published: June 2021

e15507

Background: LDL receptor related protein 2 (LRP2), a multi-ligand endocytic receptor, has been implicated in the tumourigenesis of various human cancers. However, the biological roles and underlying regulatory mechanism of LRP2 in CRC remain unclear. Methods: Real-time PCR (RT-PCR), western blot, and immunohistochemistry were used to examine LRP2 expression. Gene silencing and overexpressing efficiencies of LRP2 were confirmed by RT-PCR and western blot. Then wound-healing, migration assay and invasion assay were used to investigate the function of LRP2 in CRC cells. The protein expression and cellular localization of LRP2 and β-catenin were characterized by immunofluorescence staining. The nude mice tail vein metastasis model was established to observe the effect of LRP2 on the lung metastasis of CRC cells in vivo. In addition, gene set enrichment analysis was carried out to explore the potential mechanism of LRP2 in CRC. Results: LRP2 expression was highly upregulated in CRC compared with matched adjacent normal tissue. LRP2 overexpression was positively correlated with shorter overall survival in CRC patients. The biological function observation indicated that LRP2 promoted CRC metastasis in vitro and in vivo. Further molecular mechanism investigation demonstrated that LRP2 protein interacted with glycogen synthase kinase-3β (GSK-3β) and led to decreased expression of GSK3β at ser9, followed by enhanced β-catenin signaling pathway in CRC cells. Conclusions: Our study demonstrated that LRP2 could enhance the metastatic abilities of CRC cells in vitro and in vivo by inhibiting the expression of GSK3β and enhancing the activity of β-catenin signaling pathway, providing that LRP2 might be a novel therapeutic target for metastasis in CRC.
Correlation between driver mutation and immune microenvironment in colorectal cancer patients.
Authors: Cai Xiaochen , Bai Yuezong , Zhao Xiaochen , Cui Longgang , Chen Hui
Published: June 2021

e15513

Background: Immune checkpoint inhibitor (ICI) therapy has made great achievements, but ICI monotherapies show less effectiveness in colorectal cancer patients. Biomarker exploration have carried out from PD-L1 expression, neo-antigen, gene mutation, etc., but no satisfactory results have been obtained. Methods: Patients, Colorectal cancer patients. Methods, Multi-color immunohistochemistry (multi-IHC) was used to evaluate CD8+ T cells, macrophages and natural killer cell (NK cell) in tumors and tumor stroma. The Shapiro-Wilk method was used to test the normality of the data, and the t-test or Mann-Whitney U test was used according to the test results. A two-sided P < 0.05 was considered a significant difference. Results: The study included 72 colorectal cancer patients, including 26 female (36.7%) and 46 male (63.8%), with a median age of 59.5 (50-67.3). There were 6 patients (8.3%) with BRAF mutation, 43 patients (59.7%) with KRAS mutation, and 56 patients (77.8%) with TP53 mutation. The results of immunohistochemistry showed that, BRAF mutation Vs BRAF wild-type or KRAS mutation Vs KRAS wild-type, the number or proportion of CD8+ T cells, macrophages or NK cells in tumor and tumor stroma were not statistically different. For TP53 mutation Vs TP53 wild-type, the number and proportion of CD8+ T cells or macrophages in tumor and tumor stroma were not statistically different. There was no statistical difference in the number and proportion of NK cells in tumor. But, the median number of NK cells in tumor stroma was 345 Vs 129, p = 0.06, and the proportion of NK cells was 5.2% Vs 1.39%, p = 0.02. Conclusions: There is no significant change in the immune microenvironment of colorectal cancer patients with BRAF mutation and KRAS mutation. There are more NK cells in tumor stroma of colorectal cancer patients with TP3 mutation.
Global BRAF testing practices in metastatic colorectal cancer (mCRC).
Authors: Desai Jayesh , Kopetz Scott , Grothey Axel , Ciardiello Fortunato , Kim Tae Won , Maughan Tim , Van Cutsem Eric , Wasan Harpreet Singh , Yaeger Rona , Yoshino Takayuki , Gollerkeri Ashwin , Edwards Michelle L. , Rodriguez Lizaso Montessa , Tabernero Josep
Published: June 2021

e15523

Background: The BRAF V600E mutation is a marker of poor prognosis in patients with mCRC. Targeted therapy, such as encorafenib + cetuximab, is approved in the US/Europe for the treatment of BRAF V600E-mutated mCRC and demonstrated improved survival vs historical standard of care (SOC). Determining BRAF mutation status in mCRC is recommended by NCCN and ESMO guidelines; although adherence to these guidelines may not be uniform. This report’s objective is to communicate global survey results of mCRC BRAF testing practices. Identifying regions where BRAF testing is not SOC may help identify where education efforts are needed to improve effective treatment decision making. Methods: Oncology treatment centers were identified from a registry and from public information. Centers were selected for research experience, historic data quality, and estimated numbers of mCRC patients. A BRAF testing practices survey using an online platform of verified centers was conducted from March to November 2020; 425 sites in 39 countries responded. Results: BRAF testing is performed as SOC most commonly in Northern and Western Europe (97%) and East Asia (95%). Conversely, BRAF testing as SOC is least common in Eastern Europe (47%) and South America (52%). Surveyed regions generally test patients when confirming advanced disease prior to first-line (1L) treatment (35% to 78%) or at initial histological diagnosis (9% to 41%). Most regions test tumor tissue; few test both tumor tissue and blood; and none conduct blood mutation testing only. Testing practices in the US by type of site (academic vs community) will be presented. Conclusions: BRAF testing has global variability, impacting treatment decisions. Increased awareness and routine testing may lead to informed decisions regarding targeted therapies, such as encorafenib + cetuximab (where approved), in patients with BRAF V600E-mutant mCRC.[Table: see text]
ZEB1 expression in different stages of colorectal cancer.
Authors: Nepomnyashchaya Evgeniya M. , Ulianova Elena P. , Novikova Inna A. , Sagakyants Aleksandr B. , Chernyak Maksim N. , Gappoeva M. A. , Ezhova Maria O.
Published: June 2021

e15526

Background: Colorectal cancer (CRC) is among the most common cancers. The leading cause of high mortality is tumor progression developed due to the epithelial to mesenchymal transition (EMT). The ZEB1 protein is one of the critical regulators of this process. In this regard, our study aimed to assess the ZEB1 expression in different stages of colorectal cancer. Methods: This study included samples of 206 patients with stage II-IV CRC aged 42 to 86 years (mean age 64.2±1.7). All patients were divided into three groups: group 1 - patients with T3-4 N0 M0 (stage II) with high-risk factors for recurrence, n = 6; group 2 - patients with T1-4 N1-2 M0 (stage III), n = 88; group 3 - patients with T1-4 N0-2 M1 (stage IV), n = 58. IHC study was performed using polyclonal rabbit antibodies to ZEB1 (Biorbyt Ltd.) diluted 1:200 and a Reveal Polyvalent HRP-DAB Detection System. The staining percentage and intensity were assessed: 0, 1+ weak, 2+ moderate, 3+ strong. The nuclear reaction of the ZEB1 protein was considered positive when staining was detected in more than 10% (cut-off) of tumor cells with intensities of 2+ and 3+. Statistical analysis of the results was carried out using the STATISTICA 13.0 software (StatSoft Inc., USA). Results: A positive nuclear reaction for ZEB1 was detected in 80.6% (166 of 206 patients), while negative in 19.4% (40 of 206 patients). The maximal percentage of patients with positive staining for ZEB1 was among those with stage IV (94.8%), the minimal percentage - stage II (60%). The prevalence of ZEB1+ in patients with stages III and IV significantly increased the risk of tumor progression by 3.5 (95% CI 1.8-8.4) and 12.2 (95% CI 3.4-43.6) times, respectively, compared with stage II patients. No statistical significance was observed in the comparison between patients with stages III and IV (95% CI 0.9-11.7). The percentage of ZEB1+ samples increased in more advanced tumors. The ratio of ZEB1+/ZEB1- tumors in stage II was 1.5, in stage III - 5.8, in stage IV - 18.3 (p < 0.05). Conclusions: The immunohistochemical study revealed the features of ZEB1 expression in different stages of colorectal cancer, which can serve as prognostic factors that determine the disease progression.
Proteome and phospho-proteome profiling for deeper phenotype characterization of colorectal cancer heterogeneity.
Authors: Vowinckel Jakob , Corwin Thomas , Woodsmith Jonathan , Treiber Tobias , Bruderer Roland , Reiter Lukas , von Leitner Eike-Christin , Novy Karel , Juhl Hartmut , Rinner Oliver ,   Indivumed Authors
Published: June 2021

e15536

Background: The rise of precision oncology therapeutics requires deep understanding of the molecular mechanisms implicated in cancer biology. Colorectal cancer (CRC) is one of the first solid tumors to be molecularly characterized by defined genes and pathways. Advances in tumor profiling have revealed a profound molecular heterogeneity in CRC leading to the definition of several consensus molecular subtypes (CMS). However, this molecular heterogeneity is still largely defined on the genomic and transcriptomics level. To complement the understanding of genetically defined molecular subgroups, we performed large-scale deep proteomic and phospho-proteomic profiling of CRC patient biopsies and adjacent healthy control tissue, which has enabled to explore the phenotype and obtain more functional insights in cancer biology. Methods: Sample processing from 5-10 mg of tissue per sample was performed using a liquid handling robot. Phospho-peptide enrichment was carried out with a Kingfisher Flex device and MagReSyn Ti-IMAC magnetic beads. Data-Independent Acquisition (DIA) LC-MS/MS was performed on multiple platforms consisting of a Thermo Scientific Q Exactive HF-X mass spectrometer coupled to a Waters M-Class LC. Chromatography was operating at 5 µL/min, and separation was achieved using 45 min (whole proteome) and 60 min (phospho-proteome) gradients. Results: Indivumed has built IndivuType, the world’s first multi-omics database for individualized cancer therapy, analyzing the highest quality cancer biospecimens to generate the most comprehensive dataset, including genomics, transcriptomics, proteomics, and clinical outcome information. Enabled by the DIA technology, a mass spectrometric method developed by Biognosys that obtains peptide fragmentation data in a highly parallelized way with high sensitivity, more than 7,000 proteins in the whole proteome and 20,000 phospho-peptides in the phospho-proteome workflow were profiled across more than 900 resected tissue samples of various CMS of CRC. The resulting proteome and phospho-proteome data were integrated into the IndivuType database and cross-analyzed with genomic and transcriptomic markers. Through this combined analysis, novel insights in clinically relevant signaling pathways in CRC subtypes were revealed. Conclusions: The deep phenotypic profiling of cancer samples, using next generation proteomics and phospho-proteomics, has enabled us to go beyond the genomic level in the characterization of tumor molecular heterogeneity. This multi-omics approach provides a solid foundation to advance the understanding of cancer biology, unravel key molecular events, and support the identification of novel therapeutic targets for precision medicine in CRC.
A phase ib trial of assessing the safety and preliminary efficacy of a combination therapy of geptanolimab (GB 226) plus fruquintinib in patients with metastatic colorectal cancer (mCRC).
Authors: Bai Yuxian , Xu Nong , An Shan , Chen Wenhui , Gao Chao , Zhang Deyong
Published: June 2021

e15551

Background: A combination of anti-vascular endothelial growth factor receptor(anti-VEGFR) and anti-programmed cell death-1/ligand 1 (PD-1/L1) may synergize with each other and lead to better anti-tumor efficacy. We aimed to assess the safety and preliminary efficacy of combination therapy with geptanolimab (GB226, a highly selective, fully human monoclonal antibody PD-1 mAb) plus fruquintinib (a VEGFR inhibitor) in previously treated metastatic colorectal cancer (mCRC) patients. Methods: In this phase Ib trial, we enrolled mCRC patients who had failed one or two standard therapies. Patients were given geptanolimab (3mg/kg every 2 weeks) and fruquintinib (once daily for 21 days on/7 days off with planned dose cohorts of 3mg, 4mg, and 5mg) on a 28-day cycle. A standard 3+3 design was employed to determine the primary endpoints of the maximum tolerated dose (MTD) and/or the recommended phase 2 dose (RP2D) based on dose-limiting toxicities (DLT). Secondary endpoints included objective response rate (ORR), duration of response (DOR), disease control rate (DCR), progression free survival (PFS), and overall survival (OS). Results: By December 15, 2020, 15 patients were enrolled: 1 with MSI-H, 12 with MSS, and 2 with MS unknown. Ten out of 15 patients (66.7%) had received ≥2 previous lines of treatment including chemotherapy in combination with anti-EGFR (33.3%) or anti-VEGF (53.3%). Seven patients (46.7%) were found to have the PD-L1 combined positive score (CPS)≥1. Two DLTs (one patient with grade 3 ALT and AST elevation and one patient with grade 3 proteinuria) were identified in fruqintinib 5mg cohort (6 patients enrolled). No DLT was observed in either 3mg (3 patients enrolled) or 4mg (6 patients enrolled) cohorts. RP2D of this combination was identified as geptanolimab (3mg/kg, every 2 weeks) and fruquintinib (4mg, once daily for 21 days on/7 days off). In all evaluable patients, the overall ORR was 26.7% (4/15, 3 confirmed PR, 1 unconfirmed PR), and the ORR was 33.3% (2/6) in the RP2D group. The DCR for all evaluable patients was 80%, and the median PFS (mPFS) was 7.33 months (95% CI: 1.91 – NE). The median DOR and median OS was not reached at the data cut-off date. Among 12 patients with MSS, the ORR was 25.0% (3/12, 2 confirmed PR, 1 unconfirmed PR), DCR was 75% and mPFS was 5.45 months (95% CI: 1.84-9.66). All patients had at least 1 treatment related AE (TRAE). The common TRAE were proteinuria (46.7%), hypertension (46.7%), and elevated aspartate aminotransferase (40.0%). Grade 3 AEs were observed in 46.7% of patients and the most common grade 3 AE was hypertension (20.0%). No grade 4 and 5 TRAE was observed. Conclusions: The combination of geptanolimab and fruquintinib had manageable safety profiles and encouraging anti-tumor activity in mCRC patients. Clinical trial information: NCT03977090.
A phase II trial of pembrolizumab and poly-ICLC in patients with metastatic mismatch repair-proficient colon cancer.
Authors: Karki Nabin Raj , Bano Kulsum , Ramses Sadek , Nayak Asha
Published: June 2021

e15552

Background: Single agent programmed cell death protein 1 (PD1) inhibitor is ineffective against mismatch repair proficient (MMRp) colon cancer with response rates in single digits. Polyinosinic-Polycytidylic (Poly-ICLC) is a synthetic double stranded ribonucleic acid that generates inflammatory response increasing epitope recognition, develops tumor reactive T cells and induces interferon production which increases PD-L1 expression. In this trial, we test the effectiveness of combination of poly-ICLC and pembrolizumab in MMRp metastatic colon cancer. Methods: In this open label, single arm, single institution, phase 2 study, we enrolled 12 MMRp metastatic colon cancer patients from 1/25/2019 to 2/10/2021. Eligible patients had histologically confirmed MMRp metastatic colon cancer, ECOG 1-2 and progression on at least 2 lines of therapy. Treatment (Tx) consisted of Pembrolizumab (200 mg q3 weeks) and poly-ICLC (2 mg twice weekly, 3 days apart) for 1 year of treatment. Tx continued until progression, discontinuation or withdrawal. The primary endpoint was objective response rate by RECIST 1.1. Secondary endpoints included duration of response, adverse event profiling, progression free survival (PFS) and overall survival (OS). Intention-to-treat analyses (ITT) included all patient receiving at least one dose of the study agent. Results: 12 patients with median age 68.5 years (range 54-75) and 33% (4/12) male had been enrolled till 2/10/2021. Objective response rate was 8.3% (1 patient had partial response). The duration of response was 196 days. Among these 12 patients, median PFS was 63.5 days and median OS was 196 days. Treatment related adverse events of any grade were reported in 12/12 (100%) patients with the most common toxicities being nausea, vomiting, anorexia, dehydration and dizziness. 3/12 (25%) had serious (grade ≥ 3) toxicities and one patient died after experiencing leukocytosis, dehydration and hyperbilirubinemia attributed to the trial drugs. Conclusions: Poly-ICLC was not effective in combination with pembrolizumab for MMRp metastatic colon cancer in 3rd line setting and it did not seem to improve response rates to immunotherapy. Novel strategies for stimulating immunogenicity of cold tumors are needed. Clinical trial information: NCT02834052.
Dual-targeted therapy with pyrotinib and trastuzumab for HER2-positive advanced colorectal cancer: Preliminary results from a multicenter phase 2 trial.
Authors: Yuan Ying , Fu Xianhua , Ying Jieer , Yang Liu , Fang Weijia , Han Weidong , Zhang Suzhan
Published: June 2021

e15554

Background: HER2 is an emerging treatment target for colorectal cancer (CRC). Previous phase 2 trials have demonstrated the promising antitumor activity of dual HER2 inhibition with trastuzumab plus lapatinib or pertuzumab in HER2-positive metastatic CRC. Pyrotinib, a novel irreversible HER2/EGFR dual tyrosine kinase inhibitor, has been approved for breast cancer in 2018 in China. The antitumor effect of pyrotinib was also shown in other solid tumors, such as lung cancer and gastric cancer. The randomized phase 3 PHOEBE trial proved that the efficacy of pyrotinib was better than lapatinib when in combination with capecitabine in HER2-positive local relapsed or metastatic breast cancer. We reported preliminary results of pyrotinib plus trastuzumab in patients with HER2-positive advanced CRC from an ongoing multicenter phase 2 trial (NCT04380012). Methods: Patients with confirmed recurrent/metastatic CRC, HER2-positive disease, and ECOG performance status 0-2, received oral pyrotinib 400 mg once a day plus intravenous trastuzumab 8 mg/kg loading dose followed by 6 mg/kg once every 3 weeks. The primary endpoint was objective response rate (ORR), as assessed according to the Response Evaluation Criteria In Solid Tumors version 1.1. The data cutoff date was December 24, 2020. Results: From December 2019 to November 2020, a total of 11 patients were enrolled. The median age was 57 (range, 44-70) years and 73% (8/11) of patients were male. The number of prior therapy lines was 0, 1, and ≥2 in 1 (9%), 2 (18%), and 8 (73%) patients, respectively. One (9%) patient only showed HER2 overexpression, 7 (64%) showed HER2 amplification and overexpression, and 3 (27%) showed HER2 mutation and overexpression. The detection of co-mutations showed that 5 (45%) patients had KRAS mutations, 1 (9%) had NRAS mutation, and none had BRAF mutation. Three patients achieved partial response, with an ORR of 27% (3/11) in the total population, 50% (3/6) in KRAS wild-type patients, and 60% (3/5) in patients with wild type of both KRAS and NRAS, respectively. The disease control rate was 45% (5/11). The most common (occurring in at least 2 patients) grade ≥3 adverse event was diarrhea (73% [8/11]). Dose interruption owing to diarrhea occurred in 7 (64%) patients, and 5 (45%) patients reduced the dose to 320 mg due to diarrhea. No treatment-related death was observed. Conclusions: Pyrotinib combined with trastuzumab showed promising ORR with acceptable safety in patients with HER2-positive advanced CRC, suggesting a potential treatment option, especially in those without co-mutations. Clinical trial information: NCT04380012.
Updated results of ALTER-C002: Anlotinib combined with CAPEOX in first-line treatment of patients with RAS/BRAF wild-type unresectable metastatic colorectal cancer.
Authors: Ding Ke-Feng , Liu Yue , Du Jinlin , Zhu Yuping , Liu Zhuo , Wang Jianping , Xu Dong , Li Jun , Liao Xiujun , Sun Lifeng , He Jinjie , Xiao Qian , Wang Jianwei , Cao Hongfeng , Cai Yibo , Cai Cheng , Jin Zhekang , Yuan Ying
Published: June 2021

e15564

Background: Antiangiogenic therapy plus chemotherapy is one of the standard treatments in mCRC. Anlotinib, an oral small multi-targeted tyrosine kinase inhibitor targeting VEGFR 1/2/3, FGFR 1-4, PDGFR α/β and c-kit, has demonstrated prolonged PFS in refractory mCRC. This trial was conducted to evaluate the efficacy and safety of anlotinib combined with CAPEOX as first-line treatment for unresectable RAS/BRAF wild-type mCRC. Methods: Patients aged 18-75, with RAS/BRAF wild-type unresectable mCRC, without prior systemic treatment and ECOG status ≤ 1were enrolled in 3 hospitals in Zhejiang, China. Enrolled patients received capecitabine (850 mg/m2 p.o., bid, on day 1-14 every 3 weeks), oxaliplatin (130 mg/m2 i.v., on day 1 every 3 weeks) and anlotinib (12 mg p.o. qd, on day1-14 every 3 weeks) as inducing therapy. After 6 cycles of combined therapy, patients who achieve complete response (CR)/ partial response (PR)/ stable disease (SD) would receive capecitabine and anlotinib as maintenance therapy until tumor progression. The primary endpoint is objective response rate (ORR); secondary endpoints included safety, disease control rate (DCR) and progression-free survival (PFS). Results: From November, 2019 to February, 2021, 31 patients had been enrolled. 1 patient was excluded for refused treatment. By now, 27 patients received at least 2 cycles of treatment and were available for efficacy evaluation: 22 patients had partial response (PR), 5 patients had stable disease (SD). The ORR was 81.5% (95% CI: 61.9–93.7%), and DCR was 100% (95% CI: 87.2–100%).1 patient received radical surgery after 6 cycles of treatment. The median PFS has not been reached yet. The most common grade≥3 AEs included hypertension (45.2%), neutropenia (25.8%) and diarrhea (12.9%). No treatment-related deaths occurred. Conclusions: The combination of anlotinib and CAPEOX showed promising antitumor activity and manageable toxicity in unresectable RAS/BRAF wild-type mCRC. Furthermore, we are launching a phase 3, multicenter, double-blind trial to further assess the efficacy of this regimen. Clinical trial information: NCT04080843. [Table: see text]
Phase I dose-escalation study of desynchronized irinotecan plus bevacizumab, oxaliplatin, 5-fluorouracil, and folinic acid (bFOLFIRINOX-3) administration in chemorefractory metastatic colorectal cancer patients.
Authors: Fumet Jean-David , Hervieu Alice , Hennequin Audrey , Zanetta Sylvie , Bertaut Aurelie , Ghiringhelli François
Published: June 2021

e15573

Background: Treatment of non-resectable metastatic colorectal cancer (mCRC) involves chemotherapy based on 5-fluorouracil, oxaliplatin and irinotecan and monoclonal antibodies targeting VEGF or EGFR. Rechallenge with oxaliplatin and irinotecan bi fractionation (FOLFIRI3) have previously shown efficacy in chemorefractory patients but desynchronized triplet chemotherapy was never tested. The aim of this study was to evaluate the safety and efficacy of a new regimen so-called: FOLFIRINOX-3 bevacizumab in chemorefractory mCRC. Methods: A phase I study to test bFOLFIRINOX 3 regimen was designed using Standard “3 + 3” design for dose escalation. Patients enrolled, >18years and ECOG 0 or 1, have a pathologically confirmed mCRC and experienced treatment failure after standard chemotherapy that include 5-fluorouracil, oxaliplatin and irinotecan. Absence of residual neuropathy and previous grade 3 irinotecan related toxicity was manditory. Regimen tested consisted of bevacizumab (5mg/kg) plus simplified FOLFOX4 (folinic acid (400mg/m2), 5-fluorouracil (400mg/m2 bolus followed by 2400mg/m2 for 46h), oxaliplatin (85mg/m2) and irinotecan (administered before and after infusional 5-fluorouracil). Three irinotecan levels were planned at 60, 70 and 90 mg/m² (day 1 and day 3). Dose limiting toxicities (DLT) were identified during the first 2 cycles. Primary endpoint was assessment of maximum tolerable dose trough evaluation of acute toxicities (CTCAE v4.03). Secondary endpoints included objective response (RECIST 1.1), progression free survival, overall survival and late toxicity. Results: Thirteen patients received experimental treatment on this study. The RP2D was irinotecan 70mg/m² day 1 and day 3. Two patients experienced DLTs (G3 diarhea ) at dose level 90mg/m² and one DLT occured (G3 diarrhea) at 70mg/m² level. The most common drug-related adverse events (all grades) were fatigue (92.3%), diarrhea (76.9%), nausea (61.5%), peripheral neuropathy (61.5%), thrombopenia (46.1%) and anemia (15.3%). Among 11 response-evaluable patients, we noticed 4 partial responses, 7 stable disease and no progression as best response. Conclusions: The combination of bFOLFIRINOX-3 at the RP2D of 70mg/m² day 1 and day 3. was well tolerated and feseably. The regimen resulted in high response rate in chemorefractory metastatic colorectal cancer. Phase II is ongoing. Clinical trial information: NCT03795311.
Postoperative PET-CT in patients (pts) with pathological stage III colon cancer (CC): Interim results from the first prospective validation study.
Authors: Tschernichovsky Roi , Perl Gali , Finkel Inbar , Peretz Idit , Jacobi Oded , Sternschuss Michal , Ulitsky Olga , Kundel Yulia , Sulkes Aaron , Bernstine Hanna , Groshar David , Brenner Baruch
Published: June 2021

e15599

Background: A substantial number of pts with pathological stage III CC recur despite the absence of metastatic disease on pre-operative CT. In a previous large retrospective study from our institution on 348 pts, we reported that early postoperative PET-CT modified the staging and management of 13.4% of assumed stage III CC pts. The aim of the current study was to prospectively validate these results. Methods: A prospective, single-center study of pts with pathological stage III CC who underwent early postoperative PET-CT between the years 2013-2021. Results: 83 pts were accrued and 81 (48.1% males, median age 66y) were evaluable for the primary endpoint i.e. PET-CT results. Pathological stage was IIIA, IIIB and IIIC in 7 (8.6%), 56 (69.1%) and 17 (21%) of pts, respectively. Median number of lymph nodes examined and of positive nodes were 17 (range, 9-134) and 2 (range, 0-15), respectively. Post-operative PET-CT findings were significant in 7 pts (8.6%): 4 pts (4.9%) were upstaged to stage IV, 2 (2.5%) were diagnosed with a second primary malignancy, and 1 (1.2%) was both upstaged and diagnosed with another cancer. Three additional pts (3.7%) are currently undergoing evaluation for suspicious PET-CT findings. At a median follow-up of 30.6 months (range, 6.2-92), 13 of the 71 pts with true stage III CC recurred; the estimated 3y disease-free survival rate was 81%. The estimated 5y overall survival rates for the entire cohort and for true stage III pts were 82% and 90%, respectively. Of the 5 pts found to have metastatic disease based on PET-CT findings, one is scheduled to undergo potentially curative surgical removal of a solitary liver metastasis. Conclusions: Interim results from the first prospective study to evaluate the impact of early postoperative PET-CT in pts with pathological stage III CC seem to support earlier retrospective data: the use of PET-CT in this setting changed the staging and management of 8.6% of pts, including the possibility for early detection of potentially curable metastatic disease. Additional data, with more pts and longer follow-up, will be presented at the meeting.
Association of colon adenocarcinoma in situ in polyp with subsequent colon cancer: A population-based retrospective study.
Authors: Wang Shuai , Jayarangaiah Apoorva , Kaur Anahat , Elrafei Tarek N. , Steinberg Lewis , Kumar Abhishek
Published: June 2021

e15605

Background: Adenocarcinoma in situ (pTis) of the colon is defined as malignant cells confined within epithelium or mucosa. Since pTis is not invasive, polypectomy alone is usually adequate, especially if resection margins are cancer-free. We performed a population-based study to investigate the association of intrapolyp pTis and subsequent colon cancer. Methods: We queried the SEER database (1975-2017) for patients with pTis in adenoma. We further filtered patients with subsequent colon cancers. Standard incidence ratios (SIRs) were used to evaluate the excess risk of developing subsequent colon cancers comparing to the general population. Difference between patients who did or did not develop colon cancer were analyzed using Chi-square test. Results: A total of 15164 patients with pTis were identified. Among them, 736 (4.85%) patients developed subsequent colon cancer. Age ≥70 years, pTis in villous adenoma, polyp in hepatic flexure, splenic flexure, transverse colon, descending colon, and diagnosis year before 2000 were associated with increased risk of developing subsequent colon malignancy (all p< 0.05). Polypectomy comparing to colectomy (total, subtotal or partial) is associated with a higher rate of developing subsequent colon cancers ( p < 0.05). In patients with intrapolyp pTis, observation/expectation (O/E) of developing colon cancers are elevated to 4.76, 1.84, 1.66, and 1.28 within one year, 1-5 year, 5-10 year, and after ten years, respectively (all p< 0.05). O/E for the male and female is 1.80 and 1.63 (both p< 0.05); for the white and black is 1.64 and 2.21(both p< 0.05). Conclusions: Subsequent colon cancers developed in 4.85% of pTis patients. Excess risk of developing subsequent colon cancers is highest in the first year, and declines with time but persists beyond ten years. Male and black have the highest excess risk. Factors like older age, villous adenoma, location from hepatic flexure to descending colon, and polypectomy are associated with developing subsequent colon cancers.