bluuebunny/crossref_metadata_2025 huggingface dataset:
NRG1 fusion-driven cancers: A systematic literature review and meta-analysis.
Authors: Stalbovskaya Viktoriya , Wasserman Ernesto , Fryzek Jon , Bylsma Lauren C , Sirulnik L. Andres
Published: May 2020

e15605

Background: Neuregulin 1 (NRG1) fusion proteins have recently been identified as oncogenic drivers in diverse cancers with high unmet medical need. We recently reported promising responses in patients with cancers harboring NRG1 fusions treated with the bispecific antibody MCLA-128 (Schram 2019). The objective of this study was for the first time to quantitatively summarize the frequency of tumors harboring NRG1 fusions reported in the published literature. Methods: Neuregulin 1 (NRG1) fusion proteins have recently been identified as oncogenic drivers in diverse cancers with high unmet medical need. We recently reported promising responses in patients with cancers harboring NRG1 fusions treated with the bispecific antibody MCLA-128 (Schram 2019). The objective of this study was for the first time to quantitatively summarize the frequency of tumors harboring NRG1 fusions reported in the published literature. Results: Out of 212 articles identified in the literature as of 31-Jul-2019, 37 met the inclusion criteria and were abstracted. 13 different tumor types were identified as harboring NRG1 fusions including 5 tumor (sub)types which met the criteria for frequency meta-analysis (Table 1). NRG1 fusions were most frequent in pancreatic adenocarcinoma (3.3%, 95% confidence intervals (CI): 0.3-28.7%; apparent enrichment in KRAS WT) and NSCLC (0.8% 95% CI: 0.3-2.7%) with an enrichment in invasive mucinous adenocarcinoma (9.8%, 95% CI: 4.7-19.6%). Statistically significant heterogeneity was observed indicating substantial variation across studies in each analysis. For tumor types that did not meet the criteria for meta-analysis (uterine, renal cell, ovarian, colorectal, head and neck, bladder, prostate and sarcoma) the reported frequency of NRG1 fusions was typically less than 1%. Conclusions: NRG1 fusions are present across a wide range of different solid tumor types, most frequently in NSCLC and PDAC. NRG1 fusion-driven cancers represent a potential tumor-agnostic therapeutic target. The advent of new treatment options and increased genomic testing will allow a more precise estimation of the frequency of NRG1 fusions in cancer. [Table: see text]
The AVI-PDX: An innovative in vivo platform of miniaturized patient-derived xenografts for preclinical developments and personalized medicine.
Authors: Berget Frédéric , Costechareyre Clélia , Jarrosson Loraine , Delloye-Bourgeois Céline , Castellani Valerie
Published: May 2020

e15607

Background: The conception of preclinical paradigms to predict the patient response is a major goal for the development of novel therapies and the design of personalized treatments in oncology. Patient-Derived Xenograft (PDX) mouse models require tumoral material in significant amount, not always compatible with practiced biopsies, are limited by a very low tumor intake rate, and a long delay to obtain exploitable tumors. Moreover, xenografts in mice are usually performed subcutaneously, thus in a tissue irrelevant regarding microenvironmental specificities. Finally, these models are not scaled for global molecular analysis to uncover biomarkers of patient heterogeneity and response to treatments. Apart from shortening tumor formation, alternatives of grafting tumoral cells on the chicken chorio-allantoid membrane (CAM model) bare all inconvenient of mice models Methods: We have developed an innovative in vivo technological platform, consisting in (i) grafting tiny human tumoral samples within tissues of chicken embryos, selected for their homology to primary or metastatic sites, (ii) administrating therapeutic treatments, (iii) analyzing tumor responses using 3D imaging and identifying treatment-specific molecular signatures. Results: Originally conceived for a pediatric cancer (Delloye-Bourgeois et al, 2017), the platform was next adapted to a range of adult cancers. Grafted cells from patient samples exhibited exceptionally fast and efficient rate of tumor ingrowth, and replicas retained molecular features of the initial sample. The platform is already exploited for the identification of novel therapeutic targets, the evaluation of candidate therapies efficacy, the design of combination of therapies and the characterization of molecular signatures in several cancer indications, including germ line tumors, neuroblastoma, pancreatic cancers, triple negative breast cancer and melanoma. Conclusions: Overall, this breakthrough technology should considerably improve and shorten the process of molecule discovery and accelerate access of novel therapies to patients.
Molecular mechanism(s) of resistance to vandetanib in medullary thyroid carcinoma.
Authors: Glassberg Brittany , Khan Sophia , Pemov Alex , Hawley Robert , Widemann Brigitte C. , Khan Javed , Glod John
Published: May 2020

e15628

Background: Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor arising from parafollicular C cells of the thyroid. Pediatric cases of this cancer are associated with the diagnosis of multiple endocrine neoplasia, which is caused by a mutation in the rearranged during transfection ( RET) gene. Vandetanib, an oral receptor tyrosine kinase inhibitor, is approved for the treatment of patients with progressive MTC. While there is a response rate of 50%, the majority of patients eventually develop resistant disease. The goal of this work is to understand genetic and epigenetic underpinnings of sensitivity and resistance to vandetanib, and develop novel synergistic combination therapies in medullary thyroid carcinoma. Methods: The TT cell line (RET mutation p.C634W) was cultured in increasing concentrations of vandetanib in order to generate a vandetanib resistant cell line. Both vandetanib-sensitive and vandetanib-resistant lines were evaluated. Each line underwent exome sequencing, RNA sequencing, and methylation array analysis. In parallel we performed Genome-wide CRISPR knock-out and CRISPR activation of both cell lines using the TKO Version 3 Library, consisting of 71,090 gRNAs targeting 18,000 genes, and the Calabrese P65-HSF activation Library, using 56,762 guides for 18,000 genes. Results: Both whole exome and RNA sequencing demonstrate increased expression of RET C634W in both cell lines, to a significantly greater extent in the drug-resistant line than in the sensitive line. RNA sequencing demonstrates differential expression of transcripts between the vandetanib-sensitive and vandetanib-resistant cell lines, including multidrug-resistance 1 (which confers drug resistance in other cancers) and autotaxin (promotes cell survival). Genome-wide CRISPR knock-out showed enrichment of genes necessary for growth suppression by vandetanib, including MACROD2, GORASP2, and MAP3K genes. Gene set enrichment analysis of the CRISPR knock-out data showed enrichment of the proteasome pathway as a potential candidate of growth suppression by vandetanib, which was validated via exposure of the cell lines to bortezomib (IC50 = 3.62nM), a molecularly targeted proteasome-inhibitor. Conclusions: DNA mutations and epigenetic modification confer resistance of medullary thyroid carcinoma to tyrosine kinase inhibition. Adding further therapeutic agents to target these genetic alterations is a potential strategy for overcoming resistance.
Tolerability of enzalutamide in prostate cancer: A meta-analysis.
Authors: Karawadia Tejas , Wu Shenhong
Published: May 2020

e15629

Background: Enzalutamide, a second-generation androgen receptor inhibitor widely used in the treatment of prostate cancer, is often discontinued due to adverse events. A meta-analysis of randomized controlled trials was performed to examine the overall tolerability of enzalutamide in prostate cancer in comparison with controls. Methods: Databases including PubMed (up to December 2019) and Google scholar (up to December 2019) were searched to identify all phase II and III randomized controlled trials that compared enzalutamide with placebo (with or without other anti androgen drugs) along with reported data regarding drug discontinuation due to adverse events with enzalutamide and placebo. A random- or fixed-effects model was used to determine summary incidences, relative risks (RR), and 95% confidence intervals depending on the heterogeneity of included studies. Results: A total of 7 RCTs were eligible for analysis which included 7,343 patients (enzalutamide: n = 4116, control: n = 3227). The summary incidence of tolerability measured as discontinuation rate due to adverse events was 7.3% (95% CI: 6.1-8.7%) with enzalutamide and 5.7% (95% CI: 4.3-7.5%) with placebo or first-generation antiandrogens including bicalutamide, nilutamide or flutamide. The tolerability of enzalutamide varied with stage of prostate cancer with significantly higher incidence of discontinuation (9.8%, 95% CI: 8.0-11.9%) in non-metastatic prostate cancer group than metastatic prostate cancer group (6.7%, 95% CI: 5.8-7.6%). In comparison with controls, enzalutamide did not significantly affect the tolerability with an RR of 1.25 (95% CI: 0.95-1.66, P = 0.12). In addition, enzalutamide did not significantly affect the tolerability with an RR of 1.11 (95% CI: 0.80-1.53, P = 0.54) when compared to placebo. Conclusions: Enzalutamide may be comparable to placebo or first-generation antiandrogens in the tolerability for prostate cancer patients. Cautions should be taken to avoid unnecessary discontinuation.
Bevacizumab induced proteinuria and hypertension: A comparative analysis of anti-hypertensives utilized within a single institution.
Authors: Farooqui Marwah Wafa , Gustafson Nicholas , Patel Nisha , Danelski Erika , Patel Tirth , Srinivasan Krishnan , Stein Amy , Ghouse Masood
Published: May 2020

e15631

Background: Bevacizumab (Bev) is a recombinant monoclonal antibody associated with hypertension and proteinuria commonly used in treatment of various malignancies. Often times, treatment is interrupted due to complications. Currently, there are no evidence based medication guidelines for Bev induced hypertension (htn) and proteinuria (pu). ACE inhibitors (ACE-I) and angiotensin II receptor blockers (ARBs) are known to reduce severity of proteinuria in other disease states. However, no studies on these drugs have been conducted to verify their efficacy for Bev associated htn and pu. This study aims to provide guidance on Bev induced htn and pu management. Methods: This is a retrospective analysis of oncology patients between 2018-2019 at a single community clinic. All patients receiving Bev were selected and the control arm was patients with similar malignancies on chemo without Bev. Data was collected for 10 cycles of treatment. A comparison for htn was done using the Chi-square test between the control and the Bev group. Within the Bev group different classes of meds were studied to determine superiority for htn and pu control with Chi-square tests or independent t-tests as appropriate. Results: The data set has a total of 82 observations. The demographics of the two groups are given in Table 1. In the Bev group, 16 (46%) of the patients were on ACE-I/ARB during treatment (10 [29%] on ARB), 10 [29%] were on a diuretic, 10 [29%] were on calcium channel blocker, and 13 [37%] of patients were on ARB/thiazide (combo). On average, patients receiving Bev had an average 11 point increase in SBP compared to control. ACE-I or ARB (p value 0.028) and CCB ( p value 0.025) had the best htn control . Patients on the ARB/thiazide combo had the least proteinuria. Our study shows a significant improvement in proteinuria in patients on an ARB/thiazide combo in comparison to patients on ACE-I or CCB alone. CCB was shown to be the worst for proteinuria but it did have some benefit with htn (p < 0.05). Conclusions: ACE-I, ARB, and CCB were all equally beneficial in treatment for Bev induced htn. Previous studies have shown the potential benefit of ARB/Thiazide combo in other nephropathies. This study gives us new insight on the combination of ARB/Thiazide for therapeutic benefit in Bev induced proteinuria. Further prospective studies are needed to help us guide with therapy.
Growth modulation index (GMI) as a comparative efficacy measure of larotrectinib versus prior systemic treatments for TRK fusion cancer patients.
Authors: Italiano Antoine , Hong David S. , Briggs Andrew , Garcia-Foncillas Jesus , Lassen Ulrik Niels , Vassal Gilles , Kummar Shivaani , Van Tilburg Cornelis M. , Keating Karen N , Reeves John A. , Fellous Marc Mardoche , Childs Barrett H. , Laetsch Theodore Willis , Drilon Alexander E.
Published: May 2020

e15638

Background: Larotrectinib is a highly selective TRK inhibitor that demonstrated high response rates and durable disease control in three phase I/II single-arm studies of patients (pts) with TRK fusion cancer. While single-arm studies are often used for rare cancer populations, they do not provide comparative data. GMI utilizes pts as their own control and can be used in this setting. GMI is the ratio of progression-free survival (PFS) on the current therapy to time to progression (TTP) on the most recent prior line of therapy. A GMI ≥1.33 has been used as a threshold of meaningful clinical activity. We report GMI for TRK fusion cancer pts treated with larotrectinib. Methods: Data were pooled from 3 clinical trials of pts with TRK fusion cancer treated with larotrectinib. A retrospective, exploratory analysis of GMI was conducted in pts who had been on larotrectinib and followed up for ≥6 mos or pts who discontinued early, and had ≥1 prior line of systemic treatment for locally advanced or metastatic disease. TTP on the prior line of therapy was investigator assessed. PFS on larotrectinib was determined by independent review committee per RECIST 1.1. Pts who had not progressed were not censored from the analysis. Results: As of July 15, 2019, 122 pts were eligible for analysis. Fifteen different tumor types were represented, the most common being soft tissue sarcoma in 26 pts (21%), infantile fibrosarcoma in 22 (18%), and thyroid in 21 (17%). Median GMI was 3.35 (range 0.00–337.00; Table); In metastatic pts (n = 81), the proportion with a GMI ≥1.33 was higher in pts with a complete or partial response vs non-responders (88% vs 42%). In the whole analysis set (N = 122), median TTP on prior line of treatment was 2.7 mos (95% CI 2.0–3.1) and median PFS on larotrectinib was 33.4 mos (95% CI 13.8–NE; HR 0.20 [95% CI 0.14–0.29]). In metastatic pts (n = 81), median TTP on prior line of treatment was 2.3 mos (95% CI 1.9–3.0) and median PFS on larotrectinib was 23.4 mos (95% CI 10.9–NE; HR 0.24 [95% CI 0.16–0.36]). Conclusions: Greater than two-thirds of pts with TRK fusion cancer treated with larotrectinib had a GMI ≥1.33, demonstrating a clinically meaningful improvement in PFS compared to TTP on their prior treatment. Clinical trial information: NCT02122913, NCT02576431, NCT02637687.
A preclinical model for skin sensitization prediction of antineoplasic drugs.
Authors: Perez-Fidalgo Jose Alejandro , Montero Magallo Paula , Roger Laparra Ines , Ribera Alba Pilar , Poveda Ferriols Jesus , Milara Paya Javier , Cervantes Andres , Cortijo Gimeno Julio
Published: May 2020

e15643

Background: Skin side effects are common manifestations of antineoplastic drugs that are frequently observed in early clinical trials. Therefore, there is a need to identify skin toxic agents before clinical development in order to predict severe skin manifestations. In many cases, skin toxicity is due to sensitization, a key immunologic process mediating redness, swelling and itching that can lead to more severe skin alterations. Methods: We adapted three skin cellular in vitro techniques for cutaneous drug sensitization assessment of the Organization for Economic Cooperation and Development (OECD, 2012) in order to predict antineoplastic drug skin sensitization: 1) Direct peptide reactivity assay (DPRA) was assessed by high performance liquid chromatography (HPLC) coupled to ultraviolet detector, to detect covalent binding of antineoplastic to skin proteins (haptenation). 2) KeratinoSense skin sensitization assay was evaluated in keratinocyte cell line (HaCaT) transfected with a selectable plasmid to quantify luciferase gene induction by chemiluminescence as a measure of activation of Keap1-Nrf2-antioxidant response element involved in the cellular processes in skin sensitization and 3) The human cell line activation test (h-CLAT) represents the activation of dendritic cells by the increase of CD86 and CD54 surface markers measured by flow cytometry. An antineoplastic was considered sensitizing when at least two of these three tests were positive. Antineoplastic tested were paclitaxel, erlotinib, imatinib, sunitinib, cetuximab, olaparib, palbociclib and everolimus. Results: Paclitaxel was positive for all the three tests; the DPRA formation, keratinoSense activation and h-CLAT expression showing the highest level of sensitization. Moreover sunitinib, and imatinib were positive for two of the three in vitro cellular tests, being considered sensitizing drugs. In contrast, erlotinib, cetuximab, olaparib, palbociclib and everolimus were considered non-sensitizing antineoplastic agents. In the case of erlotinib a high proportion of apoptosis of the keratinocytes during the keratinosense test was observed, suggesting that cutaneous toxicity could be due to cytolysis instead of sensitization. Conclusions: Results obtained in this work suggest that pre-clinical assays may predict skin sensitization and be of potential value to predict skin sensitization of antineoplastic drugs before clinical development. Further assessment with in vivo tests will help to identify the cutaneous toxic mechanisms of those non-sensitizing drugs as cetuximab
Antitumor activity of tipifarnib and PI3K pathway inhibitors in HRAS-associated HNSCC.
Authors: Burrows Francis , Malik Shivani , Wang Zhiyong , Chan Stacia , Gutkind Silvio
Published: May 2020

e15658

Background: HRAS is an important driver oncogene in HNSCC and other squamous cell carcinomas (SCCs). HRAS mutations are observed in 6-10% of HNSCC cases and appear to define a unique subset of HNSCC associated with wild-type TP53, co-mutations in caspase 8 and a characteristic methylation pattern. RAS proteins undergo several posttranslational modifications that facilitate their attachment to membranes. The first and most critical modification is the addition of a farnesyl isoprenoid moiety by the enzyme farnesyltransferase (FT), prompting the development of FTIs for the treatment of RAS-driven cancers. Tipifarnib is a potent and selective FTI that has demonstrated compelling antitumor activity in a heavily pretreated cohort of recurrent/metastatic HNSCC carrying HRAS mutations. Based on these data, a pivotal study (NCT03719690) evaluating the efficacy of tipifarnib in HRAS mutant HNSCC (AIM-HN) is currently ongoing. Methods: HRAS is the predominant RAS in squamous epithelial cells and SCCs commonly overexpress the protein. In TCGA PanCancer Atlas, approximately 30% of HNSCC cases have elevated HRAS gene expression, raising the possibility that some HRAS wild-type (WT) HNSCCs may also display a degree of dependence on this oncoprotein. The PI3K-AKT-mTOR pathway is another prominent driver in HNSCC, and reports suggest HRAS and PI3K can each drive resistance to inhibitors of the alternative pathway. In this study we explored the activity of tipifarnib in cellular models and six HRAS-mutant and twelve HRAS WT HNSCC patient-derived xenograft (PDX) models alone and in combination with inhibitors of PI3K-a (BYL-719), AKT (GSK2141795) and mTORC1/2 (INK128). Results: Tipifarnib induced regression in several HRAS WT-overexpressing models. In those cases where the FTI was only moderately active, robust inhibition of tumor growth was observed in the majority of animals treated with the combination of tipifarnib and the PI3K-a inhibitor BYL-719. Similar activity was noted in a smaller panel with GSK2141795 & INK128. Regressions with the FTI-PI3K-a inhibitor doublet were observed both in tumors that were WT or harbored hotspot mutations or amplification of the PIK3CA gene and in HRAS mutants that carried or lacked PIK3CA mutations. Conclusions: Concomitant blockade of both targets may have surprisingly broad and potent anti-tumor activity in HNSCC. Additional biomarkers associated with sensitivity or resistance and alterations in gene expression (by RNAseq) and oncogenic signaling following treatment either as a monotherapy or in combinations will also be described.
Drugging the undruggable: A market readiness analysis for KRAS-G12C.
Authors: Loupakis Fotios , Bloom Kenneth Joel , Allen Wendy , Scanlon Enya , Stacey Isabel , Keeling Derry Mae , Patel Nital , Clark Jordan
Published: May 2020

e15667

Background: KRAS G12C is a distinctively aggressive, poor survival, tumor genotype conferring resistance to anti-EGFR therapies in lung, colorectal (CRC) and pancreatic cancers. Prospective therapies targeting G12C have demonstrated promising activity in Phase I trials. In the advent of potentially transformative novel inhibitor therapies, we assess the need for earlier and repeated tumor profiling between treatments to accurately guide further therapeutics and assess market readiness for specified testing. Methods: Treatment-naïve patients and cell-lines were assessed for genomic change by consensus molecular classification in CRC pre/post treatment with standard chemotherapy. Assessing mutation occurrence, prevalence and testing rates, we aimed to identify areas of translational potential for testing within common cancers. A laboratory and prescriber mapping of the US across lung, CRC and pancreatic cancer types, was carried out using Diaceutics’ proprietary Global Diagnostics Index (GDI), a real-world data diagnostic database, to determine market readiness for companion diagnostic (CDx) and follow-on testing in the dawn of transformative therapies. Potential barriers to test adoption were explored including reimbursement analysis. Results: Genomic analysis shows CRC tumors change after treatment with first-line therapies rendering the primary tumor profile result less reliable. This highlights a distinct need for repeated testing post-treatment for continued efficacy in therapeutics. Patients with pancreatic cancer would benefit the most from increased testing for G12C particularly earlier testing as KRAS mutants occur before neoplastic transformation. Although the market appears ready, reimbursement for KRAS G12C remains a challenge for pancreatic cancer compared to either lung or CRC. Conclusions: This study provides genomic evidence of the necessity for more frequent tumor testing post-treatment with chemotherapy, and earlier testing in pancreatic cancer to enhance efficacy of targeted therapies. The market is ready for increased testing volumes, yet problems surrounding reimbursement and stage of testing remain. Earlier testing may increase survival and decrease cost of patient care, suggesting more frequent testing is imperative across cancer types.
Early carcinoembryonic antigen (CEA) dynamics to predict fruquintinib efficacy in FRESCO, a 3+ line metastatic colorectal carcinoma (mCRC) phase III trial.
Authors: Bai Yuxian , Qin Shukui , Li Jin , Deng Yanhong , Yang Lei , Xu Rui-hua , Chen Zhendong , Zhong Haijun , Pan Hongming , Guo Weijian , Shu Yongqian , Yuan Ying , Xu Jianming , Shen Lin , Wang Ning , Zhang Bin , Zhang Qiang , Fan Songhua , Guo Xiaojun , Peng Mengye
Published: May 2020

e16001

Background: The FRESCO phase 3 trial demonstrated a significant survival benefit with fruquintinib vs. placebo in the third-line or later therapy of mCRC patients. CEA levels are widely used in conjunction with imaging to monitor response to systemic therapy in patients with mCRC. Herein, we undertook post-hoc analyses of FRESCO patient data to investigate the early changes in CEA during treatment, as well as potential relationships with efficacy parameters. Methods: Patients were included if baseline CEA was abnormal according to local lab reference range. Serum CEA levels were measured at baseline and Day 1 of each cycle (except for Cycle 1). Early CEA change was analyzed at first radiological evaluation (C3D1, Week 8), CEA response was defined as ≥ 50% decrease from baseline, and CEA progression was defined as ≥ 100% increase from baseline. Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier method; hazard ratio (HR) was estimated through Cox proportional hazards model; p-value was generated from log rank test. Results: 88.4% (245/277) and 94.9% (130/137) of patients had an abnormal baseline CEA in the fruquintinib group and placebo group, respectively. Median baseline CEA values were similar between treatment groups. After 2 cycles of treatment, the proportion of patients had CEA response was significantly higher in the fruquintinib group than placebo group (30.0% vs. 1.3%, p < 0.001). In the fruquintinib group, patients with early CEA response (n = 63) had longer median OS (12.8 vs. 7.8 months, HR = 0.45, p < 0.001) and median PFS (5.6 vs. 3.7 months, HR = 0.49, p < 0.001) than patients without (n = 147). 66.7% (140/210) of patients in fruquintinib group had stable disease (SD), and fruquintinib in those patients with concomitant CEA response exhibited a significantly greater OS benefit than with CEA progression (14.4 vs. 8.7 months, HR = 0.38, p = 0.004). Conclusions: Fruquintinib increased early CEA response. CEA response at first radiological evaluation after cycle 2 could be considered as a predictor for better OS and PFS. Among patients with SD at first evaluation, those with CEA response seems benefit more from fruquintinib. Clinical trial information: NCT02314819 .
Correlation of existence and number of mutations in DDR signaling pathway genes with poor survival after resection of colorectal liver metastases.
Authors: Wang Kun , Wang Hongwei , Jin Kemin , Zhang Xiaoyu , Yang Chunhe , Xing Baocai
Published: May 2020

e16004

Background: Patients of colorectal cancer with liver metastatic (CRLM) show various in recurrence and prognosis. Previous researches have revealed that the disfunction of DNA damage repair (DDR) signaling pathways was correlative with oncogenesis and poor prognosis. Here we aimed to determine the impact of DDR gene mutations on survival in patients undergoing CRLM resection. Methods: Tumor tissues from 164 patients with CRLM were collected for next generation sequencing (NGS). Single nucleotide variants, indels, and copy number variations were obtained from a 620-gene panel, including 68 genes in 7 DDR signaling pathways. Correlations of mutations in DDR genes with overall survival (OS) and recurrence-free survival (RFS) were determined by using Kaplan-Meier analysis. Results: 152/164 of patients carried at least one of DDR gene alternations. The most frequently mutated gene was TP53 (132/164), followed by CHEK2 (21/164), BRCA2 (10/164), ATM (9/164), PRKDC (8/164), FANCM (8/164), ATR (7/164), POLE (5/164), BRCA1 (4/164), POLD (3/164). Survival analysis indicated that TP53 mutations were not correlated with OS and RFS (P = 0.38 and 0.21). Further analysis in the TP53mut subgroup showed that the patients with other DDR gene mutations (64/132, 48.48%) exhibited a significantly worse OS than the wild type ones (P = 0.04). Especially, gene alternations involving in the Fanconi anemia (FA) pathway were significantly associated with worse OS and RFS (P = 0.0014 and 0.006). Interestingly, besides the TP53 mutation, patients carrying more than 2 other DDR gene mutations (10/64, 15.63%) also showed worse OS and RFS than patients with single mutation and wild type in DDR genes. (OS: 19 vs 35 months, P = 0.053; RFS: 3 vs 11 months, P = 0.084). Conclusions: Mutations in DDR signaling pathways predicted worse survival in TP53-mutated CRLM patients after surgery. These findings may be useful for clinical decision making in patients with tumor characteristics associated with poor prognosis and for risk stratification of patients in future clinical studies.
Relationship of KIAA1199 on neutrophil recruitment and promotion of colorectal cancer liver metastasis via TGF-β signaling.
Authors: Wang Haihong , Lin Zhenyu , Zhang Tao , Ren Jinghua
Published: May 2020

e16005

Background: Metastasis is the main cause of cancer-related death governed by both cancer cell-intrinsic properties and extrinsic immune contexture. Our previous reports have suggested critical roles of KIAA1199 in tumor invasion and metastasis in colorectal cancer (CRC). In the present study, we explored the potential effects of KIAA1199 on pre-metastatic niche formation. Methods: The CIBERSORT algorithm analysis for 241 patients with colorectal cancer from the Cancer Genome Atlas was performed to investigate the relationship between KIAA1199 expression and neutrophil accumulation. Neutrophils and T cells were isolated, stimulated and/or cultured for in vitro function assays. Proteins were knocked down in MC38 and HCT116 colorectal cancer cell lines, which were analyzed by immunoblotting and chemotaxis assays. Results: We demonstrate that patients with high KIAA1199 showed an increased level of liver-infıltrating neutrophils, which is further validated using flow cytometry analyses in mouse metastasis model. The increased influx of neutrophils is associated with KIAA1199-driven CRC liver metastasis. Neutrophils isolated from pre-metastatic niche decreased CD8+ T cells infiltration and IFN-r+ CD8+ T cells proportion in vivo. Moreover, they showed a N2-like phenotype and expressed higher level immunosuppressive molecules when exposed to the supernatant of normal CRC cell compared to KIAA1199-knock down cell. In CRC cells, we also found a positive correlation between expression of KIAA1199 and genes that ELR+ chemotaxis of neutrophil (CXCL1/CXCL3/CXCL5), which recruited neutrophils to CRC tumor via CXCR2. Importantly, LY2109761, a TGF-β receptor inhibitor, is sufficient to reduce the mRNA levels of these genes. Furthermore, there is a positive correlation between expression of KIAA1199 and expression of Transforming Growth Factor beta pathway genes (TGFBR1, TGFBR2, and pSMAD3), and further co-immunoprecipitation analysis suggests that KIAA1199 may activate the TGF-β signaling pathway via interacting with the TGFBR1 or TGFBR2. Conclusions: Our data indicate that the upregulation of KIAA1199 may increase the expression of cytokines mediated by TGF-β signaling, which can recruit metastasis-supporting neutrophils to promote colorectal cancer liver metastasis. Blockade of the TGF-β signaling could be a novel therapeutic approach against KIAA1199-high expression CRC.
Diffusion kurtosis imaging in predicting the chemotherapeutic response of colorectal liver metastases: The result of the FDZL-MRinCLM study.
Authors: Li Wenhua , Guo Weijian , Zhang Huan , Chen Zhiyu , Zhang Wen , Tong Tong
Published: May 2020

e16034

Background: Colorectal liver metastatic (CLM) patients are a special population who have potential of cure with effective conversion treatment. The conventional radiological imaging commonly evaluates the response 6-8 weeks after the medication. A response marker for earlier prediction could avoid further use of ineffective drugs and guide the medical change for optimal regimen. This study is to evaluate the feasibility of early parameter change assessed by functional MR in predicting clinical response to chemotherapy and investigate its prognostic value in CLM patients. Methods: From August 2016, CLM patients were consecutively enrolled and examined by functional MRI with diffusion kurtosis imaging (DKI) sequence of liver at baseline and one cycle after the initiation of chemotherapy. The whole-lesion histogram and texture analyses of DKI was analyzed and features were extracted from the inline-generated parametric maps included K and D. The primary endpoint of the study was the DKI-predicted ORR of liver metastases, and the secondary endpoint were the DKI-predicted PFS and OS. The efficacy response was assessed by the RECIST Version 1.1 every two cycles of treatment. The association between the baseline DKI parameters, value change ratio (delta-DKI parameters = (Valuebaseline-Valuecycle1)/ Valuebaseline) and ORR and survival were examined. Results: Up to Dec 2019, one-hundred consecutively enrolled patients (65 Male, 35 Female, Age from 30-75 years old) received the treatment (FOLFOX 13, XELOX 53, FOLFIRI 34) and complete the liver functional MRI scanning. A total of 42 responding (CR+PR) and 58 nonresponding (SD+PD) patients were evaluated. Lower baseline D values (D-mean, D-std and D-median, P < 0.005), higher baseline K values (K-mean, K-median, P < 0.005), lower delta-D values (delta-D-DiffEntropy, P = 0.000) and higher delta-K value (delta-K-median, P = 0.022) were significantly associated with a higher ORR, and the combination of all the significant parameters yielded an AUC of 0.834 (sensitivity 76.19%, specificity 77.59%) in predicting the early efficacy of CLMs. Patients with higher delta-D-diffEntropy value showed a longer PFS (9.0 vs 5 mons, P = 0.002) and OS (30.5 vs 14.8 mons, P = 0.032). Conclusions: The baseline value and early parameter change in DKI might be a good predictive marker for the chemotherapeutic response of CLMs, and the early increase of D value in liver metastases could be a promising factor for survival of patients undergoing standard chemotherapy. Clinical trial information: NCT03088163 .
The role of Systemic Inflammation Score (SIS) in BRAF(V600) mutant metastatic colorectal cancer (mCRC).
Authors: Martinez Lago Nieves , Covela Rúa Marta , Brozos Elena , Fernandez Montes Ana , de La Camara Gomez Juan , Méndez Méndez Carlos , Jorge Fernández Mónica , Cousillas Castiñeira Antia ,   Galician Research Group on Digestive Tumors (GITuD)
Published: May 2020

e16051

Background: Multiple studies have reported prognostic association of neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLT) and albumin levels in patients (pts) with colorectal cancer. However, it is unknown the prognostic impact in patients with BRAF(V600) mutant metastatic colorectal cancer (mCRC). Methods: Observational, retrospective, multicentric study pts with BRAF V600mt mCRC treated at 9 university Spanish hospitals in NW Spain, belonging to GITuD Group. Demographic, clinic, pathological characteristics, overall survival (OS) and progression free survival (PFS) data were retrospectively collected and analyzed. We calculated a Systemic Inflammation Score (SIS) summing the number of risk factors that each patient had: albumin levels <3.6 g/dL, Hemoglobin levels <12.5, Neutrophil to Lymphocyte ratio (NLR) >3 and Platelet to lymphocyte ratio (PLR) >175. Results: We recorded data from 71 pts between November 2010 to June 2018. Median age was 62.0 years (range 31-83y), 54.9% female, 73.2% ECOG PS0-1, 49.3% right-sided, 37.3% high grade, 70.4% synchronous presentation, 64.8% primary tumor resection. Median OS was 11.9 months (m) (95% CI, 9.7-14.0 (m)). Pts with higher NLR (>3) had a significantly lower OS: 7.8 vs 13.7 (m) HR 1.934 (95% CI 1.2-3.3) p = 0.014, which was also true for pts with low Hb (<12.5g/dL): OS 9.0 vs 13.0 (m) (HR 1.767,95% CI 1.1-3.0 p = 0.035) and low albumin (<3.6 g/dL): OS 4.9 vs 12.5 (m) (HR 2.142; 95% CI 1.1-4.5, p = 0.040). Pts. with higher PLR (>175) was associated with a non-significant trend worse OS: 5.7 vs 13.5 (m) (HR 1.555; 95% CI 0.9-2.7, p = 0.102). SIS was associated with a worse prognosis: median OS 0/1/2/3/4 factors were 16.7 vs. 11.0 vs. 11.4 vs. 4.8 vs. 4.0 (m) (p = 0.006). Pts with SIS = 0 had significantly higher OS: 16.7 vs 9.0 (m) (HR 0.357; 95% CI 0.3-0.9; p = 0.027). First-line PFS was 4.4 (m) (95% CI, 3.2-5.7 months). First line PFS according type of treatment: Bev+Triplet-CT/Bev+Doublet-CT/antiEGFR+Doublet-CT/Doublet-CT: 8.0 vs 4.8 vs 2.9 vs 2.1 (m) (p = 0.091). BEV based CT was associated with a prolonged first line PFS: median 5.2 vs. 2.3 (m) (HR 0.562; 95% CI, 0.3-0.9; p = 0.033). BEV based CT was associated with prolonged first-line PFS in SIS Score 1-4: 4.8 vs. 2.3 (m) (HR 0.426; 95% CI 0.2-0.8; p = 0.009). Nevertheless, we don’t identify differences in first-line PFS in SIS Score 0: 7.0 vs 2.1 (m) (HR 0.803; 95% CI 0.3-2.5; p = 0.700). Conclusions: SIS identifies a population with a worse prognosis and subsidiary of improvement in First-line PFS with BEV based CT.
Utility of circulating tumor DNA in genomic profiling of colorectal cancer with peritoneal metastasis.
Authors: Ma Tenghui , Cao Weiguo , Huang Jin , Song Yuguang , Zhu Lingjun , Liu Lianke , Zhao Yun-Bo , Bai Jun , Liang Li , Ma Fei , Yuan Mingming , Chen Rongrong , Wang Hui
Published: May 2020

e16057

Background: Patients (pts) with peritoneal metastatic (PM) colorectal cancer (CRC) have significantly poorer prognosis than those with other metastases. In this study, we aim to investigate genomic profiles of PM-CRC and metastatic CRC without peritoneal involvement (non-PM-CRC) and PM-CRC with other organ involvement (PM-CRC+) using circulating tumor DNA (ctDNA)-based sequencing. Methods: A total of 169 pts with metastatic CRC were enrolled irrespective of treatment history, including 53 pts with non-PM-CRC, 47 pts with PM-CRC, and 69 pts with PM-CRC+. Matched tumor-normal next-generation sequencing of 1021 cancer-related genes was performed on ctDNA and white blood cells derived from plasma samples. The differences of mutation number were examined with student t test, and the differences of mutation detection rate were examined with two tailed Fisher’s exact test. p≤0.05 was considered statistically significant. Results: Somatic mutations were identified in 96% of pts with non-PM-CRC, 77% of pts with PM-CRC, and 97% of pts with PM-CRC+. The number of somatic mutations observed in the PM-CRC cohort was significantly lower than that in the other cohorts with the median value of 2 in the PM-CRC cohort, 9 in the non-PM-CRC cohort, and 7 in the PM-CRC+ cohort (p = 0.0002 and p < 0.0001, respectively). The most frequently mutated genes in these cohorts was listed in Table. The detection rate of APC and TP53 mutations in the PM-CRC cohort was significantly lower than the other cohorts. Significant differences were also observed when comparing TCF7L2 mutations in the non-PM-CRC and the other cohorts, LRP1B mutations in the PM-CRC cohort and PM-CRC+ cohort, and NOTCH4 and PCK1 mutations in the non-PM-CRC and PM-CRC+ cohorts. In addition, BRAF mutations were more commonly observed in the PM-CRC cohort (13%) than the other cohorts (8% for non-PM-CRC cohort, 4% for PM-CRC+ cohort) (p = 0.51 and 0.16, respectively). Conclusions: Pts with PM-CRC exhibit a distinct molecular profile compared with non-PM-CRC and PM-CRC+, which may be helpful to explain their relatively poor prognosis and potentially be used in the early diagnosis of PM. [Table: see text]
The mutational landscape of the adjacent paracancerous tissues confirmed the safe margin of 2-5cm in colorectal cancer resection.
Authors: Gu Jin , Yao Jianfei , Song Lele , Huang Dandan , Gao Zhaoya , Gao Qingkun , Niu Pengfei , Zeng Qingmin , Wang Yanzhao , Wang Denglin , Liu Danni , Jing Zhang , Lei Fuming
Published: May 2020

e16060

Background: Margin of 2-5cm is regarded as the safe margin in surgical resection of colorectal cancer (CRC) by macroscopic pathological examinations. However, whether 2-5cm is safe has never been verified by molecular evidence. Methods: We systematically analyzed the mutational profile of 35 CRC tissues and paired adjacent paracancerous tissues 2-3cm and 5cm adjacent to the cancer margin by whole-exome sequencing. Results: The number of SNV/INDEL mutations in the adjacent 2-3cm and 5cm tissues was much less than that in cancer. The number of common SNV/INDEL mutations between cancer and the adjacent tissues ranged from 0 to 2. Although TP53, APC and KRAS SNV/INDEL mutations exhibited the highest frequency in CRC, the APC SNV/INDEL mutations were observed in only one adjacent 5cm tissue, and no TP53 or KRAS SNV/INDEL mutations were observed in any adjacent tissues. We further determined the potential driver gene mutations in adjacent tissues by searching databases including COSMIC CGC, IntOGen, OncoKB, TCGA and Vogelstein databases. A certain mutation was determined as a driver gene mutation if all five databases predict it to be a driver gene mutation. As a result, 9 SNV/INDEL driver gene mutations (1 ATM, 1 BRCA1, 1 BRCA2, 1 MET, 1 NF1, 3 PTEN and 1 STAG2 mutations) were found in the adjacent 2-3cm group, and 9 SNV/INDEL driver gene mutations (1 APC, 1 ARID1A, 1 FBXW7, 3 PTEN, 2 STAG2 and 1 BRCA2 mutations) were found in the adjacent 5cm group. No common SNV/INDEL driver gene mutations were found between cancer tissues and the paired 2-3cm or 5cm tissues, suggesting the driver gene mutations predicted in adjacent normal tissues may not be cancer-relevant. Conclusions: We established the mutational landscape of the adjacent 2-3cm and 5cm tissues to CRC, and found almost no key driver gene SNV/INDEL mutations in adjacent tissues. No common SNV/INDEL driver gene mutations were found between cancer and the adjacent tissues, supporting a safe resection with a margin at 2 to 5cm.
Presence of circulating tumor cells is more significant than tumor stage in characterizing cellular local immunity in colorectal cancer.
Authors: Sitkovskaya Anastasia O. , Kit Oleg I. , Zlatnik Elena Yu. , Novikova Inna A. , Sagakyants Aleksandr B. , Ulianova Elena P. , Shulgina Oksana G. , Kolesnikov Vladimir E. , Oganyan Nairi B. , Pavlov Vladislav K. , Karasev Timofey S. , Dzhenkova Elena A. , Shaposhnikov Alexander V. , Snezhko Aleksandr V. , Tolmakh Roman E. , Fomenko Yuriy A. , Petrov Dmitry S.
Published: May 2020

e16073

Background: The purpose of the study was a correlation analysis of parameters of local immunity and markers of the epithelial-mesenchymal transition (EMT) with the number of circulating tumor cells (CTCs) in patients with stage II-IV colorectal cancer (CRC). Methods: The study included 60 patients newly diagnosed with stage II-IV CRC. CTCs were detected with the Cell Search System (Janssen Diagnostics, LLC) prior to surgery. CTC≤3 were considered negative, CTC > 3 – positive. After surgery, IHC analysis of tumor infiltration with immune system cells was performed with monoclonal antibodies for human CD3, CD4, CD8, CD20 and CD56; expression of EMT-associated proteins (E-cadherin, N-cadherin) was measured. All patients were informed of the goal of the study and provided informed consent. Results: CTC-negative patients with later cancer stages showed the loss of connection between the local levels of CD4+ and CD8+, and in stage IV - between CD3+ and CD4+. Starting from stage III, a negative correlation was observed between the expressions of E- and N-cadherin, not associated with the studied indices of local cellular immunity. The presence of CTCs in all 3 investigated stages of CRC, apparently, causes the loss of many connections between the indicators of the 3 units of local cellular immunity. While negative correlations were revealed between T-, B- and NK-cells in CTC-negative status, in CTC+ their number decreased to 1. An important positive correlation was between local levels of CD3+ and CD8+, indicating the predominance of cytotoxic T cells in the tumor and detected at all stages in CTC-negative patients, losing significance in the presence of CTCs regardless of the stage. In stage II, the only correlation (inverse one) was observed between the parameters of local (CD4+) immunity and the expression of cadherins (E-cadherin), which probably reflected the presence of immunosuppressive and growth-stimulating Tregs fraction among these cells. Conclusions: In general, the presence of CTCs was more significant for the number and nature of interconnections of cellular parameters of the local immunity than the tumor stage.
Associations between oncogenic risk markers and clinical outcomes among black and white colorectal cancer patients.
Authors: Starks Victoria , Mitchell Edith P.
Published: May 2020

e16078

Background: Blacks have a 25% higher incidence of colorectal cancer compared to their white societal counterparts1. Additionally, the overall mortality rate among black colorectal cancer patients is 50% higher than that of whites2. However, little is known about the biomarkers prevalent among blacks and their possible correlation to treatment response and patient outcomes. Objective: The objective of this study is to explore disease trends that may unveil a correlation between molecular markers, pathologic stage at presentation and poor clinical outcomes among black colorectal cancer patients. Methods: De-identified patient data was obtained from The Oncology Data Services Department (Cancer Registry) of TJUH. The population cohort (n = 836) included newly diagnosed colorectal cancer patients treated at TJUH from 2000-2019, & included information regarding patient race, sex, age at presentation, stage at presentation, histological code, tumor markers: KRAS, NRAS, BRAF, MS1, treatment received, surgical findings: tumor size, lymph node involvement, presence of distant metastases at first surgery, response to chemotherapy & disease-free survival. Results: Findings reveal a higher prevalence of BRAF mutations among whites compared to blacks within this population, while black patients were diagnosed later according to AJCC pathological stage at presentation. Future analysis of this cohort will further divide the population by age ( < 50, 50-65, & > 65). This facet of the study will explore relationships between age & stage at presentation among patients of different races. Conclusions: Both oncogenic risk markers and AJCC stage at presentation differ between black and white colorectal cancer patients within this population. Additional analysis regarding age at presentation will further inform us as to how these findings may contribute to the comparatively higher incidence and mortality rates among black colorectal cancer patients. Researchers should continue to explore possible etiologies for the prevalent racial disparities seen among black colorectal cancer patients.
Clinical utility of germline genetic testing after tumor genomic testing in colorectal cancer patients.
Authors: Ngo Nhu , Lincoln Stephen E , Das Kingshuk , Pineda Alvarez Daniel Esteban , Yang Shan , Michalski Scott T. , Nielsen Sarah M. , Esplin Edward D. , Nussbaum Robert Luke
Published: May 2020

e16089

Background: Practice guidelines support genomic and biomarker testing of colorectal cancer (CRC) to inform treatment options in advanced disease and to screen for MMR deficiency/MSI/Lynch syndrome. As yet, guidelines for follow-up germline testing are not well established. In 2019 ESMO recommended reflex germline testing when pathogenic variants (PV) were found in any of 27 cancer susceptibility genes (CSG) in tumor samples (PMID 31050713). The CSGs were chosen because PV in these genes were clinically actionable and had “germline conversion rates” (GCR) of > 10% (proportion of tumor-detected PV that were germline). We examined the utility of germline testing in a cohort of CRC patients who had prior tumor sequencing. Methods: We reviewed somatic & germline PV in an unselected consecutive series of CRC patients who were referred for germline testing and had prior tumor testing. We determined the GCR for genes with pathogenic germline variants (PGV) and compared our results to ESMO data. Results: 66 of 238 (27%) patients harbored PGV. 15% of PGV were not reported in the tumor assay. High GCR for BRCA1/2 (30%), MMR genes (40%), PALB2 (57%), and BRIP1 (67%) were in keeping with ESMO. Low GCR for APC (1.4%) and TP53 (3%) were similar to ESMO, and reflective of high somatic mutation rates in these genes. We noted high GCR for CHEK2 (75%) and ATM (24%), two genes not included in ESMO guidelines due to their intermediate penetrance. Conclusions: ESMO guidelines provide a key starting point for when reflex germline testing should be pursued after tumor testing. In our study 27% (65/238) of patients had PGV that conferred potential eligibility for targeted therapy or clinical trials. For CRC, finding PV in MMR genes, BRCA1/2, and other relevant CSGs should prompt follow-up germline testing. In cases with APC PV in tumor, ESMO recommended reflex germline testing only in patients < 30 yo, where the GCR was > 10%. Our study suggests that reflex germline testing after tumor sequencing yields clinically actionable results. [Table: see text]