bluuebunny/crossref_metadata_2025 huggingface dataset:
External validation of a radiomic signature to predict HPV (p16) status from standard CT images of anal and vulvar cancer patients.
Authors: Leijenaar Ralph T.H. , Walsh Sean , Vaidyanathan Akshayaa , Zerka Fadila , Occhipinti Mariaelena , Danthine Denis , Kridelka Frederic , Hustinx Roland , Vos Wim , Guiot Julien , Leech Michelle , Gillham Charles , Lyons Ciara A. , Flavin Aileen , Lambin Philippe , Lovinfosse Pierre
Published: June 2021

e15502

Background: HPV status of anal and vulvar cancers cannot be predicted by visual inspection as well as for oropharyngeal cancers. Radiomics applied on computed tomography images can extract features that may better characterize the structure and the underlying biology of the tumor. Methods: In this multi-center study, we validated a CT based radiomic signature to predict HPV (p16) status, developed in head & neck cancer, in anal and vulvar cancer patients. The patients cohort was composed of 68 anal cancer patients and 7 vulvar cancer patients, with p16 status determined by immunohistochemistry, while a control cohort was composed of 422 lung cancer patients. The patient cohorts come from 4 different centers (Maastro Clinic - the Netherlands, CHU Liege – Belgium, St Luke’s Hospital – Ireland, Cork University Hospital - Ireland). The primary tumor volume was manually delineated for each patient on axial CT images. Prior to analysis, all images were resampled to isotropic voxels of 2 mm, using linear interpolation. A total of 37 radiomics features were calculated from five groups: tumor intensity, shape, texture, Wavelet and Laplacian of Gaussian. The signature was built using regularized logistic regression [1]. The signature was evaluated according to the Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis (TRIPOD) and the Radiomics Quality Score (RQS). Results: The signature classified anal and vulvar cancers based on their HPV status (positive or negative), with an AUROC of 0.760 comparable to the performance of the original signature developed in oropharyngeal squamous cell carcinomas (AUROC of 0.764) [1]. The model, tested in the control cohort of lung cancer patients, predicted the HPV positive status of 1% of the patients which is in line with expected European prevalence (0 – 10%). This signature is TRIPOD level 4 (57%) with an RQS of 61%. Conclusions: This study supplies an additional insight into HPV imaging phenotype, providing a proof of concept that molecular information can be inferred from standard medical images by means of radiomics. These preliminary but encouraging results may pave the road for further generalization of CT image features of HPV-related tumors and aid in the optimization of future therapy developments [2]. Reference [1] Ralph TH Leijenaar et al., The British Journal of Radiology 2018 91:1086 [2] Immunotherapy Drug with Two Targets Shows Promise against HPV-Related Cancers - accessed on 12/02/2021 - https://www.cancer.gov/
Definitive chemoradiotherapy for squamous cell carcinoma of the anal canal (SCCAC) with cisplatin and capecitabine: A prospective cohort—preliminary results.
Authors: Dornellas Abraão , Moraes Priscila Muniz , Victor Carolina Ribeiro , Bonadio Renata Colombo , Braghiroli Maria Ignez , Chen Andre Tsin Chih , Ortega Cinthia , Nahas Caio , Hoff Paulo Marcelo , Moniz Camila Motta Venchiarutti
Published: June 2021

e15506

Background: SCCAC is a rare disease. The standard care treatment with curative intent is chemoradiation with mitomycin (MMC) or cisplatin (CDDP) plus infusional 5-FU. Capecitabine may replace 5-FU in MMC doublet. However, MMC and infusional pumps are unavailable in many underdeveloped countries, and there is a lack of prospective data regarding the feasibility and safety of capecitabine combined with CDDP in definitive chemoradiotherapy. Methods: A Prospective cohort study aimed to evaluate the safety and efficacy of treatment with chemoradiation with CDDP60mg/m2 D1 and D29 plus capecitabine 825mg/m2/day BID in a population without MMC and infusional pump access. Eligible pts had T2-4/N0-3/M0 disease and were candidates to full curative CRT. Toxicity evaluation was the primary endpoint, secondary endpoint was response by RECIST v.1.1 at 8 weeks(w) and 6 months(m). The study data were prospectively collected using REDCap. Results: 23 pts were enrolled from Aug/2019 to Oct/2020 with a median follow-up of 7m. Median age 59 years; 76% (n=16) were stage III, 48% (n=11) were ECOG1, and 15% (n=3) were HIV+. All pts received concomitant radiotherapy, MVAT, with a median dose 54Gy in the primary tumor and 45Gy in elective nodes. At 8w, 18 patients were evaluable for response, 56% (n=10) had complete response (CR),39% (n=7) had partial response (PR) and 5% (n=1) progressive disease (PD). At 6 months 11 patients were evaluable for response, 64%(n=7) had CR, 18% (n=2) PR and 18% (n=2) PD. Any grade 3/4 toxicity was present in six pts, four of them radiodermatitis. The most frequent grade toxicities were nausea and radiodermatitis in all pts, anemia 81% (n=17), diarrhea 62% (n=13). Two older pts had definitive suspension of treatment due to toxicity. Three pts had hospitalization because of a skin infection. Six pts had disease recurrence, and two died by the cutoff date. One death related to diarrhea and vomiting toxicity in an older 84-year pt. OS and PFS are not reached. Conclusions: Definitive chemoradiotherapy with cisplatin and capecitabine is feasible; however, the older population is more vulnerable to treatment complications. Further prospective studies with a higher number of patients and longer follow up are required to evaluate SLP and OS.
Relationship between circulating tumor cells and ZEB1 expression in tumor cells in colorectal cancer.
Authors: Novikova Inna A. , Kit Oleg I. , Zlatnik Elena Yu. , Ulianova Elena P. , Sagakyants Aleksandr B. , Sitkovskaya Anastasia O. , Shulgina Oksana G. , Gevorkyan Yuriy A. , Soldatkina Natalya V. , Kolesnikov Vladimir E. , Aleksandrovich Maksim K. , Dashkov Andrey V. , Poluektov Sergey I. , Kaymakchi Dmitry O. , Mirzoyan Ellada A. , Pavlov Vladislav K. , Dzhenkova Elena A. , Shaposhnikov Aleksandr V. , Vereshchak Maksim A. , Katelnitskaya Oksana V.
Published: June 2021

e15509

Background: Intravasation and circulation of tumor cells involves active invasion of cells with an enhanced migration potential as a result of the epithelial-mesenchymal transition (EMT). The ZEB1 protein is one of the key regulators of this process. Our purpose was to evaluate the association between the amount of circulating tumor cells (CTCs) in the peripheral blood of patients with different stages of colorectal cancer and the expression of ZEB1 by tumor cells. Methods: The study included 299 patients (aged 42-86 years, mean age 64.2±1.7) with stage II-IV CRC T1-4N0-2M0-1; histologically verified G1-G3 adenocarcinoma in all patients. The numbers of CTCs were measured in the peripheral blood before surgery using the Veridex CellSearch system (Janssen). CTCs were registered taking into account morphological characteristics and expression of epithelial cell adhesion markers EpCAM, CD45, cytokeratins 8,18,19. The blood sample was evaluated according to the following criteria: 0 CTCs, 1-3 CTCs, and more than 3 CTCs. Tissues of surgically removed tumors were studied with IHC analysis using rabbit polyclonal anti-ZEB1 antibodies (Biorbyt Ltd.) diluted 1:200 and the Reveal Polyvalent HRP-DAB Detection System. The percentage and the intensity of staining were assessed: 0, 1+ weak, 2+ moderate, 3+ strong. ZEB1 expression was considered positive when staining was detected in more than 10% (cut-off) tumor cells with intensities of 2+ and 3+. Statistical analysis of results was performed in the Statistica 13.0 program (StatSoftInc., USA). Results: From 1 to 402 CTCs were determined in 62.9% cases (in 188 of 299 patients); CTCs were not registered in 37.1% cases (111 of 299). Positive ZEB1 expression was observed in 80.6% (241 of 299 patients), while the negative one was much more rare – 19.4% (58 of 299 patients). The rates of CTC detection significantly increased with the positive ZEB1+ expression, compared to the negative expression (75.1% vs. 12.1%). CTCs >3 were detected in the blood in 39.0% in ZEB1+ tumors, but not in ZEB1- tumors. 1-3 CTCs were observed 3 times more often in ZEB1+ tumors (36.1% vs. 12.1; p≤0.05). Conclusions: Statistically significant association was revealed between the epithelial-mesenchymal transition marker ZEB1 expression by tumor cells and the amount of CTCs in the peripheral blood (p < 0.001).
Methylated DNA markers for monitoring palliative chemotherapy response in advanced colorectal cancer.
Authors: Zhu Mojun , Mahoney Douglas W. , Burger Kelli , Foote Patrick H. , Doering Karen A. , Taylor William R. , Then Sara S. , Xie Hao , Allawi Hatim T. , Kaiser Michael W. , Lidgard Graham P. , Hubbard Joleen M. , Kisiel John B.
Published: June 2021

e15511

Background: Aberrantly methylated DNA marker (MDM) candidates are strongly associated with primary colorectal cancer (CRC) before treatment and detect CRC recurrence with high sensitivity when assayed from plasma. The relationship of these MDMs in association to chemotherapy treatment response is unknown. Methods: In a prospective cohort of patients receiving systemic therapy for advanced CRC, peripheral blood was collected serially during restaging visits. 15 patients were retrospectively identified to have partial response (PR), stable disease (SD) and progressive disease (PD) to treatment (n=5 for each group) based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Using paired samples from each patient before and after response assessment, we analyzed 11 MDMs ( GRIN2D, ZNF671, ANKRD13B, QKI, VAV3, JAM3, SFMBT2, CHST2, ZNF568, FER1L4 and CNNM1) to assess correlation with treatment response. Cell-free DNA was extracted and bisulfite treated before MDMs were quantified by target enrichment long-probe quantitative-amplified signal assay and normalized to a methylated sequence of B3GALT6. Continuous variables are summarized as a median with corresponding interquartile ranges (IQR) and comparisons between subgroups were based on the Wilcox Rank Sums test. Results: The median interval between pre- and post-response assessment visits was 69 days (IQR: 63-83 days) and the level of tumor burden at pre-assessment was similar across all response types (Table 1). Patients with PD had higher levels of methylated GRIN2D, ZNF671 and ANKRD13B than those with PR or SD at baseline and may offer additional prognostic value over CEA which was similar in the PR and PD groups before treatment (Table 1). Elevation of pre-assessment MDMs preceded radiographic evidence of disease progression by 82 days (IQR 69-83 days). Conclusions: Three MDMs, GRIN2D, ZNF671 and ANKRD13B, were found to reflect treatment response (PD vs. PR + SD) as shown in the table. Although this pilot study was limited by a small sample size, it demonstrated the feasibility of using plasma-based MDMs in monitoring treatment response to systemic therapy for advanced CRC and should be compared to CEA in a larger study.[Table: see text]
MYC as a candidate upstream controller involved in TYMS gene expression and 5-FU/folate treatment efficacy in colorectal cancer.
Authors: Drubin David A. , Hess Anne-Katrin , Catlett Natalie L. , Di Cara Alessandro , Wettergren Yvonne , Tell Roger
Published: June 2021

e15512

Background: One of the target enzymes of 5-fluorouracil (5-FU)-based therapies is thymidylate synthase (TS) encoded by the TYMS gene. To enhance the effect of 5-FU, a folate analogue is often provided as part of the treatment. In this context, it has previously been shown in the ISO-CC-005 clinical study that TYMS gene expression can be predictive of response to 5-FU + folate analogue Arfolitixorin. Methods: To better understand the role of TYMS expression as a predictor of response to 5-FU + folate-based therapies and identify potential mechanisms and biomarkers of sensitivity/resistance, we leveraged data from the publicly available cancer genome atlas database (TCGA). We combined this information with a knowledgebase of causal biological relationships extracted from peer reviewed publications, to identify other relevant genes and candidate upstream controllers directly or indirectly related to TYMS expression and 5-FU + folate efficacy. Results: In TCGA subjects suffering from colorectal cancer (CRC) (stage IV tumors, treated with FOLFOX/FOLFIRI (n = 38)), lower TYMS expression was associated with a better overall survival (OS). This is consistent with what has been observed in the ISO-CC-005 study. Applying our causal biology knowledgebase to both genes identified as correlated to TYMS expression in TCGA CRC tumors and other published sets of genes associated with FOLFOX or FOLFIRI efficacy, we identified overlap with a MYCN signature. Notably MYC has been shown to directly activate TYMS expression. Thus, the MYC family is a compelling candidate upstream controller of these genes. We scored TCGA CRC tumors for inferred MYC activity, using this MYCN gene signature, and evaluated the inferred activity with respect to OS. In stage IV tumors, higher inferred MYC activity appears to be associated with worse OS. To further characterize this inferred MYC activity, we employed a transcriptomics-based cell deconvolution estimation of immune cell population proportions in the TCGA CRC cohort. We found inferred MYC activity inversely correlated with immune cell proportions overall, specifically strongest with those of pDCs and classical monocytes. Conclusions: MYC activation, a known transcriptional regulator of TYMS, has been identified as a potentially relevant common upstream controller of a group of genes involved in 5-FU + folate analogue efficacy. Here we have also observed a similar relationship to OS between TYMS and inferred MYC activity in Stage IV CRC. MYC family activity (and activated protein forms), genes of the MYCN signature, or the identified immune cell proportions are all potential biomarker candidates to explore as factors in 5-FU + folate analogue efficacy.
Associations of mutation profiles with clinical outcomes among metastatic colorectal cancer patients at the United States-Mexico border.
Authors: Ghafouri Reshad , Philipovskiy Alexander , Corral Javier Chavez , Gaur Sumit , Hakim Nawar , McCallum Richard , Konstantinidis Ioannis , Maegava Felipe
Published: June 2021

e15519

Background: The incidence of CRC among Hispanics living in the USA varies according to their country of origin, supports the idea that differences in ancestry may contribute to the differences in the incidence of CRC. Moreover, Hispanics-Latino(HL) patients usually present with a more advanced stage and have a higher mortality rate compared to other ethnic cohorts. Although it is unknown, the incidence of CRC has been substantially increasing among younger Hispanics. We sought to characterize the tumor mutation profile of mCRC patients and associate with clinical outcomes among Hispanic population. Methods: We retrospectively collected the data from next generation sequencing of 49 patients with metastatic CRC (treated at TTUHSC from 2012 to 2020. We identified the most frequent alterations in our study sample and associated with the clinical outcomes. Association analyses were performed using chi square test, unpaired t-test, log rank test and the Cox proportional hazards regressions. Results: Of 49 patients with mCRC, the average age of patients at the time of diagnosis was 57 years with 98% Hispanic, and 32(65%) male. Most of the patients had stage IV disease (98%) and left side CRC (31, 67%). In our study cohort, the most commonly mutated genes identified as APC (37/11, 77.08%), TP53 (29/19, 60.42%), KRAS (23/25, 47.92%), NOTCH 12/36 (25.00%), BRCA 1&2 11/37 (22.92%) and FLT1 11/37 (22.92%). None of the identified mutations were found to be associated with overall survival. However, the presence of the FLT1 mutation was associated with a reduced risk of progression to additional chemotherapy (P=0.031). Compared to the left side CRC, the BRCA mutation appeared slightly higher on the right side of the CRC (p=0.057). In compare to data from larger national and international colon cancer databases ( COSMIC and METABRICS); HL patients showed a significantly higher proportion of frequent mutations. Compared to other ethnic cohorts, HL patients were relatively younger (57 vs. 63 years) and the male to female ratio was observed to be remarkably higher as well (1.77:1 vs. 1.32:1). In our study, the combination of mutations (TP53, APC, and KRAS) was associated with worse clinical outcomes. Our study demonstrated that worse clinical outcomes were correlated with. Conclusions: Our study is the first to characterize the most common genetic alterations among HL patients with mCRC. The most frequent identified mutations including TP53, APC, KRAS, NOTCH, and BRCA were even higher in HL cohort than the national and international databases ( COSMIC and METABRICS). Our data support the motion that molecular drivers of colon cancer might be different in HL patients.
Somatic and germline mutation profiles of Chinese young colorectal cancer patients.
Authors: Li Hongxia , Duan Qianqian , Tan Yuan
Published: June 2021

e15522

Background: In recently years, although CRC morbidity and mortality can be mitigated through appropriate screening and surveillance, the incidence rate of colorectal cancer (CRC) younger than 50 years old increased annually. Limited studies have investigated the underpinnings driving CRC development in Chinese younger population. In our study, we aim to explore the comprehensive mutational profile of Chinese CRC patients old (＞50) and young (≤50) diagnosed with CRC. Methods: Targeted sequencing with a 539 cancer-related genes panel was performed on 235 patients diagnosed with CRC. We investigate the landscape and difference of old and young CRC somatic and germline mutations in our Chinese cohort and compare with TCGA CRC cohort (N = 592). Results: Analysis revealed an overall 20.9% (49/235) mutation detection rate of young CRC in our Chinese cohort, which is higher than TCGA cohort (13.9%, 82/592). In our cohort, all Chinese young CRC patients can detect mutation and median mutation count is 10 mutations which is similar to old CRC patients (11 mutations). Comparing high frequency somatic mutations (young group with top 20), we found that BRCA2 mutation in young CRC group is significantly higher than old group (18.4% vs 7.0%, P = 0.025). In TCGA cohort, there is no difference between two groups with top 20 mutations and frequency of BRCA2 is 13.4% (11/82) in young CRC. For germline mutation, 12.29% (29/236) patients in our Chinese cohort harbored pathogenic and likely pathogenic (P/LP) germline mutations and 24.1% (7/29) CRC with P/LP germline mutations is young patients. In these seven P/LP mutation young patients, three patients have MMR gene mutation, two patients harbor ATM mutation, one patient has APC and another has SLX4 mutation. Moreover, young CRC have higher frequency MSI-H than old CRC patients (28.6% vs 18.2%). Conclusions: Our study has identified that young CRC patients account for a higher proportion in Chinese population and BRAC2 mutation may be an important factor in the early development of colorectal tumors in younger patients. In addition, our results also support the role of MSI statues in tumor oncogenesis in Chinese patients with early-onset CRC, indicating the need to include a more comprehensive germline mutation and genetic screening in our population.
TRIM29 expression and its survival predictor value in colorectal cancer with different primary tumor location.
Authors: Han Jing , Zhang Xue , Fan Zhisong , Wang Yudong , Feng Li , Zuo Jing , Wang Long , Li Dan , Liu Jiayin
Published: June 2021

e15528

Background: It is clear that, in colorectal cancer (CRC), patients with different primary tumor location have variant prognosis and distinct clinicopathological features.So, it is very necessary to find specific tumor markers for different tumor sites.Our previous study have found TRIM29 is higher expressed in right colon cancer(RCC) than left colon cancer(LCC) patients in a small sample size reviewed study.So we speculated TRIM29 have different effect on the patients with different tumor side.But in our previous study, we didn’t investigate the TRIM29 expression in rectal cancer patients(RECC) and observed the effect of TRIM29 on the survival by different tumor side patients.So we decide to explore whether TRIM29 plays a different role in patients with three different tumor sites in a larger sample size study. Methods: 227 CRC cases were included in our retrospectively study,the patients were divided into LCC, RCC and RECC three groups. We first tested TRIM29 mRNA and protein expression level in LCC, RCC and RECC respectively to confirm whether TRIM29 expressed differently in patients with different tumor location. Then we explore the relationship between TRIM29 and clinicopathologic features in the patients with three tumor sites respectively.At last, we explore whether TRIM29 has different effect on the survival of the patients with three different tumor location. Results: TRIM29 mRNA and protein expression was significantly higher in RCC than in LCC and RECC ( P< 0.0001, P< 0.001).High TRIM29 expression was only associated with intestinal obstruction before surgery in LCC patients( P = 0.006) and it was associated with higher frequency of stage TNM IIĨIV and younger patients in RECC( P = 0.015 and 0.000), whereas it was associated with higher frequency of male, elder, stage IIĨIV patients, N+ and intestinal obstruction patients in RCC( P = 0.000,0.000,0.000,0.000 and 0.010).Only in the RCC group, patients with high TRIM29 expression both had a significant difference in the risk of recurrence/metastasis and death compared to patients with low TRIM29 expression( P = 0.020,0.000). Conclusions: TRIM29 plays different role in the patients with different tumor sites.TRIM29 has a greater correlation with clinicopathological features and greater effect on the prognosis in right colon cancer.TRIM29 may serve as a new biomarker and a novel therapeutic target in RCC patients.
The expression of THOX2 in colorectal mucinous adenocarcinoma and its relationship with prognosis.
Authors: Zhang Xue , Han Jing , Fan Zhisong , Feng Li , Wang Long , Zuo Jing , Wang Yudong , Li Dan , Liu Jiayin
Published: June 2021

e15529

Background: The role of THOX2 in the occurrence and development of tumors has gradually attracted attention, but there is no study on the expression and function of THOX2 in colorectal mucinous adenocarcinoma (MC). The purpose of this study was to investigate the expression of thyroid oxidase 2 (THOX2) in colorectal MC and its relationship with prognosis. Methods: 30 patients with colorectal adenocarcinoma (AC) and 15 patients with MC were selected from The Fourth hospital of Hebei Medical University from October 1, 2018 to July 1, 2019. They were selected to detect the mRNA and protein levels of THOX2 in the colorectal cancer tissues of the two different pathological types using qRT-PCR and immunohistochemistry (IHC) methods. A total of 109 patients with MC who received surgical treatment between January 1, 2015 and January 1, 2015 were selected. The clinicopathological parameters of the patients were collected and survival follow-up was performed. The expression of THOX2 protein in MC tissues was detected by IHC test, and the differences in the expression of THOX2 protein in different tissues were analyzed by χ2 test. Cox univariate and multivariate analyses were used to investigate the relationship between clinicopathological characteristics, THOX2 protein expression level and DFS and OS in patients with MC. Results: The levels of THOX2 mRNA and protein in 15 cases of MC were significantly higher than those in 30 cases of AC. The high expression of THOX2 protein in MC tissues was closely correlated with tumor site, whether mixed with other pathological types, TNM stage, lymph node metastasis, M stage, and liver metastasis, peritoneal metastasis and other site metastasis occurred in patients after initial treatment. Cox regression analysis of 95 patients' survival data showed that high expression of THOX2, right colon and lymph node metastasis were influential factors for DFS in MC patients, and were independent prognostic factors for predicting DFS in MC patients. The expression of THOX2, lymph node metastasis, liver metastasis after adjuvant therapy and peritoneal metastasis are the influencing factors of OS in MC patients. Lymph node metastasis is an independent prognostic factor for OS in MC patients. Conclusions: The expression of THOX2 in MC was significantly higher than that of AC, and it was related to the malignant biological manifestations of tumor. At the same time, the high expression of THOX2 is associated with short DFS and OS in patients with MC, and may be used as a potential biomarker and efficacy predictor for MC patients.
Clinicopathological and genomic characteristics of POLE-mutated colorectal cancer in a Chinese population.
Authors: Zhang Xuhui , Wang Xicheng , Xin Ying , Bai Yuezong , Li Jian , Shen Lin
Published: June 2021

e15531

Background: DNA polymerase ε (POLE) is essential for proofreading and fidelity in DNA replication and repair. Previous studies found that mutation in POLE associated with higher tumor mutational burden (TMB), which is an approved biomarker for immunotherpy in solid tumors. However, the clinicopathological and mutational analyses of POLE-mutated colorectal cancer in a large Chinese population have not yet been reported. Methods: Hybrid capture-based next-generation sequencing (NGS) were performed in 4628 samples of colorectal tumors and matched normal pairs in a CAP/CLIA-approved laboratory (3DMed). NGS testing for gene mutations, TMB and MSI was implemented. Results: Of 4628 colorectal cancer patients, POLE mutations were observed in 67 patients (1.45%). A total of 11 different POLE mutations were identified, mostly associated with exonucleas domain. P286R(32,0.69%), V411L(13,0.28%), A456P(7,0.15%), S459F(3,0.06%) and S297F(3,0.06%) were the most frequently mutated sites of POLE. We also detected 1 V758L and 1 W1130R mutation outside the exonuclease domain in separate cases. Among the 4628 patients, 2157 patients were detectable for TMB by NGS panel, including 2128 POLE wild type and 29 POLE mutation patients. The TMB of patients with POLE mutations was significantly higher than that in wide type POLE tumors (mean TMB 252.3 vs 13.4 muts/Mb, P ＜0.0001). All the 29 POLE-mutated patients were TMB-H (≥10 muts/Mb) and 28 of them were MSS. A MSS patient with metastatic colon cancer harboring A456P POLE mutation responsed well to the immunotherpy and achieved a partial response. Conclusions: Our results realved a remarkable positive correlation between POLE mutation and TMB level in a Chinese colorectal cancer population, which suggests POLE gene will be a promising biomarker of immunotherpy for MSS colorectal tumor.[Table: see text]
Antiangiogenic drug-induced proteinuria as a predictive factor in metastatic colorectal cancer.
Authors: Marinca Mihai Vasile , Moisuc Diana Cornelia , Gafton Bogdan , Stratulat Alexa Teodora , Cianga Petru
Published: June 2021

e15538

Background: Treatment with bevacizumab, a humanized monoclonal antibody that inhibits vascular endothelial growth factor (VEGF) is known to cause adverse effects such as proteinuria, hypertension, fistulas, and thromboembolic events which, in addition to chemotherapy-induced toxicity, affect the quality of life. However, while bevacizumab-induced hypertension has been linked to increased overall survival, data on proteinuria are controversial. Methods: We performed a retrospective analysis to observe the influence of adverse effects (AEs) on the results of treatment with bevacizumab and chemotherapy in patients with metastatic colorectal cancer (mCRC). Results: Out of the 3497 mCRC patients admitted to our center between 2014 and 2019, 150 met the criteria for inclusion in our analysis. Of these, 50.7% experienced proteinuria and had reached a longer overall survival (OS, 40 versus 25 months, p = 0.015) and progression free survival (PFS, 15 versus 12 months, p = 0.039). Patients with anemia during treatment, regardless of grade, had a 20-month shorter survival. The following groups were identified as having a lower risk of death: patients with proteinuria (HR 0.630; 95% CI 0.424-0.935; p = 0.022), disease control (HR 0.436; 95% CI 0.291-0.653; p< 0.001) and non-metastatic stage at diagnosis (HR 0.477; 95% CI 0.300-0.757; p = 0.002). Anemia was a negative prognostic factor (HR 2.153; 95% CI 1.343-3.454; p = 0.001). Conclusions: Proteinuria seems to be a useful predictive factor in mCRC patients undergoing bevacizumab-based systemic therapy. Since it is already routinely assessed in this clinical setting, proteinuria could be easily integrated in the decision-making process and thus allow physicians to further individualize systemic treatments. Retrospective analyses, as our study, are setting the basis for prospective studies, required for the validation of these results.
Detailed incidence and mortality trends of early-onset colorectal cancer in Canada.
Authors: O'Sullivan Dylan E. , Ruan Yibing , Sutherland Robert Liam , Cheung Winson Y. , Heitman Steven J. , Hilsden Robert , Brenner Darren
Published: June 2021

e15539

Background: There has been a consistent increase in the incidence of early-onset colorectal cancer (eoCRC), under the age of 50, in Canada since the late 1990s. Questions remain surrounding how these trends vary by topography, histology, and stage, and related trends with CRC-specific mortality. Methods: CRC incidence data were obtained from the Canadian Cancer Registry and CRC-specific mortality data from the Canadian Vital Statistics – Death Database for the years 2000 to 2017. Age-specific average annual percent changes (AAPC) in the incidence (by topography and histology) and mortality rates of CRC were estimated using the National Cancer Institute’s Joinpoint Regression Program. To determine age-specific differences (5-year age groups) in CRC diagnosis at late stage (III and IV) for years 2011 to 2017 combined, a logistic regression model adjusting for sex with the 50-54 age group as the referent was conducted. Results: AAPCs and 95% confidence intervals in the rates of incidence (topography and histology) and mortality of eoCRC from 2000 to 2017 in Canada are presented in Table. Different trends in topography were observed across sexes with the largest increases in the distal colon (splenic flexure, descending, and sigmoid) and rectum among males and rectum only among females. Significant increases were observed for non-mucinous adenocarcinomas, while significant decreases were observed for mucinous adenocarcinomas among the 40-49 age group. Compared to the 50-54 age group, only the 45-49 group had a significantly higher odds of developing late-stage colon cancer, while men and adults 25-49 had a higher odds of developing late stage rectal cancer. Despite increases in the incidence of eoCRC there has only been a significant increase in mortality for men aged 20-39. Trends in mortality vary by site, with significant decreases observed for colon cancer-specific mortality among the 40-49 age group and increases in rectal cancer-specific mortality for adults aged 20-49. Conclusions: These results indicate that the largest increases in incidence and mortality for eoCRC have occurred in the rectum and trends have varied by sex. Further research on the etiology and treatment outcomes of eoCRC patients are warranted for this patient population.[Table: see text]
KRAS, NRAS and BRAF mutational status and first line treatment patterns in Slovenian population with metastatic colorectal carcinoma: Five year results.
Authors: Mesti Tanja , Boc Marko , Rebersek Martina , Hlebanja Zvezdana , Volk Neva , Ocvirk Janja
Published: June 2021

e15546

Background: A phase IV non-interventional study was performed from 2013 till 2018 including 650 patients with primary aim to assess KRAS, NRAS and BRAF mutational status in Slovenian population with metastatic colorectal carcinoma (mCRC) suitable for first-line treatment. The evaluation of decisions for first-line treatment regarding the biomarkers status and assessing the possible impact of the time period of the biomarker status analysis report on the treatment decision were also incorporated in the analysis. The molecular analyses for KRAS and NRAS gene mutations were performed on exons 2, 3 and 4, and for BRAF gene mutations on exon 15. The first line systemic treatment options for RAS (KRAS/NRAS) wild type (wt) and mutated type (mt) mCRC subjects were as follows: chemotherapy - Fluoropyrimidine based systemic therapy combined with oxaliplatin and/or irinotecan with/without VEGF inhibitor bevacizumab and for RAS wt subjects, with/without EGFR inhibitors, cetuximab or panitumumab. Methods: To indicate the degree of certainty of KRAS, NRAS and BRAF status frequency as being wild type or mutant type 95% confidence interval was calculated. Results: The KRAS/NRAS/BRAF mutation rates were as follows - The distribution of subjects with KRAS mutated and wild-type tumors, was almost equal, 48.8% and 47.9% respectively. Eighty nine percent of the subjects had NRAS wild type tumours and 86.1% had BRAF wild type tumours. The most frequently used treatment regardless the biomarkers status and in accordance with the treatment guidelines was bevacizumab based combination therapy (53.1%). The EGFR inhibitor (cetuximab or panitumumab) based combination therapy was used in one third of mCRC subjects (30.9%), all with mCRC RAS wt. The time period from the initial presentation of the patient until the biomarker status analysis report was two weeks. Conclusions: With this study, we have proven that the distribution of the mutations in exons 2-4 of KRAS and NRAS genes and exon 15 in the BRAF gene in the Slovenian population with metastatic colorectal cancer matches historical data. Based on this, we conclude that the treatment decision in Slovenian population with metastatic colorectal carcinoma should be in the accordance with international treatment guidelines and on evidence based medicine. The molecular analysis performed at the Institute of Oncology Ljubljana was providing necessary biomarkers status report in an acceptable time that didn’t affect the treatment decision or delay the needed cancer treatment.
Clinicopathologic features and impact of metastasectomy in patients with BRAF-mutant metastatic colorectal cancer.
Authors: Zhang Jianwei , Shen Cailu , Li Jianxia , Wu Zehua , Hu Huabin , Cai Yue , Xie Xiaoyu , Ling Jiayu , Deng Yanhong
Published: June 2021

e15547

Background: BRAF V600E mutation is associated with poor prognosis in patients with metastatic colorectal cancer (mCRC), while the non-V600E mutation mCRC patients showed better prognosis than that of V600E mutation. The clinicopathologic features between V600E and non-V600E mutation has not yet been fully evaluated. And the impact of metastasectomy for patients with BRAF-mutant mCRC was not well-known. Methods: A retrospective study was conducted to evaluate the clinical and pathological characteristics of patients with BRAF-mutant mCRC. Next generation sequencing (22-gene panel) was performed in some of the patients. Survival was also analyzed in the cohort of BRAF V600E and non-V600E mutation with or without metastasectomy. Results: Between December 2014 and August 2020, 116 patients with BRAF-mutant mCRC were enrolled, including 94 patients with BRAF V600E mutation and 22 patients with non-V600E mutation. Significant difference was observed in the prevalence of peritoneal metastasis (69.1% vs. 27.3%, P = 0.001) and lung metastasis (11.7% vs. 36.4%, P = 0.009) between BRAF V600E mutation and non-V600E mutations. In genomic profile, SMAD4 mutation (30.7% vs. 13.7%) showed higher prevalence in patients with BRAF V600E mutation than that of non-V600E mutations, while RAS mutation (18.2% vs. 6.4%) and FBXW7 mutation (13.7% vs 3.1%) had higher incidence in BRAF non-V600E mutations than that of V600E mutation. Patients with BRAF V600E mutation showed a poorer overall survival than those with non-V600E mutations (13.9 vs. 26.8 months, P = 0.038). Totally, 46 patients received metastasectomy after systemic treatment. The median survival for BRAF V600E patients with or without metastasectomy was not reach (42.3+ months) vs. 8.3 months, respectively ( P < 0.001), and for non-V600E patients with or without metastasectomy was not reach (64.2+ months) vs. 23.3 months, respectively (P < 0.001). In multivariate analysis, ECOG performance status (0-1 vs. 2) ( P = 0.001), Staging (IVa-b vs. IVc) ( P = 0.01) and metastasectomy ( P = 0.001) were independent prognostic factors of overall survival. Conclusions: BRAF V600E mutation defines a subgroup of mCRC with worse prognosis. Metastasectomy might improve the survival benefit in carefully selected BRAF-mutant mCRC patients after systemic treatment.
Metastasectomy in colorectal carcinoma (CRC) patients (pts) with mBRAF: Prospective database analysis.
Authors: Fedyanin Mikhail , Elsnukaeva Kheda , Demidova Irina , Stroyakovskiy Daniil , Shelygin Yuri , Tsukanov Alexey , Panina Maria V , Shubin Vitaliy , Moiseenko Fedor Vladimirovich , Karpenko Elena , Bolotina Larisa , Kudryavtseva Anna , Filipenko Maxim , Vladimirova Liubov Yu , Timoshkina Natalya N. , Kit Oleg I. , Stroganova Anna , Dranko Svetlana , Tryakin Alexey , Tjulandin Sergei
Published: June 2021

e15549

Background: Role of metastasectomy in pts with mBRAF metastatic CRC is still controversial. We performed analysis of prospective multicentric database of pts with mBRAF mCRC to evaluate the efficacy of metastasectomy in such group of pts in the real clinical practice. Methods: We analyzed a database of pts with mCRC in 7 cancer clinics in Russia and chose pts with metastasectomy with different mutational status. The primary endpoints were disease free survival (DFS) and overall survival (OS), which were calculated from the time of metastasectomy. Analysis was performed with the SPSS v.20 software package. Results: The study included 126 pts: 26 pts with mBRAF, 57 pts with mRAS and 43 pts with wtRAS/BRAF. Pts with mBRAF more often had synchronous metastases (50%/19,3/11,6%, p<0,01), N2 status (38,5%/11%/19,6%, p=0,04). In mBRAF cohort all but 1 pt had V600 mutations; peritonectomy performed in 19,2%, liver resection – in 34,6%, lung resection, ovariectomy, metastasectomy in brain and retroperitoneal lymph nodes dissection with removal of the local relapse – over 11,5%; R0 resection was achieved in 88,5%. Median DFS was 7 months in mBRAF pts, 14 months in mRAS and not achieved in wtRAS/BRAF group treated (HR 2,1, 95%CI 1,5-3.1, p<0.01). Median OS was 26 months in mBRAF, 38 months in mRAS and not achieved in wtRAS/BRAF group (HR 1,5, 95%CI 1,0-2,4, p=0.06). Perioperative chemotherapy didn’t improve DFS in pts with mBRAF (HR 1,9, 95%CI 0,67-5,7, p=0,2). The best median DFS were in pts after ovariectomy – 10 months, the worst - after retroperitoneal lymph nodes dissection with removal of the local relapse – 2 months. Conclusions: Prognosis of pts with mBRAF after metastasectomy is worse than with other mutational phenotypes. However in selected cases metastasectomy might be considered in such aggressive mCRC.
Fruquintinib in patients with metastatic colorectal cancer failed in previously bevacizumab-based therapy: A monocentric retrospective study.
Authors: Gu Xiaoqiang
Published: June 2021

e15555

Background: Fruquintinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, is a new targeting anti-cancer agent for refractory metastatic colorectal cancer (mCRC). Promising antitumor effect of fruquintinib monotherapy was verified in a phase III FRESCO randomized study of mCRC patients, and only 30% patients were prior bevacizumab-treated. However, comprehensive effect evaluation of fruquintinib in mCRC patients who have previously failed in bevacizumab therapy were scarce. Methods: Forty patients with metastatic CRC who had previously failed at least 2 lines of standard regimen containing bevacizumab in Longhua Hospital affiliated to Shanghai University of Traditional Chinese Medicine from March 2019 to February 2020 were enrolled. These patients were administrated with fruquintinib (5mg orally, once daily) in cycles of 3 weeks on/ 1 week off. Furthermore, the primary endpoint was overall survival (OS). Secondary endpoints mainly included progression-free survival (PFS), disease control rate (DCR), objective response rate (ORR), and safety profile. Statistical analyses were performed using IBM SPSS statistics software and ‘R’ statistical software with the ‘forest plot’ package. Subsequently, the variables were screened and verified through LASSO regression with the R software “glmnet” package. Results: The mOS was 8.1months (95%CI, 5.6667-12.8667), mPFS was 4.1833 months (95% CI, 3.5333-5.0667), and DCR was 65% (26 SD in 40 patients). Particularly, gender (HR: 7.11, 95%CI:1.86-27.16,P = 0.005), age (HR:0.91, 95%CI:0.85-0.98,P = 0.012), ECOG(HR:3.75, 95%CI:1.13-12.42,P = 0.03), medication duration (HR:0.62, 95%CI:0.48-0.81,P＜0.001),and the number of metastases(HR:2.95,95%CI:1.21-7.18,P = 0.017) identified the statistically significant association with OS. Eliminating the influence of time factor, ECOG and medication cycle obtained by Lasso regression were the risk factors for OS. The most frequently reported adverse events were mainly hypertension, proteinuria, hand-foot skin reaction, fatigue and diarrhea, and any new safety signals were not observed. Conclusions: Fruquintinib showed an acceptable safety profile and promising efficacy in patients with metastatic colorectal cancer failed in previously bevacizumab-based therapy. Future studies of fruquintinib should focus on identifying the patients most likely to benefit and on minimizing toxicity.
Variation in the use of genomic testing in patients with metastatic colorectal cancer.
Authors: Markt Sarah C. , Booker Benjamin , Bensken Wyatt , Schumacher Fredrick R , Rose Johnie , Cooper Gregory S. , Koroukian Siran M.
Published: June 2021

e15557

Background: Oncology has greatly benefited from the use of clinical genomics to aid diagnostic and treatment decisions. To inform targeted therapy, standard practice dictates molecular testing of metastatic colorectal cancer (mCRC) tumors through genomic testing (GT), including molecular biomarker, single gene, or next-generation sequencing (NGS). While persisting disparities in CRC screening, treatment, and outcomes have been well described, little is known about differences in GT for mCRC. Using all-payer electronic health record-derived de-identified data from a real-world database generated from routine clinical care across the U.S., we identified combinations of demographic and clinical characteristics, rather than individual factors, associated with GT. Methods: This study used the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database. During the study period, the de-identified data originated from approximately 280 US cancer clinics (̃800 sites of care). Our study population included 26,524 patients with mCRC during the years 2013-2020. We evaluated documentation of receipt of GT (individual biomarker or NGS) measured within one year of diagnosis of metastatic disease, by demographic (age, sex, and race/ethnicity), payer type, de novo metastatic cancer (vs. progression to metastatic disease), tumor site (colon vs. rectum), Eastern Cooperative Oncology Group (ECOG) performance status, and year of diagnosis. We identified Elixhauser comorbid conditions from ICD codes, and grouped them by count (0-4, 5+). We conducted Classification and Regression Tree (CART) analysis, a machine learning approach to identify combinations of demographic and clinical characteristics associated with receipt of GT. Results: Nearly 83% had documented GT, 90% of whom did so within 6 months of diagnosis. The largest group of patients with GT at 90% consisted of individuals with colon cancer, 64 years of age or younger, 0-4 comorbidities, and an ECOG score of 0 or 1 (n = 2,004). Conversely, the lowest rates of GT ( < 60%) were observed among women 75 years of age or older, despite having 0-4 comorbidities (n = 1,314). In this group of patients, GT was higher among those with ECOG score of 1 than among those with high ECOG scores (66% and 54%, respectively). On the other hand, 71% of patients 75 years of age or older with 5+ comorbidities and high ECOG scores received GT. Conclusions: Considerable variations exist in GT across subgroups of the population. Additional analysis is warranted to characterize young and healthy patients who did not receive GT, and those who did get tested despite their older age and compromised health status. Future analyses will investigate whether documentation of receipt of GT is associated with treatment decisions and outcomes.
Identifying an immune-related gene-pair for prognosis prediction of metastatic colorectal cancer.
Authors: Zhu Qiqi , Cai Du , Wang Wei , Zhong Min-Er , Fan Dejun , Liu Xuanhui , Li Cheng-Hang , Huang Ze-Ping , Lv Min-Yi , Hu Chuling , Duan Xin , Wu Xiaojian , Gao Feng
Published: June 2021

e15565

Background: Few robust predictive biomarkers have been applied in clinical practice due to the heterogeneity of metastatic colorectal cancer (mCRC) . Using the gene pair method, the absolute expression value of genes can be converted into the relative order of genes, which can minimize the influence of the sequencing platform difference and batch effects, and improve the robustness of the model. The main objective of this study was to establish an immune-related gene pairs signature (IRGPs) and evaluate the impact of the IRGPs in predicting the prognosis in mCRC. Methods: A total of 205 mCRC patients containing overall survival (OS) information from the training cohort ( n = 119) and validation cohort ( n = 86) were enrolled in this study. LASSO algorithm was used to select prognosis related gene pairs. Univariate and multivariate analyses were used to validate the prognostic value of the IRGPs. Gene sets enrichment analysis (GSEA) and immune infiltration analysis were used to explore the underlying biological mechanism. Results: An IRGPs signature containing 22 gene pairs was constructed, which could significantly separate patients of the training cohort ( n = 119) and validation cohort ( n = 86) into the low-risk and high-risk group with different outcomes. Multivariate analysis with clinical factors confirmed the independent prognostic value of IRGPs that higher IRGPs was associated with worse prognosis (training cohort: hazard ratio (HR) = 10.54[4.99-22.32], P < 0.001; validation cohort: HR = 3.53[1.24-10.08], P = 0.012). GSEA showed that several metastasis and immune-related pathway including angiogenesis, TGF-β-signaling, epithelial-mesenchymal transition and inflammatory response were enriched in the high-risk group. Through further analysis of the immune factors, we found that the proportions of CD4+ memory T cell, regulatory T cell, and Myeloid dendritic cell were significantly higher in the low-risk group, while the infiltrations of the Macrophage (M0) and Neutrophil were significantly higher in the high-risk group. Conclusions: The IRGPs signature could predict the prognosis of mCRC patients. Further prospective validations are needed to confirm the clinical utility of IRGPs in the treatment decision.