bluuebunny/crossref_metadata_2025 huggingface dataset:
Circulating tumor DNA in decision-making of patients with metastatic colorectal cancer after failure of first-line treatment containing cetuximab: A single-center, phase II trial.
Authors: Zou Jianling , Yang Wentao , Li Wenhua , Zhang Jieyun , Geng Qirong , Chang Jinjia , Wang Chenchen , Hu Xin , Chen Zhiyu
Published: June 2023

e15584

Background: Genetic status is constantly changing after receiving cetuximab. To analyze the molecular characteristics in mCRC after first-line treatment containing cetuximab and adjust second-line targeted therapy strategies, we conducted this prospective study. Methods: Patients with measurable mCRC were enrolled. Main eligibility criteria included initial RAS and BRAF wild-type genetic status on tumor tissue; prior first-line regimens including cetuximab, and then showed progression disease. The ctDNA status was detected: bevacizumab would be applied if there was RAS mutation; the combination of vemurafenib, cetuximab and irinotecan would be used if there was BRAF mutation; trastuzumab would be used if there was HER2 amplification; cetuximab or bevacizumab would be applied according to investigators discretion if no related secondary variation. The primary endpoint was ORR; secondary endpoints were DCR, PFS, OS, safety and tolerability. Results: Twenty-two patients were enrolled from Apr 8, 2021 to Nov 18, 2022. Fifty percent (11/22) were males and the median age was 56.5 years. 59.1% (13/22) patients received bevacizumab, 36.4% (8/22) patients received cetuximab, and 4.5% (1/22) patients received trastuzumab and pyrotinib. 52 variations were detected in 22 patients before second-line therapy, with a positive rate of 95.5%. TP53 (90.9%, 20/22) was the most mutated gene, followed by APC (86.4%, 19/22). The percentage of secondary KRAS mutation was 9.1% (2/22), BRAF mutation was 0, ERBB2 amplification was 4.5% (1/22), and ERBB2 mutation was 9.1% (2/22). For 8 patients with serial ctDNA detection, the number of gene variation was decreased during disease remission (10 vs. 23) and increased again during progression (23 vs. 10). The ORR was 40.9% (9/22) for all patients. And it was 38.5% (5/13) and 37.5 % (3/8) separately for patients received bevacizumab or cetuximab (p = n.s.). The DCR was 86.4% (19/22) for all patients. And it was 92.3% (12/13), and 75% (6/8) for patients received bevacizumab or cetuximab separately (p = 0.013). The median PFS was 8.6 months in all patients. And it was 11.6 months and 4.6 months separately in patients received bevacizumab or cetuximab (p = 0.013). The median OS was 12.4 months in all patients. And it was 14.5 months and 11 months separately in patients received bevacizumab or cetuximab (P = 0.27). In addition, no difference in treatment related serious adverse advents grade 3-5 was observed. Conclusions: Circulating Tumor DNA is a promising biomarker for assessing treatment efficiency and guiding second-line treatment decisions in patients with mCRC. The bevacizumab-based second line treatment increases DCR and PFS than continuously cetuximab-based treatment, and had a better tendency in OS. Clinical trial information: NCT04831528 .
Fruquintinib versus fruquintinib combined with PD-1 inhibitors for metastatic colorectal cancer: Real-world data.
Authors: He Lina , Cheng Xiaojiao , Tu Shuiping
Published: June 2023

e15592

Background: The treatment in patients with metastatic colorectal cancer (mCRC) have limited effectiveness and options. And research findings have revealed that combining anti-angiogenesis inhibitors with programmed death-1(PD-1) inhibitors can reverse the immunosuppressive tumor microenvironment and synergistically enhance the antitumor immune response. The goal of the study was to add more real-world data to prove the clinical efficacy and safety of this regimen. Methods: We conducted a Real-World observation study by comparison of the efficacy and safety of fruquintinib versus fruquintinib combined with PD-1 inhibitor in patients with mCRC who received treatment between June 2019 and October 2022 in our center. Results: A total of 106 patients with mCRC were observed to receive fruquintinib(F group) (n = 26, mean age = 63 years, female = 46.2%) or fruquintinib combined with PD-1 inhibitor (FP group)(n = 80, mean age = 62 years, female = 46.3%). 3.8% of patients achieved partial response (PR) in FP group and 47.5% had stable disease (SD). Of the F group, no patient had PR and SD was 50%. No difference was found for median progression-free survival(PFS) (F group 6.7 months vs. FP group 4.5 months, p = 0.271). Median overall survival(OS) was significantly prolonged with F group compared with FP group (18.7 months vs. 13.6 months, p = 0.008), which was mainly attributed to the disease course before the treatment of fruquintinib or fruquintinib combined with PD-1 inhibitor in the two groups (42.9 months vs. 31.8 months, p = 0.031). And univariate Cox regression analysis showed that clinical factors (Stage at first diagnosis, PD-L1 gene, number of organs with metastases, and operative treatment) were associated with OS in the FP group (p < 0.05), while only PD-L1 gene positive had significant difference in multivariate analysis (p = 0.024). In the F group, no factors had a significant impact on OS in Cox analysis. Further analysis on immune indices in the FP group indicated that total-MDSCs and PMN-MDSCs significantly decreased after treatment (p = 0.039), mainly resulting from the PR/SD subgroup (p = 0.019) rather than the PD subgroup (p = 1.000). Most adverse events occurred between these two groups were very similar, while any grade of myelosuppression, hepatic injury, abdominal pain, palmar-plantar erythrodysesthesia and hypothyroidism were more frequently observed in the FP group and≥grade 3 myelosuppression was more common. Conclusions: Among patients with metastatic CRC, fruquintinib combined with PD-1 inhibitor couldn't significantly prolong PFS and OS compared with only fruquintinib therapy, but could made a few patients partial response. Total/PMN-MDSCs may be an important indicator of the efficacy of the combined therapy. The combined treatment increased more side effects, yet showed an acceptable safety profile.
Influence of levothyroxine concomitant treatment on treatment responses and outcomes in patients with metastatic colorectal adenocarcinoma.
Authors: Pretta Andrea , Ziranu Pina , Donisi Clelia , Pinna Giovanna , Loi Francesco , Deias Giulia , Palmas Enrico , Cimbro Erika , Cadoni Andrea , Murgia Sara , Mariani Stefano , Rizzo Daiana , Dell'Utri Veronica , D'Agata Alessandra Pia , Bardanzellu Fabio , Maccioni Antonio , Lai Eleonora , Puzzoni Marco , Pusceddu Valeria , Scartozzi Mario
Published: June 2023

e15593

Background: Hypothyroidism is the most common thyroid disorder and levothyroxine is the mainstay treatment. Levothyroxine is mainly used to restore the euthyroid clinical and biochemical status in the gland. Recent literature has correlated chronic hormonal treatment with adverse effects on bone and heart function, as well as correlated with an increased risk of tumor onset. Data available in the literature are controversial, therefore the aim of our study was to evaluate the correlation between chronic levothyroxine intake and outcomes and response to first line treatments in patients affected by metastatic colorectal cancer. Methods: We retrospectively collected the data from 139 patients with metastatic colorectal adenocarcinoma, belonging to the Medical Oncology Department of the University Hospital of Cagliari from 2016 to 2019. All patients enrolled in the study had received metastatic first-line treatment with doublet or triplet chemotherapy associated with anti-VEGF or anti-EGR monoclonal antibody. Patients with ECOG PS ≤1 with no more than two relevant comorbidities were included in the study. The primary objective of the study was median overall survival (mOS) and secondary objectives were: median progression free progression (PFS), median overall survival (mOS) differences between RAS wild type and mutant tumour. BRAF mutant tumors were excluded from the evaluation. Results: Median age was 65 years (±10), 51% were male and 49% were female. 63% patients had an ECOG-PS 0, while 37% had an ECOG-PS 1. 67% developed from the left colon; 33% from the right colon and the transverse colon. All patients had synchronous metastases. 18% patients took levothyroxine and 82% patients did not take it. Among the patients receiving levothyroxine therapy, 64% had a RAS wild type and 36% a RAS mutated. Levothyroxine treated patients showed a significantly lower median OS than not treated patients (15 months versus not reached, p = 0,0001). Levothyroxine treated patients also showed a significantly lower median PFS than non treated patients (6 versus 8 months, p = 0,035). Within levothyroxine treated pts, no statistically significant differences were found in mOS and mPFS between RAS wt and RAS mut (mOS 15 versus 14 months, respectively, p = 0.9; mPFS 8 versus 7 months, respectively, p = 0,7). Conclusions: The results show a possible correlation between levothyroxine therapy and outcomes in mCRC. This would deserve further study to understand further biological-molecular aspects, to date partially explained by preclinical studies, in order to clarify some of the possible underlying mechanisms.
Efficacy of immunotherapy in MSI metastatic colorectal cancer patients: A Real-World Italian multicentric retrospective study (Colon-MSI Study).
Authors: Iachetta Francesco , Cremolini Chiara , Caputo Francesco , Ciardiello Giamaica , Iacono Donatella , Gelsomino Fabio , Bernardini Ilaria , Maria Germani Marco , Romagnani Alessandra , Damato Angela , Brugia Marco , Ratti Margherita , Santucci Sara , Rapisardi Stefania , Di Fabio Francesca , Garajová Ingrid , Frisinghelli Michela , Aschele Carlo , Palazzo Michele , Pinto Carmine
Published: June 2023

e15595

Background: The treatment with Immune checkpoint inhibitors (ICIs) is the gold standard therapy in metastatic colorectal cancer (mCRC) patients (pts) with microsatellite instability (MSI). The aim of the study was to describe a cohort of MSI mCRC pts treated with ICIs, before pembrolizumab approval, to evaluate efficacy and toxicity in a real-world setting and to identify possible predictive factors of response. Methods: We retrospectively collected data of pts with MSI mCRC treated with ICIs (anti-PD1 or anti-CTLA-4 antibodies, or in combination) before June 30, 2021, in 14 Italian Cancer Centers. The OS was calculated from the diagnosis of metastatic disease, and the PFS from the beginning of ICIs. Survival analyses were stratified between treatment naïve and pre-treated pts. We explored the correlation between clinicopathological factors and refractory pts who underwent progression disease (PD) within 3 months from the start of ICI. Results: In this preliminary analysis, we reported 60 consecutive pts with data available. Among all, 30 (50%) were male, 37 (62%) with ECOG PS 0-1; 21 (35%) were at stage IV, and 37 (62%) had right colon tumor site. The most common metastatic sites were lymph nodes, liver, and peritoneum, and 34 (57%) pts had a single metastatic site. 23 (38%) pts had a mucinous adenocarcinoma, and 20 (33%) were BRAF mutated. Nivolumab, Pembrolizumab, and Ipilimumab plus Nivolumab were administered in 24 (40%), 34 (57%), and 2 (3%) pts, respectively, and as first-line therapy in 13 (22%) pts. The median duration of treatment was 22 months (0-43), with 21 pts still ongoing. 13 (22%) pts were refractory to ICIs, and only 4 (7%) pts discontinued treatment for G3-G4 adverse events. The OS, PFS and DCR were different between treatment naïve and pre-treated pts with a positive trend (not statistically significant) toward untreated pts (Table 1). Male gender (p = 0.03), stage IV (p = 0.04), and ≥ 2 metastatic sites (p = 0.01) were significantly associated with refractory ICIs pts, but none of these factors was correlated with poor outcomes in multivariate analysis. Conclusions: Our preliminary data confirm that immunotherapy is an effective and well-tolerated treatment in MSI mCRC pts, with long-term clinical outcomes reported. These results suggest better outcomes when ICIs are administered in the first-line setting. Further analysis will be provided after the completion of the accrual. [Table: see text]
Adjuvant chemotherapy after surgical resection of colorectal metachronous metastases: A phase II nonrandomized trial.
Authors: Evdokimova Sevindzh , Kornietskaya Anna , Bolotina Larisa , Sidorov Dmitriy , Kaprin Andrey
Published: June 2023

e15597

Background: Currently, six months of perioperative or adjuvant chemotherapy (ACT) is a standard treatment option after radical surgical removal of metachronous metastases in patients with metastatic colorectal cancer (CRC). Data show that ACT improves relapse-free survival in such patients, although no difference in overall survival rate was observed. We conducted a non-randomized trial to examine the efficacy of ACT after radical resection of metachronous metastases from CRC. Methods: Patients older 18 years old and more with confirmed CRC and any site of resectable metachronous metastases were assigned to either surgery alone or adjuvant mFOLFOX6 for 6 months. The primary end point was 2-year disease-free survival (DFS). Results: Between June 2008 and September 2022, 123 patients were assigned to surgery alone group (51 patients) or ACT after surgery (72 patients). At a median follow-up of 27.0 months (20.9-33.1), 2-year DFS was 54.2% in surgery alone group versus 45.5% in ACT group. Median DFS (mDFS) was 25.5 months (95% CI 9.8 – 41.2) in surgery alone group versus 20.9 months (95% CI 13.5 – 28.4) in systemic chemotherapy (HR 0.75; 95% CI 0.45-1.25, P = 0.26). Conclusions: ACT didn’t improve DFS among patients after radical surgical resection of metachronous metastases from CRC.
Outcomes of early onset colorectal cancer (EOCRC) with synchronous liver oligometastasis.
Authors: Emiloju Oluwadunni Eunice , Elboraey Mohamed , Montazeri Seyed Ali , Zaazoue Karim , Jones Jeremy Clifton , Wu Christina , Toskich Beau , Hubbard Joleen M.
Published: June 2023

e15599

Background: Screening and removal of pre-malignant adenomas has reduced CRC incidence in adults older than 50 years (later onset CRC [LOCRC]), but EOCRC incidence has increased by 1-2% annually since the 1990s. The liver is the commonest site of CRC metastasis, and EOCRC presents with more advanced stage compared with LOCRC. Oligometastasis (OM) refers to potentially resectable CRC, and complete resection of CRC primary and OM is associated with improved survival and potential cure. Here, we examined treatment outcomes of EOCRC with synchronous liver oligometastases (sLiOM) at our institution. Methods: We performed a retrospective review of institutional electronic health records and identified 160 EOCRC patients with sLiOM treated with curative intent in the last decade. Demographics, treatment, and follow up data were recorded, and analysis for survival outcomes performed. The study protocol was exempt after review by Mayo Clinic institutional review board. Results: Of 160 patients, median age at diagnosis was 43 years. Primary tumor was in the left colorectum in 73% and right colon in 26% of patients. Metastasis was limited to the liver only in 64%, and liver metastasis was solitary in 14% of patients (table 1). Fluoropyrimidine doublet backbone (81%) was more commonly used compared to triplet (19%), with doublet + bevacizumab (41%) as the most common regimen. Hepatectomy only (59%), combined hepatectomy with ablation (32%), ablation only (5%), transarterial radioembolization (2%), and trans arterial embolization (1%) were the modalities employed for sLiOM. Of the 148 patients who underwent hepatectomy, R0 resection was achieved in 51%. After a median follow-up of 37 months, progression-free survival was 11.6 mos (95% CI 9-14mos) and median overall was 83.6 mos (95% CI 62-105mos). The median time to liver progression was 16 mos (95% CI 12-20 mos). At data cut off, 41 patients (26%) were alive and disease-free, and 60 patients (38%) were alive and disease free in the liver only. Conclusions: This multi-site, retrospective analysis of EOCRC patients demonstrates excellent survival outcomes with localized treatment of sLiOM. Median OS in this cohort compares favorably to previously reported mOS of 36 months in EOCRC patients (Arhin et al, 2021). Cure is not often achieved even after treatment of sLiOM in this cohort, suggesting aggressive disease biology and the need for improved patient selection. [Table: see text]
Safety and efficacy of trifluridine/tipiracil plus bevacizumab in RAS mutated patients with metastatic colorectal cancer.
Authors: Michalaki Vasiliki , Theodosopoulos Thedosios , Vezakis Antonios , Papaconstantinou Ioannis , Kontis Ioannis , Dafnios Nikolaos , Frangoulidis George , Karandrea Despina , Papadimitriou Christos
Published: June 2023

e15605

Background: Trifluridine-tipiracil (FTD/TPI) plus bevacizumab has shown efficacy inrefractory metastatic colorectal cancer (mCRC); however, evidence supporting the role of this combination in Ras mutated population, is limited. In this phase II study, we investigated the efficacy and safety profiles of FTD/TPI in mCRC according to KRAS status. Methods: Eligible patients were mCRC refractory or intolerant to all standard therapies including fluoropyrimidines, irinotecan and oxaliplatin. Patients received 4-week cycles of treatment with FTD/TPI (35 mg/m2, twice daily, days 1-5 and 8-12) and bevacizumab (5 mg/kg, days 1 and 15). Clinicopathological characteristics, overall response rate (ORR), disease control rate (DCR), PFS, and safety data were collected and analyzed. Results: Forty-two patients were enrolled. Median age was 67 years (range 41–79 years), 44% were male, 100% had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–1, 85% were KRAS and 15% NRAS mutant, and 75% underwent primary tumor resection; 68% of patients had liver metastases, 49% had lung metastases, and 18% had peritoneal carcinomatosis. The median number of previous treatment lines was 2 (range1–3), and 85% of patients received at least one previous anti-angiogenic agent. DCR was 57.1% (90% CI, 44.6 %-69.3%, P = 0.0690), respectively. The median progression-free survival (PFS) was 4.6 months. The most common grade 3 or higher adverse event was neutropenia (54%), and anemia (16%); 32% of patients required either dose delays or dose reductions due to toxicity. No treatment-related deaths occurred. Conclusions: FTD/TPI is an important therapeutic resource in refractory RAS mutated metastatic colorectal cancer that combines manageability and safety.
3D genomics identifies previously unreported yet clinically actionable gene fusions and complex rearrangements in a cohort of driver-negative colorectal carcinoma tumors.
Authors: Sikkink Kristin , Beck Alyssa , Schmitt Anthony , Sigal Darren
Published: June 2023

e15608

Background: Molecular characterization by next-generation sequencing (NGS) has been unable to detect pathogenic driver mutations in a significant number of tumors. For example, 40% of colorectal carcinomas (CRC) are RAS and BRAF wild-type and do not have therapeutic targets after comprehensive molecular characterization using FISH, IHC and NGS. Analysis of 3D genomics data produced by DNA-based chromosome conformation capture (Hi-C) assay has been shown to detect gene fusions and other rearrangements in tumor biopsies. We applied Hi-C in a cohort of CRC tumors previously characterized using FISH, IHC, whole exome sequencing (WES) and whole transcriptome sequencing (WTS) by a large commercial reference laboratory, where no targets had been reported, to evaluate the potential for Hi-C to identify novel therapeutic targets. Methods: FFPE tissue from 14 CRC tumors were subjected to Hi-C using the Arima HiC+ for FFPE kit. Hi-C libraries were sequencing to ~100M raw read-pairs on an Illumina NovaSeq, and fusions were called using the Arima-SV pipeline. To attribute clinical significance, we characterized fusions based on whether the fusion event involved a Tier 1 therapeutic level biomarker or a Tier 3 diagnostic or prognostic biomarker according to NCCN and OncoKb, or a Tier 2 biomarker if the biomarker was the target of a therapy in an ongoing clinical trial. Results: Hi-C detected fusions implicating a Tier 1 biomarker in 50% (7/14) of tumors, a Tier 2 level biomarker in 14% (2/14), and a Tier 3 level biomarker in 14% (2/14). Homologous recombination repair (HRR) gene rearrangements were detected in 29% (n = 4/14) of CRC tumors, disrupting HRR genes ( BRIP1, BRCA1, BRCA2, RAD51D). NRG1 gene fusions were detected in 14% (2/14), and amplified complex rearrangement carrying KRAS was detected in one CRC case. A complex rearrangement involving extrachromosomal DNA (ecDNA) amplification carrying EGFR was detected in two cases that were both previously found to have EGFR amplifications, but the ecDNA nature was not previously known and was confirmed by FISH. Lastly, Hi-C detected gene rearrangements involving POLE or APC in two CRC cases, alterations in which are known to increase risk for colonic polyposis. Conclusions: Fusion detection by Hi-C in CRC may uncover numerous therapeutic biomarkers not currently detected by molecular profiling. Our data suggests that homologous recombination deficiency (HRD) may frequently result from HRR gene rearrangements readily detectable by Hi-C, and this alternate mechanism for HRD may serve as a therapeutic biomarker for HRD directed therapies. Our data also suggests that therapeutically targetable gene fusions and complex rearrangements involving therapeutic level biomarkers are also readily detectable by Hi-C, detection of which may increase the number of CRC patients treatable with targeted therapies.
Comparative efficacy of later-line therapies for metastatic colorectal cancer (mCRC) using novel methods for patient survival data reconstruction and network meta-analysis (NMA) of survival curves.
Authors: Abraham Ivo , Obeng-Kusi Mavis , Roe Denise , Erstad Brian L
Published: June 2023

e15611

Background: NMAs of cancer treatments are usually based on the proportional hazard assumption (PHA) which implies a constant hazard ratio as well as treatment effect on only scale parameter and therefore not reflecting clinical dynamics of survival outcomes over time. Multivariate NMA which does not rely on the PHA is often constrained by lack of individual patient-level data (IPD). We applied a novel method of reconstructing pseudo-IPD from published survival curves that enabled application of a dynamic method of NMA of survival curves without PHA constraint to compare the efficacy of 6 later-line therapies for metastatic colorectal cancer (mCRC), compared to placebo. Methods: We identified 8 phase II/III trials reporting the efficacy of 6 later-line therapies for mCRC from PubMed, Embase, Scopus and Cochrane Library. Trial survival curves were reconstructed based on pseudo-IPD generated using the Guyot method, and the estimated survival proportions and hazard ratios (HRs) over 12 months (12m) of follow up were calculated using a random effects lognormal distribution model with placebo as the common comparator. Results: Compared to placebo, 12m PFS HRs varied from 0.29 (95%CrI = 0.19-0.44) for TAS+bevacizumab to 0.72 (95%CrI = 0.62-0.85) for atezolizumab. Similarly, OS HRs ranged from 0.55 (95%CrI = 0.26-0.92) for TAS+bevacizumab to 1.01 (95%CrI = 0.79-1.20) for atezolizumab (Table). Conclusions: In this NMA of survival curves, all therapies except atezolizumab were superior to placebo in PFS and OS over 12m follow up period. TAS+bevacizumab provided the highest survival advantage over placebo, with fruquintinib, regorafenib, and TAS-102 also showing survival benefits. TAS+bevacizumab may be the preferred choice for later-line mCRC treatment. [Table: see text]
Intraarterial chemotherapy of liver metastases of colorectal cancer. Experience of National Cancer Institute of Ukraine.
Authors: Patsko Veronika , Lukashenko Andrii , Ostapenko Yuriy
Published: June 2023

e15619

Background: Liver - is the most often site of colorectal cancer metastases. Although surgical resection of primary tumor and liver metastases is the most radical type of treatment, only 10-25% of patients are eligible for this approach. Our aim was to evaluate efficacy of intraarterial chemotherapy for patients with primary unresectable metastatic colorectal cancer (mCRC) to improve prognosis and overall response for treatment. Methods: records of 73 patients with primary unresectable mCRC, who undergone catheterization of liver artery and received intraartetial chemotherapy (with 5-FU) in period 2008-2018 years at the Clinic of National Cancer Institute (Ukraine). Results: the figure of overall response: 57.5% (n = 42) - partial response, 8.2% (n = 6) - complete radiological response, 12.3% (n = 9) - stable disease, 21.9% (n = 16) - chemoresistant tumor. 46.6% (n = 34) of patient undergone resection of previously unresectable liver metastases. In 4.1% (n = 3) complete histological response was estimated. Surgical mortality and morbidity rate were 1.3% and 6.8% respectively. Cause of postoperative mortality was lung embolism, complications included bacterial infections and hemorrhage in postoperative period. Main reason for inability to perform operations were post chemotherapeutic toxicity, which did not resolved on optimal terms for operation. The overall 5-year survival rate was 29.4% in group who undergone resection and 17.9% in group, were patients were not radically operated (p < 0.05). Conclusions: catheterization of liver artery with further intraarterial chemotherapy can potentially convert unresectable metastases into resectable, therefore improving treatment results and overall survival.
When is neoadjuvant chemotherapy indicated in rectal neuroendocrine tumors? An analysis of the National Cancer Database.
Authors: Gefen Rachel , Emile Sameh Hany , Horesh Nir , Garoufalia Zoe , Freund Michael , Wexner Steven D
Published: June 2023

e15631

Background: Rectal neuroendocrine tumors (rNET) are rare and challenging to manage. While most patients with small rNET can be definitively treated with local excision, the role of chemotherapy in general and neoadjuvant therapy specifically in managing advanced rNET has not been well established. Therefore, this study aimed to determine which patients with rNET may gain a survival benefit from neoadjuvant chemotherapy. Methods: A retrospective cohort analysis of all patients who underwent surgical resection of rNET in the US National Cancer Database (NCDB) (2004-2019) was performed. First, univariate and multivariate cox regression analyses were performed to determine the independent predictors of poor overall survival (OS) and define the high-risk groups. Afterwards, stratified OS analyses were performed for each high-risk group to assess whether neoadjuvant chemotherapy had a survival benefit in each group. Results: 1837 patients (49.8% female; mean age 56.6 ±12.3 years) underwent radical resection of a rectal neuroendocrine tumor. Tumors > 20 mm in size, clinical T4 tumors, poorly differentiated tumors, and metastatic disease were independent predictors of worse OS and were defined as high risk groups. Neoadjuvant chemotherapy did not have a significant survival benefit in any of the high-risk groups, except for patients with high-grade rNETs where neoadjuvant therapy significantly improved OS to a mean of 30.9 months compared to 15.9 months when neoadjuvant therapy was not given (p = 0.006). Conclusions: Neoadjuvant chemotherapy improved OS of patients with high-grade rNET by 15 months and may be indicated for this group.
Comparison of concomitant mutational of type I/II/III BRAF mutation in colorectal cancer between Chinese and Western populations.
Authors: Huang Yingying , Zhongkang Li , Zhao Yun-Bo , Jia Wenzhuo , Du Jun , Zhao Gang , Wu Guoju
Published: June 2023

e15634

Background: BRAF V600E CRC had a relatively poor prognosis.The efficacy of BRAFi is unpredictable just that intrinsic genetic complexity and partially unknown reason.Therefore, To understand co-mutation mechanism can help improve treatment and follow-up strategy. Methods: 339 Chinese CRC patients and 125 Western CRC data from the cBioPortal were included in study. Co-occurrence mutation analysis, GO and KEGG pathway enrichment analysis was enabled in this study. Results: 35/339 (10.32%) patients were BRAF mutation, with 17 patients were BRAFV600E in Beijing hospital. Patients with BRAF mutation had significantly associated with TMB-H (p = 0.0004) and MSI (p = 0.0003) than those with BRAF wild-type. In 125 BRAF mutation western cohort, The frequency clinicpathologic features, MSI, TMB, and BRAF mut-type were consistent with Chinese data. However, the primary tumor location showed significant statistical differences (P < 0.0001). In Chinese cohort, class 1 (BRAFV600E, A deeper classification system of BRAF mutations) were more likely to occur in Elder, Female, western cohort was consistent with above. Other clinicpathologic features were not associated with mut-type in Chinese cohort. However, Western cohort showed class 1 exhibited primary sample type predominance(vs class NA, P < 0.05; vs class 3, P < 0.05). Right-sided was more likely to occur in class 1(P < 0.05), this was inconsistent with the data analyzed above. Meantime, The data showed TMB-H (57.69% vs 11.76%, P < 0.001) and MSI-H (28.21% vs 14.29%, P < 0.005) of the class 1 were significantly higher, compared with class 3. In concurrent oncogenic mutations. Compared with non-class 1, class 1 were more likely co-passenger mutation. Data from Western populations show similar results. We also found that the class 1 was mutually exclusive with co-KRASmt in CRC, and co-APCmt appeared more frequently in non-class 1. In pathway enrichment, KEGG pathway showed that fewer proto-cancer signaling pathways were enriched in the class 1, which further confirmed that this type had stronger tumorigenicity. GO enrichment also proved that class1 had stronger tumorigenicity. Finally, Prognostic analysis showed median overall survival(OS) of 47.57 months in class 1 versus 19.43 months in non-class 1(p = 0.0002). Further study showed that the mOS of class 1/2/3/NA was 19.43 months, 28.50 months, 47.57 months and NA months(P = 0.0001), respectively. Conclusions: This study shown class 1/non-class 1 BRAF mutation in CRC have significantly differences in co-mutation features, genomic markers and prognioses. Especially, class I BRAF mutation in Chinese patients have higher TMB and MSI,maybe we could choose BRAFi and immunotherapy for them. Understanding BRAF mutation types and co-mutation mechanism will contribute to accurately grasp treatment, follow-up strategies and promote the development of precision therapy for CRC in the future.
Differences of RAS/BRAF mutations between ISCC and RSCC in a Chinese population.
Authors: Chen Yuhong , Qiu Yixian , Zhang Yanrui , Zhang Yun , Liang Xiayuan , Lou Feng , Cao Shanbo , Qin Jiayue
Published: June 2023

e15636

Background: According to the location and different clinical manifestations, colon cancer can be divided into left-sided colon cancer (LSCC) and right-sided colon cancer (RSCC). There are significant differences in morphology, molecular biology, and drug sensitivity between these two type. In addition, colorectal cancer is associated with the mutation of many essential tumor suppressor genes, such as proto-oncogene (KRAS), serine/threonine protein kinase (BRAF), etc. At that point, this study retrospectively analyzed the RAS/BRAF mutation landscape and studied the gene expression differences between RAS/BRAF-mutant and wild-type patients respectively in LSCC and RSCC, to provide some reference for potential treatment plans. Methods: We retrospectively profiled the somatic mutations of 497 patients with colon cancer from the General Hospital of Southern Theatre Command and the TCGA database using 808-gene-panel target-capture next-generation sequencing. Tumor mutation burdens (TMB) were calculated using an Acornmed panel with 808 cancer-related genes. Results: Among 415 LSCC, 48.7% (n = 202) patients harbored RAS mutations, of which 183 carried KRAS mutations and 19 had NRAS mutations. Five main subtypes of KRAS mutation were detected including G12D (28.7%), G12V (17.5%), G13D (13.2%), A146T(8.5%), G12C (7.9%). 3% (11) of LSCC patients were found to have BRAF mutation, including BRAF V600E(63.6%), D594G(18.2%), G466E(9.1%), K601E(9.1%). We explored differentially expressed genes between RAS/BRAF-mutant and wild-type patients. The top5 mutant genes found only in LSCC RAS/BRAF-mutant cohort include JAK2(3%), TERT(2%), MSH6(2%), KMT2A(1%), NOTCH1(1%). In contrast, genes found only in LSCC patients with RAS/BRAF wild type include LATS2(2%), SMARCA4(2%), CBL(1%), SLX4(1%), CDKN2A(1%). Among 82 RSCC, 50% (41) patients harbored RAS mutations, of which 39 carried KRAS mutations and 2 carried NRAS mutations. 9% (39) of RSCC patients were found BRAF mutation, and the BRAF V600E was the only subtype found in the RSCC. In terms of differentially expressed genes, the top5 mutant genes found only in RAS/BRAF-mutant RSCC include NSD1(6%), ASXL2(4%), BARD1(4%), PPP2R1A(4%), SPRED1(4%), while genes found only in RAS/BRAF wild-type RSCC include ERBB2(17.6%), DICER1(11.8%), EP300(11.8%), ARID2(9%), BRIP1(9%).The TMB of RAS/BRAF wild-type RSCC patients was 33.2 mut/Mb, significantly higher than that of RAS/BRAF wild-type LSCC patients (7.0 mut/Mb, P = 0.01). Conclusions: RAS mutation and subtype were almost the same in LSCC and RSCC cohorts. BRAF mutation mainly occurred in RSCC, and the mutation subtype in RSCC was found only V600E, but we found three other BRAF subtypes D594G, G466E, and K601E in the LSCC cohort. Considering the differential expression genes in RAS/BRAF-mutant and wild-type cohorts in RSCC and LSCC patients, there may be more options for genetic targets in the future for LSCC and RSCC treatment.
Capecitabine-oxaliplatin (CAPOX) prior to chemoradiotherapy (CRT) and surgery in magnetic resonance imaging (MRI)-defined poor-risk rectal carcinoma (PRRC): A single center experience.
Authors: Ribes Carla Bellido , Soler Jorge , Ruiz Nuria , Rubio Novella Silvia , Morillo Virginia , Molina Jorge , Busquier Hernandez Isabel
Published: June 2023

e15638

Background: Clinical trials have studied the efficacy and safety of neoadjuvant chemotherapy (CT) and CRT in PRRC. Chau published his data on PRRC studied with MRI: tumors within 1 mm of mesorectal fascia, T3 at or below levators, tumors extending > 5 mm into perirectal fat, T4 and T1-4N2 tumors (JCO 2006; 245: 668-674). Following this strategy, we present the data from our center. Methods: between February 2006- July 2018 we treated 77 PT with MRI-defined PRRC with CAPOX x 4 cycles, Capecitabine-radiotherapy, surgery and capecitabine 4 cycles (Chau strategy). Results: Our sample includes 43 men and 34 women, median age 59 (range 31-77). A patient died after the first CAPOX due to a hemorrhagic stroke. 69 PT had symptomatic improvement with CT, without identifying any progression. Surgery has performed in 75 PT and 65 had R0 resection, R1 in 6 patients, R2 in 2 patients and 2 lost. On an intent-to-treat analysis, pathological complete responses was achieved in 13 (pCR: 16,9%) of patients. The mean number of lymph nodes removed was 11. 51 patients (66,2%) started CT post-surgery. With a median follow up of 113 months [range 24-199],26 patient (33,8%) presented disease progression, 5 local and 21 distant recurrence. There were 14 deaths due to disease progression. 5-years OS was 87% (CI 95%: 79,4-94,6%) and DFS was 80,2 (CI 71-89,4%). Conclusions: Our data support the rutine use of CAPOX and following CRT prior to surgery on PT with PRRC, with promising results consistent with published trial data.
Treatment pattern and outcome of locally advanced rectal cancer in Tikur Anbessa Specialized Hospital (TASH), Addis Ababa, Ethiopia: An institution-based cross-sectional study.
Authors: Hailu Elias Amare , Woldetsadik Edom Seife , Tadesse Biruk Legesse , Kelemu Hedagewoin Friew , Zingeta Girum Tessema , Zewde Yonas Alemayehu , Aytehgeza Ruth , Dandena Abdi , Begna Kebede
Published: June 2023

e15640

Background: The standard management of locally advanced rectal cancer (LARC) is neo-adjuvant concurrent chemo radiation (CCRT) followed by total meso-rectal excision. Recently there is an increased interest in total neo-adjuvant treatment (TNT). Most patients with rectal cancer in developing countries present in advanced stage for several reasons including lack of resources and delayed health seeking behavior. Most patients are not able to get standard management. This study tries to assess treatment patterns and outcomes in LARC. Methods: A cross-sectional study was conducted in patients with LARC that are treated at TASH from Jan 1, 2020 up to Sept. 2022. The data was collected from Patient’s cards using a pre-structured format that included demographic data, laboratory, pathological and imaging information. Data analysis was conducted by using IBM SPSS version 25. Results: 100 patients were included in the study, 51% were male. The median (range) age at diagnosis was 45.5 (20-86) years. 81% of patients came to our center without getting any oncologic treatment and 75.3% of them were presented on a multi-disciplinary tumor board for their treatment decision. Upfront surgery was decided in 48.1% (39/81) of patients. Standard neo-adjuvant treatment of either TNT or CCRT was decided in 23.4% (19/81) and 8.6% (7/81) of patients respectively. There is no significant association between tumor location, TNM stage, mesorectal fascia status and first treatment decision. Only 12 (14.8%) patients were able to finish their whole treatment plan. The most common reason for not finishing all treatment was prolonged radiation waiting time, with the median (range) waiting time of 10 ± 7.1 (1-26) months. From 81 treatment naive patients, 79 were decided to have surgery; and 59.5% (47/79) underwent the planned surgery with 89.9% R0 resection rate. R0 resection rate in patients who undergo upfront surgery was 91.2% (31/34). Neo-adjuvant chemotherapy was given to 34.6% (28/81); and only 18% (5/28) underwent subsequent surgery. The most common reason for not undergoing subsequent surgery was disease progression 43.5% (10/23) during or after finishing the neo-adjuvant chemotherapy. Only 24% of the study participants received radiotherapy. From the patients who took radiotherapy, only two patients received short course radiotherapy. Conclusions: Treatment decisions for rectal cancer in our study did not conform to standard treatment recommendations. Upfront surgery maybe a better option than neoadjuvant chemotherapy, since timely administration of standard neoadjuvant treatment is not possible. Alternative radiotherapy treatment options like short course radiotherapy may be better in resource limited setting to alleviate the longer radiotherapy waiting time.
Electronic frailty index to assess post-operative healthcare utilization in veterans with non-metastatic colon cancer.
Authors: Zhu Huili , Razjouyan Javad , Yarlagadda Sudha , Sada Yvonne H
Published: June 2023

e15642

Background: Frailty is a measure of physiologic reserve and is associated with adverse perioperative outcomes in patients with cancer. Existing surgical frailty measures, such as the 11-factor and 5-factor modified frailty index, may not be routinely utilized due to time constraints. Electronic Frailty Index (EFI) serves as an efficient and automated alternative. There is limited data for the use of EFI in assessment of post-operative healthcare utilization in patients with non-metastatic colon cancer. Methods: We performed a retrospective cohort study using VA administrative files from 2016 -2020 and VA Central Cancer Registry. EFI was calculated based on the Veterans Affairs-FI (VA-FI), a validated 31-item cumulative deficit FI, to define three groups: robust (≤ 0.1), prefrail (0.1 - 0.2), and frail ( > 0.2). Cox proportional hazard analyses were conducted to evaluate survival. Logistic regression analyses were performed to examine healthcare utilization. All models were adjusted for age, gender, race, stage, and Charlson Comorbidity Index. Confidence intervals (CI) were calculated as 95%. Results: Among 2,861 patients (median age 70.7 ± 9.1 years) with stage I – III colon cancer who underwent surgery, 42.5% were robust, 36.6% were prefrail, and 20.8% were frail. The cohort was comprised of stage I (32.9%), stage II (34.9%), and stage III (32.2%) cases. Prefrail patients were at increased odds of emergency room (ER)/urgent care (UC) use at one year (adjusted odds ratio [aOR] 1.41, CI 1.09 – 1.83) compared to robust patients. Frail patients had an increased odds of ER/UC visits at 30 days (aOR 1.95, CI 1.19 - 3.20), 60 days (aOR 2.18, CI 1.42 - 3.34), and one year (aOR 2.79, CI 2.06 - 3.78). Increased risk of death was found in prefrail (adjusted hazard ratio [aHR] 1.34; CI 1.12 - 1.59) and frail (aHR 2.38; CI 1.97 - 2.86) patients when compared to robust patients. Conclusions: EFI was significantly associated with higher ER/UC utilization among frail patients with colon cancer who received curative intent surgery, independent of stage. Pre-frail and frail patients had worse survival outcomes compared to robust patients. Further work is needed to develop EFI as a risk-stratification tool in curative intent patients with colon cancer prior to surgery.
The impact of treatment adherence on overall survival in non-metastatic colorectal cancer in Latin American patients.
Authors: Namuche Fernando , Leon Jorge , Flores Claudio J.
Published: June 2023

e15644

Background: Colorectal cancer is a significant public health issue in Peru, and non-metastatic colorectal cancer patients face numerous treatment challenges. Adherence to treatment protocols has been identified as an important factor influencing patient outcomes. However, little is known about the impact of treatment adherence on overall survival in non-metastatic colorectal cancer patients in Peru. The objective of this study is to investigate the association between treatment adherence and overall survival in this patient population. Methods: We retrospectively reviewed the electronic medical files of 890 patients with non metastatic colorectal cancer between 2006 and 2020. Patients were included if they received treatment and were followed up for at least two years. Treatment adherence was measured based on the number of completed chemotherapy cycles and the time to initiate treatment after surgery. Overall survival was defined as the time from diagnosis to death or the last follow-up visit. Multivariate analysis was performed to identify factors associated with overall survival. Results: A total of 890 patients were included in the study, and the median follow-up time was 32 months. The overall adherence rate was 71.7%. Patients who adhered to treatment had a significantly higher overall survival rate compared to non-adherent patients (p < 0.001). A multivariate analysis was performed using Cox regression model with the statistically significant variables found (sex, high histologic grade, stage and adherence to treatment) in the univariate analysis. Multivariate analysis showed that treatment adherence was an independent predictor of overall survival (HR = 0.69; 95% CI, 0.54-0.88; p < 0.001). Conclusions: Our findings indicate that medication adherence is a crucial factor affecting overall survival in Peruvian patients with non-metastatic colorectal cancer. Patients who adhered to treatment had a significantly higher overall survival rate than non-adherent patients, highlighting the importance of adherence in optimizing patient outcomes. These findings have important clinical implications for healthcare providers, who should prioritize efforts to improve treatment adherence in this patient population.
Real-world impact of time-to-treatment initiation and initial treatment modality on survival in pancreatic and colorectal cancers.
Authors: Schwanke Joshua , Patterson Brooke , Marmor Schelomo , White McKenzie Joy , Jensen Eric Hans , Tignanelli Christopher , Lou Emil , Prakash Ajay
Published: June 2023

e15646

Background: Overall survival for patients with pancreatic ductal adenocarcinoma (PDAC) and colorectal cancers (CRC) has increased significantly over the past decade; however, the optimal time-to-treatment initiation (TTI) and initial treatment modality (ITM) have not been defined. These variables have likely been affected by increased adoption and changes in types of neoadjuvant treatment strategies for these cancer types. Thus, we performed a retrospective observational study of TTI and ITM in patients with CRC and PDAC within the MHealth/Fairview medical system. Methods: We identified 424 patients with stage I-III RC and 316 patients with stage I-III PDAC within the MHealth/Fairview system (Minneapolis, MN) from 2011-2021 with North American Association of Central Cancer Registries data enriched by the electronic health record. Patients were stratified by TTI from diagnoses as: 0-7 days, 8-14 days, 15-28 days, 29-42 days, and over 43 days. ITM, defined as initial chemotherapy/chemoradiation, surgery, or radiation, was analyzed independently for patients with rectal cancer (N = 267) and PDAC. Effect of TTI and ITM on overall survival was calculated using a Cox proportional Hazard (CPH) model controlling for clinical stage. Results: TTI was significantly associated with survival in CRC, with patients treated in 8-14 days and 15-28 days showing increased survival over patients treated in over 43 days (HR 0.397, p = 0.007 and HR 0.276 p < 0.001, respectively). There was no significant hazard for TTI and survival in PDAC. We also found that neoadjuvant chemotherapy/chemoradiation had a lower hazard for death in rectal cancer relative to upfront surgery (HR 0.323, p = 0.002), when controlling for stage. Surgery was significantly more likely to be correlated with stage I or II disease than chemotherapy/chemoradiation (68.5% vs 24.7%, p < 0.0001 by Spearman method). There was no significant association between ITM and survival in patients with PDAC. Conclusions: Early treatment for CRC is associated with improved survival in this population, implying that treatment delays decrease the efficacy of curative-intent therapy. Evaluation of treatment modality in the rectal sub-group showed improved outcomes with neoadjuvant chemotherapy and chemoradiation, despite upfront surgery being associated with lower stage. The lack of association between TTI and survival in PDAC is likely related to the relatively poor outcomes observed with this disease and highlights the need for better screening and treatment for resectable disease. These results are notable because they suggest that a thorough workup and appropriate therapy may be more important than rapid treatment.