bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pan-cancer analysis of IDH1 and IDH2 genomic alterations to reveal a complex molecular landscape.
Authors: Zhou Houjun , He Zhe 
Published: June 2022

e15116 Background: As a crucial enzyme involved in cell aerobic metabolism of the tricarboxylic acid cycle, IDH also plays important role in cancer biology. Somatic point mutations in IDH1/2 contribute to oncogenesis by promoting the production and secretion of an oncometabolite, the D-2-hydroxybutyrate, which could alter cellular metabolism and epigenetic regulation. However, data regarding the status and prevalence of IDH1 and IDH2 mutations in pan-cancer from Chinese cancer patients is limited. Methods: Ranging from Jan 14, 2020, to Oct 25, 2021, genomic DNA extracted from 5419 blood or tissue samples involving more than 22 solid tumors types were analyzed by NGS assay to investigate the landscape of IDH1/2 mutations and hotspots. Results: IDH mutations were identified in 205 cases (3.78%), of which 145 cases (2.68%) were from the IDH1 mutations group and 63 cases (1.16%) from the IDH2 mutations group. IDH1 mutations predominantly occurred in CNS tumors, melanoma, and endometrial cancer (with mutation frequencies of 26.09%, 7.41%, 5.26%, respectively), whereas IDH2 mutations occurred commonly in endometrial cancer (5.26%) and gastric cancer (2.90%). Among the 56 mutation sites found in IDH1, Y208(19.46%), R132(16.11%), and R20(12.08%) were the three major IDH1 mutations. M397, which accounts for 33.33% of all IDH2 mutation sites, was the most significantly mutated subtypes, followed by T146(4.76%). Conclusions: Compared with IDH2, IDH1 is more frequently mutated in terms of cancer species as well as shows higher mutation frequency, and our findings implicate mutations in IDH in the pathogenesis of cancers, especially CNS tumors.
Integration of molecular cancer classification and NGS to identify patients with metastatic cancer eligible for BRAF inhibitors.
Authors: Fuentes Bayne Harry E. , Ma Li , Wong Jenna , Treuner Kai , Halfdanarson Thorvardur Ragnar 
Published: June 2022

e15118 Background: Melanoma, non-small cell lung cancer (NSCLC), colorectal adenocarcinoma and thyroid tumors frequently harbor BRAF mutations and are tumor types eligible for treatment with FDA-approved BRAF inhibitors. Although there are many ongoing clinical trials with BRAF inhibitors in various advanced tumor types, currently eligibility requires both tumor type identification and BRAF mutation confirmation. The 92-gene assay (CancerTYPE ID) is a gene expression-based classifier of 50 tumor types and subtypes for metastatic patients with diagnostic ambiguity. Multimodal biomarker testing, including NGS, IHC and FISH, enables identification of actionable biomarkers to guide targeted therapy selection. Here, a database of metastatic cases integrating tumor type with biomarker analysis was used to identify patients eligible for BRAF inhibitor treatment. Methods: MOSAIC (Molecular Synergy to Advance Individualized Cancer Care) is an IRB-approved, de-identified database of diagnostically ambiguous cases submitted for CancerTYPE ID testing with tumor type-guided multimodal biomarker testing (Neogenomics). In this study, metastatic cancers of various tumor types with BRAF mutations were identified. Results: CancerTYPE ID determined 27 different tumor types in 2929 (92.5%) of 3168 cases. BRAF mutations were identified in 87 cases across 18 tumor types and subtypes. Out of the 87 cases, 22 (25.3%) had BRAF mutations in a tumor type eligible for FDA-approved BRAF inhibitor treatment, including melanoma, NSCLC, colorectal adenocarcinoma and thyroid cancer. Another 26 (29.9%) BRAF-mutated cases were detected in a tumor type with ongoing BRAF inhibitor clinical trials, including lymphoma, pancreaticobiliary and ovarian cancer (Table). Conclusions: This analysis identified patients with metastatic cancer with actionable BRAF mutations eligible for FDA-approved therapy, and patients who may be eligible for investigational BRAF inhibitors based on tumor type and mutation status. Notably, cancer type identification is critical given that FDA-approved BRAF inhibitor treatment regimens vary based on the tumor-specific indication. These findings support the clinical utility of molecular tumor type classification by CancerTYPE ID combined with biomarker profiling to identify additional treatment options for patients with metastatic cancer.[Table: see text]
Clinical and prognostic features of BRAF V600E-mutant resectable colorectal cancer: A single-center retrospective analysis of Chinese patients.
Authors: Liu Mengling , Xu Xiaojing , Yu Yiyi , Liu Tianshu 
Published: June 2022

e15505 Background: Molecular subtyping provides a fundamental basis for the selection of strategies for colorectal cancer treatment. Unresectable metastatic colorectal cancer (CRC) with BRAF V600E mutation have received great attentions due to the poor prognosis. Nevertheless, clinical characteristics and prognosis of Chinese patients with BRAF V600E-mutant (BM) resectable CRC remain poorly reported. Methods: Patients with BM resectable CRC were included according to the following criteria: 1) Diagnosed with colorectal adenocarcinoma at Zhongshan Hospital Fudan University from June 2015 to December 2018. 2) Underwent surgery for the primary tumor of CRC without any anti-tumor treatment before surgery. 3) With BRAF V600E mutation confirmed by the genetic test of the primary tumor tissue. 4) No other primary malignant tumors or inherited tumor history. 5) Written informed consent was obtained. Clinical information was collected by consulting electronic medical records with the approval of the Ethics Committee of Zhongshan Hospital Fudan University (Approval code: B2021-739). KRAS exon2 mutant (KM) and KRAS/BRAF wildtype (WT) patients were selected in a 1:1 ratio by matching gender, age, location and the year of surgery with the BM group. Overall survival was defined as the time from surgery to death for any reason or last follow-up (September, 2021). Categorical data were assessed by chi-square test. Survival analysis was performed using Kaplan-Meier survival curve with log-rank test, univariate and multivariate Cox regression analyses. Results: A total of 214 patients with BM resectable CRC met the inclusion criteria. Among them, 111 (51.9%) patients were females and 103 (48.1%) were males, 114 (53.3%) patients were younger than age 65 years while 100 (46.7%) were > = 65 years old, 108 (50.5%) patients’ primary lesions sited on the left side and 106 (49.5%) on the right side. Numbers of patients with resectable metastasis and with mismatch-repair- deficient (dMMR) were both 48 (22.4%). 171 KM patients and 165 WT patients were matched with BM patients and the three groups were balanced in gender, age, and location by matching. The BM group had the worst overall survival ( P < 0.001) with significant higher proportions of stage IIĨIV ( P = 0.002) and dMMR patients ( P < 0.001). Survival analysis in subgroups suggested that the inferior prognosis of the BM group was more pronounced in patients with pMMR or Stage IV CRC. Conclusions: BRAF V600E-mutant resectable CRC presented a higher incidence of dMMR but a worse prognosis than KRAS exon2 mutant or KRAS/BRAF wildtype patients.
FAT1 mutations in colorectal cancer patients are associated with the therapeutic benefit of immunotherapy.
Authors: Liang Tingbo , He Junjun , Zhu Wei , Yang Lan , Gao Yu , Zhou Yi , Shi Yuqian , Liu Kaihua , Yu Ruoying , Shao Yang , Zhang Wentong , Zhang Qi , Wu Guosheng 
Published: June 2022

e15523 Background: Immunotherapy is one of the main treatment modalities for advanced colorectal cancer. Although microsatellite instability (MSI) is widely applied as an effective immune efficacy prediction biomarker in clinical practice, the majority of the colorectal patients are microsatellite stable (MSS). This study is designed to identify new biomarkers for immune efficacy in colorectal cancer. Methods: Targeted sequencing with a 425 gene panel was performed with the tumor tissues from a total of 161 colorectal cancer (CRC) patients (discovery cohort) for mutation analysis. The association between FAT1 mutations and immunotherapy markers MSI and TMB was investigated using an external database of 727 CRC patients from cBioportal (validation cohort). Results: The discovery cohort consisted of 95(59%) males and 66(41%) females with a median age of 59 years old. There were 2(1.2%) stage II, 5(3.1%) stage III, 24(14.9%) stage IV, and 130(80.8%) unknown stage patients. The majority of the discovery cohort was MSS (154, 95.7%), which was similar to the validation cohort (518, 71.2%). FAT1 mutations were present around similar ratios in both discovery cohort (12.4%) and validation cohort (11.6%). In both cohorts, the co-occurrence analysis revealed that MSI events were often co-occurred with FAT1 mutations and patients with FAT1 mutations had a higher mutational load compared to the FAT1 wild-type patients. Analysis with survival data from the validation cohort showed that OS was significantly higher in patients with FAT1-mutated tumors than in ones with FAT1 wild-type. Compared to the FAT1 wild-type tumors, the higher infiltration rate of immune cell identified in the colorectal tumors with FAT1 mutation may also explain the good immune efficacy of patients with FAT1 mutation. Conclusions: Colorectal cancer patients with FAT1 mutations may benefit from immunotherapy. The increased immunogenicity in patients with FAT1 mutations may be due to increased immune cell infiltration.
PD-1 blockade combined chemotherapy and bevacizumab in DNA mismatch repair-proficient/microsatellite stable colorectal liver metastases.
Authors: Men Qianqian , Huang Jun , Duan Yinghua , Pei Fengyun , He Wan , Hu Huabin , Zhao Yandong , Shi Lishuo , Xie Peiyi , Liu GuangJian , Huang Meijin 
Published: June 2022

e15547 Background: Although PD-1 blockade has been recommended as the first line treatment in DNA mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC), it is worthwhile to investigate whether mCRC with DNA mismatch repair-proficient/microsatellite stable(pMMR/MSS) tumors benefit from a combination treatment with PD-1 blockade. Methods: In this cohort, ten patients with pMMR/MSS colorectal liver metastases (CRLM) treated in the 6th Affiliated Hospital of Sun Yat-sen University were enrolled. All the patients were exploratively treated with at least four doses of PD-1 monoclonal antibody combined with chemotherapy and bevacizumab as neoadjuvant/adjuvant therapy. The aim of the study was to evaluate the short-term efficacy and safety of this combined strategy. Results: All the 10 patients were confirmed pMMR/MSS by IHC or next generation sequencing (NGS). Eight of the 10 patients accepted the combined therapies before primary tumor resections, disease control rate (DCR) was 100% (8/8) and objective response rate (ORR) was 62.5% (5/8). The ORR of liver metastases was 70% (7/10) after this treatment. Pathologic complete response (pCR) was achieved in one patient’s primary tumor and was also achieved in another patient’s hepatic lesion. Four patients underwent simultaneous resection of primary tumor and liver metastases. Nine patients underwent microwave ablation for liver metastases. Five patients were assessed no evidence of disease (NED) with a median progress-free survival (PFS) of 5.0 (4.2-9.9) months after multimodality treatments for both primary and metastatic lesions. No immunotherapeutic associated sever adverse event (SAE) or operational complications were found in this cohort. Conclusions: PD-1 blockade combined chemotherapy and bevacizumab was safe and effective for patients with pMMR/MSS CRLM, which might lead to better tumor regression as well as more chances of NED. Further clinical phase II studies of evaluation of long-term efficacy of this combined strategy was needed.
Nivolumab with ipilimumab for MSI-H colorectal cancer with liver metastases.
Authors: Michalaki Vasiliki , Theodosopoulos Theodosios , Frangoulidis George , Dafnios Nikolaos , Papakonstantinou Ioannis , Vezakis Antonios , Papadimitriou Christos 
Published: June 2022

e15556 Background: Immune checkpoint inhibitor (ICI) therapy has recently demonstrated durable clinical benefit in patients with advanced mismatch repair deficient (dMMR) colorectal cancer. The aim of this study was to test the combination of nivolumab and ipilimumab in microsatellite instability-high (MSI-H) colorectal cancer patients with oligometastatic liver disease. Methods: Twelve patients with MSI-H mCRC and one prior line of treatment for metastatic disease received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg once every 2 weeks until disease progression or discontinuation. The primary endpoint was objective response rate (ORR). Results: At baseline, the patients’ median age was 58 years (range, 51-67 years), and 40.7 % of patients were women. Sites of metastases included liver (89.8%), distant lymph nodes (43.6%), and lungs (9.2%). For all 12 patients (median follow-up was 8.2 months), ORR was 71% (95% CI 46.3–78.6). Of 12 patients enrolled, 4 patients (33%) achieved a partial response, and 5 patients (41%) achieved stable disease. Responses were consistent with the overall population across subgroups including age, Eastern Cooperative Oncology Group (ECOG) performance status, prior adjuvant/neoadjuvant therapy, and mutation status. Two patients (16%) had grade 3–4 treatment-related adverse events. Conclusions: Nivolumab plus ipilimumab demonstrated significant clinical benefit and was well tolerated in patients with MSI-H mCRC. Clinical evaluation of ICIs in first-line metastatic, adjuvant and neoadjuvant settings and in combination with other therapies are ongoing.
An observational study of dose-optimization for fruquintinib in elderly patients (pts) with metastatic colorectal cancer (mCRC) who had failed standard therapy.
Authors: Gou Hongfeng , Yu Jing , Cai Xiaohong , Li Qiu 
Published: June 2022

e15560 Background: As one of the third-line standard treatment regimens for advanced colorectal cancer, fruquintinib is widely used in clinical practice, but there are limited data on safety and efficacy of fruquintinib in elderly pts. Multiple studies have shown improved tolerability, reduced grade 3-4 adverse events, and comparable efficacy in pts treated with regorafenib through a first-cycle flexible dose optimization regimen. This method of drug administration is more practical especially in elderly pts, and is worthy of clinical adoption. This observational study aims to investigate the safety, tolerability, and efficacy of a dose-optimized regimen of fruquintinib in elderly mCRC pts who had failed previous standard therapy. Methods: Pts ≥65 years with mCRC refractory to fluoropyrimidine-based chemotherapy ± anti-VEGF/EGFR were enrolled. The primary endpoint was progression-free survival (PFS) (RECIST v1.1). All pts were administered with fruquintinib 3mg (po, qd) for one week. If tolerable, fruquintinib 4mg would be administered in the second week. In the third week, fruquintinib 5mg would be administered if 4mg is tolerable, followed by a week’s rest. The maximum tolerated dose (MTD) of fruquintinib confirmed in the first cycle would be administered from the second cycle. Adverse events were evaluated using CTCAE 5.0. Results: As of February 9, 2022, 29 pts were identified, with an median age of 69.59 (65-77) years and 16 males (55.2%) included. Of the 29 pts, the MTD was 3mg in 31% (9/29) pts, 4mg in 58.6% (17/29) pts and 5mg in 10.3% (3/29) pts. Among the 24 pts available for efficacy evaluation, 14 had stable disease (SD) and 10 had progressive disease (PD) as the best response. Disease control rate (DCR) of 3mg group, 4mg group and 5mg group were 33.33% (2/6), 68.75% (11/16) and 50.00% (1/2), respectively. At a median 4.93 months follow-up, the median (m) PFS was 3.73 months [95% CI, 2.32-5.14] and the mOS was 7.97 months [95% CI, 5.05-10.89]. In addition, the median PFS of 3mg group and 4mg group were 1.87 months and 3.73 months, respectively. And the median OS of 3mg group and 4mg group was 7.97 months and 11.0 months, respectively. Treatment-related adverse events (TRAEs) were observed in all 29 pts (100%). Common TRAEs (> 40%) included fatigue (79.3%), anorexia (58.6%) and hand-foot syndrome (44.8%). The most common (> 10%) grade≥3TRAEs were hand-foot syndrome (20.7%), hypertension (17.2%) and diarrhea (10.3%). No grade 5 TRAEs were observed. There were no correlations with efficacy, toxicity, and geriatric assessment scores. Conclusions: The dose-optimized strategy of fruquintinib in pts aged ≥ 65 years showed acceptable toxicities and anti-tumor activities consistent with the overall population in FRESCO study. The dose-optimized strategy of fruquintinib is a viable alternative in older pts with mCRC. Clinical trial information: NCT05025631.
Real-world treatment outcomes from nationwide Onco-colon Turkey registry in RAS wi̇ld-type patients treated with biologics second-line mCRC.
Authors: Yildirim Mahmut Emre , Karaca Mustafa , Artac Mehmet , Cicin Irfan , Geredeli Caglayan , Alacacioglu Ahmet , Tanrikulu Simsek Eda , Bilici Ahmet , Harputluoglu Hakan , Ozcelik Melike , Bozkurt Oktay , Yuksel Sinemis , Tural Deniz , Sakin Abdullah , Cil Timucin , Oven Basak Bala , Dane Faysal , Cevik Duygu , Gumus Mahmut , Isikdogan Abdurrahman 
Published: June 2022

e15562 Background: Varieties of systemic treatments in second-line treatment for metastatic colorectal cancer (mCRC) patients have showed an improvement on survival. In this context, most of mCRC patients are likely to progress and to change from first line to second line treatment when they develop resistance to first-line treatment options. Therefore, we aimed to investigate second-line treatment selection in patients with RAS-wild type mCRC. Methods: Medical records from 28 centers were collected for patients diagnosed with RAS wild-type and were included into the study. Histopathological, molecular and clinical characteristics of the patients were recorded. The treatment duration, response rate, progression-free survival and safety results were determined. Patients were compared according to the second-line biological treatments as anti-EGFR group (Group A and B; panitumumab and cetuximab) and anti-VEGF group (group C; bevacizumab or aflibercept). Results: A total of 1064 patients with documented RAS wild-type status were evaluated. Fifty-six percent of all first line patients were treated with regimen including biologics received second line treatment. Median age was 60 years. 34,7 percent of the patients were female. Nineteen percent of the patients had a right-sided colon tumor. 16,3 %, 22,5% and 61,2 % of all second-line patients were treated with regimen including panitumumab, cetuximab and anti-VEGF, respectively. Patients received median 5 (1-21) cycles of treatment. Also, responded patients received median 4 (1-23) cycles of treatment as maintenance treatment with biologics plus fluoropyrimidine. Overall response rate was 28,5 % for all patients. Disease control rate also was 70,6 %. The median OS was 15,7, 14,3, and 14,7 months in A, B and C group respectively (p = 0.764). The median PFS of the patients in second-line setting that received panitumumab, cetuximab and bevacizumab/ aflibercept were 7,8, 6,6 and 7,4 months respectively (p = 0.848). There was not found as independent prognostic factors in multivariate analysis. Conclusions: According to the results of our real-life data study, there is no significant difference in efficacy between the combinations of biological agent and chemotherapy used in the second-line treatments. Therefore, the results of the first-line treatment become important and the use of the most effective agent at this setting also increases survival.
Molecular characterization correlates of different metastasis in advanced colorectal cancer.
Authors: Xi Yanfeng , Fang Yi , Chen Siqi , Lu Guanghua , Deng Wanglong , Ding Ran , Bu Fanfeng 
Published: June 2022

e15565 Background: As we all know that patients with advanced colorectal cancer (CRC) are often diagnosed with liver-only metastases (LM), pulmonary-only metastases (PM) and widespread metastasis (WM). Various methods have also been applied to molecular mutation detection in CRC, However, the differences in molecular mutation profiles between the different metastatic lesions are unclear. Methods: In the period of September 2019 to January 2022, 376 LM, 111 PM and 116 WM were included in this retrospective analysis. The average age of patients with LM, PM and WM were respectively 61, 63 and 63 (range, 21-86, 39-95, 29-83). The proportion of male patients accounted for about 60% of LM (246/376), PM (69/111) and WM (74/116) . In this study, we retrospectively analyzed the single nucleotide variants (SNV), copy number variation (CNV) and fusion variants, detected in patients with different metastatic lesions by using next-generation sequencing (NGS). Pearson’s chi-square test was used to test differences in mutation frequency. P-values < 0.05 were considered significant. SPSS 26.0 was used for the statistical analyses. Results: In LM, PM and WM analyzed cohorts, SNV was detected in 370, 108 and 114 patients. CNV was detected in 225, 58 and 60 patients, and fusions were detected in 25,7 and 9 patients. In LM, PM and WM analyzed cohorts, the genes with the highest mutation frequency were APC (11.60%, 8.73%, 6.40%), TP53 (8.90%, 7.70%, 5.29%), KRAS (5.90%, 6.67%, 5.03%) . In addition, the SMAD4 mutation frequency was 2.13%, 0.82% and 1.04%, respectively. APC and SMAD4 mutation frequency was higher in LM than PM ( P= 0.012, P= 0.007) and WM ( P < 0.0001, P= 0.008). 1026, 221 and 281 CNV were detected in LM, PM and WM, respectively. The genes with the highest mutation frequency were MYC (43%, 7.24%, 4.63%), MET (5.95%, 7.69%, 5.34%), EGFR (5.36%, 7.24%, 4.63%) and FLT3 (4.39%, 4.98%, 6.05%) in LM, PM and WM. The SMAD4 mutation frequency were 0.58% and 1.07% in LM and WM, which was not detected in PM. No significant difference was found in those CNVs. No characteristic fusions were found in the total analyzed cohorts. Conclusions: The SNV and CNV molecular mutation profiles were similar in LM, PM and WM. However, the genes with higher mutation probability show higher mutation frequency in LM. Compared with PM, SNV of SMAD4 displays a higher mutation frequency in LM. It has been previously reported that LM may display poorer overall survival (OS) compared with PM. Considering the effect of SMAD4 on the prognosis of CRC, this study may provide a possible analysis of the poor prognosis of LM patients. However, there is still a need for more clinical research to support these results.