bluuebunny/crossref_metadata_2025_split huggingface dataset:
Independent validation of a novel noninvasive 4-microRNA diagnostic model for multicancer early detection.
Authors: Zhang Andrew , Hu Hai 
Published: June 2022

3065 Background: Cancer early detection is critical to reduce mortality as treating early stage cancers is more likely to have better outcomes. We previously developed a diagnostic model based on 4 serum cell-free microRNAs (miRNAs) capable of detecting 12 cancer types with high accuracy (AACR 2022, Poster 2890; Manuscript submitted). In the current study, we aimed to validate this diagnostic model using independent serum microRNA microarray datasets. Methods: Four microarray datasets assessing the expression of 2588 serum miRNAs in patients with esophageal squamous cell carcinoma, gastric cancer, prostate cancer and glioma, as well as non-cancer healthy controls with a standardized platform were identified from Gene Expression Omnibus (GEO). The datasets were combined, cases that were redundant among them or with the cases used in our previous study (correlation > 0.99) were excluded. The 4-miRNA model was applied to the final combined dataset to calculate a diagnostic index and make prediction of cancer vs. no-cancer using previously determined algorithm and cut-point. The performance of the diagnostic model was assessed using Receiver Operating Characteristic (ROC) analysis, sensitivity and specificity. Results: After excluding redundant cases, the final combined dataset consisted of 3877 subjects, including 447 esophageal, 1267 gastric, 769 prostate and 196 glioma cancer patients, as well as 1198 healthy controls. The 4-miRNA model demonstrated an area under the curve (AUC) of 0.986, 0.995, 0.992 and 0.990 in the ROC analysis, with a sensitivity of 85.0%, 99.6%, 90.6% and 86.7% for esophageal, gastric, prostate and glioma cancers, respectively, while achieving a 99.1% specificity. These performance metrics were highly consistent to those reported in our previous study (Table). Conclusions: The study provided an independent validation of the previously developed 4-miRNA model, further demonstrating that the diagnostic model we developed has the potential to be developed into a simple, inexpensive and noninvasive blood test for multi-cancer early detection with high accuracy. [Table: see text]
64Cu-SAR-Bombesin PET-CT imaging in the staging of ER+/PR+/HER2- metastatic breast cancer: Safety, dosimetry, and feasibility in a phase I trial.
Authors: Wong Keith , Sheehan-Dare Gemma , Nguyen Andrew , Ho Bao , Liu Victor , Lee Jonathan , Brown Lauren Julia , Dear Rachel Fitz-Gerald , Chan Lyn , Pathmanandavel Sarennya , Sharma Shikha , Malaroda Alessandra , Smith Isabelle , Lim Elgene , Emmett Louise 
Published: June 2022

3092 Background: Breast cancers are most frequently oestrogen receptor (ER) and progesterone receptor (PR) positive and 18F-Fluorodeoxyglucose PET-CT (FDG) used in conventional staging of breast cancer has lower sensitivity for these subtypes. Gastrin releasing peptide receptors (GRPR) are a potential alternative diagnostic and theranostic target for ER+/PR+ breast cancers due to their overexpression of GRPR. This phase 1 study aims to assess the safety and potential of the novel radiotracer 64Cu-Sarcophagine(SAR)-Bombesin (BBN) in the re-staging of recurrent metastatic ER+/PR+/human epidermal growth factor 2 negative (HER2-) breast cancer. Methods: Patients with confirmed recurrent or primary metastatic ER+/PR+/HER2- breast cancer undergoing staging prior to a new treatment underwent 64Cu-SAR-BBN PET-CT with imaging at 1, 3 and 24 hours post-injection. Bloods and vital signs were acquired for patients at baseline, 1, 3 and 24 hours post-injection timepoints, and electrocardiogram (ECG) performed 1 hour pre and 1 hour post injection. Blood tracer-clearance and dosimetry was performed. GRPR receptor status was assessed in 4/7 patients from metastatic-site biopsy samples. Staging of the patients was assessed by conventional imaging (FDG, bone scan and diagnostic CT) within 3 weeks of 64Cu-SAR-BBN imaging. All PET scans were assessed visually, and quantitatively using MIM Software. Results: 9 patients were enrolled. 7/9 patients underwent all imaging modalities, while 2/9 did not undergo BBN imaging. 1/7 patient who underwent all imaging had de- novo metastatic ER+/PR+/Her 2- breast cancer and 6/7 recurrent metastatic disease. 2/7 had lobular subtype. There were no adverse events reported, and ECG, vitals and haematological, biochemical and coagulation markers remained unchanged. All 7 patients were positive on conventional imaging, while 6/7 were positive on FDG. BBN was positive in 5/7 patients. Both BBN negative patients had disease identified on FDG. Conversely, 1 patient was BBN positive but FDG negative. 4/7 patients were BBN positive and FDG positive. In these 4 patients, mean SUVmax was higher for BBN than FDG (15 vs. 12). In classical lobular subtype (2/7), BBN was highly avid compared to FDG (SUV max 20 vs 11, and 20 vs <3) and with a higher tumor volume compared to FDG (2034 vs 504, and 634 mL vs FDG negative). Conclusions: 64Cu-SAR-Bombesin is a novel tracer which appears safe and may have a diagnostic and theranostic role in patients with metastatic ER+/PR+/HER2- breast cancer, particularly lobular subtype. Further evaluation appears warranted.
Primary results from JUPITER, a phase 2 basket trial of combination therapy with trastuzumab and pertuzumab in patients with HER2-amplified solid tumors.
Authors: Ikeda Sadakatsu , Kudo Ryo , Yamashita Yamato , Kubo Toshio , Mori Yukiko , Harada Yohei , Shirota Hidekazu , Hayashi Hideyuki , Kano Masayuki , Shimizu Yasushi , Ishibashi Eri , Tateishi Ukihide , Hirakawa Akihiro , Akita Hirotoshi , Matsubara Hisahiro , Nishihara Hiroshi , Ishioka Chikashi , Sueoka-Aragane Naoko , Muto Manabu , Toyooka Shinichi 
Published: June 2022

3131 Background: Human epidermal growth factor receptor 2 (HER2) gene amplification or mutations have emerged as oncogenic drivers and therapeutic targets not limited to breast and gastric cancers, but also in a variety of cancers. Despite its considerable therapeutic potential, the evidence has not been established. To address this unmet need, we conducted an organ-agnostic basket trial targeting HER2-amplified solid tumors. Methods: JUPITER is a multicenter, single-arm, phase 2 basket trial for solid tumor patients (pts) with HER2 amplification determined by next-generation sequencing (NGS). Both tissue and liquid NGS results were allowed. HER2 amplification by ISH or HER2 overexpression by IHC were not used for inclusion. Pts had treatment-refractory metastatic tumors, or rare cancers without established standard of care. Breast, gastric, and colorectal cancers were excluded. Pts were treated with intravenous trastuzumab (8 mg/kg loading dose followed by 6 mg/kg) and pertuzumab (840 mg loading dose followed by 420 mg) every 3 weeks until disease progression or any other reason for discontinuation. Tumor response was assessed using RECIST v1.1. Primary endpoint was ORR by blinded independent central review (BICR), and secondary endpoints were ORR assessed by the investigators, progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety. We set the ORR threshold 5% and expected ORR was 20%. Estimated sample size was 38 patients with one-sided alpha 2.5% and power 80%. Results: Between April 2019 and June 2020, 42 pts were consented, and 40 pts were treated. Median age was 62 (range, 21-86) and 60% were females. The most common diagnosis was biliary tract cancer (20%), followed by salivary ductal carcinoma (12.5%) and endometrial cancer (12.5%). At data cutoff (1 Sep 2021), ORR by BICR was 22.5% (95%CI: 10.8%-38.5%). ORR assessed by the investigator was 25% (95%CI: 12.7%-41.2%). PFS, OS and DOR were not reached at data cutoff; 3 responders remained on treatment. Of 40 pts, 32.5% had grade ≥ 3 adverse events; 10% were treatment-related, including neutropenia, hypertension, peripheral sensory neuropathy and lymphoedema (all grade 3). No treatment-related death was observed. Exploratory biomarker analysis of response and resistance is in progress. Conclusions: Combination therapy with trastuzumab and pertuzumab was well tolerated and showed promising efficacy for the patients with HER2-amplified solid tumors determined by NGS. Clinical trial information: jRCT2031180150.
STRATEGIC-1: Multi-line therapy trial in unresectable wild-type KRAS/NRAS/BRAF metastatic colorectal cancer—A GERCOR-PRODIGE randomized open-label phase III study.
Authors: Chibaudel Benoist , Dourthe Louis-Marie , Andre Thierry , Henriques Julie , Bourgeois Vincent , Etienne Pierre-Luc , Desrame Jérôme , Carola Elisabeth , Dupuis Olivier , Baba-Hamed Nabil , Auby Dominique , Louvet Christophe , Maillard Emmanuel , Romano Olivier , Tournigand Christophe , Garcia-Larnicol Marie-Line , Shmueli Einat Shacham , Healey Bird Brian , Ghiringhelli François , De Gramont Aimery 
Published: June 2022

3504 Background: The management of unresectable metastatic colorectal cancer (mCRC) is a comprehensive treatment strategy involving several lines of therapy, maintenance, salvage surgery, and treatment-free intervals. Besides chemotherapy (fluoropyrimidine, oxaliplatin, irinotecan), anti-angiogenic and anti-epidermal growth factor receptor (EGFR) agents have become available. Ultimately, strategy trials are needed to define the optimal use and the best sequencing of these agents. Methods: Patients with previously untreated RAS/BRAF wild-type unresectable mCRC were randomly assigned (1:1 ratio) to receive either FOLFIRI-cetuximab followed by mFOLFOX6-bevacizumab (arm A) or OPTIMOX-bevacizumab followed by FOLFIRI-bevacizumab followed by EGFR mab +/- irinotecan (arm B). This trial was designed as a superiority study (hypothesis arm B > arm A) with Duration of Disease Control (DDC) as primary endpoint, defined as the sum of PFS of each active sequence of treatment (Chibaudel B, J Clin Oncol, 2011). Secondary endpoints were overall survival (OS), Time to Failure of Strategy (TFS), Progression-free survival (PFS) and response rate (RECIST version 1.1) per sequence, salvage surgery rate, safety, and Quality of life (QoL). Results: Between October 2013 and May 2019, 263 eligible patients were randomized (arm A, n = 131; arm B, N = 132). After a median follow-up of 51.2 months (95% CI 43.3-57.4), 188 events for DDC were observed. Efficacy outcomes are presented in table. Median DDC was similar in both arms (HR 0.97, 95% CI 0.72-1.29; P = 0.805). Salvage surgery for metastasis (+/- radiofrequency ablation) was done in 36 (27.5%) patients in arm A and 28 (21.2%) in arm B. Median time until definitive deterioration of QoL (global health status) were 18.3 and 18.0 months (P = 0.628). The safety profiles were consistent with the established safety profiles of each treatment regimen. Conclusions: STRATEGIC-1 is the first randomized phase III study comparing multi-line standard treatment strategies in patients with KRAS/NRAS/BRAF wild-type mCRC. This study did not meet its primary endpoint of DDC. The treatment strategy starting with FOLFIRI-cetuximab followed by mFOLFOX6-bevacizumab led to higher response rates and to a trend for better median OS exceeding 3 years. These findings may add to our understanding of treatment sequencing in mCRC. Clinical trial information: NCT01910610. [Table: see text]
Dietary quality in early-onset gastrointestinal malignancies: NHANES 2005-2018.
Authors: Lim Mir , Goksu Suleyman Yasin , Khatib Jude , Reddy Sarah , Beg Shaalan Shaalan , Kazmi Syed Mohammad Ali 
Published: June 2022

3549 Background: The incidence of early-onset colorectal, stomach, esophageal, and pancreatic cancer, which occur in individuals <50 years of age, is rising worldwide. However, little is known about why rates have been up trending. Previous studies have linked poor diet and nutrition to an increased risk of typical-onset gastrointestinal (GI) malignancies. In this study, we aimed to describe dietary quality in individuals with early-onset GI malignancies and compare it to typical-onset GI malignancies. Methods: We queried the 2005-2018 National Health and Nutrition Examination Survey (NHANES) database for all survey participants diagnosed with GI malignancies, including colorectal, esophageal, gallbladder, liver, pancreas, rectal, and stomach cancer. We classified early and typical-onset GI cancer based on age of diagnosis of <50 and ≥50 years, respectively. Participants <50 without a history of cancer were classified as controls. We assessed the dietary quality by calculating the healthy eating index score (HEI-2015) from NHANES database for all participants. The primary outcome was mean HEI-2015 score for early onset GI malignancies. We performed propensity score weighted analysis to balance gender, race, income, education level, and BMI between the groups. We used logistic regression analysis to assess the relationship between early-onset GI malignancies and HEI-2015 quintiles. Results: Out of 32,235 participants in NHANES database, 330 individuals (1%) reported a diagnosis of GI malignancy. Sixty-eight (20.5%) individuals had early-onset GI malignancies. We identified 17,420 controls who were <50 years old with no reported history of malignancy. Fifty-three percent of early-onset GI cancers were female vs 47% of typical-onset GI cancers; 59% vs 59% were non-Hispanic White; 66% vs 40% had a college degree; 13% vs 7% had high income and 40% vs 36% were obese. The mean HEI-2015 score in early-onset GI cancer was 52.9 (SD 14.7) compared to 53.6 (SD 13.0) in typical-onset GI cancers, which was not significantly different (p=0.72). There was no significant association between poor HEI-2015 scores in individuals with early-onset vs typical-onset GI malignancies on logistic regression analysis (OR 0.84 [0.35-2.03]). In addition, HEI-2015 quintiles were not significantly associated with those with early-onset GI malignancies compared to controls <50 years old (OR 2.06 [0.72-5.9]). Conclusions: The diet quality of early-onset GI malignancies does not align with the national Dietary Guidelines. However, in this analysis of the NHANES database, we did not find a significant difference in HEI-2015 scores between early-onset versus typical-onset GI malignancies.
Bcl-xL and association with apoptosis following KRASG12C inhibition in KRASG12C mutant colorectal cancer.
Authors: Khawaja Hajrah , Briggs Rebecca , Latimer Cheryl , Rassel Md A.M.B , Griffin Daryl , Hanson Lyndsey , Bardelli Alberto , Di Nicolantonio Federica , McDade Simon , Scott Christopher , Lambe Shauna , Maurya Manisha , Lindner Andreas Ulrich , Prehn Jochen HM , Sousa Jose , Winnington Chris , J LaBonte Melissa , Ross Sarah , Van Schaeybroeck Sandra 
Published: June 2022

3557 Background: Novel covalent inhibitors of KRASG12C have shown modest response rates in KRASG12C mutant (MT) colorectal cancer (CRC) patients. Thus, novel KRASG12C inhibitor combination strategies that can achieve deep and durable responses are needed. Methods: The small molecule KRASG12C inhibitors AZ’1569 and AZ’8037 were employed. To identify novel candidate combination strategies for AZ’1569, we performed RNA sequencing, siRNA and high-throughput drug screening. Top hits were validated in a panel of KRASG12CMT CRC cells and in vivo xenograft models. AZ’1569 acquired resistant CRC models were generated and characterised. Results: Response to AZ’1569 was heterogeneous across the KRASG12CMT models. AZ’1569 was ineffective at inducing apoptosis when used as a single agent or combined with chemotherapy or agents targeting the EGFR/KRAS/AKT axis. Using a systems biology approach, we identified the anti-apoptotic BH3-family member BCL2L1/Bcl-xL as top hit mediating resistance to AZ’1569. Further analyses identified acute increases in the pro-apoptotic protein BIM following AZ’1569 treatment. ABT-263 (Navitoclax), a pharmacological Bcl-2 family-inhibitor that blocks the ability of Bcl-xL to bind and inhibit BIM, led to dramatic and universal apoptosis when combined with AZ’1569 in a panel of KRASG12C MT CRC cells. Furthermore, this combination also resulted in dramatically attenuated tumour growth in KRASG12C MT CRC xenografts. Finally, AZ’1569 acquired resistant KRASG12C MT CRC cells showed amplification of KRASG12C, EphA2/c-MET activation, increased pro-inflammatory chemokine profile and cross-resistance to standard-of-care chemotherapy and several targeted agents. Importantly, the KRAS amplification and AZ’1569-resistance were reversible upon drug withdrawal, arguing strongly for the use of drug holidays in the case of KRAS amplification. Conclusions: Combinatorial targeting of Bcl-xL and KRASG12C is highly effective, suggesting a novel therapeutic strategy for KRAS G12CMT CRC patients. The cross-resistance to other targeted therapies and importantly conventional chemotherapy in the AZ’1569 acquired resistant cells poses a challenge, with implications for the optimal use of KRASG12C inhibitors as a second or third line option.
A phase 2 trial of sintilimab (IBI 308) in combination with CAPEOX and bevacizumab (BBCAPX) as first-line treatment in patients with RAS-mutant, microsatellite stable, unresectable metastatic colorectal cancer.
Authors: Fang Xuefeng , Zhong Chenhan , Zhu Ning , Weng Shanshan , Hu Hanguang , Wang Jian , Xiao Qian , Wang Jianwei , Song Yongmao , Sun Lifeng , Xu Dong , Liao Xiujun , Dong Caixia , Zhang Suzhan , Li Jun , Ding Ke-Feng , Yuan Ying 
Published: June 2022

3563 Background: The prognosis of metastatic colorectal cancer (mCRC) patients with RAS gene mutation and microsatellite stable (MSS) is poor. MSS patients account for 95% of CRC and have a low response rate to immunotherapy. Previous studies have reported that chemotherapy and anti-angiogenesis therapy can promote immunotherapy response. This study aims to assess the safety and antitumor activity of sintilimab (IBI308) combined with CapeOx and bevacizumab in the first-line treatment of patients with RAS-mutant and MSS mCRC. Methods: This is an open-label, single-arm, phase II trial. Eligible patients were aged 18 to 75 years with histologically confirmed unresectable metastatic colorectal adenocarcinoma by multidisciplinary team, and had RAS gene mutation and confirmed MSS status. All patients received treatment with sintilimab (200 mg, day 1) plus bevacizumab (7.5mg/kg, day 1) and oxaliplatin (135 mg/m2, day 1) and capecitabine (1g/m2, bid, day 1-14) of each 21-day cycle. The primary endpoint included objective response rate (ORR) evaluated via RECIST 1.1 criteria and adverse events according to CTCAE 5.0. Secondary endpoint was progression-free survival (PFS). Results: 25 patients were enrolled and received at least two cycle treatment. At baseline, median age was 60 years (range 45-74), 72% of patients were male, ECOG PS 0/1 was 100%, 60% had liver metastases (mets), and the primary tumor site was right-sided colon in 36.0% and left-side colorectum in 64.0%. 25 patients completed at least one efficacy evaluation. 2 (8.0%) patients showed complete response (CR), 19 (76.0%) patients had a partial response (PR) and 4 (16.0%) had stable disease (SD). Patients with liver or lung mets had a higher ORR (93.3% and 100%, respectively) compared to the overall ORR (84.0%). Disease control rate (DCR) reached 100%. Median PFS has not yet reached. No grade 5 adverse events occurred. The most common treatment-related adverse events (TRAEs) in all grades were anemia (19/25, 76.0%), peripheral neurotoxicity (6/25, 24.0%) and neutropenia (17/25, 68.0%). The most frequent grade 3/4 TRAEs were neutropenia (3/25, 12.0%), elevated aspartate transaminase (1/25, 4.0%), elevated alanine transaminase (1/25, 4.0%) and elevated bilirubin (1/25, 4.0%). Conclusions: Combination treatment with sintilimab (IBI308) plus CapeOx and bevacizumab demonstrated a high ORR (84.0%; 93.3% in patients with liver mets, and 100% in patients with lung mets) and a manageable safety profile in RAS-mutant and MSS mCRC. Clinical trial information: NCT05171660. [Table: see text]
Camrelizumab plus famitinib in patients with metastatic colorectal cancer: Results from an open-label, multicenter phase II basket study.
Authors: Liu Tianshu , Yang Mudan , Li Jin , Pan Yueyin , Yuan Ying , Yi Shanyong , Wang Junsheng , Cheng Ying , Feng Jifeng , Gao Shegan , Wang Xicheng , Qu Song , Zhang Xizhi , Lu Jin , Xiu Peng , Wang Shuni , Yang Xinfeng , Fan Jia 
Published: June 2022

3577 Background: Dual blockade of immune checkpoint and angiogenesis is an effective strategy for multiple cancers. We initiated an open-label, multicenter phase II basket study to evaluate the antitumor activity and safety of camrelizumab (an anti-PD-1 antibody) plus famitinib (a receptor tyrosine kinase inhibitor) in patients (pts) with advanced solid tumors. Herein, we report the results from the metastatic colorectal cancer (mCRC) cohort. Methods: Pts with histologically confirmed mCRC, who had received previous irinotecan, oxaliplatin, and fluoropyrimidine combination chemotherapy, and progressed after ≥ 2 lines of systemic treatment were enrolled to receive camrelizumab (200 mg i.v. every 3 weeks) and famitinib (20 mg orally once daily). Primary endpoint was objective response rate (ORR) per RECIST version 1.1. Results: Between Jul 10, 2020, and Jul 12, 2021, of all the 44 mCRC pts enrolled, 14 (31.8%) pts had colon cancer (CC) and 30 (68.2%) pts had rectal cancer (RC). As of Nov 30, 2021, the median time from enrollment to data cutoff was 10.6 months (range, 4.7-16.7). The ORR was 13.6% (95% CI, 5.2-27.4) and the DCR was 45.5% (95% CI, 30.4-61.2) in all mCRC pts. Of them, no pts with CC achieved response; six pts with RC achieved PR, with the ORR of 20.0% (95% CI, 7.7-38.6) and the DCR of 46.7% (95% CI, 28.3-65.7). Pts with RC showed a median duration of response (DoR) of 7.1 months (95% CI, 2.3-not reached [NR]). The median overall survival (OS) was 15.2 months (95% CI, 7.2-NR) in pts with RC. Of all 44 mCRC pts, 28 (63.6%) had grade 3 or higher treatment related adverse events (TRAEs), mainly hypertension (25.0%), proteinuria (18.2%), decreased platelet count (11.4%), decreased neutrophil count (11.4%) and palmar-plantar erythrodysaesthesia syndrome (11.4%). Three (6.8%) pts discontinued any study treatment due to TRAEs. No grade 5 TRAE was reported. Conclusions: Camrelizumab plus famitinib appeared to show encouraging antitumor activity in pts with mCRC, especially in those with RC, and the safety profile of this combination regimen seemed to be manageable and consistent with single agent alone. Clinical trial information: NCT04346381. [Table: see text]