bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comprehensive characterization of ERBB2 genomic alterations inlung cancer.
Authors: El Zarif Talal , Stockhammer Paul , Schillo Jacob , Goldberg Sarah B. , Politi Katerina A. , Grant Michael J 
Published: June 2024

3148 Background: ERBB2mutations () occur in 1-4% of non-small cell lung cancers (NSCLC). Trastuzumab-deruxtecan is FDA-approved for the treatment of metastatic ERBB2-mutant NSCLC based mostly on data from NSCLCs harboring tyrosine kinase domain (TKD) ERBB2mut. The genomic and clinical characteristics of NSCLC with ERBB2 mut beyond the TKD remain largely unexplored. Methods: Patients (pts) with NSCLCs with oncogenic ERBB2 mut and genomic tumor profiling data from the AACR Project GENIE database were included. The cohort was divided into pts with tumors harboring TKD, extracellular (ECD), or transmembrane (TMD) and juxtamembrane domain (JMD) ERBB2mut. Clinico-genomic characteristics were compared between the groups. The Kaplan-Meier method was used to estimate progression-free survival (PFS) with first-line systemic therapy, and log-rank tests were used for comparisons. Results: Of 483 pts with ERBB2-mutant NSCLC, 64% were female, 81% were White, and 13% were Asian. TKD, ECD, and TMD/JMD ERBB2 mut were identified in 362 (75%), 88 (18%), and 33 (7%) cases, respectively. Pts with ECD vs. TKD ERBB2mut tumors were more likely to be males (47% vs. 33%, p=0.03) and have tumors with squamous histology (7% vs. 1%, p<0.0001). Among pts with (n=39), those with ECD vs. TKD ERBB2 mut tumors were more likely to have a history of smoking (100% vs. 42%, p = 0.02). The most common TKD, ECD, and TMD/JMD ERBB2 mut were in-frame ex20ins Y772_A775dup (n=224/362, 62%), missense S310F/Y (n=45/88, 51%), and missense V659E/D (n=10/33, 30%) mut, respectively. ECD vs. TKD ERBB2-mutant tumors harbored a distinct genomic phenotype with significantly higher median tumor mutational burden (11.1 vs. 5.2 mut/Mb, p<0.003), median fraction of genome altered (0.2 vs. 0.1, p = 0.02), and rate of co-mut in EGFR (32% vs. 3.6%, p<0.0001), KRAS (17% vs. 2.5%, p<0.0001), STK11 (23% vs. 4.3%, p<0.0001), KEAP1 (23% vs 5%, p<0.0001) and SMARCA4 (19% vs 4.5%, p<0.0001). Of 343 cases with ERBB2 copy number profiling, 32 (9.3%) harbored ERBB2 amplification. ERBB2-mutant NSCLCs with vs. without ERBB2amplifications had a higher frequency of TP53 co-mut (84% vs. 48%, p <0.001). Of 39 pts with available clinical data, most had ECD (n=6) ERBB2 mut tumors and received first-line platinum-based chemotherapy (n=31). The presence of a co-mut in STK11 (HR 3.5, 0.4–27.4, p=0.03) and KEAP1 (HR 3.9, 0.7–20.6, p=0.002) conferred shorter PFS on first-line systemic therapy. Pts with ECD vs. TKD ERBB2 mut tumors had shorter PFS (HR 2.4, 95% CI 0.7–8.2, p=0.04). Conclusions: NSCLC tumors harboring ECD ERBB2 mut are associated with a distinct clinical and molecular phenotype and inferior outcomes with chemotherapy compared to pts with tumors harboring TKD mut. These findings enhance our understanding of disease heterogeneity in ERBB2-mutant NSCLC and may aid in optimizing treatment strategies for this unique population.
Trifluridine/tipiracil plus capecitabine and bevacizumab as upfront treatment for metastatic colorectal cancer: Results of the phase 1 TriComB study.
Authors: Ciracì Paolo , Conca Veronica , Moretto Roberto , Antoniotti Carlotta , Ambrosini Margherita , Murgioni Sabina , Gori Giovanni , Russo Alessandra , Bergamo Francesca , Randon Giovanni , Studiale Vittorio , Fini Elisabetta , Marmorino Federica , Borelli Beatrice , Germani Marco Maria , Vetere Guglielmo , Carullo Martina , Boccaccio Chiara , Masi Gianluca , Cremolini Chiara 
Published: June 2024

3558 Background: Capecitabine (cap) plus Bevacizumab (bev) is a standard option for previously untreated unresectable metastatic colorectal cancer (mCRC) patients (pts) deemed not fit for upfront chemotherapy doublets. A synergistic effect of the sequential administration of cap and Trifluridine/Tipiracil (FTD/TPI) has been shown both in vitro and in vivomodels. Here, we present safety and preliminary activity results of the phase 1 TriComB study, an open-label, multicenter, phase 1/2 trial, evaluating FTD/TPI in combination with cap and bev in mCRC pts. Methods: Patients with previously untreated mCRC, ineligible for oxaliplatin- and/or irinotecan- based regimens, were enrolled. A 3 + 3 dose escalation design was used to identify the recommended dose (RD) of FTD/TPI (days 15-19 and 22-26) in combination with cap (1000 mg/sqm/BID days 1-14) and bev (5 mg/kg day 1,15) in 28-days cycles. Adverse events (AEs) were reported according to CTCAE version 5.0 and tumor response was assessed by RECIST version 1.1. Results: 11 pts (5 men, 6 women; median age: 77, range: 47-84 years) were enrolled. For the first three patients (FTD/TPI: 25mg/sqm BID) no dose limiting toxicities (DLTs) were observed. At 30 mg/sqm BID dose level, 3/5 DLTs were reported: 2 pts experienced a dose delay of >7 days from the scheduled timing and 1 patient was unable to receive ≥ 75% of study drugs’ doses during the first cycle. FTD/TPI was de-escalated and 3 additional patients were treated at 25 mg/sqm BID. Since 1/6 pts experienced a DLT (grade 4 colonic perforation) that was identified as the RD. Grade 3/4 AEs are listed in the Table. As of January 2024, Overall Response Rate is 72.7% (8/11 pts) and 66.7% (4/6 pts) in the overall population and at the RD, respectively. Conclusions: The sequential combination of cap and FTD/TPI with bev is feasible. The phase 2 of the study is ongoing to evaluate antitumor activity of this regimen in the same patients' population. Clinical trial information: NCT04564898 Safety summary Clinical trial information: NCT04564898 . [Table: see text]
Updated survival results of BBCAPX-II: Sintilimab combined with bevacizumab and CapeOx as first-line treatment in patients with RAS-mutant, microsatellite stable, unresectable metastatic colorectal cancer.
Authors: Yuan Ying , Zhu Ning , Fang Xuefeng , Zhong Chenhan , Li Dan , Wang Liu-Hong , Li Jun , Weng Shanshan , Hu Hanguang , Dong Caixia , Song Yongmao , Xu Dong , Wang Jianwei , Sun LIfeng , Wang Jian , Liao Xiujun , Yu Ningjuan , Zhang Suzhan , Ding Ke-Feng 
Published: June 2024

3563 Background: Microsatellite stable (MSS) and RAS-mutant metastatic colorectal cancer (mCRC) patients are characterized by an immunosuppressive microenvironment and a low response rate to immunotherapy. Sintilimab plus bevacizumab and CapeOX (BBCAPX) has proved its efficacy and safety in above unresectable mCRC patients (Ying Yuan et al. ASCO 2023 and Xuefeng Fang et al. ASCO 2022). Here, we report updated survival results of this single arm, open-label, phase 2 trial. Methods: 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) and adverse events. Secondary endpoint was disease control rate (DCR) and progression-free survival (PFS). Results: From April 2021 to December 2021, 25 patients were enrolled. The ORR was 84% and the DCR was 100%. Six (24%) patients underwent surgical treatment and unexpectedly achieved no evidence of disease status. At the data cut-off day (January 26, 2024), the median PFS in the full analysis set was 17.9 months (95% CI, 8.84-27), and the median PFS in the per-protocol set was 9.79 months (95% CI, 6.44-24.3). Median PFS was 23.7 months (95% CI, 4.8-NA) in the patients with only liver metastasis and 11.5 months (95% CI, 4.83-24.3) in the patients with other metastasis. The PFS rate at 6 months was 84% (95% CI, 70.8-99.7). The PFS rate at 12 months was 56% (95% CI, 39.6-79.3). The most frequent grade 3 or 4 TRAEs were neutropenia (3/25) and increased alanine transaminase (2/25). No grade 5 adverse events occurred during the study. Conclusions: The combination of sintilimab plus bevacizumab and CapeOx showed promising antitumor activity and manageable toxicity in RAS-mutant, MSS, unresectable mCRC. Patients with liver metastases presented better prognosis compared other metastases. Furthermore, we are currently launching a phase III, randomized, open-label, multicentric clinical trial (NCT05171660) to further analyze the effects, safety, and prognostic biomarkers of this regimen. Clinical trial information: NCT04194359 . [Table: see text]
Comparing the efficacy and safety of HepaSphere drug-eluting bead transarterial chemoembolization combined with hepatic arterial infusion chemotherapy versus hepatic arterial infusion chemotherapy alone in unresectable colorectal liver metastases.
Authors: Feng Aiwei , Gao Song , Guo Jianhai , Kou Fuxin , Liu Shaoxing , Zhang Xin , Liu Baojiang , Wang Xiaodong , Chen Hui , Xu Haifeng , Liu Peng , Cao Guang , Gao Qinzong , Zhu Xu 
Published: June 2024

3565 Background: Drug-eluting bead transarterial chemoembolization (DEB-TACE) and hepatic arterial infusion chemotherapy (HAIC) are widely employed treatments for unresectable colorectal liver metastases (CRLM). Limited evaluation exists regarding TACE plus HAIC versus HAIC alone. This study aimed to evaluate the efficacy of combining HepaSphere DEB-TACE with HAIC compared to HAIC alone in patients with unresectable CRLM. Methods: A total of 259 CRLM patients aged over 18 years, treated at Peking University Cancer Hospital between March 2015 and November 2022, were included in this retrospective study. Among them, 157 patients received HepaSphere DEB-TACE combined with HAIC (DEB-TACE-HAIC), while 102 patients received HAIC alone. Propensity score matching (PSM) was performed to avoid selection bias and enable comparative analysis of efficacy and safety between the two cohorts. The primary endpoint was progression-free survival (PFS), while secondary endpoints comprised hepatic progression-free survival (hPFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. Results: PSM resulted in 83 pairs, achieving comparable baseline between DEB-TACE-HAIC and HAIC cohorts. Of these pairs, 116 were male and 50 were female. Notably, 51.2% of patients harbored mutations in either KRAS, NRAS, or BRAF genes. Prior to enrollment, 94.6% of patients had received systemic treatments. Median hPFS, PFS and OS were all higher in the matched DEB-TACE-HAIC cohort (median hPFS: 7.6 vs. 4.1 months, P=0.023; median PFS: 5.1 vs. 3.5 months, P=0.092; median OS: 15.5 vs. 14.7 months, P=0.513). ORR was 37.3% in the DEB-TACE-HAIC group and 27.7% in the HAIC group, with DCR of 75.9% and 69.9%, respectively. There were no treatment related deaths. Serious adverse events were comparable between the two groups, except for nausea, which occurred more frequently in the HAIC group (39.8% vs. 22.9%, P=0.019). Conclusions: DEB-TACE-HAIC demonstrated superior survival compared to HAIC alone in unresectable CRLM, even in patients refractory to systemic therapy. The combination of HepaSphere DEB-TACE and HAIC appears promising as a regional treatment option with improved outcomes and a comparable safety profile.
Efficacy of fadraciclib (CYC065), a novel dual CDK2/9 inhibitor, on patient-derived models of colorectal cancer.
Authors: Zokaasadi Mohammad , Altunel Erdem , Dayanidhi Divya Lakshmi , Mantyh John B , Watlington Wylie K , McCall Shannon J. , Blake David , Somarelli Jason A. , Hsu David S. 
Published: June 2024

3596 Background: Colorectal cancer (CRC) is the third most common type of cancer among adults in the United States. Given the heterogeneous nature of the disease and the limited number of treatments available, there is an unmet need to identify new therapeutic vulnerabilities for advanced CRC. One promising approach is targeting of cyclin dependent kinases (CDKs). In our current study, we sought to understand the potential efficacy of fadraciclib (CYC065), a novel dual CDK 2/9 inhibitor, as a novel treatment for metastatic CRC. Methods: Eighteen CRC patient-derived organoids (PDOs) were generated from patients undergoing biopsy or resection for their primary or metastatic CRC under an IRB approved protocol at Duke University. IHC and H&E staining were first performed on the established PDOs to confirm the diagnosis of CRC. PDOs were treated with standard of care chemotherapy (oxaliplatin, irinotecan (SN38) and 5-Flurouracil), CDK4/6 inhibitor palbociclib, and fadraciclib (CYC065). All drugs were used in doses ranging from 6.4nM to 100µM, and drug sensitivities were determined using Cell-Titer Glo (CTG) 72 hours after treatment. Subsequently, three matching PDXs were generated for in vivo validation and treated with fadraciclib (CYC065) via oral gavage at a dose of 25 mg/kg BID five days a week for two weeks. Target validation for CDK2/9 inhibition was performed via western blotting, cell cycle arrest was determined via flow cytometry, and killing by anaphase catastrophe was determined by immunofluorescence staining. Results: CRC PDOs were more sensitive to fadraciclib (CYC065) than chemotherapy and palbociclib, with IC50 values lower than chemotherapy or palbociclib (2.65±3.92µM for fadraciclib (CYC065) vs. 29.92±41.98µM for chemotherapy (P<0.05) or palbociclib (12.33±9.87µM)). Subsequently, we validated our findings in vivo using 3 matched PDX showing significant tumor growth inhibition (TGI) with fadraciclib (CYC065) compared to control (p<0.05) without serious adverse effects. We showed that fadraciclib (CYC065) induces G2/M cell cycle arrest, resulting in anaphase catastrophe as evident by the presence of multipolar mitosis in fadraciclib (CYC065)-treated cells. CDK2/9 inhibition leads to downregulation of c-Myc levels and upregulation of apoptosis induction as a second mechanism of action for this drug. Conclusions: Our data using both in vitro and in vivo patient-derived models support further exploration of fadraciclib (CYC065) has a potential therapy for advanced CRC. CDK2/9 inhibition impacts multiple critical pathways involved in transcription, mitosis and apoptosis. Further studies will be needed to reveal molecular biomarkers of sensitivity and resistance to this novel agent.
Phase II study of neoadjuvant short-course radiotherapy combined with CAPEOX plus envafolimab in patients with microsatellite stable locally advanced rectal cancer: Updated results of PRECAM study.
Authors: Dai Sheng , Wang Fei , Lv Yiming , Zhang Feixiang , Shi Liming , Wang Yunfei , Shen Yanbin , Xu Lingna , Hu Peng , Tang Wen , Xu Dengyong , Shan Lina , Jia Xiya , Chen Yiyi , Larson David W. , Wang Da , Lao Weifeng , Gu Hongcang , Sun Xiaonan , Huang Xuefeng 
Published: June 2024

3614 Background: Conventional neoadjuvant chemoradiotherapy (nCRT) yields a pathologic complete response (pCR) rate of about 15%–- 30% for locally advanced rectal cancer (LARC). This PRECAM study aimed to investigate the efficacy and safety of neoadjuvant short-course radiotherapy combined with CAPEOX plus Envafolimab in Patients with Microsatellite Stable (MSS) LARC, redefining the standard of care (SOC) for LARC. Methods: The study is an open-label, prospective, single-arm, phase II clinical study . Eligible patients with MSS LARC were consecutively enrolled. Participants received short-course radiotherapy (25Gy/5f) with subsequent two cycles of CAPEOX (capecitabine and oxaliplatin) and 6 cycles of Envafolimab (subcutaneous injection, 150 mg, QW ) followed by total mesorectal excision surgery. The primary endpoint was pathological complete response (pCR) rate, and the secondary endpoint was major pathologic (MPR) rate and safety. Results: From April to December 2022, 34 patients were enrolled, of whom 32 completed the study. Remarkably, The pCR rate was62.5% (20/32), and the (MPR) rate was 75% (24/32). Furthermore, 65.6% (21/32) patients achieved a neoadjuvant rectal (NAR) score below 8, suggesting an effective treatment response. Common adverse events included tenesmus (78.1%), diarrhea (62.5%), and leukocyte decrease (40.6%), with two cases of Grade 3 adverse events. Surgical procedures were performed in all 32 cases, with minor complications observed. During the follow-up period of up to 20 months, no recurrence or death were reported. Conclusions: Short-course radiotherapy combined with CAPEOX plus Envafolimab showed favorable pCR rate with manageable adverse effects and surgical complications in LARC, underscoring the potential of the combination therapy for MSS LARC. A Randomized controlled trial is warranted for further exploration and validation. Clinical trial information: NCT05216653 .
An exploratory analysis of the genetic alteration associated with early-onset gastric and colorectal cancer using a large-scale nationwide database of Japan (C-CAT).
Authors: Nakayama Izuma , Miyazaki Naoki , Ueno Risa , Fukada Ippei , Yamaguchi Kensei , Shinozaki Eiji 
Published: June 2024

4058 Background: The recent global concern about the early onset cancer (EOC) has been rising in the field of GI cancers. Precision oncology based on comprehensive genome profile (CGP) test is anticipated to attribute the improvement of cancer treatment for EOC. This study explored the genetic alteration of EOC and association with genome matched therapy in colorectal cancer (CRC) and gastric or gastroesophageal junction cancer (G/GEJC). Methods: We retrospectively assessed Japanese nationwide, the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database. Pts meets following eligibility criteria were enrolled. 1) Pts received the reimbursed CGP tests between June 2019 and May 2023 in Japan, 2) pts registered as CRC or G/GEJC, 3) pts agreed with the utilization of their data. We defined EOC as diagnosed at less than 50 and 40 in EO-CRC and EO-G/GEJC, respectively. We investigated the genomic alterations of EOC and compared the genes with a difference in frequency of 5% or more between earlier and later onset cancer of disease. The transition rate to the subsequent matched therapy was compared between EOC and non-EOC. This study was approved by both the ethics committee of Cancer Institute Hospital of JFCR (No. 2022-GB-121) and C-CAT data utilization review board (No. AP20230309-01N). Results: Among a total of 8,180 eligible pts, 1,289 (19.9%) and 123 (7.2%) EOC were identified in CRC and G/GEJC, respectively. Tissue based assay with Foundation One (n = 6.591, 80.6%) was most frequently employed as CGP test. TP53 (84.1%), APC (77.2%) and KRAS (49.5%) mutation were most frequently occurred in EO CRC. Meanwhile, TP53 (64.2%), CDH1 (36.5%) and ARID1A (17.1%) mutation were the most prevalent in EO G/GEJC. Among the top 30th somatically mutated genes in EO CRC and EO G/GEJC, 31 (96.9%) and 29 (85.3%) genes shared with non-EO in CRC and G/GEJC, respectively. Notably, the proportion of shared genes was significantly decline to 21 (71.9%) and 18 (52.9%) in CRC and G/GEJC when they compared between pts aged <30 and ≥30 years old. The proportion of pts harboring at least one actionable mutation was 42.3% in EO CRC similar to that of non-EO CRC (43.2%) and 19.5% in EO G/GEJC and lower than that of non-EO G/GEJC (32.2%), respectively. The proportions of individuals who received targeted therapy as recommended by CGP test were all approximately 5% (EOC vs. non-EOC: 6.4% vs. 5.6% in CRC and 4.1% vs. 4.4% in G/GEJC). The treatment access rate was not improved in very young pts (aged <30). Conclusions: Genomic alterations were mostly shared between EOC and non-EOC in pts with CRC and G/GEJC. The mutation profile apparently differs between earlier onset (<30) and later onset (≥30) both in CRC and G/GEJC. Very limited proportion of EOC could access the matched therapy after CGP test in the treatment of CRC and G/GEJC as well as non-EOC.
Comparative outcomes of esophageal stent placement in patients with esophageal cancer: A prospective study of 183 cases.
Authors: Chudy-Onwugaje Dilichukwu , Salem Ahmed Elsayed , Roland Bani 
Published: June 2024

4061 Background: Esophageal stent placement is vital for alleviating dysphagia, enabling immediate relief and smoother food passage. This minimally invasive procedure reduces hospital stays, enhancing quality of life and offering a safer option for high-risk patients. Effective in both malignant and benign cases, stents are cost-efficient and require skilled professionals for optimal outcomes. This study examines outcomes of various stent types in 183 esophageal cancer patients, evaluating efficacy, safety, and impact on quality of life. Methods: Between January 2022 and December 2022, 183 patients with esophageal cancer were enrolled from three tertiary health care facilities and divided into three groups based on the type of esophageal stent used: self-expanding metallic stents (SEMS, n = 84), self-expanding plastic stents (SEPS, n = 61), and fully covered self-expanding metallic stents (FCSEMS, n = 38). Stent placement was performed under endoscopic guidance. Follow-up with endoscopic assessments were conducted at 1 week, 1 month, 3 months, and 6 months post-stent placement to evaluate stent patency, dysphagia relief, and complications. Results: The technical success rates for stent placement were high across all groups, with SEMS at 96.4%, SEPS at 95.1%, and FCSEMS at 97.4%. Immediate dysphagia relief was achieved in 87.4% of patients across the three stent types. FCSEMS demonstrated a significantly longer median stent patency duration (8.0 months) compared to SEMS (6.3 months) and SEPS (5.6 months). The SEPS group experienced a higher incidence of stent migration (13.1%) compared to SEMS (8.3%) and FCSEMS (6.5%) groups. Post-interventional complications were documented in 18.0% of patients, with tissue overgrowth (8.7%) and stent migration (6.0%) being the most common. Overall survival rates at 6 months were comparable across the three groups. Notably, FCSEMS displayed superior patency (p < 0.05), suggesting its potential preference in specific cases. The study confirms the effectiveness of stent placement in enhancing patient comfort and quality of life. Conclusions: This study underscores the efficacy of esophageal stent placement as a crucial palliative intervention for dysphagia in esophageal cancer patients. Fully covered self-expanding metallic stents (FCSEMS) exhibited notable advantages, demonstrating prolonged stent patency compared to other types. However, careful consideration is warranted for patients in the self-expanding plastic stents (SEPS) group due to a higher incidence of stent migration. The high technical success rates and immediate dysphagia relief affirm the proficiency and immediate positive impact of this procedure. Overall, this research highlights the importance of tailored stent selection and ongoing investigation to optimize outcomes for esophageal cancer patients.