bluuebunny/crossref_metadata_2025_split huggingface dataset:
A blood-based screening test for colorectal cancer (CRC) using methylation sequencing.
Authors: Bahadur Urvashi , Basu Swaraj , Rathod Nihesh , Vishwanath Divya , Hiremath Prakash , RT Preetha , Chatterjee Aditi , Ghosh Arunima , Phalke Sameer , Yete Subuhi , Khan Ankita , Sanguri Sweta , Rahman Mohammed , Limaye Sewanti , Cantor Charles , Veeramachaneni Vamsi , Hariharan Ramesh 
Published: June 2024

e15089 Background: Diagnosis of CRC is biased towards later stages in India (3.8% Stage I, 16.7% Stage II, 50.7% Stage III, 28.8% Stage IV), and five-year survival at < 40% is one of the lowest in the world. A blood-based non-invasive screening test for CRC using cell-free DNA (cfDNA) methylation sequencing is developed here from the blood of 212 controls and 67 treatment naive CRC patients from 21 sites across India and processed in Strand’s reference lab in Bangalore. Methods: Steps involved cfDNA extraction, NEB Enzymatic Methyl-Seq library preparation, Twist Human Methylome hybridisation capture, 2x150bp sequencing on NovaSeq 6000/X. Methylation + fragmentomic features were calculated for each target region. Samples were split randomly into a leave-in set of 170 controls + 53 cancers (I: 8, II 16, III: 23, IV: 6) and a leave-out set of 42 controls + 14 cancers, (I: 5, II: 4, III: 2, IV: 3) with 20 rounds of 4-fold cross-validation done on the leave-in set (random splits). Feature selection per fold was performed using the KS test without access to ¼ of the leave-in set and to the entire leave-out set. Gradient boosted trees with monotonic constraints reflecting the expected association of the scores with cancer were used to build “explainable” models. Test robustness was assessed using differentially methylated regions (DMRs) from other studies, and by assessing predictability using sample metadata alone. Results: At a 91% specificity level, the ensemble model had a median sensitivity of 62.5% for Stage I (95%CI 38%-86%), 87% for Stage II (95% CI 75%-95%), 87% for Stage III (95% CI 75%-95%) and 83.4% for Stage IV (95% CI 84%-100%) in cross-validation, and 60% for Stage I (95%CI 60%-80%), 100% for Stage II (95% CI 80%-100%), 100% for Stage III (95% CI 100%-100%) and 100% for Stage IV (95% CI 100%-100%) on the leave-out set. At a ~98% specificity level, the model had a median sensitivity of 37.5% for Stage I (95%CI 37%-50%), 69% for Stage II (95% CI 56%-75%), 69% for Stage III (95% CI 60%-84%) and 67% for Stage IV (95% CI 50%-84%) in cross-validation, and 40% for Stage I (95%CI 20%-60%), 75% for Stage II (95% CI 75%-100%), 100% for Stage III (95% CI 100%-100%) and 100% for Stage IV (95% CI 66%-100%) with a slight decrease in specificity to 95.2% on the leave-out set. Using DMRs derived from TCGA data and other publications, yielded a comparable (to our models) cross-validation area under the curve (AUC: 0.93-0.95). Cross-validation performance using only the sample metadata in table 1 and without access to the data was significantly poorer (AUC 0.75-0.81). Conclusions: cfDNA-based methylation profiles are consistent across studies and ethnicities, leading to robust and “explainable” CRC screening predictions. [Table: see text]
Evaluating the significance of next-generation sequencing (NGS) testing in Indian patients with advanced malignancies: An observational study on clinical outcomes and treatment costs.
Authors: Modak Pradnya , K Muthulingeshkumar , Bhandarkar Varsha Ravindra , Maurya Poonam , Sathyanarayanan Vishwanath 
Published: June 2024

e15091 Background: The widespread use of Next-Generation Sequencing (NGS) panels to guide targeted therapy in advanced malignancies has raised questions regarding their real-world impact on clinical outcomes and affordability. Methods: This observational study included 126 patients, conducted between January 2022 and December 2023 aimed to assess the utility of NGS testing in both the initial and subsequent lines of treatment for Indian patients facing advanced malignancies. Results: In the first-line setting, NGS was extensively employed for patients with metastatic Colorectal Cancer (mCRC) and Non-Small Cell Lung Cancer (NSCLC). Analysis of RAS and BRAF mutations in mCRC patients (n=21) informed the choice between EGFR and VEGFR-directed therapy, resulting in a median Progression-Free Survival (PFS) of 7.5 months. In NSCLC patients (n=37), the NGS identified targetable mutations in 30 cases, leading to significantly improved mPFS (12 months vs 6 mo with chemotherapy alone). NGS was also employed for HRR, HRD and BRCA testing in advanced breast (n=45) and ovarian carcinoma (n=11), which helps in determining prognosis, role of targeted therapy and genetics. No adverse events noted till date. For patients undergoing subsequent lines of treatment (n=12), NGS detected targetable mutations in 9 cases. NGS revealed actionable mutations (ERBB2, CD74/NRG1fusion and KRAS12C mutation) in metastatic NSCLC patients (n=3), leading to appropriate treatment and PFS of 4-6 months. In metastatic NSCLC patients, T790M mutation was detected in 1 patient confering PFS of 6 months with change to Osimertinib and EGFR exon 20 insertion mutation detected in another, survival didn't improve with addition of amivantamab due to poor general condition. Alpelisib was started for PIK3CA mutation in metastatic Ca Breast (HR+,HEr2-), which was discontinued due to poor tolerance after 3 months. In Metastatic Neuroendocrine Carcinoma (NEC) Lung, detection of EGFR l858R mutation did not confer a PFS benefit despite the addition of Geftinib to chemotherapy. Due to financial constraints, targeted therapy couldn't be started for 2 patients with pathogenic target detected. Conclusions: The study's findings suggest that NGS testing offers tangible clinical benefits in both initial and subsequent lines of treatment for advanced malignancies in the Indian population. Despite the varying costs of NGS in India (ranging from 240 to 1800 USD), the data implies an overall affordability, making it a viable option for patients with advanced malignancies. However, NGS didn't improve outcomes in patients with rapidly progressing disease, poor general condition and financial constraints.
Antitumor activity of nab-sirolimus versus mTOR inhibitors temsirolimus, sirolimus, and everolimus in A549 NSCLC xenografts.
Authors: Hou Shihe , Zalath Maria , Kwon Andrew , Spindler Edward 
Published: June 2024

e15096 Background: The mTORC1 pathway, often activated by mutations in genes like TSC1, TSC2, PIK3CA, PTEN, STK11, and KEAP1, plays a pivotal role in cancer progression; in some settings, alterations in STK11 and KEAP1 may be associated with treatment resistance and poor prognosis. Despite the broad importance of the mTORC1 pathway in cancer cell growth and survival, mTOR inhibitors (mTORis) temsirolimus (TEM), sirolimus (SIRO), and everolimus (EVE) have limited clinical application in the cancer setting. nab-Sirolimus, an injectable form of albumin-bound SIRO that leverages unique transport properties of albumin known to increase tumor drug accumulation, is approved for treatment of malignant PEComa. Here, we report the antitumor activity of nab-sirolimus in comparison to other mTORis in A549 NSCLC ( KRAS G12S, STK11 Q37*, and KEAP1 G333C) xenografts, and the correlation of antitumor activity, tumor PK profile, and mTOR pathway suppression. Methods: Athymic mice bearing subcutaneous A549 NSCLC xenografts were treated with either saline or equal weekly doses of nab-sirolimus (administered intravenously [IV]; 5 or 15 mg/kg/week), TEM (IV; 5 mg/kg/week), or SIRO or EVE (both oral; 15 mg/kg/week). Tumors were harvested at different time points after mTORi treatment and analyzed for tumor drug levels (LC-MS/MS) and mTOR pathway biomarkers (pS6 and p4EBP1) via western blot (WB). Results: In A549 xenografts, nab-sirolimus (IV) treatment resulted in significantly greater suppression of tumor growth compared with TEM (IV), SIRO (oral), and EVE (oral) (Table). Average intratumoral drug concentrations 24 hours after IV mTORi treatment were significantly higher with nab-sirolimus (420-539 ng/g) compared with TEM (TEM [parent] 34.9 ng/g; SIRO [active metabolite measured from TEM] 13.2 ng/g) and compared with 7-day steady-state concentrations for oral SIRO (17 ng/g) and EVE (10 ng/g). WB confirmed that nab-sirolimus consistently inhibited mTOR targets pS6 and p4EBP1, whereas TEM, SIRO, and EVE were less effective. Conclusions: nab-Sirolimus resulted in significantly higher intratumoral drug concentration, stronger inhibition of mTOR targets, and greater antitumor activity compared to other IV and oral mTORis in a KRAS/STK11/KEAP1 mutated NSCLC xenograft model. These results support further clinical evaluation of nab-sirolimus as a single agent or in combination with other therapeutic agents in oncology. [Table: see text]
Effect of targeting FAK by ifebemtinib and immunogenic cell death of Kras G12C/G12D inhibition on the efficacy of PD1 blockade.
Authors: Zhang Baoyuan , Gao Jiaming , Pang Ran , Zhang Ping , Cheng Jingwen , Qin Natasha , Liu Leo , Wang Zaiqi 
Published: June 2024

e15102 Background: Focal adhesion kinase (FAK) is one major component of focal adhesion complex and is important in regulating cancer cell survival. Previously, we found that a clinical-stage FAK inhibitor, ifebemtinib (aka IN10018) can overcome drug resistance of Kras G12C inhibitors by down regulating the FAK-YAP signaling. Combination of Kras G12Ci and FAKi has demonstrated encouraging efficacy in NSCLC. Here, we reported that targeting Kras G12D by selective Kras G12Di can also be enhanced by ifebemtinib. Further, Kras G12C inhibition plus PD1 blockade has demonstrated clinical benefits in PD-L1 high expression patient population, but ≈30% of patients experienced early disease progression; this might be attributed to loss-of-function of LKB1 and others. Immunogenic cell death (ICD) of Kras inhibition is enhanced by ifebemtinib, ICD reportedly enhances anti-PD1 activity. Thus, Kras inhibition and PD1 blockade plus ifebemtinib may be an ideal combination for patients with Kras G12D. Methods: Cell killing and apoptosis assays were performed to test the combination of Kras G12D inhibition and ifebemtinib. FACs analysis evaluated exposure levels vs. ICD biomarkers. The mice inoculated with CRC GP2D and PDAC PC-07-0013 were used for evaluating the combinational effects of Kras G12Di and ifebemtinib. The tumor bearing mice with Kras G12D mutant/LKB1 loss, NSCLC KPL, and CRC CT26 with knock-in Kras G12C were used for testing the effects of Kras inhibition, ifebemtinib, and PD1 blockade. Results: Ifebemtinib enhances the drug effects of Kras G12D inhibition in vitro and in vivo. The dual regimen of ifebemtinib and Kras inhibition outperformed either monotherapy with significant ICD induction in vitro (calreticulin/GRP94 exposure). The triple regimen of Kras inhibition, FAK inhibition and PD1 blockade exhibited stronger anti-cancer effects compared to the other related therapies, especially in a Kras G12D mutant, LKB1 loss animal model which is intrinsically resistant to PD1 blockade/Kras G12D inhibition. Conclusions: We discovered that targeting FAK by ifebemtinib enhances the anti-cancer effects of Kras G12D inhibition. It promotes ICD by targeting Kras G12D or G12C, further primes the dual regimen of Kras inhibition and ifebemtinib towards a response to anti PD1 therapy. The preclinical results warrant a further evaluation in the clinic.
First-in-human phase 1 study of SPH4336, a novel cyclin-dependent kinase 4/6 inhibitor, in patients with advanced solid tumors.
Authors: Wang Yong-Sheng , Jiang Yu , Sun Meili , Liang Xu , Li Huiping 
Published: June 2024

e15107 Background: The inhibition of cyclin-dependent kinases (CDKs) is a highly promising and attractive strategy for the development of anticancer drugs. SPH4336, a novel oral inhibitor with high selectivity and improved inhibition for CDK4/6, has demonstrated promising anti-tumor activity in preclinical studies. This was a first-in-human, multicenter, phase 1 dose-escalation and -expansion study to assess the safety, pharmacokinetics (PK) and preliminary efficacy of SPH4336 in patients with advanced solid tumors. Methods: Patients aged 18-70 years with histologically or cytologically confirmed advanced solid tumors that were refractory or intolerant to standard treatment or for which no standard treatment exists were included. Dose escalation of SPH4336 was conducted at doses of 50 mg, 100 mg, 200 mg, 300 mg, 400 mg and 600 mg once a day. Primary endpoint was to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and pharmacokinetics of SPH4336. Secondary endpoints included assessment of adverse events (AEs) and efficacy. Descriptive statistics summarized safety, efficacy and PK parameters. Kaplan-Meier method was used to analyze time-to-event variables. Results: A total of 29 patients were enrolled with a median age of 55.0 years (23–66) and 72% being females. The most common tumor types were breast cancer (n=14, 48.3%) and sarcoma (n=8, 27.6%). No DLT was observed within 50 to 600 mg and MTD was not determined. Treatment-related adverse events (TRAEs) were reported in 29 (100%) patients, the most common TRAEs were white blood cell count decreased (n=21, 72.4%), diarrhea (n=20, 69.0%), neutrophil count decreased (n=19, 65.5%) and anemia (n=18, 62.1%). No grade 4 TRAEs were observed and death occurred in 1 patient (200 mg cohort) due to disease progression. Of the 27 evaluable patients, 1 patient achieved partial response lasting 169 days, and disease control rate was 59.3% (95% CI: 38.8%-77.6%). Regression of target lesion was observed in 100, 400 and 600 mg cohorts from baseline. PK assessments showed that the exposure of SPH4336 increased in a dose-dependent manner except with 600 mg dose. SPH4336 reached a steady state at 2 weeks of continuous dosing administration at 400 mg. Conclusions: This study demonstrated that SPH4336 was well tolerated at doses ranging from 50 to 600 mg dose levels. A dose of 400 mg could be considered for further clinical trials. Clinical trial information: NCT05905614 .
KEYNOTE-158: Final analysis of pembrolizumab in patients of Chinese descent with microsatellite instability-high/mismatch repair deficient advanced solid tumors.
Authors: Xu Jianming , Mao Yimin , Xu Nong , Bai Yuxian , Wang Dong , Chen Xiaojun , Yin Xianli , Deng Yanhong , Yang Jianwei , Zhang Jieqing , Tang Jie , Huang Yi , Li Jiayi , Luo Suxia , Xu Miaomiao , Li Nan , Mao Yixiang , Gozman Alexander , Wu Xiaohua 
Published: June 2024

e15137 Background: The multicohort non-randomized, phase 2 KEYNOTE-158 (NCT02628067) trial supported the FDA approval of pembrolizumab for unresectable or metastatic microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) solid tumors. Incidence of advanced MSI-H/dMMR tumors in patients (pts) of Chinese descent is similar to that in Western populations. In KEYNOTE-158 cohort L, we evaluated the antitumor activity of pembrolizumab in pts of Chinese descent with MSI-H/dMMR solid tumors. We previously reported an ORR of 70% in 20 pts from cohort L. Here we present results of the final analysis for 30 pts with 18 months (mo) of follow up. Methods: Eligible pts of Chinese descent from China aged ≥18 years were enrolled. Pts had to have confirmed unresectable or metastatic MSI-H/dMMR tumors, and ≥1 prior lines of therapy. Pts received 200 mg pembrolizumab Q3W for up to 35 cycles, until progression, unacceptable toxicity, or pt/investigator withdrawal. MSI-H/dMMR status was assessed centrally by PCR and IHC. The primary endpoint was ORR per RECIST 1.1 by central review. Secondary endpoints were DOR, PFS, OS and safety. The database cut-off date was May 5, 2023. Results: A total of 30 pts were enrolled; 7 (23%) were aged ≥65 years, and 20 (67%) were female. At data cut-off, 14 (47%) pts discontinued treatment; 12 (40%) due to progressive disease, 1 (3%) due to adverse events (AE), and 1 (3%) due to physician decision. The median follow-up (range) was 18.0 mo (6.4 – 32.7). The ORR was 66.7% (6 CR; 14 PR [95% CI: 47.2%- 82.7%]). The median DOR was not reached (NR) (range, 1.8+ - 29.5+) with a 12-mo DOR rate of 85.9%. Median PFS was NR (95% CI: 8.1-NR) with an 18-mo PFS rate of 63.0%. The median OS was NR (95% CI: 19.1, NR) with an 18-mo OS rate of 78.8%. Treatment-related AEs were reported in 22 (73%) pts. Grade 3-4 treatment-related AEs occurred in 7 (23%) pts. There were no grade 5 AEs. Immune-mediated AEs occurred in 11 pts (37%); 2 (7%) had grade 3 AEs (myositis or rash in 1 pt each). No grade 4-5 immune-mediated AEs occurred. Conclusions: Pembrolizumab continues to provide clinically meaningful antitumor activity and durable responses with a manageable safety profile in pts of Chinese descent with MSI-H/dMMR tumors. No new safety signals were identified. These results are consistent with those reported in the global population and further support the use of pembrolizumab in pts of Chinese descent with MSI-H/dMMR tumors. Clinical trial information: NCT02628067 .
EXPRESS study: A trial exploring the association of low level of genomic alteration with exceptional and unexpected response to targeted therapies in patients with advanced solid tumors.
Authors: Le Saux Olivia , Girard Elodie , Leslie Lori , Bachelot Thomas , Pierga Jean-Yves , Barlesi Fabrice , Albiges Laurence , Lebbe Celeste , Boige Valerie , Frenel Jean-Sebastien , Spaeth Dominique , Guillot Aline , Heudel Pierre Etienne , Gardner Miriam , Durando Xavier , Peron Julien , Kamal Maud , Legrand François , Lusque Amelie , Bieche Ivan ,   Centre Léon Bérard
Published: June 2024

e15140 Background: Small subsets of pts treated with targeted therapies (TT) present exceptional and unexpected response (1-10%), which could be driven and correlated by a low level of genomic alterations in genes identified as causally implicated in cancer. Conversely, the multiplication of the genomic alterations in such genes would decrease the oncogenic de-addiction process. Methods: EXPRESS is an exploratory, multicenter, prospective trial conducted in pts with locally advanced or metastatic solid tumors, who presented an exceptional and unexpected response to an antineoplastic TT. This research aimed to explore whether tumors with a low level genomic alteration (mutation, amplification, deletion) as assessed by whole exome sequencing (WES) are associated with exceptional and unexpected response. Secondary endpoints including the identification of novel candidate somatic molecular profiles and host immunologic characteristics susceptible to drive exceptional and unexpected response will be reported later. Results: 439 pts were identified over 32 centres from December 2016 to April 2021. Out of 270 pts confirmed with an exceptional response by our review committee of cases, 183 were included in the EXPRESS study. Exceptional responder population is summarised (Table). Out of 183, WES analysis was performed for 103 pts (56.3%). Genomic analysis failure was predominant in the breast and lung cohort (60.9% and 52.5%). The number of genomic alterations in the EXPRESS cohort was lower than in the TCGA control cohort (median[Q1-Q3]: 11[7-17] vs 19 [11-32], p<0.001). A lower number of genomic alterations was also reported in the melanoma (8[5-13] vs 33[17-51], p<0.001) and lung cancer cohort (8[5-17] vs 22[13-34], p<0.001) but not in the breast and kidney cohorts (13[10-21] vs 17[10-29], p=0.41 and 12[9-14] vs 11[7-17], p=0.89). Conclusions: Compared to the TCGA cohort, a low level of genomic alteration is associated with exceptional response in pts with lung cancer and melanoma. A comparison with a matched population based on genomic criteria in the TCGA is undergoing and will be presented at the conference. Clinical trial information: NCT02701907 . [Table: see text]
Overcoming chemoresistance in triple-negative breast cancer (TNBC): Targeting PD-L1 stability and ferroptosis through integrated lipid metabolism and immune modulation.
Authors: Yang Sujin , Tang Jinhai , Zhang Jian 
Published: June 2024

e15149 Background: Triple-negative breast cancer (TNBC) is notorious for its aggressive nature and high recurrence rates, exacerbated by the lack of specific molecular targets, leading to poor prognosis and emergent chemoresistance. Our study explores ferroptosis mechanisms in TNBC, focusing on the interaction between lipid metabolism and immune system modulation to identify targets that enhance chemosensitivity, potentially improving chemotherapy efficacy. Methods: We employed RNA transcriptomics, proteomics, metabolomics, and lipidomics to compare gene transcription, protein expression, and metabolic profiles between TNBC cell lines MDA-MB-231/ADR (doxorubicin-resistant) and MDA-MB-231/S (sensitive). The impact of the ferroptosis inducer Erastin on MDA-MB-231/ADR was assessed through lipidomics. We also performed gene expression profiling on 152 TNBC patients unresponsive to Anthracycline-based chemotherapy, correlating with data from TCGA and METABRIC. Functional loss and gain experiments were undertaken to explicate the role of the SCD1-TRIM28-PD-L1 axis in mediating ADR resistance. Immunohistochemistry and RT-qPCR analyses were performed on tumor tissues and serum EVs from TNBC patients to identify chemosensitivity-enhancing targets. Results: Our investigation revealed marked transcriptional and proteomic variances between MDA-MB-231/ADR and MDA-MB-231/S cell lines, with SCD1 showing significant upregulation at both mRNA and protein levels. Metabolomic analyses revealed distinct lipid metabolic profiles between these two cell lines. Further studies found that Erastin treatment increased PD-L1 expression, along with changes in SCD1, p53, and TNFAIP3 expression levels. These molecules are closely associated with poor prognosis and resistance to therapy. Our findings also elucidated that TRIM28 modulates PD-L1 stability via SUMOylation and facilitates p53 ubiquitination and degradation through a TRIM28-MDM2 dependent pathway, thereby impacting immune surveillance and therapeutic response. Additionally, in TNBC patients treated with anthracycline-based chemotherapy, higher SCD1 and TNFAIP3 but lower TRIM28 expressions were observed in the PD/SD group compared to PR/CR. Similar expression patterns were observed in serum EVs. Conclusions: Our study highlights the potential of targeting the SCD1-TRIM28-PD-L1 axis in TNBC to overcome chemoresistance. We propose combining SCD1 inhibition with ferroptosis inducers to enhance PD-L1 blockade efficacy, offering a promising approach for TNBC patients with limited response to Anthracycline-based chemotherapy. This investigation represents a pivotal step towards advancing targeted therapeutics in TNBC, potentially transforming the clinical management of this aggressive and refractory breast cancer subtype.