A plain language summary of the results from the phase 2b HERIZON-BTC-01 study of zanidatamab in participants with HER2-amplified biliary tract cancer.

WHAT IS THIS SUMMARY ABOUT?: Researchers wanted to study whether the research drug zanidatamab could help people with a type of cancer called biliary tract cancer. In some people, biliary tract cancer cells make extra copies of a gene called HER2 (also called ERBB2). This is known as being HER2-amplified. Zanidatamab is an antibody designed to destroy cancer cells that have higher-than-normal HER2 protein or gene levels. Zanidatamab is currently under research and is not yet approved for any diseases. Participants in this phase 2b clinical study had tumors that were HER2-amplified and at the advanced or metastatic stage. Participants also had cancer which had become worse after previous chemotherapy or had side effects that were too bad to continue chemotherapy. They also had to meet other requirements to be enrolled. Researchers measured the amount of HER2 protein in the tumor samples of the participants who were enrolled. There were 80 participants with tumors that were both HER2 amplified and had higher-than-normal HER2 protein amounts (considered to be 'HER2-positive'). There were 7 participants with tumors that were HER2-amplified, but had little-to-no levels of the HER2 protein (considered to be 'HER2-low'). All participants in the study were treated with zanidatamab and no other cancer treatments once every 2 weeks. WHAT ARE THE KEY TAKEAWAYS?: In the HER2-positive group, 33 of 80 (41%) participants had their tumors shrink by 30% or more of their original size. In half of these participants, their tumors did not grow for 13 months or longer. No participant in the HER2-low group had their tumors shrink by 30% or more. In total, 63 of 87 participants (72%) had at least one side effect believed to be related to zanidatamab treatment. Most side effects were mild or moderate in severity. No participant died from complications related to zanidatamab. Diarrhea was one of the more common side effects and was experienced by 32 of 87 participants (37%). Side effects related to receiving zanidatamab through the vein, such as chills, fever, or high blood pressure, were experienced by 29 of 87 participants (33%). WHAT ARE THE CONCLUSIONS REPORTED BY THE RESEARCHERS?: The results of this study support the potential for zanidatamab as a new therapy for people with HER2-positive biliary tract cancer after they had already received chemotherapy. More research is occurring to support these results.Clinical Trial Registration: NCT04466891 (HERIZON-BTC-01 study).

The HERIZON-BTC-01 study revealed zanidatamab as a potentially effective treatment for HER2-positive biliary tract cancer after standard chemotherapy fails. Read more in the lay summary by @hardingjjmd, @DrShubhamPant, and coauthors. #BiliaryTractCancer #HER2 #zanidatamab.

Atlas of metastatic gastric cancer links ferroptosis to disease progression and immunotherapy response.

BACKGROUND & AIMS: Metastases from gastric adenocarcinoma (GAC) lead to high morbidity and mortality. Developing innovative and effective therapies requires a comprehensive understanding of the tumor and immune biology of advanced GAC. Yet, collecting matched specimens from advanced, treatment-naïve GAC patients poses a significant challenge, limiting the scope of current research, which has predominantly focused on localized tumors. This gap hinders a deeper insight into the metastatic dynamics of GAC. METHODS: We performed in-depth single-cell transcriptome and immune profiling on 68 paired, treatment-naïve, primary-metastatic tumors to delineate alterations in cancer cells and their tumor microenvironment (TME) during metastatic progression. To validate our observations, we conducted comprehensive functional studies both in vitro and in vivo, employing cell lines, multiple PDX and novel mouse models of GAC. RESULTS: Liver and peritoneal metastases exhibited distinct properties in cancer cells and dynamics of TME phenotypes, supporting the notion that cancer cells and their local TMEs co-evolve at metastatic sites. Our study also revealed differential activation of cancer meta-programs across metastases. We observed evasion of cancer cell ferroptosis via GPX4 upregulation during GAC progression. Conditional depletion of Gpx4 or pharmacological inhibition of ferroptosis resistance significantly attenuated tumor growth and metastatic progression. Additionally, ferroptosis-resensitizing treatments augmented the efficacy of CAR T-cell therapy. CONCLUSIONS: This study represents the largest single-cell dataset of metastatic GACs to date. High-resolution mapping of the molecular and cellular dynamics of GAC metastasis has revealed a rationale for targeting ferroptosis defense in combination with CAR T-cell therapy as a novel therapeutic strategy with potential immense clinical implications.

Anti-PD-1/L1 antibody plus anti-VEGF antibody vs. plus VEGFR-targeted TKI as first-line therapy for unresectable hepatocellular carcinoma: a network meta-analysis.

Background: This article is based on our previous research, which was presented at the 2023 ASCO Annual Meeting I and published in Journal of Clinical Oncology as Conference Abstract (JCO. 2023;41:e16148. doi: 10.1200/JCO.2023.41.16_suppl.e16148). Both anti-programmed death 1/ligand-1 (PD-1/L1) antibody + anti-vascular endothelial growth factor (VEGF) antibody (A + A) and anti-PD-1/L1 antibody + VEGF receptor (VEGFR)-targeted tyrosine kinase inhibitor (A + T) are effective first-line therapies for unresectable hepatocellular carcinoma. However, there lacks evidence from head-to-head comparisons between these two treatments. We conducted a network meta-analysis on the efficacy and safety of them. Methods: After a rigorous literature research, 6 phase III trials were identified for the final analysis, including IMbrave150, ORIENT-32, COSMIC-312, CARES-310, LEAP-002, and REFLECT. The experiments were classified into three groups: A + A, A + T, and intermediate reference group. The primary endpoint was overall survival (OS), and secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and incidence of treatment-related adverse events (TRAEs). Hazard ratio (HR) with 95% confidence intervals (CI) for OS and PFS, odds ratio (OR) for ORR, and relative risk (RR) for all grade and grade ≥3 TRAEs were calculated. Under Bayesian framework, the meta-analysis was conducted using sorafenib as intermediate reference. Results: With the rank probability of 96%, A + A showed the greatest reduction in the risk of death, without significant difference from A + T (HR: 0.82, 95% CI: 0.65-1.04). A + T showed the greatest effect in prolonging PFS and improving ORR with the rank probability of 77%, but there were no statistical differences with A + A. A + A was safer than A + T in terms of all grade of TRAEs (RR: 0.91, 95% CI: 0.82-1.00) and particularly in those grade ≥3 (RR: 0.65, 95% CI: 0.54-0.77). Conclusions: A + A had the greatest probability of delivering the longest OS, while A + T was correlated with larger PFS benefits at the cost of a lower safety rate.

Tislelizumab in previously treated, locally advanced unresectable/metastatic microsatellite instability-high/mismatch repair-deficient solid tumors.

Objective: The open-label, phase II RATIONALE-209 study evaluated tislelizumab (anti-programmed cell death protein 1 antibody) as a tissue-agnostic monotherapy for microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) tumors. Methods: Adults with previously treated, locally advanced unresectable or metastatic MSI-H/dMMR solid tumors were enrolled. Patients received tislelizumab 200 mg intravenously every 3 weeks. Objective response rate (ORR; primary endpoint), duration of response (DoR), and progression-free survival (PFS) were assessed by independent review committee (Response Evaluation Criteria in Solid Tumors v1.1). Results: Eighty patients were enrolled and treated; 75 (93.8%) patients had measurable disease at baseline. Most had metastatic disease and received at least one prior therapy for advanced/metastatic disease (n=79; 98.8%). At primary analysis (data cutoff July 8, 2021; median follow-up 15.2 months), overall ORR [46.7%; 95% confidence interval (95% CI), 35.1-58.6; one-sided P<0.0001] and ORR across tumor-specific subgroups [colorectal (n=46): 39.1% (95% CI, 25.1-54.6); gastric/gastroesophageal junction (n=9): 55.6% (95% CI, 21.2-86.3); others (n=20): 60.0% (95% CI, 36.1-80.9)] were significantly greater with tislelizumab vs. a prespecified historical control ORR of 10%; five (6.7%) patients had complete responses. Median DoR, PFS, and overall survival were not reached with long-term follow-up (data cutoff December 5, 2022; median follow-up 28.9 months). Tislelizumab was well tolerated with no unexpected safety signals. Treatment-related adverse events (TRAEs) of grade ≥3 occurred in 53.8% of patients; 7.5% of patients discontinued treatment due to TRAEs. Conclusions: Tislelizumab demonstrated a significant ORR improvement in patients with previously treated, locally advanced unresectable or metastatic MSI-H/dMMR tumors and was generally well tolerated.

Potential mechanisms and targeting strategies of the gut microbiota in antitumor immunity and immunotherapy.

BACKGROUND: Immunotherapies, notably immune checkpoints inhibitors that target programmed death 1/programmed death ligand 1(PD-1/PD-L1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), had profoundly changed the way advanced and metastatic cancers are treated and dramatically improved overall and progression-free survival. AIMS: This review article aimed to explore the underlying molecular mechanisms by which the gut microbiota affects antitumor immunity and the efficacy of cancer immunotherapy. METHODS: We summarized the latest knowledge supporting the associations among the gut microbiota, antitumor immunity, and immunotherapy. Moreover, we disscussed the therapeutic strategy for improving immunotherapy efficacy by modulating gut microbiota in cancer treatment. RESULTS: The potential molecular mechanisms underlying these associations are explained in terms of four aspects: immunomodulation, molecular mimicry, mamps, and microbial metabolites. CONCLUSION: The gut microbiota significantly impacts antitumor immunity and alters the effectiveness of cancer immunotherapy.

Apatinib Plus Toripalimab (Anti-PD1 Therapy) as Second-Line Therapy in Patients With Advanced Gastric or Esophagogastric Junction Cancer: Results From a Randomized, Open-Label Phase II Study.

BACKGROUND: This study aimed to assess the activity of apatinib plus toripalimab in the second line for patients with advanced gastric or esophagogastric junction cancer (GC/EGJC). METHODS: In this open-label, phase II, randomized trial, patients with advanced GC/EGJC who progressed after first-line chemotherapy were enrolled and received 250 mg apatinib per day plus 240 mg toripalimab on day 1 per 3 weeks (arm A) or physician's choice of chemotherapy (PC, arm B). The primary endpoint of this study was the 1-year survival rate. Progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and safety were assessed as secondary endpoints. RESULTS: Twenty-five patients received apatinib plus toripalimab while 26 were enrolled in arm B. The 1-year survival rates of the 2 groups were 43.3% and 42.3%, respectively (P = .903). The PFS was 2.77 versus 2.33 months (P = .660). The OS was 8.30 versus 9.88 months (P = .539). An objective response was reported in 20.0% of patients in arm A compared to 26.9% in arm B (P = .368), respectively. A total of 6 (24.0%) patients experienced adverse events of grade ≥ 3 in arm A, while 9 (34.6%) patients suffered from adverse events of grade ≥ 3 in arm B. No drug-related deaths occurred in either group. CONCLUSION: Toripalimab plus apatinib treatment in second-line therapy of advanced GC/EGJC showed manageable toxicity but did not improve clinical outcomes relative to PC treatment (ClinicalTrials.gov Identifier: NCT04190745).

Efficacy, safety and genomic analysis of SCT200, an anti-EGFR monoclonal antibody, in patients with fluorouracil, irinotecan and oxaliplatin refractory RAS and BRAF wild-type metastatic colorectal cancer: a phase â ¡ study.

BACKGROUND: Limited therapeutic options are available for metastatic colorectal cancer (mCRC) patients after failure of first- and second-line therapies, representing an unmet medical need for novel therapies. METHODS: This is an open-label, single arm, multicenter, phase Ⅱ study aiming to perform the efficacy, safety and genomic analysis of SCT200, a noval fully humanized IgG1 anti-epidermal growth factor receptor (EGFR) monoclonal antibody, in patients with fluorouracil, irinotecan and oxaliplatin refractory RAS and BRAF wild-type mCRC. SCT200 (6 mg/kg) was given weekly for the first six weeks, followed by a higher dose of 8 mg/kg every two weeks until disease progression or unacceptable toxicity. Primary endpoint was independent review committee (IRC)-assessed objective response rate (ORR) and secondary endpoints included ORR in patients with left-sided tumor, disease control rate (DCR), duration of response (DoR), time to response (TTR), progression-free survival (PFS), overall survival (OS) and safety. FINDINGS: From February 12, 2018 to December 1, 2019, a total of 110 patients aged between 26 and 77 years (median: 55; interquartile range [IQR]: 47-63) with fluorouracil, oxaliplatin, and irinotecan refractory RAS and BRAF wild-type mCRC were enrolled from 22 hospitals in China. As the data cut-off date on May 15, 2020, the IRC-assessed ORR and DCR was 31% (34/110, 95% confidence interval [CI] 22-40%) and 75% (82/110, 95% CI 65-82%), respectively. Thirty one percent (34/110) patients achieved confirmed partial response (PR). The median PFS and median OS were 5.1 months (95% CI 3.4-5.2) and 16.2 months (95% CI 11.1-not available [NA]), respectively. The most common ≥ grade 3 treatment-related adverse events (TRAEs) were hypomagnesemia (17%, 19/110) and acneiform dermatitis (11%, 12/110). No deaths occurred. Genomic analysis suggested positive association between MYC amplification and patients' response (P = 0.0058). RAS/RAF mutation and MET amplification were the most frequently detected resistance mechanisms. Patients with high circulating tumor DNA (ctDNA) at baseline or without ctDNA clearance at the 7th week after the first dose of SCT200 administration before receiving SCT200 had worse PFS and OS. INTERPRETATION: SCT200 exhibited promising clinical efficacy and manageable safety profiles in RAS and BRAF wild-type mCRC patients progressed on fluorouracil, irinotecan and oxaliplatin treatment. The baseline ctDNA and ctDNA clearance status at the 7th week after the first dose of SCT200 administration before receiving SCT200 could be a potential prognostic biomarker for RAS and BRAF wild-type mCRC patients with SCT200 therapy. FUNDING: This study was sponsored by Sinocelltech Ltd., Beijing, China and partly supported by the National Science and Technology Major Project for Key New Drug Development (2019ZX09732001-006, 2017ZX09304015).

The promise and challenges of combination therapies with antibody-drug conjugates in solid tumors.

Antibody-drug conjugates (ADCs) represent an important class of cancer therapies that have revolutionized the treatment paradigm of solid tumors. To date, many ongoing studies of ADC combinations with a variety of anticancer drugs, encompassing chemotherapy, molecularly targeted agents, and immunotherapy, are being rigorously conducted in both preclinical studies and clinical trial settings. Nevertheless, combination therapy does not always guarantee a synergistic or additive effect and may entail overlapping toxicity risks. Therefore, understanding the current status and underlying mechanisms of ADC combination therapy is urgently required. This comprehensive review analyzes existing evidence concerning the additive or synergistic effect of ADCs with other classes of oncology medicines. Here, we discuss the biological mechanisms of different ADC combination therapy strategies, provide prominent examples, and assess their benefits and challenges. Finally, we discuss future opportunities for ADC combination therapy in clinical practice.

XYA-2: a marine-derived compound targeting apoptosis and multiple signaling pathways in pancreatic cancer.

Background: Pancreatic cancer is a highly aggressive and fatal disease with limited treatment options and poor prognosis for patients. This study aimed to investigate the impact of XYA-2 {N-(3,7-dimethyl-2,6-octadienyl)-2-aza-2-deoxychaetoviridin A}, a nitrogenated azaphilon previously reported from a deep-sea-derived fungus on the progression of pancreatic cancer cells. Methods: The inhibitory effects of XYA-2 on cell proliferation, clonogenic potential, cell cycle progression, apoptosis, migration, and invasion were assessed using various assays. The CCK-8 assay, clone formation assay, flow cytometry assay, wound healing assay, and transwell assay were employed to evaluate cell proliferation, clonogenic potential, cell cycle progression, apoptosis, migration, and invasion, respectively. Moreover, we employed RNA-seq and bioinformatics analyses to uncover the underlying mechanism by which XYA-2 influences pancreatic cancer cells. The revealed mechanism was subsequently validated through qRT-PCR. Results: Our results demonstrated that XYA-2 dose-dependently inhibited the proliferation of pancreatic cancer cells and induced cell cycle arrest and apoptosis. Additionally, XYA-2 exerted a significant inhibitory effect on the invasion and migration of cancer cells. Moreover, XYA-2 was found to regulate the expression of genes involved in multiple cancer-related pathways based on our RNA-seq and bioinformatics analysis. Conclusion: These findings highlight the potential of XYA-2 as a promising therapeutic option for the treatment of pancreatic cancer.

Spatiotemporal Quantification of HER2-targeting Antibody-Drug Conjugate Bystander Activity and Enhancement of Solid Tumor Penetration.

PURPOSE: Antibody-drug conjugate (ADC) has had a transformative effect on the treatment of many solid tumors, yet it remains unclear how ADCs exert bystander activity in the tumor microenvironment. EXPERIMENTAL DESIGN: Here, we directly visualized and spatiotemporally quantified the intratumor biodistribution and pharmacokinetics of different ADC components by developing dual-labeled fluorescent probes. RESULTS: Mechanistically, we found that tumor penetration of ADCs is distinctly affected by their ability to breach the binding site barrier (BSB) in perivascular regions of tumor vasculature, and bystander activity of ADC can only partially breach BSB. Furthermore, bystander activity of ADCs can work in synergy with coadministration of their parental antibodies, leading to fully bypassing BSBs and enhancing tumor penetration via a two-step process. CONCLUSIONS: These promising preclinical data allowed us to initiate a phase I/II clinical study of coadministration of RC48 and trastuzumab in patients with malignant stomach cancer to further evaluate this treatment strategy in humans.

The Chinese Society of Clinical Oncology (CSCO): Clinical guidelines for the diagnosis and treatment of gastric cancer, 2023.

The 2023 update of the Chinese Society of Clinical Oncology (CSCO) Clinical Guidelines for Gastric Cancer focuses on standardizing cancer diagnosis and treatment in China, reflecting the latest advancements in evidence-based medicine, healthcare resource availability, and precision medicine. These updates address the differences in epidemiological characteristics, clinicopathological features, tumor biology, treatment patterns, and drug selections between Eastern and Western gastric cancer patients. Key revisions include a structured template for imaging diagnosis reports, updated standards for molecular marker testing in pathological diagnosis, and an elevated recommendation for neoadjuvant chemotherapy in stage III gastric cancer. For advanced metastatic gastric cancer, the guidelines introduce new recommendations for immunotherapy, anti-angiogenic therapy and targeted drugs, along with updated management strategies for human epidermal growth factor receptor 2 (HER2)-positive and deficient DNA mismatch repair (dMMR)/microsatellite instability-high (MSI-H) patients. Additionally, the guidelines offer detailed screening recommendations for hereditary gastric cancer and an appendix listing drug treatment regimens for various stages of gastric cancer. The 2023 CSCO Clinical Guidelines for Gastric Cancer updates are based on both Chinese and international clinical research and expert consensus to enhance their applicability and relevance in clinical practice, particularly in the heterogeneous healthcare landscape of China, while maintaining a commitment to scientific rigor, impartiality, and timely revisions.

Beyond ENO1, emerging roles and targeting strategies of other enolases in cancers.

Aerobic glycolysis is a hallmark property of cancer metabolism. Enolase is a glycolytic enzyme that catalyzes the conversion of 2-phosphoglycerate into phosphoenolpyruvate. In mammals, enolases exist in three isoforms, encoded by the genes ENO1, ENO2, and ENO3. The altered expression of enolases is a common occurrence in various types of cancer. Although most published studies on enolases have predominantly focused on the role of ENO1 in cancer, ENO2 and ENO3 have recently emerged as crucial regulatory molecules in cancer development. Significant progress has been made in understanding their multifaceted roles in oncogenesis. In this comprehensive review, we provide an overview of the structure, subcellular localization, diagnostic and prognostic significance, biological functions, and molecular mechanisms of ENO2 and ENO3 in cancer progression. The importance of enolase in cancer development makes it a novel therapeutic target for clinical applications. Furthermore, we discuss anticancer agents designed to target enolases and summarize their anticancer efficacy in both in vitro and in vivo studies.

A benzochalcone derivative synchronously induces apoptosis and ferroptosis in pancreatic cancer cells.

Background: Pancreatic cancer is a highly aggressive and lethal disease with limited treatment options. In this study, we investigated the potential therapeutic effects of compound KL-6 on pancreatic cancer cells. Methods: The study involved assessing the inhibitory effects of KL-6 on cell proliferation, clonogenic potential, cell cycle progression, apoptosis, migration, and invasion. Additionally, we examined the action mechanism of KL-6 by RNA-seq and bioinformatic analysis and validated by qRT-PCR and western blot in pancreatic cancer cells. Results: Our results demonstrated that KL-6 effectively inhibited the growth of pancreatic cancer cells in a dose-dependent manner. It induced G2/M phase cell cycle arrest and apoptosis, disrupting the cell cycle progression and promoting cell death. KL-6 also exhibited inhibitory effects on cell migration and invasion, suggesting its potential to suppress the metastatic properties of pancreatic cancer cells. Furthermore, KL-6 modulated the expression of genes involved in various cancer-related pathways including apoptosis and ferroptosis. Conclusion: These findings collectively support the potential of KL-6 as a promising therapeutic option for pancreatic cancer treatment. Further research is needed to fully understand the underlying mechanisms and evaluate the clinical efficacy of KL-6 in pancreatic cancer patients.

Cancer cell-intrinsic PD-1: Its role in malignant progression and immunotherapy.

Programmed cell death protein-1 (PD-1), also called CD279, is coded by the PDCD1 gene and is constitutively expressed on the surface of immune cells. As a receptor and immune checkpoint, PD-1 can bind to programmed death ligand-1/programmed death ligand-2 (PD-L1/PD-L2) in tumor cells, leading to tumor immune evasion. Anti-PD-1 and anti-PD-L1 are important components in tumor immune therapy. PD-1 is also expressed as an intrinsic variant (iPD-1) in cancer cells where it plays important roles in malignant progression as proposed by recent studies. However, iPD-1 has received much less attention compared to PD-1 expressed on immune cells although there is an unmet medical need for fully elucidating the mechanisms of actions to achieve the best response in tumor immunotherapy. iPD-1 suppresses tumorigenesis in non-small cell lung cancer (NSCLC) and colon cancer, whereas it promotes tumorigenesis in melanoma, hepatocellular carcinoma (HCC), pancreatic ductal adenocarcinoma (PDAC), thyroid cancer (TC), glioblastoma (GBM), and triple-negative breast cancer (TNBC). In this review, we focus on the role of iPD-1 in tumorigenesis and development and its molecular mechanisms. We also deeply discuss nivolumab-based combined therapy in common tumor therapy. iPD-1 may explain the different therapeutic effects of anti-PD-1 treatment and provide critical information for use in combined anti-tumor approaches.

Development of potent antibody drug conjugates against ICAM1+ cancer cells in preclinical models of cholangiocarcinoma.

As a highly lethal adenocarcinoma of the hepatobiliary system, outcomes for cholangiocarcinoma (CCA) patients remain prominently poor with a 5-year survival of <10% due to the lack of effective treatment modalities. Targeted therapeutics for CCA are limited and surgical resection of CCA frequently suffers from a high recurrence rate. Here we report two effective targeted therapeutics in this preclinical study for CCA. We first performed a quantitative and unbiased screening of cancer-related antigens using comparative flow cytometry in a panel of human CCA cell lines, and identified intercellular adhesion molecule-1 (ICAM1) as a therapeutic target for CCA. After determining that ICAM1 has the ability to efficiently mediate antibody internalization, we constructed two ICAM1 antibody-drug conjugates (ADCs) by conjugating ICAM1 antibodies to different cytotoxic payloads through cleavable chemical linkers. The efficacies of two ICAM1 ADCs have been evaluated in comparison with the first-line chemodrug Gemcitabine in vitro and in vivo, and ICAM1 antibodies coupled with warhead DX-8951 derivative (DXd) or monomethyl auristatin E (MMAE) elicit a potent and consistent tumor attenuation. In summary, this study paves the road for developing a promising targeted therapeutic candidate for clinical treatment of CCA.

Performance evaluation of a CRISPR Cas9-based selective exponential amplification assay for the detection of KRAS mutations in plasma of patients with advanced pancreatic cancer.

AIMS: Pancreatic ductal adenocarcinoma (PDAC) is highly malignant, with shockingly mortality rates. KRAS oncoprotein is the main molecular target for PDAC. Liquid biopsies, such as the detection of circulating tumour DNA (ctDNA), offer a promising approach for less invasive diagnosis. In this study, we aim to evaluate the precision and utility of programmable enzyme-based selective exponential amplification (PASEA) assay for rare mutant alleles identification. METHODS: PASEA uses CRISPR-Cas9 to continuously shear wild-type alleles during recombinase polymerase amplification, while mutant alleles are exponentially amplified, ultimately reaching a level detectable by Sanger sequencing. We applied PASEA to detect KRAS mutations in plasma ctDNA. A total of 153 patients with stage IV PDAC were enrolled. We investigated the relationship between ctDNA detection rates with various clinical factors. RESULTS: Our results showed 91.43% vs 44.83% detection rate in patients of prechemotherapy and undergoing chemotherapy. KRAS ctDNA was more prevalent in patients with liver metastases and patients did not undergo surgical resection. Patients with liver metastases prior to chemotherapy showed a sensitivity of 95.24% (20/21) with PASEA. Through longitudinal monitoring, we found ctDNA may be a more accurate biomarker for monitoring chemotherapy efficacy in PDAC than CA19-9. CONCLUSIONS: Our study sheds light on the potential of ctDNA as a valuable complementary biomarker for precision targeted therapy, emphasising the importance of considering chemotherapy status, metastatic sites and surgical history when evaluating its diagnostic potential in PDAC. PASEA technology provides a reliable, cost-effective and minimally invasive method for detecting ctDNA of PDAC.

Zanidatamab for HER2-amplified, unresectable, locally advanced or metastatic biliary tract cancer (HERIZON-BTC-01): a multicentre, single-arm, phase 2b study.

BACKGROUND: HER2 is overexpressed or amplified in a subset of biliary tract cancer. Zanidatamab, a bispecific antibody targeting two distinct HER2 epitopes, exhibited tolerability and preliminary anti-tumour activity in HER2-expressing or HER2 (also known as ERBB2)-amplified treatment-refractory biliary tract cancer. METHODS: HERIZON-BTC-01 is a global, multicentre, single-arm, phase 2b trial of zanidatamab in patients with HER2-amplified, unresectable, locally advanced, or metastatic biliary tract cancer with disease progression on previous gemcitabine-based therapy, recruited at 32 clinical trial sites in nine countries in North America, South America, Asia, and Europe. Eligible patients were aged 18 years or older with HER2-amplified biliary tract cancer confirmed by in-situ hybridisation per central testing, at least one measurable target lesion per Response Evaluation Criteria in Solid Tumours (version 1.1), and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were assigned into cohorts based on HER2 immunohistochemistry (IHC) score: cohort 1 (IHC 2+ or 3+; HER2-positive) and cohort 2 (IHC 0 or 1+). Patients received zanidatamab 20 mg/kg intravenously every 2 weeks. The primary endpoint was confirmed objective response rate in cohort 1 as assessed by independent central review. Anti-tumour activity and safety were assessed in all participants who received any dose of zanidatamab. This trial is registered with ClinicalTrials.gov, NCT04466891, is ongoing, and is closed to recruitment. FINDINGS: Between Sept 15, 2020, and March 16, 2022, 87 patients were enrolled in HERIZON-BTC-01: 80 in cohort 1 (45 [56%] were female and 35 [44%] were male; 52 [65%] were Asian; median age was 64 years [IQR 58-70]) and seven in cohort 2 (five [71%] were male and two [29%] were female; five [71%] were Asian; median age was 62 years [IQR 58-77]). At the time of the data cutoff (Oct 10, 2022), 18 (21%) patients (17 in cohort 1 and one in cohort 2) were continuing to receive zanidatamab; 69 (79%) discontinued treatment (radiographic progression in 64 [74%] patients). The median duration of follow-up was 12·4 months (IQR 9·4-17·2). Confirmed objective responses by independent central review were observed in 33 patients in cohort 1 (41·3% [95% CI 30·4-52·8]). 16 (18%) patients had grade 3 treatment-related adverse events; the most common were diarrhoea (four [5%] patients) and decreased ejection fraction (three [3%] patients). There were no grade 4 treatment-related adverse events and no treatment-related deaths. INTERPRETATION: Zanidatamab demonstrated meaningful clinical benefit with a manageable safety profile in patients with treatment-refractory, HER2-positive biliary tract cancer. These results support the potential of zanidatamab as a future treatment option in HER2-positive biliary tract cancer. FUNDING: Zymeworks, Jazz, and BeiGene.

Exploring potential molecular resistance and clonal evolution in advanced HER2-positive gastric cancer under trastuzumab therapy.

HER2-positive gastric cancer (GC) makes up 15-20% of all GC incidences, and targeted therapy with trastuzumab is the standard of treatment. However, the mechanisms of resistance to trastuzumab are still not fully understood and presents a significant challenge in clinical practice. In this study, whole exome sequencing (WES) was performed on paired tumor tissues before trastuzumab treatment (at baseline) and at progressive disease (PD) in 23 GC patients. Clinicopathological and molecular features that may be associated with primary and/or acquired resistance to trastuzumab were identified. Lauren classification of intestinal type was associated with a more prolonged progression-free survival (PFS) than diffuse type (HR = 0.29, P = 0.019). Patients with low tumor mutation burden (TMB) showed significantly worse PFS, while high chromosome instability (CIN) was correlated with prolonged OS (HR = 0.27; P = 0.044). Patients who responded to treatment had a higher CIN than nonresponders, and a positive trend towards increasing CIN was observed as response improved (P = 0.019). In our cohort, the most common genes to acquire mutations are AURKA, MYC, STK11, and LRP6 with four patients each. We also discovered an association between clonal branching pattern and survival, with an extensive clonal branching pattern being more closely related to a shorter PFS than other branching patterns (HR = 4.71; P = 0.008). We identified potential molecular and clinical factors that provide insight regarding potential association to trastuzumab resistance in advanced HER2-positive GC patients.

Does resection after neoadjuvant chemotherapy of docetaxel, oxaliplatin, and S-1 (DOS regimen) benefit for gastric cancer patients with single non-curable factor? a multicenter, prospective cohort study (Neo-REGATTA).

BACKGROUND: The Neo-REGATTA study evaluated the effectiveness and safety of Docetaxel, oxaliplatin, and S-1 (DOS regimen) followed by radical resection vs. chemotherapy in advanced gastric adenocarcinoma patients with single non-curable factor. METHODS: This cohort study prospectively enrolled advanced gastric adenocarcinoma patients with single non-curable factor between November 2017 and June 2021. Patients without progression after four cycles of DOS were divided into resection group and chemotherapy group. The outcomes included overall survival (OS), progression-free survival (PFS) and safety. Effectiveness analysis was also performed by propensity score matching (PSM). RESULTS: A total of 73 patients were enrolled and 13 patients were withdrawn due to disease progression after 4 cycles of DOS. Afterwards, 35 and 25 participants were in the resection and chemotherapy groups, respectively. After a median follow-up time of 30.0 months, the median PFS and OS were 9.0 months, and 18.0 months for the chemotherapy group, but not reached in the resection group. After PSM, 19 matched participants were in each group, and the median PFS and OS were longer in resection group than that in chemotherapy group. The most common grade 3 or 4 adverse events both in the resection group and chemotherapy groups were neutropenia (5.7%, 8.0%) and leukopenia (5.7%, 8.0%). CONCLUSIONS: Radical resection might provide survival benefit compared with continuous chemotherapy alone in advanced gastric adenocarcinoma patients who had a disease control after DOS, with a good safety profile. TRIAL REGISTRATION: The study protocol was registered on ClinicalTrial.gov (NCT03001726, 23/12/2016).

Chebulagic acid suppresses gastric cancer by inhibiting the AURKA/ß-catenin/Wnt pathway.

Gastric cancer (GC) is a prevalent malignant neoplasm that poses a serious threat to human health. Overexpression of Aurora A (AURKA) is frequently associated with the self-renewal and tumorigenicity of various cancers. Chebulagic acid (CA) has been examined as a potential tumor suppressor based on its ability against numerous tumor biological activities. However, the possible mechanisms of CA inhibition of the progression of GC by mediating the AURKA/ß-catenin/Wnt signaling pathway have not been investigated. The present study investigated the level of AURKA expression in GC. We further examined the effect of CA on cell proliferation, migration, and apoptosis in the MKN1 and NUGC3 GC cell lines, and its efficacy in suppressing tumor growth was assessed in tumor bearing mice model. We demonstrated that AURKA was highly expressed in GC and associated with poor prognosis. We demonstrated that treatment with CA significantly inhibited the proliferation and migration of GC cells and induced apoptosis. Compared to the vehicle group, CA treatment severely diminished the volume and weight and the metastasis of tumors. CA also inhibited the expression of AURKA and the AURKA/ß-catenin/Wnt signaling pathway in vitro and in vivo. Collectively, the present results demonstrated that high expression of AURKA may be an independent factor of poor prognosis in patients with GC, and CA significantly suppressed the tumor biological functions of GC and inhibited the AURKA/ß-catenin/Wnt pathway.