tbuckley/cabot-search huggingface dataset:
Phase II study of modulation of sorafenib (SOR)-induced autophagy using hydroxychloroquine (HCQ) in advanced hepatocellular cancer (HCC).
Authors: Sukeshi Patel Arora, Jennifer L. Moseley, Luisa Marie Arellano, Mary Salazar, Brittany Altermatt, Lorena Fuentes, Vincent Truong Pham, Gang Huang, LuZhe Sun, Joel Michalek, Devalingam Mahalingam
Journal: Journal of Clinical Oncology (2025)

586 Background: SOR is the first systemic therapy approved for advanced HCC, but has shown only modest improvements in survival. Resistance to SOR in pre-clinical models has been attributed to autophagy induction. Autophagy inhibition with HCQ enhanced SOR-induced cell death and apoptosis in early pre-clinic and clinical studies. Data from the phase I study of SOR plus HCQ in advanced solid tumors at showed clinical safety and efficacy. Therefore, we conducted a prospective study to evaluate efficacy of SOR and HCQ in advanced HCC patients (pts) (NCT03037437) and report the final efficacy analysis. Methods: Prospective phase II study of SOR 400 mg po BID + HCQ 400 mg daily in pts with advanced HCC (CP A-B8 cirrhosis). Cohort 1: first-line SOR/HCQ. Cohort 2: add HCQ upon progressing on SOR. CP B pts started at 200 mg BID, with dose escalation as tolerated. Cycle = 4 weeks. Primary endpoint: mTTP. Secondary endpoints: mOS, objective response rate (ORR) by RECIST; AEs (NCI-CTCAEv3.0); PD analysis for markers of autophagy and immunity. Pts evaluable for efficacy if completed C1. Historically, the mTTP for patients treated with sorafenib is 5.5 mo (SHARP trial). We predicted the addition of HCQ will improve mTTP by 50% to 8.2 months. Results: N=33 completed C1. Median age 64.1 years SD 8.6 (46- 80). 88% Male; 58% Hispanics. ECOG 0-1: 100%. CP B cirrhosis: 35%. Etiology of cirrhosis: HCV 68%, ETOH 32%, NASH 11%. BCLC B 19%, C 81%. AFP&gt;400: 43%, PVT: 27%, extrahepatic/metastases: 68%, post-transplant: 27%. N=5 (14%) were in cohort 2 (prior SOR). Reason off study: PD (n=21), toxicity (n=5), lost to f/u (n=1), withdrew (n=3). mTTP is 8.0 months (95% CI: 4.0-19.0). mOS 10.0 months (95% CI: 6.0-22.0). ORR (CR+PR): 27%. Best response: CR n=1 (3%), PR n=8 (24%), SD n=14 (42%). 4+ cycles: n=19 (58%). AE on treatment: grade 1 (68%), 2 (24%), 3 (7%), 4 (0.6%), 5 (0.3%). No Gr 4/5 related to SOR or HCQ. Dose interruption (20%), dose reduction (10%). Conclusions: SOR/HCQ had a better mTTP (8.0 months) than historical control (mTTP=5.5 months, p=0.03), and the trial met its primary endpoint. SOR/HCQ ORR (27%) was higher than historically SOR alone (ORR 2%, SHARP) in pts with advanced HCC, predominantly BCLC C, with CP A and B cirrhosis (35%), and was tolerable. While immune checkpoint inhibitors (ICIs) are taking the forefront in advanced HCC, SOR/HCQ may still have a role in patients with CP B cirrhosis, post-transplant, or contraindications to ICIs. Further, analysis of predictive markers of response is ongoing. Clinical trial information: NCT03037437 .
Risk of proteinuria with atezolizumab plus bevacizumab versus lenvatinib in first-line systemic treatment for hepatocellular carcinoma.
Authors: JIwon Yang, Won-Mook Choi, Hyung-Don Kim, Jonggi Choi, Changhoon Yoo, Danbi Lee, Ju Hyun Shim, Kang Mo Kim, Young-Suk Lim, Han Chu Lee
Journal: Journal of Clinical Oncology (2025)

558 Background: Proteinuria presents a challenging complication during systemic therapy for hepatocellular carcinoma (HCC). This study aims to identify risk factors for proteinuria in patients with HCC treated with atezolizumab plus bevacizumab (Atezo/Bev) or lenvatinib (LEN) as first-line systemic treatment. Methods: A retrospective analysis was conducted on 622 consecutive patients with unresectable HCC who received Atezo/Bev or LEN as first-line systemic treatment between October 2013 and October 2022. Cumulative incidence of proteinuria was estimated using Kaplan–Meier curves and compared using log-rank tests. Risk factors for proteinuria were identified using Cox proportional-hazard models, along with propensity score-matched and subgroup analyses. Results: Among 367 patients treated with Atezo/Bev and 255 with LEN, the cumulative incidence of proteinuria at 12 months was 27.5%. In the multivariable analysis, Atezo/Bev treatment (HR, 1.57; 95% CI, 1.03–2.42), diabetes (HR, 1.64; 95% CI, 1.03–2.61), Child–Pugh class B (HR, 3.43; 95% CI, 1.34–8.78), macrovascular invasion (MVI; HR, 1.58; 95% CI, 1.04–2.38), and an estimated glomerular filtration rate ≤60 mL/min/1.73 m 2 (HR, 3.21; 95% CI, 1.84–5.62) were identified as risk factors for proteinuria. A higher risk of proteinuria in Atezo/Bev patients compared with LEN was consistently observed in the PS-matched cohort, particularly pronounced in subgroups with MVI (HR, 2.84; 95% CI, 1.23–6.54) compared with those without MVI (HR, 1.31; 95% CI, 0.69–2.47). Conclusions: Patients treated with Atezo/Bev as first-line systemic treatmentfor HCC exhibited a higher risk of proteinuria compared with those with LEN, particularly when accompanied by MVI.
5-hydroxymethylcytosine as a liquid biopsy biomarker in colorectal cancer.
Authors: Christopher Maher, Netra Navadkar, Muheng Liao, De'Vana Crutcher, Jacqueline L. Mudd, Ceyda Coruh, Gulfem Guler, Yuhong Ning, Shimul Chowdhury, Emily Rozycki, Amy Ly, Samuel Levy, Ryan Fields
Journal: Journal of Clinical Oncology (2025)

291 Background: 5-hydroxymethylcytosine (5hmC) is an epigenetic modification which regulates gene expression and is associated with active transcription. The optimization of 5hmC sequencing in cell-free DNA (cfDNA) could therefore enable assessment of gene activity through a liquid biopsy. We aimed to investigate the 5hmC landscape of colorectal cancer (CRC) in plasma-derived cfDNA to evaluate the potential of 5hmC modifications as a liquid biopsy-based biomarker of CRC. Methods: Genome-wide 5hmC modifications were analyzed with a low-input whole-genome 5hmC sequencing method based on selective chemical labeling in cfDNA from 72 CRC patients and 70 healthy samples. Differential 5hmC analysis between CRC and healthy samples was conducted using DESeq2 (padj &lt; 0.05 and log2FC &lt;= -1 and &gt;=1). Low-pass whole genome sequencing (LP-WGS) was performed on all cfDNA samples. Tumor fraction was estimated using ichorCNA to classify samples into high ct-fraction (&gt;=0.1) and low ct-fraction (&lt;0.1) groups. Nucleosome profiling was performed on LP-WGS to reveal chromatin accessibility patterns. Elastic Net Regression (ENR) was applied to identify changes in 5hmC levels for classifying samples as cancerous or healthy. Results: Differential cfDNA 5hmC levels of 139 genes distinguished high ct-fraction CRC (n=16) and healthy samples (n=70). Although the remaining CRC samples (n=56) had similar ct-fractions as the healthy samples, as estimated by ichorCNA, we found a differentially hydroxymethylated gene signature could discriminate between these low ct-fraction CRC and healthy samples. Nucleosome profiling analysis with LP-WGS in cfDNA was used to identify active transcriptional drivers of the genes with increased 5hmC levels. The analysis revealed increased chromatin accessibility near the binding sites for the transcription factor caudal-related homeobox transcription factor 2 ( CDX2 ), a master transcriptional regulator of intestinal cell fate and cancer, in CRC patients relative to healthy samples. Corroborating this, CDX2 and its downstream targets had increased 5hmC levels in cfDNA in CRC relative to healthy samples, consistent with colorectal-derived tumor DNA in CRC plasma samples. Conclusions: Genes with differential 5hmC levels in cfDNA can discriminate CRC and healthy samples. Our 5hmC signature identified CRC samples that did not harbor copy number gains or losses; which is typically used to estimate ct-fraction and routinely included in targeted ctDNA sequencing assays. Integration of 5hmC and LP-WGS can be used to identify gene activation in disease. In the context of CRC, CDX2 displayed increased chromosome accessibility in the promoters of its target genes which in turn displayed increased 5hmC levels. Further studies are aimed at optimizing and validating 5hmC-based biomarkers throughout patient treatment.
A phase II study of peri-operative NovoTTF-200T(P) in combination with gemcitabine and nab-paclitaxel for resectable pancreatic adenocarcinoma: Big Ten Cancer Research Consortium (BTCRC-GI21-500).
Authors: Adam Khorasanchi, Anne M. Noonan, Ning Jin, John L. Hays, Sameek Roychowdhury, Pannaga Malalur, Shafia Rahman, Jordan M. Cloyd, Mary Dillhoff, Susan Tsai, Arjun Mittra, Ashish Manne
Journal: Journal of Clinical Oncology (2025)

TPS795 Background: The recurrence rates and outcomes in resectable pancreatic ductal adenocarcinoma (R-PDA) is concerningly high. The benefit of neoadjuvant chemotherapy over traditional upfront surgery followed by adjuvant therapy is not clear. Electromagnetic fields generate bi-directional forces on highly polar intracellular components, causing abnormal microtubule polymerization during spindle formation and irregular cleavage furrow formation. We will leverage these anti-proliferative effects in managing R-PDA by tumor treating fields (TTF) with chemotherapy backed by strong in vitro and in vivo evidence. The PANOVA phase II trial (n=40) gave us safety and efficacy data of this combination in advanced PDA. No systemic effects were associated with TTF. The only notable safety issue was a small incidence of grade 3 device-related dermatitis. Methods: Our phase II single arm study will investigate perioperative use of TTF with gemcitabine and nab-paclitaxel (G-NP) combination. Eligible patients R-PDA (visible pancreatic mass, measurable disease, absence of arterial interface, venous interface ≤ 180°, patent portal splenic confluence, and no metastatic disease, including lymphadenopathy outside the surgical area) will wear TTF and receive three cycles of G-NP before restaging. Patients are expected to wear TTF for &gt; 80% of the time during this period. If they proceed with resection, additional 3 cycles of Gem-NP with TTF will be given to the patient. This study employs a Bayesian Optimal Phase 2 (BOP2) design with primary endpoints of overall survival (OS) at 2 years and resection rate. The null hypothesis posits a 40% OS rate compared to a target of 60%, and a resection rate null hypothesis of 60% versus a target of 75%. The trial aims to enroll 30 patients, with an interim futility analysis planned after 15 participants. Enrollment will be terminated early if 8 or fewer patients undergo resection in the initial stage, providing 83% power and a type I error rate of 10%. Secondary endpoints include adverse events, overall response rate, TTFields compliance rate, relative dose intensity, and overall survival. The trial started actively recruiting patients in April 2024. The accrual goal is 38 patients. At the time of submission, one patient was enrolled. Clinical trial information: NCT05624918 .
Adequate racial and ethnic representation in cancer clinical trial enrollment: Real-world evidence from an NCI-designated cancer center in a minority-majority county.
Authors: Farshid Dayyani, Aditya Mahadevan, Armon Azizi, Jennifer Brooke Valerin, Nataliya Mar, Deepa Jeyakumar, Frank Lee
Journal: Journal of Clinical Oncology (2025)

803 Background: Despite strides to increase diversity in clinical trial enrollment, significant racial and ethnic disparities persist. This limits the generalizability of clinical trial data and consequently the application of novel therapeutics for diverse populations. We hypothesized that enrollment of underrepresented minorities (URM) is feasible, with improved access to clinical care and a tailored clinical trial portfolio addressing the unmet needs in URM. Methods: A retrospective cohort study was conducted at the University of California Irvine Chao Comprehensive Cancer Center (CFCCC), an NCI-Designated cancer center located in Orange County (OC), CA (a minority-majority county). Clinical trial enrollment data from 2015-2023 through the CFCCC clinical research database was included. Collected data on patient demographics, tumor types, and trial enrollment was compared to data provided by the NIH SEER reports in both OC and United States. Results: Between 2015-2023, 2317 subjects were enrolled in clinical trials at CFCC. Demographics were as follows: White, Asian, Black, American Indian/Alaska Native, mixed/unknown race (66.4%/20.1%/2.4%/0.7%/0.7%/9.3%). Non-Hispanic vs Hispanic ethnicity (77.8%/20.5%). Female vs Male sex (47.6%/52.3%). Age &lt;70 vs &gt;70 years (73.3%/26.7%). Study Phase: Phase I/II (35.6%), Phase II (25.4%), Phase II/III (2.8%), Phase III (26.6%), and Phase IV (0.3%). Study sponsor: Industry (61.1%), Institutional (23.6%), National (14.8%), and Externally Peer Reviewed (0.3%). Most notably, the Asian enrollment (20.1%) and Hispanic enrollment (20.6%) exceeded demographic representation of Asians (17%, RR 1.18) and Hispanics (19%, RR 1.07) at CFCCC. Lastly, Asian patients enrolled at significantly higher rates in lung and liver cancer trials, while Hispanic patients and Black patients enrolled at higher rates in breast cancer and prostate cancer trials respectively. Conclusions: Our results demonstrate that robust URM clinical trial enrollment, particularly among Asian and Hispanic populations, is feasible at an NCI-designated cancer center despite minority-specific barriers. These findings suggest that minority populations can be optimally enrolled in clinical trials when these trials are accessible and tailored to the population at hand. Further research is necessary to investigate factors that influence clinical trial participation in the pursuit of equitable cancer care.
Communication of cancer biomarker testing results: What patients need.
Authors: Julie Saliba Clauer, Anne Nesathurai, Manju George
Journal: Journal of Clinical Oncology (2025)

51 Background: As colorectal cancer (CRC) biomarker testing becomes more widespread and important for treatment decisions, understanding testing results can improve patient engagement, shared decision-making, and facilitate clinical trial enrollment. Our experience in the online 12,000+ member CRC community COLONTOWN (CT), suggests that communication of biomarker results to patients is not ideal. To learn more, we surveyed CT members on their biomarker testing experience. Methods: An online survey posted in CT in September 2024 had questions on testing received (what was tested and how), test results experience (communication before testing and after results, patient understanding and resulting impact), suggested provider statements on biomarker results (statements patients prefer) and disease and respondent details. Results: Of 83 respondents, 70% had testing that included at least 3 common CRC biomarkers; the following are results from this group. Until receipt of results, 30% were unaware that biomarker testing was being done, and 56% first reviewed results without a clinician. Only 17% of respondents felt that nothing was lacking in the clinician communication of biomarker testing results. Upon receipt of biomarker test results, respondents’ feelings improved (30%,18%), did not change (63%, 55%) or worsened (7%, 27%) about treatment options and prognosis, respectively. Test results made 51% feel more confident in their care, and reduced stress for 25%, but increased stress for 39%, with 1/3 citing sub-par communication of results as at least partly driving the stress increase. The value of clear communication was evident, as the most appealing sample provider statements on results with no actionable biomarkers included confirmation of proposed treatment plan and clarity on non-actionable biomarkers. Not surprisingly, 58% learned the most about their biomarker results from COLONTOWN. Conclusions: Our survey highlights the gaps in communication of biomarker testing results and provides insights on what may improve them. The perceived value of biomarker test results for patients seem to go beyond actionability as traditionally defined. Context-specific, nuanced communication of “what the results really mean” and a discussion of its impact on patient experience needs to be part of clinician communication of test results. We plan to develop resources to help, and we implore clinicians and testing companies to consider our findings and make changes in how they share test results with patients.
Development and validation of the SPEAR scoring model and predicting overall survival in unresectable hepatocellular carcinoma patients treated with TACE, molecular targeted therapies, and immune checkpoint inhibitors.
Authors: Wenli Li, Mingjian Lu, Feng Shi, Xiao Cheng, Ruyi Lu, Wenzhe Fan, Mengya Zang, Xiaoyun Hu, Qi Li, Rong Li, Peilin Zhu, Yongru Chen, Kaiyan Su, Qingxian Cai, Guosheng Yuan, Jinzhang Chen
Journal: Journal of Clinical Oncology (2025)

533 Background: To develop and validate a predictive model to identify hepatocellular carcinoma (HCC) patients likely to benefit from combined treatment of transarterial chemoembolization (TACE), molecular targeted therapies (MTTs), and immune checkpoint inhibitors (ICIs). Methods: Data from 500 patients with unresectable HCC treated with TACE, MTTs, and ICIs (2019-2023) were analyzed. Patients were divided into a training set (241 from Nanfang Hospital) and a validation set (259 from various hospitals). Key prognostic variables were identified using random forest survival analysis, and the top five were used to construct a Cox proportional hazards model. Model performance was assessed using time-dependent AUC values, calibration curves, clinical decision curves (DCA), and net reclassification improvement (NRI) indices. Risk scores and optimal cut-off values for risk stratification were determined and validated. Results: Five key survival variables were identified: serum alpha-fetoprotein (AFP), red cell distribution width coefficient of variation (RDW-CV), aspartate aminotransferase (AST), platelet-to-lymphocyte ratio (PLR), and extrahepatic metastasis (EHM). The Cox model had a C-index of 0.694 in the training and 0.691 in the validation set. The training set's 1-year, 2-year, 2.5-year, and 3-year AUC values were 0.77, 0.73, 0.73, and 0.72, respectively, and 0.74, 0.74, 0.76, and 0.66 in the validation set. The ARAPE model demonstrated a more significant net benefit than existing models. Median overall survival (mOS) was 33.9 months for low-risk, 20.4 months for intermediate-risk, and 14.2 months for high-risk groups in the training set; in the validation set, mOS was 30.8, 18.7, and 10.5 months, respectively. Conclusions: The SPEAR model (Serum AFP, PLR, EHM, AST, and RDW-CV) model effectively stratifies risk for HCC patients receiving TACE combined with MTTs and ICIs, aiding in personalized treatment decisions.
XPO1 inhibition as a clinically viable strategy to enhance durability of response to KRAS <sup>G12D</sup> inhibitor in pancreatic ductal adenocarcinoma.
Authors: Mohammed Najeeb Al Hallak, Husain Yar Khan, Amro Aboukameel, Sahar Bannoura, Khalil Choucair, Eliza W. Beal, Miguel Tobon, Rafic Beydoun, Anthony F. Shields, Ramzi Mohammad, Jennifer Lynn Beebe-Dimmer, Philip Agop Philip, Boris Pasche, Asfar S. Azmi
Journal: Journal of Clinical Oncology (2025)

736 Background: The OFF State (GDP bound) KRASG 12D inhibitor MRTX1133 is currently being evaluated in pancreatic ductal adenocarcinoma (PDAC) patients. Nevertheless, as with other OFF state KRAS G12C inhibitors sotorasib and adagrasib, the KRAS G12D inhibitor may yield only a modest increase in disease-free survival due to emergence of drug resistance. This underscores the need to identify strategies that can enhance the efficacy of KRAS inhibitors in PDAC. Nuclear protein transport plays an important role in several pro-tumorigenic pathways and has been shown to be a therapeutic vulnerability in KRAS mutant cancers. XPO1 is the major nuclear exporter and plays a pivotal role in shuttling various critical tumor suppressors, genome surveillance proteins, and transcription factors out of the nucleus and is frequently overexpressed in various cancers, including PDAC. In this study, we employed a KRAS G12D inhibitor resistant model and evaluated its sensitivity to nuclear exporter protein inhibitor. Methods: We examined the cytotoxic and molecular effects of KRAS G12D inhibitor MRTX1133 in combination with nuclear transport inhibitor eltanexor in KRAS G12D inhibitor resistant models. The preclinical antitumor efficacy of the combination was evaluated in KRAS G12D mutant PDAC cell derived xenograft (CDX) subcutaneous and orthotopic models. Results: Eltanexor treatment reversed MRTX1133 resistance in vitro yielding suppressed proliferation of KRAS G12D mutant 2D and 3D cultures of PDAC cell lines and patient derived primary tumors cells. High throughput P-kinome analysis showed suppression of a larger repertoire of MAPK substrates in combination treatment compared to single agent group. Eltanexor and MRTX1133 combination led to reduction in protein expression of KRAS downstream effectors and cell cycle markers. Furthermore, a combined administration of eltanexor and MRTX1133 at sub-optimal doses resulted in remarkable tumor growth inhibition in multiple subcutaneous and orthotopic KRAS G12D mutant mice models. Moreover, eltanexor as a maintenance therapy also prevented tumor relapse indicating durability of response in PDAC. Conclusions: This is the first study demonstrating that nuclear transport inhibitors can overcome KRAS G12D inhibitor MRTX1133 resistance in PDAC cells. This study provides a rationale for combining MRTX1133 with eltanexor for the treatment of PDAC patients with KRAS G12D mutant tumors.
Is treatment delivery of perioperative FLOT therapy in locally advanced OGA associated with recurrence-free survival?
Authors: Keiji Sugiyama, Sacheen Kumar, M. Asif Chaudry, Nikhil Patel, Pranav Patel, David Cunningham, Naureen Starling, Sheela Rao, Charlotte Victoria Fribbens, Ian Chau
Journal: Journal of Clinical Oncology (2025)

391 Background: Although perioperative FLOT therapy is a standard for locally advanced oesophagogastric adenocarcinoma (LA-OGA), completing all cycles, especially in the adjuvant chemotherapy (ACT) phase, is often challenging. This study examined the survival impact of treatment delivery in LA-OGA patients receiving FLOT therapy. Methods: 423 patients who underwent radical resection at The Royal Marsden Hospital from 2017 to 2023 were screened. Major inclusion criteria included patients with LA-OGA (cT2≤ and Nany or Tany and N+), treated with FLOT (at least one cycle of neoadjuvant chemotherapy) and radical resection, with an ECOG performance status of 0–2. Patients were divided into therapy incomplete (Tx Incomp, less than eight cycles of FLOT) and therapy (Tx comp) groups. We performed univariate and multivariate analyses, as well as propensity score matching (PSM) analysis, to evaluate whether treatment delivery was associated with recurrence-free survival (RFS) and overall survival (OS). Kaplan-Meier curves and restricted mean survival times (RMST) up to 36 months were used to evaluate the survival time. The primary endpoint was the 3-year RFS and OS rate. Results: Of the screened patients, 210 met the inclusion criteria, with 79 (38%) in the Tx Incomp and 131 (62%) in the Tx comp group, and 50 (24%) patients did not receive ACT. The median follow-up time was 26.5 months. The 3-year RFS and OS rates in the Tx Incomp and Tx comp groups after PSM were 54% vs 59% (p=0.14) (RMST difference: 4.04 months, p=0.09) and 58% vs 78% (p=0.04) (RMST difference: 6.15 months, p&lt;0.001), respectively. Multivariable analysis showed a significant impact of Tx comp on OS (HR 0.53, 95% CI: 0.32-0.88). In the subgroup of ypN-positive patients, a significant difference of RMST in OS rate was observed between those who started ACT and those who did not start ACT (RMST difference: 7.89 months, p=0.01), whereas no significant difference was found in the ypN-negative group (RMST difference: 0.65 months, p=0.75). Conclusions: This study suggests that completing FLOT therapy is associated with better OS. The impact of ACT might differ according to ypN stage.