tbuckley/cabot-search huggingface dataset:
Mutational analysis of cfDNA to identify predictive biomarkers in previously untreated patients with metastatic pancreatic cancer receiving the GSK-3 inhibitor elraglusib (9-ING-41) in combination with gemcitabine/nab-paclitaxel in the 1801 phase 2 study.
Authors: Andrey Ugolkov, Taylor Weiskittel, Austin Koukol, Caroline Kellinger, Hu Li, Andrew Paul Mazar
Journal: Journal of Clinical Oncology (2024)

e16306 Background: Glycogen Synthase Kinase-3beta has been well-credentialed as a therapeutic target in patients with advanced cancer including pancreatic cancer. Elraglusib (9-ING-41), a novel best-in-class GSK-3 inhibitor, is being developed in combination with gemcitabine/nab-paclitaxel (GnP) as first-line therapy for patients with metastatic pancreatic cancer (mPDAC). Using liquid biopsy samples from an ongoing randomized phase 2 trial (1801 Part 3B; NCT03678883), we examined whether gene mutations in cfDNA correlated with clinical outcomes in mPDAC patients treated with GnP or elraglusib/GnP. Methods: Pre-dose plasma samples were obtained from 37 (GnP arm) and 89 (elraglusib/GnP arm) mPDAC patients previously untreated for advanced disease. Mutational analysis of cfDNA extracted from plasma samples was performed by Tempus (Chicago, IL) using the xF+ platform. The Tempus xF+ assay is an NGS cfDNA liquid biopsy tumor profiling assay for identifying genomic alterations in 523 genes. Tempus xF+ reports were used for analysis of gene mutations. Results: In 126 pancreatic cancer patients, frequently mutated genes ( &gt; 10%) consisted of KRAS (93/126, 74%), TP53 (79/126, 63%), CDKN2A (26/126, 21%), DNMT3A (25/126, 20%), NOTCH1/2 (25/126, 20%), and MLL3 (23/126, 18%). Gain-of-function mutations in KRAS, and loss-of-function mutations of TP53, and CDKN2A genes were associated with worse overall survival (OS) in patients treated with elraglusib/GnP (P &lt; 0.05) but not in GnP-treated patients. Multivariate analysis of frequently mutated genes showed that patients with double (KRAS+TP53) and triple (KRAS+TP53+CDKN2A) mutations had significantly worse OS only in the elraglusib/GnP arm. The presence of DNMT3A, NOTCH1/2 or MLL3 gene mutations did not correlate with any clinical outcomes. Conclusions: Our preliminary analysis of gene mutations in liquid biopsy samples obtained from patients in the ongoing 1801 Part 3B phase 2 trial identified potential predictive biomarkers of clinical outcome in mPDAC patients treated with combination of elraglusib/GnP. Clinical trial information: NCT03678883 .
NXL-004: A novel trans-differentiation therapy for glioblastoma treatment.
Authors: Yuchen Chen, Ming Chen, Tsangchih Kuo, Kai Zhou, Sen Jin, Meng Liu, Ming Moon Chen, Shiyuan Chen, Xuetao Li, Zuoyu Jiang, Liting Pu, Adalia Chen, Xiang Gao, Jie Xu, Jian Sheng, Yulun Huang, Gong Chen
Journal: Journal of Clinical Oncology (2024)

e14020 Background: Gliomas, tumors originating from glial cells in the brain and spinal cord, constitute 80% of all malignant primary tumors affecting the central nervous system, with glioblastomas (GBM) as the most prevalent and aggressive subtype accounting for approximately 60% of cases. Current treatment options for GBM, including surgery, radiation therapy, and chemotherapy, have limited effectiveness in improving patient outcomes. Therefore, there is a critical need for more effective therapeutic approaches to treat GBM. Methods: We present NXL-004, an adeno-associated virus (AAV) vector delivering the neural transcription factor NeuroD1 directly into GBM tumor cells, as a novel therapy for GBM. Various GBM models were utilized to investigate NXL-004 treatment for GBM, including U87 intracranial and subcutaneous models in mice, PDX model and GBM organoid. Results: The results demonstrated that NXL-004 significantly reduced tumor size compared to the control group; (D) NXL-004 exhibited a significant effect in prolonging the survival of the GBM mouse model. The median survival of mice treated with NXL-004 was 34 days post tumor implantation, whereas the control group had a median survival of only 16 days. Conclusions: Preclinical studies of NXL-004 have demonstrated that this intervention effectively reprograms tumor cells, downregulating glial cell- and tumor-related gene expression, while concurrently upregulating neuron-related gene expression. The induced differentiation towards non-dividing neurons results in significant inhibition of tumor cell proliferation, substantial reductions in tumor volume and prolonged survival in GBM-bearing mice. Additionally, NXL-004 has exhibited a favorable safety profile in toxicity studies in rats and non-human primates. These preclinical outcomes paved the way for subsequent clinical evaluation, representing a potential breakthrough in GBM treatment.
Unfavourable carcinoma of unknown primary (CUP) with gastrointestinal profile: A retrospective study.
Authors: Lorenzo Guidi, Carmine Valenza, Elena Battaiotto, Luca Boscolo Bielo, Edoardo Crimini, Carmen Belli, Lorenzo Gervaso, Chiara Alessandra Cella, Davide Ciardiello, Konstantinos Venetis, Luca Bottiglieri, Mariacristina Ghioni, Elena Guerini Rocco, Nicola Fazio, Maria Giulia Zampino, Giuseppe Curigliano
Journal: Journal of Clinical Oncology (2024)

e16374 Background: According to European Society of Medical Oncology (ESMO) guidelines, CUP are classified in favorable and unfavorable subsets. Favorable CUPs (20% of pts) have clinical aspects and either pathology highly suggestive for specific site of origin or with amenable metastases for localized treatment with curative intent; they are treated with site-specific chemotherapy (CT). All other CUPs (80%) are defined unfavorable and are treated with empiric CT regimens. There is no data about the best CT regimen for unfavourable CUPs with GI profile, i.e., those CUPs that do not meet the criteria of favourable colon-like CUP (CK7-/CK20+/CDX2+) but have a morphological/immunohistochemical profile suggestive for the digestive system. Methods: We conducted a single-center retrospective study to describe outcomes and prognostic factors of pts with unfavourable CUPs with GI profile, referred to our center from Jan 2000 to Aug 2023, who received at least one cycle of first-line CT. The definition of GI profile was: a) negativity for GATA-3, PAX-8 and TTF-1 and b) CK7+/CK20-/anyCDX2 or CK7-/CK20+/CDX2- or CK7-/CK20-/CDX2+, or c) presence of an abundant mucinous component and/or a signet ring cell component. The primary endpoint was the progression free survival (PFS) of first line chemotherapy for advanced disease. Results: 43 pts were included (characteristics in table). After a median follow-up of 43.9 months, 33 deaths were registered and the mOS was 12.6 months (95% CI, 8.7-16.5). Forty PFS events were registered and the mPFS was 6.1 months (95% CI, 3.5-8.9). At univariate analysis, male pts (p=0.034), peritoneal metastases (p=0.0282), residual tumor after surgery (p=0.002), suspected biliopancreatic origin (p=0.033), PS ECOG &gt; 1 (p&lt;0.001) and CDX2- status (p=0.025) were associated with shorter PFS. No CT regimen was superior in terms of PFS at both univariate (p=0.282) and multivariable analysis after adjusting for peritoneal metastases, suspected origin, gender and baseline ECOG PS. Conclusions: Although limited by the small sample size, this study showed that all CT regimens were comparable in terms of PFS among patients with unfavorable CUP with gastrointestinal profile. Keywords (3/10): cancer of unknown primary; peritoneal metastases; chemotherapy. [Table: see text]
Effect of the timing of recurrence on survival among patients with breast cancer with brain metastasis.
Authors: Kendall Miller, Myla S. Strawderman, Sujan Niraula, Ramandeep Babbra, Niraj Neupane, Asis Shrestha, Sugam Gouli, Zeni Kharel, Carey K. Anders, Nimish Mohile, Ruth O'Regan, Carla Isadora Falkson, Anna Weiss, Allison Magnuson, Sarah Stanford, Ajay Dhakal
Journal: Journal of Clinical Oncology (2024)

e14005 Background: Patients with Metastatic Breast Cancer (MBC) and brain metastasis (BM) have poor prognosis. There is a lack of data on the effects of timing of MBC diagnosis [de novo (d) vs recurred (r) MBC] and BM diagnosis [dBM vs later onset (lo) BM] on overall survival (OS). We conducted a natural history-type study to investigate these effects among MBC BM patients. Methods: The data for this retrospective single institute study was extracted from a database of MBC BM patients diagnosed with BM from Jan 2010 to June 2021. Definitions: dMBC= MBC at initial diagnosis (Dx); rMBC= MBC with prior history of early stage BC; dBM= BM diagnosed&lt; 6 weeks (wk) from MBC Dx; loBM= BM diagnosed ≥ 6 wk from MBC Dx. The following endpoints were compared between dMBC vs rMBC: 1. interval from MBC to BM Dx (Interval MBC-BM) 2. OS from MBC Dx 3. OS from BM Dx. OS from BM Dx was compared between dBM vs loBM. Median endpoints were estimated using the Kaplan-Meier method and reported with 95% confidence intervals (CI). Cohorts were compared using the Logrank test and adjusted for other variables using Cox models. Results: Interval MBC-BM, OS from MBC Dx, and BM Dx were not statistically different between dMBC and rMBC groups in unadjusted analyses (See Table) and when adjusted in multivariate analyses. Median OS from BM Dx was significantly longer in dBM group vs loBM group (See Table). In multivariate model adjusting for variables at BM Dx (age, race, performance status, visceral disease, number of BM &gt;1cm, leptomeningeal disease, BC receptor types), risk of death was higher in loBM group vs dBM group (Hazard Ratio, HR = 0.499; p=0.006). In dMBC group, 28.1% had dBM compared to 45.6% in the rMBC (p=0.083, Chi-square test). Subset analyses: Among rMBC group, median OS from BM Dx with dBM (n=42, OS=44.3 months (m), 95% CI 19.0-Not evaluable (NE)) was significantly longer compared to loBM (n=50, OS=13.7m (6.6-21.4)), p=0.002 (LogRank Test); but among dMBC group, there was no significant difference in OS from BM Dx with dBM (n=9, OS=32.4m (12.9-122.5)) vs. with loBM (n=23, OS= 17.8m (6.6-NE)), p=0.885. Conclusions: In a retrospective database of patients with BM from BC, time from MBC to BM diagnosis, OS from MBC diagnosis, and OS from BM diagnosis did not differ between those with recurrent vs de novo MBC. Interestingly, in unadjusted and adjusted analyses, OS from BM diagnosis was longer for those with de novo BM diagnosed at/around MBC diagnosis than those whose BM was later in onset. Earlier-onset BM in the MBC disease course could be more sensitive to cancer-directed therapies. Studies are needed to test this hypothesis.[Table: see text]
Laparoscopic versus open hepatectomy for exophytic hepatocellular carcinoma: A multicenter propensity-matched comparative study.
Authors: Lin Kongying, Yong-Kang Diao, Bin Huang, Guo-Yue Lv, Xian-Ming Wang, Wei-Min Gu, Zhong Chen, Ying-Jian Liang, Hang-Dong Jia, Hong Wang, Ting-Hao Chen, Shi-Chuan Tang, Jia-Hao Xu, Ming-Da Wang, Feng Shen, Yong-Yi Zeng, Tian Yang
Journal: Journal of Clinical Oncology (2024)

e16268 Background: As laparoscopic hepatectomy (LH) gains traction in the surgical management of hepatocellular carcinoma (HCC), its efficacy for exophytic HCC, a subtype with unique surgical challenges, remains under scrutiny. This study aims to compare the long-term outcomes of LH with traditional open hepatectomy (OH) in treating exophytic HCC. Methods: A multicenter retrospective analysis was conducted on patients with solitary exophytic HCC undergoing LH or OH at 10 hepatobiliary centers. Propensity score matching (PSM) and inverse probability treatment weighting (IPTW) were employed to balance the LH and OH groups for overall survival (OS) and recurrence-free survival (RFS) comparisons. Multivariable Cox-regression analysis determined the independent impact of surgical approach on OS and RFS. Results: The study included 270 patients, with 132 undergoing OH and 138 LH. Post-PSM, 97 matched pairs were analyzed. In this cohort, LH was associated with significantly lower 5-year OS (36.1% vs. 53.5%, P = 0.021) and RFS (31.7% vs. 44.9%, P = 0.013) compared to OH. Additionally, LH patients exhibited a higher rate of abdominal seeding metastases (19.6% vs. 8.2%, P = 0.023). Multivariable analysis in the PSM cohort revealed LH as an independent factor for reduced OS (HR, 1.62; 95% CI, 1.06-2.47; P = 0.025) and RFS (HR, 1.79; 95% CI, 1.22-2.64; P = 0.003), corroborated by IPTW cohort findings. Conclusions: This study indicates that LH may be less favorable than OH for exophytic HCC, potentially contraindicating its use in such cases. These findings highlight the necessity for further prospective research to refine surgical protocols for exophytic HCC.
A reassessment of the clinical utility of <sup>68</sup>Ga-DOTATATE PET/CT in patients with gastroenteropancreatic neuroendocrine tumors.
Authors: Orjola Prela, Brennen Caveney, Myla S. Strawderman, Darren R. Carpizo
Journal: Journal of Clinical Oncology (2024)

e16294 Background: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a rare and biologically diverse group of tumors that can be challenging to image. Gallium-68 (Ga-68) DOTATATE positron emission tomography/computed tomography (PET/CT) is the most sensitive imaging tool for these tumors and has now been in clinical practice for over a decade. While its use has increased over time, its clinical impact remains unclear for specific stages of disease and indications for imaging. We sought to investigate this to provide information to guide its future use in clinical management. Methods: This retrospective cohort study identified adults with pathologically confirmed GEP-NETs between 1/1/2020 and 9/1/2022 at a tertiary care academic medical center. The electronic medical record was reviewed for demographic, clinical, and radiographic data. The primary objective was to determine if the use of 68 Ga-DOTATATE PET/CT was associated with a change in clinical management, medical or surgical. The secondary objective was to determine if 68 Ga-DOTATATE PET/CT was more effective in identifying primary or metastatic lesions compared to traditional imaging such as CT or magnetic resonance imaging (MRI) performed less than 90 days of the PET/CT scan. Percentages are reported with 95% Confidence Intervals (CI). Results: Overall, 124 patients with pathologically confirmed GEP NETs underwent a total of 207 68 Ga-DOTATATE PET/CT scans. The majority (92.7%) of GEP NETs were moderately/well differentiated and the primary sites included the small intestine (50%), pancreas (23.4%), appendix/colon (8.9%), gastric (8.1%), mesentery (2.4%), and unknown (7.3%). Following PET/CT scan, 51 patients (41.1%; 95% CI = 32.4-49.8) had a change in clinical management, with the proportion of patients who had a change being higher among those with metastatic disease (44.9% vs 14.5%). Of the 124, 72 patients had traditional imaging 90 days or less prior to PET/CT available for comparison. In this subgroup, 34 patients (47.2%; 95% CI = 35.7-58.7) had new lesions identified on PET/CT that were not identified using traditional imaging and of the 34 patients with new lesions identified, 79.4% (95% CI = 66-93) had a change in their clinical management. The majority of these patients had M1 disease (50% vs 15.4%). Conclusions: This study highlights the impact of 68 Ga-DOTATATE PET/CT imaging in the clinical management of patients with gastroenteropancreatic neuroendocrine tumors (GEP NETs). Notably this imaging technique resulted in a change in clinical management for 41% of these patients, particularly benefiting those with metastatic (M1) disease, where the change in management was more pronounced (44.9% vs. 14.5%). Furthermore, 68 Ga-DOTATATE PET/CT proved superior to traditional imaging revealing new lesions in 47.2% of the patients, with the majority being patients with metastatic disease.
Efficacy and safety of donafenib as adjuvant therapy for patients with hepatocellular carcinoma undergoing curative resection: A retrospective, multicenter cohort study.
Authors: Xin-Rong Yang, Sen-Quan Zhang, Zhong Chen, Zheng-Ping Yu, Sheng-dong Wu, Jia Fan, Jian Zhou
Journal: Journal of Clinical Oncology (2024)

e16234 Background: A growing incidence of hepatocellular carcinoma and its high risk of recurrence after curative-intent treatment underscore the need for effective adjuvant treatment options. This study aimed to assess the efficacy of adjuvant donafenib in patients with hepatocellular carcinoma (HCC) following radical resection. Methods: This multicenter, real-world study retrospectively gathered clinical data of 82 patients who had undergone radical resection of HCC and received adjuvant therapy with donafenib. The primary endpoint was recurrence-free survival (RFS). The secondary endpoints included overall survival (OS) and safety. Kaplan-Meier analysis was performed to evaluate RFS and OS, while the Cox proportional-hazards model was used to estimate risk factors for tumor recurrence and death. Results: A total of 82 patients with HCC who received donafenib following surgical resection were included in the study, of which were classified as high risk for tumor recurrence (with multiple or large tumor, microvascular invasion, poor tumor differentiation). The median duration of donafenib adjuvant therapy was 10.6 months (range: 0.2–26.1 months). All patients completed follow-up as required, with a median follow-up time of 19.4 months (range: 2.8–57.6 months). During the follow-up period, a totally postoperative recurrence rate was 15.9% (13/82). 1-year recurrence rate and 2-year recurrence rate were 7.3% (6/82) and 12.2% (10/82), and 1-year survival rate and 2-year survival rate were 95.1% (78/82) and 93.9% (77/82). Kaplan-Meier analysis demonstrated that patients with higher preoperative AFP level (AFP &gt; 400ng/mL), higher preoperative PIVKA-II level (PIVKA-II &gt; 40mAU/mL), or poor tumor differentiation (Edmondson stage III-IV) exhibited higher rate of tumor recurrence after operation (all p value &lt; 0.05). Multivariate analysis indicated that preoperative AFP level was an independent risk factor for tumor recurrence in patients with donafenib treatment. Treatment-related adverse events (TRAEs) occurred in 67.1% (55/82) of patients, of which the most frequent were hand-foot syndrome (25.6%, 21/82), diarrhea (20.7%, 17/82), and fatigue (17.1%, 14/82). Only 8.5% (7/82) of patients had a grade ≥3 TRAEs, with the most common being hand-foot syndrome (2.4%, 2/82) and hypertension (2.4%, 2/82). No treatment-related deaths were reported. Conclusions: This study represents the largest multicenter investigation of adjuvant therapy with donafenib to date, and the findings indicate that donafenib has the potential to be an effective treatment option for preventing postoperative recurrence in HCC. Furthermore, the preoperative AFP ≤400ng/mL can serve as an effective biomarker for postoperative administration of donafenib in HCC patients.
A phase II randomized double-blind placebo-controlled study of fisetin to improve physical function in frail older breast cancer survivors (TROFFi).
Authors: Jingran Ji, Marie Bae, Florence Lennie Wong, Catherine M Crespi, Lisa D Yee, Mina S. Sedrak
Journal: Journal of Clinical Oncology (2024)

TPS1645 Background: Among postmenopausal breast cancer survivors treated with chemotherapy, one-third experience a persistent decline in physical function even 12 months after completing treatment. This decline has been associated with loss of independence, disability, and death. One mechanism that is thought to drive chemotherapy-related decline in physical function is cellular senescence, a state of terminal growth arrest. Chemotherapy increases the burden of senescent cells (Sncs), which develop a senescence-associated secretory phenotype (SASP) that over time leads to functional decline. Preclinical mouse studies have demonstrated that eliminating chemotherapy-induced Sncs in mice led to reductions in SASP and improved physical activity. In patients with stage I-III breast cancer treated with chemotherapy, expression of p16 INK4a (p16), a known Snc marker, rapidly increased after chemotherapy and persisted over time. Higher levels of pretreatment p16 have also been associated with increased frailty in older breast cancer survivors. Novel senolytic agents have been developed to eliminate Sncs. Among existing senolytics, fisetin is a natural dietary supplement with a favorable safety profile and preclinical efficacy to reduce Snc burden and alleviate frailty in mice. There are multiple ongoing studies of this plant flavonoid in humans, but few are studying the effects of fisetin on chemotherapy-related functional decline in breast cancer survivors. Therefore, we hypothesize that targeting Sncs with fisetin after chemotherapy will improve physical function in frail older breast cancer survivors by reducing systemic Snc burden. Methods: This phase II randomized, placebo-controlled study will enroll 88 postmenopausal women with stage I-III breast cancer who experience physical functional decline after completing neo/adjuvant chemotherapy. Key eligibility criteria include being postmenopausal and within 12 months of completing neo/adjuvant chemotherapy at the time of enrollment. All participants must have evidence of physical functional decline, as measured by a 6-minute walk distance (6MWD) &lt;400 meters, prior to enrollment. Participants will be randomized 1:1 to either placebo or oral fisetin (20mg/kg) on days 1-3 of 14-day cycles for a total of 4 cycles. The primary objective is to determine the effect of fisetin on physical function, as assessed by the change in 6MWD from baseline to end of treatment. Secondary objectives include studying the effect of fisetin on quality of life and additional measures of function including fatigue, cognition, and neuropathy. We will also determine the effect of fisetin on biomarkers of aging, including circulating markers of senescence, as well as the safety of and adherence to fisetin. Enrolment on this study began March 2023 and is currently ongoing. Clinical trial information: NCT05595499 .