tbuckley/cabot-search huggingface dataset:
Comparative efficacy of TAS-102 and chemotherapy rechallenge in the third-line setting and beyond in patients with advanced colorectal cancer: A retrospective study.
Authors: Kanan Alshammari, Rakan Alanazi, Khalid Alotaibi, Murtada Mohamed Ali, Ahmed Abushara, Zainab Albahrani, Afrah Alsehali, Reem Almesfir, Razan Alsubaie, Mohammad Alkaiyat, Husam Shehata, Fouad Sabatin, Mohammed Ahmed Algarni
Journal: Journal of Clinical Oncology (2025)

78 Background: The optimal approach to third line therapy for patients with metastatic colorectal cancer remains a subject of debate. Options include Trifluridine/Tipiracil (TAS-102), TAS-102 with bevacizumab, regorafenib, chemotherapy rechallenge with or without an anti-EGFR agent, or fruquintinib. This study aims to evaluate the efficacy of standard of care TAS-102, TAS-102 with bevacizumab, or regorafenib versus chemotherapy rechallenge in patients with metastatic colorectal cancer in the third line setting and beyond. Methods: We conducted a retrospective analysis of patients with metastatic colorectal cancer who received either TAS-102 with or without bevacizumab, regorafenib or chemotherapy rechallenge with or without an anti-EGFR agent between 2018 and 2023, at the Ministry of National Guard for Health Affairs in Riyadh, Saudi Arabia. Patients received such agents in the third line setting and beyond. Results: A total of 75 patients were included in this study, with 39 patients receiving TAS-102 with or without bevacizumab, or regorafenib, and 36 receiving chemotherapy rechallenge. The median patient age was 58 years (range 28-81), with the majority being males at 55%. Among the chemotherapy rechallenge group, 31% were treated with cetuximab and 6% had panitumumab rechallenge, some of which were guided by cell free DNA liquid biopsy testing. In the other group, 66% received regorafenib, 26% TAS-102 alone, and 8% TAS-102 with bevacizumab. At the time of analysis, 56% of patients had passed away. Median overall survival for patients who received TAS-102 with our without bevacizumab, and regorafenib in the third line setting was found to be 13.1 months. Whereas for patients who received chemotherapy rechallenge, their median overall survival was 19.5 months. Conclusions: Patients with metastatic colorectal cancer who received chemotherapy rechallenge in the third line setting survived longer compared with patients who received TAS-102 with or without bevacizumab, or regorafenib.
The role and molecular mechanism of GDF5 in regulating cell migration and angiogenesis via the Hippo-YAP signaling pathway in colorectal cancer.
Authors: Peijie Lei, Tao Jiang
Journal: Journal of Clinical Oncology (2025)

292 Background: Distant metastasis is a leading cause of poor prognosis and mortality in colorectal cancer (CRC) patients, with angiogenesis playing a crucial role in tumor progression. The TGF-β superfamily has been shown to significantly influence tumor angiogenesis, yet the biological function and molecular mechanism of Growth Differentiation Factor 5 (GDF5), a member of this superfamily, remain unexplored in CRC. Given that the efficacy of current anti-angiogenic therapies is limited to a subset of patients, identifying new therapeutic targets involved in tumor angiogenesis is of great clinical importance. GDF5, with its potential role in angiogenesis regulation, presents a promising candidate to bridge this therapeutic gap. Methods: In this study, we analyzed GDF5 expression in CRC tissue samples using both the TCGA dataset and samples from our center, revealing significantly lower GDF5 expression in tumors compared to adjacent normal tissues. Moreover, GDF5 downregulation correlated with lymph node metastasis and disease recurrence. Functional assays in vitro demonstrated that GDF5 overexpression reduced tumor cell migration and invasion, while its knockdown produced the opposite effect. Co-culture assays showed that GDF5 knockdown significantly enhanced endothelial cell migration and angiogenesis, whereas overexpression diminished these effects. Additionally, F-actin cytoskeletal staining indicated that GDF5 overexpression led to cytoskeletal remodeling in endothelial cells. Mechanistically, we found that GDF5 overexpression in tumor cells downregulated the epithelial-mesenchymal transition (EMT) marker Slug and upregulated E-cadherin, while downregulating N-cadherin. In endothelial cells, GDF5 inhibited the Hippo-YAP signaling pathway, increasing YAP phosphorylation and reducing nuclear YAP levels. Conversely, GDF5 knockdown suppressed YAP phosphorylation and promoted its nuclear translocation. Results: Our findings demonstrate that GDF5 functions as a tumor suppressor in CRC by regulating cell migration and angiogenesis. This study reveals that GDF5 exerts its anti-cancer effects by modulating both EMT in tumor cells and cytoskeletal changes in endothelial cells, leading to the inhibition of the Hippo-YAP signaling pathway and reduced angiogenic potential. These results identify GDF5 as a promising new target for anti-angiogenic therapy in CRC, offering potential avenues for improving treatment strategies in patients resistant to current therapies. Conclusions: GDF5 acts as a tumor suppressor in colorectal cancer by inhibiting cell migration and angiogenesis through modulation of the Hippo-YAP signaling pathway, making it a promising therapeutic target for anti-angiogenic treatment in patients resistant to current therapies.
Retrospective study of fluoropyrimidine chemotherapy dosing and toxicity in patients with screen-detected deleterious <i>DPYD</i> gene variants.
Authors: Chanbormey Leatheng, Adam Ephraim, Gabriel A. Brooks
Journal: Journal of Clinical Oncology (2025)

293 Background: Fluoropyrimidine chemotherapy agents are commonly used to treat solid tumors. Fluoropyrimidines are degraded by the enzyme dihydropyridine dehydrogenase (DPD), encoded by the DPYD gene. Deleterious variants in DPYD leads to functional DPD deficiency and increased toxicity risk. Methods: We conducted a retrospective study of patients with screen-detected deleterious DPYD variants who were treated with fluoropyrimidine chemotherapy between 01/01/15-04/15/23. Outcomes of interest were initial fluoropyrimidine dosing, dose adjustments (cycles 2-6), and early toxicities. Results: We identified 12 patients with heterozygous DPYD variants, including *2A (n=5), c.2846A&gt;T (3), c.1129-5923C&gt;G (2) and *13 (2). Initial chemotherapy regimens included FOLFOX (7), mFOLFIRINOX (3) and CAPEOX (1). Of 11 patients receiving FOLFOX/mFOLFIRINOX, nine began treatment with a 50-60% reduction of the 5-FU infusion dose, one received a 25% reduction, and one received a standard dose (due to treatment initiation prior to return of the genotype result). Seven patients tolerated the initial 5-FU infusion dose without further dose reductions, including three who tolerated limited dose-escalation. Four patients required further dose reduction from the cycle 1 dose, due to toxicity. The patient who received a standard 5-FU infusion dose in cycle 1 experienced grade 3 toxicity, but tolerated subsequent treatment after 50% dose reduction. The patient treated with CAPEOX tolerated 4 planned cycles with a 50% capecitabine dose reduction. Conclusions: Most patients who screened positive for deleterious DPYD gene variants tolerated fluoropyrimidine chemotherapy with a 50% dose reduction. However, 3 of 12 patients experienced toxicity requiring treatment discontinuation or dose reduction to less than 50% of the standard 5-FU dose.
Validation of PDACai v2.0 in predicting relative benefit from frontline FOLFIRINOX (FFX) and gemcitabine/nab-paclitaxel (GA) for patients (pts) with metastatic pancreatic cancer (mPDAC).
Authors: Michael J. Pishvaian, Edik Matthew Blais, Lynn M. Matrisian, Jonathan R Brody, Dzung Thach, Patricia Miren de Arbeloa, Flavio G. Rocha, Jennifer W. Chuy, Raymond Couric Wadlow, Andrew Eugene Hendifar, Emanuel Petricoin
Journal: Journal of Clinical Oncology (2025)

776 Background: Novel biomarkers beyond genomic alterations in DDR pathway genes (e.g. BRCA1/2 ) have the potential to optimize frontline and subsequent treatment decisions for mPDAC. This real-world evidence (RWE) study validates PDACai v2.0, a machine learning framework that leverages clinical NGS data to predict progression-free survival (PFS) on FFX vs GA in individual pts with mPDAC. Methods: We analyzed outcomes from 774 pts with mPDAC who underwent genomic profiling via the Know Your Tumor program or were referred to Perthera by treating oncologists. Independent training and validation cohorts receiving either 1st line FFX or GA were split (60:40). PDACai v2.0 integrates an updated set of clinical (age &lt; 63, sex) and lab-agnostic molecular features derived from genomic testing reports (specific KRAS variants, TP53 GOF vs LOF, DDR pathway redefined). Relative benefit scores predicted by FFX or GA models were evenly binned into three PDACai signature categories representing lower, middle, and upper tertiles for each independent cohort. Statistical differences in median PFS were evaluated using ordinal Cox regression. Results: Median PFS followed PDACai predicted trends for each therapy’s training and validation cohorts. The predictive utility of PDACai was confirmed in the independent validation cohorts when comparing PFS on FFX (p = 0.01637; HR = 0.73 [95% CI: 0.56-0.94]) and GA (p = 0.0007506; HR = 0.62 [95% CI: 0.47-0.82]) across tertiles. Conclusions: Using RWE, the PDACai v2.0 signature successfully predicted PFS differences in pts treated with 1st line FFX or GA in mPDAC. Prospective validation efforts and additional data-driven insights into 2nd line PFS on FOLFOX vs 5FU/nal-irinotecan are underway. Summary of actual PFS in months on 1st line therapies in pts assigned to lower, middle, and upper thirds based on relative PDACai v2.0 scores. Independent Cohort (# Pts) Lower TertilemPFS [95% CI] Middle TertilemPFS [95% CI] Upper TertilemPFS [95% CI] 1st line FFX Training (243) 6.5 [5.5-8.1] 9.3 [6.5-13.3] 15.8 [14.1-N/R] 1st line FFX Validation (165) 9.4 [7-13.3] 8.6 [5.6-11.4] 13.2 [9.9-39.6] 1st line GA Training (218) 5.6 [4.7-6.3] 6.9 [5.2-8.2] 11.2 [8.8-13.4] 1st line GA Validation (148) 5.6 [4.2-8.4] 7.5 [6.5-13.1] 8.5 [7.7-11.5]
Real-world biomarker testing and first-line treatment patterns among locally advanced, unresectable or metastatic gastric and gastroesophageal junction adenocarcinoma patients in the US.
Authors: Lia Tzala, Maria Wellen, Tony Luu, Michelle Kathleen Gleason, Istvan Matyas Majer, Stephanie Rummans Reading
Journal: Journal of Clinical Oncology (2025)

348 Background: Advanced-stage gastric cancer and gastroesophageal junction adenocarcinoma (advG/GEJC) are leading causes of cancer-related morbidity and mortality. Chemotherapy is the traditional first-line (1L) therapy for patients in the advanced setting, with targeted and immunotherapy considered based on biomarker expression. This study aimed to describe real-world HER2 and PD-L1 testing practices and 1L treatment patterns among advG/GEJC patients. Methods: A retrospective cohort study was conducted among adult patients diagnosed with advG/GEJC between 01 Jan 2017 and 30 Jun 2023 usingthe US-based Flatiron Health electronic health record-derived de-identified database. HER2 and PD-L1 testing practices were evaluated prior to and up to 1-month post-1L treatment initiation or 6 months post-advG/GEJC diagnosis date in untreated patients. 1L treatment regimens were described overall and stratified by HER2 and PD-L1 expression. Results: Among 4,256 advG/GEJC patients, the average age was 67 years with the majority male (68%), non-Hispanic white (44%), and with metastatic disease (64%). Nearly three quarters (72%) of patients included received a HER2 test and 55% had a HER2 test with a valid result within the timeframe mentioned above. More than a quarter of patients (27%) received a PD-L1 test and 25% had a PD-L1 test with a valid result. PD-L1 testing before the approval of nivolumab in 1L (i.e. before 2021) showed testing at 19% (490/2,629; 17% with a valid result) and from 2021 onward at 40% (643/1,627; 37% with a valid result). Across the full cohort, half of the patients received chemotherapy alone (52%) and one quarter received no treatment (25%). Similar treatment patterns were observed in the subset of 1,117 patients who did not receive a HER2 or PD-L1 test; 54% received chemotherapy alone and 36% no treatment. Of the 340 patients who were tested for HER2 and were HER2 positive, half (52%) received trastuzumab combination therapy, 23% received chemotherapy alone, and 18% had no treatment. Of the 301 patients who received a PD-L1 test with a combined positive score (CPS) ≥5 from 2021 onward, 41% received immunotherapy, 34% received chemotherapy alone and 18% had no treatment. Prior to 2021, most patients with a PD-L1 test and CPS &gt;5 used chemotherapy alone (57%; 132/233), 13% (31/233) received PD-L1 targeted therapies and 19% (43/233) received no treatment. Conclusions: This study describes a potential subset of US advG/GEJC patients who do not receive a HER2 or PD-L1 test and/or do not receive eligible targeted or immunotherapy as part of routine clinical practice. As precision medicine options continue to evolve, these data suggest an opportunity to further understand the drivers for biomarker testing as well as the factors impacting the use of biomarker-informed treatment options.
Can overall survival (OS) benefit be predicted from improvements in progression-free survival (PFS) for previously untreated metastatic colorectal cancer (mCRC)?
Authors: Jeanine Roodhart, Kiran Dave, Matthew Dixon, Murat Kurt, Divya Pushkarna, Mir-Masoud Pourrahmat, Mir Sohail Fazeli
Journal: Journal of Clinical Oncology (2025)

222 Background: With improvements in treatment of mCRC, OS maintains its gold standard efficacy measure but takes longer to mature than intermediate endpoints. This study analyzed the association between treatment effects on PFS and OS using aggregate-level data from RCTs in previously untreated mCRC patients. Methods: A systematic literature review identified RCTs in previously untreated mCRC patients published from 2010–2021 reporting hazard ratios on PFS (HR PFS ) and OS (HR OS ). All treatments in comparison to chemotherapy alone or chemotherapy with anti-VEGF (bevacizumab) or anti-EGFR (cetuximab) targeted therapy were considered. Correlation between HR PFS and HR OS was evaluated using bivariate random-effects meta-analysis (BRMA) and weighted linear regression (WLR). Predictive performance of the surrogacy equations from WLR was assessed using leave-one-out cross-validation (LOOCV). Surrogate threshold effects (STE), defined as the minimum PFS benefit that would translate into a statistically significant OS benefit with 95% probability, were also derived to gauge the practical utility of the models. Primary analysis consisted of all included trials. Sensitivity analyses omitted trials that (I) had anti-EGFR medications, (II) had anti-VEGF medications, (III) violated proportional hazards assumptions, and (IV) permitted treatment crossover. Results: In the primary analysis 47 trials were included. The estimated correlation between PFS and OS was 0.67 (95% CI: 0.48–0.80) using BRMA and 0.70 (95% CI: 0.48–0.84) using WLR. The surrogacy equation derived from WLR was log(HR OS ) = −0.03 + 0.56 log(HR PFS ) with a statistically insignificant intercept and significant slope. Estimated STEs corresponding to sample sizes of 200 and 300 patients were 0.55 and 0.62, respectively. Observed HR OS ’s were within their 95% prediction intervals predicted from HR PFS for 93.6% of studies in LOOCV. Sensitivity analyses produced moderate correlations with &gt;90% coverage in LOOCV (Table). Conclusions: Moderate correlations were found between HR PFS and HR OS using both modeling approaches, highlighting the stability of the findings. Cross-validations of surrogacy equations indicated promising predictive value of PFS benefit for OS benefit in previously untreated mCRC. Analysis Set​ # of Studies​ Correlation (95% CI) STE LOOCV​Coverage Rate​ BRMA WLR N = 200 N = 300 Sensitivity Analysis I​ 34​ 0.75 ​(0.57, 0.86)​ 0.78 ​(0.55, 0.90)​ 0.55​ 0.61​ 94.1​% Sensitivity Analysis II​ 14​ 0.44 ​(-0.08, 0.77)​ 0.62 ​(-0.05, 0.90)​ 0.44​ 0.52​ 92.9​% Sensitivity Analysis III​ 36​ 0.61 ​(0.36, 0.77)​ 0.59 ​(0.26, 0.80)​ 0.46​ 0.55​ 94.4​% Sensitivity Analysis IV 43​ 0.68 ​(0.48, 0.81)​ 0.67​(0.41, 0.83)​ 0.52​ 0.60​ 93.0​%
Efficacy and safety of fruquintinib alternating with bevacizumab plus capecitabine as maintenance therapy after first-line treatment in metastatic colorectal cancer (mCRC): A multicenter, open-label, phase II study.
Authors: Wangjun Liao, Min Shi, Xiaoxiang Rong, Siting Zheng, Shaowei Li, Weiwei Peng, Xiangcai Wang, Xia Yuan, Wei Zeng, Chunlin Wang, Qiong Deng, Futing Zhang
Journal: Journal of Clinical Oncology (2025)

166 Background: Maintenance therapy with bevacizumab (Bev) plus capecitabine (Cap) is widely recommended to unresectable mCRC patients (pts). Fruquintinib (Fru) is a highly selective TKI that inhibits vascular endothelial growth factor receptor (VEGFR)-1,2,3. This study is to compare the therapeutic potential of alternating treatment with fruquintinib and bevacizumab plus capecitabine as maintenance therapy for mCRC (NCT05659290). Methods: Eligible mCRC pts aged 18-75 years with stable disease or better after induction treatment with chemotherapy in combination with Bev, ECOG PS 0-2, adequate bone marrow, liver, and renal function were enrolled. Forty patients were included (20 in phase IIa, 40 in phase IIb). In phase IIa, pts were orally administered with Fru (5 mg, qd, d1-14, q3w) alternating with Bev (7.5 mg/kg, iv.gtt, d1, q3w) plus Cap (850 mg/m 2 , orally, twice daily, d1-14, q3w). In phase IIb, pts were randomly assigned (1:1) to either maintenance treatment with Fru alternating with Bev plus Cap or Bev plus Cap. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR) and safety. Results: At cutoff date of Sep 5, 2024, In phase IIa, 20 pts (14 males and 6 females) were enrolled with the median age was 59.0 years (range 27-75), ECOG PS 1 (95.0%), liver metastasis (55.0%), left-sided colon and rectal primary (70.0%). 11 pts had received at least one tumor assessment. the DCR was 100.0% (11/11) and the mPFS was immature, but 4 pts showed the PFS of ≥ 8 months (8.3, 8.6, 9.2, 13.4 m, respectively). The most common treatment-emergent adverse events (TEAEs) were proteinuria (60.0%), hypoalbuminemia (40.0%), hypertension (35.0%); The most common grade ≥ 3 adverse events were hypertension (10.0%), proteinuria (5.0%), and platelet count decreased (5.0%). After fully considering about patient′s tolerance and safety, the phase IIb of Fru was adjusted from 5mg to 3mg, these results provided further evidence that 3mg can ensure the safety and tolerance. Conclusions: Fruquintinib alternating with bevacizumab plus capecitabine as maintenance therapy after first-line treatment in mCRC showed preliminary anti-tumor activity and manageable toxicity. The phase IIb is ongoing and warrants further exploration in mCRC. Clinical trial information: NCT05659290 .
A phase 2, multicenter, open-label study of AlloStim in-situ cancer vaccine immunotherapy as 3L therapy in MSS/pMMR metastatic colorectal cancer.
Authors: Wirote Lausoontornsiri, Wirote Lausoontornsiri
Journal: Journal of Clinical Oncology (2025)

TPS317 Background: Neoantigen therapeutic cancer vaccines have had limited clinical benefit in metastatic tumor settings. Tumor immunoediting selects tumor clones over time that are non-immunogenic. In addition, the metastatic tumor microenvironment (TME) becomes profoundly immunosuppressive. Microsatellite stable (MSS) and mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) tumors do not accumulate mutations, resulting in low mutational burden (TMB) and a lack of neoantigen targets. Consequently, therapeutic vaccine approaches for mCRC have had difficulty in demonstrating clinical effectiveness. Novel approaches that boost the immune response in low TMB tumors may benefit mCRC patients. AlloStim is an allogeneic, non-genetically manipulated, living Th1-like cell immunotherapy. The Th1-like cells are ex-vivo differentiated and expanded from healthy blood donors and activated prior to infusion. These cells are designed to be rejected upon intradermal (ID) injection. Repeated ID injections elicit high titers of allo-specific Th1 memory cells in circulation. In allo-primed patients, intravenous (IV) infusion of AlloStim causes a rejection response that releases cytokines, such as IL-12, which non-specifically activate circulating memory T cells and NK cells. Activated host memory T-cells and NK cells extravasate and traffic to metastatic tumor sites. This creates the conditions for “in-situ vaccination”. Activated NK cells cause disruption of the cell membrane and release of chaperoned neoantigens into the tumor microenvironment, a process known as immunological cell death (ICD). The release of neoantigens into the microenvironment in the context of inflammation mediated by infiltrating Th1 memory cells creates conditions for in-situ vaccination. In situ vaccination represents an alternative immunotherapy approach in which a therapeutic cancer vaccine is generated in vivo without the need to previously identify and isolate tumor neoantigens. Methods: To investigate this novel in-situ vaccine mechanism, a phase 2, multicenter, single-arm clinical trial in 3L MSS/pMMR mCRC subjects that have been previously treated with oxaliplatin-containing and irinotecan-containing chemotherapy regimens, anti-EGFR (RAS wt and left-sided) and anti-VEGF was initiated. Patients were administered weekly AlloStim in three 28-day cycles consisting of 4 ID injections and a combination ID and IV infusion on the final week in each cycle to create self-amplifying waves of allo-specific and tumor-specific host immune cells in circulation which traffic to tumors upon IV infusion. The primary end-point is overall survival. 21 evaluable patients have been enrolled and are currently being followed for maturity of the survival data. Clinical trial information: NCT04444622 .