tbuckley/cabot-search huggingface dataset:
Sorafenib plus hepatic arterial infusion of oxaliplatin and fluorouracil vs sorafenib plus transarterial chemoembolization for advanced hepatocellular carcinoma: A biomolecular exploratory, randomized, phase III trial (SHATA-001).
Authors: Zhicheng Lai, Anna Kan, MinKe He, Zefeng Du, Ming Shi
Journal: Journal of Clinical Oncology (2024)

4113 Background: Several recent studies had demonstrated the superiority of Sorafenib/lenvatinib plus transcatheter arterial chemoembolization (TACE) over sorafenib/lenvatinib alone in advanced hepatocellular carcinoma (HCC). Herein, we compared the efficacy and safety between sorafenib plus TACE (SoraTACE) and sorafenib plus hepatic arterial infusion chemotherapy (SoraHAIC) in advanced HCC. Additionally, we validated a predictive model from our previous phase III trial (NCT02973685, cohort1). Methods: In this phase III trial (NCT02856126), patients with advanced HCC were enrolled. Eligible patients were randomly assigned (2:1) to receive Sorafenib (400mg orally twice daily) plus HAIC with oxaliplatin &amp; fluorouracil per 3 weeks or TACE (50mg of epirubicin and lobaplatin mixed with lipiodol and polyvinyl alcohol) until disease progression or unacceptable toxicity. Primary endpoint was overall survival (OS). Whole-Exome Sequencing and RNA Sequencing of tumor biopsy samples were performed for predictive biomarker exploration (cohort 1) and validation (SHATA-001). Results: Between August 4, 2016, and October 25, 2020, 207 patients were assigned to treatment (SoraHAIC, n=141; SoraTACE, n=66). Primary endpoint was met, with the median OS of 15.6 (95% CI, 12.7-18.6) months in SoraHAIC group and 11.2 (7.6-14.6) months in SoraTACE group (HR, 0.53 [0.38-0.74], p&lt;0.001). Median progression-free survival was 6.9 (5.4-8.5) months and 4.2 (2.9-5.3) months in the respective groups (HR, 0.51[0.37-0.69], p&lt;0.001). Safety analyses (n=200) showed frequencies of grade 3-4 elevated alanine aminotransferase (5% vs 21.7%; p&lt;0.001) and elevated aspartate aminotransferase (16.4% vs 35%; p&lt;0.001) significantly higher with SoraTACE than SoraHAIC. Serious adverse events occurred more frequently with SoraTACE (56.7%) than SoraHAIC (39.3%) (p=0.023). In cohort 1, we analyzed the metabolic activity of fatty acid degradation (FAD) pathway using FAD score, which was positively correlated with longer OS, especially in patients received TACE. Furthermore, we found a down regulation of FAD activity in patients enrolled in SHATA-001. And higher FAD score showed a better tumor response to SoraTACE, while FAD had no difference between responders and non-responders in SoraHAIC. Conclusions: This trial demonstrated SoraHAIC significantly improved OS over SoraTACE in patients with advanced HCC. However, patients with high FAD activity might have a better tumor response and survival benefit to SoraTACE than SoraHAIC. Clinical trial information: NCT02856126 .
Treatment landscape, outcome and quality of life in patients with pancreatic cancer: IKF642/PARAGON study.
Authors: Thorsten Goetze, Ruediger Liersch, Lars Scheuer, Thomas Göhler, Ulrich Kaiser, Claudio Denzlinger, Daniel Pink, Jan Wierecky, Jorge Klagges, Claudia Pauligk, Bianca Zäpf, Ralf-Dieter Hofheinz, Salah-Eddin Al-Batran
Journal: Journal of Clinical Oncology (2024)

4155 Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with a 5-year relative survival rate of only 13% for all stages combined (1). All treatment options available to date are options that can prolong survival and/or alleviate symptoms, but rarely cure. Therefore, it seems important to obtain more real-world data covering the entire clinical life cycle of PDAC patients, including quality of life (QoL) for all therapies used. Methods: Since November 2019 until October 2021 the multicenter, prospective, PARAGON study (NCT04119362) included patients (pts) diagnosed with PDAC planned for or recently started with neoadjuvant, adjuvant or 1st line therapy. Pts were followed during the entire course of their disease and all treatment lines for efficacy and QoL. Follow up ended June 2023. 46 German study sites participated at the study. Analysis included data on demography, comorbidities, treatments, and efficacy as well QoL (EORTC QLQ-C30). Results: PARAGON enrolled 468 PDAC pts, comprising 52% male, median age of 69 years [31- 90] with ECOG 0 to 1 in 76% at baseline. Six percent of all pts started in a neoadjuvant setting (FFX, 50%; NP-G, 38%), 32% in the adjuvant setting (FFX, 52%; gemcitabine, 28%; NP-G, 4%), and 76% in the first-line setting (NP-G, 44%; FFX, 36%; gemcitabine, 13%). 37% of all pts received 2 nd line therapy with NP-G (39,5%), NalIRI-5FU (12%) and gemcitabine (6%). 14% of all pts started a 3 rd line therapy and 4% a 4 th line therapy. The median overall survival (mOS) in the adjuvant-therapy setting was 30 months, median progression free survival (mPFS) 16 months. mOS in the 1 st line therapy was 10.0 months, mPFS 5.6 months. mOS in 2 nd line was 7.7 months, mPFS 3.0 months. Differences can be described, among others, for mOS in 1 st line FFX with 12.7 months, in NP-G with 10.7 months and in the Gemcitabine subgroup with 8.3 months. QoL data is available for all pts at baseline and throughout the further course of therapy. Results according to treatment line will be presented in detail at the meeting. Conclusions: PARAGON is the largest study on QoL and treatment landscape in PDAC so far. Data allow broad insight in real-world efficacy and QoL in the different treatment lines, regimens, and subgroups of pts. 1. American Cancer Society. Cancer Facts &amp; Figures 2024. Atlanta: American Cancer Society; 2024. Clinical trial information: NCT04119362 .
GATA6 expression in advanced pancreatic ductal adenocarcinoma (PDAC) as a prognostic and predictive biomarker in the Canadian COMPASS trial and the Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS.
Authors: Ronan Andrew Mc Laughlin, Lisa Salvatore, Diletta Barone, Yangqing Deng, Faiyaz Notta, Gun Ho Jang, Sergio Alfieri, Giuseppe Quero, Geny Piro, Carmine Carbone, Marta Chiaravalli, Maria Bensi, Cinzia Bagalà, Shawn Hutchinson, Anna Dodd, Sandra Fischer, Steven Gallinger, Jennifer J. Knox, Giampaolo Tortora, Grainne M. O'Kane
Journal: Journal of Clinical Oncology (2024)

4150 Background: Modified FOLFIRINOX (mFFX) and gemcitabine + nab-paclitaxel (GnP) are current 1 st line options in advanced PDAC. GATA6 expression, a transcription factor identifies the classical phenotype and is associated with superior overall survival (OS), low GATA6 predicts a basal-like phenotype, associated with a poorer prognosis. We have previously established high concordance between GATA6 expression by RNAseq and in situ hybridization (ISH). Recent studies suggest a survival difference between primary tumor anatomical locations, it is unknown if GATA6 expression influences this. This multicentre study evaluates GATA6 as a prognostic and predictive biomarker and determines its impact on primary tumor location. Methods: Patients were included from COMPASS and a retrospective IRCCS cohort. COMPASS participants had GATA6 by RNAseq and IRCCS cohort by ISH, all treated in 1 st line metastatic setting with mFFX or GnP. The primary endpoint was OS by GATA6 expression and by 1 st line treatment. We investigate if there are OS differences between primary tumor anatomical locations. The Kaplan Meier method was used to assess OS. The log-rank test was used to examine whether there is a significant difference between the OS in different groups. GATA6 as a predictive biomarker to response to therapy was assessed by the interaction term for GATA6 and treatment group in a Cox proportional hazards model. Results: The combined analysis included 465 pts (253 COMPASS and 212 IRCCS). Baseline characteristics were similar. The combined median age was 64 yrs (28, 84); 402 (86%) had metastatic PDAC and 63 (14%) locally advanced. 56 (12%) had prior surgery, 40 (9%) had prior adjuvant therapy. In total, 296 (64%) and 169 (36%) were GATA6 high and low respectively. OS in months (m) analyses by GATA6 expression are summarized (Table). We demonstrate no difference between OS based on primary tumor location (p=0.09), however, regardless of location, GATA6 high tumors show statistically significant better OS. We confirm, by interaction term, GATA6 as a predictive biomarker, with GATA6 high predictive of response to mFFX while low expression demonstrates less benefit with mFFX (p=0.003). Conclusions: GATA6 is a highly prognostic biomarker. We did not find an association with tumor location, which also was not prognostic in this study. Importantly GATA6 was predictive of survival in patients receiving mFFX, suggesting GATA6 low tumors should receive 1 st line GnP based regimens. Clinical trial information: NCT02750657 . [Table: see text]
Integrated genomic and transcriptomic analysis to predict FOLFIRINOX response in metastatic pancreatic ductal adenocarcinoma.
Authors: Marjolein Francisca Lansbergen, Mark Pui Gien Dings, Jan Koster, Johanna Wilmink, Hanneke W.M. Van Laarhoven, Maarten F. Bijlsma
Journal: Journal of Clinical Oncology (2024)

4153 Background: Given the lack of benefit of first-line chemotherapy (FOLFIRINOX) for a large proportion of metastatic pancreatic ductal adenocarcinoma (mPDAC) patients, predictive markers for treatment outcome are urgently needed. Previous studies showed that transcriptome-based classifiers and homologous recombination deficiency (HRD) associate with outcome in this patient group. Here, we aimed to validate the benefit of RNA and whole genome sequencing (WGS) in predicting treatment outcome in a Dutch mPDAC FOLFIRINOX-treated cohort. Methods: Patients with mPDAC who intended to start FOLFIRINOX were included in the CPCT-02 cohort. 108 patients started FOLFIRINOX and had successful WGS and RNA sequencing of their pretreatment biopsies. 51 mPDAC samples of non-FOLFIRINOX treated patients were also included in the cohort in order to explore the relation between transcriptome-based subtype and somatic mutational status with more power. Transcriptomic subtypes were established according to literature. HRD labels were derived from the previously published CHORD algorithm. Results: 88 percent of the included samples had a KRAS mutation and 82 percent had mutated TP53. The KRAS wild-type patients showed MYC amplifications, gene fusions in NTRK1, NTRK3, BRAF, NRG1, ALK, FGFR2 and RAF1, and mutations in mismatch repair proteins. Patients with a KRAS wild-type tumor had a better survival following FOLFIRINOX treatment (p = 0.009) compared to KRAS mutated tumors. No other mutations were found to be prognostic. As described before, transcriptome-based classification according to Moffitt revealed a cluster of tumors with a “Moffitt-negative” subtype, showing low expression of classical and basal-like signature genes. We found that KRAS wild-type tumors were enriched for this Moffitt negative subtype (p &lt; 0.0001), while they did not have lower tumor cellularity. The gene expression of these Moffitt negative tumors correlated with neural-like and neuroendocrine gene sets. In contrast to previous studies, we did not observe a better response to FOLFIRINOX for patients with an HRD-tumor (OS: p = 0.21, PFS: p = 0.054). We noted an increased expression for the alternative non-homologous end joining pathways in HRD samples (p = 0.049) that might have countered the advantageous effect of HRD. Conclusions: We found that KRAS wild-type tumors do not fit in the classical – basal-like classification schemes. We could not prove a significant prognostic effect for HRD. Both KRAS status and transcriptome-based subgroup were prognostic for FOLFIRINOX treatment response and should therefore be further validated for incorporation in diagnostic practice.
Differences in genomic and transcriptomic landscapes of human papillomavirus (HPV)–positive neuroendocrine neoplasms and HPV-positive carcinoma.
Authors: Emil Lou, Harris Benjamin Krause, Andrew Elliott, Marya Wahidi, Janet S. Rader, Deanna Gek Koon Teoh, Soo J Park, John Wallbillich, David Joseph Benjamin, Arash Rezazadeh, Penelope Duerksen-Hughes, Robert Morris, Radhika Gogoi, Fadi Zaiem, Thomas J Herzog, Premal H. Thaker, Matthew James Oberley, Heloisa P. Soares, Rouba Ali-Fehmi
Journal: Journal of Clinical Oncology (2024)

4127 Background: HPV is an infectious cause of several malignancies. Neuroendocrine neoplasms (NEN) are highly heterogeneous, ranging from low-grade indolent tumors to high-grade clinically aggressive carcinomas. Aside from cervical NENs, most have not traditionally been associated with HPV, but our initial studies uncovered a subset of NENs that are HPV 16/18 positive. To identify actionable differences between HPV+ NEN and non-NENs, genomic and transcriptomic landscapes were investigated. Methods: 101343 solid tumors were sequenced at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing of DNA (whole or hybrid exome) and RNA (whole or hybrid transcriptome) and assayed for HPV16/18 positivity (HPV+) via DNA sequencing. Mutation prevalence for pathogenic SNVs/indels (-Mt) and copy number amplification (CNA) were calculated. Expression of Ki-67 mRNA ( MKI67) was used to infer high grade vs low grade NEN. Gene expression profiles were analyzed for a transcriptional signature predictive of response to immunotherapy, interferon 𝛾"&gt;γ score (IFN). Differentially regulated pathways were assessed by gene set enrichment analysis (GSEA). Fisher’s exact/χ2 tests were applied as appropriate with p-values adjusted for multiple comparisons ( p &lt; .05). Results: Among all solid tumor types, rates of HPV+ were highest in cervical carcinomas (70%, 1200/1716), followed by vulvar squamous cell carcinoma (31%, 126/410) and head and neck (HN) carcinomas (28%, 668/2413), with HPV+ tumors also found in NENs (6%, 96/1620). Within NENs, the highest HPV+ rates were observed for those with a tumor origin of cervical (76%, 55/58), anorectal (AR, 27%, 29/106), female genitourinary tract (23%, 12/52) and HN (19%, 7/36). Amongst HPV+ NEN, 93% were high grade compared to 54% of HPV- NEN (p &lt; .001). Focusing on AR, cervical and HN primary sites, significant differences in the genomic landscape were observed between non-NEN v NEN tumors (Table 1). Non-NEN tumors had a significantly higher IFN compared to NEN across sites (Cervical: -0.20 v -0.61, AR: -0.33 v -0.58, HN: -0.16 v -0.54 arbitrary units, p &lt; .001 all). Non-NEN tumors at AR, cervical and HN sites were significantly enriched for several genes sets related to immune response (Interferon α/γ, TNFα/NF-κβ, IL6/JAK/STAT3 and inflammatory response). Conclusions: Our data suggest that non-NEN HPV+ tumors are enriched for gene sets related to immunotherapy response, and that HPV+ NENs have alterations that vary by anatomic site. We uncover a category of HPV+ NENs with distinct genomic and transcriptomic landscapes compared to non-NEN tumors. [Table: see text]
Long-term survival comparison of adjuvant FLOT versus XELOX chemotherapy for locally advanced gastric cancer in a large real-world cohort.
Authors: Zuoyi Jiao, Shiying Gan, Bo Long, Huinian Zhou, Zyuaun Yu, Jie Mao
Journal: Journal of Clinical Oncology (2024)

4080 Background: Recent Attraction-5 study has shown that logically advanced gastric cancer (LAGC) patients can't benefit from postoperative immunochemotherapy. The preferred adjuvant regimen for LAGC remains two-drug based chemotherapy as XELOX protocol, though three-drug based adjuvant FLOT regimen has not been well studied yet. This studyaimsto explore 10-year survival advantages of adjuvant FLOT versus XELOX regimen for LAGC. Methods: We retrospectively collected and analyzed data from 248 LAGC patients mainly composed of pathological T (pT) 3-4 stage, who received at least 4 cycles of FLOT or XELOX adjuvant chemotherapy at Lanzhou University Second Hospital from 2013 to 2018. To eliminate interference of confounding factors, we conducted a propensity score matching (PSM). The median follow-up time for all patients was 90.90 months. Results: After PSM, the median overall survival (OS) was 44.80 months in FLOT group and 34.87 months in XELOX group, with 5-year OS rate of 41.4% versus 25.3% and 10-year OS rate of 31.9% versus 11.8%. Subgroup analysis showed that patients with ECOG performance status 0 or pT3-4 stage attained significant survival benefits from adjuvant FLOT regimen. Grade 3-4 treatment-related adverse events occurred in 57.9% patients of FLOT group and 33.6% patients of XELOX group, while most of them were manageable. Conclusions: This study demonstrates that adjuvant FLOT regimen exhibits significantly long-term survival advantages for LAGC patients with good performance status and late disease stage compared with XELOX regimen, facilitating adjuvant FLOT regimen as a prospectively alternative option for LAGC.
Serial circulating tumor DNA monitoring for predicting treatment response and prognosis in patients with pancreatic cancer.
Authors: Jongchan Lee, Jinwoo Ahn, Kwangrok Jung, Jong-chan Lee, Yuna Youn, Jin-Hyeok Hwang
Journal: Journal of Clinical Oncology (2024)

4154 Background: Circulating tumor DNA (ctDNA) is considered an effective indicator for real-time monitoring of therapeutic efficacy and prognosis prediction in various malignant tumors. We conducted a study to investigate whether serial ctDNA monitoring can predict recurrence, disease progression, and prognosis in pancreatic cancer. Methods: A total of 231 with pancreatic cancer were prospectively enrolled. Among them, 167 patients (52 in the resection group, 115 in the palliative treatment group) were assessable for serial ctDNA at scheduled intervals (total ctDNA evaluations: 614). CtDNAs were analyzed using individualized droplet digital PCR to measure the mutant allele fraction of KRAS G12/13 screening multiplex Kit, with the results reported as variant allele fraction (VAF). The percent changes of ctDNA (Δ ctDNA) were correlated with radiologic response at each evaluation. Associations between ctDNA and recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS) were evaluated. Results: CtDNAs were detected in 143 of 167 eligible patients (85.6%). The detection rate increased with the advancing stage ( P= 0.016) and varied based on the metastatic site (liver: 98.0% vs. peritoneum, 88.9%; P= 0.011). In the resection group, there was no significant difference in Δ ctDNA regarding recurrence, nor were there statistically significant difference in terms of RFS and OS based on postoperative ctDNA detection. Conversely, in the palliative treatment group, patients with progressive disease (PD) exhibited significantly higher Δ ctDNA compared to those with stable disease (SD) or partial response (PR) ( P&lt; 0.001). Patients whose Δ ctDNA increased before radiologically PD had their Δ ctDNA levels increased an average of 2.53 months earlier. Notably, higher ctDNA were linked to shorter PFS (HR 1.84; 95% CI 1.07 to 3.18, P = 0.03) and OS (HR 2.15; 95% CI 1.20 to 3.86, P = 0.01) in metastatic patients. Patients who achieved ctDNA clearance at 8 weeks demonstrated more favorable outcomes in terms of PFS (HR 0.53; 95% CI 0.30 to 0.92, P = 0.02) and OS (HR 0.50; 95% CI 0.28 to 0.90, P = 0.02). Similar benefits were observed for those who experienced at least one ctDNA clearance (PFS, HR 0.27; 95% CI 0.16 to 0.44, P &lt; 0.001; OS, HR 0.31; 95% CI 0.19 to 0.50, P &lt; 0.001). Conclusions: Our findings suggest that serial ctDNA monitoring holds promise in predicting treatment response and prognosis for unresectable pancreatic cancer patients.
Cabozantinib plus atezolizumab in patients with advanced and progressive neuroendocrine neoplasms (NENs): A prospective multi-cohort basket phase II trial (CABATEN / GETNE-T1914).
Authors: Jorge Hernando, Javier Molina-Cerrillo, Enrique Grande, Marta Benavent Viñuales, Rocio Garcia-Carbonero, Alex Teule, Ana Custodio, Paula Jimenez-Fonseca, Cinta Hierro, Carlos López López, Isabel Sevilla, Marta Llanos, Alberto Carmona-Bayonas, Vicente Alonso, Javier Gallego, Inmaculada Gallego Jiménez, Alberto Orta, Fernando Franco, Alejandro García-Álvarez, Jaume Capdevila
Journal: Journal of Clinical Oncology (2024)

4128 Background: Early results with immune-checkpoint inhibitors (ICI) in NENs when used as single agents achieve limited response rates. Angiogenesis plays a key role in development and progression of NENs and synergism has been observed when antiangiogenics are combined with ICI in other tumors, whereas. We aimed to assess the efficacy and safety of cabozantinib (Cabo) plus atezolizumab (Atezo) in advanced and progressive NENs. Methods: CABATEN was a single-arm basket study using Atezo 1200 mg every 3 weeks plus Cabo 40 mg/day until progression or unacceptable toxicity in 6 NENs independent cohorts. We here focus in: well-differentiated lung neuroendocrine tumors (LungNET), pheochromocytoma paraganglioma (PPGL), well-differentiated gastroenteropancreatic (GEPNET) and grade 3 extrapulmonary neuroendocrine carcinomas (G3 EP-NEN). Primary endpoint was Overall Response Rate (ORR) by RECIST 1.1. The study had a Simon-II design. Here we present a subgroup analysis of efficacy for NENs (n=55), and for Cabo reduction using a relative dose intensity (RDI)&lt;81% threshold and 3-month interval by Landmark analysis. Baseline characteristics were analyzed in subgroups with prolonged disease stability (PFS&gt;12m or &gt;15m) Results: Median (95%CI) age was 60 (56.0, 63.0) years and 62% were male. Cabo and Atezo treatment were administered for a median of 8.7m (95%CI: 6.2-11.9) and 9.0m (95%CI: 6.8-13.5) and interrupted due to AE’s in 80.0% and 40.0% of pts respectively. Cabo was reduced to 20 mg/day in 58,2% of patients. The 12-m PFS was 50% (95%CI: 29.6-84.4) RDI&lt;81% vs 55.6% (95%CI: 39.7-77.9) RDI≥81% (p=0.9), 12-m OS was 86.7% (CI 95%: 71.1-100) RDI&lt;81% vs 84.7% (CI 95%: 72.0-99.7) RDI≥81% (p=0.6), Cox. LungNET, PPGL, GEPNET and G3 EP-NEN presented a median PFS (m, 95% CI) of 8.4 [7.7-NR], 8.4 [5.7-NR], 13 [11.2-NR] and 2.7 [2.6-NR] respectively. PFS&gt;12m subgroup had a trend towards better ECOG. PFS&gt;15m GEP-NET presented a non-significant trend towards a lower Ki67 index and less previous treatment (no chemotherapy). ORR were 15.4% (95%CI:1.9-45.5) in PPGL and 16.7% (95%CI:4.7-37.4) in GEP-NET. LungNETs and G3 EP-NEN had no responses. Duration of response (DoR) were 12.2m (5.5-19.0) and 15.8m (10.6 - 20.2) in PPGL and GEP-NET cohorts, respectively. Conclusions: Cabo and Atezo showed limited activity but achieved prolonged disease control in a small group of patients with PPGL and GEPNET but not in LungNET and G3 EP-NEN, regardless of RDI of Cabo. Clinical trial information: 2019-002279-32.