tbuckley/cabot-search huggingface dataset:
Real-world effectiveness and safety of pembrolizumab in mismatch repair-deficient (dMMR) gastrointestinal non-colorectal tumors.
Authors: Nieves Martinez Lago, Paula Gonzalez Villarroel, Antia Cousillas Castiñeira, Begona Grana Suarez, Elena Gallardo Martin, Sara Agraso Busto, Alberto Carral Maseda, Ana Fernandez Montes, Maria Francisca Vazquez, Margarita Reboredo Lopez
Journal: Journal of Clinical Oncology (2024)

733 Background: The KEYNOTE-158 trial demonstrated durable clinical efficacy with pembrolizumab in long-term follow-up of previously treated unresectable or metastatic MSI-H/dMMR non-colorectal cancer. Our study, the GAIN study, aims to evaluate effectiveness and safety of pembrolizumab in dMMR Gastrointestinal Non-Colorectal Tumors in real-world clinical practice. Methods: We conducted a multicenter, retrospective, observational study on patients with Mismatch Repair-Deficient (dMMR) Gastrointestinal Non-Colorectal Tumors treated with pembrolizumab in real-world practice at six university hospitals affiliated with the Galician Research Group on Digestive Tumors (GiTUD) in Northwest Spain. Results: Between January 2018 and April 2023, 35 patients were enrolled. The median age was 66 years (range 33-88), with 54.3% being male. Tumor locations included 23 (65.7%) gastroesophageal adenocarcinomas, 3 (8.6%) pancreatic adenocarcinomas, 2 (5.7%) duodenal adenocarcinomas, 2 (5.7%) intrahepatic cholangiocarcinoma, 2 (5.7%) jejune adenocarcinomas, 2 (5.7%) esophageal squamous cell carcinomas, and 1 (2.8%) tumor of unknown origin. 54.3% of tumors were poorly differentiated. The most frequent alteration was the loss of MLH1-PMS2 expression (71.4%). By tumor location, 100% of gastroesophageal, jejune, and unknown origin tumors showed MLH1-PMS2 loss; while 100% of duodenal, pancreatic, and biliary tumors exhibited MSH2-MSH6 loss. All patients received pembrolizumab, with 57.1% having no prior metastatic disease treatment, 80% having ECOG PS0-1, and 31.4% having hepatic metastases. Among 33 evaluable patients, the overall response rate (ORR) was 81.8% (including 30.3% complete response) and the disease control rate (DCR) was 90.9%. Specifically, in gastroesophageal adenocarcinomas, the ORR was 81%, and the DCR was 90.5%. In the overall population, the median progression-free survival (PFS) was 34.76 months (95% CI 5.33 – 64.19 months), and the median overall survival (OS) was 39.75 months (95% CI 4.33-75.18 months). Treatment was well-tolerated; only 3 patients discontinued treatment due to nephritis, sarcoidosis-like symptoms, or diarrhea. No treatment-related deaths occurred. Conclusions: Our study underscores the real-world effectiveness of pembrolizumab in patients with dMMR Gastrointestinal Non-Colorectal Tumors. The high ORR, DCR, and favorable safety profile support its use in this challenging patient group, providing valuable real-world evidence for clinical decision-making.
Survival benefit and clinical characteristics of patients with metastatic colorectal cancer (mCRC) receiving pulmonary metastasectomy.
Authors: Javier Soto Alsar, Roberto Jiménez Rodríguez, Marianela Bringas Beranek, Natalia Gutiérrez Alonso, Rocío Martín Lozano, Irene Gonzalez Caraballo, Sara Pérez Pérez, Guillermo González Casaurrán, Andrés Muñoz, Laura Ortega Morán, Aitana Calvo, Gabriela Torres Pérez-Solero, Miguel Martin, Carlos María Simón Adiego, Pilar Garcia-Alfonso
Journal: Journal of Clinical Oncology (2024)

59 Background: The role of lung metastasectomy in mCRC remains a topic of particular controversy, being uncertain which patients benefit more from it and whether it leads to better survival outcomes. Our aim was to identify clinical and molecular differences and survival data in a cohort from a tertiary care hospital. Methods: We retrospectively analyzed 115 patients with lung metastases from colorectal cancer (CRC) in a tumor registry from 2015 to 2021, analyzing clinical and molecular characteristics, as well as overall survival (OS) data of patients who received lung metastasectomy versus patients who did not. Results: Among all patients, 36 (31.3%) received pulmonary metastases surgery. Patients undergoing metastases resection had more frequently ECOG 0 (51.4% vs 20.8%, p = 0.0011), resected primary tumor (100% vs 78.5%, p = 0.0026), metachronous metastatic disease (75% vs 46.8%, p = 0.0048) and a single metastatic location (79.4% vs 41%, p = 0.0002). In addition, none of them had BRAF mutation (0% vs 17.1%, p = 0.04); however, no statistically significant differences were found regarding KRAS, NRAS, PI3K, HER2 or presence of microsatellite instability (MSI). Patients who received lung metastasectomy had higher BMI (26.1 vs 24.4, p = 0.037) and lower mean levels of CEA (19.5 vs 142.9, p = 0.007), CA 19.9 (30.6 vs 244.9, p = 0.011) and LDH (159 vs 211.9, p = 0.018). We found an OS benefit in patients undergoing metastatic surgery (median not reached (NR) vs 41.4 months, HR for death 0.27, 95% CI, 0.14 - 0.53, p &lt; 0.000); a multivariate analysis confirmed that this benefit was independent from the characteristics mentioned above. The median progression-free survival (PFS) after metastases resection was 53.3 months. Conclusions: In our study, patients who were more likely to receive lung metastasectomy were those with ECOG 0, resected primary tumor, metachronous disseminated disease, a single metastatic location, native BRAF mutation status and low CEA, CA 19.9 and LDH levels, with a significant OS benefit associated.
Clinical presentation and delay to diagnosis and treatment in Mexican patients with gastric cancer.
Authors: Jorge Humberto Hernandez-Felix, Mónica I. Isabel Meneses-Medina, Marco Antonio Jiménez Meza, Emilio Conde Flores, Vanessa Rosas Camargo, Fidel David David Huitzil Melendez
Journal: Journal of Clinical Oncology (2024)

291 Background: Gastric cancer is the fifth leading cause of cancer-related deaths in Mexico. Diagnosis is often made at advanced stages, resulting in a poor prognosis. The delay from the onset of the first symptom to diagnosis and treatment could influence the poor prognosis of gastric cancer patients (pts) in our country. In Mexico, information on this topic is limited. We aim to investigate the time delay between the onset of symptoms, histological diagnosis, and initiation of oncological treatment in pts with gastric adenocarcinoma. Methods: We conducted a retrospective review of the clinical records at our institution of all pts with confirmed histological diagnosis of gastric adenocarcinoma (GC) treated between Jan 2005 and Dec 2017. Overall Survival (OS) was estimated using the Kaplan-Meier method. Groups were compared using Log-Rank test. Results: We included 270 pts with confirmed histopathological diagnosis of GC, 53.3% (n=144) women, median age 58 years (IQR 25-75); 44% (n=121) reported family history of cancer, 39.6% (n=107) smoking, H. pylori infection was documented in 22% (n=61). Symptoms before diagnosis were present in 98.5% (n=266) of pts, most common were: weight loss 77.4% (n=209), fatigue 51.9% (n=140), early satiety 51.1% (n=138), nausea 48.9% (n=132), vomiting 48.1% (n=130), dysphagia 21.5% (n=58), and gastrointestinal bleeding 37.8% (n=102). The most common method for histological diagnosis was endoscopy with biopsy in 86.7% (n=234). The median time between the onset of symptoms and histopathological diagnosis was 4.21 (IQR 2.25–8.48) months (m), between the onset of symptoms and the initiation of oncological treatment 5.28 (IQR 2.86–9.52) m, and between histopathological diagnosis and oncological treatment 0.60 (IQR 0.13–1.21) m. 72.6% (n=196) of cases were stage IV, 14.1% (n=38) stage III, 8.1% (n=22) stage II, 4.8% (n=13) and stage 0 or I. The median OS for the entire cohort was 7.2 m, 3.7 m for stage IV, 17.3 m for stage III, and 84 m for stage I. Median OS for stage II was not reached, and it was 58% at 5 years. Symptoms associated with worse or better survival are shown in table. Conclusions: Reducing delays in histopathological diagnosis from symptom onset could lead to earlier detection and curative treatments. Identifying alarm signs and appropriate patient navigation would enable earlier diagnosis and early treatment. [Table: see text]
Pathological complete response (pCR) to 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) with or without durvalumab (D) in resectable gastric and gastroesophageal junction cancer (GC/GEJC): Subgroup analysis by region from the phase 3, randomized, double-blind MATTERHORN study.
Authors: Yelena Y. Janjigian, Salah-Eddin Al-Batran, Zev A. Wainberg, Eric Van Cutsem, Daniela Molena, Kei Muro, Woo Jin Hyung, Lucjan S. Wyrwicz, Do-Youn Oh, Takeshi Omori, Markus Moehler, Marcelo Garrido, Sulene CS Oliveira, Moishe Liberman, Victor Castro Oliden, Mehmet Bilici, John F. Kurland, Ioannis Xynos, Helen Mann, Josep Tabernero
Journal: Journal of Clinical Oncology (2024)

LBA246 Background: FLOT was established as a perioperative therapy for GC/GEJC following the Phase 2/3 FLOT4 study conducted in Germany, with a pCR rate of 16% (Al-Batran et al, Lancet Oncol 2016). The global MATTERHORN study (NCT04592913) showed a statistically significant improvement in pCR with perioperative D + FLOT vs placebo (P) + FLOT in GC/GEJC at first interim analysis (Janjigian et al, ESMO Congress 2023). Subgroup analyses by region and country were completed to assess pCR rates with FLOT and benefit of D + FLOT across the global study population. Methods: Participants (pts) with resectable GC/GEJC were randomized 1:1 to D 1500 mg or P every 4 weeks (Q4W) on Day 1 plus FLOT Q2W on Days 1 and 15 for 4 cycles (2 doses of D or P and 4 doses of FLOT pre- and post-operative), followed by D 1500 mg or P on Day 1 Q4W for 10 further cycles. Randomization was stratified by Asia vs non-Asia. pCR (Modified Ryan; central review) was assessed in prespecified (Asia) and post hoc regional subgroups, including 6 countries with the highest numbers of randomized pts. Results: Of 948 pts randomized globally, 180 pts (19%) were in Asia. pCR outcomes with FLOT in Asia were consistent with the global outcomes. pCR rates were improved with D + FLOT vs P + FLOT in all regions (Asia, Europe, North America and South America; Table), despite some imbalances in baseline characteristics and numerical differences in pCR rates by geographic location. The pCR rate with P + FLOT in the German subgroup (13%; 95% CI, 6.1–23.0) was similar to that with FLOT in the FLOT4 study. Improvement in pCR with D + FLOT vs P + FLOT was observed across subgroups by country. Similar trends across regional subgroups were observed for combined complete and near-complete response rate. Conclusions: In MATTERHORN, pCR was consistently improved with the addition of D to perioperative FLOT in GC/GEJC across geographic regions. The study is ongoing for the primary objective of event-free survival. Clinical trial information: NCT04592913 .[Table: see text]
The prognostic significance of extramural venous invasion detected via contrast-enhanced computed tomography colonography in colon cancer.
Authors: Takeharu Kato, Shunsuke Tsukamoto, Hiroshi Nagata, Yasuyuki Takamizawa, Konosuke Moritani, Yukihide Kanemitsu
Journal: Journal of Clinical Oncology (2024)

167 Background: The precise effects of extramural venous invasion (EMVI) and Spiculation on colon cancer recurrence remain poorly understood. This study investigated the clinical significance of ctEMVI and ctSpiculation as diagnosed via preoperative contrast-enhanced CT colonography (CTC) using three-dimensional multiplanar reconstruction (3D MPR) images. Methods: Patients with stage I–Ⅲ colon cancer (T2 or deeper) diagnosed via CTC at the National Cancer Center Hospital in Japan between 2013 and 2018 were retrospectively evaluated for ctEMVI and ctSpiculation, diagnosed by two observers using 3D MPR images of slices 0.5 mm thick. The interobserver reliability was assessed with Cohen’s kappa statistic, and recurrence-free survival (RFS) was analyzed using Kaplan–Meier curves. Preoperative clinical factors were subjected to Cox regression analysis in relation to RFS. Results: Of 922 patients, 544 eligible cases were analyzed. There were 50 (9.2%) ctEMVI-positive cases and 494 (90.8%) ctEMVI-negative cases, along with 186 (34.2%) ctSpiculation-positive cases and 358 (65.8%) with negative findings. Kappa coefficients for ctEMVI and ctSpiculation were 0.830 and 0.718, respectively. Kaplan–Meier analysis and log-rank tests demonstrated lower RFS in ctEMVI- and ctSpiculation-positive cases (p&lt;0.001). In multivariable analysis, ctT4 (HR 2.95, 95% CI 1.73–5.02) and ctEMVI (2.97, 1.81–4.87) were independent factors associated with RFS. When stratifying TNM stages based on ctEMVI status, in N(+) (i.e., Stage III), ctEMVI-positive group had worse prognoses than negative group (5-year RFS rates; 52.0% vs. 78.5%, p=0.003). Similarly, in N(–) (i.e., Stage I and II), T3N0EMVI(+) cases had significantly worse prognoses than T3N0EMVI(–) and Stage I cases (50.6% vs. 89.3% and 90.1%) and were comparable to the T4N0 group (50.6% vs. 46.7%, p=0.844). Conclusions: Both ctEMVI and ctSpiculation are associated with RFS. ctEMVI is an independent predictor of recurrence and may be valuable in combination with preoperative TNM staging to identify patients at high risk for recurrence. [Table: see text]
An open-label, multicenter study investigating RP3 oncolytic immunotherapy in combination with first- or second-line systemic atezolizumab plus bevacizumab in patients with locally advanced unresectable or metastatic hepatocellular carcinoma.
Authors: Kevin Kim, Anwaar Saeed, Davendra Sohal, Julien Edeline, Jeong Heo, Aditya Bhansali, Shaheen Kumar, Guy Ungerechts
Journal: Journal of Clinical Oncology (2024)

TPS576 Background: Despite advances in treatment for unresectable hepatocellular carcinoma (HCC), long-term survival rates remain poor. The combination of atezolizumab (Atezo) plus bevacizumab (Bev) is approved frontline therapy for advanced HCC, but a minority of patients (pts) respond and secondary resistance usually occurs within months. HCC has an immune-suppressed tumor microenvironment (TME), mediated by activated immune checkpoint signaling and angiogenesis pathways, which may contribute to therapeutic resistance. RP3 is a genetically modified herpes simplex virus type 1 (HSV-1) that expresses the fusogenic gibbon ape leukemia virus glycoprotein with the R sequence deleted (GALV-GP-R–), an anti–CTLA-4 antibody-like molecule, CD40 ligand, and 4-1BB ligand. The direct oncolytic effect coupled with immune stimulation by RP3 in the TME is intended to provide systemic antitumor activity and synergize with anti–PD-1/PD-L1 agents, such as Atezo. Preclinical data have demonstrated improved distribution of oncolytic HSV within tumors in combination with Bev, supporting the clinical combination of RP3 with Bev. This study will evaluate the safety and efficacy of RP3 combined with Atezo plus Bev as first- (1L) and second-line (2L) systemic therapies for unresectable and advanced HCC (NCT05733598). Methods: The 1L and 2L cohorts will each enroll up to 30 pts. Pts in the 1L cohort may not have received prior systemic treatment; pts in the 2L cohort must have progressed on or following 1 prior line of systemic therapy, which must have included a PD-1/PD-L1–directed agent. Key inclusion criteria include advanced unresectable HCC with ≥1 measurable tumor of ≥1 cm in longest diameter, Child-Pugh class A, and an Eastern Cooperative Oncology Group performance status of 0 to 1. Key exclusion criteria include untreated esophageal and/or gastric varices with bleeding or at high risk for bleeding and macroscopic invasion of the tumor into any major blood vessel(s) and/or main bile ducts. Pts with a history of medically refractory hepatic encephalopathy and/or hepato-renal syndrome are also excluded. Pts in the 1L cohort will receive Atezo 1200 mg and Bev 15 mg/kg every 3 weeks (Q3W) together with RP3 intratumorally Q3W for a total of up to 8 doses. Pts in the 2L cohort will receive RP3 every 2 weeks for 4 doses with Bev Q3W starting on cycle (C)1 day (D)1, then RP3 and Bev Q3W for up to 4 more doses with Atezo Q3W being added on C4D1. The primary endpoint is the overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary endpoints are safety, ORR using HCC modified RECIST, duration of response, complete response rate, and progression-free survival. Clinical trial information: NCT05733598 .
Trifluridine/tipiracil (TAS-102) in combination with anti-EGFR re-challenge versus TAS-102 plus anti-VEGF in patients with mCRC who experienced first-line anti-EGFR-based chemotherapy.
Authors: Ching Tso Chen, Yi-Hsin Liang, Kun-Huei Yeh
Journal: Journal of Clinical Oncology (2024)

120 Background: TAS-102 is one of the standard treatments for refractory metastatic colorectal cancer (mCRC). Add-on bevacizumab to TAS-102 has been proved to improve progression-free survival (PFS) and overall survival (OS). However, the two strategies of combination with anti-EGFR or anti-VEGF in RAS/RAF wild-type mCRC patients have not been compared. Methods: We retrospectively collected mCRC patients who received TAS-102 treatment from December 2018 to March 2023 at National Taiwan University Hospital. The key inclusion criteria included RAS/RAF wild-type, first-line treatment with anti-EGFR therapy, and TAS-102 in combination with anti-EGFR re-challenge, or with anti-VEGF therapy. Concurrent use of other chemotherapies was allowed. The patients with combination duration less than 4 weeks were excluded. Results: A total of 30 patients were enrolled. There were 20 patients who received TAS-102 plus anti-EGFR re-challenge, and 10 were treated with TAS-102 plus anti-VEGF. The median treatment line of TAS-102 combined with targeted therapies was 5 (Range 3-11). There was no significant difference in baseline characteristics between the two groups (Table). For TAS-102 plus anti-EGFR vs VEGF, the ORR was 30.0% vs 0%, and the DCR was 70.0% vs 30.0%, respectively. The median PFS was 4.0 vs 2.3 (p=0.389) months, respectively. The median OS was 12.67 vs 9.93 (p=0.722) months, respectively. Conclusions: TAS-102 plus anti-EGFR re-challenge showed a higher ORR than TAS-102 plus anti-VEGF. The PFS and OS were comparable in both arm and numerically longer in the TAS-102 plus anti-EGFR re-challenge group.[Table: see text]
Characterizing the genomic landscape of locally advanced pancreatic cancer.
Authors: Galileo Arturo Gonzalez Conchas, Grainne M. O'Kane, Robert Edward Denroche, Gun Ho Jang, Sandra Fischer, Anna Dodd, Sarah Louise Picardo, Spring Holter, Julie Wilson, George Zogopoulos, Elena Elimova, Rebecca M. Prince, Raymond Woo-Jun Jang, Malcolm J. Moore, James Joseph Biagi, Faiyaz Notta, Robert C Grant, Steven Gallinger, Erica S Tsang, Jennifer J. Knox
Journal: Journal of Clinical Oncology (2024)

697 Background: Locally advanced pancreatic cancer (LAPC) accounts for approximately 30% of pancreatic ductal adenocarcinomas (PDAC). Optimal management for LAPC is controversial and combination treatments are extrapolated from treatment guidelines for metastatic disease. The biological underpinnings of LAPC remain unclear, although the loss of tumor suppressor SMAD4 has been associated with metastatic disease. Here we characterize the genomic landscape of LAPC in a large series of prospectively sequenced PDAC. Methods: Clinical, genomic and survival data were obtained from the COMPASS trial (NCT02750657), a prospective multi-institutional study that included patients with treatment-naïve advanced PDAC, with predominantly metastatic cases due to ease of biopsy. Fresh tumor tissue was acquired by percutaneous core biopsy for real-time whole genome sequencing (WGS) and RNA sequencing (RNAseq). Laser capture micro-dissection was performed for all cases. Response to therapy was assessed every 8 weeks, and patients were followed prospectively. Results: Of 268 patients (268 with available WGS and 253 with RNAseq), 37 (14%) had LAPC. Baseline epidemiological variables were similar, with no differences between sex, age, smoking status, or history of diabetes. Patients with LAPC had a lower BMI (median 22 vs 24, p=0.005) and lower baseline CA19-9 (median 488 vs 2551, p=0.002) than metastatic cases. All patients with LAPC had a low (&lt;2 points) Gustave Roussy Immune Score, previously shown to be prognostic in our dataset. Driver alternations were similar in LAPC and metastatic cases with no differences in SMAD4 loss between the two groups; however, major imbalances in mutant KRAS were absent in the LAPC group. The burden of SNVs, indels and SVs was significantly lower in LAPC (Table). All LAPC cases demonstrated a classical RNA subtype, compared to 23% in metastatic cases ( p=0.0008). Median OS measured 12.5 and 8.3 months for LAPC and metastatic cases, respectively (HR 0.65, 95% CI 0.48-0.89, p=0.003). In addition, when measuring CD8+ T cell infiltration by IHC using median cut-off values, primary site biopsies had a higher CD8+ T cell infiltrate compared to metastatic sites (77% vs 56% CD8-high, respectively, p=0.01). Conclusions: These integrated genomic, RNA subtyping and early immunophenotyping results suggest that LAPC demonstrate less genomic instability and classical programming. Further study will delineate how these genomic differences, along with better clinical features, may influence treatment decision-making and design of future clinical trials. Clinical trial information: NCT02750657 . [Table: see text]
Neutrophil-to-lymphocyte ratio to predict metachronous cancer after curative resection of early gastric cancer.
Authors: Sunsuk Kim, Moon Kyung Joo, Jong-Jae Park, Chan Mi Kwon, Jun Hee Kim, Ji Min Kang, Min Hyung Kang, Si Eun Lee, Won Shik Kim, Seung Han Kim, Beom Jae Lee, Hoon Jai Chun
Journal: Journal of Clinical Oncology (2024)

313 Background: We investigate the predictive value of inflammatory markers for occurrence of metachronous cancers among patients who underwent endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) and are judged as curative resection (CR). Methods: We enrolled patients who were diagnosed as EGC and underwent ESD during 2006 and 2020. We retrospective collected data of inflammatory indexes such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and erythrocyte sediment ratio (ESR). Results: A total of 1,011 patients underwent ESD for EGC, achieved CR and were followed up more than 12 months. Among them, 86 patients had metachronous cancers (85/1011, 8.4%) during 53.4 months of follow-up. Compared with patients without metachronous cancers, those with metachronous cancers were significantly older (66.9 vs. 63.8 years, P=0.004) and had higher NLR (2.1 vs. 1.8, P=0.002), however, other inflammatory indexes such as PLR and ESR were not significantly different between two groups. Kaplan-Meier analysis showed that patients with NLR ≥ 2.0 had significantly higher possibility of metachronous cancer compared with patients with NLR &lt; 2.0 ( P=0.049 by log rank test). After adjusting age, atrophy and Helicobacter pylori status, NLR was the only significant risk factor for metachronous cancer (odds ratio: 1.33, 95% confidence interval: 1.007-1.665, P=0.011). Conclusions: NLR may have a predictive value for occurrence of metachronous cancer after CR of EGC by ESD. Further thorough investigation is necessary to validate this outcome.