tbuckley/cabot-search huggingface dataset:
The prognostic impact of <i>SLFN11</i> gene expression in metastatic colorectal cancer (mCRC).
Authors: Hiroyuki Arai, Yan Yang, Joshua Millstein, Karam Ashouri, Fang-Shu Ou, Federico Innocenti, Francesca Battaglin, Sandra Algaze, Shivani Soni, Wu Zhang, Alan P. Venook, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2025)

254 Background: SLFN11 was recently identified as a dominant determinant of response to DNA-damaging anticancer agents. Several studies showed SLFN11 expression led to better sensitivity to topoisomerase inhibitors and PARP inhibitors. However, clinical evidence in mCRC has been lacking. Methods: Two independent cohorts (CALGB/SWOG 80405 trial and a real-world patient [Caris CODEai] cohort) were included in this study. Patients were stratified into SLFN11 -high and -low groups based on the median SLFN11 gene expression levels. Survival outcomes were compared between SLFN11 -high and SLFN11 -low in irinotecan-treated and oxaliplatin-treated patients. Median time was estimated using Kaplan-Meier method and Cox models were used for covariate adjustment. Endpoints of interest were progression-free survival (PFS) and overall survival (OS). Results: In the CALGB/SWOG 80405 trial cohort, 433 patients were included (110 treated with FOLFIRI-based chemotherapy and 323 treated with FOLFOX-based chemotherapy). In patients treated with FOLFIRI-based chemotherapy, SLFN11 -low patients exhibited numerically better PFS (median PFS, 13.4 vs 11.2 months, log-rank p = 0.03, adjusted hazard ratio [HR] = 0.86, 95% confidence interval [CI] 0.55-1.39, p = 0.50) and OS (median OS, 39.6 vs 30.3 months, log-rank p = 0.02, adjusted HR = 0.73, 95% CI 0.46-1.16, p = 0.19) compared to SLFN11 -high patients. In patients treated with FOLFOX-based chemotherapy, SLFN11 -low patients exhibited numerically better PFS (median PFS 11.2 vs 9.8 months, log-rank p = 0.03, adjusted HR = 0.83, 95% CI 0.65-1.05, p = 0.12) and OS (31.1 vs 26.1 months, log-rank p = 0.07, adjusted HR = 0.84, 95% CI 0.65-1.08, p = 0.16) compared to SLFN11 -high patients. No significant interaction was observed between treatment and SLFN11 expression in terms of PFS ( p = 0.69) and OS ( p = 0.44). In the Caris CODEai cohort, a better OS in SLFN11 -low patients than in SLFN11 -high patients was observed in irinotecan-treated patients ( N = 2906) (median OS, 25.5 vs 21.7 months, HR = 0.90, 95% CI 0.82-1.00, p = 0.048). However, no significant difference in OS between SLFN11 -low and SLFN11-high was observed in oxaliplatin-treated patients ( N = 4428) (median OS, 39.5 vs 35.8 months, HR = 0.98, 95% CI 0.90-1.06, p = 0.56). Conclusions: Low SLFN11 expression showed a potential for better prognosis in mCRC patients receiving irinotecan- and oxaliplatin-containing chemotherapies. These findings are not consistently aligned with preclinical data and clinical evidence in other cancer types previously reported. Further investigation is warranted to better understand the biological role and clinical implication of SLFN11 in mCRC.
Adjuvant capecitabine in resected biliary tract cancers: Real life data from a multicenter study (PRODIGE83-ACABi-PRONOBIL).
Authors: Anthony Turpin, Claire Noe, Brice Chanez, Dewi Vernerey, Thierry Lecomte, Thomas Walter, Eric Assenat, Julien Edeline, Alexandra Heurgue, David Tougeron, Sylvain Manfredi, Vincent Hautefeuille, Cindy Neuzillet, Gael Roth, Jean-Paul Lagasse, Christophe Tournigand, Aude Guillemin, Antoine Hollebecque, Julie Henriques, Pauline Parent
Journal: Journal of Clinical Oncology (2025)

596 Background: Biliary tract cancers (BTCs) are rare and heterogeneous tumors with a poor survival even in early-stage patients treated with a curative surgery. Since 2019 the current standard of care in the adjuvant setting is oral chemotherapy (CT) with capecitabine for 6 months, as an option following BILCAP phase III trial results. Nevertheless, outside of this trial, real-world data are lacking. Methods: We conducted a French, retrospective, multicenter study from the ACABi-PRONOBIL cohort. Eligible patients had intrahepatic, perihilar, distal cholangiocarcinoma or gallbladder carcinoma treated by surgery with curative intent without prior therapy. Two groups were compared, patients who received capecitabine (Cape group) as adjuvant CT and patients without adjuvant treatment before 2017 (surveillance group). The primary endpoint was overall survival (OS). Secondary endpoints were disease-free survival (DFS) and toxicity. Results: 324 patients were included, 200 in the Cape group and 124 in the surveillance group. The median OS was 43.5 months (CI95%= 35.4-48.0) and 44.6 months (CI95% 37.7-54.8) in the Cape and surveillance group, respectively. ECOG performance status ≥ 2, pT3 stage, vascular and node invasion were associated with a poorer OS. The DFS was 15.8 months (CI95%= 14.1-20.3) in the Cape group and 13.3 months (CI95%= 10.1-17.5) in the surveillance group. In inverse probability of treatment weighting (IPTW) analysis we observed a significant statistical association between Cape group and DFS (IPTW HR (CI95%) Cape group vs surveillance group = 0.76 (0.60-0.96), pvalue=0.0224) but not with OS. In the Cape group, 49% of patients had at least one dose reduction, 35% had to discontinue treatment due to toxicity (mainly gastrointestinal,13.3% of grade 3-4; and cutaneous, 27% of grade 3-4). Conclusions: In this retrospective analysis, adjuvant capecitabine appears to increase DFS without statistically significant impact on OS in patients undergoing surgery for BTC, confirming in real life the BILCAP study results.
Randomized phase II trial of olaparib + pembrolizumab vs olaparib alone as maintenance therapy in patients with metastatic pancreatic cancer with germline BRCA1 or BRCA2 mutations: SWOG S2001 NCT04548752.
Authors: Vincent Chung, Katherine A. Guthrie, Michael J. Pishvaian, Andrew M. Lowy, Davendra Sohal, Kim Anna Reiss, Nina Niu Sanford, Carmen Allegra, Sarah Colby, Eileen M. O'Reilly, E. Gabriela Chiorean, Philip Agop Philip
Journal: Journal of Clinical Oncology (2025)

TPS793 Background: Olaparib was approved in 2019 as maintenance therapy for gBRCA1/2+ metastatic pancreatic cancer (mPDA) patients (pts). The POLO trial showed an improvement in median progression-free survival (mPFS) with olaparib compared to placebo (7.4 vs 3.8 months) for platinum sensitive gBRCA1/2+ mPDA pts. Preclinical studies have demonstrated that PARP inhibitors modulate the immune microenvironment by increasing genomic instability, PD-L1 expression and activating the immune inflammatory stimulator of interferon genes (STING) pathway. Results of the phase 2 pembrolizumab and olaparib (POLAR) maintenance trial in patients with germline or somatic BRCA1/2 or PALB2 mutations responding to platinum-based chemotherapy for at least 4 months was presented at ESMO 2024. In 33 patients, a 35% overall response rate with 90% disease control rate at 6 months was observed. S2001 is an important randomized study to better define the impact of the combination. Methods: S2001 was developed in collaboration with the Alliance and was activated in SWOG in October 2020. Key eligibility criteria include: mPDA pts with gBRCA1/2 mutations identified with standard of care germline genetic testing and progression-free after receiving at least 4 months of platinum-based chemotherapy (FOLFIRINOX, FOLFOX or gemcitabine/cisplatin +/- nab-paclitaxel). One cycle of gemcitabine and nab-paclitaxel is allowed while waiting for germline testing. Zubrod performance status (PS) 0 or 1 pts are eligible. Pts are stratified according to first line chemotherapy, PS 0 vs 1, and disease status after 1st line treatment. The primary objective of this study is to evaluate the PFS of mPDA pts treated with olaparib + pembrolizumab compared to olaparib alone as maintenance therapy. Based upon the POLO trial, we expect a mPFS of 7 months in the control arm. Targeting a mPFS of 11.7 months in the experimental arm (hazard ratio 0.6) and assuming 15 months follow-up, 80% power and a 1-sided alpha = 0.10, this design requires 78 evaluable pts with a total sample size of 88 pts. Prospective serial blood samples will be collected to bank DNA and RNA for future correlative studies. Support: NIH/NCI grants U10CA180888 and U10CA180819, U10CA180821 and U10CA180868. Clinical trial information: NCT04548752 .
The use of liquid biopsy comprehensive genomic profiling to identify the molecular landscape of patients with metastatic colorectal cancer who are candidates for anti-EGFR rechallange therapy: Findings from the CAVE-2 GOIM trial.
Authors: Stefania Napolitano, Luca Boscolo Bielo, Giulia Martini, Filippo Pietrantonio, Salvatore Pisconti, Andrea Sartore-Bianchi, Livio Blasi, Giampaolo Tortora, Alberto Zaniboni, Carmine Pinto, Giuseppe Santabarbara, Antonio Avallone, Silvana Leo, Claudio Lotesoriere, Tiziana Latiano, M. Giulia Zampino, Erika Martinelli, Teresa Troiani, Fortunato Ciardiello, Davide Ciardiello
Journal: Journal of Clinical Oncology (2025)

221 Background: In the era of precision medicine, biomarker guided therapies are necessary for patients with chemorefractory metastatic colorectal cancer (mCRC). Circulating tumor DNA (ctDNA) comprehensive genomic profiling (CGP) may contribute to the development of more effective treatments. Methods: CAVE-2 GOIM trial (ClinicalTrials.gov ID: NCT05291156) is the first randomized phase II study to assess the efficacy of avelumab plus cetuximab compared to cetuximab alone as rechallenge strategy in pre-treated plasma ctDNA RAS, BRAF WT mCRC patients. Before being enrolled in the trial, patients were selected by baseline plasma ctDNA analysis by Foundation One Liquid CDx (F1L CDx) 324 genes to identify ctDNA RAS/BRAF WT cases. Results: As of July 31th 2024, 229 (out of approximately 310) patients have been screened. A total of 1562 pathogenic variants (PV) were detected, with TP53 (86.0%), APC (84.2%), DNMT3A (30.5%) representing the most common altered genes. In these anti-EGFR pretreated patients different acquired mechanisms of resistance were observed. In particular, 72/229 (31.4%) patients had RAS or BRAF V600E PV (102 KRAS , 21 NRAS and 8 BRAF V600E mutations, respectively). Additionally, in these 72 patients, multiple RAS/BRAF V600E gene alterations (median of 1 PV, range 1-7) were observed in 41.6% cases. MAPK, RTK , and PI3K/AKT/mTOR PV were detected in 43.2%, 24.5% and 24.5% patients, respectively. Of note, the variant allele frequency of resistant PV was lower than other gene alterations, suggesting a high tumor heterogeneity as a consequence of the development and/or expansion of EGFR-inhibitor resistant cancer cell sub-clones. All patients were assessed for tumor mutational burden (TMB). Median TMB was 6 (IQR 4-10) mut/Mb, with 29.6% cases showing a TMB ≥10 mut/Mb. Finally, a total of 258 actionable genomic alterations were detected in 52,4% of patients according to the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT). Eighty-one tier I alterations were detected in 32.3% patients, which included TMB high (29,7%), BRAF V600E (3,5%), KRAS G12C (6,5%), and RET fusions (0,4%). Conclusions: These findings support liquid biopsy-based GCP for individualized therapeutic choices in chemorefractory mCRC. Up-dated final analyses of the entire screened patient population of the CAVE-2 GOIM trial will be presented. Clinical trial information: NCT05291156 .
VEGF-A as a prognostic indicator in advanced gastric and colorectal cancers and correlation with immune suppression involving myeloid-derived suppressor cells (MDSC).
Authors: Masahiko Shibata, Koji Kono, Seiichi Takenoshita
Journal: Journal of Clinical Oncology (2025)

250 Background: VEGF-A is important molecule should be controlled in cancer treatment since hypoxic and immunosuppressive conditions of tumor microenvironment are induced by VEGF-A. Myeloid-derived suppressor cells (MDSC), activated by chronic inflammation and VEGF-A, play critical roles in immunosuppression in patients with cancer. Methods: Serum levels of VEGF-A were measured by ELISA and circulating levels of MDSC were measured by Flow Cytometry (CD11b+, CD14-, CD33+). Patients with gastric and colorectal cancers were divided into two groups, high VEGF group (serum VEGF-A&gt;330pg/ml) and lo group (≤330pg/ml). Results: Prognosis of stages III and IV gastric cancer with high VEGF-A was significantly worse than in low VEGF-A group, while difference was not significant in stages I and II. In colorectal cancer, the results were exactly same as found in gastric cancer. The levels of MDSC were significantly correlated with the levels of VEGF-A in patients with gastric and colorectal cancers. The levels of VEGF-A were also correlated with inflammatory markers including CRP and NLR (neutrophil to lymphocyte ratio), and inversely did to stimulation index of lymphocyte proliferation (SI: parameter of cellular immune reaction) and nutritional parameters such as albumin or rapid turnover protein. Conclusions: The observation in the present study suggest that VEGF-A is closely associated with inflammation-associated disease progression especially in advanced stages, and serve as useful marker of immunosuppression involving MDSC and prognosis in patients with gastric and colorectal cancers.
Seven-year efficacy and safety in a randomized phase III trial investigating duration of adjuvant oxaliplatin-based therapy (3 vs. 6 months) for patients with high-risk stage II colon cancer: ACHIEVE-2 trial.
Authors: Eiji Sunami, Kentaro Yamazaki, Manabu Shiozawa, Dai Manaka, Masahito Kotaka, Yasuhiro Sakamoto, Akio Shiomi, Yudai Shinohara, Yoshinori Munemoto, Toshiki Rikiyama, Mutsumi Fukunaga, Takashi Ueki, Kohei Shitara, Jun Yamada, Nobuyuki Tanida, Toshihiro Misumi, Atsushi Ohtsu, Yoshihiko Maehara, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2025)

169 Background: ACHIEVE-2 was conducted as one of four phase III trials for patients with high-risk stage II colon cancer (CC) investigating the duration of adjuvant (adj) oxaliplatin-based therapy in a prospective pooled analysis, IDEA collaboration. The results of the 7-year follow-up are presented here. Methods: From Feb 2014 to Jan 2017, 525 Asian patients with high-risk stage II CC (T4, inadequate nodal harvest, poorly differentiated, obstruction, perforation, or vascular invasion) were randomly assigned to 3- or 6-month mFOLFOX6/CAPOX treatment after curative surgery. The cutoff date for the data was Jan 2024. Results: Of the 525 randomized patients, 11 were not treated. Among the 514 participants (255 in the 3-month arm; 259 in the 6-montharm), 432 (84%) received CAPOX and 184 (36%) presented with T4 as a high-risk factor for recurrence. The baseline characteristics of the patients in each arm were well balanced between the treatment arms and two therapy regimens. The 7-year disease-free survival (DFS) rates were 83.4% and 81.8% in the 3- and 6-month arms, respectively (hazard ratio [HR]= 1.00 [95% CI, 0.66-1.53]). The 7-year overall survival (OS) rates were 88.4% and 88.8% in the 3- and 6-month arms, respectively (HR= 1.16 [95% CI, 0.70-1.93]). With CAPOX, the HR for DFS and OS of the 3-month arm compared with the 6-month arm were 0.97 (95% CI, 0.61-1.52) and 1.09 (95% CI, 0.64-1.89), respectively. Multivariate analysis of the six high-risk factors for recurrence showed that T4 and inadequate nodal harvest were independent risk factors for both DFS and OS. The rates of any grade of peripheral sensory neuropathy (PSN) lasting up to 96 months in the 3- vs. 6-month arms were 7.9% vs. 25.0% ( P= 0.0189 ). With CAPOX, the incidence of PSN lasting up to 96 months in the 3- vs. 6-month arms were 9.4% vs. 27.5%. Conclusions: The incidence of long-lasting PSN was significantly lower at 3 months than at 6 months of therapy. Three months of CAPOX therapy may be appropriate for high-risk stage II CC, as shorter treatment did not worsen the outcome, even after a long follow-up. Clinical trial information: UMIN000013036 .
A liquid biopsy analysis of exosomal miRNA to detect lymph node metastasis in early gastric cancer.
Authors: Masaaki Nishi, Yuma Wada, Chie Takasu, Toshiaki Yoshimoto, Daichi Ishikawa, Hideya Kashihara, Takuya Tokunaga, Mitsuo Shimada
Journal: Journal of Clinical Oncology (2025)

469 Background: Additional surgical resection is required to achieve a complete cure in patients with early gastric cancer (EGC) due to the potential risk for lymph node metastasis (LNM) after pathological analysis. However, LNM is estimated to occur in approximately 10% of patients with high-risk EGC. In this study, we investigated a blood-based liquid biopsy assay of exosomal miRNA for the noninvasive detection of LNM in patients with high-risk EGC. Methods: Two genome-wide miRNA expression profiling datasets (GSE164174 and TCGA) were analyzed to prioritize biomarkers in pretreatment plasma samples from clinical training and validation cohorts of GC patients. An integrated exosomal miRNA panel was developed and a risk stratification model combining the miRNA panel with clinical risk factors was established. Results: Using comprehensive expression profiling of public datasets, we identified a transcriptomic panel of four miRNAs (miR-34b, miR-130a, miR-375, and miR-627) that robustly identified patients with LNM [area under the curve (AUC) = 0.86, 95% confidence interval (CI) = 0.77-0.92]. We assessed panel performance in a training cohort (AUC=0.86, 95% CI=0.67-0.96) and validated it in an independent validation cohort (AUC=0.84, 95% CI=0.64-0.95). Our risk stratification model was more accurate than the panel and was an independent predictor of LNM identification (AUC=0.97). Conclusions: A novel noninvasive, liquid biopsy-based method for patients with EGC may predict those traditionally classified as high-risk patients with LNM who are unlikely to benefit from surgical resection.
Unbiased transcriptomic analysis of primary early-onset vs late-onset colorectal cancer.
Authors: Alessandro La Ferlita, Samantha M Ruff, Huocong Huang, Nilesh Verma, Alex Kim
Journal: Journal of Clinical Oncology (2025)

228 Background: Colorectal cancer is the 3rd most diagnosed and 2nd leading cause of cancer death. Despite the decline in incidence late-onset colorectal cancer (LOCRC), there is an increase in early onset of colorectal cancer (EORC). Clinicopathologic examinations from single centers revealed left-sided and rectal enrichment, poorly differentiated, and higher stage at presentation. Genomic studies examining the potential germline mutations/variants for EOCRC demonstrated mixed results. Transcriptomic analysis of the EOCRC compared to LOCRC remains limited. We hypothesized that EOCRC present with enrichment in aggressive molecular signatures consisting of CMS4 and iCMS3 signatures. To understand the mechanism behind EOCRC, we performed an unbiased RNA-Seq analysis in age groups of 32-82 in 95 patients. Methods: We utilized RNA-Seq data from the Orien Network, a collaborative between 19 NCI/NCCN cancer centers. We identified 95 patients diagnosed with colorectal cancer ranging in age from 32-82 and undergone RNA-sequencing of their primary tumors. Clinicopathologic assessment were analogously performed. We collected unnormalized raw-count RNA-Seq data from these patients. To account for differences in sequencing depth across samples, raw counts were scaled using the Reads Per Million (RPM) formula. The scaled reads in RPM were then utilized to assess the Consensus Molecular Subtypes (CMS) classification through two distinct approaches: the R package CMScaller and a deconvolution analysis using the R package SpatialDecon with the iCMS gene signature. Differences in age at the sample collection across patients with different CMS classifications were assessed by performing two-tailed unpaired T-tests. Additionally, differential expression analysis between EOCRC and LOCRC patients, defined by the upper and lower quartiles of the patients’ ages at the sample collection, was conducted using the LIMMA R package. Results: Clinicopathologic assessment of the primary tumors revealed left-sided tumors with poorly differentiated phenotype. Differential gene expression analysis between EOCRC and LOCRC demonstrated no significant differences. Stratification of transcriptomic data by decades also did not reveal any significant differences. Furthermore, there were no differences in CMS or iCMS classifications between different age groups. Conclusions: The RNA-Seq analysis comparing EOCRC and LOCRC did not identify any differential gene expression patterns. There was no significant differences were observed in CMS or iCMS classifications. These findings suggest that EOCRC and LOCRC share similar tumor biology based on molecular phenotypes. This implies that the initiating events for the disease may occur earlier in life while triggering a same disease process. As such, the findings underscores the importance of considering preventive measures, including earlier colonoscopy screenings.
Prognostic and biological divergence of upper gastrointestinal adenocarcinomas.
Authors: Arun Dang, Minggui Pan, Jack Stover, Tina Huang, Meng Tong, Chen Jiang, Laurel A. Habel, Ninah Achacoso, Jeffrey Bien, Aleyda V Solorzano-Pinto, Pamela Tse, Elaine Chung, Dean W. Felsher, George A. Fisher, Sachdev P. Thomas
Journal: Journal of Clinical Oncology (2025)

350 Background: Esophageal (EAC), gastroesophageal junction (GEJ) or gastric (GAC) adenocarcinoma share similar etiologies and treatment approaches. However, it is not clear if they possess similar or different prognostic and biological characteristics. We aimed to examine overall survival (OS) in associations of the common genomic alterations with these three anatomically closely linked adenocarcinomas. Methods: Eligible patients had recurrent or de novo metastatic GAC, GEJAC or EAC whose tumors had undergone next generation sequencing (NGS) performed from November 2017 to December 2023. We used Cox regression modeling to examine the association between GAC, GEJAC, EAC and OS, adjusting for demographics, performance status, Charlson comorbidity index, receipt of chemotherapy, and HER2 overexpression or amplification (HER2 positive), p53 (mutp53 ) , KRAS (mutKRAS), CDKN2A , PIK3CA co-mutations and MYC amplification. Results: Of 875 total eligible patients, 173 had EAC, 276 had GEJAC and 426 had GAC. GEJAC had substantially better OS than EAC (HR = 0.68, [95% CI, 0.54-0.86]), and modestly better OS than GAC (HR = 0.85, [95% CI, 0.67-1.09]). HER2 positivity was associated with substantially better OS among EAC (HR = 0.62; [95% CI, 0.40-0.96]) and GEJAC (HR = 0.59; [95% CI, 0.38-0.87]) but not among GAC (HR = 0.98; [95% CI, 0.78-1.23]) patients. In addition, p53 gain-of-function versus non-gain-of-function mutations were associated with substantially worse OS among GAC (HR = 1.41; [95% CI, 0.98-2.01]) but not among EAC or GEJAC. MutKRAS was associated with substantially worse OS among EAC (HR = 1.81; [95% CI, 1.10-2.99]) but not among GEJAC or GAC. Surprisingly, MYC amplification was associated with dramatically better OS among EAC (HR = 0.19; [95% CI, 0.08-0.42]) but substantially worse OS among GEJAC (HR = 1.98, 95% CI, 1.14-3.40]) and GAC (HR = 1.75; [95% CI, 1.10-2.80]). Conclusions: GEJAC, EAC and GAC possess substantially different OS that appears differentially associated with HER2 status, mutp53, mutKRAS and MYC amplification. These results suggest distinct prognostic and biological characteristics of these three anatomically closely linked adenocarcinomas that could have important implications in clinical practice and on further investigations on their biological and topological mechanisms.