tbuckley/cabot-search huggingface dataset:
Role of heat shock protein 90 in hypoxia-induced angiogenesis and epithelial-mesenchymal transition for esophageal squamous cancer cells.
Authors: Ching Tzao, Jin-Kun Wang
Journal: Journal of Clinical Oncology (2024)

395 Background: Hypoxia is known as an important trigger for the development and progression of human cancers. Heat shock proteins (Hsps) may be up-regulated in response to cellular stressors including hypoxia. To date, the functional role of Hsps within hypoxic tumor microenvironment for esophageal squamous cell cancer (ESCC) remains poorly defined. Methods: CoCl2 was used to induce hypoxia that mimics a hypoxic tumor microenvironment in cultured ESCC cells. Successful induction of hypoxia was confirmed by 2’,7’ –dichlorofluorescein diacetate (DCFDA) assay by detection of cellular reactive oxygen species (ROS). 7-Dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a selective Hsp90 inhibitor, was used to treat 2 ESCC cell lines, KYSE-170 and -510 cells pretreated with or without CoCl2, an agent to induce a hypoxic tumor microenvironment. Cytotoxicity (MTT) and migration assays were conducted in KYSE-17 and -510 ESCC cells in response to different concentrations of CoCl2, followed by protein expression of Hsp 90, vascular endothelial growth factor (VEGF), hypoxia-inducible factor-1a (HIF-1a), mTOR as well as markers related epithelial-mesenchymal transition (EMT) such as snail or E-cadherin, by immunoblot or ELISA. In parallel, cell proliferation and migration assays of ESCC cells were analyzed. Results: CoCl2 induced hypoxia was supported by an induction of reactive oxygen species (ROS). CoCl2 (200 mM) significantly suppressed cell viability and proliferation with a concomitant up-regulation of VEGF and HIF-1a in a dose-dependent fashion. In contrast, cell migration was significantly increased in response to CoCl2, while down-regulating E-cadherin with concomitant increase in Snail expression. 17-DMAG decreased expression of VEGF and HIF-1a. In addition, it inhibited cell migration and invasion of ESCC cells were analyzed. Conclusions: Our data have shown that CoCl2 induced hypoxia promotes EMT and angiogenesis, which are inhibited by 17-DMAG, suggesting that hypoxia induced EMT and angiogenesis is Hsp 90 dependent in ESCC.
<i>Helicobacter pylori</i> infection and response of gastric cancer to immunotherapy.
Authors: Yinghong Wang, Malek Shatila, Gabriel Sperling, Antonio Pizuorno Machado, Muhammad Vohra, Elliot Baerman, Enrico N. De Toni, Helga-Paula Török, Dan Zhao, Yan Zhou, Mehnaz Shafi, Anusha Thomas, Mazen Alasadi
Journal: Journal of Clinical Oncology (2024)

277 Background: Helicobacter pylori is a known risk factor for gastric cancer, possibly via the PD-1/L1 pathway. Some suggest that H. pylori infection may counteract the action of immune checkpoint inhibitors in few studies with limited sample size. This study explores the effects of H. pylori infection status on survival outcomes in patients with gastric cancer. Methods: This single-center, retrospective chart review included patients with gastric adenocarcinoma between June 1985 and August 2022. Patients with different histological subtypes were excluded. Primary variables of interest included H. pylori infection status and treatment with ICIs. Other clinical information included demographics, cancer histology, the presence of other cancers, and vital status. Results: 2,930 patients were included in the initial analysis. 206 (7.0%) received ICIs, 196 (6.7%) had prior H. pylori infection, and 1,037 (35.4%) had a mucinous subtype. Mucinous cancer subtypes were associated with improved survival (p&lt;0.05) at 3 and 5 years compared to non-mucinous adenocarcinomas. Mucinous cancers demonstrated better survival outcomes than non-mucinous at 10 years, but only among H. pylori-positive patients (p=0.013). H. pylori positivity was associated with worse survival at 3 years (OR: 2.0, p=0.041) among patients taking ICIs but not for patients not receiving ICIs (OR: 0.8; p=0.325). Conclusions: H. pylori infection may negatively impact the therapeutic effect of ICIs. These findings suggest H. pylori infection may be an obstacle to successful immunotherapy and may interact with cancer subtypes to differentially impact survival. Future studies are needed to validate the potential prognostic value of H. pylori positivity in gastric cancer.
Anlotinib combined with penpulimab and nab-paclitaxel as first-line treatment for advanced esophageal squamous cell carcinoma (ESCC): A single-arm, open-label phase II clinical trial.
Authors: Zhiwei Chang, Xiao-Lei Liu, Dan-Dan Yu, Hui-Qiong Han, Jian He, Rui-Rui Wang, Yan-ru Qin
Journal: Journal of Clinical Oncology (2024)

340 Background: Recently, PD-1 blockades combined with dual chemotherapy in first-line setting exhibited encouraging efficacy for patients with ESCC. However, the safety profile of conventional dual chemotherapy remained unsatisfactory. Therefore, PD-1 blockades combined with anti-angiogenic tyrosine kinase inhibitors (TKIs) and single chemotherapy regimen might be a promising strategy. Anlotinib, a novel multitarget TKI primarily targeting VEGFR1-3, demonstrated promising therapeutic activity as first-line combination therapy or second-line monotherapy for patients with ESCC in China clinically. Therefore, this study was designed to explore the efficacy and safety of anlotinib combined with penpulimab (PD-1 blockade) and nab-paclitaxel as first-line therapy in advanced ESCC. Methods: Patients with previously untreated metastatic or locally advanced ESCC were recruited and treated with anlotinib (12mg, po, d1~14, q3w) and penpulimab (200mg, iv, d1, q3w) plus nab-paclitaxel (220mg/m 2 , iv, d1, q3w) until disease progression or unacceptable toxicity. The tumor response was assessed according to RECIST 1.1 using CT scans every two cycles. Adverse events were recorded by severity in accordance with the NCI CTC AE Version 5.0. The predefined sample size was 30. Primary endpoint was PFS and secondary endpoints included safety, ORR, DCR and OS. Results: From Jul 2022 to Aug 2023, a total of 23 patients were enrolled, 19 patients who had received first tumor response were included in this analysis. The best overall response indicated that there were 14 PR (73.7%), 2 SD (10.5%) and 3 NE (15.8%). Therefore, the preliminary ORR was 73.7% (95%CI: 48.8%-90.9%), DCR was 84.2% (95%CI: 60.4%-96.6%). Median PFS of the 19 patients was not yet reached. Additionally, safety profile exhibited that the regimen was tolerable. The most common treatment-emergent adverse events among the 23 patients with the incidence &gt;20% were leukopenia (30%) and anemia (30%). Common grade ≥3 treatment-emergent adverse events were leukopenia (9%), glutamic-pyruvic transaminase was elevated (4%), glutamic oxaloacetic transaminase increased (4%), hypertension (4%) and diarrhea (4%). Conclusions: The combination of anlotinib plus penpulimab and nab-paclitaxel as first-line therapy for advanced ESCC demonstrated promising efficacy and manageable safety profile. The conclusions needed to be confirmed in subsequent trials.
Microscopic residual disease (MRD) monitoring with circulating tumor DNA (ctDNA) across gastrointestinal (GI) malignancies.
Authors: Harrison David Winters, Paul Sackstein, Benjamin Adam Weinberg, Dipanjan Debnath, Xue Geng, Hongkun Wang, Saavan Chintalacheruvu, John Marshall, Aiwu Ruth He, Marcus Smith Noel, Reetu Mukherji
Journal: Journal of Clinical Oncology (2024)

176 Background: ctDNA is a powerful tool that can detect early evidence of tumor relapse, or MRD. There are limited studies characterizing the performance of ctDNA in non-colorectal GI cancer patients (pts). We describe the clinical outcomes of GI cancer pts who underwent real-world MRD testing at our institution. Methods: We retrospectively analyzed GI cancer pts with ≥1 ctDNA test (Natera, Inc) ordered for MRD testing between June 2020-August 2022. Descriptive statistics were used to characterize rates of ctDNA positivity (ctDNA+) and relapse rates (RR). Median relapse-free survival (mRFS) and overall survival (mOS) were calculated using Kaplan-Meier method, group comparisons by log-rank test, and hazard ratios (HR) by Cox proportional hazard models. Associations between initial mean tumor molecules per milliliter (MTM/mL) (continuous variable) and clinical factors were assessed by Kruskal-Wallis or Wilcoxon Rank-sum tests. Results: ctDNA testing was successful in 222/228 pts (table). The median follow-up was 15 months (mo) (Interquartile Range 8.6-24.7). 61/222 (27.5%) of pts had ≥1 ctDNA+ test of which 59% had relapse on their next scan obtained after a median of 40 days from the first + test. Of all relapsed pts (62/222), ctDNA detected relapse before imaging in 69.4% with a median lead time of 57 days. The positive and negative predictive values of ctDNA for relapse were 82% and 92.5%, respectively. The mRFS was 10.8 mo vs. not reached (NR) (HR 18.6; p&lt;0.0001) and mOS 43.1 mo vs. NR (HR 5.0; p=0.002) in anytime vs. never ctDNA+ pts with similar trends in the colorectal and pancreas subgroups. Of ctDNA+ pts with &gt;1 test, 49.2% (29/59) cleared ctDNA with 79.3% of clearances on/after therapy. Between ctDNA clearers and non-clearers, RR were 72.4% vs. 93.3%, mRFS 12.4 vs. 7.6 mo (HR 0.3; p=0.6), and mOS NR vs. 43.1 mo (log-rank test p=0.01). No significant associations existed between initial MTM/mL and tumor types (p=0.6), relapse status (p=0.2), or number of relapse sites (p=0.4). Conclusions: ctDNA is a prognostic tool able to detect early relapse with high accuracy in GI cancers. The initial MTM/mL in ctDNA+ pts did not correlate with tumor histology or relapse patterns. Pts clearing ctDNA tended to have improved outcomes; however, RRs were higher than anticipated. More pts and longer follow up will help characterize the performance of ctDNA across rarer GI subtypes. [Table: see text]
Liver steatosis and fibrosis as independent prognostic factors affecting survival in colorectal cancer with liver metastases.
Authors: Nikhil Gupta, Eashwar Somasundaram, Andrew Dhawan, Jacob Scott
Journal: Journal of Clinical Oncology (2024)

165 Background: Colorectal cancer is one of the leading causes of cancer-related death, and the liver represents the most common site of metastases. Greater depth of tissue invasion and lymph node metastases (more advanced T and N stage) are associated with increased risk of liver metastases, but how co-pathologies of the liver associate with disease progression and survival are not known. Further, prognostic factors associated with overall survival in patients with colorectal liver metastases (CRLM) remain poorly understood. Clinical factors affecting liver morphology and biomechanical properties, such as preexisting fibrosis or steatosis, may impact the pathogenesis of CRLM and thus the clinical prognosis. Current literature is mixed about whether prior steatosis and fibrosis contribute significantly to CRLM pathogenesis and prognosis. The purpose of this study is to evaluate whether liver steatosis and fibrosis impact outcomes in patients with CRLM. Methods: All CLRM cases (n = 197) that underwent resection between 2003 and 2007 from The Cancer Imaging Archive were included in our study cohort. For each clinical covariate, we generated a univariate model for overall survival and those meeting a modest predictive threshold (p &lt; 0.15) were included in a multivariable model. These included: presence of major comorbidity, chemotherapy preceding resection of liver metastases, clinical risk score, presence of extrahepatic disease at time of diagnosis, presence of steatosis on CT imaging, percentage of residual tumor after treatment, and presence of fibrosis on CT. All statistics were performed in R (v.2022.12.0). Results: A multivariable Cox proportional hazards model identified four statistically significant clinical factors predictive of overall survival: clinical risk score (HR = 1.60, p = 0.026), presence of extrahepatic disease (HR = 2.33, p = 0.027), presence of steatosis (HR = 0.51, p = 0.0057), and fibrotic proportion of liver tissue less than 40% (HR = 2.63, p = 0.033). There were also four statistically significant clinical factors predictive of disease-free survival in the liver: chemotherapy preceding resection of liver metastases (HR = 2.28, p = 0.0011), presence of extrahepatic disease (HR = 2.18, p = 0.024), presence of steatosis (HR = 0.49, p = 0.0030), and fibrotic proportion of liver tissue less than 40% (HR = 2.74, p = 0.016). Conclusions: Our findings suggest that increased steatosis and fibrosis, as assessed by CT scans, are paradoxically protective in CRLM, showing longer disease-free survival and overall survival rates. We hypothesize that liver fibrosis and steatosis impact the microenvironment of the neoplastic cells in the liver, impairing tumor progression in this milieu. Further research is needed to assess how non-neoplastic co-pathologies resulting in biophysical changes affect tumor growth and overall survival.
Comparison of colorectal cancer (CRC) characteristics across genetic ancestries: Implications for early cancer detection (ECD).
Authors: Parvathi Myer, Preethi Srinivasan, Sara L. Bristow, Shifra Krinshpun, Omid Solari, Vasily N. Aushev, Adham A Jurdi, Minetta C. Liu, Breeana L. Mitchell, Alexey Aleshin, Johannes G. Reiter, Jeffrey N. Weitzel, Yoshiaki Nakamura, Takayuki Yoshino, Jeffrey Wall, Alexander Ioannidis, Carlos Bustamante
Journal: Journal of Clinical Oncology (2024)

164 Background: Blood-based ECD has the potential to reduce mortality rates by improving strategies for, adoption of, and adherence to screening. A deeper understanding of the cancer genomic landscape across genetic ancestries will aid comparable detection performance across a broad population. We evaluated the mutational landscape in patients with CRC across genetic ancestries. Methods: 16,080 de-identified patients with stage I-IV CRC who had personalized, tumor-informed commercial ctDNA testing (Signatera) based on whole exome sequencing (WES) were included. Genetic ancestry determined via supervised local ancestry inference (pmid36042219) included African (AFR), East Asian (EAS), European (EUR), Latino (LAT), and South Asian (SAS). Patients assigned to a single ancestry were included (except SAS due to small cohort size). Somatic single nucleotide variants called from WES were used for mutational signature inference. EUR was the reference group for standard statistical tests with corrections for multiple hypothesis testing. Results: A single genomic ancestry was assigned for 16,257 (99.2%) patients (AFR n=1697, 10%; EAS n=2247, 14%; EUR n=10,526, 64%; LAT n=1291, 1%; SAS n=184, 1%). Across AFR, EAS, EUR, and LAT, approximately half of patients were male (range, 47-54%) and most were aged &gt;50 years. Microsatellite instability (MSI) rates were significantly higher in EUR (14.5%) v AFR (11%, p&lt;0.001), EAS (8%, p&lt;0.001), and LAT (11%, p=0.002). Compared to EUR (range 0.027-875.1 mut/Mb), the distribution of TMB was significantly higher in EAS (0.304-906.2 mut/Mb, p&lt;0.001) and lower in LAT (0.053-476.7 mut/Mb, p&lt;0.001). The POLE hyper-mutator signature was seen in 1.2% of all patients and in 7.6% of all hyper-mutated cases. Patients with the POLE signature were less common in EUR (1.1%) v AFR (2%, p=0.001). There were significant differences in the frequency of driver mutations in APC, BRAF, KRAS, TP53, and PIK3CA between EUR and the other ancestry groups in both MSI and MSS tumors (Table). Median exposure levels to alkylation were higher in EAS v EUR. Conclusions: These data confirm previous results in AFR populations, and reveal novel differences in the EAS and LAT populations. Findings from this study may provide information for developing risk stratification and prevention strategies for the early detection of cancer and provide rationale for precision treatment based on ancestry. [Table: see text]
Real-world analysis of irinotecan (iri) with or without fluorouracil (5FU) in the second line treatment (2L) of metastatic colorectal cancer (mCRC).
Authors: Robert William Lentz, Junxiao Hu, Hannah Ruth Robinson, Nicole Baranda Balmaceda, Emily Eyoung Baiyee Ebot, Alexis Diane Leal, Sunnie S. Kim, S. Lindsey Davis, Wells A. Messersmith, Christopher Hanyoung Lieu
Journal: Journal of Clinical Oncology (2024)

102 Background: The most used 1 st line (1L) chemotherapy backbone for mCRC is fluoropyrimidine (FP) + oxaliplatin. In the 2L, iri alone or with 5FU (FOLFIRI), ± a biologic agent (biologic), are options. It is unclear whether adding 5FU to iri is beneficial following disease progression on prior FP. Methods: This study used the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database to identify patients diagnosed with mCRC from 01-01-2013 to 02-13-2023, who received 1L with FP + oxaliplatin ± biologic, and 2L with irinotecan ± 5FU ± biologic. Baseline patient/tumor characteristics were obtained. The number of major comorbidities was computed using ICD-9-CM/10 codes within 1 year prior to 2L (Quan, 2005). Time to next treatment (TTNT) was defined from the start of 2L to the start of next line treatment (excluding maintenance). For survival outcomes, the median survival time and 95% confidence interval (CI) were estimated using the Kaplan-Meier method. Uni- and multi-variable analyses (UVA and MVA) were performed with the cox proportional hazard model. All covariates were evaluated in UVA, and those significant were included in MVA with adjusted hazard ratio (HR) and 95% CI. Results: 3,215 patients met criteria; most previously received a biologic with 1L (70.5% prior anti-angiogenesis and 5.9% prior anti-EGFR) and had 0 structured major comorbidity diagnoses (82.1%). In the 2L, FOLFIRI was the most used chemotherapy backbone (90.6%, vs iri 9.4%), 79% of patients also received a biologic, and patients who received FOLFIRI were younger (median age 61 vs 65 years) and had better ECOG performance status (87.8% vs 81.8% ECOG 0-1). Overall survival (OS) was longer with FOLFIRI than iri (median 14.4 vs 9.8 months, p&lt;0.001), as was TTNT (median 7.6 vs 5.3 months, p&lt;0.001). In MVA, when controlling for age, comorbidities, CEA, ECOG performance status, and 1L, iri was associated with shorter OS than FOLFIRI (HR 1.38, 95% CI 1.21-1.57, p&lt;0.001). In MVA, the addition of a biologic to FOLFIRI and iri prolonged OS and TTNT in some subgroups (Table). Conclusions: In this retrospective real-world analysis of 3,215 patients with mCRC who received 1L with FP + oxaliplatin ± biologic, 2L FOLFIRI was associated with longer OS compared to iri alone (both ± biologic). [Table: see text]
A retrospective analysis of the prognostic impact of <i>KRAS</i> G12D mutation in patients with <i>RAS</i>-mutated metastatic colorectal cancer.
Authors: Toshiharu Hirose, Kunihito Matsuguma, Hidekazu Hirano, Natsuko Tsuda Okita, Hirokazu Shoji, Atsuo Takashima, Ken Kato
Journal: Journal of Clinical Oncology (2024)

105 Background: KRAS is an oncogene that is mutated in about half of all metastatic colorectal cancers (mCRC). Recently, a novel therapy targeting KRAS G12C mutation has demonstrated promising efficacy for advanced solid tumors, including mCRC. A therapy targeting KRAS G12D mutation is also under development and promising efficacy is expected. However, the prognostic impact of the KRAS G12D mutation in patients with mCRC is still unclear. Methods: We retrospectively reviewed the medical records of patients with mCRC harboring RAS mutation who received first-line chemotherapy between January 2013 and December 2022 at our hospital in Japan. We compared the survival outcomes between patients with KRAS G12D mutation (G12D group) and those with non- KRAS G12D mutations (non-G12D group) in terms of progression-free survival (PFS) and overall survival (OS), using the Kaplan–Meier method and the log-rank test. Hazard ratios (HRs) and 95% confidence intervals (95%CIs) were estimated by univariate and multivariate Cox regression analysis. Results: A total of 340 patients were included in this study. The main RAS mutations were KRAS G12D in 80 patients (23.4%), KRAS G12V in 72 (21.2%), KRAS G13D in 43 (12.6%) and KRAS G12C in 16 (4.7%). There were 80 patients in the G12D group and 260 in the non-G12D group. Patient backgrounds did not differ significantly in terms of age (median 61/63), sex (male 49%/48%), performance status (PS0 32%/32%), site of primary tumor (right 33%/32%), number of metastatic sites (3≤ 28%/23%), treatment regimen (doublet 90%/92%, triplet 3%/4%), or first line bevacizumab (yes 81%/79%). Median PFS was 9.2 months (95%CI: 7.8-12.2) in the G12D group vs. 11.5 months (95%CI: 9.2-13.1) in the non-G12D group (HR 0.97 [95%CI: 0.73-1.28]; p=0.81). Median OS was 25.8 months (95%CI: 18.8-39.8) vs 32.9 months (95%CI: 28.5-36.1) (HR 0.84 [95%CI: 0.60-1.19]; p=0.33). Second-line treatment was administered in 55 (69%) vs 192 (74%) patients in the G12D and non-G12D group, respectively. Conversion surgery was performed in 4 (5%) vs 18 (7%) patients in the G12D and non-G12D group, respectively. Multivariate analysis adjusted for PS, sex, age, site of primary tumor, number of metastatic sites and treatment regimen showed no significant differences in PFS and OS between the G12D and non-G12D groups. Conclusions: The KRAS G12D mutation did not show a detrimental prognostic impact on PFS and OS compared to KRAS non-G12D mutations in patients with RAS-mutated mCRC.