tbuckley/cabot-search huggingface dataset:
A new prognostic tool for metastatic colorectal cancer patients receiving anti-angiogenic treatment, the PALM score: A single-center experience.
Authors: Eleonora Lai, Enrico Palmas, Francesco Loi, Pina Ziranu, Stefano Mariani, Andrea Pretta, Alessandra Pia D'Agata, Veronica Dell'Utri, Giulia Papalexis, Giulia Deias, Daiana Rizzo, Dario Spanu, Giorgia Sanna, Giusy Moledda, Andrea Cadoni, Mattia Cucca, Clelia Donisi, Valeria Pusceddu, Marco Puzzoni, Mario Scartozzi
Journal: Journal of Clinical Oncology (2024)

e15575 Background: Even if anti-angiogenic agents are crucial for metastatic colorectal cancer (mCRC) patients (pts) treatment, to date, no validated prognostic biomarkers are available. We conducted at our Centre a retrospective research to identify a prognostic tool to be applied in clinical practice in this population. Methods: We retrospectively collected laboratory, radiological and clinical data of mCRC pts treated with anti-angiogenic agents at the Medical Oncology Unit of Cagliari University Hospital (2018- 02/2024) in order to identify a potential prognostic tool. Statistical analysis was performed with MedCalc (survival distribution: Kaplan-Meier; survival comparison: log-rank test; cut-off: ROC curves; differences among variables: Chi-square test). Results: Globally, 33 mCRC pts were evaluated in our study (19 male, 14 female; 13 RAS wild-type, 22 left-sided primary). 10 were treated with anti-angiogenic drugs in the 1st-line, 13 in the 2nd-line (bevacizumab and aflibercept) and 10 in 1st-2nd line. Median OS was 39.5 months (m) (95%CI:28.2-41.3), median Progression Free Survival (PFS) was 14.9 m (95%CI:9.5-18.5). Pts with lower platelet to lymphocyte ratio (P; ≤253; p &lt; 0.0001, HR = 0,00000048; 95%CI 24.7-39.5 versus [vs] 95% CI 8.2-10.5), alkaline phosphatase (A; &lt; 136 U/l; p = 0.0001, HR = 0.0001; 95%CI 12-39.5 vs 95% CI 8.2-10.5) and lactate dehydrogenasis (L; &lt; 365 U/l; p &lt; 0.0001, HR = 0.0000004; 95%CI 24.7-39.5 vs 95% CI 8.2-10.5) and higher monocyte count (M; &gt; 0.3x10 3 /μL; p = 0.0093, HR 0.01; 95%CI 26.5-39.5 vs 95%CI 8.2-24.7), showed a statistically improved OS. We created the “PALM score” and separated pts in two prognostic groups: good prognostic group (0 unfavorable variables: PALM = 0) and poor prognostic group (≥1 unfavorable variable, PALM = 1). OS was significantly improved in the good prognostic group (PALM = 0): 31.5 m (95%CI:24.7-39.5) vs 10.5 m (PALM = 1) (p = 0.0031, HR = 0.00006). Chi-square test revealed also a statistically significant correlation of upfront resection of primary tumor with the PALM score (73.9% of patients belonging to the PALM = 0 group had undergone surgery for primary tumor and all patients with resected primary belonged to the PALM = 0 group (p = 0.0352). Conclusions: Our research showed a promising prognostic role of easy-to-use PALM score tool in mCRC patients treated with anti-angiogenic drugs in a limited population at our center. Further prospective studies with larger sample size are needed to confirm our findings.
A propensity score–matched comparison of fruquintinib (FRU) versus FRU combined with PD-1 inhibitors for microsatellite stability (MSS) metastatic colorectal cancer: Real-world data.
Authors: Lina He, Xiaojiao Cheng, Xin Cheng, Cong Zhou, Qingli Li, Shuiping Tu
Journal: Journal of Clinical Oncology (2024)

e15564 Background: FRU has been approved for previously treated metastatic colorectal cancer (mCRC) in China and the United States, moreover it has shown synergistic effects in combination with immunotherapy in MSS CRC through immunomodulation of the tumor microenvironment. However, comparing the efficacy of FRU monotherapy (FM) and FRU combined with PD-1 inhibitors (FP) directly was rarely reported due to baseline differences in patient characteristics. To address this, we utilized the propensity score matching (PSM) to enhance the accuracy of efficacy prediction by matching relevant baseline features between the two groups. Methods: Our real-world observational study retrospectively included MSS CRC patients who have received 3 rd line and above treatments from June 2019 to July 2022, and patients diagnosed with mCRC were eligible, and all patients received at least 2 cycles of FM or FP. As a result, 16 patients in the FM group and 51 patients in the FP group were enrolled. Utilizing stable LASSO (Least Absolute Shrinkage and Selection Operator) regression, we identified key clinical features relevant to outcomes for PSM. These included liver metastasis, lung metastasis, and prior chemotherapy with VEGF inhibitors. Based on these selected features, we conducted a 1:2 nearest neighbor matching algorithm to align the patients from the two groups more accurately for comparative analysis and subsequent survival analysis. The primary endpoint was progression-free survival (PFS). Results: The PSM process resulted in a matched cohort comprising 16 patients from the FM group and 32 patients from the FP group, totaling 48 patients in the analysis. The baseline characteristics of the included population were shown in Table 1. With a median follow-up of 22.87 months (95% CI: 17.00-26.07months), the median PFS in the FP group (13.27 months, 95% CI: 9.97-15.03 months) exhibited a noticeable extension compared to the FM group (4.30 months, 95% CI: 2.83-13.60 months). Additionally, the median overall survival (OS) in the FM group was 16.93 months (95% CI: 11.70-NA), and in the FP group, it was 21.30 months (95% CI: 13.67-NA). Conclusions: The FP group showed a significant increase in PFS compared to FM and PSM increased the comparability of real-world efficacy in MSS mCRC patients receiving FRU and FRU combined with PD-1 inhibitors. Further increasing the sample size may yield more valuable results. [Table: see text]
Analysis of patch-based GCN risk score distribution corresponding to gene mutations in colorectal cancer using whole slide images.
Authors: Li Liang, Jie Lin, Xikai Deng, Weihao Qiu
Journal: Journal of Clinical Oncology (2024)

e15650 Background: Colorectal cancer (CRC) is one of the most common malignancies, with the third highest incidence and the second highest mortality in the world. Risk scores are typically employed to predict outcomes such as disease risk, prognosis, or treatment response. Risk scores are usually calculated by combining biomarkers or genetic variants with statistical models, such as logistic regression or Cox proportional hazards models, and then observe the relationship between genetic variations and survival time through survival analysis. We have constructed a deep learning model based on Graph Convolutional Networks (GCNs), which is capable of predicting risk scores using Whole Slide Images (WSIs). Statistical analyses were applied to explore the distribution of risk scores associated with different variants in colorectal cancer. Methods: We performed risk scores prediction on a total of 384 samples from TCGA-COAD and TCGA-READ using our patch-based GCN model. We analyzed the distribution of risk scores in colorectal cancer samples and investigated the effects of gene mutations in key pathways on these risk scores. Results: Risk score predictions by our patch-based GCN model were conducted on 384 samples, revealing that the maximum, minimum, median, mean, and standard deviation of risk scores were -0.78, -1.89, -1.34, -1.34, and 0.20, respectively. The data overall conformed to a normal distribution ( p &lt; 0.05 ). We selected core genes in key pathways combined with top ten genes with the highest mutation frequency in colorectal cancer for statistical analysis to explore the correlation with the predicted risk scores. These gene mutations were found in a total of 346 patients. The results indicated that mutations in the TP53 and OBSCN genes led to significant differences in risk scores as predicted by our model ( p &lt; 0.05 ). The risk scores based on gene mutations also have significant differences and consistent trend in these genes. Conclusions: Our results indicate the risk scores generated by the patch-based GCN model have the consistent trend with the risk scores generated by mutation information of core genes in colorectal cancer. Whether risk scores based on digital pathology prediction can replace mutation detection in predicting patient survival status requires further exploration.
PREVECOL, a predictive model for early detection of colorectal cancer and precancerous lesions in liquid biopsy.
Authors: Lourdes Planelles, Ipek Guler, Marta Jiménez-Martínez, Rashid Babiker, Lourdes Castillo, Carmen Monsalve, Elena Sanchez-Viñes, Rocío Arroyo
Journal: Journal of Clinical Oncology (2024)

3629 Background: Colorectal cancer (CRC) is the second cause of cancer-related deaths worldwide. Most of these deaths could have been prevented by increasing the effectiveness of CRC screening programs, which exhibit a low participation rate, partly due to the limited available screening options, alongside discomfort associated with the screening procedure (faecal test). Liquid biopsy-based technology offers new alternatives to improve CRC early detection. CRC and advanced adenoma (AA) patients show molecular alterations at different biological levels that can be detected in peripheral blood and used for diagnostic purposes. AMADIX has developed PreveCol, an innovative blood test based on molecular biomarkers and clinical features for early detection of CRC and AA, before the onset of the first symptoms. We present the validation of PreveCol predictive model through a European prospective clinical study involving average-risk population actively engaged in a real CRC screening program. PreveCol has been granted with the Breakthrough Device Designation by the FDA in December 2023. Methods: Samples from two prospective clinical studies were used for training and validation. A case-control study (n= 538 individuals: 173 CRC, 181 AA, 184 Controls; 13 Spanish sites) and a clinical study based on a real CRC screening program (n= 3163 individuals: 78 CRC, 156 AA, 146 HRPL, and 2783 Controls; 9 European sites). PreveCol molecular signature (11 proteins and 10 miRNAs), was determined in plasma samples using RT-qPCR and ELISA/CLIA. Machine learning techniques were used to develop an ensemble algorithm. K-fold cross validation techniques were used in the training to set the hyperparameters for each model. Hyperparameter optimalization was performed to find the best parameters of the grid. Once the algorithm was locked and the clinical cut-off was established in the training set, the signature was validated in the European prospective study sub-cohort. Results: For CRC detection, PreveCol demonstrates an Area Under the ROC curve (AUC) of 92%, with a sensitivity (SS) of 81.8% and specificity (SP) of 86%. Moreover, the model exhibits high sensitivity (above 90%) in identifying CRC in early stages (stages 1 and 2), as well as lesions located in the proximal colon. In addition, the AUC of PreveCol for Advanced Adenomas detection is 86.88%, (SS of 70.8% and SP of 86%), showing that PreveCol presents higher sensitivity compared to other identified tests for detecting precancerous lesions. Conclusions: These findings highlight PreveCol's potential to significantly impact on patient prognosis and survival by facilitating the early detection of CRC and premalignant lesions as well as lesions in critical areas of the colon, thereby contributing to improved screening efficacy and patient outcomes.
Cost-effectiveness analysis of later-line treatments for refractory metastatic colorectal cancer.
Authors: Sang Cho, Tanios S. Bekaii-Saab, Brian Thomas Hocum, Jamie Grossman, Sreevalsa Appukkuttan, Svetlana Babajanyan, Min Yang, Woojung Lee, Afsaneh Barzi
Journal: Journal of Clinical Oncology (2024)

3525 Background: Recent clinical trials support regorafenib dose optimization (ReDO), a combination therapy with trifluridine/tipiracil and bevacizumab (TAS-BEV), and fruquintinib (FRUQ) for the treatment of refractory metastatic colorectal cancer (mCRC). This study evaluated relative cost-effectiveness of ReDO, TAS-BEV, and FRUQ for mCRC from a payer perspective in the United States. Methods: A Markov model was constructed to estimate total costs and quality-adjusted life years (QALY) for each treatment. In the base case, clinical parameters were obtained from the ReDOS study for ReDO, the SUNLIGHT study for TAS-BEV, and the FRESCO study for FRUQ. Economic parameters were obtained from IBM Micromedex RED BOOK for treatment costs and from the Centers for Medicare &amp; Medicaid Services and the Agency for Healthcare Research and Quality for health care resource use. Incremental cost-effectiveness ratio (ICER) was used to evaluate relative cost-effectiveness of treatments. Model robustness was checked with deterministic (DSA) and probabilistic sensitivity analysis (PSA). A subgroup analysis was performed in patients with and without previous use of anti-VEGF therapy, but using the FRESCO-2 study for FRUQ because OS and PFS for this subgroup was unavailable in the FRESCO study. Results: In the base case, ReDO provided a higher QALY at a lower cost than TAS-BEV and FRUQ. During the first two months following treatment initiation, TAS-BEV had a higher total cost ($67,862) than ReDO ($44,695) and FRUQ ($48,688), partly due to the cost of managing neutropenia and using concomitant granulocyte colony stimulating factors (GCSF). The base case results were robust in DSA and PSA. Most influential parameters determining relative cost-effectiveness were related to treatment cost and effectiveness. In patients with previous anti-VEGF therapy, ReDO provided a higher QALY at a lower cost (0.571 QALY; $86,694) than TAS-BEV (0.490 QALY; $148,784) and FRUQ (0.411 QALY; $101,236). In patients without previous anti-VEGF therapy, TAS-BEV had a higher QALY (0.755 vs 0.571) and a higher cost ($232,701 vs $86,694) than ReDO, resulting in an ICER of $790,988 per QALY. Conclusions: ReDO was cost-effective compared with TAS-BEV and FRUQ, regardless of previous use of anti-VEGF therapy. In the base case, ReDO had a lower treatment cost than TAS-BEV and FRUQ, especially during the first month of dose optimization. TAS-BEV had the highest total cost, partly due to the cost of managing neutropenia and GCSF use. [Table: see text]
Predictors of survival outcome of TAS102 combined with bevacizumab compared to TAS102 alone in Saudi patients with metastatic colorectal cancer beyond second line of systemic therapy.
Authors: Shereef Ahmed Elsamany, Hosam Alghanmi, Emad M Tashkandi, Ahmed Saleh Al-Shehri, Fayza Hassanin, Nashwa A. Abdulaziz, Mai Alhowari, Mervat Mahrous, Mohammed Abdullah Alghamdi
Journal: Journal of Clinical Oncology (2024)

e15545 Background: Significant proportion of metastatic colorectal cancer (mCRC) patients receive systemic therapy beyond second line. This study aims to assess predictors of survival outcome in patients treated with TAS 102/bevacizumab compared to TAS102 alone beyond 2nd line. Methods: In this retrospective study, we assessed patients with mCRC treated with TAS102/bevacizumab or TAS102 alone beyond second line in 4 institutes in Saudi Arabia from January 2020 to December 2022. We checked progression-free survival (PFS) and overall survival (OS) of the study group and we assessed different parameters that may affect the survival outcomes. Results: We included 68 patients in this analysis (39 treated with TAS102/bevacizumab, 29 with TAS102 alone) with a median follow up of 20 months. Noteworthy, 39.7% of patients received treatment in third line (56.4% vs. 17.2%, respectively, p = 0.001) and 48.5% developed neutropenia with first cycle (51.3% vs. 44.8%, p = 0.59). Time from stage IV diagnosis to study treatment (TTAS102) was &gt; 18 months in 56.4% vs. 44.8 %, respectively, p = 0.34. The two treatment arms were balanced for other parameters including site of primary tumour, tumour stage at diagnosis. Median PFS was significantly higher with TAS102/Bevacizumab compared to TAS102 alone (5 vs 3 months, HR = 0.59, 95% CI 0.35-0.98, p = 0.043). Similarly, median OS was significantly improved with TAS102/bevacizumab (15 vs 8 months, HR = 0.55, 95% CI: 0.30-0.98. p = 0.034). After adjustment of line of study treatment, TTAS102 and number of metastatic sites, PFS and OS were significantly improved with TAS102/bevacizumab compared to TAS102 alone (PFS: HR = 0.48, 95% CI: 0.26-0.89, p = 0.021), (OS: HR = 0.54, 95% CI: 0.26-0.91, p = 0.034). Survival outcomes were higher with TAS102/bevacizumab compared to TAS102 in patients with TTAS102 &gt; 18 months (PFS: 5 vs. 3 months, HR = 0.27, 95% CI: 0.12-0.62, p = 0.002), (OS: 22 vs. 6 months, HR = 0.28, 95% CI: 0.11-0.68, p = 0.005) and in patients with neutropenia with first cycle (PFS: 6 vs 3 months, HR = 0.45, 95% CI: 0.21-0.98, p = 0.043), (OS: 26 vs 8 months, HR = 0.33, 95% CI: 0.13-0.81, p = 0. 0.016). No difference in survival outcomes in patients with TTAS102≤ 18 months and those with no neutropenia with first cycle. Conclusions: TAS102 with bevacizumab is associated with improved PFS and OS beyond 2nd line compared to TAS 102 alone especially in patients with longer TTAS102 and first cycle neutropenia.
Exploring CK2 transcriptional regulation and signaling pathways in cancer.
Authors: Nicholas Wilson, Cristián Figueroa, Isabelle Kreber, Isabel M. Dominguez
Journal: Journal of Clinical Oncology (2024)

e15199 Background: CK2 genes have been implicated in oncogenic processes in different cancer types, and their expression is known to be increased in many cancers relative to their normal tissue types. However the regulation of the three CK2 alpha transcripts and beta transcript is not well understood. Studies investigating the alpha gene ( CSNK2A1) and beta gene ( CSNK2B) found NFκB, ETS1, and SP1 as likely transcription factor regulators in lymphoid and fibroblast cell lines. Our study seeks to explore correlations between CK2 gene expression and the expression of these transcription factors in cancer. Since CK2 also regulates intracellular signaling through pathways such as PI3K-Akt, Jak-Stat, NFkB, Wnt, IL-6, TGF-β, Ras and Notch, this study also seeks to explore the correlation between CK2 expression and gene expression of known downstream signaling pathways across a variety of cancers. Methods: 32 non-overlapping cancer datasets were obtained from the The Cancer Genome Atlas (TCGA) and Broad GDAC Firehose projects which were obtained via cBioPortal.org and analyzed using a combination of cBioportal and RStudio statistical analysis packages. For each cancer type, mRNA expression of each of the four CK2 genes in cancer was compared to expression of transcription factors both previously identified in the literature and predicted generated by TFBIND analysis (via the transcription factor database TRANSFAC R3.4) of the CK2 minimal promoter regions. CK2 gene expression was also compared to expression of genes in known CK2 signaling pathways. Results: Our analysis found CSNK2A1 and CSNK2A3 expression to have a significant, strong positive correlation in nearly all cancer types studied, except pancreatic adenocarcinoma. CSNK2A1 demonstrated significant positive correlation with expression of the transcription factors NFKB1 and c-Rel in lymphoma, thymoma, and other cancers. CSNK2B demonstrated a significant, strong positive correlation with the transcription factors NELFE in every cancer examined. CK2 transcripts also showed significant correlations with other transcription factors and genes involved in IL-6, TGF-β, MAPK, and several other CK2 signaling pathways in many different cancer types. Conclusions: Overall this study demonstrates significant correlations between CK2 gene expression and previously proposed transcriptional regulation mechanisms as well as known CK2 signaling pathways in cancer.
The safety and efficacy of immune checkpoint inhibitor in combination with FOLFOX as neoadjuvant/adjuvant therapy in patients with locally advanced colon cancer.
Authors: Changjing Cai, Ying Han, Yinghui Peng, Xiangyang Zhang, Pingping Gan, Youhong Tang, Lanhua Tang, Yiping Liu, Hong Shen, Shan Zeng
Journal: Journal of Clinical Oncology (2024)

e15621 Background: The recurrence rate of locally advanced colon cancer (T3-4 or N+, M0) after surgery is significantly high. Emerging data indicate that the combination of immunotherapy and chemotherapy demonstrates synergistic effects in other solid tumors. Consequently, a combination of immunotherapy and chemotherapy holds the potential to benefit patients with MSS and pMMR colon cancer. We have designed a prospective trial to investigate whether the immune checkpoint inhibitor (ICI) in combination with chemotherapy represents a safe and beneficial treatment approach for locally advanced colon cancer. Methods: Inclusive Criteria: Patients with locally advanced colon cancer (T3-4 or N+, M0) confirmed through pathological biopsy, with confirmed indications for neoadjuvant/adjuvant chemotherapy by the multidisciplinary team. Patients must be eligible for surgery, and a measurable mass must be identified according to RECIST version 1.1. All individuals aged over 18 years, with an estimated life expectancy of over one year and an ECOG score within 0-1, are eligible. The neoadjuvant chemoimmunotherapy group (NACI) includes mFOLFOX 6 (Q2W) and the anti-PD-1 monoclonal antibody (Toripalimab) (3mg/kg, Q2W), while the neoadjuvant chemotherapy group (NAC) receives only mFOLFOX 6 for neoadjuvant/adjuvant therapy (a total of 12 cycles, 6 cycles pre-surgery and 6 cycles post-surgery). The primary endpoint is the pathological complete response (pCR) rate. Results: From 2019 to 2022, a total of 22 patients were enrolled in the study, with 13 in the NACI group and 9 in the NAC group. The research findings indicate that in the NACI group, over 30% (4/13) of patients achieved a pathological complete response (pCR), whereas none of the patients in the NAC group reached pCR (0/9). Among the pCR patients, one was identified as MSI-H/dMMR, two as MSS/pMMR, and one had an unknown status. Tumor regression grade (TRG) levels also revealed that all patients in the NACI group were below grade 2, significantly outperforming the NAC group (P &lt; 0.05), with statistically significant differences. However, no significant differences were observed between the NAC and NACI groups in terms of CT regression percentage, R0 resection, vascular cancer emboli, and the level of neural invasion. Adverse reactions did not show significant differences between the two groups. Conclusions: The combination of immunotherapy and chemotherapy exhibits a synergistic effect in treating locally advanced colorectal cancer. Tolerable adverse reactions suggest that neoadjuvant chemoimmunotherapy could potentially serve as a novel therapeutic option. Clinical trial information: NCT03985891 .