tbuckley/cabot-search huggingface dataset:
Predictors of receiving targeted treatment among eligible patients with metastatic colorectal cancer.
Authors: Alexa Woodward, Jean Lucia Bazan-Williamson, Pallavi Mohanty, Ashley Brenton
Journal: Journal of Clinical Oncology (2024)

e15594 Background: Colorectal cancer is among the most frequently diagnosed cancers and ranks as the third leading cause of cancer-related mortality globally with increasing prevalence among younger patients and high mortality. While targeted therapies have revolutionized treatment and tripled the median survival over the past two decades, many eligible patients fail to receive them. This study sought to identify factors associated with receiving targeted treatment among eligible patients. Methods: We identified a cohort of patients with metastatic colorectal cancer diagnosed between 2007 and 2023 (n = 521,074) in Optum’s clinicogenomic database. Eligible patients were identified based on clinical and treatment history, broad-panel next-gen sequencing (NGS) results and the drug indications for targeted treatments available at time of diagnosis (n = 8,533), including MSI/MMR status, RAS WT status, presence of BRAF V600E, and other biomarkers. In total, we considered tucatinib, encorafenib, pembrolizumab, nivolumab, ipilimumab, panitumumab, cetuximab, and regorafenib. Most patients did not receive targeted treatment; we applied a synthetic minority oversampling technique to correct this class imbalance. We assessed how factors including sex, race, and receipt of genetic counseling services influenced the likelihood of receiving targeted treatment using logistic regression. Results: In the fully adjusted multivariable logistic regression analysis, all variables were significant with p &lt; 0.05. Notably, patients receiving genetic counseling had 68% greater odds of receiving targeted treatment (OR, 1.68 [95% CI, 1.20-2.36]). African American (OR, 0.37 [95% CI, 0.27-0.50]) and Asian patients (OR, 0.10 [95% CI, 0.04-0.24]) had lower odds of receiving targeted treatment compared to Whites. Similarly, patients treated in community settings had 86% lower odds compared to patients in academic settings (OR, 0.14, [95% CI, 0.11-0.18]) as did male patients (OR, 0.39, [95% CI, 0.33-0.44]). Conclusions: This study underscores the challenges in receiving targeted treatments despite clinical eligibility. Our findings highlight the significance of genetic counseling in facilitating access to targeted therapies, and the stark gap in uptake among minority patients. These results can inform strategies to increase access to these treatments. Future research will attempt to better understand the mechanisms underlying receipt of targeted treatment.
Upregulation of GREB1 in colorectal cancer ovarian metastases may be a potential therapeutic target.
Authors: Samantha M. Ruff, Alessandro La Ferlita, Manoj Palavalli, Robert Connor Chick, Joal D. Beane, Susan Tsai, Oliver S. Eng, Alex Kim
Journal: Journal of Clinical Oncology (2024)

e15596 Background: Classification of ovarian metastases (OM) in colorectal cancer (CRC) as peritoneal metastasis (PM) remains controversial. Moreover, OM demonstrate resistance to systemic therapy, suggesting distinct molecular tumorigenesis. Gene expression profiling and transcriptomic analysis was performed to distinguish OM, PM, and primary CRC (pCRC) and identify potential therapeutic targets. Methods: RNA sequencing was performed on tissue from the Total Cancer Care database. Raw counts were scaled in reads per million to filter out low-expressed genes. Afterward, raw counts of retained genes were normalized in trimmed mean of M-values and then log2-transformed using the Limma R package. Genes with a |Log2FC| &gt; 0.58 and an adjusted p-value &lt; 0.05 were considered dysregulated. In silico motif enrichment analysis of estrogen receptor 1 (ESR1) on growth regulating estrogen receptor binding 1 (GREB1) was conducted via the FIMO program. Results: There were 115 patients with tissue from OM (n = 6), PM (n = 4), and pCRC (n = 105). The average age was 58 years and most patients were male (57.4%), Caucasian (89.5%), and had microsatellite stable disease (69.6%). Most patients underwent cytotoxic chemotherapy (67%), while fewer underwent targeted therapy (38.3%) or radiation therapy (27.8%). The median overall survival for the pCRC, OM, and PM populations was 7.1, 3.4, and 4.0 months, respectively. Among upregulated genes, LAMC3, SCUBE1, and GREB1 had the highest differential expression in OM compared to PM and PEG3, C7, and GREB1 had the highest differential expression in OM compared to pCRC (all p &lt; 0.001). Among downregulated genes, IGLC1, IGHG2, and IGHG1 had the greatest differential expression in OM compared to PM and IGHG1, IGKV4-1, and MMP12 had the greatest differential expression in OM compared to pCRC (all p &lt; 0.001, Figure 1). GREB1 was upregulated in OM compared to both PM and pCRC. There are two estrogen response element (ERE) sites within the promoter region of GREB1. ESR1 transcription factor was shown to bind to these ERE (p &lt; 0.001). Conclusions: Transcriptomic analysis demonstrated clear molecular distinction between OM, PM and pCRC. Differences in gene expression profiling suggest distinct underlying mechanisms of metastasis. We identified a significant upregulation of GREB1 in OM compared to PM and pCRC. GREB1 contains both ERE and ESR1 in the upstream promoter regions implying potential upstream transcription regulation mediated by ESR1. GREB1 is a potential novel, hormonal target in treatment of OM in CRC. Continued analysis is ongoing to identify other potential targets.
Colon adjuvant chemotherapy based on evaluation of residual disease (CIRCULATE-NORTH AMERICA): NRG-GI008.
Authors: Arvind Dasari, Guan Yu, Scott Kopetz, Shannon L. Puhalla, Peter C. Lucas, Ibrahim Halil Halil Sahin, Dustin A. Deming, Philip A. Philip, Theodore S. Hong, Yesenia Rojas-Khalil, Jonathan M. Loree, Norman Wolmark, Greg Yothers, Thomas J. George, Christopher Hanyoung Lieu
Journal: Journal of Clinical Oncology (2024)

TPS3641 Background: Currently, there are no biomarkers validated prospectively in randomized studies for resected colon cancer (CC) to determine need for adjuvant chemotherapy (AC). However, circulating tumor DNA (ctDNA) represents a highly specific and sensitive approach (especially with serial monitoring) for identifying minimal/molecular residual disease (MRD) post-surgery in CC patients (pts), and may outperform traditional clinical and pathological features in prognosticating risk for recurrence. CC pts who do not have detectable ctDNA (ctDNA-) are at a much lower risk of recurrence and may be spared the toxicities associated with AC. Furthermore, for CC pts with detectable ctDNA (ctDNA+) who are at a very high risk of recurrence, the optimal AC regimen has not been established. We hypothesize that for pts whose CC has been resected, ctDNA status may be used to risk-stratify for making decisions about AC. Methods: In this prospective phase II/III trial, up to 1,912 pts with resected stage IIB, IIC, and III CC will be enrolled. Based on the post-operative ctDNA status using personalized and tumor-informed assay (Signatera, bespoke assay), those who are ctDNA- (Cohort A) will be randomized to immediate AC with fluoropyrimidine (FP)+oxaliplatin (Ox) for 3-6 mos per established guidelines vserial ctDNA monitoring. Patients who are ctDNA+ post-operatively, or with serial monitoring (Cohort B), will be randomized to FP+Ox v more intensive AC with addition of irinotecan (I) for 6 mos. One cycle of chemotherapy is allowed while awaiting ctDNA testing results for cohort assignment. The primary endpoints for Cohort A are time to ctDNA+ status (phase II) and disease-free survival (DFS) (phase III) in the immediate v delayed AC arms. The primary endpoint for Cohort B is DFS in the FP+Ox v FP+Ox+I arms for both phase II and phase III portions of the trial. Secondary endpoints include prevalence of detectable ctDNA post-operatively, time-to-event outcomes (overall survival and time to recurrence) by ctDNA status, and the assessment of compliance to adjuvant therapy. Biospecimens including archival tumor tissue, as well as post-operative plus serial matched/normal blood samples, will be collected for exploratory correlative research. Active enrollment across the NCTN started in June 2022 with CCTG sites joining in August 2023. Current accrual (as of 02-02-2024) is 240/1,912. NCT05174169. Support: U10-CA-180868, -180822; UG1CA-189867; Natera, Inc. Clinical trial information: NCT05174169 .
NRG Oncology/RTOG 0848: Results after adjuvant chemotherapy +/- chemoradiation for patients with resected periampullary pancreatic adenocarcinoma (PA).
Authors: Ross A. Abrams, Kathryn A. Winter, Karyn A. Goodman, William Regine, Howard Safran, Adam C. Berger, Chandan Guha, Lisa A. Kachnic, Michael Gillin, Samantha A. Seaward, Abraham Jing-Ching Wu, Jennifer J. Wu, Raid Aljumaily, Thomas A. DiPetrillo, Ravit Geva, Pramila R. Anne, Jennifer Yannucci, Darla K. Liles, Jennifer Moughan, Christopher H. Crane
Journal: Journal of Clinical Oncology (2024)

4005 Background: If 5FU/Capecitabine sensitized radiotherapy (RT) is beneficial in the adjuvant (adj) management of PA after adj chemotherapy (chemo) is controversial. NRG/RTOG 0848 was designed to address this issue. Methods: This was a 2 step NCTN randomized (rndmzd) trial. Step 1 rndmzd patients (pts) to 5 cycles of gemcitabine +/- Erlotinib. Step 2 rndmzd pts to a 6 th cycle of the same chemo +/- 5FU/Capecitabine with 50.4 Gy in 28 fractions RT (chemo+CRT). Step 1 eligibility included: R0/R1 resection, M0, ECOG PS 0-1, CA19-9≤180. Step 2 eligibility included &gt; 4 cycles chemo (gem, gem combo, (m)FOLFIRINOX). RT included real time 3D/IMRT treatment (RX) plan review, scoring, and approval. At Step 2, pts stratified by nodal status (+ vs -), CA19-9 (≤90 vs &gt; 90-180), surgical margins (R0 vs R1), and adjuvant chemo. Primary endpoint was OS. Secondary endpoints are DFS and AEs (CTCAEv4). Assuming 17 months median OS (chemo) and hypothesized 22.5 months (chemo+CRT), sample size was 354 pts (HR = 0.76, 80% power, 1-sided α = 0.05, 316 OS events). Due to lower than projected event rate, trial was amended to report at the earlier of (a) 316 observed OS events or (b) 5 years of follow-up time from Step 2 accrual closure (265 OS events, 72% power, same α). OS and DFS were estimated by Kaplan-Meier and arms compared using log-rank test. Multivariable analyses (MVA) used Cox proportional hazards models. Results: Accrual began 11/2009; closed 10/2018. 354 pts rndmzd (174 chemo, 180 chemo+CRT). Median follow-up for all &amp; alive pts = 2 &amp; 7 years, respectively, with 270 OS events. Median age 63, 45% female, 81% white, 13% AA. 83% R0, 26% node negative, 96% CA19-9 &lt; 90. 13% of chemo+CRT pts did not receive RT. AEs were comparable (grade 4: 10% [chemo] vs 11% [chemo+CRT] and 1 grade 5 AE in each arm). Univariate OS/DFS results shown in Table. In initial MVA, RX, CA19-9, surgical margins were not statistically significantly associated with OS or DFS, but nodal status (OS, DFS) and race (OS) were. In further analyses, significant interactions were found between RX and nodal status for both OS and DFS. Node negative pts treated with chemo+CRT had better outcome than chemo pts; node positive pts did not (Table). Conclusions: Chemo+CRT did not improve OS overall, but did improve DFS. Both OS and DFS were improved with Chemo+CRT in node negative pts. Chemo+CRT did not increase Gr 4 or 5 AEs compared to chemo. Clinical trial information: NCT01013649 . [Table: see text]
The utility of multiple clinical variables in predicting survival outcome for patients with rectal cancer: An integrated regression and retrospective cohort analysis.
Authors: Jiasheng Zhong, Fuming Lei, Qingkun Gao, Jingyi Shi, Zhuang Sun, Wensheng Huang, Zhichao Zhai, Changming Ding, Ke An, Shufang Wang, Jialin Zhang
Journal: Journal of Clinical Oncology (2024)

e15610 Background: Prior studies have investigated clinical factors impacting the survival rates of rectal cancer patients. However, a robust and precise model for discerning these risks, which can be identified by integrated regressions analysis has yet to be established. The aim of this study is to develop and evaluate the diagnostic value of the constructed prediction model based on selected clinical variables. Methods: Patients diagnosed with stage II-III rectal cancer (April 2015-June 2021) were retrospectively enrolled as the primary cohort. Individual variables were extracted and then subjected to a K-adaptive partitioning algorithm for cut-off point determination and grouping. The Cox and least absolute shrinkage and selection operator regression (LASSO) regression were applied for independent predictors selection over significant overall survival (OS), and a nomogram was subsequently constructed. The performance of the constructed model was evaluated using the receiver operating characteristics (ROC) curves, calibration curves, and decision curve analysis (DCA), and stepwise compared with data cohorts derived from TCGA and SEER databases. Results: The Cox-LASSO analysis results considered the four independent variables as significant predictors, yielding the risk score equation: 1.086(for CEA level≥7.5 ng/ml) -1.7756(if gender is male) +1.829*(pT stages) +0.582*(pN stages). Notably, the distal resection margin (DRM) was excluded from the final model following the analysis (p = 0.060, 95%CI: -0.04-2.17). The constructed model (C-index:0.790, 95%CI: 0.673-0.743, AUC:0.873) outperformed the conventional TNM staging models (C-index:0.539, 95%CI:0.121-0.957, AUC:0.735). It stratified patients into low- or high-risk groups with significant OS differences (93% vs. 37%, p≤0.0001, respectively). The calibration curves for OS probability showed strong homogeneities between predictions and actual observations. DCA revealed positive net benefits at evaluated first, third, and fifth years. Moreover, the external validations confirmed the accurate prediction following the constructed model, with AUC of 0.745 and 0.705 for the TCGA and SEER datasets, respectively. Conclusions: This study resulted in a novel and effective prediction model for rectal cancer patients based on conventional clinical characteristics. It demonstrated solid performance and can serve as a convenient tool for OS prediction, aiding in rectal cancer patients' risk scoring and clinical decision-making.
Adjuvant chemotherapy with mFOLFOXIRI versus mFOLFOX6 in MRD-positive stage II-III colorectal cancer.
Authors: Jianwei Zhang, Huabin Hu, Yue Cai, Xiaoyu Xie, Zehua Wu, Jiayu Ling, Dianke Chen, Ping Liu, Liang Kang, Yanhong Deng
Journal: Journal of Clinical Oncology (2024)

TPS3642 Background: About 25% to 30% of resectable high-risk stage II and stage III colon cancers might relapse after radical resection and adjuvant chemotherapy with FOLFOX regimen. Recent studies have underscored the significance of circulating tumor DNA (ctDNA)-based minimal residual disease (MRD), representing a residual presence of cancer cells, as a prognostic factor for postoperative recurrence in CRC. Patients exhibiting positive MRD predicted a considerable high risk of recurrence and metastasis, even after adjuvant chemotherapy. In the realm of postoperative adjuvant chemotherapy, Comparing with FOLFOX, whether the early introduction of intensified chemotherapy, mFOLFOXIRI, could further eradicate MRD and improve the long-term prognosis remains unclear. Methods: This multicenter phase III study (NCT05427669) plans to enroll 340 colorectal cancer patients with MRD positive after curative-intent R0 surgical resection, age 18 to 70 years, ECOG performance status 0-1. Patients were randomized (1:1) to receive mFOLFOXIRI (oxaliplatin 85 mg/m², leucovorin 400 mg/m², irinotecan 150 mg/m², and 5-FU 2.4 g/m²over 46 h) or mFOLFOX6 (oxaliplatin 85 mg/m², leucovorin 400 mg/m², 5-FU bolus 400 mg/m2 then 2.4 g/m² over 46 h) every two weeks for 24 weeks (12 cycles). Patients will be followed for 5 years after the end of adjuvant chemotherapy. The primary endpoint was 3-year DFS. A gain of 14% in 3-yr DFS is expected (74% in the experimental arm vs. 60% in the control arm; α, 5% [two-sided log-rank test]; 1-β, 80%). Secondary endpoints included overall survival, 3-year distant metastasis-free survival, QoL and toxicity. Clinical trial information: NCT05427669 .
Exploratory biomarker analysis for predicting treatment effects of aflibercept in the VELOUR trial.
Authors: Ting Pu, Allyson Peddle, Pratyaksha Wirapati, Yourae Hong, Leslie Samuel, Jayesh Desai, Maigo Riener, Zacharenia (Zenia) Saridaki, David Cunningham, Sabine Tejpar, Petros Tsantoulis
Journal: Journal of Clinical Oncology (2024)

3592 Background: Second-line treatment with aflibercept and FOLFIRI in patients with metastatic colorectal carcinoma (mCRC) previously treated with oxaliplatin improved overall survival (OS) versus placebo [Hazard ratio (HR), 0.81; 95% CI, 0.71–0.93; P=0.003] 1 . However, colorectal cancer (CRC) is a heterogenous disease and the new intrinsic consensus molecular (iCMS) allows for tumours to be subtyped into unique genetic and transcriptional features 2 . We present a post hoc analysis of VELOUR patient data, to assess the impact of KRAS or BRAF mutation status and iCMS on efficacy parameters. Methods: Patient samples were classified as either KRAS or BRAF mutant or wild-type (WT) via a targeted mutation panel 1 . Gene expression data was used to classify samples as either iCMS2 or iCMS3 using a modified classifier based on iCMS signatures which are specifically up-regulated in tumour samples 2 . Results: Of the 439 patients with available RNA data, 54.9% (241/439) were classified as iCMS2; 45.1% (198/439) as iCMS3; 48.3% (212/439) as RAS mutant and 8.4% (37/439) as RAF mutant. A favourable aflibercept treatment effect was observed for patients within the KRAS WT group (Median OS from 11 to 17.7 months; HR 0.87; 95% CI 0.79-0.96, P=0.005), particularly for patients with KRAS WT iCMS2 tumours (Median OS from 15.5 to 30.4 months; HR 0.81; 95% CI 0.70-0.94, P=0.004). This is in comparison to the KRAS WT iCMS3 patients where no treatment benefit was seen (HR 0.97; 95% CI 0.82-1.14, P=0.683). In addition, no treatment benefit was seen in the KRAS mutant group (OS HR 1.03; 95% CI 0.96-1.12, P=0.405). Progression-free survival (PFS) data followed the same trend. Aflibercept seemed to also strongly benefit the 37 patients with BRAF-mutated tumours, (PFS HR 0.46, 95% CI 0.20-1.09; OS HR 0.65, 95% CI 0.29-1.48), although differences were not statistically significant. Irrespective of treatment, improved OS (HR 0.60; 95% CI 0.48-0.75, P&lt; 0.001) and PFS (HR 0.75; 95% CI 0.60-0.94, P=0.011) were observed in all patients with iCMS2 versus iCMS3 tumours, as expected. Treatment-by-mutation status interaction tests (OS P=0.40, PFS P=0.33) indicated that the aflibercept benefit was not statistically different among the mutation sub-groups, although the small sample size limited the analysis. Conclusions: In the VELOUR study, the benefit of the addition of aflibercept to FOLFIRI appears to be primarily in patients with KRAS WT tumours, especially those with KRAS WT iCMS2. The improved OS and PFS seen in all patients with iCMS2 tumours in comparison to iCMS3 is prognostic but not predictive of aflibercept treatment response in addition to FOLFIRI. On the contrary, the addition of aflibercept to FOLFIRI provided a numerical benefit in BRAF-mutated tumours, however the P-values were not statistically significant.
Simultaneous operations in patients with colorectal cancer with liver metastases.
Authors: Hurshid Islamov, Mirzagaleb Tillyashaykhov, Sunnatilla Saydullaev, Yakhyo Ziyaev, Yakov Ten, Abdurakhmon Sobitov, Sanzhar Khudoyorov, Karakhodjaev Botir, Adxamjon Yusupov
Journal: Journal of Clinical Oncology (2024)

e15586 Background: Metastatic colorectal cancer (CRC) treatment is a complex process involving surgical oncologists, chemotherapy specialists, and radiation oncologists. Objective: To assess the long-term outcomes of treating patients with metastatic CRC who has gone through simultaneous liver operations. Methods: Data and medical records of 61 patients with primary metastatic CRC treated at the Republican Specialized Scientific-Practical Center of Oncology and Radiology of the Republic of Uzbekistan between 2016 and 2020 were reviewed. Disease diagnosis and treatment were conducted following the current recommendations of the Ministry of Health of the Republic of Uzbekistan. The median follow-up period was 35 months. Results: The mean age of the patients included in the study was 59.1 years (ranging from 36 to 81 years). Of them, 32 male and 29 female patients. Metastatic cancer of the rectum was diagnosed in 18 patients (29.5%), rectosigmoid junction in 9 (14.8%), and colon in 34 (55.7%). Among the patients, 3 had low-grade tumor differentiation, 24 had medium-grade, and 34 had high-grade. According to the "T" criterion, 65.6% of the tumors were categorized as T3, 29.5% as T4, and 4.9% as T2. Different types of surgeries were performed for primary tumor localization, including abdominoperineal resection of the rectum (2 patients), right hemicolectomy (10 patients), rectal resection (5 patients), rectosigmoid junction resection (4 patients), colon resection (6 patients), left hemicolectomy (5 patients), and transabdominal rectal resection (4 patients). Postoperative complications were observed in 16 patients (bile leakage from drainage, wound suppuration, pneumonia, bladder atony). Anastomotic complications were detected in 2 patients. There were no deaths in the early postoperative period. The median overall survival was 36 months. The one-year overall survival rate in the overall group was 91.7% ± 3.7%, two-year - 76.2% ± 5.6%, three-year - 51.9% ± 7.5%. For colon cancer, the three-year overall survival was 62.7% ± 9.3%, rectosigmoid junction - 43.2% ± 20.8%, rectal cancer - 36.8% ± 13.7 (p = 0.974). Conclusions: Simultaneous operations for CRC and liver metastases combined with combination therapy contribute to stabilizing the tumor process and increasing overall survival rates.