bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic landscapes of early-onset versus average-onset colorectal cancer populations.
Authors: Storandt Michael H. , Shi Qian , Eng Cathy , Lieu Christopher Hanyoung , Stoppler Melissa Conrad , George Thomas J. , Mauer Elizabeth , Teslow Emily , Mahipal Amit , Jin Zhaohui 
Published: June 2023

3536 Background: Early-onset colorectal cancer (eoCRC, initial CRC diagnosis at age < 50 years) has been increasing in the past two decades especially in Western countries. This study evaluates somatic and germline profiles in eoCRC compared to average-onset CRC (aoCRC, initial CRC diagnosis at age ≥ 50 years). Methods: This is a retrospective, cross-sectional study utilizing data from de-identified records of colorectal cancer patients tested with the Tempus xT assay from 2017 to 2022. Briefly, the assay is a targeted panel that detects single nucleotide variants, insertions and/or deletions, and copy number variants in 598-648 genes, as well as chromosomal rearrangements in 22 genes with high sensitivity and specificity. Baseline characteristics and immunologic markers were compared between eoCRC and aoCRC by Wilcoxon Rank Sum or Chi-squared test (reporting p-values). Somatic and germline mutations were compared between two age groups with false discover rate adjustments (reporting q-values). Results: In this study, 2,379 eoCRC and 8,627 aoCRC patients were included, with the majority diagnosed with stage IV disease. Additionally, germline alterations were assessed on a subset of 6,311 patients with tumor/normal match testing (eoCRC = 1,413 and aoCRC = 4,898). Left-sided primaries were more common in eoCRC (85% left/rectum in eoCRC vs. 75% left/rectum in aoCRC (p < 0.001), and rates of microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) were lower compared to aoCRC (4.2% vs. 6.8%, p < 0.001). eoCRC has a unique somatic mutation profile compared to aoCRC. A higher prevalence of germline mutations was observed in eoCRC overall (6.9% vs. 5%, p = 0.006); however, no statistically significant differences were observed in individual germline genes compared to aoCRC, likely due to relatively small numbers. Conclusions: eoCRC has a unique mutational profile and presence of germline mutations in 6.9% of eoCRC, indicating a potential role for universal germline testing in CRC. [Table: see text]
Impact of sex on the efficacy of first-line mFOLFOX6 (plus or minus bevacizumab) versus mFOLFOX6 (plus or minus bevacizumab) plus Y90-radioembolization in patients with metastatic colorectal cancer: An exploratory, retrospective analysis of the phase III SIRFLOX trial.
Authors: Heinrich Kathrin , Heinemann Volker , Westphalen Benedikt , Oecal Osman , Van Hazel Guy A. , Gibbs Peter , Seidensticker Max , Ricke Jens , Seidensticker Ricarda 
Published: June 2023

3564 Background: Clinical trials in metastatic colorectal cancer (mCRC) investigating systemic and local treatment options are usually conducted irrespective of sex. However, sex-associated differences relating to safety and efficacy in the treatment of mCRC are of gaining interest. Methods: The SIRFLOX trial investigated the efficacy and safety of adding radioembolization using yttrium-90 resin microspheres (SIRT) to standard fluorouracil, leucovorin, and oxaliplatin (FOLFOX)–based chemotherapy in patients with previously untreated mCRC comparing it to standard treatment with FOLFOX-based chemotherapy. In this post-hoc analysis, the study population was stratified for sex (male versus female) using Propensity Score Matching (PSM) with baseline variables with difference (p-value < 0.20) in a gender specific comparison serving as matching covariates (age, BSA, sidedness, bilirubin). Groups were matched in a 1:1 ratio, with the nearest calculated propensity logit, with a caliper width of ≤0.20 of the SD of the propensity score logit. Evaluated efficacy endpoints were progression-free survival (PFS, primary endpoint of the trial) and overall survival (OS). Results: 356 (67.2%) male and 173 (32.6%) female patients were randomized and treated in the SIRFLOX trial. In the overall study population, there was no difference regarding PFS or OS between male and female patients. No difference in PFS and OS between male (n = 101) and female (n = 101) patients could be observed independently of treatment arm. After PSM, female patients showed significant benefit regarding PFS from SIRT + chemotherapy compared to chemotherapy alone (12.2 [9.9-17] vs. 9.9 [7.5-12.7], p = 0.047) that translated into a trend to longer OS (27.3 [25.6-36.5] vs. 23.7 [17.8-28.8] months, p = 0.094, HR 0.68 [0.43-1.10]) while male patients did not show a difference regarding PFS and OS between treatment arms (p = 0.170, HR 1.41 [0.87-2.10]). In the experimental arm, female patients had significantly longer OS compared to male patients (27.3 [25.6-36.5] vs. 21.0 [17.9-26.7] months, p = 0.031, HR 0.64 [0.42-0.96]). Sex did not impact on OS in the chemotherapy arm (p = 0.410, HR 1.22 [0.76-2.02]). Conclusions: In the SIRFLOX trial, female patients seem to benefit from the addition of SIRT to chemotherapy regarding PFS and OS. This was not observed in male patients. To our knowledge, this is the first analysis to show sex-differences in the application of SIRT in patients with mCRC. Our results support the development of specific protocols according to sex. Clinical trial information: NCT00724503 .
Associations between early tumor shrinkage (ETS)/depth of response (DpR) and overall and post-progression survivals (OS/PPS) from the Analysis and Research in Cancers of the Digestive System (ARCAD) database.
Authors: Bando Hideaki , Takeda Yuriko , Misumi Toshihiro , Suzuki Motoko , Wakabayashi Masashi , Yamazaki Kentaro , Oki Eiji , Douillard Jean-Yves , Punt Cornelis J. A. , Koopman Miriam , Van Cutsem Eric , Bokemeyer Carsten , Venook Alan P. , Lenz Heinz-Josef , Maehara Yoshihiko , Andre Thierry , Shi Qian , De Gramont Aimery , Yoshino Takayuki 
Published: June 2023

3566 Background: According to the various types of clinical trials for metastatic colorectal cancer (mCRC), ETS and DpR are suggested as the surrogates of OS. Whereas associations between ETS/DpR and OS/PPS in the era of chemotherapy (chemo) +anti-EGFR antibody (ab)/bevacizumab (bev) in 1st line therapy have not been elucidated. Methods: From 40,889 Individual patient data (IPD) from 59 studies in ARCAD mCRC database, 2,138 treatment-naïve pts with RAS wild-type (wt) mCRC were selected from 7 randomized studies (PRIME, CAIRO2, CRYSTAL, OPUS, CALGB80495, WJOG4407G, ATOM) of chemo with/without anti-EGFR ab or bev. The ETS was defined as 20%≥ tumor shrinkage at 8 ± 2wks (ETS+: ≥20%, ETS-: <20%). Multivariate Cox regression models for OS/PPS were performed to investigate associations between ETS+ and ETS- by primary tumor location (overall/left-sided/right-sided), adjusting for potential confounders. DpR was defined as tumor shrinkage at nadir. OS/PPS were evaluated across quartile limits of DpR by multivariate Cox regression models. Results: In pts with overall or left-sided RAS wt mCRC, adjusted hazard ratios (HRs) of OS/PPS between ETS- and ETS+ for chemo +anti-EGFR ab, chemo +bev, and chemo alone showed great improvement, respectively (Table). In pts with overall or left-sided RAS wt mCRC, HRs of ETS for OS/PPS are higher in pts treated with chemo +anti-EGFR ab compared to those treated with chemo +bev or chemo alone. Compared to the pts with highest quartile (defined as ≥ 75th percentile (Q3)) of DpR, HRs of OS/PPS for lower quartile groups showed upward trends in pts with RAS wt & overall (Table). Conclusions: ETS/DpR in pts with RAS wt mCRC might be a potential prognostic marker of OS/PPS regardless of targeted therapy and primary tumor location. Superior prognostic values of ETS+ are expected in pts treated with anti-EGFR ab. [Table: see text]
Prognostic impact of depth of response (DpR) and early tumour shrinkage (ETS) in patients (pts) with BRAF V600E mutated (mut) metastatic colorectal cancer (mCRC) receiving targeted therapy (TT) as second-line treatment.
Authors: Vetere Guglielmo , Germani Marco Maria , Bensi Maria , Antoniotti Carlotta , Lonardi Sara , Passardi Alessandro , Ghelardi Filippo , Calegari Maria Alessandra , Borelli Beatrice , Santucci Sara , Intini Rossana , Cristarella Eleonora , Persano Mara , Puccini Alberto , Lavacchi Daniele , Noto Laura , Zichi Clizia , Giampieri Riccardo , Salati Massimiliano , Cremolini Chiara 
Published: June 2023

3568 Background: Encorafenib and cetuximab (EC) is the standard of care for pre-treated patients (pts) with BRAF V600E mut mCRC. DpR and ETS previously showed a strong correlation with survival outcomes in mCRC pts receiving 1st-line therapy. We assessed these tumour dynamic response parameters and their association with clinical outcome in pts with BRAF V600E mut mCRC treated with TT in second-line. Methods: Patients treated in a real-life setting with EC or EC plus binimetinib (ECB) in 20 Italian centres were included. Pts with measurable disease and at least one available disease reassessment by CT scan were eligible. Pts experiencing disease progression as best response (i.e. primary resistant) were not evaluable for DpR and ETS. Associations between DpR and ETS and progression free survival (PFS) and overall survival (OS) were tested by univariate and multivariate models. Results: 105 pts were included: 89 (85%) and 16 (15%) pts were treated with EC and ECB, respectively. Median PFS and OS were 5.2 and 10.3 mos, respectively. Twenty-nine pts (28%) were primary resistant, while 76 (72%) pts achieved disease control (51 [48%] and 25 [24%] pts had SD or CR/PR, respectively). Among baseline characteristics, the presence of peritoneal metastases was a predictor of primary resistance (p = 0.04). Among pts evaluable for response parameters (n = 76), median DpR was 15% and ETS occurred in 28 pts (37%). Mucinous histology was associated with a significantly lower magnitude of DpR (p = 0.005) and a lower rate of ETS (p = 0.002). A significant association between DpR and PFS was observed, both as a dichotomous ( ie, ≥ or < median value) and continuous variable in univariate and multivariate analyses. Also RECIST response correlated with PFS in the two models (table). DpR was associated with OS in the univariate analyses, but this was not confirmed in the multivariate models (table). No correlation between ETS and survival, either as a dichotomous ( ie, ≥ or < 20%) or a continuous variable, was observed. Conclusions: Having a DpR of at least 15% predicts longer PFS and OS in patients with BRAF V600E mut mCRC receiving TT as second-line treatment. An independent cohort of pts treated with second-line chemotherapy +/- antiangiogenic is under investigation as control group. [Table: see text]
Impact of WNT/B-catenin alterations and metastasis location among patients with metastatic colorectal cancer (mCRC) treated with immune checkpoint inhibitors (ICI) combinations.
Authors: Ros Montañá Javier , Baraibar Iosune , Navarro Garces Victor , Saoudi Gonzalez Nadia , Vega Sharela , Bueno Sergio , Garcia Ariadna , Salva Francesc , Comas Raquel , Rodríguez Castells Marta , Saavedra Omar , Alonso Guzman , Garralda Elena , Tabernero Josep , Vivancos Ana , Elez Elena 
Published: June 2023

3573 Background: Emerging evidence suggests that WNT mutations and liver/peritoneal metastases in mCRC may have an immunosuppressive role that could affect ICI activity. Aim: To evaluate the impact of WNT alterations and liver/peritoneal metastasis among patients with mCRC treated with ICi. Methods: Patients from Vall d’Hebron Hospital, with mCRC treated with ICI from 2017-2022 were included. WNT alterations (APC, AXIN1/2, CTNNB1, FBXW7, EPHB2, RNF43 and SOX9) were evaluated using NGS (tissue). Clinical outcomes were calculated using survival Kaplan-Meier curves. Patients' characteristics were collected retrospectively. Results: Overall, 104 patients were included (66 MSI patients and 38 MSS patients). Among MSI patients, median age was 63 years (22-95), with 53% female, and 64% of patients received immunotherapy in 1st or 2nd line. Regarding tumor characteristics, 72% were right-sided and 82% harbored WNT alterations. 75% of patients presented with liver/peritoneal metastases. Patients with WNT mutations and peritoneal/liver metastases exhibit lower ORR (46% vs 57% p 0.5 and 45% vs 75%, p 0.03 respectively). Peritoneal/liver metastases were associated with lower PFS (HR 3.6 CI95% 1.27-10.24 p 0.02 respectively). Overall, tumors with WNT pathway alterations tend to have shorter PFS and OS. Liver metastases were associated with lower OS (NR vs 34 months HR 2.49 CI95% 1.01-6.17 p 0.05). Table summarizes outcomes. Among MSS patients, median age was 57 years (41-75), with 25% female and 92% of patients receiving immunotherapy > = 3rd line. Regarding tumor characteristics, 78% were left-sided and 90% harboured WNT alterations. 79%, of patients presented with liver or peritoneal metastases. WNT mutations were not associated with ORR, patients without liver/peritoneal metastases tend to have higher ORR (12.5% vs 3.3% p 0.335). Patients with WNT alterations had worse PFS (9.23 vs 1.87 months, p 0.12), and liver metastases were associated with lower PFS (6.98 vs 1.79 months HR 2.87 CI95% 1.17-7.09 p:0.02). Regarding OS, tumors harboring WNT alterations have shorter OS (8.4 vs 12 months p 0.63). The presence of liver or peritoneal metastases was associated with lower OS (NR vs 7.85 months HR 3.69 CI95% 1.09-12.55 p: 0.04). Conclusions: In our cohort, WNT pathway mutations, and liver metastases were associated with worse ORR, PFS, and OS regardless of MSI status. These findings need further validation in a prospective cohort. [Table: see text]
Deep learning-derived spatial organization features on histopathology images to predict prognosis in patients with colorectal liver metastasis, after hepatectomy.
Authors: Wang Xin , Li Yu-hong , Xing Baocai , Qi Lin , Liang Jie-Ying , Li Zhong-Wu , Xi Shao-Yan , Lai Yu-Ni , Gao Feng , Wang De-Shen , Hu Ming-Tao , Cao Yi , Zhang Xian-Rui , Xu Li-Jian , Chan Ronald CK 
Published: June 2023

3581 Background: Histopathological images of colorectal liver metastasis (CRLM) contain rich morphometric information that may predict patient outcomes, but current indicators depend on labor-intensive and subjective visual estimation. Herein, we aimed to develop an automated framework for tissue classification of routine H&E stained whole-slide images and establish a risk-scoring model for better prognosis prediction in patients with CRLM. Methods: Using 161,371 hand-delineated image patches, we trained a robust deep convolutional neural network- CRLM-SPA for accurate classification of CRLM into seven tissue types. With the tissue classification results on two independent in-house cohorts (SYSUCC: n = 433, BJCH: n = 404), we systematically quantified spatial organization features (SOFs), involving whole-slide, tumor-infiltrating and tumor-distal SOFs for different tissue types as well as the interactions between tumor and non-tumor tissues. Subsequently, univariate Cox proportional hazards regression analysis was performed to investigate the association between various SOFs and patient outcomes. Nonredundant SOFs that are clinically relevant were selected to build a risk-scoring model for prognosis using multivariate Cox regression analysis in the SYSUCC cohort, followed by validation in the BJCH cohort. Results: CRLM-SPA achieved an overall classification accuracy of > 93% in an independent set of 17,653 image patches. With the classification result, we calculated various SOFs and built a four-SOF risk-scoring model that significantly predicted overall survival (OS) in the discovery cohort, SYSUCC ( P = 1.40 10-5; HR = 2.26; 95%CI: 1.55 - 3.29) and the independent validation cohort, BJCH ( P = 4.59 × 10-4; HR = 2.00; 95%CI: 1.35 - 2.97). The prognostic performance of our SOF risk-scoring model is independent of the clinical risk score (CRS) system. Further stratification analyses in patients without preoperative chemotherapy (CTx) indicated that adjuvant CTx consistently improved OS in the SOF high-risk subgroups in both cohorts ( P = 0.018 and 0.049), but not in the SOF low-risk subgroups. Furthermore, a combined scoring system incorporating SOF and CRS considerably improved the prognostic performance in both cohorts over the individual SOF and CRS systems. Conclusions: CRLM-SPA showed a high accuracy in tissue classification and robustness in extracting prognostic information from H&E images. The SOF risk-scoring system demonstrated a strong and robust prognostic value that is independent of CRS, and could therefore provide a time- and cost-efficient tool to assist clinical decision making for patients with CRLM.
The impact of sodium-glucose cotransporter-2 inhibitors on the outcome of patients with colorectal adenocarcinoma.
Authors: Chiang Cho Han , Chiang Cho Hung , HSIA YUANPING , See Xin Ya , Wang Shih-Syuan , Chen Yuan-Jen , Peng Chun-Yu , Horng Chuan-Sheng , Wong Kit Yee , Jaroenlapnopparat Aunchalee , Liu Weitao , Chiang Cho Hsien , Shiah Her-Shyong , Neilan Tomas G. 
Published: June 2023

3583 Background: The mortality of colorectal cancer remains high despite the development of novel anti-neoplastic agents. Preclinical studies have shown that colorectal cancer upregulates the expression of sodium-glucose cotransporter 2 (SGLT2) channels and inhibition of these channels by SGLT2 inhibitors (SGLT2i) reduces tumor proliferation. We aimed to investigate the impact of SGLT2i on the outcome of patients with colorectal cancer. Methods: We conducted a retrospective cohort study by including all adult patients with colorectal adenocarcinoma and type 2 diabetes mellitus in two tertiary centers in Taiwan. SGLT2i and non-SGLT2i patients were matched 1:1 based on age, sex, and cancer stage. The primary outcome was overall survival (OS) and progression-free survival (PFS), and the secondary outcomes were previously reported serious adverse events associated with the use of SGLT2i. Results: We identified 1347 patients with colorectal cancer and type 2 diabetes mellitus, from which 92 patients in the SGLT2i cohort were matched to the non-SGLT2i cohort. Compared to non-SGLT2i recipients, SGLT2i recipients had a higher rate of OS (5-year OS: 86.2% [95% CI: 72.0-93.5] vs. 62.3% [95% CI: 50.9-71.8], p = 0.013) and PFS (5-year PFS: 76.6% [95% CI: 60.7-86.7] vs. 57.0% [95% CI: 46.2-66.4], p = 0.021). In Cox proportional hazard analyses, the use of SGLT2i was associated with a 50-70% reduction in the risk of all-cause mortality and disease progression. The rate of cancer-associated mortality was lower in the SGLT2i group (7% vs. 21%, p = 0.005). SGLT2i were not associated with an increased risk of sepsis, hypoglycemia, or acute kidney injury. We did not detect any cases of urosepsis or diabetic ketoacidosis in the SGLT2i group. Conclusions: The use of SGLT2i was associated with a higher rate of survival in colorectal cancer patients with diabetes mellitus. [Table: see text]
Optimal molecular-targeted therapies as first-line treatment for RAS wild-type, right-sided metastatic colorectal cancer from the Analysis and Research in Cancers of the Digestive System (ARCAD) database.
Authors: Yamazaki Kentaro , Takeda Yuriko , Misumi Toshihiro , Suzuki Motoko , Wakabayashi Masashi , Bando Hideaki , Oki Eiji , Douillard Jean-Yves , Punt Cornelis J. A. , Van Cutsem Eric , Bokemeyer Carsten , Venook Alan P. , Maehara Yoshihiko , Heinemann Volker , Cremolini Chiara , Nakayama Goro , Andre Thierry , Shi Qian , De Gramont Aimery , Yoshino Takayuki 
Published: June 2023

3588 Background: Although anti-EGFR antibody plus doublet chemotherapy has become the standard of first-line treatment for RAS wild-type (wt), left sided metastatic colorectal cancer (mCRC), the optimal molecular-targeted therapy for RAS wt, right-sided mCRC is not clear. Methods: To evaluate the efficacy between anti-EGFR antibody vs. bevacizumab combination therapy, from 40,889 Individual patient (pt) data from 59 studies in ARCAD mCRC database, 723 pts with RAS wt, right-sided mCRC who received a first-line molecular-targeted therapy with backbone chemotherapy (FOLFOX/FOLFIRI when anti-EGFR antibody combination, and FOLFOX/FOLFIRI/CAPOX/FOLFOXIRI when bevacizumab combination) were selected from 10 randomized studies (FIRE-3, CALGB80495, CRYSTAL, PRIME, CAIRO2, OPUS, TRIBE, TRIBE2, ATOM, and CCOG1201). Primary objective was overall survival (OS), and secondary objectives were progression-free survival (PFS) and overall response rate (ORR); Hazard ratio (HR) and Odds ratio (OR) were adjusted for ECOG-PS, age, and gender. Propensity score matching (PSM) and inverse probability treatment weighting (IPTW) as sensitivity analysis were also performed. Secondary analyses were limited to BRAF wt pts. Results: Anti-EGFR antibody and bevacizumab were administrated in 329 and 394 pts, respectively, of whom 162 and 151 pts were BRAF wt, respectively. Baseline characteristics were as follows (anti-EGFR antibody/bevacizumab): median age, 63.0 years both; female, 47.1/46.4%; and ECOG-PS 0, 53.2/65.2%. The OS and PFS were significantly prolonged in pts receiving bevacizumab combination therapy compared to those receiving anti-EGFR antibody combination therapy (Table). These trends were more pronounced when limited to BRAF wt pts (Table). There were no significant differences in ORR for both overall and BRAF wt pts. These results were similar in the sensitivity analysis (Table). Conclusions: For patients with RAS wt or RAS/ BRAF wt, right-sided mCRC, bevacizumab combination therapy is preferred first-line treatment. [Table: see text]