bluuebunny/crossref_metadata_2025 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]
MicroOrganoSpheres as a clinically applicable precision oncology platform for the discovery of novel therapies in colorectal cancer.
Authors: Dayanidhi Divya Lakshmi , Rupprecht Gabrielle , Watlington Wylie , Mantyh John , Kim So Young , McCall Shannon J. , Somarelli Jason A. , Hsu Shiaowen David
Published: June 2023

3592

Background: Patient-derived models of cancer, such as cell lines, patient-derived organoids, and patient-derived xenografts, are useful models of patient response in the clinic. However, these models are often not clinically applicable within the time periods necessary to inform clinical decision making, as they can take weeks to months to develop. An ideal platform using patient-derived models would be generated from a core biopsy with a subsequent drug screen within 10-14 days to minimize delay in therapy. We recently reported the development of MicroOrganoSpheres (MOS) that can be used in drug screens within 14 days of obtaining a biopsy. In the current study, we use this MOS system as precision oncology platform in colorectal cancer (CRC) to identify new therapies and predict response to therapy. Methods: CRC patient tissue samples were collected under a Duke Institutional Review Board approved protocol (Pro00089222). Resections or biopsies were mechanically and enzymatically digested to obtain a single cell suspension. Cells were then plated in Matrigel at a ratio of 20,000 cells:5 µL Matrigel to establish “mini-bulk” organoid cultures. After establishment for 5-7 days, cultures were harvested with subsequent generation of MOS at a ratio of 50 cells per MOS. After growing for 3-4 days, MOS were used for dose-response curves using oxaliplatin, SN38, and 5-Fluorouracil (5-FU) as well as high-throughput drug screens with the NCI Approved Oncology Drugs Set VI library. Results: We developed and optimized a MOS pipeline on over 50 CRC specimens, including 9 primary rectal, 35 primary CRC, 12 CRC liver metastasis, and 1 CRC lung metastasis lines with a success rate of 80% and an average of 10-21days from biopsy to MOS generation. The high success of generating CRC MOS in a clinically applicable time frame led to the next phase of the project where a total of 10 CRC MOS were tested against standard of care chemotherapy agents used in CRC (oxaliplatin, irinotecan and 5-FU) as well as the NCI Approved Oncology Drugs Set VI within 14-21days of establishment. We noted a range of sensitivity of approximately 100-fold for standard of care agents. The most sensitive drugs found in the high-throughput screen were Bortezomib, Carfilzomib, and Panobinostat and the most resistant were Gefitinib, Chlorambucil, and Procarbazine hydrochloride. Conclusions: These results demonstrate that our MOS pipeline can be used as a precision oncology platform within a clinically applicable time frame to potentially guide therapy. We are now in the process of correlating drug response in MOS to patient outcome data and these findings will be presented at the annual meeting.
VIC regimen (vemurafenib/irinotecan/cetuximab) versus bevacizumab plus chemotherapy as first-line treatment for BRAF V600E-mutated advanced colorectal cancer.
Authors: Chen Yijiao , Zhu Dexiang , Wei Ye , Xu Jianmin
Published: June 2023

3596

Background: The need for safe and effective therapies for untreated, BRAF V600E-mutated, unresectable locally advanced or metastatic colorectal cancer remains unmet. The purpose of this study was to compare the efficacy and safety of the VIC (Vemurafenib/Irinotecan/Cetuximab) regimen versus bevacizumab plus chemotherapy as first-line setting in Asian patients. Methods: In the single-center prospective cohort study, 78 untreated, BRAF V600E-mutant, locally advanced or metastatic CRC patients were enrolled. Every two weeks, the VIC regimen and bevacizumab plus doublet or triplet chemotherapy are administered. We evaluated the objective response rate (ORR), the disease control rate (DCR), and the conversion resection rate. In progression-free survival (PFS) and overall survival, the Kaplan-Meier method was utilized (OS). Results: In the evaluable population, 32 patients received VIC regimen and 35 patients received bevacizumab plus chemotherapy. The ORR and DCR in the VIC group were significantly higher than in the bevacizumab-therapy group (ORR: 68.8% versus 40.0%, P = 0.018; DCR: 100.0% versus 80.0%, P = 0.023). The VIC regimen was significantly superior to bevacizumab plus chemotherapy for PFS (median, 11.9 vs 7.9 months; hazard ratio [HR] = 0.48, 95% CI, 0.27-0.87; P = 0.012) and OS (median, 24.5 vs 14.4 months; HR = 0.36, 95% CI, 0.16-0.78; P = 0.007). In the VIC group, the conversion resection rate for liver metastases was 42.1% (8 of 19 patients), and for local CRC it was 66.7% (6 of 9 patients with initially unresectable local CRC). Rates of treatment-related adverse events of Grade 3 to 4 were 32.4% and 31.1% for the VIC regimen and bevacizumab plus chemotherapy, respectively. Conclusions: Among Asian patients with BRAF V600E-mutated advanced CRC, the VIC regimen was superior to bevacizumab plus chemotherapy in terms of tumor response and oncological survival, with a tolerable and manageable toxicity profile in the first-line setting. Clinical trial information: NCT05540951 .
Early tumor shrinkage (ETS) as clinical factor to select maintenance with cetuximab (cet) monotherapy in patients (pts) with RAS/BRAF wild-type (wt) metastatic colorectal cancer (mCRC): A secondary endpoint analysis of the ERMES study.
Authors: Orlandi Armando , Pinto Carmine , Calegari Maria Alessandra , Normanno Nicola , Maiello Evaristo , Antonuzzo Lorenzo , Bordonaro Roberto , Zampino M. Giulia , Bergamo Francesca , Tonini Giuseppe , Tamberi Stefano , Avallone Antonio , Latiano Tiziana Pia , Rosati Gerardo , Pazzola Antonio , Ballestrero Alberto , Zaniboni Alberto , Formica Vincenzo , Barone Carlo
Published: June 2023

3603

Background: ERMES study aimed to demonstrate non-inferior PFS of maintenance with cetuximab (cet) monotherapy (arm B) compared to FOLFIRI+cet until progression (arm A) in RAS and BRAF wt mCRC pts. Although study did not meet its primary endpoint it showed better toxicity profile and OS for cet alone and comparable ORR between arms. Here we present results of ETS, a secondary endpoint. Methods: ETS was defined as ≥20% reduction of the sum of target lesions at 8 weeks from the start of treatment, and was assessed by blinded independent central review. PFS and OS were compared between ETS+ and ETS- pts according to treatment arm in the modified Per-Protocol (mPP) population. Results: 327 of 337 (97%) pts were evaluable for ETS. In arm A, no statistically significant differences were observed between ETS+ and ETS- cohort for PFS (11.9 m, 95%CI 11.28-13.19, vs 12.2 m, 95%CI 10.82-14.93; HR 1.05, 95%CI 0.73-1.50; p 0.77) and OS (30.75 m, 95%CI 25.09-37.73, vs 25.46 m, 95%CI 19.96-34.63; HR: 0.79, 95%CI 0.50-1.24; p 0.29). In arm B, a statistically significant difference was observed between ETS+ and ETS- cohort for PFS (10.62 m, 95%CI 9.86-13.09, vs 8.52 m, 95%CI 7.89-9.37; HR 0.70, 95%CI 0.49-1.00; p 0.036) and for OS (38.88 m, 95%CI 34.53-43.25, vs27.43 m, 95%CI 20.59-36.64; HR 0.60, 95%CI 0.38-0.93; p 0.019). ETS+ pts reported no statistically significant difference between arm B and arm A in terms of PFS (HR 1.12, 95%CI 0.83-1.49; p 0.43) while experiencing a better OS for arm B compared to arm A (HR 0.72, 95%CI 0.50-1.05; p 0,08). Conclusions: In pts achieving ETS, induction treatment with FOLFIRI+cet may be de-escalated to cet alone without detrimental effect on PFS, resulting in less toxicity and better OS. These data support the hypothesis that ETS might be a clinical dynamic predictor of efficacy of a less intensive maintenance strategy, allowing to plan de-escalation to cet alone after 4 months of FOLFIRI+cet induction. Clinical trial information: NCT02484833 .
Subgroup analyses of safety and efficacy by number and types of prior lines of treatment in FRESCO-2, a global phase III study of fruquintinib in patients with refractory metastatic colorectal cancer.
Authors: Dasari Arvind , Lonardi Sara , Garcia-Carbonero Rocio , Elez Elena , Yoshino Takayuki , Sobrero Alberto F. , Yao James C. , Garcia-Alfonso Pilar , Kocsis Judit , Cubillo Antonio , Sartore-Bianchi Andrea , Satoh Taroh , Randrian Violaine , Tomasek Jiri , Chong Geoff , Yang Zhao , Pallai Rajash , Carton Iris , Tabernero Josep , Eng Cathy
Published: June 2023

3604

Background: Effective treatment options are limited for patients (pts) with refractory metastatic colorectal cancer (mCRC). Fruquintinib (F), a highly selective, potent, oral tyrosine kinase inhibitor of VEGFR-1, -2, and -3, was evaluated in the global phase III FRESCO-2 study (NCT04322539) and demonstrated a clinically meaningful and statistically significant improvement in OS and PFS with a favorable safety profile. Here we report subgroup analyses of efficacy and safety by prior lines (PL) and types of anti-cancer treatment (Tx) for metastatic disease (MD). Methods: FRESCO-2 was conducted in the US, Europe, Japan & Australia, comparing F + best supportive care (BSC) with Placebo (P) + BSC. Pts were given 5 mg PO, QD, 3 wks on, 1 wk off, in a 28-day cycle. Eligible pts received prior chemotherapy, anti-VEGF, and if RAS wild type, anti-EGFR therapies; if BRAFV600E mutant or MSI-H, and appropriate targeted regimen; and had progressed on, or were intolerant to, trifluridine/tipiracil (TAS-102) and/or regorafenib (R). Subgroup (sbgrps) analyses for efficacy and safety were performed according to number of prior lines of tx (LOT) and by types of therapy. Results: A total of 691 pts were randomized; F:461 vs P:230. The median number of prior lines of anti-cancer tx for metastatic disease F vs P was 4 (2, 16) vs 4 (2, 12). F improved OS and PFS compared to P for all sbgrps and prior tx for MD, consistent with those of the ITT population (pop). (Table: OS reported by sbgrps and prior tx for MD). Occurrence of adverse events (AEs) and serious adverse events were generally balanced between F vs P and consistent across all subgroups. The most common ≥ G3 AEs in ≥5% of pts on F within majority of sbgrps were hypertension, asthenia and palmar plantar erythrodysesthesia and were consistent with the overall safety population. Additional analyses based on duration of prior anti-VEGF and last therapy prior to F will be presented at the conference. Conclusions: F demonstrated clinically meaningful improvement in OS, PFS with an acceptable safety profile across all sbgrps. These results were consistent with the effect observed in the overall population; irrespective of previous tx with anti-VEGF, anti-EGFR, TAS-102 and R further supporting F as a potential new tx option for pts with refractory mCRC. Clinical trial information: NCT04322539 . [Table: see text]
Cancer of unknown primary with gastrointestinal profiles: A distinct CUP subset.
Authors: Shah Aakash Tushar , Estrella Jeannelyn , Dasari Priyadarsini , Willett Anneleis , Allam Joelle , Higbie Victoria , Le Phat , Lee Michael Sangmin , Matamoros Aurelio , Lano Elizabeth A , Raghav Kanwal Pratap Singh , Huey Ryan W
Published: June 2023

3606

Background: Cancer of unknown primary (CUP) with a “gastrointestinal (GI) profile” appears to be a clinically distinct subset, based on immunophenotyping, specifically staining with cytokeratins 20 (CK20) and 7 (CK7), a type I and II keratin, respectively and caudal type homeobox 2 (CDX2) protein, a transcription factor expressed in nuclei of intestinal epithelial cells. However, only a limited clinicomolecular account of this entity exists. Comprehensive profiling is needed to substantially impact personalized therapeutics and improve prognosis. Methods: We identified 401 pts evaluated at MD Anderson Cancer Center. Pts were classified into 3 cohorts based on immunohistochemistry: lower GI profile CUP (LGI-CUP), other-GI profile CUP (OGI-CUP), or non-GI CUP (NGI-CUP). A control group of known lower GI primary cancers was derived from MSK-IMPACT data (cBioPortal, 1075 patients, LGI-KP). Clinical and pathological data including molecular profiling, therapy and survival were logged. Fisher-exact test was used. Kaplan-Meier method was used to estimate overall survival (OS) and compared with log-rank test. Results: Among 748 pts, 401 (53.6%) had adequate immunostaining for analysis. Of these, 72 (18.0%), 226 (56.4%) and 103 (25.7%) were classified as LGI-CUP, OGI-CUP, and NGI-CUP, respectively. LGI-CUP were enriched for adenocarcinoma (88% v 86% v 35%, P < 0.0001) and good risk Culine score (59% v 51% v 37%, P = 0.02), compared to OGI-CUP and NGI-CUP, respectively. While NGI-CUP had greater proportions of poorly differentiated histology (91% v 55% vs 66%, P < 0.0001) and bone metastases (30% vs 7% v 24%, P = 0.0001) compared to LGI-CUP and OGI-CUP, respectively. Comparison of key mutations is shown in table. Median OS of LGI-CUP (14.6 months [95%CI: 12.0 – 17.2]) was similar to OGI-CUP (14.3 months [95%CI: 10.7 – 18.0]) and NGI-CUP (16.2 months [95%CI: 12.4 – 20.0]), P = 0.75, but significantly lower than LGI-KP cohort (28.6 months, [95%CI 24.4 – 32.7], p < 0.001). LGI-CUP was treated preferentially with fluoropyrimidine-based GI regimen [5-FU/capecitabine +/- oxaliplatin or irinotecan] (77% vs 43% v 5%) compared to OGI-CUP and NGI-CUP, respectively. However, median OS for LGI-CUP treated with 5-FU-based regimens was higher (16.0, 95%CI 13.0 – 19.0) than those treated with non-5-FU-based treatments (10.9, 95%CI 5.6 – 16.2), P = 0.002. Conclusions: LGI-CUP appears to be a molecularly distinct entity from and NGI-CUP, as well as lower GI CUP from known entities. LGI-CUP patients treated with 5-FU-based regimens appear to have improved survival. [Table: see text]
Predictive value of tumor-infiltrating lymphocyte (TIL) dynamics in the tumor microenvironment (TME) during preoperative chemoradiotherapy (CRT) on pathologic complete response (pCR) in microsatellite-stable (MSS) locally advanced rectal cancer (LARC).
Authors: Imai Mitsuho , Bando Hideaki , Tsukada Yuichiro , Kato Takeshi , Komatsu Yoshito , Uemura Mamoru , Yuki Satoshi , Taketomi Akinobu , Fujisawa Takao , Nakamura Yoshiaki , Kojima Motohiro , Koyama Shohei , Oum Chiyoon , Shin Seunghwan , Ock Chan-Young , Nishikawa Hiroyoshi , Ito Masaaki , Yoshino Takayuki
Published: June 2023

3608

Background: Preoperative CRT followed by consolidation nivolumab before surgery showed a promising pCR rate in MSS LARC; both high PD-L1 expression and an elevated CD8+ T cell/effector regulatory T cell ratio analyzed by pre-CRT samples were independently related to high pCR rate (Bando H, Clin Cancer Res. 2022). Here, we applied AI-powered spatial TIL analysis to the VOLTAGE study to investigate whether dynamic change of TIL in TME may predict pCR in MSS LARC. Methods: The VOLTAGE study is a multicenter phase I/II study to evaluate the efficacy of CRT followed by 5 cycles of nivolumab and surgery in patients (pts) with LARC. In this study, tumor samples were obtained at multiple time points; pre-CRT (B1), post-CRT/pre-nivolumab (B2), post-3 cycles of nivolumab (B3), and surgery. In this analysis, a total of 86 H&E whole-slide images (WSI) harvested at B1 and B2 time points from all the pts enrolled in the VOLTAGE study were included in the analysis. Lunit SCOPE IO (Lunit, Republic of Korea), AI-powered H&E-WSI analyzer developed based on 16,443 WSI with pathologists' annotations, was applied to quantify TIL density in TME. Results: In a total of 43 pts, pCR rate of MSS and microsatellite instability-high (MSI-H) were 28.9% (11/38) and 60% (3/5), respectively. In MSS subgroup (n = 38), which has a higher unmet need for pCR prediction, tumor samples with pCR (n = 11) had increased TIL density in TME (tTIL) in post-CRT (B2, median [IQR] 726 [249-1607] /mm2) compared to pre-CRT (B1, 598 [366-905] /mm2), whereas those without pCR (n = 27) had decreased tTIL in post-CRT (405 [148-748] /mm2), compared to pre-CRT (B1, 748 [460-1153] /mm2). Intratumoral TIL density changes were more prominent than stromal TIL density changes in MSS tumor samples with pCR (mean fold change x17.7 vs. x1.5). MSS Pts with tTIL change from B1 to B2 (during CRT) more than x1.8 times achieved 75% (6/8) pCR rate, whereas those with tTIL change less than x1.8 had 16.7% (5/30) pCR rate (p = 0.0035). Conclusions: Change of TIL density in TME during CRT was significantly correlated with favorable clinical outcome of preoperative CRT and consolidation nivolumab, resulting in high pCR rate in MSS LARC.
Combined associations of a healthy lifestyle and body mass index on colorectal cancer recurrence and survival: A cohort study.
Authors: Barot Shabane , Rantanen Petri , Nordenvall Caroline , Lindforss Ulrik , Hallqvist Everhov Asa , Larsson Susanna , Lindblom Annika , Liljegren Annelie
Published: June 2023

3609

Background: Colorectal cancer (CRC) risk is associated with modifiable lifestyle factors including smoking, physical inactivity, Western diet, and excess body weight. The impact of lifestyle factors on survival is less known. A cohort study was conducted to investigate the combined effects of a pre-diagnostic healthy lifestyle and body mass index (BMI) on prognosis following CRC diagnosis. Methods: Treatment and follow-up data were collected from the patient files of 1098 participants from the Swedish Colorectal cancer low-risk study cohort including stage I-III CRC patients. A healthy lifestyle and BMI (HL) score was computed using self-reported data on smoking status, physical activity, adherence to a Mediterranean diet pattern, and BMI five years before diagnosis, and divided into four categories ranging from least to most healthy. Survival analyses were performed to assess recurrence-free survival and overall survival across categories of exposure, using the Kaplan-Meier method and Cox proportional hazards model, the latter adjusted for age, sex, and educational level. Results: Among 1098 participants with stage I-III CRC, 233 (21.2%) had an HL score of 0-1 (least healthy), 354 (32.2%) HL score of 2, 357 (32.5%) HL score of 3 and 154 (14.0) HL score of 4 (most healthy). Participants missing follow-up data (n = 29) or relapsing ≤ 6 months (n = 29) were excluded from the recurrence-free survival analysis. 221 events of cancer recurrence were observed among 1040 participants during a median follow-up time of 4.3 years, and 542 deaths among 1098 participants during a median follow-up time of 6.3 years. Patients with the healthiest lifestyle had an improved recurrence-free survival (HL 4 vs HL0-1, HRadj 0.51 (95% CI 0.31-0.83) and overall survival (HL 4 vs HL 0-1, HRadj 0.52 (95% CI 0.38-0.70)). Stratifying these results for cancer stage (I-III) and tumor site (colon/rectum) did not alter estimated HR:s or 95% CI:s. Avoidance of smoking and being physically active were independently associated with improved recurrence-free survival and overall survival: non-smoking vs smoking HRadj 0.62 (95% CI 0.43-0.90), high vs low levels of physical activity HRadj 0.71 (95% CI 0.54-0-94)). Conclusions: Our study indicates that pre-diagnostic adherence to a healthy lifestyle may increase the recurrence-free and overall survival of patients with stage I-III CRC. Avoidance of smoking and being physically active were the strongest risk-reducing factors for these outcomes. [Table: see text]
Immunotherapy for localized MSI-H colorectal cancer: Characterizing endoscopic and imaging response.
Authors: Fox Daniel Aaron , Konishi Tsuyoshi , Kaur Harmeet , You Y. Nancy , Raghav Kanwal Pratap Singh , Ge Phillip S. , Messick Craig , Johnson Benny , Morris Van K. , Thomas Jane V , Shah Preksha , Bednarski Brian K. , Kopetz Scott , Chang George J. , Ludford Kaysia , Higbie Victoria , Overman Michael J. , Bhamidipati Deepak
Published: June 2023

3610

Background: Early data suggests that immunotherapy (IO) for localized colorectal cancer (CRC) is associated with high rates of pathologic complete response (pCR) and durable remission. This study aims to characterize endoscopic, imaging, and pathological outcomes among patients who received IO for localized CRC. Methods: This was a single-institution retrospective analysis of patients with MSI-H CRC who received at least one cycle of anti-PD-1 therapy for localized (stage I-III) MSI-H CRC. Patient and tumor characteristics were obtained from the clinical record. Endoscopy reports were assessed using standardized criteria to determine response and imaging was assessed using RECIST v1.1 where applicable. Endoscopic complete response (endoCR) was characterized by flat, white scar and/or telangiectasia without residual ulcer or nodularity. Categorical variables were compared using Fisher’s exact test. Results: 37 patients who received a median of 8 cycles of pembrolizumab (n = 36) or nivolumab (n = 1) for localized CRC were identified, of which 16 (43%) had a rectal primary. 10 patients (27%) had mucinous features on pathology. The best endoscopic response was complete response (CR) in 13 of 30 (43%) patients, which was achieved after a median of 6 cycles. The rate of endoCR after ≤ 4 cycles of IO was similar to the rate of endoCR after > 4 cycles (29% vs 50%, p = 0.284). The best imaging response was CR in 6 of 32 (19%) of patients. The rate of CR on imaging after ≤ 4 cycles and > 4 cycles of IO was 6% and 36% respectively (p = 0.064). In cases where imaging and endoscopy were available (n = 24), discrepancy in best response was noted in 14 (58%) cases. The most common discrepancy was partial response on imaging when endoCR was noted (n = 6 cases). 16 patients proceeded to surgical resection (after a median of 8 cycles) of which 11 (69%) had pCR despite non-CR on either endoscopy (n = 7) or imaging (n = 9). The endoscopic reports indicating residual disease prior to surgery included findings such as ulceration, scarring, strictures, and an obstructing mass. Of 15 patients who did not proceed to surgery and had follow-up more than 6 months after completion of IO, 13 (87%) had no evidence of progression at a median follow-up of 19.3 months from IO start. Conclusions: Discrepancies between endoscopic, imaging, and pathological outcomes were frequent, indicating a need for improved clinical response criteria. Nevertheless, immunotherapy was associated with deep and durable responses in most patients with localized MSI-H CRC.
The number of lymph nodes examined as a poor prognosis factor in stage II and stage III colon cancer patients undergoing curative surgery.
Authors: JEON JEONGSEOK , Shen Lingjie , Kim Yitak , Kim Hyunwook , van Gestel Anna J. , Han Yoon Dae , Han Dai Hoon , You Seng Chan , Ahn Joong , Shin Sangjoon , Geleijnse Gijs , Kim Han Sang
Published: June 2023

3612

Background: The number of lymph nodes (LN) examined is a key factor in determining the stage of colorectal cancer. Over the past 20 years, the examination of fewer than 12 LN has been regarded as a poor prognosis. However, surgical procedures and pathologic examination improvements have increased the number of LN examined. This raised the question of reassessing the best cutoff point for staging colon cancer patients undergoing curative surgery. Methods: We reviewed a total of 3,126 eligible patients with stage II-III colon cancer collected from the Yonsei Cancer Center Registry (YCC) database between 2005 and 2015. As a validation cohort, we used clinicodemographic data from 9,604 patients with stage II-III colon cancer identified by the Netherlands Cancer Registry (NCR) between 2006 and 2015. The hazard ratio (HR) obtained from Cox-proportional regression was used to investigate the effect of LNs' yield on 6-year overall survival (OS). The optimal LN yield was evaluated by analyzing every cutoff from 3 to 165. We used the Kaplan-Meier method to compare the effect of higher vs. lower optimal LN yield on a 6-year OS. Univariate and multivariate Cox regressions were conducted. Results: The proportion of patients with fewer than 12 LN examined dramatically decreased between 2005 and 2015 (17.4% in 2005 vs. 0.6% in 2015, P< 0.001). Based on the 12 LN examined as the conventional cutoff number, there was no significant association between 6-year OS and LN yield in all stages II-III patients (HR = 1.21, P= 0.116; n = 3,126), stage II (HR = 1.39, P= 0.068; n = 1,570), and stage III (HR = 1.18, P= 0.297; n = 1,557) colon cancer. Interestingly, a higher cutoff of 20 LN examined was associated with a significant increase in 6-year OS in all patients (HR = 1.51, P< 0.001 in patients with LN examined less than 20). Multivariate Cox-proportional hazard regression showed a significant decrease in 6-year OS in stage II (HR = 1.39, P= 0.026) and stage III (HR = 1.54, P< 0.001) with less than 20 LN yield. Consistent with the result in the YCC database, less than 20 of LN yield was associated with poorer 6-year OS in stage II-III patients (HR = 1.25, P< 0.001; n = 9,604), stage II (HR = 1.43, P< 0.001; n = 4,689), and stage III (HR = 1.13, P= 0.007; n = 4,915) in the NCR, respectively. Conclusions: Less than 20 LN examined is associated with a poorer prognosis in patients with surgically treated colon cancer, compared to the current cutoff value of 12. Further validation of re-evaluating criteria on the inadequacy of LN retrieval in high-risk stage II colon cancer is warranted.