scholarly journals A Promising Role of TGF-β Pathway in Response to Regorafenib in Metastatic Colorectal Cancer: A Case Report

Medicina ◽  
2021 ◽  
Vol 57 (11) ◽  
pp. 1241
Author(s):  
Simona De Summa ◽  
Katia Danza ◽  
Brunella Pilato ◽  
Giuseppina Matera ◽  
Rossella Fasano ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Cancer Progression ◽  
Primary Tumor ◽  
Somatic Mutations ◽  
Kinase Inhibitor ◽  
Predictive Biomarkers ◽  
Immunological Response ◽  
Cell Junction ◽  
Ion Torrent Pgm

Colorectal cancer (CRC) is one of the most common cancer types around the world. The prognosis of patients with advanced diseases is still poor in spite of currently available therapeutic options. Regorafenib is an oral tyrosine kinase inhibitor (TKI) approved to treat refractory metastatic colorectal cancer (mCRC). We investigated Somatic mutations in several genes involved in immunological response and cancer progression in both long/short responder mCRC patients who underwent third-line therapy with regorafenib to identify predictive biomarkers of response using Ion Torrent PGM sequencing and bioinformatic tools. We found Somatic mutations in TGFBR1, TGFBR2, and TGFBR3 genes in primary tumor and metastases samples of long-responder patients. Furthermore, our bioinformatic results show that they were mainly enriched in immune response, cell junction, and cell adhesion in long responder patients, particularly in primary tumor and metastatic sites. These data suggest that the TGF-b pattern could be the leading actor of a prolonged response to this drug.

Blood-based biomarkers in metastatic colorectal cancer patients treated with FOLFIRI plus regorafenib or placebo: Results from LCCC1029.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 587-587
Author(s):  
Yingmiao Liu ◽  
Kirsten Burdett ◽  
Mark D. Starr ◽  
J. Chris Brady ◽  
Ace Joseph Hatch ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Multiple Testing ◽  
Kinase Inhibitor ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Fold Change ◽  
Response To Treatment ◽  
Colorectal Cancer Patients

587 Background: The LCCC1029 trial demonstrated that addition of the multitargeted kinase inhibitor regorafenib (Rego) to FOLFIRI in metastatic colorectal cancer (mCRC) patients (pts) modestly prolonged progression-free survival (PFS). In this preplanned analysis, circulating angiogenic and inflammatory proteins were explored as potential prognostic and predictive biomarkers of Rego benefit. Methods: Plasma samples from 149 mCRC pts (107 in Rego + FOLFIRI and 42 in placebo + FOLFIRI) were evaluated for 20 markers at baseline (n = 149) and cycle 1 day 21 (C1D21, n = 81). Predictive and prognostic values of each marker at baseline were analyzed for both PFS and overall survival (OS) using Cox proportional hazard models. On-treatment changes were quantified as fold change [log2(C1D21/baseline)] and differences between arms were evaluated using the Mann-Whitney test. Results: The primary objective of this study was to determine whether any marker was predictive of benefit with Rego for PFS. Although no treatment by marker interactions were significant after adjusting for multiple testing, the top three markers of interest were OPN (unadjusted p-values of 0.02), VCAM-1 (0.02), and PDGF-AA (0.04). VCAM-1 was also predictive for OS benefit in pts treated with Rego (unadjusted p = 0.01). Baseline levels of multiple markers (including HGF, IL-6, PlGF, VEGF-R1, OPN) were prognostic for both PFS and OS. Higher levels of these markers were associated with worse survival. Biomarker changes in response to treatment were explored and compared between arms. Fold change of three markers (PlGF, VEGF-A, VCAM-1) were significantly different between arms (p < 0.0001), all being markedly up-regulated in the Rego arm compared to the placebo after treatment. Conclusions: In this hypothesis generating report, VCAM-1, OPN, and PDGF-AA were the top biomarkers when analyzing the potential predictive association with PFS, where a lower hazard was observed for pts receiving Rego. Candidate prognostic markers were identified, including PlGF and VEGF-R1, key factors in VEGF biology. Biomarker changes observed here may offer insights into potential combinatorial strategies with Rego for future studies.

scholarly journals Baseline and Kinetic Circulating Tumor Cell Counts Are Prognostic Factors in a Prospective Study of Metastatic Colorectal Cancer

Diagnostics ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 502
Author(s):  
Virgílio Souza e Silva ◽  
Emne Ali Abdallah ◽  
Angelo Borsarelli Carvalho de Brito ◽  
Alexcia Camila Braun ◽  
Milena Shizue Tariki ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Drug Resistance ◽  
Prospective Study ◽  
Metastatic Colorectal Cancer ◽  
Clinical Outcomes ◽  
Predictive Biomarkers ◽  
Multi Drug Resistance ◽  
Cell Counts ◽  
Potential Clinical Benefit ◽  
A Prospective Study

The discovery of predictive biomarkers in metastatic colorectal cancer (mCRC) is essential to improve clinical outcomes. Recent data suggest a potential role of circulating tumor cells (CTCs) as prognostic indicators. We conducted a follow-on analysis from a prospective study of consecutive patients with mCRC. CTC analysis was conducted at two timepoints: baseline (CTC1; before starting chemotherapy), and two months after starting treatment (CTC2). CTC isolation/quantification were completed by ISET® (Rarecells, France). CTC expressions of drug resistance-associated proteins were evaluated. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan–Meier method. Seventy-five patients were enrolled from May 2012 to May 2014. A CTC1 cut-off of >1.5 CTCs/mL was associated with an inferior median OS compared to lower values. A difference of CTC2−CTC1 > 5.5 CTCs/mL was associated with a reduced median PFS. By multivariate analysis, CTC1 > 1.5 CTCs/mL was an independent prognostic factor for worse OS. Multi-drug resistance protein-1 (MRP-1) expression was associated with poor median OS. CTC baseline counts, kinetics, and MRP-1 expression were predictive of clinical outcomes. Larger studies are warranted to explore the potential clinical benefit of treating mCRC patients with targeted therapeutic regimens guided by CTC findings.

Exploratory biomarker findings from cohort 2 of MODUL: An adaptable, phase 2, signal-seeking trial of fluoropyrimidine + bevacizumab ± atezolizumab maintenance therapy for BRAFwt metastatic colorectal cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3570-3570
Author(s):  
Josep Tabernero ◽  
Axel Grothey ◽  
Dirk Arnold ◽  
Michel Ducreux ◽  
Peter J. O'Dwyer ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Maintenance Treatment ◽  
Predictive Biomarkers ◽  
Experimental Treatment ◽  
Progression Free Survival ◽  
Phase 2 ◽  
First Line ◽  
Tissue Samples ◽  
First Line Therapy

3570 Background: MODUL is an adaptable, phase 2, signal-seeking trial testing novel agents as first-line therapy for predefined subgroups of patients with metastatic colorectal cancer (mCRC). Previously reported findings demonstrated that adding atezolizumab to fluoropyrimidine (FP)/bevacizumab as first-line maintenance treatment after induction with FOLFOX + bevacizumab did not improve efficacy outcomes in BRAFwt mCRC. Given these efficacy results, exploratory assessments on tumour samples were conducted to provide insights into factors that might affect efficacy of maintenance treatment and provide guidance on appropriate therapeutic strategies for BRAFwt mCRC. Methods: In patients with BRAFwt tumours (Cohort 2), experimental treatment was FP/bevacizumab + atezolizumab. Primary efficacy endpoint: progression-free survival (PFS). Overall survival (OS) was a secondary endpoint. Archival tissue samples from 104 patients were analysed by immunohistochemistry (IHC) at HistoGeneX (PD-L1; CD8/GrB/FoxP3). SP142 antibody was used for PD-L1 IHC analysis, which evaluated PD-L1low (IC 0–1) vs PD-L1high (IC > 1) in correlation with PFS and OS in the control and experimental arms. CD8/GrB/FoxP3 triplex staining was also performed to evaluate potential correlations with efficacy. Results: 445 patients with BRAFwt mCRC were randomised (2:1 ratio) to maintenance treatment in Cohort 2. Archival samples from 104 patients were analysed: FP/bevacizumab + atezolizumab (n = 82); FP/bevacizumab (n = 22). The biomarker evaluable population (BEP) for PD-L1 was n = 81 for FP/bevacizumab + atezolizumab [PD-L1low n = 35 (43%); PD-L1high n = 46 (57%)] and n = 22 for FP/bevacizumab [PD-L1low n = 16 (72%); PD-L1high n = 6 (28%)]. The BEP for CD8/GrB was n = 50 for FP/bevacizumab + atezolizumab and n = 16 for FP/bevacizumab. No difference in PFS or OS was observed in the FP/bevacizumab + atezolizumab vs FP/bevacizumab arms for PD-L1high [PFS: HR = 1.5 (95% CI 0.45−4.8), p = 0.51; OS: HR = 1.3 (95% CI 0.38−4.1), p = 0.71] or PD-L1low [PFS: HR = 0.92 (95% CI 0.47−1.8), p = 0.81; OS: HR = 0.78 (95% CI 0.4−1.5), p = 0.48]. Similar results were observed with CD8/GrBhigh [PFS: HR = 0.73 (95% CI 0.27−2.0), p = 0.55; OS: HR = 0.66 (95% CI 0.24−1.8), p = 0.44], CD8/GrBlow [PFS: HR = 1.0 (95% CI 0.42–2.5), p = 0.96; OS: HR = 0.73 (95% CI 0.3–1.8), p = 0.5], FoxP3high [PFS: HR = 0.97 (95% CI 0.37−2.5), p = 0.95; OS: HR = 0.95 (95% CI 0.36−2.5), p = 0.91] and FoxP3low [PFS: HR = 0.73 (95% CI 0.29−1.9), p = 0.53; OS: HR = 0.5 (95% CI 0.19−1.3), p = 0.18]. Conclusions: These findings suggest that PD-L1, CD8/GrB and FoxP3 might not be predictive biomarkers in BRAFwt mCRC. Further analyses are needed to further evaluate potential predictive and prognostic factors of response in this setting. Clinical trial information: NCT02291289.

Tumor bulk as a prognostic biomarker and predictor of benefit from anti-EGFR therapy in patients with metastatic colorectal cancer: Analysis of 476 patients from the ARCAD Clinical Trials Program.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 108-108
Author(s):  
Benjamin Adam Weinberg ◽  
Manel Rakez ◽  
Benoist Chibaudel ◽  
Tim Maughan ◽  
Richard Adams ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Primary Tumor ◽  
Lung Metastases ◽  
Performance Status ◽  
Progression Free Survival ◽  
Predictive Biomarker ◽  
Wild Type ◽  
Cox Models ◽  
Study Results

108 Background: Primary tumor sidedness has emerged as a prognostic and predictive biomarker for patients (pts) with metastatic colorectal cancer (mCRC). Tumor bulk has also been postulated to predict response to anti-EGFR therapy. We sought to evaluate the role of tumor bulk as a predictive biomarker to anti-EGFR therapy in pts with left- (LS) and right-sided (RS) mCRC. Methods: Data from 476 pts with mCRC enrolled across 2 first-line trials of anti-EGFR plus chemotherapy versus chemotherapy were pooled. Pts were included if there was available information on tumor sidedness and tumor bulk. All were KRAS wild-type and BRAF wild-type or unknown BRAF status. The right colon was defined as the cecum through the transverse colon, and the left colon as the splenic flexure through the rectum. Tumor bulk was the mean tumor size of target lesions at baseline, bulky defined as > 3.5 cm. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier and Cox models adjusting for performance status (PS), platelet count, primary tumor (PT) resection, number of metastatic sites, and stratified by study. Results: Pts with bulky tumors (211, 44%) had higher PS, white blood cell and platelet counts, higher CEA, fewer sites of metastatic disease, more liver than lung metastases, and fewer had PT resection. OS and PFS medians in months (mos) are presented in the table with 95% confidence intervals (95%CIs). Bulky tumors had inferior median OS compared with non-bulky (mOS, 17.9 vs. 21.3 mos, HRadj 1.33, 95% CI 1.05-1.69, P = 0.016) although median PFS was similar (mPFS, 8.6 vs. 8.7 mos, HRadj 1.15, 95% CI 0.92-1.42, P = 0.21). Conclusions: Tumor bulk is an independent prognostic factor for OS in KRAS wild-type and BRAF wild-type or unknown BRAF status pts. Pts with non-bulky RS tumors have survival outcomes similar to pts with bulky LS tumors. Although the mPFS for pts with RS tumors treated with anti-EGFR therapy was the lowest across subgroups, this finding was not statistically significant. Further research is warranted into whether pts with bulky RS tumors benefit from anti-EGFR therapy. Clinical trial information: NCT00182715, NCT00640081. [Table: see text]

scholarly journals Regorafenib in metastatic colorectal cancer: more data for clinical decisions

2021 ◽  
Vol 23 (3) ◽  
pp. 436-441
Author(s):  
Vladislav V. Petkau ◽  
Alisa A. Karimova ◽  
Zinaida V. Akishina
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trials ◽  
Tumor Microenvironment ◽  
Metastatic Colorectal Cancer ◽  
Kinase Inhibitor ◽  
Cancer Drug ◽  
Efficacy And Safety ◽  
Tumor Immunogenicity ◽  
Metastatic Activity ◽  
Multiple Kinase Inhibitor

Regorafenib is a multiple kinase inhibitor. It influences/blocks angiogenesis (VEGFR1-3, TIE2), proliferation (KIT, RET, RAF-1, BRAF), metastatic activity (VEGFR2-3, PDGFR), tumor immunogenicity (CSF1R), tumor microenvironment (PDGFR-, PDGFR-, FGFR1-2). Regorafenib has several indications including metastatic colorectal cancer. Efficacy and safety of regorafenib data from clinical trials (CORRECT, CONCUR, CONSIGN) and observational trials from real world (REBECCA, CORRELATE, RECORA, PMS, REGOTAS) are summarized and presented in this issue. State of the matter of molecular-biologic predictors (KRAS, PIK3CA ANG-2, VEGF-A, LDH, CCL5/CCR5, CA 19-9) and radiological predictors (RadioCORRECT and other trials) is highlighted. Regimens with dose modification and its influence on effectiveness and tolerability of regorafenib are described according to the data from ReDOS, RESET, REARRANGE trials. The results from retrospective trials comparing regorafenib and another approved for refractory metastatic colorectal cancer drug trifluridine/tipiracil are presented.

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