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Microvascular density assessed by CD31 predicts clinical benefit upon bevacizumab treatment in metastatic colorectal cancer: results of the PassionATE study, a translational prospective Phase II study of capecitabine and irinotecan plus bevacizumab followed by capecitabine and oxaliplatin plus bevacizumab or the reverse sequence in patients in mCRC.

ABSTRACT: Background:Targeted therapies offer novel opportunities to explore biomarkers based on their mode of action. Taking this into consideration, we evaluated six angiogenesis-related proteins as potential predictive biomarkers, which expression might predict the benefit of bevacizumab treatment in patients with metastatic colorectal cancer (mCRC). Methods:This was a phase II multicenter, two-armed, randomized study, in which patients with mCRC were treated with XELIRI (capecitabine and irinotecan) plus bevacizumab followed by XELOX (capecitabine and oxaliplatin) plus bevacizumab (Arm A) or the reverse sequence (Arm B). Tissue expression level of six prespecified candidates [microvessel density assessed by CD31, PTEN, ?V integrin, CD98hc, uPAR and NRP-1] was analyzed via immunohistochemistry. The prognostic impact on survival was quantified using the Cox regression model. The predictive potential for benefit from Arm A versus Arm B treatment was investigated by fitting an interaction between the biomarkers and treatment assignment within a multivariable Cox model. Results:In total, 74 out of 126 patients were included in the analysis. The expression of PTEN, ?V integrin, uPAR and NRP-1 was not associated with progression-free survival (PFS) or overall survival (OS). For the first time, we identified that patients with tumors expressing CD98hc had a longer PFS than patients without CD98hc-expression (p?=?0.032). More importantly, and in accordance with previous studies, low microvessel density was found to be associated with a reduced PFS [adjusted HR per doubling of CD31-expression (p?=?0.53, 95% confidence interval: 0.30-0.95, p?=?0.034)]. Conclusions:These results can contribute to the development of a personalized strategy for the treatment of mCRC with bevacizumab.

SUBMITTER: Bianconi D

PROVIDER: S-EPMC7446555 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Microvascular density assessed by CD31 predicts clinical benefit upon bevacizumab treatment in metastatic colorectal cancer: results of the PassionATE study, a translational prospective Phase II study of capecitabine and irinotecan plus bevacizumab followed by capecitabine and oxaliplatin plus bevacizumab or the reverse sequence in patients in mCRC.

Bianconi Daniela D Herac Merima M Posch Florian F Schmeidl Margit M Unseld Matthias M Kieler Markus M Brettner Robert R Müllauer Leonhard L Riedl Jakob J Gerger Armin A Scheithauer Werner W Prager Gerald G

Therapeutic advances in medical oncology 20200818

<h4>Background</h4>Targeted therapies offer novel opportunities to explore biomarkers based on their mode of action. Taking this into consideration, we evaluated six angiogenesis-related proteins as potential predictive biomarkers, which expression might predict the benefit of bevacizumab treatment in patients with metastatic colorectal cancer (mCRC).<h4>Methods</h4>This was a phase II multicenter, two-armed, randomized study, in which patients with mCRC were treated with XELIRI (capecitabine an ...[more]

PMID: 32922518

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Project description:Several randomized trials have indicated that combination chemotherapy applied in metastatic colorectal cancer (mCRC) does not significantly improve overall survival when compared to the sequential use of cytotoxic agents (CAIRO, MRC Focus, FFCD 2000-05). The present study investigates the question whether this statement holds true also for bevacizumab-based first-line treatment including escalation- and de-escalation strategies.The AIO KRK 0110/ML22011 trial is a two-arm, multicenter, open-label randomized phase III trial comparing the efficacy and safety of capecitabine plus bevacizumab (Cape-Bev) versus capecitabine plus irinotecan plus bevacizumab (CAPIRI-Bev) in the first-line treatment of metastatic colorectal cancer. Patients with unresectable metastatic colorectal cancer, Eastern Cooperative Oncology Group (ECOG) performance status 0-1, will be assigned in a 1:1 ratio to receive either capecitabine 1250 mg/m(2) bid for 14d (d1-14) plus bevacizumab 7.5 mg/kg (d1) q3w (Arm A) or capecitabine 800 mg/m(2) BID for 14d (d1-14), irinotecan 200 mg/m(2) (d1) and bevacizumab 7.5 mg/kg (d1) q3w (Arm B). Patients included into this trial are required to consent to the analysis of tumour tissue and blood for translational investigations. In Arm A, treatment escalation from Cape-Bev to CAPIRI-Bev is recommended in case of progressive disease (PD). In Arm B, de-escalation from CAPIRI-Bev to Cape-Bev is possible after 6 months of treatment or in case of irinotecan-associated toxicity. Re-escalation to CAPIRI-Bev after PD is possible. The primary endpoint is time to failure of strategy (TFS). Secondary endpoints are overall response rate (ORR), overall survival, progression-free survival, safety and quality of life.The AIO KRK 0110 trial is designed for patients with disseminated, but asymptomatic mCRC who are not potential candidates for surgical resection of metastasis. Two bevacizumab-based strategies are compared: one starting as single-agent chemotherapy (Cape-Bev) allowing escalation to CAPIRI-Bev and another starting with combination chemotherapy (CAPIRI-Bev) and allowing de-escalation to Cape-Bev and subsequent re-escalation if necessary.ClinicalTrials.gov Identifier NCT01249638 EudraCT-No.: 2009-013099-38.

Project description:BackgroundThe randomized phase III study (WJOG4407G) showed equivalent efficacy between FOLFOX and FOLFIRI in combination with bevacizumab as the first-line treatment for metastatic colorectal cancer (mCRC). We studied whole genome copy number profiles using array-based comparative genomic hybridization (aCGH) analysis of tumor tissue samples obtained in this study. The aim of this study was to identify gene copy number alterations that could aid in selecting either FOLFOX or FOLFIRI in combination with bevacizumab for patients with mCRC.Materials and methodsDNA was purified from 154 pretreatment formalin-fixed paraffin-embedded tissue samples (75 from the FOLFOX arm and 79 from the FOLFIRI arm) of 395 patients enrolled in the WJOG4407G trial and analyzed by aCGH. Genomic regions greater than 1.2-fold were regarded as copy number gain (CNG).ResultsPatient characteristics between the treatment arms were well balanced except for tumor laterality (left side; 64% in FOLFOX arm and 80% in FOLFIRI arm, p = .07). FOLFIRI showed a trend toward better response rate (RR), progression-free survival (PFS) and overall survival (OS) than FOLFOX in the patients with CNG of chromosome 8q24.1 (Fisher's exact test, p = .134 for RR; interaction test, p = .102 for PFS and p = .003 for OS) and 8q24.2 (Fisher's exact test, p = .179 for RR; interaction test, p = .144 for PFS and p = .002 for OS).ConclusionChromosome 8q24.1-q24.2 may contain genes that could potentially serve as predictive markers for selecting either FOLFOX or FOLFIRI in combination with bevacizumab for treatment of patients with mCRC.Implications for practiceBevacizumab has been used as a standard first-line treatment for patients with metastatic colorectal cancer (mCRC) in combination with either oxaliplatin-based or irinotecan-based chemotherapy. Until now, there has been no predictive marker to choose between the two combination chemotherapies. This array-based comparative genomic hybridization analysis revealed that the difference in therapeutic effect between the two combination chemotherapies is prominent in patients with mCRC with gene copy number gain in chromosome 8p24.1-p24.2. Such patients showed more favorable response and survival when treated with irinotecan-based combination chemotherapy. Overlapping genes commonly found in this region may be predictive biomarkers of the efficacy of the combination chemotherapy with bevacizumab.

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