Inclusion of targeted therapies in the standard of care for metastatic colorectal cancer patients in a German cancer center: the more the better?!

Moehler, Markus; Thomaidis, Thomas; Zeifri, Chourouk; Barhoom, Tareq; Marquardt, Jens U.; Ploch, Philippe; Schattenberg, Jörn M.; Maderer, Annett; Schimanski, Carl Christoph; Weinmann, Arndt; Woerns, Marcus A.; Kranich, Anne L.; Warnecke, Jens M.; Galle, Peter R.

doi:10.1007/s00432-014-1829-6

Cited by 10 publications

(9 citation statements)

References 28 publications

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“…Second, our data indicate that tumor cell intravasation could be sensitive even to moderate diminishment of EGFR-dependent production of VEGF and IL-8 proteins, IL-8–dependent neutrophil influx, and ensuing delivery of neutrophil MMP-9 releasing matrix-bound VEGF. The dependence of intravasation-sustaining intratumoral vessels on VEGF that regulates their permeability and integrity could be reflected in increased benefits of anti-EGFR therapies combined with anti-VEGF agents, a combinatorial approach currently used in clinic, albeit mainly for late-stage cancers [49] , [69] , [70] , [71] . Furthermore, our newly established mechanism suggests that additional beneficiary effects may come from combining EGFR-targeted therapy with anti–IL-8 and/or anti-inflammatory drugs [72] .…”

Section: Discussionmentioning

confidence: 99%

EGFR Regulates the Development and Microarchitecture of Intratumoral Angiogenic Vasculature Capable of Sustaining Cancer Cell Intravasation

et al. 2015

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Many malignant characteristics of cancer cells are regulated through pathways induced by the tyrosine kinase activity of the epidermal growth factor receptor (EGFR). Herein, we show that besides directly affecting the biology of cancer cells per se, EGFR also regulates the primary tumor microenvironment. Specifically, our findings demonstrate that both the expression and signaling activity of EGFR are required for the induction of a distinct intratumoral vasculature capable of sustaining tumor cell intravasation, a critical rate-limiting step in the metastatic cascade. An intravasation-sustaining mode of intratumoral angiogenic vessels depends on high levels of tumor cell EGFR and the interplay between EGFR-regulated production of interleukin 8 by tumor cells, interleukin-8–induced influx of tumor-infiltrating neutrophils delivering their unique matrix metalloproteinase-9, and neutrophil matrix metalloproteinase-9–dependent release of the vascular permeability and endothelial growth factor, VEGF. Our data indicate that through VEGF-mediated disruption of endothelial layer integrity and increase of intratumoral vasculature permeability, EGFR activity significantly facilitates active intravasation of cancer cells. Therefore, this study unraveled an important but overlooked function of EGFR in cancer, namely, its ability to create an intravasation-sustaining microenvironment within the developing primary tumor by orchestrating several interrelated processes required for the initial steps of cancer metastasis through vascular routes. Our findings also suggest that EGFR-targeted therapies might be more effective when implemented in cancer patients with early-staged primary tumors containing a VEGF-dependent angiogenic vasculature. Accordingly, early EGFR inhibition combined with various anti-VEGF approaches could synergistically suppress tumor cell intravasation through inhibiting the highly permeable angiogenic vasculature induced by EGFR-overexpressing aggressive cancer cells.

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Section: Discussionmentioning

confidence: 99%

EGFR Regulates the Development and Microarchitecture of Intratumoral Angiogenic Vasculature Capable of Sustaining Cancer Cell Intravasation

et al. 2015

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“…These findings from preclinical [19][20][21]28] and retrospective clinical studies [18] collectively suggest that prolonged treatment with anti-EGFR antibody shifts the cancer cells toward a less EGFR-dependent phenotype and more VEGF-dependent angiogenesis; therefore, the use of an anti-EGFR antibody before bevacizumab appears to be a beneficial sequence for a targeted molecular therapy approach.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, a recent retrospective analysis of the sequential use of bevacizumab and anti-EGFR antibody found that the prior use of bevacizumab had an ad- verse effect on the subsequent activity of the anti-EGFR antibody [25][26][27] . On the other hand, the prior use of the anti-EGFR antibody was suggested to elicit some biological changes to the tumors that made them more sensitive to subsequent bevacizumab-containing therapy [18,28] .…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Second-Line Bevacizumab-Containing Chemotherapy for Patients with Metastatic Colorectal Cancer following First-Line Treatment with an Anti-Epidermal Growth Factor Receptor Antibody

Hasegawa¹,

Taniguchi²,

Mitani³

et al. 2017

Oncology

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Objective: Anti-epidermal growth factor receptor (EGFR) antibodies and bevacizumab are commonly used, sequentially, as palliative chemotherapies for patients with metastatic colorectal cancer. However, little is known about the efficacy of second-line treatments containing bevacizumab after first-line treatment with an anti-EGFR antibody. Methods: We retrospectively reviewed 128 patients who received second-line bevacizumab-containing chemotherapy and evaluated the effect of prior use of anti-EGFR antibody on the efficacy of the second-line treatment. Results: As first-line treatments, 35 of these patients received only cytotoxic chemotherapy (cohort A), 58 received bevacizumab-containing chemotherapy (cohort B), and 35 received anti-EGFR-containing chemotherapy (cohort C). The median progression-free survival (PFS) with the second-line bevacizumab-containing therapy was 8.3 months in cohort C, 6.9 months in cohort A (hazard ratio [HR], 1.43; 95% confidence interval [CI], 0.83-2.51), and 5.6 months in cohort B (HR, 1.95; 95% CI, 1.18-3.22). Multivariate analysis showed that PFS in cohort C was the same as that in cohort A, but better than that in cohort B. The overall response rate in cohort C (25.7%) was also similar to that in cohort A (20.0%), but better than that in cohort B (10.3%). Conclusions: Prior use of anti-EGFR antibody did not adversely affect the efficacy of subsequent bevacizumab-containing chemotherapy.

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“…Consistent with this notion, a recent retrospective analysis of 103 patients noted a trend towards improved OS in patients receiving first-line EGFR inhibitors and second-line VEGF inhibitors, compared with patients receiving first-line VEGF inhibitors and second-line EGFR inhibitors [78]. Similarly, a prior study involving 58 patients with mCRC reported that previous exposure to VEGF inhibitors decreased the efficacy of subsequent EGFR inhibitor-based therapy [79].…”

Section: Z a Wainberg And A Drakakimentioning

confidence: 84%

The importance of optimal drug sequencing in metastatic colorectal cancer: biological rationales for the observed survival benefit conferred by first-line treatment with EGFR inhibitors

Wainberg

Drakaki

2015

Expert Opinion on Biological Therapy

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Inclusion of targeted therapies in the standard of care for metastatic colorectal cancer patients in a German cancer center: the more the better?!

Cited by 10 publications

References 28 publications

EGFR Regulates the Development and Microarchitecture of Intratumoral Angiogenic Vasculature Capable of Sustaining Cancer Cell Intravasation

EGFR Regulates the Development and Microarchitecture of Intratumoral Angiogenic Vasculature Capable of Sustaining Cancer Cell Intravasation

Efficacy of Second-Line Bevacizumab-Containing Chemotherapy for Patients with Metastatic Colorectal Cancer following First-Line Treatment with an Anti-Epidermal Growth Factor Receptor Antibody

The importance of optimal drug sequencing in metastatic colorectal cancer: biological rationales for the observed survival benefit conferred by first-line treatment with EGFR inhibitors

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