EGFR, BRAF and KRAS Status in Patients Undergoing Pulmonary Metastasectomy from Primary Colorectal Carcinoma: A Prospective Follow-Up Study

Schweiger, Thomas; Hegedűs, Balázs; Nikolowsky, Christoph; Hegedüs, Zita; Szirtes, Ildikó; Mair, Rudolf; Birner, Peter; Döme, Balázs; Láng, György; Klepetko, Walter; Ankersmit, Hendrik Jan; Höetzenecker, Konrad

doi:10.1245/s10434-013-3386-7

Cited by 54 publications

(40 citation statements)

References 31 publications

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“…Neither COX-2 nor PGE were independent prognostic factors. However, the KRAS mutational status and the presence of lymphatic vessel invasion were associated with an impaired prognosis, as previously published (17,18).…”

Section: Impact Of Cox-2 and Pge2 Expression On Outcome Parameterssupporting

confidence: 76%

“…It seems that a certain tumor biology determines the site of recurrence. KRAS mutations for example are associated with increased lung metastasis, whereas loss of Smad4 expression seems to predict liver metastasis (17,37,38). This is an important information since repeated pulmonary and hepatic metastasectomy can be offered to the patients with good results and low morbidity (39).…”

Section: Discussionmentioning

confidence: 99%

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Impact of cyclooxygenase-2 and prostaglandin-E2 expression on clinical outcome after pulmonary metastasectomy

et al. 2017

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Background: Pulmonary metastasectomy (PM) is a standard procedure in the treatment of stage IV colorectal cancer (CRC). In most centers the indication for PM is solely based on clinical factors without taking the tumor biology into account. This results in diverse outcomes ranging from long-term remission to early recurrence. Inflammation is considered a hallmark of cancer development and progression. On the other hand the accessibility of CRC cells to the immune system reflects the grade of tumor aggressiveness.We sought to investigate the impact of cyclooxygenase-2 (COX-2) and prostaglandin-E2 (PGE2) expression in pulmonary metastases on different outcome parameters following PM. Results: COX-2 and PGE2 were detected in nearly every pulmonary CRC metastasis. Staining intensities of pulmonary metastases correlated only weakly with intensities found in primary tumors. When dividing metastases in high expressing and low expressing tumors, a trend towards longer recurrence free survival and improved survival was found in tumors with strong COX-2 and PGE2 staining. Conclusions:In conclusion, this pilot study shows that COX-2 and PGE2 are uniformly overexpressed in pulmonary metastases from CRC. High expression of COX-2 and PGE2 seems to reflect a beneficial tumor biology with late tumor recurrence and prolonged overall survival after PM.

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Section: Impact Of Cox-2 and Pge2 Expression On Outcome Parameterssupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Impact of cyclooxygenase-2 and prostaglandin-E2 expression on clinical outcome after pulmonary metastasectomy

et al. 2017

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“…Recently, markers that determine tumor behavior and aggressiveness have been in the spotlight of research. 4,5 Programmed death-1 (PD-1) and its ligands PD-L1 and PD-L2 are important immune checkpoints. PD-1 is an inhibitory co-signal on activated lymphocytes and plays a crucial role in regulating the magnitude and quality of T-cell responses.…”

Section: Introductionmentioning

confidence: 99%

494 PD1-positive tumor-infiltrating lymphocytes are associated with poor clinical outcome after pulmonary metastasectomy for colorectal cancer

Chang

Ignatova

Kollmann³

et al. 2018

Journal of Investigative Dermatology

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Pulmonary metastasectomy (PM) is routinely performed in colorectal cancer (CRC) patients with oligometastatic spreading to the lungs. Patients with an aggressive tumor phenotype should be excluded from PM, since its benefit is outweighed by early tumor recurrence and impaired prognosis. Expression of PD-1 and its ligands are prognostic factors in a variety of primary tumors. However, their impact on patients' outcome in the setting of PM for CRC has not been evaluated before. 53 CRC patients with pulmonary metastases receiving PM with curative intent were included in this study. Tissue samples of resected pulmonary metastases and available corresponding primary tumors were collected and assessed for PD-1, PD-L1 and PD-L2 expression by tumor-infiltrating lymphocytes (TILs) and tumor cells. Expression patterns were correlated with clinical outcome parameters. PD-1 and PD-L1 expression was commonly found in TILs and tumor cells. Expression levels significantly differed between metastases and primary tumors. High PD-1 expression by TILs was associated with impaired overall survival (low vs high expression (mean, 95% CI): 78 mo (60-96) vs 35 mo (25-44); p = 0.011). Additionally, the subgroup of patients, who experienced an upgrading in their TILs/PD1 status between primary and metastasis had a worse survival outcome compared with patients with the same grade or a downgrading (34 mo (26-42) vs 96 mo (72-120); p = 0.004). Thus, PD-1 expression by TILs is a strong prognostic marker in CRC patients with pulmonary spreading treated by PM. Moreover, this study provides a rationale for a therapeutic PD-1 pathway blockade in the treatment of CRC lung metastases. Future, large-scale studies are warranted to validate the findings of this single-center, retrospective analysis. Conclusions PD-1 expression by TILs is a strong prognostic marker in CRC patients with pulmonary spreading treated by PM. Moreover, this study provides a rationale for a therapeutic PD-1 pathway blockade in the treatment of CRC lung metastases. Further studies are warranted to confirm these findings in a larger study cohort

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“…The EGFR is activated by mutation or overexpression in a variety of epithelial cancers including colorectal cancer, nonsmall cell lung cancer (NSCLC), and head and neck squamous cell carcinoma (1,2), making anti-EGFR strategies an attractive therapeutic option for solid tumors. Imgatuzumab (GA201/ RG7160) is a novel humanized anti-EGFR monoclonal antibody (mAb) with a dual mode of action.…”

Section: Introductionmentioning

confidence: 99%

Premedication and Chemotherapy Agents do not Impair Imgatuzumab (GA201)-Mediated Antibody-Dependent Cellular Cytotoxicity and Combination Therapies Enhance Efficacy

Gonzalez-Nicolini

Herter

Lang

et al. 2016

Clinical Cancer Research

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Purpose: Imgatuzumab (GA201) is a novel anti-EGFR mAb that is glycoengineered for enhanced antibody-dependent cellular cytotoxicity (ADCC). Future treatment schedules for imgatuzumab will likely involve the use of potentially immunosuppressive drugs, such as premedication therapies, to mitigate infusion reactions characteristic of mAb therapy and chemotherapy combination partners. Because of the strong immunologic component of mode of action of imgatuzumab, it is important to understand whether these drugs influence imgatuzumab-mediated ADCC and impact efficacy.Experimental Design: We performed a series of ADCC assays using human peripheral blood mononuclear cells that were first preincubated in physiologically relevant concentrations of commonly used premedication drugs and cancer chemotherapies. The ability of common chemotherapy agents to enhance the efficacy of imgatuzumab in vivo was then examined using orthotopic xenograft models of human cancer.Results: A majority of premedication and chemotherapy drugs investigated had no significant effect on the ADCC activity of imgatuzumab in vitro. Furthermore, enhanced in vivo efficacy was seen with imgatuzumab combination regimens compared with single-agent imgatuzumab, single-agent chemotherapy, or cetuximab combinations.Conclusions: These data indicate that medications currently coadministered with anti-EGFR therapies are unlikely to diminish the ADCC capabilities of imgatuzumab. Further studies using syngeneic models with functional adaptive T-cell responses are now required to fully understand how chemotherapy agents will influence a long-term response to imgatuzumab therapy. Thus, this study and future ones can provide a framework for designing imgatuzumab combination regimens with enhanced efficacy for investigation in phase II trials.

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EGFR, BRAF and KRAS Status in Patients Undergoing Pulmonary Metastasectomy from Primary Colorectal Carcinoma: A Prospective Follow-Up Study

Cited by 54 publications

References 31 publications

Impact of cyclooxygenase-2 and prostaglandin-E2 expression on clinical outcome after pulmonary metastasectomy

Impact of cyclooxygenase-2 and prostaglandin-E2 expression on clinical outcome after pulmonary metastasectomy

494 PD1-positive tumor-infiltrating lymphocytes are associated with poor clinical outcome after pulmonary metastasectomy for colorectal cancer

Premedication and Chemotherapy Agents do not Impair Imgatuzumab (GA201)-Mediated Antibody-Dependent Cellular Cytotoxicity and Combination Therapies Enhance Efficacy

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