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Expression profiling of blood samples from an SU5416 Phase III metastatic colorectal cancer clinical trial: a novel strategy for biomarker identification.

DePrimo SE, Wong LM, Khatry DB, Nicholas SL, Manning WC, Smolich BD, O'Farrell AM, Cherrington JM - BMC Cancer (2003)

Bottom Line: This study describes an approach used to identify gene expression changes that might serve as surrogate biomarkers of drug activity.Results from matched pairs of PBMC samples from 23 patients were queried for expression changes that consistently correlated with SU5416 administration.These results establish a foundation for the further exploration of peripheral blood cells as a surrogate system for biomarker analyses in clinical oncology studies.

View Article: PubMed Central - HTML - PubMed

Affiliation: Preclinical Research and Exploratory Development, SUGEN, Inc, South San Francisco, CA 94080, USA. samuel-deprimo@sugen.com

ABSTRACT

Background: Microarray-based gene expression profiling is a powerful approach for the identification of molecular biomarkers of disease, particularly in human cancers. Utility of this approach to measure responses to therapy is less well established, in part due to challenges in obtaining serial biopsies. Identification of suitable surrogate tissues will help minimize limitations imposed by those challenges. This study describes an approach used to identify gene expression changes that might serve as surrogate biomarkers of drug activity.

Methods: Expression profiling using microarrays was applied to peripheral blood mononuclear cell (PBMC) samples obtained from patients with advanced colorectal cancer participating in a Phase III clinical trial. The PBMC samples were harvested pre-treatment and at the end of the first 6-week cycle from patients receiving standard of care chemotherapy or standard of care plus SU5416, a vascular endothelial growth factor (VEGF) receptor tyrosine kinase (RTK) inhibitor. Results from matched pairs of PBMC samples from 23 patients were queried for expression changes that consistently correlated with SU5416 administration.

Results: Thirteen transcripts met this selection criterion; six were further tested by quantitative RT-PCR analysis of 62 additional samples from this trial and a second SU5416 Phase III trial of similar design. This method confirmed four of these transcripts (CD24, lactoferrin, lipocalin 2, and MMP-9) as potential biomarkers of drug treatment. Discriminant analysis showed that expression profiles of these 4 transcripts could be used to classify patients by treatment arm in a predictive fashion.

Conclusions: These results establish a foundation for the further exploration of peripheral blood cells as a surrogate system for biomarker analyses in clinical oncology studies.

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Related in: MedlinePlus

Differential expression of four transcripts in a second Phase III trial as measured by quantitative RT-PCR. Percentage of cases in CPT-11/5-FU/LV (control) and CPT-11/5-FU/LV + SU5416 trial arms with increased expression (at predose day 42 relative to predose day 1) of 4 candidate biomarker transcripts in a second SU5416 Phase III clinical trial is displayed. The convention is the same as in panel B in Figure 2. A total of 36 sample pairs was included in this analysis; 18 from the SU5416 arm and 18 from the control arm (8 PR and 10 SD responses at end cycle 1 in each group). The relative expression values for each patient in this group are displayed (see Additional File 1).
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Figure 3: Differential expression of four transcripts in a second Phase III trial as measured by quantitative RT-PCR. Percentage of cases in CPT-11/5-FU/LV (control) and CPT-11/5-FU/LV + SU5416 trial arms with increased expression (at predose day 42 relative to predose day 1) of 4 candidate biomarker transcripts in a second SU5416 Phase III clinical trial is displayed. The convention is the same as in panel B in Figure 2. A total of 36 sample pairs was included in this analysis; 18 from the SU5416 arm and 18 from the control arm (8 PR and 10 SD responses at end cycle 1 in each group). The relative expression values for each patient in this group are displayed (see Additional File 1).

Mentions: Figure 3 summarizes the overall frequency of induction of 2-fold or greater in each arm of the trial. It is clear that these transcripts are more frequently induced at day 42 of treatment in the SU5416 arm than in the control arm. This is supported by statistical analysis, as indicated in results of the Mann-Whitney U Test (Table 4). A visual representation of hierarchical clustering analysis of the qRT-PCR relative expression values from both trials for the each of the transcripts is displayed in Figure 4. This clustering pattern displays the distinction between the SU5416 and control arms based on relative expression data, and also indicates further distinctions among subsets of patients as well as the degree of overlap between trial arms in the clustering pattern. The extent of similarity between the relative expression patterns for each transcript (represented in columns) is also indicated; the pattern of MMP-9 is distinct from the others as it appears in a separate branch in the dendrogram structure. A table containing the raw relative expression measurements included in this dataset can be viewed in Additional file 1 .


Expression profiling of blood samples from an SU5416 Phase III metastatic colorectal cancer clinical trial: a novel strategy for biomarker identification.

DePrimo SE, Wong LM, Khatry DB, Nicholas SL, Manning WC, Smolich BD, O'Farrell AM, Cherrington JM - BMC Cancer (2003)

Differential expression of four transcripts in a second Phase III trial as measured by quantitative RT-PCR. Percentage of cases in CPT-11/5-FU/LV (control) and CPT-11/5-FU/LV + SU5416 trial arms with increased expression (at predose day 42 relative to predose day 1) of 4 candidate biomarker transcripts in a second SU5416 Phase III clinical trial is displayed. The convention is the same as in panel B in Figure 2. A total of 36 sample pairs was included in this analysis; 18 from the SU5416 arm and 18 from the control arm (8 PR and 10 SD responses at end cycle 1 in each group). The relative expression values for each patient in this group are displayed (see Additional File 1).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC152639&req=5

Figure 3: Differential expression of four transcripts in a second Phase III trial as measured by quantitative RT-PCR. Percentage of cases in CPT-11/5-FU/LV (control) and CPT-11/5-FU/LV + SU5416 trial arms with increased expression (at predose day 42 relative to predose day 1) of 4 candidate biomarker transcripts in a second SU5416 Phase III clinical trial is displayed. The convention is the same as in panel B in Figure 2. A total of 36 sample pairs was included in this analysis; 18 from the SU5416 arm and 18 from the control arm (8 PR and 10 SD responses at end cycle 1 in each group). The relative expression values for each patient in this group are displayed (see Additional File 1).
Mentions: Figure 3 summarizes the overall frequency of induction of 2-fold or greater in each arm of the trial. It is clear that these transcripts are more frequently induced at day 42 of treatment in the SU5416 arm than in the control arm. This is supported by statistical analysis, as indicated in results of the Mann-Whitney U Test (Table 4). A visual representation of hierarchical clustering analysis of the qRT-PCR relative expression values from both trials for the each of the transcripts is displayed in Figure 4. This clustering pattern displays the distinction between the SU5416 and control arms based on relative expression data, and also indicates further distinctions among subsets of patients as well as the degree of overlap between trial arms in the clustering pattern. The extent of similarity between the relative expression patterns for each transcript (represented in columns) is also indicated; the pattern of MMP-9 is distinct from the others as it appears in a separate branch in the dendrogram structure. A table containing the raw relative expression measurements included in this dataset can be viewed in Additional file 1 .

Bottom Line: This study describes an approach used to identify gene expression changes that might serve as surrogate biomarkers of drug activity.Results from matched pairs of PBMC samples from 23 patients were queried for expression changes that consistently correlated with SU5416 administration.These results establish a foundation for the further exploration of peripheral blood cells as a surrogate system for biomarker analyses in clinical oncology studies.

View Article: PubMed Central - HTML - PubMed

Affiliation: Preclinical Research and Exploratory Development, SUGEN, Inc, South San Francisco, CA 94080, USA. samuel-deprimo@sugen.com

ABSTRACT

Background: Microarray-based gene expression profiling is a powerful approach for the identification of molecular biomarkers of disease, particularly in human cancers. Utility of this approach to measure responses to therapy is less well established, in part due to challenges in obtaining serial biopsies. Identification of suitable surrogate tissues will help minimize limitations imposed by those challenges. This study describes an approach used to identify gene expression changes that might serve as surrogate biomarkers of drug activity.

Methods: Expression profiling using microarrays was applied to peripheral blood mononuclear cell (PBMC) samples obtained from patients with advanced colorectal cancer participating in a Phase III clinical trial. The PBMC samples were harvested pre-treatment and at the end of the first 6-week cycle from patients receiving standard of care chemotherapy or standard of care plus SU5416, a vascular endothelial growth factor (VEGF) receptor tyrosine kinase (RTK) inhibitor. Results from matched pairs of PBMC samples from 23 patients were queried for expression changes that consistently correlated with SU5416 administration.

Results: Thirteen transcripts met this selection criterion; six were further tested by quantitative RT-PCR analysis of 62 additional samples from this trial and a second SU5416 Phase III trial of similar design. This method confirmed four of these transcripts (CD24, lactoferrin, lipocalin 2, and MMP-9) as potential biomarkers of drug treatment. Discriminant analysis showed that expression profiles of these 4 transcripts could be used to classify patients by treatment arm in a predictive fashion.

Conclusions: These results establish a foundation for the further exploration of peripheral blood cells as a surrogate system for biomarker analyses in clinical oncology studies.

Show MeSH
Related in: MedlinePlus