Limits...
ERCC1 and TS Expression as Prognostic and Predictive Biomarkers in Metastatic Colon Cancer.

Choueiri MB, Shen JP, Gross AM, Huang JK, Ideker T, Fanta P - PLoS ONE (2015)

Bottom Line: After accounting for the covariates age, sex, tumor grade and ECOG performance status in a Cox proportional hazard model the association of low ERCC1 with longer OS (HR 0.18, 95% CI 0.14 to 0.26, p = 0.0448) and TTF (HR 0.16, 95% CI 0.14 to 0.21, p = 0.0053) remained significant.Patients with low TS expression (n = 29) had significantly longer median OS (36.0 vs. 14.8 mo, HR 0.25, 95% CI 0.074 to 0.82, log-rank p = 0.022) relative to those with high expression (n = 12).Overall, these findings suggest that measurement of ERCC1 and TS expression has potential clinical utility in managing patients with metastatic colorectal cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of California San Diego, La Jolla, California, United States of America; Moores Cancer Center, University of California San Diego, La Jolla, California, United States of America.

ABSTRACT
In patients with metastatic colon cancer, response to first line chemotherapy is a strong predictor of overall survival (OS). Currently, oncologists lack diagnostic tests to determine which chemotherapy regimen offers the greatest chance for response in an individual patient. Here we present the results of gene expression analysis for two genes, ERCC1 and TS, measured with the commercially available ResponseDX: Colon assay (Response Genetics, Los Angeles, CA) in 41 patients with de novo metastatic colon cancer diagnosed between July 2008 and August 2013 at the University of California, San Diego. In addition ERCC1 and TS expression levels as determined by RNAseq and survival data for patients in TCGA were downloaded from the TCGA data portal. We found that patients with low expression of ERCC1 (n = 33) had significantly longer median OS (36.0 vs. 10.1 mo, HR 0.29, 95% CI .095 to .84, log-rank p = 9.0x10-6) and median time to treatment to failure (TTF) following first line chemotherapy (14.1 vs. 2.4 mo, HR 0.17, 95% CI 0.048 to 0.58, log-rank p = 5.3x10-4) relative to those with high expression (n = 4). After accounting for the covariates age, sex, tumor grade and ECOG performance status in a Cox proportional hazard model the association of low ERCC1 with longer OS (HR 0.18, 95% CI 0.14 to 0.26, p = 0.0448) and TTF (HR 0.16, 95% CI 0.14 to 0.21, p = 0.0053) remained significant. Patients with low TS expression (n = 29) had significantly longer median OS (36.0 vs. 14.8 mo, HR 0.25, 95% CI 0.074 to 0.82, log-rank p = 0.022) relative to those with high expression (n = 12). The combined low expression of ERCC1/TS was predictive of response in patients treated with FOLFOX (40% vs. 91%, RR 2.3, Fisher's exact test p = 0.03, n = 27), but not with FOLFIRI (71% vs. 71%, RR 1.0, Fisher's exact test p = 1, n = 14). Overall, these findings suggest that measurement of ERCC1 and TS expression has potential clinical utility in managing patients with metastatic colorectal cancer.

No MeSH data available.


Related in: MedlinePlus

Combination of ERCC1 and TS.(A) Correlation between ERCC1 and TS expression. (B) Time to treatment failure of all patients per combination of ERCC1/TS. (B) Overall survival of all patients per combination of ERCC1/TS
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4470586&req=5

pone.0126898.g003: Combination of ERCC1 and TS.(A) Correlation between ERCC1 and TS expression. (B) Time to treatment failure of all patients per combination of ERCC1/TS. (B) Overall survival of all patients per combination of ERCC1/TS

Mentions: We then evaluated if ERCC1 and TS could be combined to form a composite marker capable of identifying sub-populations with significant differences in TTF, ORR and OS. Twenty-nine patients had low expression levels of both ERCC1 and TS, eight had low expression levels of ERCC1 but elevated TS, and four patients had elevated levels of both ERCC1 and TS. No patient displayed the combination of high ERCC1 with low TS. Interestingly, expression levels of ERCC1 and TS were significantly correlated (Pearson r = 0.53; p = 0.0004) (Fig 3A). Patients with high ERCC1 and TS had the shortest TTF of only 2.4 months, compared to 14.1 months in patients with low ERCC1 and high TS and 15.5 months in patients with low levels of both ERCC1 and TS (Fig 3B). The difference in median TTF between the low ERCC1-low TS cohort relative to high ERCC1-high TS (15.5 vs. 2.4 mo, HR 0.17, 95% CI 0.0012 to 0.11, log-rank p = 4.6x10-4) was statistically significant and remained significant after control for covariates (HR 0.13, 95% CI: 0.11 to 0.16, p = 0.0029). Similar trends were seen with OS, high ERCC1-high TS patients having the shortest median OS of 10 months compared to 15 months for low ERCC1-high TS and 36 months for low ERCC1-low TS. The difference in median OS between the low ERCC1-low TS cohort relative to high ERCC1-high TS (36 vs. 10 mo, HR 0.10, 95% CI 3.4x10-5 to 0.0088, log-rank p = 3.8x10-7) was also statistically significant and remained so after control for covariates (HR 0.092, 95% CI: 0.078 to 0.11, p = 0.014).


ERCC1 and TS Expression as Prognostic and Predictive Biomarkers in Metastatic Colon Cancer.

Choueiri MB, Shen JP, Gross AM, Huang JK, Ideker T, Fanta P - PLoS ONE (2015)

Combination of ERCC1 and TS.(A) Correlation between ERCC1 and TS expression. (B) Time to treatment failure of all patients per combination of ERCC1/TS. (B) Overall survival of all patients per combination of ERCC1/TS
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4470586&req=5

pone.0126898.g003: Combination of ERCC1 and TS.(A) Correlation between ERCC1 and TS expression. (B) Time to treatment failure of all patients per combination of ERCC1/TS. (B) Overall survival of all patients per combination of ERCC1/TS
Mentions: We then evaluated if ERCC1 and TS could be combined to form a composite marker capable of identifying sub-populations with significant differences in TTF, ORR and OS. Twenty-nine patients had low expression levels of both ERCC1 and TS, eight had low expression levels of ERCC1 but elevated TS, and four patients had elevated levels of both ERCC1 and TS. No patient displayed the combination of high ERCC1 with low TS. Interestingly, expression levels of ERCC1 and TS were significantly correlated (Pearson r = 0.53; p = 0.0004) (Fig 3A). Patients with high ERCC1 and TS had the shortest TTF of only 2.4 months, compared to 14.1 months in patients with low ERCC1 and high TS and 15.5 months in patients with low levels of both ERCC1 and TS (Fig 3B). The difference in median TTF between the low ERCC1-low TS cohort relative to high ERCC1-high TS (15.5 vs. 2.4 mo, HR 0.17, 95% CI 0.0012 to 0.11, log-rank p = 4.6x10-4) was statistically significant and remained significant after control for covariates (HR 0.13, 95% CI: 0.11 to 0.16, p = 0.0029). Similar trends were seen with OS, high ERCC1-high TS patients having the shortest median OS of 10 months compared to 15 months for low ERCC1-high TS and 36 months for low ERCC1-low TS. The difference in median OS between the low ERCC1-low TS cohort relative to high ERCC1-high TS (36 vs. 10 mo, HR 0.10, 95% CI 3.4x10-5 to 0.0088, log-rank p = 3.8x10-7) was also statistically significant and remained so after control for covariates (HR 0.092, 95% CI: 0.078 to 0.11, p = 0.014).

Bottom Line: After accounting for the covariates age, sex, tumor grade and ECOG performance status in a Cox proportional hazard model the association of low ERCC1 with longer OS (HR 0.18, 95% CI 0.14 to 0.26, p = 0.0448) and TTF (HR 0.16, 95% CI 0.14 to 0.21, p = 0.0053) remained significant.Patients with low TS expression (n = 29) had significantly longer median OS (36.0 vs. 14.8 mo, HR 0.25, 95% CI 0.074 to 0.82, log-rank p = 0.022) relative to those with high expression (n = 12).Overall, these findings suggest that measurement of ERCC1 and TS expression has potential clinical utility in managing patients with metastatic colorectal cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of California San Diego, La Jolla, California, United States of America; Moores Cancer Center, University of California San Diego, La Jolla, California, United States of America.

ABSTRACT
In patients with metastatic colon cancer, response to first line chemotherapy is a strong predictor of overall survival (OS). Currently, oncologists lack diagnostic tests to determine which chemotherapy regimen offers the greatest chance for response in an individual patient. Here we present the results of gene expression analysis for two genes, ERCC1 and TS, measured with the commercially available ResponseDX: Colon assay (Response Genetics, Los Angeles, CA) in 41 patients with de novo metastatic colon cancer diagnosed between July 2008 and August 2013 at the University of California, San Diego. In addition ERCC1 and TS expression levels as determined by RNAseq and survival data for patients in TCGA were downloaded from the TCGA data portal. We found that patients with low expression of ERCC1 (n = 33) had significantly longer median OS (36.0 vs. 10.1 mo, HR 0.29, 95% CI .095 to .84, log-rank p = 9.0x10-6) and median time to treatment to failure (TTF) following first line chemotherapy (14.1 vs. 2.4 mo, HR 0.17, 95% CI 0.048 to 0.58, log-rank p = 5.3x10-4) relative to those with high expression (n = 4). After accounting for the covariates age, sex, tumor grade and ECOG performance status in a Cox proportional hazard model the association of low ERCC1 with longer OS (HR 0.18, 95% CI 0.14 to 0.26, p = 0.0448) and TTF (HR 0.16, 95% CI 0.14 to 0.21, p = 0.0053) remained significant. Patients with low TS expression (n = 29) had significantly longer median OS (36.0 vs. 14.8 mo, HR 0.25, 95% CI 0.074 to 0.82, log-rank p = 0.022) relative to those with high expression (n = 12). The combined low expression of ERCC1/TS was predictive of response in patients treated with FOLFOX (40% vs. 91%, RR 2.3, Fisher's exact test p = 0.03, n = 27), but not with FOLFIRI (71% vs. 71%, RR 1.0, Fisher's exact test p = 1, n = 14). Overall, these findings suggest that measurement of ERCC1 and TS expression has potential clinical utility in managing patients with metastatic colorectal cancer.

No MeSH data available.


Related in: MedlinePlus