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Epidermal Growth Factor Receptor (EGFR) mutation analysis, gene expression profiling and EGFR protein expression in primary prostate cancer.

Peraldo-Neia C, Migliardi G, Mello-Grand M, Montemurro F, Segir R, Pignochino Y, Cavalloni G, Torchio B, Mosso L, Chiorino G, Aglietta M - BMC Cancer (2011)

Bottom Line: Gene expression profiling using oligo-microarrays was also carried out in 51 of the PC samples.Four of the down-regulated genes, U19/EAF2, ABCC4, KLK3 and ANXA3 and one of the up-regulated genes, FOXC1, are involved in PC progression.Having been generated in a relatively small sample of patients, our results warrant confirmation in larger series.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Clinical Oncology, University of Torino Medical School, Institute for Cancer Research and Treatment, Candiolo, Turin, Italy. caterina.peraldoneia@ircc.it

ABSTRACT

Background: Activating mutations of the epidermal growth factor receptor (EGFR) confer sensitivity to the tyrosine kinase inhibitors (TKi), gefitinib and erlotinib. We analysed EGFR expression, EGFR mutation status and gene expression profiles of prostate cancer (PC) to supply a rationale for EGFR targeted therapies in this disease.

Methods: Mutational analysis of EGFR TK domain (exons from 18 to 21) and immunohistochemistry for EGFR were performed on tumour tissues derived from radical prostatectomy from 100 PC patients. Gene expression profiling using oligo-microarrays was also carried out in 51 of the PC samples.

Results: EGFR protein overexpression (EGFRhigh) was found in 36% of the tumour samples, and mutations were found in 13% of samples. Patients with EGFRhigh tumours experienced a significantly increased risk of biochemical relapse (hazard ratio-HR 2.52, p=0.02) compared with patients with tumours expressing low levels of EGFR (EGFRlow). Microarray analysis did not reveal any differences in gene expression between EGFRhigh and EGFRlow tumours. Conversely, in EGFRhigh tumours, we were able to identify a 79 gene signature distinguishing mutated from non-mutated tumours. Additionally, 29 genes were found to be differentially expressed between mutated/EGFRhigh (n=3) and mutated/EGFRlow tumours (n=5). Four of the down-regulated genes, U19/EAF2, ABCC4, KLK3 and ANXA3 and one of the up-regulated genes, FOXC1, are involved in PC progression.

Conclusions: Based on our findings, we hypothesize that accurate definition of the EGFR status could improve prognostic stratification and we suggest a possible role for EGFR-directed therapies in PC patients. Having been generated in a relatively small sample of patients, our results warrant confirmation in larger series.

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Kaplan-Meier estimates of time to biochemical relapse according to EGFR immunohistochemical status. The solid line represents patients with EGFRlow tumours and the dashed line represents those with EGFRhigh tumours. Median time to biochemical relapse was 104 and 30 months for patients with EGFRlow and EGFRhigh tumours, respectively (log-rank test, p=0.01).
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Figure 2: Kaplan-Meier estimates of time to biochemical relapse according to EGFR immunohistochemical status. The solid line represents patients with EGFRlow tumours and the dashed line represents those with EGFRhigh tumours. Median time to biochemical relapse was 104 and 30 months for patients with EGFRlow and EGFRhigh tumours, respectively (log-rank test, p=0.01).

Mentions: One hundred PC samples were evaluated for EGFR protein expression by immunohistochemistry. EGFR immunostaining was predominantly found in the membrane and the cytoplasm. EGFR was expressed at low levels in normal glands in 90 out of 100 samples (90%), and in 36 out of 100 cases (36%), tumour areas were classified as overexpressing EGFR (EGFRhigh) (additional file 1, table S1). Figure1 provides an example of the immunohistochemical pattern of EGFR protein expression in normal and tumour tissues. The impact of clinical and pathological variables on biochemical relapse was studied in a subgroup of 59 patients who underwent regular visits at the same Institution where they had undergone surgery, and for whom we had detailed follow-up information. The median follow-up for these patients was 207 months (range 16-366 months). The other 41 patients, who underwent follow-up visits at different Institutions after surgery, were excluded from this analysis because of incomplete or missing follow-up information. Twenty-eight out of 59 patients experienced biochemical relapse (overall median TTBR 84 months). Univariate analyses revealed a significant effect of EGFR immunohistochemical status on TTBR (figure2). Median TTBR was 104 and 30 months for patients with EGFRlow and EGFRhigh tumours, respectively (hazard ratio-HR 2.53, p= 0.02). Furthermore, a strong trend towards a worse median TTBR was observed in patients with high vs low Gleason Score tumours (63 months vs not reached respectively, HR 2.80, p= 0.10) (figure3). Neither median age nor tumour stage at diagnosis correlated significantly with TTBR. When EGFR immunohistochemical status and Gleason Score were entered together in a Cox Proportional Hazards model, results did not change significantly, suggesting that EGFR immunohistochemical status (multivariate HR 2.67, p = 0.01) and Gleason Score (multivariate HR 3.04, p = 0.08) were independent predictors of TTBR.


Epidermal Growth Factor Receptor (EGFR) mutation analysis, gene expression profiling and EGFR protein expression in primary prostate cancer.

Peraldo-Neia C, Migliardi G, Mello-Grand M, Montemurro F, Segir R, Pignochino Y, Cavalloni G, Torchio B, Mosso L, Chiorino G, Aglietta M - BMC Cancer (2011)

Kaplan-Meier estimates of time to biochemical relapse according to EGFR immunohistochemical status. The solid line represents patients with EGFRlow tumours and the dashed line represents those with EGFRhigh tumours. Median time to biochemical relapse was 104 and 30 months for patients with EGFRlow and EGFRhigh tumours, respectively (log-rank test, p=0.01).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3040720&req=5

Figure 2: Kaplan-Meier estimates of time to biochemical relapse according to EGFR immunohistochemical status. The solid line represents patients with EGFRlow tumours and the dashed line represents those with EGFRhigh tumours. Median time to biochemical relapse was 104 and 30 months for patients with EGFRlow and EGFRhigh tumours, respectively (log-rank test, p=0.01).
Mentions: One hundred PC samples were evaluated for EGFR protein expression by immunohistochemistry. EGFR immunostaining was predominantly found in the membrane and the cytoplasm. EGFR was expressed at low levels in normal glands in 90 out of 100 samples (90%), and in 36 out of 100 cases (36%), tumour areas were classified as overexpressing EGFR (EGFRhigh) (additional file 1, table S1). Figure1 provides an example of the immunohistochemical pattern of EGFR protein expression in normal and tumour tissues. The impact of clinical and pathological variables on biochemical relapse was studied in a subgroup of 59 patients who underwent regular visits at the same Institution where they had undergone surgery, and for whom we had detailed follow-up information. The median follow-up for these patients was 207 months (range 16-366 months). The other 41 patients, who underwent follow-up visits at different Institutions after surgery, were excluded from this analysis because of incomplete or missing follow-up information. Twenty-eight out of 59 patients experienced biochemical relapse (overall median TTBR 84 months). Univariate analyses revealed a significant effect of EGFR immunohistochemical status on TTBR (figure2). Median TTBR was 104 and 30 months for patients with EGFRlow and EGFRhigh tumours, respectively (hazard ratio-HR 2.53, p= 0.02). Furthermore, a strong trend towards a worse median TTBR was observed in patients with high vs low Gleason Score tumours (63 months vs not reached respectively, HR 2.80, p= 0.10) (figure3). Neither median age nor tumour stage at diagnosis correlated significantly with TTBR. When EGFR immunohistochemical status and Gleason Score were entered together in a Cox Proportional Hazards model, results did not change significantly, suggesting that EGFR immunohistochemical status (multivariate HR 2.67, p = 0.01) and Gleason Score (multivariate HR 3.04, p = 0.08) were independent predictors of TTBR.

Bottom Line: Gene expression profiling using oligo-microarrays was also carried out in 51 of the PC samples.Four of the down-regulated genes, U19/EAF2, ABCC4, KLK3 and ANXA3 and one of the up-regulated genes, FOXC1, are involved in PC progression.Having been generated in a relatively small sample of patients, our results warrant confirmation in larger series.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Clinical Oncology, University of Torino Medical School, Institute for Cancer Research and Treatment, Candiolo, Turin, Italy. caterina.peraldoneia@ircc.it

ABSTRACT

Background: Activating mutations of the epidermal growth factor receptor (EGFR) confer sensitivity to the tyrosine kinase inhibitors (TKi), gefitinib and erlotinib. We analysed EGFR expression, EGFR mutation status and gene expression profiles of prostate cancer (PC) to supply a rationale for EGFR targeted therapies in this disease.

Methods: Mutational analysis of EGFR TK domain (exons from 18 to 21) and immunohistochemistry for EGFR were performed on tumour tissues derived from radical prostatectomy from 100 PC patients. Gene expression profiling using oligo-microarrays was also carried out in 51 of the PC samples.

Results: EGFR protein overexpression (EGFRhigh) was found in 36% of the tumour samples, and mutations were found in 13% of samples. Patients with EGFRhigh tumours experienced a significantly increased risk of biochemical relapse (hazard ratio-HR 2.52, p=0.02) compared with patients with tumours expressing low levels of EGFR (EGFRlow). Microarray analysis did not reveal any differences in gene expression between EGFRhigh and EGFRlow tumours. Conversely, in EGFRhigh tumours, we were able to identify a 79 gene signature distinguishing mutated from non-mutated tumours. Additionally, 29 genes were found to be differentially expressed between mutated/EGFRhigh (n=3) and mutated/EGFRlow tumours (n=5). Four of the down-regulated genes, U19/EAF2, ABCC4, KLK3 and ANXA3 and one of the up-regulated genes, FOXC1, are involved in PC progression.

Conclusions: Based on our findings, we hypothesize that accurate definition of the EGFR status could improve prognostic stratification and we suggest a possible role for EGFR-directed therapies in PC patients. Having been generated in a relatively small sample of patients, our results warrant confirmation in larger series.

Show MeSH
Related in: MedlinePlus