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10.1245/ASO.2006.07.011
Annals of Surgical Oncology 13:933-939 (2006)
© 2006 Society of Surgical Oncology
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Original Article

Activated Akt and Erk Expression and Survival After Surgery in Pancreatic Carcinoma

Krishdeep S. Chadha, MD1, Thaer Khoury, MD2, Jihnhee Yu, PhD3, Jennifer D. Black, PhD4, John F. Gibbs, MD5, Boris W. Kuvshinoff, MD5, Dongfeng Tan, MD2, Michael G. Brattain, PhD4 and Milind M. Javle, MD1

1 Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York 14263
2 Department of Pathology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York 14263
3 Department of Biostatistics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York 14263
4 Department of Pharmacology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York 14263
5 Department of Surgery, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York 14263

Correspondence: Address correspondence and reprint requests to: Milind M. Javle, MD; E-mail: milind.javle{at}roswellpark.org.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Long-term survival of surgically resectable pancreatic cancer patients is uncommon. The epidermal growth factor receptor (EGFR) and the phosphoinositol-3-kinase pathways are often activated in pancreatic cancer, and an understanding of their role in resected cases may help refine adjuvant therapy.

Methods: We investigated the expression of EGFR, Erk, Akt, and their phosphoforms (p-) in pancreatectomy specimens and correlated these with survival. Thirty-nine consecutive surgically resected pancreatic adenocarcinoma cases were included. Immunohistochemical staining of paraffin-embedded blocks was performed by using monoclonal antibodies against EGFR, Erk, p-Erk, Akt, and p-Akt. A standard immunoperoxidase technique was used to detect the avidin-biotin peroxidase complex. Immunostaining was visually scored with the histoscore method by two surgical pathologists.

Results: Patient characteristics were as follows: 17 men and 22 women; median age, 66 years; and American Joint Committee on Cancer stage I, 5 patients; stage II, 4 patients; stage III, 27 patients; and stage IV, 3 patients. The tumor was World Health Organization grade 1 in 4, grade 2 in 17, and grade 3 in 18 cases. Adjuvant therapies were chemotherapy (n = 6), radiotherapy (n = 1), and chemoradiotherapy (n = 17). Immunohistochemistry revealed positive expression of EGFR in 30.8%, Erk in 92.3%, p-Erk in 45.9%, Akt in 71.8%, and p-Akt in 20.5% of cases. On univariate analyses, tumor grade (P = .0098), p-Akt (P = .0003), and p-Erk (P = .0052) expression correlated with survival. On multivariate analyses, age (P = .0002; hazard ratio [HR], 1.8), grade (P = .00318; HR, 3.0), Akt (P = .0433; HR, .4), p-Akt (P = .0002; HR, .2), and p-Erk (P = .0003; HR, 3.5) expression correlated significantly with survival.

Conclusions: p-Erk and p-Akt expression may have prognostic and therapeutic implications in pancreatic cancer.

Key Words: Pancreatic neoplasms • Pancreatectomy • Akt protein • Erk MAP kinase


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Patient outcomes in some gastrointestinal malignancies, such as colorectal cancer, have improved. However, the long-term survival of patients with pancreatic carcinoma remains dismal, and the overall survival of these patients has not improved over the last two decades.1 An estimated 31,800 Americans died of pancreatic cancer in 2005, thus making this the fourth leading cause of cancer death overall.2

Most of these patients present with advanced disease; only 10% to 15% cases have surgically resectable tumors. The use of adjuvant therapy after pancreatectomy is supported by the National Comprehensive Cancer Network guidelines.3 Current adjuvant therapy includes fluoropyrimidine- or gemcitabine-based chemotherapy with or without radiation and results in long-term survival for only 10% to 30% patients.3 An understanding of the molecular pathways involved in progression of this disease would help in the development of effective, targeted adjuvant therapies in this patient population.

Growth factor alterations were described in pancreatic cancer. Alteration of the epidermal growth factor receptor (EGFR) and related signaling plays a role in metastatic spread of this disease.4–7 EGFR is a receptor tyrosine kinase of the ErbB family that is abnormally activated in many epithelial tumors. Cytoplasmic EGFR overexpression was associated with increased invasiveness and poor prognosis in pancreatic adenocarcinoma.8,9

The availability of small-molecule tyrosine kinase inhibitors directed against the EGFR pathway has led to several clinical studies in solid tumors such as pancreatic cancer with these agents. There are two classes of anti-EGFR agents: monoclonal antibodies directed at the extracellular domain of the receptor and small molecule inhibitors of the receptor’s tyrosine kinase. Anti-EGFR monoclonal antibodies have shown antitumor activity in advanced colorectal carcinoma, squamous cell carcinomas of the head and neck, non–small-cell lung cancer, and pancreatic cancer.10–14 Small molecule tyrosine kinase inhibitors (gefitinib and erlotinib) are used for metastatic non-small-cell lung cancer and pancreatic cancer patients. Their role at an earlier stage for operable patients is uncertain at this time. Clinical studies are under way with these agents in the adjuvant or neoadjuvant setting. A systematic examination of EGFR and related signaling proteins such as Erk and Akt in operable patients is required as a prelude to these clinical studies.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Population
Thirty-nine consecutive patients with pancreatic ductal adenocarcinoma who underwent pancreatectomy and subsequent treatment at Roswell Park Cancer Institute from 1996 to 2002 were included. Patient selection was based on the availability of adequate tissue for immunohistochemistry studies. A retrospective analysis of their clinical data was performed. Relevant data collected included age, sex, smoking status, American Joint Committee on Cancer (AJCC) stage at presentation, presence of metastases, tumor grade, therapy administered, and survival from the time of diagnosis. Institutional review board approval was obtained for this investigation.

Immunohistochemical Staining and Scoring
Formalin-fixed, paraffin-embedded blocks of pancreatic carcinoma were obtained from the pathology archives. Immunohistochemical staining for EGFR, Erk (both phosphorylated and unphosphorylated isoforms), and Akt (both phosphorylated and unphosphorylated isoforms) was performed. Antibodies used were EGFR (Zymed, Carlsbad, CA), Erk (Cell Signaling Technology, Danvers, MA), p-Erk (Santa Cruz Biotechnology, Santa Cruz, CA), Akt (Santa Cruz Biotechnology, Santa Cruz, CA), and p-Akt (Cell Signaling Technology).

Sections were cut at 5 µm, placed on charged slides, and dried in a 60° oven for 1 hour. Upon return to room temperature, the slides were deparaffinized in three changes of xylene and rehydrated by using graded alcohols. Endogenous peroxidase was quenched with aqueous 3% hydrogen peroxide for 15 minutes and washed with PBS-T (phosphate-buffered saline with .05% Tween-20). Antigen retrieval was then performed. After a PBS-T wash, casein .03% (in PBS-T) was used as a block for 30 minutes, and then the primary antibody was applied to slides and left for 1 hour or overnight. A PBS-T wash was followed by the biotinylated secondary antibody for 30 minutes. A PBS-T wash was followed by streptavidin complex for 30 minutes. PBS-T was used as a wash, and the chromagen 3,3'-diaminobenzidine (DAKO, Carpinteria, CA) was applied for 5 minutes (the color reaction product was brown). The slides were then counterstained with hematoxylin.

Immunostain for EGFR was detectable in the cell membrane and cytoplasm, whereas Erk, Akt, and their respective phosphoforms were detectable in both the cytoplasm and nucleus. However, for each biomarker, a subcellular location with a staining intensity greater than background was used for histoscore and statistical analysis. The methodology for the biomarkers used in this study, their controls, and the interpretation of results have been described extensively by our group previously.15–18

The expression of signaling proteins in pancreatic carcinoma tissue specimens was independently recorded by two pathologists (D.T. and T.K.). A semiquantitative scoring system was used. The stain was graded as 0 (negative), 1 (weak), 2 (moderate), and 3 (strong). The final score was the sum total of the product of the staining intensity and corresponding tumor percentage. For example, if a tumor showed 50% moderate staining and 50% strong staining, the final score would be (50 x 2) + (50 x 3) = 250. A final score of at least 100 was considered as positive expression.

These tissue specimens were also stained by routine hematoxylin and eosin staining. Tumor specimens were graded on the basis of the degree of tumor differentiation by using the World Health Organization grading system.19

Statistical Analysis
The association between different signaling proteins expression was investigated by using the Kendall’s tau estimate. The association between grade and signaling protein expression was investigated with the cumulative logit model. The signaling protein expression in malignant cells was classified as high and low on the basis of whether their scores were above or below the median value, and survival between low and high expressions was tested by using the log-rank test. The comparisons of survival between different levels for other diagnostic variables were also performed by using the log-rank test. Multivariate relationships between patient survival and biomarkers (two levels: low and high) together with other diagnostic parameters were investigated by using the Cox proportional hazard model. Patient demographics including age, sex, smoking status, tumor grade, AJCC stage, treatment received, and expression of all signaling proteins in tumor tissue were considered as possible candidates for explanatory variables in the model. A final model was chosen by using the stepwise model selection and the significance of the variables included into the model. Overall survival was calculated as the time from the date of diagnosis to the date of death or the date of last follow-up examination (censored) for living patients. All statistical tests were two sided, with a statistical significance level of 5%.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Demographics
Patient demographics are listed in Table 1Go. There were 17 men and 22 women in the study sample. The median age was 66 years (range, 38–84 years). Twelve patients were nonsmokers, 17 patients were previous smokers, and 9 patients were actively smoking at the time of presentation; smoking status was unknown in 1 patient. AJCC stage distribution was as follows: stage I, 5 patients; stage II, 4 patients; stage III, 27 patients; and stage IV, 3 patients. These three cases had microscopic evidence of peritoneal disease in the pathologic resected specimen. Surgical resection was performed in all patients. Additional postoperative adjuvant therapies included chemotherapy (n = 6), radiotherapy (n = 1), and combined chemoradiotherapy (n = 17). Administered chemotherapy for all patients included 5-fluorouracil concurrently with radiation (n = 17) and gemcitabine (n = 6).


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  		TABLE 1. Patient demographics and immunostaining in pancreatic carcinoma
 
Histopathology and Immunohistochemical Staining
All 39 cases had pancreatic ductal adenocarcinoma. According to the World Health Organization classification, the tumor grade was 1 in 4, grade 2 in 17, and grade 3 in 18 cases. Immunohistochemical staining of the pancreatic carcinoma tissue revealed increased expression (histoscore value >100) of EGFR in 30.8%, Erk in 92.3%, p-Erk in 45.9%, Akt in 71.8%, and p-Akt in 20.5% of cases. See Figs. 1Go and 2Go, which depict p-Akt and p-Erk expression in pancreatic cancer specimens. There was a positive, but not statistically significant, correlation between EGFR and Erk expression in pancreatic carcinoma (Kendall’s tau, .258; P = .0606). Furthermore, the cumulative logit model showed that the higher expression (greater than the median) in EGFR correlated with the higher tumor grade (odds ratio, 9.3; P = .0021).


Figure 1
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  		FIG. 1. Diffuse, moderate immunostaining for p-mitogen activated protein kinase (p-Erk; magnification, x20).

 

Figure 2
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  		FIG. 2. Diffuse, strong staining for p-Akt (magnification, x20).

 
Survival
In a univariate analysis of survival using the log-rank test, a high tumor grade (grade 3) was identified as a factor associated with poor prognosis (P = .0098). Use of adjuvant chemotherapy and radiotherapy seemed to improve patient survival, but it did not reach statistical significance (P = .3444 and .1092, respectively). Sex and smoking also did not demonstrate significant associations with survival (P = .3161 and .2889, respectively). Table 1Go summarizes the survival data and hazard ratios (HRs) in different subgroups.

In the comparison of survival between high (greater than median) and low (median or lower) expression of signaling proteins (Fig. 3Go), high expression of p-Erk (n = 14) was associated with a significantly shorter median survival (10 months) than low expression (n = 25; 21 months; P = .0052). In contrast, high expression of p-Akt (n = 18) signified a longer median survival (24 months) than low expression (n = 21; 11 months; P = .0003). Multivariate analysis using the Cox proportional hazard model identified age (HR, 1.8; P = .0002), grade (HR, 3.0; P = .0318), expression of p-Akt (HR, .2; P = .0002), Akt (HR, .4; P = .0433), and p-Erk (HR, 3.5; P = .0030) as significant prognostic variables, where low expression of p-Akt and Akt, high expression of p-Erk, and older age were associated with poor outcomes. Note that p-Akt, Akt, and p-Erk had no associations with smoking (P = .9448, .3843, and .3514, respectively) in our patient group.


Figure 3
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  		FIG. 3. Kaplan-Meier survival results based on the median value of each biomarker. (a) p-Akt: low versus high. Median survival: low expressers (11 months; n = 21) and high expressers (24 months; n = 18). (b) p-Erk and survival. p-Erk: low versus high. Median survival: low expressers (21 months; n = 25) and high expressers (10 months; n = 14).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Despite improvements in surgical outcomes, pancreatic cancer carries a dismal prognosis, and cures after pancreaticoduodenectomy are rare.20 Further survival improvement is unlikely to result from surgical therapy alone, and an understanding of the molecular pathways involved in this stage of the disease may help to refine adjuvant therapy. This study investigated the expression of EGFR and its downstream signaling intermediates in resected cases of pancreatic cancer. We used validated immunohistochemical techniques to detect these proteins, and findings were confirmed by two surgical pathologists.

Positive EGFR expression was noted in 31% of cases. High EGFR expression was associated with a high histological grade, but there was no correlation with tumor stage, presence of metastases, and survival. High-grade tumors in this study were associated with a worse clinical outcome. Our study demonstrated Erk expression in 92% and p-Erk in 46% of resected pancreatic carcinoma cases. Activation of Erk (p-Erk expression) was independently associated with poor survival. There was a correlation between EGFR and Erk expression. Akt and p-Akt expression occurred in 72% and 21%, respectively. It is interesting to note that high Akt or p-Akt expression was associated with improved survival in our study. Shah et al.21 described similar results in lung cancer. These investigators examined 82 surgically resected non–small-cell lung cancer samples for p-Akt and Akt by Western blotting and for p-Akt by immunohistochemistry. They reported a favorable outcome in cases with increased p-Akt expression.

These findings are surprising because Akt may be expected to play the opposite role. Akt kinases have an antiapoptotic role; they regulate diverse cellular processes, including cell proliferation, survival, tissue invasion, and angiogenesis.22,23 However, on the basis of our data and those of Shah et al., we hypothesize that surgical resection itself may counter any negative effect of p-Akt expression. Our study demonstrated that p-Erk expression may have a negative prognostic effect for surgically resected patients. Several investigators demonstrated a similar role for of Erk in pancreatic cancer.24–27 In fact, the median survival of high p-Erk expressers (11 months) is comparable to the survival of unresectable, locally advanced cases of pancreatic cancer. It is possible that tumors expressing low levels of p-Erk require higher p-Akt levels for survival. This may explain the survival advantage for the high p-Akt expressers.

However, Yamamoto et al.,28 in a recent immunohistochemical study of 65 patients with pancreatic cancer, demonstrated a significant association of p-Akt expression with poor prognosis; these results are contrary to our findings. There may be several reasons for these discordant results. The expression of p-Akt in the Yamamoto study was higher than in our study (46% vs. 21%, respectively). The 5-year survival reported in the Yamamoto study was 32.3%, which is higher than that reported in the literature and in our study. It can be hypothesized that the improved overall survival noted in the Yamamoto study was due to the higher p-Akt expression seen in their patients. In the Yamamoto study, there was no significant correlation between p-Erk and prognosis. The use of histoscoring and verification of results by two surgical pathologists adds to the strength of our study. Both studies, however, have limited statistical power to make any definitive statement regarding the prognostic value of p-Akt expression. A larger database, such as from the Radiation Therapy Oncology Group 97-04 study, may be useful to clarify these results.29 Phosphatase and tensin homologue deleted on chromosome ten mutations were described in pancreatic cancer.30–32 These mutations lead to activation of Akt and a dependence on this pathway for oncogenesis. Ultimately, the importance of p-Akt expression may lie in this dependence, and, therefore, it may be a target for intervention rather than a prognostic indicator. We hypothesize that the p-Akt/p-Erk ratio may have prognostic value in this disease.

In conclusion, expression of EGFR signaling intermediates in surgically resected pancreatic carcinoma cases has clinical significance. Therapies targeting p-Erk and p-Akt in the adjuvant setting are worthy of exploration.


   ACKNOWLEDGMENTS
 
The authors thank Donna Oleszek for performing immunohistochemical staining for EGFR signaling intermediates. Supported by National Institutes of Health grants CA62502 and CA16056.

Received for publication July 12, 2005. Accepted for publication January 5, 2006.


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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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