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Ann Thorac Surg 2006;81:1982-1987
© 2006 The Society of Thoracic Surgeons

Original article: General thoracic

Serum Protein Expression Predicts Recurrence in Patients With Early-Stage Lung Cancer After Resection

Thomas A. D'Amico, MD * , Kelli R. Brooks, MD, Mary-Beth Moore Joshi, BS, Debbi Conlon, James Herndon, II, PhD, Rebecca P. Petersen, MD, David H. Harpole, Jr, MD

Department of Surgery, Duke University Medical Center, Durham, North Carolina

Accepted for publication January 9, 2006.

* Address correspondence to Dr D'Amico, Department of Surgery, Duke University Medical Center, Box 3496, Durham, NC 27710 (Email: damic001{at}mc.duke.edu).

Presented at the Fiftieth Annual Meeting of the Southern Thoracic Surgical Association, Bonita Springs, FL, Nov 13–15, 2003.


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Discussion
 Acknowledgments
 References
 
BACKGROUND: Patients with early stage nonsmall-cell lung cancer who have undergone complete resection have a recurrence rate of approximately 50%, predominately due to the development of systemic metastases. This study is a prospective analysis of the expression of seven serum protein markers of invasion and metastasis, collected preoperatively (baseline) and serially after resection, to determine the relationship between marker expression and recurrence.

METHODS: Serum was collected from 196 patients with clinical stage I nonsmall-cell lung cancer who underwent resection over a 5-year period (1996 to 2000). Samples were drawn before resection and 1, 4, 6, 12, 18, and 24 months postoperatively. All patients were followed for at least 24 months or until death. Serum protein levels of vascular endothelial growth factor, hepatocyte growth factor), E-selectin, CD44, basic fibroblast growth factor, urokinase plasminogen activator, and urokinase plasminogen activator receptor were determined using enzyme-linked immunosorbent assay.

RESULTS: To date, 73 patients (37%) have demonstrated recurrence. Baseline levels of only 1 marker (CD44) correlated with pathologic stage (p = 0.02). Analysis of the serial samples demonstrated that recurrence was predicted (before clinical or radiographic determination) by decreasing levels of E-selectin (p = 0.002), increasing levels of CD44 (p = 0.001), and increasing levels of urokinase plasminogen activator receptor (p = 0.03).

CONCLUSIONS: This study demonstrates the potential to predict recurrence after resection in patients with early-stage nonsmall-cell lung cancer using a panel of serum protein markers. Early identification of patients with recurrence may improve the efficacy of systemic therapy.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Discussion
 Acknowledgments
 References
 
Nonsmall-cell lung cancer (NSCLC) is the leading cause of cancer deaths in the United States and is accountable for nearly 170,000 deaths per year [1]. Approximately 50% of patients with stage I or II NSCLC will have systemic metastases, despite aggressive staging and complete resection [2]. Currently, patients with early-stage lung cancer are treated with surgical resection alone. Recently, adjuvant chemotherapy has been demonstrated to improve survival after complete resection, demonstrating the potential for chemotherapy to cure minimal residual disease [3, 4]. If it were possible to identify patients with systemic recurrence before the development clinical or radiographic evidence, systemic chemotherapy may be more effective in improving the outcomes of patients in whom metastatic disease develops after resection.

Molecular analysis of the primary tumor has demonstrated the ability to identify patients with increased risk of recurrence from NSCLC [5], although this technology has not yet been investigated in phase III clinical trials and clinical efficacy has not yet been proved. Tumor-related proteins may be secreted into the peripheral circulation of patients with cancer and may be detectable by protein analysis. Although serum tumor markers are used in the diagnosis and staging of a variety of solid tumors, such as {alpha}-fetoprotein and ß-human gonadotropin in mediastinal germ cell tumors, the use of serum proteins to detect the presence or recurrence of NSCLC has not been established. This study uses a panel of seven markers, assessed preoperatively and serially during follow-up, to investigate the potential to detect recurrence before the appearance of symptomatic or radiographic evidence. The markers chosen are implicated in the processes of tumor angiogenesis, basement membrane invasion, or metastasis.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Discussion
 Acknowledgments
 References
 
Patients with clinical stage I NSCLC (known or suspected) were recruited to participate in this study under an Institutional Review Board–approved, informed consent protocol at Duke University Medical Center and the Durham Veterans Administration Hospital. The outcomes of patients recruited between March 1996 and December 2002 are analyzed herein. All patients were staged with computed tomography (CT) of the chest and abdomen, and the majority of patients underwent positron emission tomography (PET). In addition, the majority of patients underwent cervical mediastinoscopy before resection, including all patients with T size of 3 cm or greater in diameter or mediastinal adenopathy as defined by greater than 1 cm (short axis) by CT or hypermetabolism on PET scans. Brain imaging by CT or magnetic resonance imaging was performed selectively. All patients underwent anatomic resection (lobectomy and pneumonectomy) and mediastinal lymph node dissection.

Patients who enrolled underwent blood draws preoperatively at the time of resection and at serial intervals of 1, 4, 6, 12, 18, and 24 months postoperatively. The strategy of using serial serum protein analysis enabled each patient to serve as the control (preoperative sample). Clinical follow-up included chest radiograph at 1, 4, 6, and 18 months; CT of the chest was performed annually (12 and 24 months). Chest CT, PET, brain imaging, and bone scan were performed as indicated as well when history, physical examination, or chest radiographic findings dictated further radiographic analysis. Patients who developed recurrent disease underwent their last draw at time of detection of recurrence. Patients who did not complete all draws were excluded from analysis.

Samples and Measurement of Serum Tumor Markers
Blood samples were processed within 12 hours by centrifugation at 3 600 rpm for 10 minutes to isolate the serum. The serum samples were stored at -80C in 1 mL aliquots until time of analysis. Samples did not undergo any additional freeze-thaw cycles before analysis. Commercially available enzyme-linked immunosorbent assays (ELISAs) for each biomarker were used to measure serum concentrations against a known standard curve according to manufacturers' instructions: hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and E-selectin (R&D Systems, Minneapolis, Minnesota); urokinase plasminogen activator (uPA) and urokinase plasminogen activator receptor (uPAR [American Diagnostica, Stamford, Connecticut]); and CD44 (Biosource International, Carmillo, California.) The specific biomarkers analyzed in this study are listed in Table 1.


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  		Table 1. Serum Protein Markers
 
Statistical Analysis
POWER SAMPLE SIZE CALCULATION. Before beginning the study, statistical estimation of the size of a patient population needed for an adequate multivariate evaluation of stage I NSCLC was obtained. Preliminary sample size estimates indicated that if the proportion of patients who failed (recurrence or cancer-death in stage I NSCLC) were approximately 40%, a minimum of 250 patients would be needed to observe a sufficient number of failures to satisfy the statistical power considerations. Specifically, assuming a dichotomous biomarker covariate where the number of failures were in a 4:1 ratio, a total of 100 failures would be needed to detect a doubling of the hazards ratio associated with the covariable with 85% power (beta = 0.15; alpha = 0.05, two-sided).

The Kruskal-Wallis test was used to identify associations between preoperative serum marker levels and tumor stage, lymph node stage and pathologic stage. Univariate and multivariate logistic regression analyses, in addition to Cox proportional hazards survival regression analysis were used to identify the effect of preoperative marker serum levels on overall survival. The Wilcoxon signed-rank test was then used to compare the preoperative marker serum level to the first draw postoperative serum marker level. Logistic and Cox proportional hazards regression analyses, both univariate and multivariate, were carried out to identify the effect of postresection measurements and overall change (first draw postresection measurements – pre-resection levels) on overall and cancer-free survival.

Finally, serial marker levels were analyzed in univariate and multivariate logistic regression analyses. The last value included for serial analysis was that drawn before clinical detection of disease recurrence. If a patient demonstrated clinical evidence of recurrence 18 months postoperatively, the last blood draw utilized in analysis was the 12-month sample. Patients were their own internal control and analysis was performed for both the absolute values as well as change between samples. Kaplan-Meier survival analysis was performed to display the relationship between marker change and time to cancer recurrence.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Discussion
 Acknowledgments
 References
 
To date, 563 patients have been enrolled in this study. There are 196 patients who have completed the 24-month assessment, and 170 patients are still within 2 years of resection and are undergoing serial analysis. Thirty patients who underwent initial draw were found to have pathology other than NSCLC at time of resection and were removed from the study; 167 patients did not complete their serial blood draws by volition. Of note, the survival for the patients who did not complete the 2 years is equivalent to those included in this analysis.

Table 2 demonstrates the characteristics of the 196 patients and tumors included in this analysis. There were 25 patients who at the time of resection were found to have stage III or IV disease, owing to the presence of unsuspected N2 disease, unsuspected involvement of the mediastinal pleura with concurrent N1 disease (T3N1), or to having satellite lesions in either same lobe (T4) or different lobe (M1).


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  		Table 2. Patient and Tumor Characteristics
 
After 24-month follow-up, 73 patients have demonstrated recurrent disease, while 123 patients have no evidence of recurrence. Preoperative (baseline) serum levels of only 1 marker, CD44, correlated with pathologic stage, and no marker correlated with T status or N status. All markers, with the exception of E-selectin, demonstrated significant decline between the preoperative blood draw and the first postoperative sample (p < 0.0001). Multivariable analysis revealed that high levels of E-selectin preoperatively (p = 0.03) and low levels of HGF postoperatively (p = 0.006) correlated with a decreased risk of recurrence. On multivariable analysis of serial blood draws, decreasing levels of E-selectin (p = 0.002), increasing levels of CD44 (p = 0.001) and increasing levels of uPAR (p = 0.03) were associated with an increased risk of cancer recurrence. Cox proportional hazards model also demonstrated that increasing levels of CD44 (p = 0.005) and decreasing levels of E-selectin (p = 0.003) were significantly associated with cancer recurrence. The Kaplan-Meier survival curves for CD44 and E-selectin (Figs 1 and 2) Go demonstrate the recurrence rate and survival probability with respect to time for patients with changing levels of these markers.


Figure 1
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  		Fig 1. A Kaplan-Meier curve demonstrates the increased recurrence rate and decreased survival for patients with decreasing levels of E-selectin from baseline. (Solid line = decreasing; dotted line = increasing; crosses = individual data points.)

 

Figure 2
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  		Fig 2. A Kaplan-Meier curve demonstrates the increased recurrence rate and decreased survival for patients with increasing levels of CD44 from baseline. (Solid line = decreasing; dotted line = increasing.)

 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Discussion
 Acknowledgments
 References
 
Patients with early-stage NSCLC are at significant risk for cancer recurrence. Identifying these patients at increased risk may allow for earlier and more effective therapeutic intervention. The measurement of serum proteins involved in the pathophysiology of invasion and metastases may be effective in providing prognostic stratification and allowing earlier therapeutic intervention.

Tumors must undergo angiogenesis and invasion in order to spread. Angiogenic factors secreted by the tumor signal the formation of neovascular capillaries to deliver nutrients to an enlarging tumor. Basic fibroblast growth factor and VEGF serum titers have demonstrated prognostic significance in patients with prostate and breast cancer [6–8].

Tumor invasion involves the degradation of the basement membrane surrounding the tumor cells. Tumor cells secrete uPA in its inactive form. This is converted to the active form upon binding to its specific membrane bound receptor, uPAR, expressed on both tumor and normal cells. The UPA then converts plasminogen to plasmin, which degrades the protein components of the extracellular matrix. Patients whose tumors cells have expressed uPAR have demonstrated decreased survival in patients with breast and ovarian cancer [9, 10].

Circulating tumor cells must adhere to the endothelial lining and migrate through interstitial spaces in order to metastasize. The marker CD44 is a membrane glycoprotein primarily located on hematopoietic cells, which allows for cell to cell and cell to matrix interactions. Several isoforms are expressed on tumor cells, and serum levels have prognostic significance in gastric carcinomas [11]. Although tumor expression is an independent predictor of cancer recurrence in both colorectal cancer and NSCLC, serum levels have not been investigated [12]. Hepatocyte growth factor, a cytokine secreted by mesenchymal derived cells, functions to promote cell growth, adhesion, migration and invasion. High serum HGF titers have been demonstrated to correspond to poor prognosis in patients with breast and NSCLC [13, 14]. Finally, E-selectin is the endothelial ligand for sialyl carbohydrate antigens expressed on the surface of tumor cells. Its secretion is reportedly stimulated by tumor cells, and serum titers have correlated with prognosis in patients with breast cancer [15–17]. Small studies have also demonstrated a similar result in NSCLC [18, 19].

The use of serum markers has not yet reached acceptance in assessing prognosis or assigning therapy after complete resection for NSCLC. In 1997, the American Thoracic Society and the European Respiratory Society jointly published guidelines for assessment of NSCLC, indicating that no serum tumor markers had sensitivity and specificity sufficient to reliably detect occult disease or influence treatment [20]. Finally, they did not recommend routine measurement of any biomarkers in the screening, staging, or evaluation of disease progression. The most thoroughly studied serum marker is carcinoembryonic antigen (CEA). Several reports demonstrate that increased preoperative serum CEA levels are associated with more advanced disease and with poor survival after complete resection for NSCLC [21–23]. These studies suggest that normalization of CEA levels after surgery was a significant favorable prognostic sign in patients with an elevated CEA level before surgery; even after complete resection, patients with a elevated CEA level are at increased risk for resection. However, elevated CEA does not universally predict recurrence [23]. Moreover, CEA is elevated in only approximately one third of patients before resection, making serial CEA measurements futile in the majority of patients. Using a panel of markers allows a majority of patients to be eligible for surveillance.

While prognostic information may be attained from initial serum titers of tumor markers, these markers continue to be secreted into the peripheral circulation of patients with continued and recurrent disease. The use of serial serum determinations enables analysis of protein expression over time, and changes in protein levels may be more important than the absolute value of the protein. At this time, recurrence detection is limited by clinical symptoms and current radiological techniques that can detect a metastasis only after it reaches 1 cm3 or approximately 109 tumor cells [24]. Tumor proteins in the serum, however, may be detectable before the point at which a recurrent tumor can be identified.

In this study, patients with early clinical stage NSCLC had baseline serum determinations and were subsequently followed after complete resection with serial blood draws for a period of 2 years. Serial measurements were used to define the utility of serum protein analysis at the time of the detection of clinical recurrence and to determine the predictability of recurrence, based on circulating tumor markers. As patients served as their own controls, the analysis was based on the changes in levels with respect to time, rather than on absolute values. Furthermore, the analysis included only the samples that predated the clinical and radiologic detection of recurrent disease. Based on this, one can utilize trends in E-selectin, CD44, and uPAR to identify patients most likely to develop recurrent disease before currently available detection methods.

Although this study has identified three markers with significance in the early detection of recurrence in patients with NSCLC, additional investigation into this area must be performed. It may be possible to use postoperative changes in serum protein expression as an indication for the administration of systemic therapy; this strategy may have the ability to improve survival, utilizing chemotherapy when only microscopic disease is present. This strategy, however, has not been tested to date. Furthermore, the involved protein itself may be used to select therapy. For example, if angiogenic serum proteins are manifested, antiangiogenic therapy such as VEGF antibody, may be employed. As proteomics research identifies novel proteins implicated in NSCLC, these also need to be evaluated for their prognostic significance as circulating tumor markers in the sera of these patients. As NSCLC is a diverse disease, a panel of tumor markers will likely be required in order to accurately predict those patients most likely to develop recurrent disease.

The results of this study should be reexamined in a large multicenter trial. Patients then identified at increased risk may be targeted for adjuvant chemotherapy or biologic therapy under clinical protocols in order to define whether earlier interventions and therapies in these patients correlate with improved outcomes.


   Discussion
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Discussion
Acknowledgments
 References
 
DR DAVID R. JONES (Charlottesville, VA): Doctor Brooks, I very much enjoyed your presentation in that it continues the work of the thoracic surgery laboratory at Duke. I have a couple of questions for you.

Are there any specific markers or groups of markers related to local recurrence or were all these distant recurrences? If they were distant recurrences, which organ was most commonly involved? Based on previous studies from your laboratory, do you have any immunohistochemistry data available on the expression of these proteins in the tumor itself relative to the serum levels?

And finally, do you have any data on the expression of these proteins in patients who have no cancer whatsoever? Again, I enjoyed your presentation and I am anxious to hear your response.

DR BROOKS: Thank you, Dr Jones, for your questions. The first, the majority of these patients had distant recurrences. I unfortunately do not have that data in front of me. There were a number of recurrences to the brain primarily that I remember, but I don't have the exact breakdown.

We do not have the data on this set of patients with relation to the immunohistochemistry (IHC) of the tumors. That is certainly something that we could do. Our analysis of the serial IHC tumors that we have done was done before the beginning of this study, primarily.

On your third part, data on the levels in patients without cancer, we do have those 30 patients who we resected who subsequently were found to have benign disease. Those patients we did run for analysis, and in those patients there was no significant expression of any of the markers that we found.

DR ROBERT J. CERFOLIO (Birmingham, AL): Again, this represents very good work, it was a great presentation, and you are carrying on the history of Duke. I congratulate you. A couple of quick questions. You said the majority of your patients had PET scanning, and I am wondering if you have any data on the maximum standardized uptake value (SUV) or the mean SUV as a possible predictor of some of these proteins. We are UAB are studying the max and mean SUV and believe the SUV of the primary tumor is an independent predictor of stage, and it may also be a predictor of recurrence after resection. Further, it may then be an potential indicator, besides staging procedures like mediastinoscopy, of whom should be selected for preoperative neoadjuvant therapy. Have you thought about correlating your serum tumor markers with your SUV data to see a correlation?

DR BROOKS: We do not have any corollary data, and actually haven't even thought about doing that with relation to the protein expression, but I think that is an excellent thought, and we certainly can apply that. At this point, Duke is almost the only place that doesn't generally include the SUV analysis on their PET scans. It is a calculation that our radiologists no longer perform.

DR CERFOLIO: You don't routinely get a max or a mean SUV on the FDG-PET report? Can they go back and generate that number retrospectively?

DR BROOKS: They probably can.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Discussion
 Acknowledgments
References
 
This study was funded by the VA Merit Review: Serum Marker Analysis in Patients With Clinical Stage I Nonsmall-Cell Lung Cancer.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Discussion
 Acknowledgments
 References
 

  1. Jemal A, Murray T, Ward E, et al. Cancer statistics 2005 Ca Cancer J Clin 2005;55:10-30.[Abstract/Free Full Text]
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  9. Seir C, Stephens R, Bizik J, et al. The level of urokinase-type plasminogen activator receptor is increased in serum of ovarian cancer patients Cancer Res 1998;58:1843-1849.[Abstract/Free Full Text]
  10. Kim SJ, Shiba E, Taguchi T, et al. Urokinase type plasminogen activator receptor is a novel prognostic factor in breast cancer Anticancer Res 1997;17:1373-1378.[Medline]
  11. Guo Y-J, Liu G, Wang X, et al. Potential use of soluble CD44 in serum as indicator of tumor burden and metastasis in patients with gastric or colon cancer Cancer Res 1994;54:422-426.[Abstract/Free Full Text]
  12. Wielenga VJM, Heider KH, Offerhaus JA, et al. Expression of CD44 variant proteins in human colorectal cancer is related to tumor progression Cancer Res 1993;53:4754-4756.[Abstract/Free Full Text]
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  18. Roselli M, Mineo TC, Martini F, et al. Soluble selectin levels in patients with lung cancer Int J Biolog Marker 2002;17:56-62.
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