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Ann Thorac Surg 2003;76:187-193
© 2003 The Society of Thoracic Surgeons

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Original article: general thoracic

Measurement of chemoresistance markers in patients with stage iii non–small cell lung cancer: a novel approach for patient selection

^a Thoracic Oncology Program, Comprehensive Cancer Center, Duke University Medical Center, Durham, North Carolina, USA

^* Address reprint requests to Dr Harpole, DUMC Box 3627, Durham, NC 27710, USA.
e-mail: harpo002{at}surgerytrials.duke.edu

Presented at the Forty-eighth Annual Meeting of the Southern Thoracic Surgical Association, San Antonio, TX, Nov 8–10, 2001.

	Abstract

Top Abstract Introduction Patients and methods Results Comment Conclusions Acknowledgments Discussion References

 
BACKGROUND: The long-term survival of patients with stage III non–small cell lung cancer treated with a combination of chemotherapy and radiation is 10% to 20%. Survival could potentially be increased and toxicity limited if one could identify patients most likely to respond to a particular treatment regimen. This project prospectively evaluated a panel of potential immunohistochemical markers of chemoresistance in a population of patients with pathology-confirmed stage III non–small cell lung cancer in order to determine the prognostic value of each marker in relation to response to chemotherapy or survival.

METHODS: Immunohistochemical staining was performed on histologically positive mediastinal nodal specimens obtained from 59 patients (mean age, 62 years; range, 41 to 79 years) without evidence of distant metastatic disease treated with navelbine-based chemotherapy and external beam radiation therapy between 1996 and 2001. Included were markers for apoptosis (p53, bcl-2), drug efflux/degradation (MDR, GST-), growth factors (EGFr, Her2-neu), and mismatch repair (hMLH1, hMSH2). After chemotherapy, patients underwent radiologic evaluation for response measured by standard criteria.

RESULTS: After a median 41 months of follow-up (range, 17 to 55 months), 43 patients had recurrent disease and 38 of these patients were dead of cancer (median cancer-free survival of 10 months and overall survival of 18 months). Patients who demonstrated a complete or partial response (n = 38) had a significantly improved survival (p = 0.002) compared with those with stable or progressive cancer (n = 21). Multivariable Cox step-wise regression analysis of marker expression associated overexpression of p53 and low expression of hMSH2 with poor treatment response and cancer death.

CONCLUSIONS: These preliminary data suggest that marker expression may allow the separation of patients into low- and high-risk groups with respect to survival after combined navelbine-based chemotherapy and XRT. This could represent a novel method of selecting patients for a particular treatment regimen if these data are reproduced in a larger prospective trial.

	Introduction

Top Abstract Introduction Patients and methods Results Comment Conclusions Acknowledgments Discussion References

 
The overall survival of patients with non–small cell lung cancer (NSCLC) hovers between 10% and 20% because the majority of patients present to their physician with stage III or IV disease [1]. It is unlikely that a significant impact on survival will be accomplished for treating patients with metastatic disease due to the large tumor burden present. However, the combination of systemic chemotherapy and external beam radiation with or without surgical resection appears to be improving survival for selected patients with N2- or N3-positive stage III disease [2]. If one could predict chemotherapeutic response based on molecular tumor markers, one could maximize therapeutic benefit while limiting toxicity. This project prospectively evaluated a panel of potential molecular markers of chemoresistance on pretreatment tumor tissue in a population of patients with stage III NSCLC in order to determine the prognostic value of each marker in relation to response to chemotherapy and survival.

	Patients and methods

Top Abstract Introduction Patients and methods Results Comment Conclusions Acknowledgments Discussion References

 
Population
Patients enrolled in Duke Thoracic Oncology Protocol (TOP) 9602 and 9802 who had stage III disease determined by mediastinoscopy were eligible for inclusion in this study. Additional inclusion criteria were: (1) pathologically confirmed stage IIIA (N2-positive) or IIIB (N3-postive) NSCLC; (2) no evidence of distant metastatic disease with negative head and abdominal computed tomography, radionuclide bone scan (all 59 patients), and full-body FDG-PET scan (35/59 patients); (3) no previous malignancies or pulmonary resections; (4) subsequent navelbine-based chemotherapy before any surgical resection; and (5) complete radiologic re-staging after chemotherapy in order to evaluate response to therapy.

There were a total of 59 patients from May 1996 to August 2001 who met these criteria and were included in this study. Median age was 62 years, with a range of 41 to 79 years. Additional demographic information is listed in Table 1. The Duke TOP protocols are as follows: (9602) 7-week cycle of navelbine at a dose of 5 mg/m² three times per week with concurrent XRT for a total dose of 6,600 cGy; (9802) two 4-week cycles of navelbine at a dose of 17.5 mg/m² weekly and carboplatin at an area under curve of 6 on week 1 with concurrent XRT for a total dose of 4,500 cGy. Thirty-eight of the 59 patients who met the above criteria were enrolled on protocol 9802, and 21 patients were enrolled on protocol 9602. Of note, we evaluate approximately 120 stage III NSCLC patients each year in the Thoracic Oncology Program at Duke, and less than 5% of the patients who met criteria for either TOP 9802 or TOP 9602 refused inclusion in the study.

The mismatch repair (MMR) genes, hMLH1 and hMSH2, function to detect and repair small insertions and deletions as well as nucleoside mismatches and many types of DNA adducts. This is beneficial in the repair of lesions resulting from external beam radiation therapy [9, 10], and overexpression of this function is associated with resistance to XRT. Presently, there is conflicting information on mismatch repair deficiency and resistance to platinum drugs, as animal models suggest that the association of overexpression of MMR genes confers resistance to platinum agents [10–12]. However, studies in humor tumor cells lines indicate that MMR-deficient cells are resistant to platinum agents because cells have lost the ability to detect DNA damage and thus to generate an apoptotic signal [13].

Immunohistochemistry
Consecutive 4- to 6-µm slides were cut from formalin-fixed, paraffin-embedded routine pathologic specimens of histologically positive mediastinal lymph nodes after verification of the presence of viable tumor. Slides were deparaffinized in three changes of xylene and then rehydrated in graded alcohols. After quenching endogenous peroxidase, the slides were gradually brought to water, placed in citrate buffer, pH 6.0, and then either underwent Antigen Retrieval (US Patent no. 5,244,787) or were incubated in pepsin at 37°C for 10 minutes. The slides were placed on the OptiMax PLUS automated slide stainer (BioGenex Laboratories, Inc, San Ramon, CA) and the following procedure was carried out. The sections were rinsed in three washes of phosphate-buffered saline, preincubated in Power Block (BioGenex Laboratories, Inc) for 8 minutes, and then incubated in a humidity chamber with primary antibodies. The following mouse monoclonal IgG antibodies were used: anti-p-glycoprotein (JSB-1), anti-p53 (p1801), anti-Her2-neu, anti-bcl-2, anti-EGFr (all from BioGenex Laboratories, Inc), antihMLH1, and antihMSH2 (both from BD PharMingen, San Diego, CA). The reaction product was developed using the peroxidase-antiperoxidase (PAP) method of detection, using the BioGenex BS-A (biotin streptavidin amplified) HRP (horseradish peroxidase) kit. This procedure included a 20-minute incubation with a biotinylated, affinity-purified secondary antibody, followed by a 20-minute incubation with Avidin DH (biotinylated horseradish peroxidase H complex). The slides were developed with the chromogen diamibenzidine. Finally, the slides were counterstained with hematoxylin.

Slide evaluation
Known positive blocks, as well as IgG-negative control slides, were simultaneously prepared with each tissue assay. Slides were read by three independent observers blinded to clinical information and were classified as either positive or negative on a semiquantitative scale: 0+ (none), 1+ (1% to 20%), and 3+ ( > 50%). This reproducible scale measures the number of tumor cells stained, not the intensity of the stain, which may vary with the age and treatment of the paraffin blocks. Discrepant scores were resolved by consensus [14, 15].

Statistical considerations
Overall survival was calculated from the date of mediastinoscopy until date of death or last follow-up. Cancer-free survival was defined as the time between mediastinoscopy and first recurrence or last follow-up. Cancer-free survival was censored for patients who died without recurrence of their disease. Patients who died without disease progression are considered censored. The markers were dichotomized into high-level expression and low-level expression utilizing what was qualitatively felt to be the optimal cutpoint. These cutpoints were then verified statistically. ² statistic and step-wise regression analyses were used to examine the effect of the demographic variables and the various markers on the endpoint of response to therapy. The log-rank test and Cox’s proportional hazards model were used to examine the effect of the various markers on the endpoints of overall survival and cancer-free survival. The Cox model was also used to assess the joint influence of predictors on these survival endpoints. The product limit estimator developed by Kaplan and Meier was used to display graphically the survival experience of patient subgroups defined by potential prognostic variables.

	Results

Top Abstract Introduction Patients and methods Results Comment Conclusions Acknowledgments Discussion References

 
There were no therapy-related deaths and follow-up was complete in all patients for a median of 41 months (range, 17 to 55 months). The median cancer-free survival was 10 months (43 patients having recurrent cancer), and the overall survival was 18 months (38 patients having died of cancer) (Fig 1A, 1B). Patients with complete (n = 5) or partial response to therapy (n = 33) measured by standard radiologic criteria had a significantly improved survival compared with those with stable (n = 5) or progressive disease (n = 16) (Fig 2A, 2B). Sixteen of the 38 patients who demonstrated a significant response to induction therapy underwent subsequent surgical resection. Table 1 demonstrates demographic variables of the populations and the radiologic responses. There were no significant demographic variables identified on the endpoint of response to therapy.

View larger version (14K): [in this window] [in a new window]   Fig 1. Kaplan Meier survival estimates for overall (A) and cancer-free (B) survival for the entire population are shown. The tic marks denote censored patients who were alive at last follow-up or died of unrelated causes (ie, motor vehicle accidents).

View larger version (20K): [in this window] [in a new window]   Fig 2. Kaplan Meier survival estimates for overall (A) and cancer-free (B) survival for the population divided by posttreatment radiologic response (complete [CR] or partial response [PR] versus stable disease [SD] or progressive disease [PD]) are shown. Censored data are demonstrated by tic marks or numbers on the plots.

View larger version (22K): [in this window] [in a new window]   Fig 3. Kaplan Meier survival estimates for overall (A) and cancer-free (B) survival for the population divided by marker expression for the three markers identified by multivariable analysis. Each line represents an increased number of variables expressed by patients from none (0), to one (1), to two or three (2). Censored data are demonstrated by numbers on the plots.

	Comment

Top Abstract Introduction Patients and methods Results Comment Conclusions Acknowledgments Discussion References

Proper assessment of molecular markers of chemotherapy resistance in patients at the time of their initial bronchoscopy/mediastinoscopy may allow a better selection of patients who may benefit from specific chemotherapy regimens. Furthermore, prescreening patients for markers of resistance may help to avoid unnecessary toxicity from low-yield chemotherapy regimens and to allow the patient the option of pursuing alternative regimens earlier in the course of their treatment. Whereas several molecular markers have been identified for their association with chemotherapy resistance in breast, colon, and esophageal cancers, the data currently available in NSCLC are not as abundant and the studies that are available tend to contain a variety of drugs without a single primary agent [16–18].

Currently, the first-line therapy for treating advanced NSCLC is a combination of a platinum-containing agent and a taxane or navelbine with or without radiation therapy. In fact, navelbine-based regiments are the standard for the National Cancer Institute-Canada and most cooperative group trials in Europe due to its relatively low cost and favorable toxicity profile.

Navelbine (aka, vinorelbine) is a semisynthetic derivative of the vinca alkaloid vinblastine. Its mechanism of action is through binding to low-affinity tubulin binding sites. This results in the splitting of microtubules into spiral aggregates or spiral protofilaments, leading to microtubule disintegration and arrest of cell division in metaphase. Vinca alkaloids may also affect the microtubules involved in numerous other cellular activities, such as chemotaxis, migration, intracellular transport, organelle movement, secretion, membrane trafficking, receptor signal transmission, and cell structure integrity. However, navelbine has a lower affinity for neuronal microtubules and thus results in a lower neurotoxicity profile [19, 20].

The immunohistochemical markers chosen for this study were based on the mechanisms of action of navelbine and XRT. Each marker corresponded to different pathways for potential drug resistance: drug efflux or degradation, blocked apoptosis, stimulated tumor growth, or defective mismatch repair. On the cellular level, the multidrug resistance (MDR) phenotype is associated with the overexpression of the mdr-1 gene that codes for the membrane protein p-glycoprotein (P-gp), an effective "drug efflux pump," that can decrease intracellular drug accumulation and retention [17, 19–23]. We have previously demonstrated that overexpression of MDR was an independent predictor of chemotherapy resistance and decreased survival in patients treated with chemotherapy for esophageal cancer [24]. Similarly, it appears that overexpression of MDR is associated with decreased navelbine treatment response and decreased cancer-free survival in this stage 3 NSCLC population.

GST- is a protein involved with cellular detoxification by degrading oxygen free radicals [25]. Aria and associates observed an association with overexpression of GST- and poor response to platinum-based chemotherapy in 89 patients with NSCLC [6]. We observed a similar relationship in esophageal cancer [24]. Unfortunately, no relationship was observed in this study in either the group who received navelbine and carboplatin or the navelbine only cohort, suggesting that GST- may not play a significant role in resistance in this population.

Inhibition of the normal mechanisms of apoptosis through overexpression or underexpression of factors, such as bcl-2 and p53, in the apoptosis pathway has also been studied for the relationship to chemotherapy resistance in tumor cells [21, 22, 26]. Normal p53 acts as a tumor suppressor by initiating apoptosis. The expression of p53 is normally not detectable by immunohistochemistry. It is believed that mutant p53 proteins, however, have an extended half-life and thus accumulate in tumor cells and result in the apparent p53 overexpression on immunohistochemistry. These mutant variants may lack apoptotic activity and thus promote tumor growth [22, 27]. Our results in this project support this hypothesis, as the presence of high levels of p53 was associated with poor response to therapy and decreased survival. The bcl-2 family of proteins controls the downstream signaling for apoptosis [7]. This investigation demonstrated no association between the lack of normal bcl-2 expression (blocked apoptosis signaling) and lack of treatment response or decreased survival.

Abnormalities in tyrosine kinase growth factor receptors, such as EGFr and Her-2/neu, may also play a role in the tumor growth and thus in poor patient response to chemotherapy and survival [18]. Preclinical data suggest that navelbine downregulates the expression of these receptors, thereby decreasing tumor growth. It was hoped that we would observe an association between overexpression of receptors and a lack of response to therapy. Although none was observed, we are presently examining tumor tissue for a measurable decrease in the level of growth factor expression before and after navelbine-based chemotherapy.

The mismatch repair genes hMLH1 and hMSH2 function to repair DNA damage resulting from faulty replication, XRT, and chemotherapeutic agents. Whereas no relationship was seen for the expression of hMLH1 and response to therapy, a significant association was noted for low levels of hMSH2 expression and the lack of response to therapy and decreased cancer-free and overall survival. This supports the role of hMSH2 as a repair agent for XRT-induced injury.

	Conclusions

Top Abstract Introduction Patients and methods Results Comment Conclusions Acknowledgments Discussion References

 
In patients with pathologically proven stage 3 NSCLC, the standard treatment modality includes neoadjuvant chemotherapy followed by surgical resection whenever possible. However, even the most active chemotherapeutic agents produce only an average of 30% to 50% response rates [28]. Still, studies have shown that chemotherapy in properly selected patient populations does improve surgical resectability and confers a median survival increase compared with patients who do not undergo chemotherapy [28]. Given the low response rates and high side effect profiles of chemotherapy, the ability to screen for patients whose tumors may be resistant to a particular treatment regimen would avoid unnecessary toxicities and allow patients the option of pursuing alternative regimens earlier in the course of their treatment. These preliminary data suggest that marker expression may allow the separation of patients into low- and high-risk groups with respect to survival after navelbine-based chemotherapy and XRT. This could represent a novel method of patient selection for particular treatment regimens if these data are reproduced in a larger prospective trial.

	Acknowledgments

Top Abstract Introduction Patients and methods Results Comment Conclusions Acknowledgments Discussion References

 
Funded in part by National Cancer Institute grant R-29 CA69648 and an educational grant from Glaxo Smith Kline, Inc.

	Discussion

Top Abstract Introduction Patients and methods Results Comment Conclusions Acknowledgments Discussion References

 
DR W. ROY SMYTHE (Houston, TX): I would like to congratulate Dr D’Amico and his group for continuing to pioneer the evaluation of expression of prognostic biomarkers in thoracic malignancies. There is no doubt that in the future, with progress in genomics and proteomics, that you will have many more targets to evaluate.

I do have a couple of questions. One being that it seems somewhat counterintuitive that under-expression of BCL-2, which, as you know, is an anti-apoptotic protein, would render a poorer prognosis rather than the converse. In addition, as you know, there are more than 10 pro-apoptotic and 10 anti-apoptotic proteins that have been characterized at this point. In many studies where combinations of BCL-2 protein family expression have been evaluated, it is even more important that you have under-expression of pro-apoptotic proteins such as BAK, BAX, and BAD. In addition, in malignancies that downregulate BCL-2 expression, such as non-small cell lung carcinoma, the expression of BCL-XL is seemingly much more important as a mitochodrial anti-apoptotic "gate-keeper." Are you planning to look at these other proteins in your larger study?

And lastly, there is difficulty with immunohistochemistry making distinctions between protein over-expression and under-expression, with sampling error, technical reproducibility concerns, as well as the subjectivity of evaluation. In your planned larger study, will you use more objective measures of expression such as mRNAse protection assays or quantitative PCR?

Again, it is a great study and presentation and we appreciate your continued hard work in this area.

DR D’AMICO: Thank you very much for your comments, Dr Smythe. Regarding your question about bcl-2, I think, as you understand, the cascade of apoptotic, both anti-apoptotic and pro- apoptotic, factors is not as clearly well understood now as it is going to be in the future. There is an excellent recent publication in the Journal of Clinical Oncology that demonstrates the cascade as we know it, including bax and bag, and how bcl and p53 and p16 fit into those cascades. I canot answer why bcl-2 has its role in our study, but I can say that in the future, to answer your other question, we are using quantitative PCR, and we are currently working on a library of apoptotic factors, because also, as you know, the intact mechanism of one or two or even three of the pathways does not guarantee progression to apoptosis, and that failure of any of these factors is going to alter the apoptotic mechanism. In the absence of a final common pathway, or at least one that I know of, there is not one factor you can check for apoptosis. So given the results of this study and the lack of the influence of other factors in chemoresistance, our strategy now is to build a library of apoptotic factors and measure them in a panel, similarly as we have done here, using quantitative PCR.

DR THOMAS M. DANIEL (Charlottesville, VA): I have two questions. You are trying to bring a knowledge of molecular biomarkers to all of us who treat lung cancer. I would like to correlate this presentation with a report you have already published on using biologic markers to predict the outcome of stage I lung cancers. Do you think that, instead of showing a chemoresistance here, you have simply selected out with these biomarkers, just like you did in your stage I lung cancers, that group of patients whose cancers are going to do better, and that is why the bcl-2 and the p53 appear to be important correlates?

And secondly and unrelated, you showed no significant difference between the N2 and N3 group (ie, IIIa and IIIb). Are you beginning to question that that clinical staging may be irrelevant?

DR D’AMICO: Those are excellent questions. Thank you for your commentary. Regarding the first question, you are absolutely right. Just because we have designed this study to measure factors that may be related to navelbine chemoresistance doesnot mean that that is actually what they are doing, and in order to prove that, we would have to have a larger group of patients with multiple different chemotherapy regimens to demonstrate that these factors actually select out navelbine chemoresistance. The point of the study is to demonstrate that we are using navelbine, patients are not doing as well as we think, and whether the factors predict chemoresistance specific to navelbine or whether they are just general prognostic indicators we can not say with this study. That is an excellent question.

However, I will say that neither bcl-2 or p53 would be expected to be as predictive in such a small group, and in fact, in our 400 stage I patients, p53 was predictive only in women, not in men at all, and bcl-2 was not predictive [1]. There is something different obviously about a stage I and stage III patient, and I think it may have to do with the navelbine chemotherapy, but I canot say that for sure. We need more numbers and different treatment regimens. This is a relatively small study.

Regarding N2 and N3 staging, I think with a small study like this it would be difficult to say. None of the N3 patients would have gone on to surgery; some of the N2 patients were induction therapy patients. I think we need a larger number. But I will say that the absence of resolution of N2 disease after treatment certainly portends exactly the same prognosis of the presence of N3 disease. And if we can use molecular markers to predict that, we could more accurately select patients for the potential of going on to surgery versus patients that you know, despite your intention, are not going to respond and should just get the full dose of radiation and not have it interrupted for surgical restaging.

	References

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