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J Thorac Cardiovasc Surg 2007;133:352-363
© 2007 The American Association for Thoracic Surgery
General Thoracic Surgery |
a Jefferson Medical College, Division of Cardiothoracic Surgery, Philadelphia, Pa
b University of Pittsburgh Medical Center Presbyterian-Shadyside, Heart, Lung and Esophageal Surgery Institute, Pittsburgh, Pa
c Oncotech, Inc, Tustin, Calif.
Read at the Thirty-second Annual Meeting of the Western Thoracic Surgical Association, Sun Valley, Idaho, June 21-24, 2006.
Received for publication June 19, 2006; revisions received September 25, 2006; accepted for publication October 9, 2006. * Address for reprints: Thomas A. d’Amato, MD, PhD, Division of Cardiothoracic Surgery, Jefferson Medical College of Thomas Jefferson University, 1025 Walnut St, Suite 607, Philadelphia, PA 19107. (Email: thomas.damato{at}jefferson.edu).
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METHODS: Chemotherapy resistance to doublets—carboplatin and paclitaxel, cisplatin and navelbline, cisplatin and docetaxel, and cisplatin and gemcitabine—was analyzed in 4571 non–small cell lung cancer tumors with the extreme drug resistance assay. Chemotherapy resistance is defined as follows: extreme drug resistance, 1 SD above the median chemotherapy resistance; intermediate drug resistance, between the median and extreme drug resistances; and low drug resistance, 1 SD below the median. Chemotherapy resistance was compared with DNA ploidy measured by flow cytometry, and markers p53 and epithelial growth factor receptor were assayed by immunohistochemistry.
RESULTS: Tumors with extreme or intermediate drug resistance were noted in 30% to carboplatin-paclitaxel, in 24% to cisplatin-navelbline, in 42% to cisplatin-gemcitabine, and in 27% to cisplatin-docetaxel. Extreme or intermediate drug resistance to at least one drug occurred in 74% to carboplatin-paclitaxel, in 68% to cisplatin-navelbline, in 88% to cisplatin-gemcitabine, and in 68% to cisplatin-docetaxel. More intermediate plus extreme chemotherapy resistances occurred in aneuploid tumors to etoposide (53% vs 36%, P = .0002) and topotecan (48% vs 36%, P = .0094), with less intermediate or extreme chemotherapy resistance to gemcitabine (88% vs 81%, P = .0345). p53-Positive tumors had more intermediate or extreme resistance to etoposide (57% vs 44%, P = .0009) and doxorubicin (73% vs. 58%, P = .0324) and less intermediate or extreme resistance to cisplatin (44% vs 54%, P = .0125), to carboplatin (47% vs 57%, P = .0129), to taxol (47% vs 57%, P = .0056), and to gemcitabine (78% vs 87%, P = .0108). Fewer epithelial growth factor receptor–positive tumors were extremely drug resistant to cisplatin (13% vs 26%, P = .0074) and carboplatin (13% v. 30%, P = .0008).
CONCLUSIONS: Multi-drug chemotherapy resistance in non–small cell lung cancer tumor cultures is common, and associations between molecular markers and in vitro chemotherapy resistance are noted. Clinical validation through integration of such testing into clinical trials seems warranted.
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Introduction |
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Platinum-based adjuvant chemotherapy, which has been reported to improve survival (4%–15%) for some patients with early-stage non–small cell lung cancer (NSCLC), is now recommended for those with good performance status and completely resected stage IB-IIIA disease,2-5 yet only one study3 showed benefit for patients with stage IB disease. Accordingly, the majority of patients endure a predictable toxicity from empiric chemotherapy without a survival advantage.
In contrast to targeted therapeutic agents, such as trastuzumab inhibition of epithelial growth factor receptor (EGFR), which may hold promise toward patient-tumor specific treatment,6 empiric platinum-based chemotherapy regimens represent a "hit or miss" approach in hopes for a therapeutic benefit despite the calculable risk of significant toxicity.
By avoiding a particular drug by testing a specific tumor’s phenotypic chemotherapy resistance, unnecessary toxicity may be avoided. In vitro chemotherapy resistance testing of fresh human tumor cells may accurately (90%) predict that an agent may be ineffective, whereas chemotherapy sensitivity testing is less accurate (60%) largely because it is impossible to predict the impact of important host and tumor biologic determinants affecting a drug’s clinical efficacy.7 For some solid tumors,8-10 clinical unresponsiveness to antineoplastic agents correlates with in vitro chemotherapy resistance, yet little correlative data exist for NSCLC.
Recently, the prevalence of chemotherapy resistance in resected NSCLC tumor cultures to several individual antineoplastic drugs was reported.11 In an effort to further characterize in vitro chemotherapy resistance patterns in NSCLC, agents used clinically as platinum-based doublets were analyzed for simultaneous in vitro 2-drug resistance, and the association of chemotherapy resistance in NSCLC was compared with DNA ploidy and examined for correlations with molecular markers that may act as surrogates to predict tumor chemotherapy resistance.
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Materials and Methods |
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The Extreme Drug Resistant (EDR) Assay
Fresh tumor specimens are mechanically and enzymatically disaggregated into single cells and small cellular aggregates and cultured in a cellular proliferation assay described previously in detail.7 Tumor cultures were exposed to single chemotherapeutic agents: cisplatin, carboplatin, etoposide, doxorubicin, topotecan, paclitaxel, docetaxel, vinorelbine, or gemcitabine in duplicate or triplicate assays at final concentrations 5 to 10 times higher than expected in vivo peak plasma levels. After a 72-hour exposure, 5 µCi of 3H-thymidine (Amersham Biosciences, Piscataway, NJ) is added and incubation is continued for an additional 48 hours. Cell suspensions are harvested and cellular proliferation is determined by 3H-thymidine incorporation into DNA and measured by scintillation counting (Beckman-Coulter, Inc, Fullerton, Calif). Positive controls (supralethal cisplatin resulting in 100% cell death) prepared in duplicate and negative controls (media exposed only) prepared in quadruplicate are used to determine the percent colony inhibition (PCI) by an individual drug compared with media-exposed cultures correcting for positive controls.
From a historical database of over 140,000 human tumors of varied histologic type submitted for the EDR assay, the PCI values are compared with the median PCI of the entire population for any given drug tested. Tumors exhibiting PCI values 1 SD above the population median are defined as low drug resistant (LDR); tumors with PCI values between the population median and 1 SD below the median are defined as intermediate drug resistant (IDR); and tumors with PCI values that are 1 SD below the median PCI are defined as EDR.
DNA Ploidy and S-phase Analyses by Flow Cytometry
Analyses were performed on nuclear suspensions prepared from fresh tissue as described12 using a Becton-Dickenson FACScan flow cytometer (Becton-Dickinson, Franklin Lakes, NJ) with DNA cell cycle and S-phase parameters programmed with ModFit LT software (Variety Software House, Inc, Topsham, Maine).
Immunohistochemistry
From paraffin-embedded tissue sections, both mutant and wild-type isoforms of p53 were detected with the DO-1 monoclonal antibody (Santa Cruz Biotechnology, Inc, Santa Cruz, Calif) followed by automated immunostaining on a Ventana Benchmark (Vantana Medical Systems, Inc, Tucson, Ariz) or the BioGenex i6000 (BioGenix, Inc, San Ramon, Calif) instrument. The 3,3'-diaminobenzidine/horse radish peroxidase reagent (Genetex, Inc, San Antonio, Tex) was used for secondary detection. Positive staining was defined as more than 20% of cells exhibiting nuclear staining.13
Automated measurement of EGFR expression was detected with the 31G7 monoclonal antibody (Invitrogen Corp, Carlsbad, Calif) after antigen retrieval with 0.25% trypsin. Positive staining was defined by calculating the histoscore, which equals the product of the percent EGFR positive cells times the staining intensity scored on a scale from zero (no staining) to 3 (intense staining) as described.14 An EGFR histoscore of 120 or more is considered positive.
Statistical Analysis
Patient tumor cultures were tested against a panel between 3 and 9 individual drugs. From cultures tested with agents used in the 4 clinically relevant platinum-based doublets—carboplatin plus taxol; cisplatin plus navelbine; cisplatin plus docetaxel; or cisplatin plus gemcitabine—concordant resistance patterns were determined by plotting PCI values for individual tumors tested with the first drug (ordinate) versus the same tumor tested against the second drug (abscissa). Assuming that some frequency of EDR, IDR, and LDR to any given drug exist in a population of separate tumors tested against 1 drug, if a set of tumors is tested against 2 independent drugs, then a 3 x 3 matrix can be created in which 9 possible resistance patterns are possible for the population. Within this population, each tumor has a unique resistance to each agent; for example, one subset of tumors will be EDR to both drugs and a subset will be LDR to both drugs. Seven other combinations of EDR, IDR, and LDR are possible. From this matrix, subpopulations exhibiting any EDR plus IDR combination to both drugs tested and those exhibiting EDR or IDR to at least one agent were calculated. Correlation coefficients from scatter plot analysis using linear regression analysis were performed with the Spotfire statistical package (Spotfire, Inc, Sommerville, Mass) to illustrate tumor resistance patterns for any given doublet pair analyzed.
Potential associations between drug resistance to a single agent and DNA ploidy or the molecular markers p53 and EGFR were also abstracted from the database with Spotfire and analyzed with SPSS software (SPSS, Inc, Chicago, Ill) by 
2 testing.
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Discussion |
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Advances in cell culture technology, test availability, reliability, and reproducibility attest to the robust nature of some chemotherapy-resistant assays and prompted the Medicare approval of chemotherapy resistance (not sensitivity) testing.19 Two types of assays are described below to illustrate differences between chemotherapy resistance and sensitivity. Older clonogenic assays relied on brief exposures to chemotherapy at or below peak serum concentrations, frequently used cell culture techniques permitting growth of stromal elements, required long incubation times, which limited clinical usefulness, and often used inaccurate manual cell-counting methods. Assumptions that in vitro tumor sensitivity equates with clinical response accounts for neither tumor factors of anatomic permeability and vascularity nor host factors of absorption, metabolism, activation, or elimination.
In contrast, the EDR assay is a cellular proliferation assay in which tumors are exposed for 120 hours to suprapharmacologic doses of chemotherapy up to 10-fold higher than peak plasma concentrations. Stromal cell growth is inhibited by cell platting on soft agarose, and cellular proliferation is reliably measured by 3H-thymidine incorporation into DNA. When the relative cellular growth of a specific culture is compared with well over 140,000 human tumors exposed to the same drug, tumor growth inhibition 1 SD below the median inhibition identifies resistant tumors without reference to clinical sensitivity. Comparing clinical response to chemotherapy with an independent tumor set of 450 human tumor cell cultures, 20 of which were NSCLC, the ability of the EDR assay to detect tumor resistance to a particular chemotherapeutic agent was over 99% specific.7 Recently, we have rekindled an interest in the clinical application of chemotherapy resistance assays not only to help predict an observed response to adjuvant chemotherapy, but in hopes of avoiding unnecessary toxicities related to potentially ineffective cytotoxic agents.
Adjuvant Chemotherapy in Resected NSCLC
Enthusiasm to administer platinum-based adjuvant chemotherapy after complete resection of stage IB-IIIA NSCLC has been fueled from the results of 4 randomized clinical trials. Controversy regarding the universal application of adjuvant chemotherapy after resection of stage IB disease continues. In the International Adjuvant Lung Cancer Trial (IALT), patients with stage IA-IIIA disease received cisplatin plus etoposide (57%) or a vinca alkaloid (43%). Although an overall 4% increase in 5-year survival was noted, only patients with stage IIIA disease benefited. Grade 4 toxicity occurred in 24%, and non–dose dependent lethal platinum toxicity occurred in up to 2.4% of patients.2
Both the National Cancer Institute of Canada Clinical Trial Group–JBR.10 trial and the Adjuvant Navelbine International Trialist Association (ANITA) trial used the cisplatin plus vinorelbine doublet for adjuvant therapy after complete resection. JBR.10 included patients with stages IB-II disease, but a survival benefit occurred only in patients with stage II disease. Grade 3 or 4 neutropenia occurred in 73% of patients in the chemotherapy arm. In the ANITA trial, survival advantage with adjuvant chemotherapy was noted for patients with stage II-IIIA disease, but no observed survival benefit was noted in patients with stage IB disease.4,5
The Cancer and Leukemia Group B (CALGB)– 9633 trial randomized only patients with stage IB (T2 N0) disease either to adjuvant carboplatin plus paclitaxel or to observation alone after complete resection. These data, presented in abstract form at ASCO in 2005, are yet to be published otherwise. They reported an improvement in overall survival among the adjuvant chemotherapy patient arm of the study of 12% at 4 years’ follow-up. Grade 4 neutropenia occurred in 36%, and 45% of patients either did not complete therapy or required dose reductions. This recent trial is alone in reporting a demonstrable survival benefit for adjuvant chemotherapy in patients with stage IB disease.3 Subsequent reanalysis of the data from this trial suggests that the study design was underpowered to definitely suggest a long-term survival benefit of adjuvant chemotherapy for stage IB disease.20 These more recent findings provoke continued skepticism with the utility of presently available empiric adjuvant chemotherapy for completely resected stage IB disease.
Multiple Drug Chemotherapy Resistance
In this study, the resistance of NSCLC tumor cultures exposed to several individual chemotherapy agents of clinical relevance was analyzed. The results are consistent with our previously reported prevalence of chemotherapy resistance in both NCSLC tumor cultures11 and other solid tumors.14,21 Despite potential limitations of not exposing tumors to two drugs simultaneously to test for chemotherapeutic agent synergy, these data illustrate that tumors are frequently resistant to at least one agent in chemotherapy doublet regimens commonly used throughout North America and Europe today. Even though the frequency of tumors exhibiting extreme chemotherapy resistance to both agents is less impressive, the frequency of extreme or intermediate resistance to at least one chosen agent is alarmingly high, suggesting that patients may benefit from only one drug with empiric "doublet chemotherapy" selection. Accordingly, Mehta and associates8 examined this phenomenon in breast cancer and found that the median time to disease progression and survival was significantly shorter for patients treated with any combination of agents exhibiting either extreme or intermediate in vitro drug resistance in comparison with patients having tumors with low in vitro resistance to both drugs. In vitro drug resistance correlated with a shorter survival similar to that associated with advanced stage or positive lymph node status. It is interesting to note that in our study, tumor resistance observed in doublet analysis is in parallel with the observed clinical response reported in the JBR.10 and ANITA trials, where the greatest survival advantage is reported with the cisplatin plus vinorelbine doublet.4,5
DNA Ploidy, Molecular Markers, and Chemotherapy Resistance
We report an association between tumor chemotherapy resistance and DNA ploidy for some antineoplastic agents. Aneuploid tumors were likely to be less resistant to gemcitabine, yet were more resistant to etoposide and topotecan. The potential clinical relevance of this association for these drugs is interesting but obscure. Other investigators have also identified a possible relationship between tumor ploidy and chemotherapy resistance. Doubre and associates22 reported a 3-fold increase in levels of multiple drug resistance protein (MDR1) in 84 previously untreated aneuploid NSCLC tumors and found that DNA aneuploidy resulted from an increased gain of chromosome 16 where the MDR1 gene is located. Volm and colleagues23 analyzed 240 patients with NSCLC having aneuploid tumors with more than one stem line. In vitro chemotherapy resistance was associated with an observed decreased survival in patients undergoing chemotherapy having aneuploid tumors compared with patients with diploid and in vitro sensitive tumors.
Our investigation has also identified a possible association between p53 expression and chemotherapy drug resistance. We found that p53-positive tumors were more often less resistant to cisplatin, carboplatin, paclitaxel, and gemcitabine, but were more often associated with increased resistance to etoposide and doxorubicin. This association for cisplatin in vitro resistance in p53-positive tumors is inconsistent with clinical results from others24,25 in which 26% patients with p53-positive tumors in chemotherapy naive advanced NSCLC responded to cisplatin versus 57% of patients with p53-negative tumors. This discrepancy may be related to the ability of suprapharmacologic doses of some chemotherapeutic agents to overcome the suppressor gene checkpoint imparted by p53. Interestingly, d’Amico and coworkers26 showed that female patients with stage I lung cancer and p53-positive tumors had a decreased survival of 49% compared with 77% of women with p53-negative tumors.
Increasing interest in the prognostic importance of EGFR expression related to targeted therapy for NSCLC stimulated us to examine this molecular marker with regard to resistance to "standard" chemotherapy agents for this disease. Onn and associates27 reported a trend toward decreased survival from 84.4 months to 44.2 months among 111 patients with stage 1 NSCLC who had synchronous expression of EGFR and the HER2-neu protein. The finding of EGFR gene polymorphisms measured by polymerase chain reaction–restriction fragment polymorphism has been evaluated in advanced colorectal cancer and has been found to be associated with an increased likelihood of disease progression with 5-fluorouracil/oxaliplatin chemotherapy when the increased gene copy number was identified.28 Observations from our study revealed that increased EGFR expression, measured by immunohistochemistry, is associated with a decreased in vitro resistance to platinum agents and increased in vitro resistance to gemcitabine. Our study lacks clinical correlation and distinction between EGFR expression levels, the presence of specific mutations determined by polymerase chain reaction, or measurements of gene copy number by florescent in situ hybridization. Comparisons of these assay modalities may warrant additional study. Further analysis of associations between EGFR and chemotherapy resistance should be considered for early-stage patients based on the decreased survival noted for EGFR-positive tumors in patients with stage I disease.27
The Cellular Proliferation Chemotherapy Resistance Assay and the Relationship to the Cancer Stem Cell Hypothesis
In regeneration of normal (nontransformed) tissue, quiescent stem cells are activated to enter the cell cycle and the formation of new replacement tissue occurs in response to environmental stress. The cancer stem cell hypothesis states that the cancer-initiating cell is a transformed tissue stem cell, which retains the essential property of self-renewal through the activity of MDR transporters.29 In normal tissue, the genetic regeneration program is turned off after tissue restoration once homeostasis is restored. Unlike normal tissues, homeostasis in progenitor cancer cells is abnormal. Thus, tumor cells can overcome anticancer therapy not only by the activation of mechanisms specific for transformed cells, but also by taking advantage of a normal tissue regeneration genetic program.30
Human tumors are composed of nonhomogeneous cell populations including cancer stem cells and transformed progenitor cells. These heterogeneous populations are all represented in cell culture conditions used in the EDR assay and include subpopulations of cancer stem cells that constitutively express the MDR phenotype and are inherently chemotherapy resistant. An example of how the EDR assay can predict clinical chemotherapy resistance and may be related to the proliferation of cancer stem cells is noted in a study of breast cancer tumor cultures that exhibited an in vitro chemotherapy resistance to both paclitaxel and doxorubicin.14 Overall, MDR1 P-glycoprotein expression was shown to occur in 17% of these patients’ tumors. When further stratified, tumors from chemotherapy naive patients showed an 11% incidence of MDR1 expression compared with a 30% incidence of MDR1 expression in tumors from previously treated patients. The clinical response to doxorubicin and paclitaxel was lower in the previously treated MDR1-positive groups than in the untreated MDR1-negative groups.14
It should be noted that tumors might possess in vitro drug sensitivity because of an agents’ anticancer activity or might exhibit resistance because of the tumors’ phenotypic resistance to the agent. In the EDR assay, some agents may overcome unfavorable cellular transport kinetics or permeability barriers because of high drug concentration gradients that favor intracellular drug accumulation. These cells may exhibit in vitro sensitivity even if they are inherently resistant stem cells. This relates clinically to anticancer therapy and the cancer stem cell hypothesis where an agent might eliminate the main population (non-stem) cells, resulting in selection of cancer stem cells. It follows that transformation of this small population of cancer stem cells might ultimately result in clinical tumor progression, recurrence, or metastatic disease. A priori, a potential limitation of the ability of cellular proliferation assays to accurately predict clinical sensitivity, other than patient host factors, may be due to a relatively decreased potential for a small population of cancer stem cells to proliferate significantly relative to other tumor cells under tissue culture conditions of the EDR assay. Further studies on the relationship between in vitro chemotherapy resistance testing as it relates to the cancer stem cell hypothesis are ongoing.
Randomized Trials and the Clinical Utility of Chemoresistance Testing
We11 previously reported that extreme or intermediate in vitro chemotherapy resistance in NSCLC patient tumor cultures was prevalent, particularly for platinum agents (63%–68%) and for gemcitabine (72%). From the analysis of a larger database representing 4571 NSCLC fresh tumor cultures in this study, the incidence of resistance to platinum agents (62%–63%) and gemcitabine (80%) was similar. More important, we frequently found that many tumors exhibited simultaneous resistance to both agents used in four of the most commonly prescribed platinum-based chemotherapy doublets. These results raise concern regarding the widespread use of empiric adjuvant chemotherapy, where few patients may benefit, and in particular, consternation exists with the recommendation of adjuvant chemotherapy to patients with completely resected stage IB disease in whom a survival advantage is questionable.20
In patients with stage IV NSCLC, a randomized clinical trial by the Eastern Cooperative Oncology Group (ECOG) compared overall survival in patients treated with cisplatin plus gemcitabine, cisplatin plus docetaxel, or cisplatin plus paclitaxel in reference to the efficacy of carboplatin plus paclitaxel. An overall 19% response rate and median survival of 7.9 months was observed with 1-year and 2-year survivals of 33% and 11%, respectively. Neither response rates nor survival differed significantly with any regimen (Figure 4). Schiller and associates31 concluded that none of the four regimens offered a significant advantage over the others, yet the carboplatin plus paclitaxel doublet was chosen as the ECOG reference for future studies because of reduced toxicity. On the basis of these data showing similar clinical efficacy among several regimens, empiric selection of any doublet combination is without significant predictable value to the patient with regard to "doublet" efficacy. The application of tumor chemotherapy resistance testing therefore may be of clinical benefit.
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Despite the intriguing possibilities of using chemoresistance testing to improve response and reduce toxicity related to therapy, its use for the purpose of "assay directed" treatment is currently lacking clinical validation in NSCLC. The recent ASCO technology assessment15 has recommended that future studies be designed comparing empiric chemotherapy with resistance assay–directed chemotherapy. Despite these recommendations, it has been emphasized that despite the availability and reliability of chemotherapy resistance testing, the general medical oncology community has yet to integrate this concept into any cooperative group trial.18 In Weiands’ rebuttal32 to this ASCO report, he suggests that the clinical utility of resistance testing be validated in a single-arm, noninterventional assay accuracy trial using two or more therapies known to have similar response rates to determine whether the assay is predictive of response. We agree with Weiand’s assessment of this concept and would support such as trial for NSCLC.
Validation of the clinical utility of the EDR assay may be best achieved by correlating in vitro resistance to clinical outcome in patients considered for adjuvant chemotherapy who are eligible for enrollment in an existing adjuvant chemotherapy trial, or as a companion to a surgical trial with an adjuvant chemotherapy arm. The recently proposed ECOG 1505 phase III trial will randomize 1500 eligible patients with resected stage IB-IIIA NSCLC to adjuvant chemotherapy with the four most accepted platinum-based "doublets" with or with out bevacizumab. Drug resistance testing is well suited as a companion to this trial, irrespective of a potential bevacizumab response.
Recently, members at Duke University developed a genomic strategy to estimate prognosis in patients with resected stage I NSCLC using RNA micro array analysis. By developing a multiple gene expression profile, they created a lung metagene model and validated it with two independent tumor sets. The prognostic accuracy to predict recurrence and survival approached 90%.33 These results have prompted the development of a CALGB trial designed to prospectively validate the lung metagene models’ ability to differentiate low-risk from high-risk patients. Patients with completely resected stage IA NSCLC will be separated in a 1:2 ratio into a low-risk (observation only) group and high-risk group. High-risk patients will then be randomized to receive one of the four NSCLC adjuvant chemotherapy doublet regimens (similar to those proposed for ECOG 1505) or observation alone. Although this model may help distinguish between patients with a favorable prognosis who only require observation, half of the high-risk patients will be prescribed cytotoxic chemotherapy with an uncertain benefit. Despite these efforts to "target" therapy based on prognosis, empiric adjuvant chemotherapy is still applied in this study. Clinical observations of recurrence and survival in the high-risk patient arm, if correlated with chemotherapy resistance testing, may help further define the clinical utility of an in vitro chemoresistance testing assay.
As the public continues to cry out to "wage the war on cancer,"34 identifying genomic profiles that predict prognosis, and using molecular marker assays to predict therapeutic response, developing clinically relevant studies for more selective therapies will become increasingly important. Integrating molecular testing and chemotherapy resistance assays into future adjuvant chemotherapy trials for NSCLC will facilitate avoiding yet another decade of pure empiricism in patient care. This paradigm shift appears necessary and justified.
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