Annals of Oncology Advance Access originally published online on April 6, 2006
Annals of Oncology 2006 17(7):1120-1127; doi:10.1093/annonc/mdl077
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© 2006 European Society for Medical Oncology
Insulin-like growth factor receptor 1 (IGFR-1) is significantly associated with longer survival in non-small-cell lung cancer patients treated with gefitinib
1 University of Colorado Cancer Center, Department of Medicine/Medical Oncology and Pathology, Aurora, CO, USA; 2 Bellaria-Maggiore Hospital, Department of Medical Oncology, Bologna, Italy; 3 Istituto Clinico Humanitas, Department of Medical Oncology, Rozzano, Italy; 4 CINECA-Interuniversity Consortium, Bologna, Italy
* Correspondence to: Dr F. Cappuzzo, Bellaria Hospital, Division of Medical Oncology, Via Altura 3, 40139 Bologna, Italy. Tel: +39-051-6225696; Fax: +39-051-6225057; E-mail: federico.cappuzzo{at}ausl.bo.it
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Abstract |
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Background: The aim of the study was to assess whether loss of PTEN and expression of insulin-like growth factor receptor 1 (IGFR-1) could be responsible for intrinsic resistance to the tyrosine kinase inhibitor (TKI) gefitinib.
Patients and methods: One hundred and twenty-four gefitinib-treated patients with advanced non-small-cell lung cancer (NSCLC) were analyzed for PTEN and IGFR-1 expression by immunohistochemistry.
Results: IGFR-1 was evaluated in 77 patients and resulted positive in 30 (39.0%). IGFR-1 expression was not significantly associated with clinical or biological characteristics. No difference in response to gefitinib treatment (16.7% versus 12.8%, P = 0.74) and time to progression (2.6 versus 3.06 months, P = 0.83) was observed between IGFR-1+ and IGFR-1–. Median survival was significantly longer in IGFR-1+ patients (17.8 versus 7.3 months, P = 0.013). PTEN expression was successfully evaluated in 93 cases. Loss of PTEN was detected in 19 tumors (20.4%) and was not associated with any clinical or biological characteristic. No difference in terms of response, time to progression and survival was observed between PTEN+ and PTEN– patients. In multivariable analysis IGFR-1 negative status was significantly associated with higher risk of death (hazard ratio 2.21, P = 0.012).
Conclusions: IGFR-1 expression and loss of PTEN are not associated with intrinsic resistance to gefitinib. Clinical relevance of these two biomarkers as determinant for acquired resistance, and the prognostic role of IGFR-1 expression in patients not exposed to TKIs should be evaluated further.
Key words: IGFR-1, PTEN, EGFR, tyrosine kinase inhibitor, gefitinib, non-small-cell lung cancer
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introduction |
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Non-small-cell lung cancer (NSCLC) has been the leading cause of cancer death in the world [1
]. During the last years, several new agents targeting specific and critical pathways for lung cancer cell survival have been evaluated in both preclinical and clinical models. Among them, agents targeting the epidermal growth factor receptor (EGFR) or interfering with the vascular endothelial growth factor were shown to prolong survival significantly in patients with advanced disease [2, 3]. The EGFR signaling pathway represents a key target for intervention in cancer therapy. Ligand-induced EGFR activation initiates a signal transduction cascade implicated in tumor cell survival, proliferation and invasion [4–7]. Numerous strategies have been employed to specifically target EGFR, including small molecule inhibitors of the EGFR tyrosine kinase activity [7]. Among the most extensively investigated new drugs are gefitinib (ZD 1839, Iressa®, AstraZeneca, UK) and erlotinib (OSI 774, Tarceva®, Genentech, USA), which are orally active selective EGFR tyrosine-kinase inhibitors (EGFR-TKI) that demonstrated antitumor activity in approximately 10% of unselected NSCLC [8–10].
Biological mechanisms underlying EGFR-TKI sensitivity and resistance have recently been identified. EGFR gene gain and activating EGFR gene mutations, particularly deletions in exon 19, were demonstrated to confer a sensitive phenotype [11–13] and recent findings demonstrated that EGFR overexpressing patients are sensitive to the inhibitory effects of both gefitinib or erlotinib [11, 14]. Conversely, mutations in the KRAS gene or in exon 20 of the EGFR gene were demonstrated to be responsible for intrinsic or acquired TKI resistance, respectively [15–17].
It is feasible that intrinsic or acquired resistance to TKIs may be related to the ability of tumor cells to utilize alternative growth factor pathways. Although a growing number of studies addressed the mechanisms of gefitinib resistance, they are all based on in vitro models, distant from the clinical setting [18–20]. Insulin-like growth factor receptor 1 (IGFR-1) is a transmembrane heterotetrameric protein, encoded by the gene IGF1R gene located on chromosome 15q25–q26, implicated in promoting oncogenic transformation, growth and survival of cancer cells [21–24]. IGFR-1 activation triggers a cascade of reactions involving two signal transduction pathways [25, 26]: one activates Ras, Raf and mitogen-activated protein kinase, and the other involves phosphoinositol-3-kinase (PI3K). Previous studies demonstrated that EGFR dependent activation of the antiapoptotic protein Akt was significantly associated with gefitinib sensitivity [11, 27, 28]. Moreover, data on cell lines suggested that IGFR-1 mediates resistance to anti-EGFR therapy through continued activation of the PI3K-Akt pathway [20]. In breast cancer, IGFR-1 expression and activation have been linked to disease progression, increased resistance to radiotherapy and poor prognosis [29, 30]. In lung cancer, no data exist on IGFR-1 expression, and the effect of this receptor on TKI sensitivity is unknown.
Human PTEN, also called MMAC1 or TEP1, is encoded by a tumor suppressor gene located on chromosome 10q23 [31–33]. Mutation or deletion of the PTEN gene has been found in a variety of human cancers, such as glioblastomas, endometrial tumors and prostate cancer and in familial cancer predisposition syndromes [34]. PTEN functions primarily as a lipid phosphatase and plays a key role in the regulation of the PI3K-Akt pathway, thereby modulating cell proliferation and survival [35]. Recent data showed that PTEN expression was associated with longer survival [36], while loss of PTEN was an independent poor prognostic factor for patients with NSCLC [37]. Sensitivity to gefitinib therapy requires intact EGFR-stimulated Akt signalling activity, and loss of PTEN can lead to aberrant Akt activation and ultimately to gefitinib resistance [18, 19, 38]. Functional loss of PTEN results not only from physical loss of the PTEN gene loss but also from other mechanisms, particularly promoter methylation [39]. Moreover, recent findings also suggested that PTEN may inhibit the IGFR-1 induced Akt activity [35].
In clinical practice, identification of NSCLC patients with intrinsic resistance to TKI therapy is of crucial importance, because these patients should be excluded from this treatment approach. Preliminary data indicated that KRAS mutation [15] and the epithelial membrane protein-1 (EMP-1) [40] are markers associated with intrinsic resistance to TKIs, but additional mechanisms are probably involved.
The aim of the present study was to assess whether loss of PTEN and expression of IGFR-1 could be responsible for intrinsic gefitinib resistance and, therefore, whether assessment of these biomarkers could be useful for selection of NSCLC patients to therapy with EGFR-TKIs.
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patient population
A total of 124 patients were included in the study. PTEN analysis was performed in a cohort of 102 advanced NSCLC patients previously studied for EGFR and Phospho-Akt (P-Akt) status [11
]. Because only 55 patients from the previous cohort had tumor tissue available for biomarker analyses, IGFR-1 was assessed in an additional 22 patients treated at the Istituto Clinico Humanitas in Milan (Italy) within the Expanded Access Study (EAS) of gefitinib. No clinical or biological characteristic was used for patient selection; the single criterion considered was the availability of tumor tissue. All patients included in the study had evaluable disease. All patients had histologically confirmed NSCLC with measurable, locally advanced or metastatic disease, progressing or relapsing after chemotherapy, or with medical contraindications for chemotherapy. Patients were classified as never smoker (<100 cigarettes per lifetime), former smoker (quit smoking more than 6 months before starting gefitinib therapy), or current smoker (quit smoking less than 6 months before starting gefitinib therapy or active smokers). The IRB approved the EAS according to good clinical practice and a specific written informed consent was obtained from each patient before enrollment (EAS consent form, Italian version). Patients gave their consent for biomarker analyses.
Patients received gefitinib (250 mg/day) and were evaluated for response after 2 months according to the RECIST criteria [41]. Tumor response was assessed by computer tomography scan, with a confirmatory evaluation repeated in patients with complete response, partial response and stable disease at least 4 weeks after the initial determination of response.
tissue preparation and IHC analysis
Sections from paraffin-embedded tissue blocks containing representative malignant cells obtained at the time of diagnosis were used for this analysis. Histopathological classification was determined on hematoxylin–eosin (HE) stained sections based on the World Health Organization criteria [42]. Paraffin-embedded tissue sections were stained with antibodies against IGFR-1 (Novus Biologicals, Littleton, CO), and against PTEN (Novocastra Laboratories Ltd, Newcastle, UK) according to the manufacturers' recommended protocols. Briefly, 4 µm-thick tissue sections were placed on glass slides and deparaffinized. The tissue sections were incubated in 1 mM EDTA (pH 8) for 40 min at 98°C to unmask the antigens. The sections were then incubated with IGFR-1 mouse antibody (1:50 diluted in phosphate buffer) or with PTEN mouse antibody (1:150 in phosphate buffer).
Immunohistochemical staining was performed at the Pathology Department of the University of Colorado Cancer Center and slides were interpreted independently by three pathologists (GT at the Bellaria Hospital Pathology Department and LT and WAF at the University of Colorado Cancer Center) who were blinded to all patient information.
There are at present no validated scoring systems for interpreting immunohistochemical staining for IGFR-1 and for PTEN. We used a system that was based on staining intensity and percentage of stained cells, as previously described for EGFR [43]. The percentage of stained cells (0%–100%) was multiplied by the dominant intensity pattern of staining, considering 1 as negative or trace, 2 as weak, 3 as moderate and 4 as strong. Therefore, the overall score ranged from 0 to 400.
statistical analysis
Differences between and among groups were compared by Fisher's exact test or 
2 test for qualitative variables and by Student's t-test or ANOVA for continuous variables. Normality of the distribution was assessed by the Kolmogorov–Smirnov test. Time to progression (TTP), overall survival (OS) and the 95% confidence intervals were evaluated by the Kaplan–Meier method [44], comparing the different groups by log rank test. Risk factors associated with survival were evaluated using Cox's proportional-hazards regression model with a step-down procedure [45]. Only those variables with significant results in univariate analysis were included in the multivariate analysis. To ensure that only relevant factors were retained in the multivariable model, the backward regression technique was used at the 10% significance level.
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patient characteristics
Characteristics of the 124 patients included in the study are reported in Table 1. Median age was 62 years (range 25–83), the majority of patients were male (66.9%), former or current smokers (83.9%), with good performance status (ECOG performance score 0–1: 85.5%) and with stage IV disease (85.5%). Adenocarcinoma was the most frequent histological type (54.8%), followed by squamous-cell carcinoma (24.2%) and undifferentiated carcinoma (11.3%). All patients received at least one previous chemotherapy line, including platinum in 79.8% of cases (99 patients).
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In the whole population, the overall response rate (OR) was 12.1%, including one complete (CR) and 14 partial responses (PR), disease control rate (DCR), including CR, PR and stable disease (SD), was 39.5%, median time to progression (TTP) was 3.0 months and median survival was 8.3 months (Table 2).
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Response to therapy was significantly associated with female gender (P = 0.001) and a history of never smoking (P = 0.003). Time to progression (TTP) was significantly longer in females than males (5.0 versus 2.6 months, P = 0.004), in patients with PS 0–1 than PS 2 (3.2 versus 1.5 months, P = 0.02) and in stage III than stage IV disease (6.0 versus 2.6 months, P = 0.02). No association was found between response and histology and a non-significant trend favoring never-smokers over smoker patients was detected (5.2 versus 2.6 months, P = 0.07). Median survival was significantly longer in patients with PS 0–1 (9.5 versus 2.5 months, P < 0.001) and in patients with adenocarcinoma and bronchioloalveolar carcinoma subtype (10.9 versus 6.0 months, P = 0.03). Survival was longer in females than in males (10.9 versus 6.9 months, P = 0.052) and in never-smokers than in former or current smokers (10.9 versus 7.3 months, P = 0.3), although these differences were not statistically significant.
outcome according to IGFR-1 expression
The levels of IGFR-1 expression were determined in tumors from 77 patients, who were classified in four groups according to the ascending IGFR-1 protein expression (score 0–99, 100–199, 200–299, 300–400; Figure 1). Although the outcome of these four groups was similar in terms of OR, DCR and TTP, the median survival time was longer in patients with high IGFR-1 expression (Figure 2A). Patients with IGFR-1 protein expression score of 0–99 had a median survival of 7.3 months, lower than that observed in patients with a score of 100–199 (11.4 months), score 200–299 (20.8 months), or score 300–400 (median survival not reached). The group of patients with the shortest survival (score 0–99) were considered as IGFR-1 negative (IGFR-1–) and the other three groups were merged and considered as IGFR-1 positive (IGFR-1+).
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IGFR-1 expression was positive in 30 (39.0%) and negative in 47 (61.0%) cases. IGFR-1 expression was not significantly associated with any clinical or biological characteristic (Table 3), nor with response to first-line chemotherapy. No difference in OR (16.7% versus 12.8%, P = 0.74), DCR (40.0% versus 40.4%, P = 0.97), and TTP (median 2.6 versus 3.0 months, P = 0.83) was observed between IGFR-1+ and IGFR-1–. Median survival was significantly longer in the IGFR-1 positive cohort (17.8 versus 7.3 months, P = 0.013; Figure 2B).
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outcome according to PTEN expression
PTEN expression was successfully evaluated in tumors of 93 individuals. Patients were classified in four groups according to the ascending PTEN protein expression (score 0–99, 100–199, 200–299, 300–400; Figure 3) and no difference was observed among these groups in terms of OR, DCR, TTP and median survival. Patients with no or minimal PTEN expression (score 0–99) were considered as negative (PTEN–), and patients with a score of at least 100 were considered as positive (PTEN+). A total of 74 patients (79.6%) were positive and in 19 cases (20.4%) no PTEN expression was detected. PTEN status was not significantly associated with any clinical or biological characteristic (Table 4). No difference in terms of OR (15.8% versus 14.9%, P = 1.0), DCR (57.9% versus 40.5%, P = 0.17), TTP (5.2 versus 3.2 months, P = 0.7) and median survival (9.0 versus 11.3 months, P = 0.82) was observed among PTEN– and PTEN+ patients, respectively.
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multivariate analysis
Multivariate survival analysis included IGFR-1, histology and performance status, which were statistically associated with survival in univariable analysis. Gender was also included into the model because the P value was of borderline significance. Performance status 0–1 (hazard ratio = 0.20, 95% CI 0.09–0.46, P <0.001) and female gender (hazard ratio = 0.53, 95% CI 0.29–0.97, P = 0.041) remained significantly associated with reduced risk of death. Importantly, the analysis confirmed that IGFR-1 positive status was significantly associated with lower risk of death (hazard ratio = 0.43, 95% CI 0.23–0.80, P = 0.008).
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discussion |
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In the present study we investigated whether IGFR-1 expression or loss of PTEN expression could be responsible for intrinsic resistance to gefitinib and we observed that outcome of patients was not dependent on gefitinib pretreatment expression of these two biomarkers. It is well known that sensitivity to TKIs depends on increased EGFR gene copy number [11
] and presence of activating EGFR gene mutations [12, 13], with a survival benefit also in patients with high EGFR protein expression [14]. In clinical practice, identification of a sensitive as well as resistant subset of patients is of crucial importance. This is because TKI therapy cannot be denied to individuals with a potential survival benefit and should be avoided in patients with no expected survival advantage, not only because the drug is ineffective but also because a detrimental effect cannot be ruled out. In the TRIBUTE trial, a large phase III study comparing chemotherapy plus placebo versus chemotherapy plus erlotinib, among patients with KRAS mutation the median survival was significantly longer in the cohort of individuals receiving placebo [46]. It seems clear that KRAS mutation is not the only mechanism responsible for TKI intrinsic resistance, because its incidence cannot account for all refractory cases and because additional factors have been recently identified [40]. We have previously observed that EGFR dependent Akt activation enhances gefitinib sensitivity [11, 27], and we hypothesized that EGFR-independent Akt activation may result in a survival advantage for tumor cells that are not influenced by TKIs. In the present study we have investigated two of the most relevant biomarkers that could be responsible for aberrant Akt activation. No difference in response rate and TTP was observed in gefitinib-treated patients irrespective of PTEN status and IGFR-1 expression, suggesting that these biomarkers are not useful for the assessment of intrinsic TKI resistance. Our study did not explore the role of PTEN and IGFR-1 expression for acquired TKI resistance because study specimens were collected at the time of original diagnosis and not at the time of gefitinib progression. It is possible that loss of PTEN and IGFR-1 expression are particularly relevant for acquired resistance, as demonstrated in preclinical models [20, 47]. Chakravarty et al. [20] demonstrated that IGFR-1 can compensate for loss of EGFR function in primary glioma cell lines, and more recently, Jones et al. [47] showed that in breast and prostate cancer cells increased signaling via the IGFR-1 pathway leads to acquired resistance to gefitinib. Moreover, IGFR-1 was demonstrated to interfere with the growth inhibitory action of the anti-HER2 monoclonal antibody trastuzumab in breast cancer [48]. Bianco et al. [19] showed that although gefitinib treatment blocks EGFR autophosphorylation, in resistant cell lines Akt activity is independent of EGFR signals, and introduction of functional PTEN gene with PTEN protein expression results in restoring gefitinib-induced Akt inhibition, indicating that loss of PTEN could be responsible for acquired resistance.
In the present study, PTEN expression was not associated with Akt phosphorylation nor with patient survival. Using immunohistochemistry, Tang et al. [37] showed a significant negative association between P-Akt and PTEN, and recent data showed that loss of PTEN and Akt activation confer poor prognosis in NSCLC [36, 37,49–50]. The different results observed in our trial, as well as in previous studies [51, 52], could be related to tissue specificity or technical differences, such as different antibody used or different scoring system for immunohistochemistry.
The IGF system of ligands, receptors and soluble binding proteins offers excellent candidates for involvement in local and distant tumor spreading. The demonstration of IGFR-1 involvement in malignant transformation [53, 54] and the frequent detection of IGFR-1 expression in human cancer have fired the efforts to develop IGFR-1 targeted therapy. To the best of our knowledge, this is the first study evaluating IGFR-1 in NSCLC, and we observed IGFR-1 expression in more than one-third of cases. Importantly, IGFR-1 expression was significantly associated with better survival. A similar pattern has been observed in other malignancies [55, 56], whereas in some others the opposite situation was found [57–60]. The significant association with survival observed in the present study is of particular relevance, and should be confirmed in cohorts of patients not exposed to TKIs. This aspect is of crucial importance considering the number of strategies interfering with the IGFR pathway under evaluation in solid cancers, including NSCLC.
In conclusion, this study showed that IGFR-1 and PTEN assessment by IHC is not useful for identification of patients with intrinsic resistance to gefitinib. Clinical relevance of these two biomarkers as determinants for acquired resistance, and the prognostic role of IGFR-1 expression should be evaluated further.
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Acknowledgements |
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We are indebted to the Department of Pathology of the Bellaria Hospital-Bologna and Istituto Clinico Humanitas for providing patient tissues and clinical data, and to AstraZeneca for providing the drug for treatment. FC was a Visiting Professor at the University of Colorado Health Sciences Center sponsored in part by the Department of Medical Oncology of the Bellaria Hospital, Bologna, Italy and in part by the Associazione Italiana Ricerca sul Cancro (AIRC).
Received for publication October 14, 2005. Revision received March 1, 2006. Accepted for publication March 3, 2006.
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