Research ArticleClinical Studies

Insulin-like Growth Factor Receptor 1 mRNA Expression as a Prognostic Marker in Advanced Non-small Cell Lung Cancer

ADAM VILMAR, ERIC SANTONI-RUGIU, JESUS GARCIA-FON CILLAS, MARSISOL HUARRIZ and JENS BENN SØRENSEN
Anticancer Research June 2014, 34 (6) 2991-2996;

Abstract

Background: The insulin-like growth factor 1 receptor (IGF1R) has yet to be established as a biomarker in non-small cell lung cancer (NSCLC) but could prove useful in customized chemotherapy. We explored its prognostic value using both quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). Materials and Methods: Analyses of IGF1R were performed on patients with advanced NSCLC, included in a randomized chemotherapy trial, having large, representative tissue samples. IGF1R mRNA and protein expression were correlated to clinical end-points. Results: Surgical tissue samples were available from 33 patients deemed inoperable. IGF1R status varied according to histopathology. Patients with tumors positive for IGF1R mRNA expression had a shorter progression-free and overall survival when compared to the negative sub-group (6.1 vs. 7.4 months, p=0.039 and 10.9 vs. 14.3 months, p=0.038, respectively). IGF1R protein expression showed a similar, although non-significant tendency. Conclusion: IGF1R mRNA expression may be a prognostic biomarker in advanced NSCLC and should be investigated in a larger population.

Non-small cell lung cancer (NSCLC) is emerging as an increasingly heterogenous disease primarily due to the expanding knowledge of disease mechanisms on a molecular level.

Treatment-of-choice for the majority of patients with advanced NSCLC is platinum-based chemotherapy, with a median survival below one year (1).

The importance of histopathology is reflected by numerous biomarker studies (2-4) and many treatment options are available for patients with non-squamous NSCLC depending on oncogenic driver status or the possibility of adding bevacizumab to classical chemotherapy in selected sub-groups (5, 6). In patients with squamous cell carcinoma NSCLC (SCC), an aggressive histological subtype often observed in heavy smokers, treatment efficacy is limited and novel options are rquired. Predictive markers for the efficacy of targeted-agents and for classical chemotherapy are important tools to achieve such progress.

The insulin receptor (IR) and the insulin-like growth factor (IGFR)1R are both key players in the regulation of metabolism (7). The IGF1R gene is located on chromosome 15q26.3 and translated into a transmembrane, heterotetrameric protein. However, isoforms of the IR, IGF1R–IR hybrids and multiple regulation steps make the system complex to interpret. The receptor is activated by its ligands IGF I and II, which are produced in the liver and at extra-hepatic sites, including in tumor cells (7).The IGF1R and its ligands are involved in metabolism and growth through two major pathways: the RAS–RAF–MAP kinase pathway stimulating cellular proliferation and the phosphoinositide-3 kinase (PI3K)–AKT mammalian target of rapamycin (mTOR) pathway mediating cellular survival (8-10).

Pre-clinical evidence has demonstrated that elevated levels of IGF1R induce key steps in the carcinogenic process (11, 12). In a clinical setting, however, the prognostic role of IGF1R remains controversial, with a few reports of a correlation between high expression and poor outcome (13), while other studies have failed to confirm such findings (14, 15). A combination of the IGF1R inhibitor and chemotherapy led to initial promising results (16) but failed in a subsequent confirmatory phase III trial (17). Among other reasons, lack of biomarker-based patient selection predicting sensitivity to IGF1R inhibitors could explain these results.

The foundation for reliable biomarker evidence is robust methodology and it remains uncertain which method is currently the most appropriate to determine IGF1R status as well as its predictive or prognostic impact. Immunohistochemistry (IHC) and quantitative reverse transcriptase–polymerase chain reaction (qRT-PCR) are two popular approaches but have yielded conflicting results.

Accordingly, we aimed to explore the prognostic value of IGF1R using both IHC and qRT-PCR on a cohort of advanced patients with NSCLC with representative tissue samples.

Materials and Methods

Patient population. A total of 443 chemotherapy-naïve patients aged 18-75 years with histologically-verified, inoperable NSCLC, performance status 0-2 and normal organ function where included in the study (LU2007) and randomized to regimen A (180 mg/m2 paclitaxel and 100 mg/m2 cisplatin day 1, with gemcitabine at 1,000 mg/m2 day 1 and 8 every three weeks) or regimen B (100 mg/m2 cisplatin day 1 every four weeks and weekly i.v. vinorelbine for a maximum of six cycles). Patients with brain metastases were excluded. Patients gave informed written consent. The biomarker study and LU2007 were approved by the The Danish National Committee on Biomedical Research Ethics (Approval number: H-B-2008-068 and the Danish Data Protection Agency (Approval number: 2013-41-1856). Clinical end-points in the IGF1R tumour marker study were response rates(RR) (according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria (18)), disease-free survival (DFS) and median overall survival (overall survival). Patients' characteristics are summarized in Table I.

Tissue samples. Archival paraffin blocks containing formalin-fixed NSCLC tissue from the 443 patients enrolled in LU2007 were obtained from Danish Departments of Pathology. A total of 261 patients (58.9%) had sufficient biopsy material for IHC biomarker evaluation, as previously published (18). In the current correlation study, we decided a priori to only use large tissue samples containing at least 90% viable tumour cells as these are appropriate for macrodissection and secure sufficient amounts of malignant tissue for mRNA extraction and optimal comparison. Surgical tissue samples obtained during diagnostic and staging procedure were available from 33 patients (7.5%) deemed inoperable. Thus, sufficient tissue was available for evaluation in this correlation study (see Figure 1 for more detailed information).

Sample preparation and mRNA extraction. Corresponding hematoxylin eosin staining paraffin sections were evaluated for identification of the tumour tissue by two observers (AV and ESR) prior to macrodissection. For 20 μm-thick unstained formalin-fixed paraffin-embedded sections were cut and mounted on coated slides. The tissue sections were submerged in to 70% ethanol and the surrounding non-tumourous tissue discarded. The tumour tissues were scraped in to 1.5 ml Eppendorf tubes for tissue digestion.

The mRNA was extracted using RecoverAll™ Total Nucleic Acid Isolation Kit (Ambion, Applied Biosystems, Life Technologies S.A., Madrid, Spain) according to manufacturer's instructions. Briefly, the sections were digested in 1 ml 100% xylene and incubated at 50°C for 1.5 h. Following centrifugation, the pellet was washed twice with 1 ml 100% ethanol and air-dried for 10 min. One hundred microlitres of Digestion Buffer was added to the sample together with 4 μl of Protease and incubated for 15 minutes at 50°C followed by 15 minutes at 80°C. For nucleic acid isolation, 120 μl of isolation additive and 275 μl of 100% ethanol were added and mixed well by pipetting and washed through a filter cartridge. Nucleases were digested using 60 μl DNase mix followed by wash and final nucleic acid purification with 30, 15 and 40 μl of Elution Solution, respectively.

RNA concentration was quantified using a Nanodrop Spectrophotometer (NanoDrop Technologies, Wilmington, Delaware, USA).

Real time quantitative reverse transcriptase polymerase chain reaction. cDNA was synthesized from total RNA using High-Capacity cDNA Archive Kit (Applied Biosystems). Reverse transcriptase reactions contained 1 μg of RNA sample, 1× RT buffer, 4 μl of dNTPs 100 mM, 1× of Random Primers, 5 μl of MultiScribe Reverse Transcriptase 50 units/μl and 0.005 μl of RNase Inhibitor 0.20 units/μl. The reactions were incubated in a GeneAmp PCR System 2400 of Applied Biosystems for 10 min at 25°C and 2 h at 37°C.

Each cDNA sample was analyzed in triplicate using the Applied Biosystems 7300 Sequence Detection system. RT-PCR with 5’ nuclease (Taqman) detection of IGF1R was carried out using Taqman Universal PCR Master Mix (Applied Biosystems), containing ROX™ reference dye to normalize fluorescence values. Primers and probes were purchased from Applied Biosystems as ‘Assay on Demand’ for IGF1R (Hs00609566_m1). For thermal cycling, the following conditions were applied: 10 minutes at 95°C, then 45 cycles of 15 seconds at 95°C and 1 minute at 59°C. β2-Microglobulin was used as an endogenous control and data obtained are given as as 2−ΔCT values.

The threshold cycle (Ct) data were determined using default threshold settings. The Ct is defined as the fractional cycle number at which the fluorescence passes the fixed threshold.

Immunohistochemical preparation of tissue samples. Formalin-fixed paraffin-embedded sections of tissue samples were cut 4-mm thick and mounted on coated glass slides. Sections stained with HE from each tissue specimen were histologically evaluated for verification of diagnosis and eligibility for IHC analysis. The tissue sections were pretreated and immunostained using the BenchMark ULTRA automated slide preparation system (Ventana Medical Systems, Inc., Tucson, AZ, USA). This included antigen retrieval of tissue sections by a pre-treatment of 64 min withVentana's Ultra CC1 buffer, followed by incubation with Ventana's CONFIRM rabbit monoclonal antibody, clone G11, to IGF1R for 32 min at 36°C, and then with UltraView Universal DAB detection kit (Ventana Medical Systems, Inc.) according to the manufacturer's instructions. The slides were then counterstained with Ventana haematoxylin. The accuracy of the antibody used has been previously documented (14).

Immunohistochemical evaluation of biomarker status. The expression of IGF1R (membranous and to a lesser extent cytoplasmic) was analysed as previously described (19). Briefly, two observers (AV, ESR) blinded to the clinical data, independently evaluated the immunostaining of the eligible tissue samples under a light microscope at a magnification of ×400. A semiquantitative H-score for each tissue sample was calculated by multiplying the staining intensity of tumour cells (0: no expression, 1: weak expression, 2: moderate expression, 3: strong expression) by a proportion score based on the percentage of positively stained tumour cells (0 if 0%, 0.1 if 1% to 9%, 0.5 if 10% to 49%, and 1.0 if 50% or more). As positive controls for intensity 2 and 3 immunostaining with the G11 antibody, we used plancenta and breast carcinoma tissue samples, respectively, according to the manufacturer's instructions. Omission and substitution of primary antibodies with nonspecific IgG were used as negative control. In the event of discordance between the observers, the tissue section was re-evaluated in order to reach consensus.

View this table:
Table I.

Characteristics of the patients.

The cut-off point was chosen a priori as the median value of the H-scores to separate IGF1R-positive (H-score >median) tumors from IGF1R-negative (H-score ≤median) ones.

Statistical analyses. All statistical analyses were performed with the SPSS-software (SPSS version 17.0, SPSS Inc., Chicago, USA). Proportions were compared by Chi-square test or Fisher's exact test. Spearman's rank correlation coefficient (rho) was calculated including two-tailed significance levels for correlation between gene and protein expression. Survival curves are shown as Kaplan–Meier plots and compared by log-rank analyses. Examination for independent prognostic variables was analysed by Cox regression that yielded hazard ratios. p-Values below 0.05 were considered statistically significant.

Results

Patients. A total of 443 patients were randomized in the chemotherapy trial (LU2007) and tumor samples from 261 patients (58.9%) were available for immunohistochemical evaluation. Thirty-three patients (7.5%) had optimal tissue samples for this study. Among those with IGF1R-positive tumors there was a significant prevalence of the squamous cell carcinoma sub-type when compared to IGF1R-negative tumors, as assessed both by qRT-PCR (9 vs. 2, p=0.051) and IHC (10 vs. 2, p=0.001) respectively). See Table I for more details.

Figure 1.
Figure 1.

Median overall survival according to insulin-like growth factor 1 receptor (IGF1R) levels by quantitative real time reverse transcriptase analyses.

Quantitative RT-PCR and IHC evaluation. The 2−ΔCT median of 8.41×10−2 dichotomized the population analysed for IGF1R mRNA expression. Using IHC evaluation a median H-score of 1 separated the population into 14 (42.4%) IGF1R-positive cases (H-score >1) and 19 (57.6%) IGF1R-negative ones (H-score ≤1). Considerable variation of immunostaining intensity and frequency of positive tumour cells was observed within different areas of the same tumour.

Correlation between gene and protein expression. A scatter-plot (not shown) demonstrated a correlation between 2−ΔCT values and H-scores. When calculated as Spearman's rho, a significant correlation was observed (rho=0.473, p=0.007).

Efficacy. Significant differences in disease control rates ((DCR=complete remission plus partial remission plus stable disease), DFS and OS were found in the qRT-PCR analysis, favouring patients with IGF1R-negative mRNA expression compared to patients having IGF1R-positive mRNA expression (p=0.008, 0.039 and 0.038, respectively) (Figure 1 and Table II). In contrast, no significant differences in outcome were found when IGF1R protein expression was analysed by IHC (p= 0.184, 0.302 and 0.395, respectively) (Table II), although a trend towards better OS in patients with tumours negative for IGFR1 protein expression was observed (Figure 2).

View this table:
Table II.

Outcome according to methodology.

Multivariate analyses of survival. A Cox proportional hazard model was fitted to test specific variables in multivariate analyses. IGF1R mRNA positivity emerged as a borderline significant prognostic variable with a hazard ratio of 2.19 (95% confidence interval=0.96-4.99, p=0.063).

Discussion

Efficient treatment options for patients with advanced non-squamous NSCLC are continuously expanding and include several lines of therapy based on molecular features of the individual patient's tumor biology.

Patients with advanced SCC are usually treated with classical platinum-based doublet chemotherapy, with modest impact on survival (PFS ~6 months and OS ~10 months). The individualized treatment approach based on biomarkers remains to be proven beneficial in patients with SCC. Moreover, an impressive RR of 78% was observed in a small SCC sub-group in a phase II study randomizing patients to paclitaxel and carboplatin with/without figitumumab, a monoclonal antibody targeting IGF1R (16). Disappointingly, the subsequent phase III trial ADVIGO 1016 (17) was discontinued because an analysis by an Independent Data Safety Monitoring Committee indicated futility. An imbalance of deaths, asthenia and hyperglycaemia was noted in the experimental arm.

Many reasons could potentially explain this outcome, including the lack of biomarker-based patient selection. If a reliable biomarker for IGF1R inhibition were available, one could predict which patients would benefit from the treatment. The disappointing results of the ADVIGO trial (17) emphasizes such need. IGF1R could prove to be a useful prognostic/predictive biomarker but there is conflicting evidence (13-15), perhaps partly due to methodological issues.

Our results suggest that qRT-PCR may be an option as patients positive for IGF1R mRNA expression progressed significantly worse than their counterparts. IHC analysis for IGF1R protein expression was, in contrast, without significant impact. Although our study population consisted of only 33 patients, the tissue samples were large and representative, thus making the findings reliable and not prone to random observations due to intra-tumoural heterogeneity as compared to smaller biopsies. Furthermore, our mRNA results appear robust as they remain significant across DCR, PFS and OS.

Figure 2.
Figure 2.

Median overall survival according to insulin-like growth factor 1 receptor (IGF1R) levels by immunohistochemical analysis.

IGF1R mRNA expression as a prognostic biomarker represents a novel observation to the best of our knowledge, while the insignificant value of protein expression has been demonstrated in previous reports, including the findings by Dziadziuszko et al. (14). Their research group failed to demonstrate prognostic value of IGF1R among 189 patients with early-stage NSCLC when analysed by IHC, fluorescent in situ hybridization and qRT-PCR. Interestingly, high IGF1R gene copy number was associated with improved survival.

The contradicting results concerning the prognostic value of IGF1R mRNA expression could possibly be ascribed to early- versus advanced-stage NSCLC and to different treatment modalities. It should be noted that the results of Dziadziuszko et al. showed a trend in line with our IHC results but without statistical significance. Perhaps most importantly, our patients had a predominance of adenocarcinomas (58%) compared to 29% of the patients in the American group's cohort (14). Our previous research indicates that in advanced NSCLC, biomarker expression may interact significantly with histology (19, 21). qRT-PCR is largely an automated method, not prone to human errors or subjectivity. This method is, however, highly dependent on the quality of tissue samples.

IHC analysis for protein expression is an economical, feasible, and widely used method for examining tumor tissue for biomarker status. It detects the functional product of the biomarker gene. However, it may be limited by inter- and intra-observer variability, as well as a potential lack of specificity and sensitivity of the antibody. The fact that qRT-PCR was superior to IHC in our study indicates that one size doesn't fit all when it comes to the methodology of choice in biomarker research. Our group and others have previously demonstrated predictive capabilities of IHC concerning potential biomarkers in NSCLC, such as excision cross complementation group 1 (19, 20, 22) and class III β-tubulin (21), including a correlation study showing qRT-PCR to be inferior to IHC (23). Our results concerning the insignificant prognostic value of IGF1R protein expression and overexpression in the SCC subtype in this study of NSCLC is in accordance with previous findings (15, 24).

To the best of our knowledge, only one previous article describes a significant prognostic value of IGF1R in NSCLC by IHC. However, the results of Merrick et al. were confined to patients with stage 1 disease and, more controversially, adenocarcinomas were predominantly IGF1R-positive (13).

Taken together, IGF1R mRNA expression deserves further research that could hopefully reproduce our results in a larger population with advanced NSCLC, while the prognostic value of IGF1R protein expression has yet to be established.

Among the limitations of our study is that the low number of patients represents a small fraction of the originally randomized population and the fact that the biomarker study was not pre-planned in the randomized trial. Furthermore, the patients were treated with two different chemotherapy regimens and no untreated control group was available for comparison.

In conclusion, a significant prognostic value of IGF1R mRNA expression on optimal archival tissue samples was demonstrated in a sub-group of patients with advanced NSCLC included in a randomized trial. Histopathology may interact with IGF1R status.

Acknowledgements

We thank Lone Svendstrup and Camilla C. Mortensen for expert technical assistance and Claus B. Andersen for excellent assistance in design and conception. The Harboe foundation, Augustinus foundation, The Danish Cancer Society and the Research Council of Rigshospitalet supported this study.

  • Received March 8, 2014.
  • Revision received April 13, 2014.
  • Accepted April 16, 2014.

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Insulin-like Growth Factor Receptor 1 mRNA Expression as a Prognostic Marker in Advanced Non-small Cell Lung Cancer
ADAM VILMAR, ERIC SANTONI-RUGIU, JESUS GARCIA-FON CILLAS, MARSISOL HUARRIZ, JENS BENN SØRENSEN
Anticancer Research Jun 2014, 34 (6) 2991-2996;
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