Predictors of EGFR mutation and factors associated with clinical tumor stage at diagnosis: Experience of the INSIGHT study in Poland
- Authors:
- Published online on: September 7, 2017 https://doi.org/10.3892/ol.2017.6907
- Pages: 5611-5618
Abstract
Introduction
Treatment of non-small cell lung cancer (NSCLC) requires a complex regimen involving surgery, radiotherapy, and systemic therapy. Molecular status of individual tumors is considered as a predictive factor for response to chemo- or biological therapy or as a prognostic marker for disease progression (1–3). Driver mutations that are known to promote carcinogenesis have been identified in certain genes-mutations in EGFR (for epidermal growth factor receptor; EGFR), PI3K (for phosphatidylinositol 3-kinase; PI3K), BRAF (for B-Raf), and KRAS (for k-Ras) are considered to have a predictive value in NSCLC patients (4) and the highest incidence of mutations is observed in the EGFR and KRAS genes (5,6).
Mutations in EGFR occur in exons 18–21 which encode the tyrosine kinase domain of EGFR. These cause a loss in autoinhibition of the tyrosine kinase and a continually activated state of its kinase function. Deletion in exon 19 and a L858R (leucine to arginine substitution at position 858) substitution in exon 21 comprise approximately 90% of EGFR mutations found in adenocarcinomas of the lung (7–16). Patients with diagnosed mutations in EGFR are referred to as EGFR-positive. The incidence of EGFR mutation in Caucasian NSCLC patients in Europe is estimated to be 10% (7,9) and is more common in women and non-smokers.
While platinum-based chemotherapy has been the mainstay of NSCLC treatment, advances in molecular diagnostics and targeted therapies have resulted in a paradigm shift with a focus on individualized medicine based on histologic classification, pathologic staging, prognostic markers of survival, and predictive markers of therapeutic response (17). The discovery of EGFR mutations in 2004 and subsequent therapeutic response in terms of response rate (RR), progression-free survival (PFS), and quality of life (QoL) elicited in EGFR-positive patients by targeted therapy with EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib have been adequately documented in large-scale clinical trials (12–15,18–24). These results have led to a consensus that the presence of EGFR mutations is a strong predictor of TKI treatment response and various associations and working groups, internationally and in Poland, now recommend screening newly diagnosed patients with advanced NSCLC for specific mutations in order to customize the modality of treatment (9,19–32). Despite these, the incidence rates of EGFR mutations are found to vary substantially between different regions and countries (8,10,15). Possible reasons for this discrepancy could be lack of clarity in selection criteria for EGFR-positivity testing, differences in molecular methods employed for screening, and issues with sampling and tissue preservation. In addition, improper sample collection, preparation, and storage techniques can render it unamenable for molecular analysis. However, rapid advancement in diagnostics and the use of modern methods such as quantitative polymerase chain reaction (qPCR) allows for detection of EGFR mutation in samples containing as low as 1% tumor cells (33) and the use of these techniques as a standard screening procedure in NSCLC categorization could resolve the issue of accurate detection and treatment optimization.
Despite developments in treatment of advanced NSCLC and widely accepted guidelines in place, there is paucity in real-life data on management of EGFR-positive NSCLC in the Central/Eastern European (CEE) region. The main goal of the ImplementatioN of perSonalized medicine In NSCLC in Central Europe: EGFR testing, Histopathology, and clinical feaTures (INSIGHT) registry was to address these shortcomings (34). In this sub-analysis of the INSIGHT study, we report the real-life scenario in clinical management, including diagnosis and treatment, of EGFR-positive advanced NSCLC in Poland. Furthermore, we aimed at identifying predictors of EGFR mutation as well as factors associated with the clinical tumor stage at the time of diagnosis.
Patients and methods
Patient enrollment and data collection
The INSIGHT study (34) was a multicenter, observational registry of patients with NSCLC and tested for EGFR mutation, conducted between November 2011 and March 2013 in five CEE countries including Poland. Patients were ≥18 years of age, were diagnosed with advanced and/or metastatic NSCLC and had biopsy tissue available for EGFR testing, and provided an informed consent to participation in the study. Also included were patients who had already tested positive for EGFR mutation and had either commenced or were scheduled to begin treatment with EGFR TKIs.
Data collected included demographics, NSCLC diagnosis, performance status, smoking status, histopathological examination (including EGFR mutation), molecular method used for determination of EGFR mutation, and prior and current treatment regimens (including EGFR TKIs).
Performance status was assessed according to the Eastern Cooperative Oncology Group (ECOG) scale (35): ECOG=0: Fully active, able to carry on all pre-disease performance without restriction; ECOG=1: Restricted in physically strenuous activity but ambulatory and able to carry our work of a light or sedentary nature; ECOG=2: Ambulatory and capable of all self-care but unable to carry out any work activities; up and approximately more than 50% of waking hours; ECOG=3: Capable of only limited self-care; confined to bed or chair >50% of waking hours; ECOG=4: Completely disabled; cannot carry on any self-care; totally confined to bed or chair; ECOG=5: Dead.
The INSIGHT registry was approved by Ethics Committees and followed all local laws and regulations.
Statistical analysis
Patient characteristics were summarized using descriptive statistics. Categorical variables were compared using Fisher's exact test.
Predictors of presence of EGFR mutation were determined by logistic regression analysis. For each pre-chosen parameter, a univariate model was first developed. Subsequently, these were used to derive a multivariate model through backward elimination. Odds ratio (OR), 95% confidence interval (95% CI) for OR and Wald test P-value were reported.
Factors influencing clinical tumor stage at diagnosis were identified with ordered logistic regression analysis. Clinical tumor stage was divided into four categories-I/II, IIIA, IIIB and IV. A multivariate model was derived as described in the preceding paragraph. Proportional OR, 95% CI for proportional OR (proportional 95% CI) and Wald test P-value were reported.
P<0.05 was considered to indicate a statistically significant difference. Statistical analysis was performed using the R software version 3.1.2 (36).
Results
Patient population
Data from 696 patients collected from four centers in Poland were included in the analysis. The majority of the patients were ≥60 years of age [median: 61.4 years, interquartile range (IQR) 57.0–67.2 years], white Caucasian (n=696, 100%), and male (n=417, 59.9%). Regarding smoking status, 196 (28.2%) patients were currently smoking and 285 (40.9%) were ex-smokers.
Most of the NSCLC cases were advanced and metastases were identified in 140 (20.1%) patients at diagnosis. Common sites of metastases were supraclavicular lymph node (n=36, 25.7%), brain (n=25, 17.9%), lung (n=7, 5.0%), and bone (n=5, 3.6%) and these are classified and compared based on their EGFR mutation status in Table I. The primary tumor was identified in 571 (82.0%) patients.
Performance status at the time of diagnosis as defined by ECOG rating was ‘good’ in a substantial proportion of the patients [ECOG=0 in 16 (3.9%) patients; ECOG=1 in 308 (74.9%) patients] and ‘moderate’ (ECOG=2) in 81 (19.7%) patients (Table II).
Histopathological diagnosis
Diagnosis of NSCLC was based on evaluation of histological specimen in 82.4% of the patients and of cytological sample in 16.8% of the patients. The most commonly employed methods of sample collection were surgical biopsy (32.1%), transbronchial biopsy (25.8%), and endoscopic/endobronchial ultrasound guided needle biopsy (15.5%). Other methods also used were computed tomography guided transpareital biopsy (9.2%), intraluminal biopsy (3.0%), fine needle biopsy without X-ray guidance (2.4%), mediastinoscopy (2.4%), brush cytology (1.7%), computed tomography guided bronchoscopic biopsy (0.9%), bronchial lavage (0.9%), and others (6.0%).
Most of the NSCLC tumors in study patients were of adenocarcinomatous (AC) origin-36.5% of the patients presenting non-mucinous AC, 30.2% presenting non-specified AC, and 3.6% with mucinous AC. A total of 1.3% patients presented with an adenosquamous carcinoma, a tumor type with a mixed histology. A majority of EGFR-TKI treated patients present with adenosquamous carcinomas with a predominance of adenomas.
Clinical management of NSCLC
A substantial proportion of study patients (79.6%) received systemic therapy-of these, 85.0% as palliative therapy, 11.3% in neoadjuvant setting, and 3.8% in adjuvant setting (data not shown). In patients not considered for systemic therapy, low performance status and poor compliance were the major individual reasons for the decision. Surgery as a therapeutic intervention was performed in 26.6% of the patients while 13.7% received radiation therapy.
EGFR mutation
A total of 82 (11.8%) study patients were determined to have EGFR mutations. Most commonly reported mutations were deletion on exon 19 and L858R substitution on exon 21. Details of distribution of EGFR mutations are given in Fig. 1.
Factors associated with presence of EGFR mutation
Patients with EGFR mutation were predominantly female [45 of 82 (54.9%) EGFR-positive patients] in comparison to patients without such mutations (38.1% of EGFR-negative patients) (P=0.005). An EGFR-positive status was strongly associated with gender and males were less likely to be EGFR-positive (male vs. female OR: 0.51; 95% CI: 0.32–0.80; P=0.004). The proportion of never-smokers was higher in EGFR-positive patients (26 of 69 patients, 37.7%; smoking status unknown in 13 patients) than in EGFR-negative patients (6.8%) (P<0.001) and the propensity for EGFR-positive status was lower in patients who were current or past smokers (OR: 0.16; 95% CI: 0.09–0.28; P<0.001). Performance status at the time of diagnosis had a wider distribution and proportion of patients in advanced disease stage was higher in EGFR-positive patients (Table III). Moreover, EGFR-positive patients had a higher predilection to be in clinical stage IV than in stage I/II at the time of diagnosis (OR: 2.89; 95% CI: 1.22–8.50; P=0.029).
EGFR mutation and metastasis
With the exception of metastasis to the bone, no association was observed between the EGFR status and metastatic potential of primary tumors. Incidence of metastasis to the bone was higher (3.7%) in patients with EGFR mutation in comparison with EGFR-negative patients (0.3%; P=0.013). The odds of EGFR mutation in patients with bone metastasis in comparison to the patients without bone metastasis in the entire population or those with any but bone metastasis was also significantly higher (bone metastasis vs. no bone metastasis in the entire group OR=11.62; 95% CI: 1.90–89.23; P=0.008 and bone metastasis vs. any but bone metastasis in metastasis group OR=10.41; 95% CI: 1.62–83.51; P=0.014).
EGFR mutation and histopathological tumor staging
An association between histopathological diagnoses of NSCLC and presence of EGFR mutation is given in Table IV. The most striking observation is decreased probability of EGFR mutation in not otherwise specified (NOS) type NSCLC in comparison to adenocarcinoma (OR=0.23; 95% CI: 0.06–0.64; P=0.015). Patients without EGFR mutation were noted to undergo surgical treatment more frequently than EGFR-positive patients but this difference could not be statistically validated (27.9 vs. 19.5%; P=0.151). We also observed that more patients with EGFR mutation received radiotherapy in comparison to EGFR-negative patients (24.4 vs. 11.7%; P=0.004).
Factors associated with presence of EGFR mutation
As shown in Table V, multivariate regression analysis revealed that NSCLC patients who were past or current smokers or had lower performance as per ECOG scale were less likely to carry a EGFR mutation.
Factors associated with clinical tumor stage at diagnosis
The proportional OR between stages I/II, IIIA, IIIB, and IV for ECOG=1 vs. ECOG=0 was 1.515 (95% CI: 0.580–3.958; P=0.397). In contrast, the proportional OR between stages when comparing ECOG=2–3 and ECOG=0 was 4.076 (95% CI: 1.394–11.923; P=0.010) thereby indicating that performance status substantially diminished with progression in clinical stages.
The NOS type NSCLC was associated with greater odds of more advanced clinical tumor than adenocarcinoma. Odds of more advanced clinical tumor in bronchoalveolar carcinoma, large cell carcinoma, mixed carcinoma, or squamous cell carcinoma did not differ significantly from odds in adenocarcinoma diagnosis. In contrast, the mixed type carcinoma had lower odds of more advance clinical stage than adenocarcinoma.
The results of multivariate regression modelling (Table III) confirm previous findings that patients with poor ECOG scores, EGFR mutation, and diagnosed with NSCLC of a histopathological type other than adenocarcinoma or squamous cell carcinoma have a higher likelihood of being diagnosed with advanced clinical tumors.
Discussion
We found that the incidence of EGFR mutation in the Polish subpopulation of the INSIGHT study is similar that reported for the general European population (5). We also reiterate previous findings that EGFR-positive status is associated with female gender and never-smoker status. The clinical stage of NSCLC at the time of diagnosis was usually more advanced in EGFR-positive patients thereby precluding radical surgery and promoting radiotherapy and systemic therapy in these patients. However, one must take note that the presentation of advanced stage in NSCLC patients with EGFR mutations is not always associated with an increased probability of bearing such a mutation; the late diagnosis could simply be because patients in Stage I or II are not routinely tested for mutations. We also discovered that the propensity to develop bone metastasis, usually associated with a poor prognosis (37), was almost 12-fold higher in EGFR-positive NSCLC patients in comparison to their EGFR-negative counterparts. However, this statistic may not be an accurate reflection of the actual risk when we take in consideration the small patient number in the reported study.
The choice of appropriate molecular methods is important for reliable detection of EGFR mutations, especially in samples with low tumor cell count. The effectiveness of these methods could be jeopardized by suboptimal procedures of tumor sampling and preservation techniques. Nevertheless, results from a multicenter, retrospective study designed to evaluate effectiveness of various methods for EGFR mutation testing showed no substantial difference in detected frequency of mutations between cytological and histological samples (33). This implies that the low tumor cellularity evidenced with cytological and small biopsy samples did not hinder the sensitivity of the real-time PCR assay employed in the study for detecting EGFR mutations. This offers a substantial benefit in screening NSCLC patients with poorer performance status or those in whom invasive procedures are contraindicated. Despite the demonstrated benefits of TKI therapy in EGFR-positive NSCLC and guidelines recommending timely screening and treating at-risk patients with TKI as first-line chemotherapy (38), these are not widely applied in clinical practice in Poland. While we cannot identify any particular reason for this, it has been demonstrated that routine nationwide molecular profiling of NSCLC patients is feasible and provides immense benefit in terms of frequency of driver mutations and their specific type (39). Of special interest are NSCLC with uncommon EGFR mutations that occur in approximately 1.0% of NSCLC cases (40), or those with poor prognosis such as adenosquamous carcinoma (41), detected in 1.3% of our study patients, and EGFR-positive NSCLC metastasizing to the bone (42). The heterogeneous molecular profiles presented in these types need to be studied in detail in order to not only study the occurrence and pathological differences arising from various mutations but also to design specific therapies aimed at molecular targets (40).
The database of the INSIGHT registry is the first of its kind for Poland in our knowledge and it provides robust data on sampling methods, molecular testing, frequency and types of EGFR mutations, treatment modalities, and prognostic factors related to Polish patients with EGFR-positive NSCLC. In comparison to conventional chemotherapy, EGFR TKI therapy has been demonstrated to be more effective and safer in NSCLC patients with EGFR mutations. A notable conclusion of a meta-analysis of 13 phase III trials was that targeted therapy with EGFR TKIs noticeably improved PFS [Hazard ratio (HR): 0.43; 95% CI: 0.38–0.49] but had no such effect on overall survival (OS) (HR: 1.01; 95% CI: 0.87–1.18) (43). A plausible reason for this lack of improvement in OS could be that EGFR TKIs were used as second or further lines of therapy, once conventional chemotherapy was found to lack therapeutic effect. Results from the OPTIMAL study have shown that erlotinib as a first-line treatment enhances PFS and has a better safety profile in comparison with conventional chemotherapy (24). Similar beneficial effects on PFS have been reported from two landmark phase III trials on the irreversible EGFR TKI, afatinib (21,22). In addition, while no statistically significant differences were evident in these studies between afatinib and cisplatin (latter in combination with either permetrexed or gemcitabine) as first-line treatment in EGFR-positive stage IIIB and IV lung adenocarcinoma patients, subgroup analysis has shown that OS of patients with del19 EGFR mutation who were administered afatinib was substantially improved (23). In the LUX-Lung 3 trial, afatinib-treated patients presenting del 19 mutation had median OS of 33.3 months (95% CI: 26.8–41.5) in comparison to 21.1 months (95% CI: 16.3–30.7) in those who received conventional chemotherapy (HR: 0.54; 95% CI: 0.36–0.79; P=0.0015). Similarly, in the LUX-Lung 6 trial, patients with del 19 mutations who received afatinib had median OS of 31.4 months (95% CI: 24.2–35.3) vs. OS of 18.4 months (95% CI: 14.6–25.6) in those on conventional therapy (HR: 0.64; 95% CI: 0.44–0.94; P=0.020).
Despite being the first of its kind disease registry that gathered information on clinical management of EGFR-positive NSCLC in the CEE region, the INSIGHT study and our sub-analysis have some inherent limitations. Being an observational study, we could only capture a snapshot of current practices at predetermined locations in Poland and the nationwide situation could differ. One way to rectify this could be drafting and implementing guidelines that would require participation from all tertiary cancer centers in Poland in a national NSCLC registry. Another drawback of the INSIGHT registry is that since it was not prospective by nature, we could not assess the long-term benefits and effectiveness of current strategies in the therapeutics of EGFR-positive NSCLC in Poland and the CEE region. These questions can only be answered by elaborate prospective studies and we hope that our registry serves as an impetus to such investigations.
In conclusion, EGFR TKIs are effective agents against EGFR-positive NSCLC and should be routinely considered as first-line treatment in these patients; therefore EGFR testing should be performed at the earliest. Data from the INSIGHT registry could be used to improve guidelines, standardize screening techniques, as well as create a predictor algorithm for example a nomogram (44). Such an approach that will integrate individual risk factor analysis and improve EGFR-targeted therapies could lead to personalized gene-directed therapies for EGFR-positive NSCLC patients.
Acknowledgements
The editorial help with this manuscript was provided by Mateusz Spalek, Satyen Shenoy and Agnieszka Linkiewicz-Zegan.
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