|LCC-A SYMPOSIUM-ORIGINAL ARTICLE
|Year : 2013 | Volume
| Issue : 2 | Page : 94-101
Clinicopathologic features of non-small cell lung cancer in India and correlation with epidermal growth factor receptor mutational status
AD Bhatt1, R Pai2, G Rebekah3, G Arun Nehru2, S Dhananjayan2, A Samuel1, A Singh1, A Joel1, A Korula2, RT Chacko1
1 Department of Medical Oncology, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of Pathology, Christian Medical College, Vellore, Tamil Nadu, India
3 Department of Biostatistics, Christian Medical College, Vellore, Tamil Nadu, India
|Date of Web Publication||27-Aug-2013|
R T Chacko
Department of Medical Oncology, Christian Medical College, Vellore, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Introduction: We performed retrospective analysis of 106 patients with lung cancer for which formalin-fixed paraffin-embedded tissues was available. Their epidermal growth factor receptor (EGFR) mutation status and treatment outcomes are described. Materials and Methods: All patients with confirmed non - small cell lung cancer (NSCLC) during Jan 2008 to Dec 2010 were included. EGFR sequencing was performed with ABI PRISM 310 genetic analyzer. Results: Forty-two (39.6%) patients had mutation in one of the four exons characterized. Patients whose EGFR mutational status was not available at presentation before the start of treatment were started on chemotherapy, n = 46 (43.39%). If EGFR mutational analysis was available and mutations were present, the patients were started on either upfront tyrosine kinase inhibitor (TKI), n = 15 (14.15%) or if on chemotherapy arm were allowed to finish six cycles and then start with maintenance TKIs, n = 26 (24.52%). The median progression free survival for patients with and without mutations was 11 months (95% CI,7-14) and 9 months (95% CI,7-10) respectively. A median PFS of 14 months (95%CI, 12-16) was seen in the mutation-positive group that received both chemotherapy followed by switch maintenance with TKIs versus 8 months (95%CI, 7-8 months) in the group that received only TKI. Conclusion: The prevalence of EGFR mutations in this population of NSCLC patients was 39.6% with exon 19 mutation being the most common. The observed benefit of addition of chemotherapy over TKI in EGFR mutation-positive group raises the question, can we offer the therapy of chemotherapy-TKI combination to EGFR mutation-positive lung cancer patients as shown in the present study.
Keywords: Chemotherapy, epidermal growth factor receptor , lung, tyrosine kinase inhibitors
|How to cite this article:|
Bhatt A D, Pai R, Rebekah G, Nehru G A, Dhananjayan S, Samuel A, Singh A, Joel A, Korula A, Chacko R T. Clinicopathologic features of non-small cell lung cancer in India and correlation with epidermal growth factor receptor mutational status. Indian J Cancer 2013;50:94-101
|How to cite this URL:|
Bhatt A D, Pai R, Rebekah G, Nehru G A, Dhananjayan S, Samuel A, Singh A, Joel A, Korula A, Chacko R T. Clinicopathologic features of non-small cell lung cancer in India and correlation with epidermal growth factor receptor mutational status. Indian J Cancer [serial online] 2013 [cited 2019 May 19];50:94-101. Available from: http://www.indianjcancer.com/text.asp?2013/50/2/94/117016
| » Introduction|| |
Non-small cell lung cancer (NSCLC) is among the leading causes of cancer death in Asia. According to the GLOBOCAN 2008 report, India had 47,010 new lung cancer cases in males and 11,557 new lung cancer cases in females.  An increased incidence of lung cancer has been reported from several parts of the country in both hospital- and population-based registries. ,,, A population-based survey showed that overall 5-year observed and relative survivals for lung cancers were 12.5% and 15.9%, respectively, suggesting that in spite of all the advances in treatment, the impact on survival of these patients has been small. 
Tumor histopathology has played a significant role in the treatment selection of these cancers. , and recent identification of predictive molecular markers has considerably improved their management. ,, Some somatic mutations in the epidermal growth factor receptor (EGFR) gene that are heterozygous and are clustered within the ATP-binding pocket in the receptor tyrosine kinase (TK) domain cause ligand-independent activation of EGFR ("activating mutations"). Tumors with activating mutations show an increased sensitivity to EGFR-tyrosine kinase inhibitors (EGFR-TKIs).  Most activating mutations are found within exons 18-21 of the EGFR TK domain.  Small in-frame deletions in exon 19 and a substitution in (L858R) make up for ~90% of all such mutations. Point mutations in exon 18 and 20 have also been described in 5% of patients with NSCLC. Several other mutations have been found at a lower frequency; however, their significance is yet to be deduced.  EGFR-TKIs are being increasingly used in the management of NSCLC and are known to significantly improve response rates when used as firstline therapy and prolong overall survival (OS) in patients with lung adenocarcinoma harboring such mutations. , The prevalence of activating EGFR mutations has been found to vary by ethnicity ranging from 25% to 50% in Asian populations to about 10% in Western European and North American populations.  There is scanty information on the prevalence of mutations in the Indian region. A prevalence of 51.8% was reported from a single center in India. 
We performed a retrospective analysis of 154 patients with carcinoma of the lung for whom formalin-fixed paraffin-embedded (FFPE) tissues were available. The details of clinicopathologic profile, EGFR mutational status, treatment given, and outcomes were collected, analyzed, and are described.
| » Materials and Methods|| |
All patients with histopathologically confirmed NSCLC who were treated during the 2-year period - Jan 2008 to Dec 2010 and
- Had received treatment at our center
- Sufficient tissue was available for EGFR mutational analysis
- Had a minimum of 3 months follow-up were included.
A review of patient records was done to obtain relevant demographic and clinical data. This protocol was approved by the Review Board of the Institution. EGFR mutational status was assessed and correlated with clinicopathologic parameters, including age, gender, histopathology, smoking status, stage of disease, and treatment undertaken. All the patients were staged based on the American Joint Committee on Cancer (AJCC) TNM staging manual, 7 th edition.  Response to therapy, recorded as part of routine follow-up visits during treatment and after completion of chemotherapy was obtained by review of the hospital charts.
The EGFR mutational status testing was started in our center in June 2010 and hence was not available for most patients at the initiation of the treatment. Typically, patients were started on chemotherapy as per standard protocols. Non-squamous NSCLC was started on a platinum doublet with pemetrexed. Patients with squamous histology were treated with platinum doublet with gemcitabine. Six cycles of chemotherapy were offered to the patients. Evaluation was done at the end of three and six cycles. Patients on chemotherapy who finished six cycles and whose EGFR mutational status turned out to be positive were offered switch maintenance with TKIs. Those who had EGFR wildtype were offered continuation maintenance therapy with Pemetrexed.
Detection of EGFR mutations
FFPE blocks of patients with NSCLC were retrieved. The hematoxylin and eosin-stained sections were examined by the pathologist and the area with maximum tumor cellularity was identified and tumors with more than 50% cellularity were included. Extraction was carried out using the DNA tissue extraction kit from QIAGEN India Pvt. Ltd, New Delhi. The DNA was quantified using the Nanodrop (NanoDrop Technologies, Thermo Fisher Scientific Inc, Wilmington, DE, USA) and the 260/280 ratio was determined.
The polymerase chain reaction (PCR) for four exons was performed using published primer sequences used by Lynch et al.  All reactions were carried out in 25 μL volume. The following thermal cycling profile was followed for all PCRs: 95C for 8 min, 95C for 30 s, optimized anneal for 30 s, 72C for 1 min, and final extension of 72C for 10 min. The PCR product was detected using a 1.5% agarose gel. Sequencing of both the sense and antisense strands for all four exons was performed with an automated DNA sequencer (ABI PRISM 310 genetic analyzer) using the ABI PRISM BigDye Terminator Cycle Sequencing Ready Reaction Kit (Applied Biosystems, Invitrogen BioServices India Pvt. Ltd, Bangalore). Mutational analysis was performed by comparing the sequence with the wildtype and by looking for the presence all known mutations in these exons.
Descriptive analysis of all demographic variables was performed. Independent sample t-test was used to assess continuous variable and Chi-square test for categorical variables. Survival analysis was done by Kaplan-Meier test and log rank test. Binary logistic regression analysis was performed to determine odds ratio. All analyses were done using SPSS software (Version 16.0 Corporation, Bangalore, India).
| » Results|| |
[Figure 1]a shows the patients and their follow-up results. Of the 154 cases included in the study, 48 were excluded because they were either treated elsewhere or the duration of follow-up was less than 3 months. FFPE tissues of the remaining 106 patients were analyzed for EGFR mutations. Forty-two patients (39.6%) included in the study had a mutation in one of the four exons characterized [Table 1]. The most common mutation in exon 19 was a 15 bp deletion (n = 26, del E746-A750), whereas two patients had a 12 bp deletion (K745-A750). del L747-P753 ins A and delL747-p753 ins S were the other mutations seen in exon 19. All patients with exon 21 mutations carried the L858R mutations. Only two patients had mutations in exons 20 (mutation H773 ins NPH and T790M). A unique three bp deletion was seen in the exon 18 of one patient (del E709-T710), which was the only mutation observed in this exon. Two patients had more than one mutation; one had a D761Y mutation in exon 19 along with an L858R mutation, whereas the other had an L858R with a T790M mutation.
|Figure 1: (a) Flow diagram of study patients. (b) Treatment given. EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor|
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Clinical and demographic features
The demographic and some clinical features are presented in [Table 2]. The mean age for men was 59 years and for women, it was 49 years.
Pathologic classification and staging
Seventy-three (68.9%) patients presented with metastasis at onset, whereas locally advanced disease was present on evaluation in 33 (31.1%) Brain metastasis at presentation was found in seven patients (6.60%), whereas bone scan was positive for osseous metastasis in one third of the patients (33.02%). The most common histology was adenocarcinoma, 76 (72%). The histologic subtypes of adenocarcinoma, squamous cell carcinoma (n = 12) and NSCLC-NOS (n = 13) were equally distributed between smokers and nonsmokers. Bronchioalveolar carcinoma (n = 5) was found only in nonsmokers. [Table 1] shows the correlation of EGFR mutational pattern and clinical characteristics of the patients.
[Figure 1]b shows the treatment given to these patients. EGFR mutational analysis was available in our hospital from June 2010 and hence was done for most patients retrospectively. Patients whose EGFR mutational status was not available at presentation before the start of treatment were started on chemotherapy, n = 46 (43.39%). If EGFR mutational analysis was available and mutations were present, the patients were started on either upfront TKI, n = 15 (14.15%) or if on chemotherapy arm were allowed to finish six cycles and then start with maintenance TKIs, n = 26 (24.52%). Maintenance pemetrexed was started in 15 patients (14.15%).
Logistic regression analysis showed that female patients were found to be 1.42 times more likely to carry an EGFR mutation. Nonsmokers and patients whose tumors were TTF1 positive were 3.8 and 4.1 times more likely to harbor EGFR mutations (P = 0.005 and 0.012), respectively.
The median follow-up period was 10 months (95%CI, 4-26 months). Patients having EGFR mutations had higher response rates of 90.5% as compared with patients without EGFR mutations (70.3%) irrespective of the treatment that they received [Table 3]. Patients in the upfront TKI group with EGFR mutations had better response rates (93.3%). Response rate of 88.8% was seen in groups that were positive for EGFR mutation receiving chemotherapy and among those receiving chemotherapy followed by TKI. Whereas in patients without EGFR mutations, best response was seen in maintenance chemotherapy (93.3%). Response rate in chemotherapy group was 67.6% and chemotherapy followed by TKI group (62.5%) [Table 3].
There was no difference in progression-free survival (PFS) among smokers and nonsmokers (P = 0.965). The Kaplan-Meier curves are shown in [Figure 2]a. The median PFS for smokers and nonsmokers was 10 months (95% CI, 7-12) and 9 months (95% CI, 7-10), respectively.
|Figure 2: (a) PFS estimates according to smoking status. (b) PFS estimates according to EGFR mutation status. (c) PFS estimates according to EGFR mutation - positive patients. (d) PFS estimates according to EGFR mutation - negative patients. PFS, progression - free survival; EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor|
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A difference in PFS (log rank test, P = 0.111) was seen when the two groups with and without EGFR mutations were compared, as demonstrated in the survival curves in [Figure 2]b. The median progression free survival for patients with and without mutations was 11 months (95% CI,7-14) and 9 months (95% CI,7-10) respectively.
Better PFS was seen in the EGFR mutation-positive group who received chemotherapy followed by TKI (log rank test, P = 0.027) as compared with those who received only TKIs. A median PFS of 14 months (95%CI, 12-16) was seen in the mutation-positive group that received both chemotherapy followed by switch maintenance with TKIs versus 8 months (95%CI, 7-8 months) in the group that received only TKI [Figure 2]c.
A similar trend was also observed among patients without EGFR mutations where PFS was better for the group who received either TKI or pemetrexed following chemotherapy (log rank test P = 0.002). Median PFS was highest for the group that received chemotherapy followed by TKI (13 months, 95%CI, 8-17). PFS in chemotherapy followed by maintenance with pemetrexed was (10 months, 95%CI, 8-11) and was the least among patients who received only chemotherapy (8 months, 95%CI, 6-9) among those who did not have EGFR mutations [Figure 2]d.
| » Discussion|| |
The prevalence of EGFR mutations in this population of NSCLC patients was 39.6% with exon 19 mutation being the most common. The response rate of patients with an activating EGFR mutation was 93.3%.
The demographic data of our study population with regard to age, gender, smoking status, and histologic patterns had differences when compared with some of the recent reports from India [Table 4]. Our study had a larger proportion of females, nonsmokers, and adenocarcinoma, than the previously reported ones. The probable reason for more females and nonsmokers may be due to the differing geographic location of populations in each study, ,,, the latter feature of an increase in the number of adenocarcinoma is in keeping with a worldwide trend. Devesa et al., first described a changing histology among lung cancers and several studies in recent times have concurred with this changing pattern. 
EGFR Mutation Profile
Our results show relative high prevalence of mutations in EGFR at 39.6%, which is higher than the published data in western world and lower than that reported by a previous report from India, which found mutations in 51.8% of patients.  The difference in methodology for EGFR mutational analysis between the two studies in India could probably explain the differing prevalence, where Sahoo et al., used ARMS PCR, which is known to be more sensitive than the PCR sequencing method that was used in the present study.  EGFR mutational analysis for this study was done only on tissues that had >50% tumor cellularity, minimizing false negativity.  The present study did not find any significant associations between those who were positive for mutations in either exon 19 or 21, when compared by age, gender, or histology although a number of studies have reported an association of these features with mutation positivity. , There was predominance of exon 19 mutations (76%) in our study perhaps indicating that this is a subset that is likely to respond better to a TKI. 
Initial studies focusing on EGFR TKI responsiveness suggested potentially excellent activity with response rates in the 40%-90% range in patients with tumors harboring activating EGFR mutations. , The iTARGET trial enrolled chemonaïve patients with nonsquamous histology and demonstrated a 55% -response rate, PFS of 9.2 months, and OS of 17.5 months in EGFR mutation-positive patients.  Another recent trial, IRESSA Pan-ASia Study) (IPASS), showed improved PFS among those who received gefitinib than among those who received carboplatin-paclitaxel (hazard ratio for progression or death, 0.48; 95%CI, 0.36-0.64; P < 0.001) thus confirming the predictive value of EGFR mutations for the responsiveness of pulmonary adenocarcinoma to gefitinib as compared with carboplatin-paclitaxel. 
Majority of patients, 37 (57.8%) in EGFR mutation-negative group received chemotherapy with platinum doublet, whereas only 4 (6.2%) patients were unfit for chemotherapy and referred for best supportive care in this study. We had 15 patients (23.4%) on maintenance pemetrexed after initial chemotherapy. In the EGFR mutation-positive group, we had 15 patients (35.7%) who received upfront TKI. A majority of patients, 18 (42.9%) were already on chemotherapy before their EGFR status was known. They were given switch maintenance TKI after completion of chemotherapy.
An overall response rate of 90.5% was seen in EGFR mutation-positive group, whereas in EGFR mutation absent group overall response rate was 70.3%. The best response rates in EGFR mutation-positive group were for patients who received upfront TKI group, 93.3% followed by 88.8% in both chemotherapy and chemotherapy followed by TKI group. The best response in EGFR mutation absent group was seen in maintenance chemotherapy (93.3%) followed by similar responses in chemotherapy (67.6%) and chemotherapy followed by TKI group (62.5%).
Survival analysis according to treatment received factoring for EGFR mutation status, showed better PFS in EGFR mutation-positive group who received chemotherapy followed by TKI as compared with EGFR mutation-positive group who received only TKIs. Even in EGFR mutation-negative group, PFSs were better for the group who received chemotherapy followed by maintenance TKI in patients with stable disease as best response.
These findings are similar to some of the recently reported trials that have supported the use of maintenance chemotherapy. Presently, erlotinib and pemetrexed are approved as maintenance treatment in NSCLC patients after platinum doublet chemotherapy. The Paramount trial provided evidence of clinical benefit of maintenance pemetrexed in patients who did not progress after completion of four cycles of induction therapy.  Dickson et al., reported a statistically significant increase in both PFS and OS in patients with stable disease receiving switch maintenance with erlotinib compared with placebo for the maintenance treatment of NSCLC after previous platinum-containing chemotherapy.  A Phase II study of sequential erlotinib and chemotherapy as firstline treatment for advanced NSCLC by Mok et al., also showed sequential administration of erlotinib following gemcitabine/platinum chemotherapy led to a significant improvement in PFS.  Similarly, Coudert et al., showed that patients with advanced NSCLC following firstline platinum-based doublet chemotherapy derive a significant OS benefit from maintenance erlotinib therapy. 
Our study supports this concept of maintenance therapy in the Indian context. The observed benefit of addition of chemotherapy over TKI in EGFR mutation-positive group raises the question: Are EGFR mutation-positive lung cancer patients treated with upfront TKIs alone robbed of the benefits offered by combination chemotherapy and can we offer the therapy of chemotherapy-TKI combination to EGFR mutation-positive lung cancer patients as shown in the present study. A randomized controlled trial giving sequential TKIs followed by chemotherapy at progression compared with chemotherapy followed by maintenance TKIs and chemotherapy at progression in patients that are EGFR mutation positive is needed to answer this question.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]
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