The range of estimated prevalence of EGFR mutations and ALK translocations across South Asian populations with non-small cell lung cancer (NSCLC) varies. Estimates range from 20 to 35% for EGFR and 4-8% for ALK. These results come largely from tertiary referral centres in India, however, there is limited data on patients of Indian (or more largely, South Asian) origin and mutational characteristics from areas outside of the country. This is of specific interest given the interest in exploring the impact of ethnicity on tumour mutational frequency, noting the significant difference with EGFR-activating mutations as an example, where up to 50% of lung adenocarcinomas in East Asians may harbour this mutation, while only 15% North Americans and Europeans are diagnosed with lung adenocarcinoma harbouring these mutations. These discrepancies in mutational rates in different populations led to this brief report, evaluating the differences in mutational changes in South Asians (largely those of Indian origin) at a United States (US) academic institution compared to an Indian academic institution.
We performed a retrospective review of NSCLC cases at the Stanford Cancer Centre (Stanford, CA, US) and the Postgraduate Institute of Medical Education and Research (PGIMER) (Chandigarh, India). At Stanford, we identified 1,915 patients with a self-identified race of “Asian” in the electronic medical record, who also had a diagnosis of “adenocarcinoma”, and who had had an encounter with a thoracic medical oncologist at the Stanford Cancer Centre from January 2005 to December 2019. The “adenocarcinoma” criteria included all types of cancers, and resulted in a large number of patients, as a thoracic medical oncologist may have had an encounter with non-thoracic oncology patients also. From this cohort of 1,915 patients, we identified 72 patients with NSCLC, who had a South Asian name and who we confirmed with manual chart review as having identified their ethnicity as originating from India, Pakistan, Bangladesh, or Sri Lanka. Patients were excluded if they did not have a confirmation of their ethnicity in the electronic medical record. Staging was done using the 7th edition of the TNM classification at both centres. Patients diagnosed at PGIMER (all of whom identified from Indian ethnicity) were included if diagnosed from January 2011-December 2019. At both sites, molecular testing results were recorded and compared. We collected data on sex, smoking status, pathologic diagnosis, tumour histology, disease stage and the type of molecular testing conducted. Molecular testing was performed as part of routine clinical care at Stanford but the methodologies have varied over the study period: DNA sequencing (2007-2011), SNaPshot (2011-2013) and Stanford Solid Tumour Actionable Mutation Panel (STAMP) (2013-Present). For EGFR mutation testing at PGIMER, real-time polymerase chain reaction (RT-PCR) and Sanger sequencing were mainly used with the rising use of next-generation sequencing (NGS). The latter, however still comprised a minority in the testing methods used. ALK relocations were ascertained using immunochemistry (D5F3 clone). The ROS1 rearrangement was tested using immunochemistry (D4D6 clone) and positive samples were confirmed by fluorescence in situ hybridisation (FISH). Frequencies of oncologic mutations and alterations were compared among different subgroups with descriptive statistics.
Demographics and testing characteristics for both cohorts are shown in Table 1. The Stanford cohort included 72 South Asian patients (diagnosed 2005-2019), of whom, 64 patients had mutational testing (from 2009 to 2019). Twenty-one of the sixty-four patients (33%) had the two main activating EGFR mutations (14 with Exon 19 deletions and 7 with exon 21 L858R). Other molecular alterations included eight ALK rearrangements (12.5%), seven KRAS mutations (amplifications, G12V and G12C, 20.5% of NGS testing performed), two ROS1 fusions (3.1%), and two BRAF V600E mutations (5.9%, of NGS testing performed). In assessing the co-mutations, three ARID1A and three STK11 mutations were noted. At the progression of the disease (n = 61), the most common resistance mutations, if tested and resulted, included TP53, EGFR (T790M,), ERBB2 and KRAS.
The PGIMER cohort included 1,264 patient cases with mutational testing (2011-2019). Twenty-six percent (298/1163) had EGFR mutations, with 22.5% (262/1163) being the two main EGFR-activating mutations (exon 19 deletion and exon 21 L858R mutation). Nine and a half percent (88/928) of the patients tested had ALK rearrangements, and one patient (out of 62 tested) had a confirmed ROS1 fusion [Figure 1]. At the progression of the disease (n = 90), the most common mutations were EGFR (T790M in 35% of cases) in 81 patients with progression on EGFR-targeted treatments. EGFR was also detected in three patients who were initially EGFR wild-type.
Both cohorts largely included adenocarcinomas (94% in the Stanford cohort and 95% in the PGIMER cohort), and presented with advanced-stage disease (63% in the Stanford cohort and 72% in the PGIMER cohort). Figure 2 shows the distribution of all EGFR mutations (including non-exon 19 and exon 21 mutations) and ALK mutations by sex. In assessing the EGFR mutation prevalence on only men in the PGIMER cohort, the current or former smokers had a prevalence of 15.9% (79/497) while non-smokers had a prevalence of 32.6% (60/184) (x2 23.09, P < 0.0001). There was limited broader NGS panel testing in the PGIMER cohort (n = 25), limiting frequency analysis of rarer and secondary mutations. For patients with EGFR mutations at PGIMER and experiencing disease progression on first/second generation EGFR TKIs, liquid biopsy detected the presence of exon 20 T90M resistance mutation in 35% (data presented in a separate scientific communication).
CONCLUSIONS AND DISCUSSION
South Asian (largely Indian) patients with NSCLC appear to have a high chance of harbouring oncogenic drivers, especially EGFR mutations and ALK rearrangements, at two distinct geographical locations. These findings corroborate before single-institution findings, including those at a large tertiary cancer centre in western India. Given the paucity of data on comparing frequencies of these oncogenic drivers from different institutions in different geographical settings, this collaboration adds to the data related to the impact of ethnicity on these oncogenic drivers. To our knowledge, this is one of the first reports of EGFR mutation and ALK rearrangement prevalence in the South Asian/Indian population based out of the US.
While our data are limited given their retrospective analysis, and susceptible to selection bias, we do report on the full available data at both institutions. The Stanford cohort is limited by its small sample size (about 3.7% of the screened Asian cohort), however, with the strength of manual verification of Indian/South Asian ethnicity through electronic medical record review. We may have missed patients who did not self-identify as “Asian” in the medical record and those with non-traditional names or those who changed their names through marriage or otherwise. The PGIMER cohort is limited by the scope of mutation testing for patients, hence, we report on those tested for each mutation type.
There are also some notable differences between these two populations: the PGIMER cohort had notably more men (67%) and also more smokers (54%), which reflects both cultural and social differences between the two populations. There is a high prevalence of smoking in North India, and by extension, in India in general, which has been documented in prior work. For example, in a large cohort of over 73,000 subjects aged 15 years or older, the prevalence of ever smoking was 28.5% in men versus 2.1% in women. Therefore, most lung cancer patients seen in North India are men (estimated ratio of 4.4 to 1 for male to female), with also a high prevalence of smoking bidi (a hand-rolled form of tobacco). In a prior work from PGIMER, we have noted that up to 56% of current or ex-smokers were exclusively bidi smokers. Bidi smoking, however, still appears to have a similar risk association for developing lung cancer, compared with cigarette smoking. Comparatively, Stanford’s location in the greater Bay Area in California has more female patients. In the United States (US) as a whole, there has been a higher lung cancer incidence noted in young women, with the historical trend of higher rates in men reversing among non-Hispanic Whites and Hispanics. The estimated prevalence of smoking in the greater Bay Area is estimated to be 10% in Asians/Pacific Islanders, however, there are no specific data on the specific prevalence in the Indian/South Asian community, or among women in that community. The PGIMER cohort confirms the known association of EGFR mutations in non-smoking patients, and thus, the overall lower prevalence of these mutations compared to the Stanford cohort, where there were no smokers among women and only 28.6% of male smokers.
We also note that the PGIMER cohort has one of the lowest rates of EGFR mutation in India. Patients from the southern parts of India have been reported to have much higher rates of EGFR mutation (40-50%). The observed higher mutation rate in the Stanford cohort could be because of a greater diversity in the cohort as well. As for ALK rearrangements/fusions, prior reports note an estimated prevalence of about 4-8% in the Indian populations. Interestingly, in an exclusively South Indian population, the ALK rates were also slightly higher at 11% of patients, although with the limitation of this being a single report. We report a rate of 9% at PGIMER and 13% at Stanford, which again shows a similar distribution, although with the same considerations of the Stanford cohort being a mixed population.
Lastly, there is also a substantial difference in the testing methodology employed at the two centress, with largely PCR methodology used at PGIMER, but rising use of NGS at Stanford over the years of this cohort analysis. However, even in considering these limitations, we believe that these similar rates of mutations seen here in two distinct geographical populations underline the importance of ethnicity despite geographical differences. For example, earlier work has shown that polymorphism frequencies within the EGFR gene are influenced by ethnicity. These frequencies also mirror what is known about NSCLC in East Asia, where approximately one-third of patients are non-smokers, and many are diagnosed with adenocarcinoma with oncogenic driver mutations (as high as 90% in some analyses). Interestingly though, EGFR mutations are seen at higher rates (around 50%) for the East Asian populations (including Vietnamese, Thai, Chinese, and Filipino), but are much lower in the Indian and South Asian patients. These findings prompt the question of why the mutation rate (at least for EGFR) appears to be lower in the Indian and South Asian populations, than in those of other Asian countries. Further research is needed to better elucidate these differences in the mutation rates and underlying mechanisms as treatment of these subsets of NSCLC continues to advance.
IRB approval for molecular analysis September 2020 at Stanford, revised February 2022. (PGIMER : Ethics Committee Approval date June 2020).
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
1. Prabhash K Treatment of advanced non-small cell lung cancer:First line, maintenance and second line –Indian consensus statement update South Asian J Cancer 2019 8 1–17
2. Doval DC, Prabhash K, Patil S, Chaturvedi H, Goswami C, Vaid AK, et al Demographic and epidemiological characteristic of Egfr mutation and Alk gene rearrangement among Indian patients with lung adenocarcinoma Ann Oncol 2014 25 doi:10.1093/annonc/mdu349.82
3. Midha A, Dearden S, McCormack R EGFR mutation incidence in non-Small-cell lung cancer of adenocarcinoma histology:A systematic review and global map by ethnicity (mutMapII) Am J Cancer Res 2015 5 2892–911
4. Choughule A, Noronha V, Joshi A, Desai S, Jambhekar N, Utture S, et al Epidermal growth factor receptor mutation subtypes and geographical distribution among Indian non-small cell lung cancer patients Indian J Cancer 2013 50 107–11
5. Singh R, Rohtagi N Clinicopathological and molecular epidemiological study of lung cancer patients seen at a tertiary care hospital in Northern India South Asian J Cancer 2017 6 171–5
6. Kaur H, Sehgal IS, Bal A, Gupta N, Behera D, Das A, et al Evolving epidemiology of lung cancer in India:Reducing non-small cell lung cancer-not otherwise specified and quantifying tobacco smoke exposure are the key Indian J Cancer 2017 54 285–90
7. Singh N, Aggarwal AN, Gupta D, Behera D, Jindal SK Quantified smoking status and non-small cell lung cancer stage at presentation:Analysis of a North Indian cohort and a systematic review of literature J Thorac Dis 2012 4 474–84
8. Jindal SK, Aggarwal AN, Chaudhry K, Chhabra SK, D'Souza GA, Gupta D, et al Tobacco smoking in India:Prevalence, quit-rates and respiratory morbidity Indian J Chest Dis Allied Sci 2006 48 37–42
9. Gupta D, Boffetta P, Gaborieau V, Jindal SK Risk factors of lung cancer in Chandigarh, India Indian J Med Res 2001 113 142–50
10. Jemal A, Miller KD, Ma J, Siegel RL, Fedewa SA, Islami F, et al Higher lung cancer incidence in young women than young men in the United States N Engl J Med 2018 378 1999–2009
12. Parikh P, Puri T Personalized medicine:Lung cancer leads the way Indian J Cancer 2013 50 77–9
13. Sahoo R, Harini VV, Babu VC, Patil Okaly GV, Rao S, Nargund A, et al Screening for EGFR mutations in lung cancer, a report from India Lung Cancer 2011 73 316–9
14. Rana V, Ranjan P, Jagani R, Rathi KR, Kumar D, Khera A A study of therapy targeted EGFR/ALK mutations in Indian patients with lung adenocarcinoma:A clinical and epidemiological study Med J Armed Forces India 2018 74 148–53
15. Paliwal P, Rajappa S, Santa A, Mohan M, Murthy S, Lavanya N Clinical profile and outcomes of patients with Stage IV adenocarcinoma of lung:A tertiary cancer centre experience Indian J Cancer 2017 54 197–202
16. Tarigopula A, Ramasubban G, Chandrashekar V, Govindasami P, Chandran C EGFR mutations and ROS1 and ALK rearrangements in a large series of non-small cell cancer in South India Cancer Rep 2020 3 e1288
17. Nomura M, Shigematsu H, Li L, Suzuki M, Takahashi T, Estess P, et al Polymorphisms, mutations, and amplification of the EGFR gene in non-small cell lung cancers PLoS Med 2007 4 e125
18. Liam CK, Pang YK, Poh ME EGFR mutations in Asian patients with advanced lung adenocarcinoma J Thoracic Oncol 2014 9 E70–1