The future of lung cancer therapy: Striding beyond conventional EGFR and ALK treatments.

Lung cancer, one of the most frequently diagnosed cancers worldwide has long relied on testing for the molecular biomarkers EGFR/ALK. However, achieving superior clinical outcomes for patients with lung cancer requires developing comprehensive techniques beyond contemporary EGFR/ALK testing. Current technologies are on par with molecular testing for EGFR/ALK in terms of efficacy, most of them failing to offer improvements perhaps primarily due to skepticism among clinicians, despite being recommended in the NCCN guidelines. The present study endeavored to minimize chemotherapy-dependence in EGFR/ALK-negative patient cohorts, and use evidence-based methods to identify ways to improve clinical outcomes. In total, 137 lung cancer cases obtained from 'PositiveSelect NGS data', comprising 91 males and 46 females, were investigated. EGFR- and ALK-positivity was used for data dichotomization to understand the therapeutic utility of rare gene alterations beyond just EGFR/ALK. Statistics obtained from PositiveSelect were collated with data from international studies to construct a meta-analysis intended to achieve better clinical outcomes. Upon dichotomization, 23% of cases harbored EGFR variants indicating that treating with EGFR TKIs would be beneficial; the remaining 77% exhibited no EGFR variants that would indicate favorable results using specific currently available chemotherapy practices. Similarly, 28% of cases had EGFR+ALK variants favoring EGFR/ALK-based targeted therapeutics; the remaining 72% harbored no EGFR/ALK variants with known beneficial chemotherapy routes. The present study aimed to overcome current inadequacies of targeted therapies in patients with a conventional EGFR/ALK-positive diagnosis and those in EGFR+ALK-negative cohorts. Upon analysis of the negative cohorts, significant and clinically relevant single nucleotide variants were identified in KRAS, ERBB2, MET and RET, with frequencies of 7, 1, 2 and 3% in patients who were EGFR-negative and 6, 1, 1, and 3% in patients who were EGFR and ALK-negative, respectively, enabling the use of targeted therapeutics aside from EGFR/ALK TKIs. From the results of the current study only 35% of the two negative arms (EGFR negative and EGFR+ALK negative) would be recommended NCCN or off-label chemotherapy; prior to the current study, the entire cohorts would have been recommended this treatment. The present study emphasizes the potential of comprehensive genomics in identifying hallmarks of lung cancer beyond EGFR/ALK, using broad-spectrum genetic testing and data-sharing among medical professionals to circumvent ineffective chemotherapy.

Association of CETP and LIPC Gene Polymorphisms with HDL and LDL Sub-fraction Levels in a Group of Indian Subjects: A Cross-Sectional Study.

There is an increasing interest to understand the molecular basis of high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) subfractions and their association with coronary artery disease (CAD). The formation of these subfractions is greatly influenced by hepatic lipase (HL) and cholesteryl ester transfer protein (CETP) enzymes. To identify genetic markers influencing LDL and HDL subfractions and their role in CAD we performed a case-control genetic association study on 117 healthy controls and 119 angiographically verified CAD patients. Biochemical analysis was performed using standard assays. HDL-C and LDL-C subfractions were estimated using precipitation methods. Genotyping of C-514T (rs1800588) in the LIPC gene for HL and I405V (rs5882) in the CETP gene was done using PCR-based restriction enzyme analysis and sequencing. Both the polymorphisms were not associated with CAD. The C-514T was associated with increased HDL3-C levels in controls (P = 0.049). The I405V polymorphism was found to be associated with low levels of small dense, LDL (P = 0.038). A multiple regression analysis showed that the effects were dependent on gender and triglyceride levels. We conclude that these polymorphisms are not associated with CAD but are important determinants of HDL-C and small dense LDL particles in our population.

Association of Sp1 tandem repeat polymorphism of ALOX5 with coronary artery disease in Indian subjects.

Lipoxygenases have been implicated in the pathogenesis of coronary artery disease (CAD) for its potent proinflammatory role. The Sp1 addition/deletion polymorphism in promoter region of the 5-lipoxygenase gene (ALOX5) has been associated with increased risk of carotid atherosclerosis and myocardial infarction. To determine the role of this polymorphism in our population we performed a case-control-genetic association study on 117 healthy controls and 119 angiographically verified CAD patients. Biochemical analysis was performed using standard automated assays. High-density lipoprotein cholesterol (HDL-C) and LDL-C subfraction levels were estimated using precipitation methods. Genotyping of polymorphism in the ALOX5 (Sp1 variants) was done using PCR-based heteroduplex analysis and automated sequencing. The Sp1 promoter repeat variants were found to be associated with CAD (p < 0.0001, OR = 4.47, 95% confidence interval = 2.58-7.74). Furthermore, the 5/5 genotype of the ALOX5 polymorphism in the healthy subjects was found to be associated with elevated HDL-C (p= 0.004), HDL(3) -C (p= 0.04), apo A1 (p= 0.011) and sdLDL (p= 0.001). We conclude that this polymorphism influences LDL and HDL subfraction levels and is a risk factor for CAD in our population. Clin Trans Sci 2012; Volume 5: 408-411.

Prevalence of metabolic syndrome in urban India.

Background. Metabolic syndrome (MS) is characterised by a constellation of individual risk factors of cardiovascular disease. Materials and Methods. The current study was a population-based survey of cohort of subjects in the metropolitan city of Mumbai. A total of 548 subjects, who attended the CARDIAC evaluation camp, were recruited in the study. Participants with complete fasting lipid profiles, blood glucose, and known cardiac risk markers were evaluated. Results. On applying modified NCEP ATP III, we found out that nearly 95% of the subjects had at least one abnormal parameter. We found the prevalence of MS in our study population to be 19.52%. The prevalence of MS in males was almost double than females (P = .008). The overall prevalence of BMI (>23 kg/m(2)) was 79.01%. Increased hypertriglyceridemia and decreased levels of HDL-C were found to be more in males (P < .0001). Conclusion. The low percentage of subjects with normal and controlled parameters suggests that there is a need for awareness programs and lifestyle interventions for the prevention and control of MS.

Platelet polymorphisms: frequency distribution and association with coronary artery disease in an Indian population.

Platelets play a critical role in normal blood hemostasis and thrombus formation in myocardial infarction (MI). Several polymorphisms of genes involved in platelet activation and fibrinolysis have been reported to be associated with MI. The aim of the present study was to determine the frequency distribution and association of polymorphisms in these genes with coronary artery disease (CAD) among Indians. A case-control genetic association study was performed for polymorphisms in platelet glycoprotein receptors (GPIIb/IIIa [HPA1a/1b], GPIb-IX-V [VNTR], and GPIa/IIa [C807T]), fibrinogen ß-chain (BclI), α-chain (Aα312), tissue plasminogen activator (tPA) [I/D] and plasminogen activator inhibitor-I (PAI-1) [4G/5G] in 473 healthy controls and 446 patients with stable and unstable angina. Genotyping was either by PCR-based restriction endonuclease digestion or allele-specific primers. The I allele frequency of the tPA I/D polymorphism was significantly higher in our patients (χ(2)=7.33, P<0.01) and no other polymorphisms varied significantly between patients and controls. Also, none of the polymorphisms seemed to affect the severity of the disease, the only exception being the mutant alleles of ß chain of fibrinogen gene, which were significantly elevated in single vessel disease. This is the first study to evaluate the role of gene polymorphisms in both the thrombotic and fibrinolytic pathway in the Indian population and suggests that tPA I/D polymorphism confers CAD risk in our population.

Lipid, lipoprotein, apolipoprotein and lipoprotein(a) levels: reference intervals in a healthy Indian population.

The role of lipids, lipoproteins and lipoprotein(a) [Lp(a)] in coronary artery disease (CAD) is known but the role of major apolipoproteins (apos) other than apo A-I and apo B remains unclear. In this study, using immunoturbidimetry we have estimated serum levels of total cholesterol, HDL-C, LDL-C, triglyceride, LDL-apoB and all major apos; A-I, A-II, B, C-II, C-III and E, in 751 healthy Indian subjects (470 men and 281 women, age 25-65 years), determined their percentiles, and established reference intervals. The effects of age, smoking and alcohol on all these analytes were also evaluated. This is the first study to provide reference intervals for all apos, in both sexes from a general population. The percentiles and the reference intervals have clinical relevance and will be useful in assessing the risk of CAD in patients with hyperlipidemia and other diseases.

Establishment of reference intervals in Indian population.

The central role of the laboratory scientist is to aid the clinician, in interpreting observed values, by providing relevant reference values in a convenient and practical form. In India, reference values used in laboratories have been established in the western population. But these can be questioned due to differences in genetic load, lifestyle, and diet. This review highlights the approach for establishing reference values in our population using the IFCC guidelines and our observations from our data as compared to the reported values in our laboratory.

Health status of Indian population--current scenario.

OBJECTIVE: We aimed at establishing reference intervals for the various biochemical and hematological analytes in healthy population. We also tried to find the percentage of people with coronary artery disease (CAD) and the associated risk factors in 39,940 subjects who had attended the health check up program at our hospital from the years 1996 to 2001. METHODS: The medical record folders of all the subjects were screened manually. Reference values were established using SPSS-8.0 package and the percentiles calculated and with it the corresponding 90% confidence interval (CI). RESULTS: The prevalence of hypertension, diabetes mellitus, and coronary artery disease was found to be 22.5%, 14.2%, and 3.9% respectively. In addition only 41.1% of the population was found to be normolipemic. Most of the analytes showed reference intervals which were in agreement with our reporting values. There was no influence of diet on the reference intervals. Also, there were some analytes like lipids where it was felt that changing the reference values would assign the subjects at greater risk for CAD. CONCLUSION: Implementation of reference intervals in case of lipids poses a dilemma. Lifestyle and diet modifications would have to be implemented to reduce the burden of CAD in this population.

Apolipoprotein E polymorphism and coronary heart disease.

Apolipoprotein E is a constituent of various lipoproteins and plays an important role in the transport of cholesterol and other lipids among cells of various tissues. The gene is polymorphic with three alleles (epsilon2, epsilon3, and epsilon4) coding for isoforms E2, E3, and E4 and having different binding affinities for the apo E receptors. While the epsilon2 allele is associated with elevated triglyceride levels, epsilon4 allele is associated with increased cholesterol levels. Though several studies support the role of apo E polymorphism in CHD either directly or indirectly via its influence on lipid and lipoprotein levels, there are some studies, which show no association. With the increasing incidence of CHD among Indians, it becomes imperative to identify genetic markers that may predispose individuals to coronary events. It would be of importance to determine if apo E gene will become a usefuladjunct to assess cardiovascular risk profile when performing genetic studies in families.

Gene polymorphism and coronary risk factors in Indian population.

Asian Indians who have settled overseas and those in urban India have increased risk of coronary events. Reasons for this increased risk are thought to be genetic but are yet unclear. Advances in molecular cardiology have revealed a number of single nucleotide polymorphisms associated with atherosclerosis. In this review, gene polymorphisms that have been associated with coronary diseases among Indians are discussed. Topics include the genes involved in hyperlipidemia, hypertension, and homocysteine. Mutations in the low-density lipoprotein receptor (LDLR) gene resulting in familial hypercholesterolemia have strong association with premature atherosclerosis. Common polymorphism of the apolipoproteins (apo) B-100 and E genes have been associated with variation in lipid and lipoprotein levels. Recently identified polymorphisms in the apoC3 (T-455C, C-482T), and cholesteryl ester transfer protein (CETP) (B1/B2 allele) genes are associated with increased triglycerides and reduced high-density lipoprotein (HDL)-levels, a feature now also common among Asian Indians. Angiotensin-converting enzyme-deletion (DD) polymorphism has been shown to influence beta-blocker therapy in heart failure. Mutations in methylenetetrahydrofolate reductase (C667T), cystathionine beta-synthase (T833C), and methionine synthase (A2756G) genes cause hyperhomocysteinemia, an independent risk factor for atherothrombosis. As the genetics of atherosclerosis continues to evolve, these factors along with the newer emerging factors may become a part of the routine assessment, aiding prediction of future coronary events.

Apolipoprotein E4 polymorphism as risk factor for coronary heart disease among Indian subjects.

Apolipoprotein E genotypes and lipid and lipoprotein levels were determined in hypercholesterolemic and angiographically vertified CHD subjects and compared against 90 normolipidemic controls. The ε4 allele was significantly prevalent in the hypercholesterolemic and CHD subjects. Significant increase in total cholesterol levels in apo ε4 containing subjects were observed in the hypercholesterolemic and CHD group. The study suggests that the ε4 allele by influencing the lipid levels could act as a risk factor for CHD.