Individualized Chemotherapy Benefit Prediction by EndoPredict in Patients With Early Breast Cancer in an Indian Cohort.

PURPOSE: There are new advancements in the modulation of the treatment of patients with early-stage breast cancer, including the use of several molecular profiling tests to identify or select those patients who require additional adjuvant chemotherapy together with hormonal therapy on the basis of a recurrence score. One such tool is EndoPredict (Myriad Genetics; Salt Lake City, UT), which provides support in clinical decision making. The objective of this analysis was to study the landscape of absolute chemotherapy benefit and the likelihood of recurrence within 5 to 15 years in Indian patients with breast cancer who are undergoing EndoPredict testing. PATIENTS AND METHODS: This study included 308 patients with hormone-positive, human epidermal growth factor receptor 2-negative early breast cancer. Their postsurgical blocks were analyzed using the EndoPredict test. The MEDCALC statistical tool (Panum Education; Seoul, Republic of Korea) was used to estimate the correlation coefficient and to conduct multiple regression analysis. RESULTS: On the basis of the EndoPredict EPclin Risk Score, 52.12% of patients were classified as being in the low-risk category and could safely forgo adjuvant chemotherapy. For every unit increase in the EPclin Risk Score, the percentage increase in absolute chemotherapy benefit was 6.82%. Similarly, the correlation between the likelihood of recurrence within 5 to 15 years and the EPclin Risk Score suggested that there is a 10.34% increase in recurrence for each unit of EPclin Risk Score. CONCLUSION: The EPclin Risk Score has good prognostic and predictive power; it also provides the range of chemotherapy benefit for Indian patients.

Genetic Variants in the Wingless Antagonist Genes (sFRP, DKK, and Axin2) Predict the Overall Survival and Prognosis of North Indian Lung Cancer Patients Treated with Platinum-Based Doublet Chemotherapy.

Background: To investigate the prognostic implication of genetic variants within the wingless (Wnt) antagonist genes (DKK, sFRP, and Axin2) in North Indian lung cancer patients. Materials and Methods: A total of 212 subjects were genotyped using polymerase chain reaction-restriction fragment length polymorphism technique for 18 polymorphic sites in DKK4, DKK3, DKK2, sFRP3, sFRP4, and Axin2. Overall survival (OS) was estimated using the Kaplan-Meier survival analysis, and adjusted hazard ratio (HR) was obtained using the Cox regression method. Results: It was observed that the unfavorable genotypes of the three DKK2 variants collectively (rs447372, rs419558, and rs17037102) exhibited a highly decreased rate of death (adjusted HR = 0.37, p = 0.03). Adenocarcinoma (ADCC) patients carrying the heterozygous (CT) genotype for DKK4 rs2073664 showed a better OS compared with wild genotype (log rank p = 0.01). The two exonic variants (148 and 1386) of Axin2 gene showed contrasting results, where the ADCC subjects having TT genotype for Axin2 148 showed a better prognosis (adjusted HR = 0.48, p = 0.003) and those with TT genotype for Axin2 1386 showed a poor prognosis in small-cell lung carcinoma patients (adjusted HR = 2.33, p = 0.02). The intronic Axin2 1712 + 19 variant on the other hand indicated a highly increased death risk in ADCC patients with GG genotype. Survival tree analysis depicted DKK4 rs2073664 as the major contributor in predicting the survival of the lung cancer patients. Node 3 exhibited the lowest death rate (HR = 0.04, p = 0.008) and better median survival time (9 months vs. 3 months) when compared with reference node. Conclusions: A cumulative effect of three variants of DKK2 gene along with DKK4 rs2073664 can jointly predict the survival as shown by tree analysis.

Functional role of CyclinD1 polymorphism (G870A) in modifying susceptibility and overall survival of North Indian lung cancer patients.

PURPOSE: The purpose of this study was to investigate the potential role of the cyclin D1 gene G870A polymorphism in the likelihood of the development of lung cancer and the overall survival of lung cancer patients in the North Indian population. METHODS: The study consisted of 353 lung cancer cases and 351 age- and gender-matched healthy controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLPP) was done for the CCND1 gene. The association analysis was done using the multiple linear regression, and the survival analysis was done using the Kaplan-Meier and the Cox regression models. RESULTS: The GA genotype was associated with an increased risk for overall lung cancer (odds ratio [OR] = 1.63; p = 0.01). Combined variant genotype showed a significant association for overall lung cancer (OR 1.50; p = 0.03). In addition, smokers with the carrier genotype of CCND1 were found to have a significantly higher risk for lung cancer (OR 1.57; p = 0.04). No significant correlation was observed between the overall survival of lung cancer patients and CCND1 polymorphism. However, on stratifying the subjects on the basis of histology, it was evident that small-cell lung cancer (SCLC) patients carrying the mutant (AA) genotype showed nearly a fivefold increased mortality rate compared to the wild (GG) genotype (p = 0.03). CONCLUSIONS: Our results suggest that polymorphic CCND1 may increase the risk of lung cancer in smokers from North India, and it may be associated with the overall survival of SCLC patients.

Role of Sequence Variations in AhR Gene Towards Modulating Smoking Induced Lung Cancer Susceptibility in North Indian Population: A Multiple Interaction Analysis.

BACKGROUND: AhR, a ubiquitously expressed ligand-activated transcription factor, upon its encounter with the foreign ligands activates the transcriptional machinery of genes encoding for bio-transformation enzymes like CYP1A1 hence, mediating the metabolism of Poly aromatic hydrocarbons and nitrosamines which account for the maximally found carcinogen in cigarette smoke. Polymorphic variants of AhR play a significant role and are held responsible for disposing the individuals with greater chances of acquiring lung cancer. OBJECTIVE: To study the role of AhR variants (rs2282885, rs10250822, rs7811989, rs2066853) in affect-ing lung cancer susceptibility. METHODS: 297 cases and 320 controls have been genotyped using PCR-RFLP technique. In order to find out the association, unconditional logistic regression approach was used. To analyze high order in-teractions Multifactor Dimensionality Reduction and Classification and regression tree was used. RESULTS: Subjects carrying the variant genotype for AhR rs7811989 showed a two-fold risk (p=0.007) and a marginal risk was also seen in case of individuals carrying either single or double copy of suscep-tible allele for rs102550822 (p=0.02). Whereas the variant allele for rs2066853 showcased a strong pro-tective effect (p=0.003). SQCC individuals with mutant genotype of rs2066853 also exhibited a protec-tive effect towards lung cancer (OR=0.30, p=0.0013). The association of rs7811989 mutant genotype and rs10250822 mutant genotype was evident especially in smokers as compared to non-smokers. AhR rs2066853 showed a decreased risk in smokers with mutant genotype (p=0.002). MDR approach gave the best interaction model of AhR rs2066853 and smoking (CVC=10/10, prediction error=0.42). CONCLUSION: AhR polymorphic variations can significantly contribute towards lung cancer predisposi-tion.

Interactive potential of genetic polymorphism in Xenobiotic metabolising and DNA repair genes for predicting lung cancer predisposition and overall survival in North Indians.

INTRODUCTION: Cancer, a multi-step, multifactorial and multi-gene disease, not only damages the genomic integrity of the cell but also hinders the DNA repair mechanisms of the body. Gene-gene and gene environment interactions amongst the genetic polymorphisms together modulate the susceptibility towards a cancer. We have studied the high order gene interactions between the genetic polymorphism of detoxifying genes (CYP1A1, Ahr, XRCC and GST1) that play a key role in the metabolism of the xenobiotics and have been proved to be prognostic markers for lung cancer METHODS: 237 cases and 250 controls have been genotyped using PCR-RFLP technique. In order to find out the association, unconditional logistic regression approach was used and to analyse high order interactions MDR and CART was used. RESULTS: In the MDR analysis, the best model was one factor model which included GSTM1 (CVC 10/10, Prediction error = 0.43, p < .001). The best three factor model comprised of XRCC1 632, XRCC1 206, GSTM1 (CVC 10/10, Prediction error = 0.45, p < .0001). The CART analysis exhibited that Node 1 carrying mutant type of GSTM1 imposed the highest risk towards lung cancer (OR = 11.0, 95%C.I. = 6.05-20.03, p = .000001). Wild type of GSTM1 when combined with mutant type of CYP1A1 M2 and XRCC1 632, an 8 fold risk towards lung cancer was observed (95%C.I. = 4.07-16.29, p = .00001). The high order interactions were used to predict the prognosis of lung cancer patients. Of all the genetic variants, XRCC1 632, GSTM1 and AhR rs2066853 was the most important determinant of overall survival of lung cancer patients CONCLUSION: Through the study we introduced the concept of polygenic approach to get an insight about the various polymorphic variants in determining cancer susceptibility. Lesser number of subjects were found in the high risk subgroups. Further studies with larger sample size are required to warranty the above findings.

Association study between genetic variations in Axin2 gene and lung cancer risk in North Indian population: A multiple interaction analysis.

Wnt pathway has been implicated in the process of human carcinogenesis. Axis inhibition protein2 ( Axin2), a major scaffold protein is an antagonist of Wnt pathway and is potent to act as a tumor suppressor gene in various human cancers. Therefore, the seven polymorphic sites of Axin2 gene were analyzed, in relation to lung cancer susceptibility in North Indians. A total of 608 subjects were genotyped using PCR-RFLP technique for each polymorphic site including 303 cases and 305 controls. Further association analysis was carried out using logistic regression approach to obtain adjusted odds ratio and statistical significance. MDR and CART analysis were applied to evaluate high order interactions between the SNP's. Three out of seven studied polymorphic sites showed a strong protective effect in subjects having mutant genotype for Axin2 148 C >T and heterozygous genotype for 1365 G > A and 1712 + 19 G > T towards lung cancer risk. The other important finding was the significant association of Axin2 148 C >T in SQCC patients having variant (TT) genotype. Axin2 1712 + 19 G >T showed a decreased risk for all the histological subtypes in patients with heterozygous (GT) genotype. MDR analysis predicted a best interaction model ( Axin2 148, Axin2 2062 and Axin2 1712 +19) with maximum CVC (10/10) and minimum prediction error (0.38) along with significant permutation p-value. CART analysis gave a wide spectrum of interactive combinations which exhibited a major contribution in modulating lung cancer susceptibility. Axin2 148 and Axin2 1712 + 19 were found to play a major role in modulating lung cancer risk.

High-order gene interactions between the genetic polymorphisms in Wnt and AhR pathway in modulating lung cancer susceptibility.

AIM: Genetic variations present within Wnt and AhR pathway might be related to the lung cancer susceptibility. METHODS: A total of 555 subjects were genotyped using PCR-RFLP technique for polymorphic sites in DKK4, DKK3, DKK2, sFRP3, sFRP4, Axin2 and AhR. Multifactor dimensionality reduction method and classification and regression tree analysis was used. RESULTS: Overall sFRP4rs1802073 which has a cross validation consistency of 10/10, prediction error = 0.43 (p > 0.0001) is the best factor model. The second best model was sFRP4rs1802073 and DKK2rs419558 with cross validation consistency of 9/10 and prediction error = 0.40. In classification and regression tree analysis, DKK2 rs419558 came out to be a significant factor; DKK2rs17037102 (M)/DKK2rs419558 (M) showed a tenfold risk of acquiring lung cancer, p = 0.0001. DKK2rs17037102 (M)/AhRrs2066853 (W)/AhRrs10250822 (M) showed an 11-fold risk of developing lung cancer, p = 0.00001. CONCLUSION: Both DKK2 and sFRP4 polymorphisms are found to play a crucial role; especially for smokers towards modulating risk for lung cancer. AhR variants are contributing maximally toward lung cancer risk.

Functional Role of CyclinD1 Polymorphism (G870A) in Modifying Susceptibility and Overall Survival of North Indian Lung Cancer Patients.

Purpose The purpose of this study was to investigate the potential role of the cyclin D1 gene G870A polymorphism in the likelihood of the development of lung cancer and the overall survival of lung cancer patients in the North Indian population. Methods The study consisted of 353 lung cancer cases and 351 age- and gender-matched healthy controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLPP) was done for the CCND1 gene. The association analysis was done using the multiple linear regression, and the survival analysis was done using the Kaplan-Meier and the Cox regression models. Results The GA genotype was associated with an increased risk for overall lung cancer (odds ratio [OR] = 1.63; p = 0.01). Combined variant genotype showed a significant association for overall lung cancer (OR 1.50; p = 0.03). In addition, smokers with the carrier genotype of CCND1 were found to have a significantly higher risk for lung cancer (OR 1.57; p = 0.04). No significant correlation was observed between the overall survival of lung cancer patients and CCND1 polymorphism. However, on stratifying the subjects on the basis of histology, it was evident that small-cell lung cancer (SCLC) patients carrying the mutant (AA) genotype showed nearly a fivefold increased mortality rate compared to the wild (GG) genotype (p = 0.03). Conclusions Our results suggest that polymorphic CCND1 may increase the risk of lung cancer in smokers from North India, and it may be associated with the overall survival of SCLC patients.

Association of polymorphisms in Dickopff (DKK) gene towards modulating risk for lung cancer in north Indians.

AIM: To investigate the association between the genetic variants of DKK4 (rs2073664), DKK3 (rs2291599, rs3206824 and rs7391689) and DKK2 (rs447372, rs419558 and rs17037102) and lung cancer predisposition in north Indians. MATERIALS & METHODS: A total of 600 subjects were genotyped using PCR restriction fragment length polymorphism technique. Association analysis was carried out using logistic regression approach. RESULTS: DKK3 rs7396187 showed a protective effect (p = 0.01). Subjects with heterozygous genotype of DKK2 rs17037102 and rs419558 showed an increased risk. The variant genotype of the genotypic combination, DKK3 rs3206824 and DKK2 rs419558 showed a twofold increased risk (p = 0.008). Lung cancer risk increased four-times in subjects with variant genotype of all the three DKK2 variants. CONCLUSION: DKK2 is certainly playing a crucial role in modulating cancer susceptibility.

Association of p53 codon 72 polymorphism and survival of North Indian lung cancer patients treated with platinum-based chemotherapy.

p53 helps in maintaining genomic stability by undergoing cellular arrest, DNA repair or cellular apoptosis during DNA damage. So, as to find the association of p53Arg 72 Pro towards lung carcinogenesis and overall survival of North Indian lung cancer patients, single nucleotide polymorphic variant (rs1042522) was analyzed. 840 subjects including 420 cases and 420 controls were recruited and genotyped using PCR-RFLP technique for p53Arg 72 Pro polymorphic site. Association was analyzed using adjusted odds ratio along with its confidence intervals (95 % CI) and p value predicted from logistic regression whereas overall survival for lung cancer patients was obtained using Kaplan-Meir and Cox regression model for different parameters to obtain hazard ratio and survival time with statistical significance (log-rank p value). None of the variant genotypes for p53Arg 72 Pro showed any association towards lung cancer risk or any specific histological subtype. Lung cancer subjects with Pro/Pro genotype had better median survival time as compared to Arg/Pro genotype (10 months; HR = 0.65; 95 % CI = 0.45-0.95; p = 0.03). Furthermore, female lung cancer patients with Arg/Pro (HR = 0.08; 95 % CI = 0.02-0.34; p = 0.0005) and Pro/Pro (HR = 0.21; 95 % CI = 0.06-0.67; p = 0.008) genotypes showed a better overall survival and hence a better prognosis as compared to males. Our data also reveals that lung cancer patients with ECOG scores between 0 and 1 and carrying the Pro/Pro had better chances of survival. p53 codon 72 polymorphism could play a role as a prognostic marker in lung cancer patients.

Functional genetic variants in pre-miR-146a and 196a2 genes are associated with risk of lung cancer in North Indians.

OBJECTIVE: To find the association of two pre-miRNA polymorphisms with risk of lung cancer in North Indians. MATERIALS & METHODS: Genotyping of 250 cases and 255 controls for miR-146a and miR-196a2 using PCR-RFLP. RESULTS: Heterozygous subjects showed a risk toward lung cancer (LC), especially for adenocarcinoma (OR: 1.82; 95% CI: 1.04-3.20; p = 0.03) in miR-146a gene. TT genotype for miR-196a2 gene also showed 3.2-fold risk toward LC and the risk was fivefold higher for squamous cell carcinoma. Survival rate was significantly lower in subjects with TT genotype as compared with the CC genotype in miR-196a2. CONCLUSION: Both the single nucleotide polymorphism variants showed a positive association toward risk of lung cancer.