Impact of ABCB1, ABCC1, ABCC2, and ABCG2 variants in predicting prognosis and clinical outcomes of north Indian lung cancer patients undergoing platinum-based doublet chemotherapy

Abstract

Background: ABC transporters are membrane proteins expressed in the lungs and are crucial for efflux of various chemotherapeutic agents. Polymorphisms of ABC transporters have a certain impact on the transporter activity because their expression levels may influence the extent and longevity of chemotherapeutic drug outflow, affecting patient outcomes. The present study aimed to assess the impact of ABCB1, ABCC1/2, and ABCG2 gene variants in predicting prognosis and clinical outcomes in lung carcinoma patients.

Methods: In total, 502 lung cancer patients undergoing platinum-based chemotherapy were recruited in this prospective study. Genotyping of ABCB1 (C¹²³⁶ T, C³⁴³⁵ T, and G²⁶⁷⁷ T/A), ABCC1 (G³¹⁷³ A and G²¹⁶⁸ A), ABCC2 (G⁴⁵⁴⁴ A), and ABCG2 (C⁴²¹ A) polymorphisms in Northern Indian lung carcinoma patients were evaluated using polymerase chain reaction-restriction fragment length polymorphism analysis.

Results: Poor survival outcomes were noted in patients carrying a heterozygous genotype (CT) for the ABCB1 C¹²³⁶ T polymorphism compared to the wild-type genotype (CC) (p = 0.04). The mutant genotype (AA) for ABCC1 G³¹⁷³ A exhibited a lower median survival time compared to the reference genotype (GG) (p = 0.009). Lower survival was observed in individuals carrying a heterozygous genotype (GA) for ABCC2 G⁴⁵⁴⁴ A polymorphism compared to the wild-type genotype (GG) (p = 0.017). Small cell lung cancer patients with the ABCB1 G²⁶⁷⁷ A polymorphism having a heterozygous genotype (GA) showed poor survival compared to the wild-type genotype (GG) (p = 0.03). For ABCC1 G³¹⁷³ A, adenocarcinoma patients having a mutant genotype (AA) had reduced survival compared to the wild-type (GG) genotype (p = 0.03). For ABCB1 C³⁴³⁵ T, individuals carrying a heterozygous (CT) (p = 0.018) and mutant (TT) genotype (p = 0.007) had poor survival compared to the wild-type (CC) genotype in patients treated with pemetrexed and cisplatin. The patients administered cisplatin and irinotecan and having mutant alleles (AA) for the ABCB1 G²⁶⁷⁷ A polymorphism showed a lower survival compared to the individuals carrying wild-type alleles (GG) (p = 0.009).

Conclusions: Our findings suggest that ABCB1 C¹²³⁶ T, ABCB1 C³⁴³⁵ T, ABCB1 G²⁶⁷⁷ A, ABCC1 G³¹⁷³ A, and ABCC2 G⁴⁵⁴⁴ A are involved in predicting prognosis. Genotyping of the ABC polymorphism is essential for predicting prognosis in lung carcinoma patients.

Keywords: ABC transporter; lung cancer; platinum-based chemotherapy; polymorphism; survival.