Integration of liquid biopsy and pharmacogenomics for precision therapy of EGFR mutant and resistant lung cancers

Abstract

The advent of molecular profiling has revolutionized the treatment of lung cancer by comprehensively delineating the genomic landscape of the epidermal growth factor receptor (EGFR) gene. Drug resistance caused by EGFR mutations and genetic polymorphisms of drug metabolizing enzymes and transporters impedes effective treatment of EGFR mutant and resistant lung cancer. This review appraises current literature, opportunities, and challenges associated with liquid biopsy and pharmacogenomic (PGx) testing as precision therapy tools in the management of EGFR mutant and resistant lung cancers. Liquid biopsy could play a potential role in selection of precise tyrosine kinase inhibitor (TKI) therapies during different phases of lung cancer treatment. This selection will be based on the driver EGFR mutational status, as well as monitoring the development of potential EGFR mutations arising during or after TKIs treatment, since some of these new mutations may be druggable targets for alternative TKIs. Several studies have identified the utility of liquid biopsy in the identification of EGFR driver and acquired resistance with good sensitivities for various blood-based biomarkers. With a plethora of sequencing technologies and platforms available currently, further evaluations using randomized controlled trials (RCTs) in multicentric, multiethnic and larger patient cohorts could enable optimization of liquid-based assays for the detection of EGFR mutations, and support testing of CYP450 enzymes and drug transporter polymorphisms to guide precise dosing of EGFR TKIs.

Dose Optimization in Oncology Drug Development: The Emerging Role of Pharmacogenomics, Pharmacokinetics, and Pharmacodynamics

“…Like TKIs in RCC and CML, epidermal growth factor receptor (EGFR) TKIs are also metabolized by cytochrome P450s and are substrates of p-glycoprotein and BCRP. Gefitinib, for example, is metabolized by CYP3A4 and CYP2D6 , and erlotinib is metabolized by CYP1A2 and CYP3A4 [ 45 ]. The gefitinib/ CYP2D6 interaction is listed in Section 1 of the FDA Table of Pharmacogenetics, stating that CYP2D6 PMs have higher systemic concentrations and higher adverse reaction risk, but no specific dose modification is recommended [ 46 ].…”

“…Lastly, mobocertinib is metabolized by CYP3A4 and 3A5 . It is well-recognized that SNPs exist in all these genes, and some evidence suggests they play a role in modulating drug exposure [ 45 ]. Further, some genes like CYP1A2 are also affected by environmental stimuli like smoking.…”

Early ctDNA kinetics as a dynamic biomarker of cancer treatment response

“…Indeed, ctDNA analyses have been proposed for a variety of clinical purposes, including early cancer detection, detection of tumor recurrence, general surveillance of treatment response, and assessment of minimal residual disease (e.g. [28, 11, 35, 30, 3, 23, 32, 16]). Serial ctDNA kinetics have also been explored as a possible predictor of response to treatment in a variety of cancer types, such as colorectal cancer [36, 10, 33, 8, 25] and non-small cell lung cancer [1, 38, 2, 37].…”

Patient-derived organoids of lung cancer based on organoids-on-a-chip: enhancing clinical and translational applications

“…Lung cancer was the second most incident malignant tumor and the leading cause of cancer-related death in 2020 (Sung et al, 2021). Although targeted therapy and immunotherapy have accurately treated lung cancer and effectively improved the remission and disease control rates, prolonging the overall and progression-free survival of patients (Chen et al, 2021;Liang et al, 2021;Kolesar et al, 2022), this cancer still has one of the highest mortality rates. Some main reasons for the poor prognosis of lung cancer are the genetic differences between patients, the inherent phenotypic and genetic heterogeneity of tumor tissues, and the difficulty of explaining the internal causes of tumorigenesis and developing individualized treatments.…”