Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancers.  In recent years, new therapeutic modalities that have targeted epidermal growth factor receptor (EGFR)-mutant and anaplastic lymphoma kinase (ALK)-rearranged variants of NSCLC have revolutionized care. However, for patients lacking these biomarkers, there has been little assistance in guiding therapy.

Advances in pharmacogenetics point to functional genetic polymorphism in the AGXT gene, which may impact toxicity and prognosis in NSCLC patients receiving platinum therapy. The AGXT gene is responsible for encoding alanine-glyoxylate aminotransferase, an enzyme that catalyzes the transamination between L-alanine and glyoxylate to produce pyruvate and glycine. This process detoxifies glyoxylate and reduces oxalate production. Both oxalate and glyoxylate generate reactive oxygen species (ROS).

Approximately 15% to 20% of Europeans and North Americans possess a missense genetic variant, AGXT rs34116584, which can result in primary hyperoxaluria and toxic levels of oxalates leading to renal damage. AGXT rs34116584 may also affect progression-free survival (PFS) and overall survival (OS) in patients exposed to platinum agents.

In a retrospective, cohort study involving 168 patients with histologically confirmed NSCLC, the single nucleotide polymorphism AGXT rs34116584 was studied for its effects on PFS, time-to-disease progression, and OS. Of these patients, 8.3% had the EGFR mutation and 3.0% had the ALK-rearrangement. Platinum-based doublet chemotherapy was administered as first-line therapy in 85.7% of NSCLC patients with 84% receiving cisplatin and 16% carboplatin. Targeted therapy was first-line therapy in 14.3% of study patients.

Investigators found that in those who were T-allele carriers, there was a significantly shorter PFS and OS compared with the CC homozygous genotype (for PFS, 5.4 months vs. 9.4 months [P <.0001] and for OS, 22.2 months vs. 43.6 months [P = .015], respectively).

In a subset analysis, wild-type EGFR in AGXT rs34116584 T-carriers were associated with both a decrease in PFS and OS, but mutated EGFR was only associated with decreased PFS. Univariate analysis found that AGXT T-carriers had an increased risk of progression (HR = 2.0) and cancer-specific death (HR = 1.8), regardless of tumor size, distant metastasis at diagnosis, type of systemic therapy, and type of treatment modality.

Among those who were treated with first-line platinum-based doublet chemotherapy, there was longer PFS in the C homozygous group (median 8.6 months) compared with T-carriers (median 5.1 months). Time-to-death was also longer in the CC homozygous group (median 34.9 months) versus T-carriers (median 19.8 months). Similar results for a higher risk of disease progression for T-carriers were found in multivariate analysis. In platinum-treated NSCLC patients, the occurrence of febrile neutropenia, but not myelotoxicity, was also more often associated with the presence of the T-allele.

It is theorized that ROS increase mutational burden, tumor progression, and dissemination. T-allele carriers have higher levels of oxalates, which may account for their poorer prognosis.

Pharmacists can help promote effective use of the AGXT biomarker to improve the pharmacologic management of patients with NSCLC cancer.

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