Folate, excision biomarkers not predictive for small-cell lung cancer response

By Andrew Czyzewski

Biomarkers associated with the folate metabolism and excision repair pathways are not sufficiently prognostic to aid chemotherapy decisions for patients with extensive-stage disease small-cell lung cancer (ED-SCLC), results of a phase III trial show.

The GALES (Global Analysis of pemetrexed in SCLC Extensive Stage) phase III study was a large randomized trial comparing pemetrexed-carboplatin (PC) with etoposide-carboplatin (EC) in patients with ED-SCLC. The trial was stopped for futility with respect to progression-free survival (PFS) after a planned interim analysis of 733 patients.

As a secondary end point, protein expression (measured by immunohistochemistry [IHC)]) and single-nucleotide polymorphism (SNP) genotypes were evaluated for potential biomarkers of overall survival (OS), PFS, and overall response (OR).

The biomarkers of interest, reported in the present study, included thymidylate synthase (TS), excision repair cross complementing-1 (ERCC1), glycinamide ribonucleotide formyltransferase (GARFT), and folylpolyglutamate synthetase (FPGS). SNPs were genotyped for TS, FPGS, γ-glutamyl hydrolase (GGH), methylenetetrahydrofolate reductase (MTHFR), folate receptor-α FR-α, and solute carrier 19A1.

Examining biomarkers for 679 GALES patients, Egbert Smit (Vrije Universiteit Medical Center, Amsterdam, the Netherlands) and co-workers found that none of the IHC biomarkers (folate pathway or ERCC1) were predictive for outcomes and benefits of individual treatments.

By contrast SNPs associated with SLC19A1, GGH, FPGS - genes that are specifically involved in folate transport or metabolism - had significant treatment-independent association with OS.

Furthermore, an interaction of the rs3788205 (SLC19A1) and the rs13270305 (GGH-exon 1 Ala31Thr) SNPs significantly predicted OS for patients in the PC arm of the study.

"It appears that these associations are predictive (treatment dependent) as all these interactions were nonsignificant for the EC arm," Smit et al comment.

However, even in the most favorable subgroup this improved survival did not exceed that observed for the EC arm (10.6 months) in the entire study's intent-to-treat population, nor was the survival within any of the subgroups longer on the PC arm than on the corresponding subgroup of the EC arm.

"Such results suggest that the folate metabolism pathway may not provide meaningful therapeutic targets in ED-SCLC," Smit et al conclude in the Annals of Oncology.

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