Gene Variant Linked To RCC Everolimus Response

Patients with metastatic renal cell carcinoma with a single nucleotide polymorphism in the PI3KCA gene may be at risk of a poor response to everolimus treatment

medwireNews: Research has identified several predictors of a poor response to everolimus therapy in patients with metastatic renal cell carcinoma (RCC), including a genetic polymorphism.

“The PIK3CA gene variant rs6443624 might be an independent predictor and prognostic factor”, say Lubomir Bodnar, from the Military Institute of Medicine in Warsaw, Poland, and co-authors in the Annals of Oncology.

The team looked for biomarkers of everolimus response in the PI3K/AKT/mTOR pathway in 58 patients with metastatic RCC who were given everolimus 10 mg/day on a 30-day cycle.

Median progression-free survival (PFS) and overall survival (OS) were 7.95 and 15.55 months, respectively, with 69.0% of patients achieving stable disease and 3.4% a partial response, while 27.6% experienced disease progression.

The researchers did not find a significant correlation between PI3K/AKT/mTOR pathway protein expression and survival outcomes.

However, patients with the AC or AA genotypes of the single nucleotide polymorphism (SNP) PI3KCA rs6443624 were twice as likely to die as those carrying the variant CC form.

Multivariate analysis of PFS found a poor response to everolimus therapy in patients with histological grade 1 or 2 disease (hazard ratio [HR]=2.68), elevated levels of lactate dehydrogenase (LDH; HR=2.55) and PI3KCA rs6443624 carriers (HR=2.08).

Meanwhile, multivariate analysis indicated that poor OS was significantly predicted by elevated corrected calcium level (HR=4.17) and PI3KCA rs6443624 (HR=1.97).

The team says that genetic variation in the PI3K/AKT/mTOR pathway may be partly responsible for resistance to cancer treatments but admits there are no studies demonstrating a direct impact of this pathway in metastatic RCC.

Nevertheless, the researchers summarise: “Serum levels of LDH and histologic grade may be new simple tests which, together with SNPs of the PI3KCA gene, can predict improved outcomes with everolimus therapy.

“Corrected calcium level and the PI3KCA polymorphism can predict the prognosis of patients with RCC.”

They conclude: “Further investigation is needed to confirm and validate these findings prospectively in other RCC trials.”


Bodnar L, Stec R, Cierniack, S et al. Clinical usefulness of PI3K/Akt/mTOR genotyping in companion with other clinical variables in metastatic renal cell carcinoma patients treated with everolimus in the second and subsequent lines. Ann Oncol 2015; Advance online publication 10 May. doi: 10.1093/annonc/mdv166

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