812P - Role of genetic variants in the PI3K/AKT/mTOR pathway in renal cell carcinoma patients treated with everolimus- a pilot study

Date 29 September 2012
Event ESMO Congress 2012
Session Poster presentation I
Topics Renal Cell Cancer
Pathology/Molecular Biology
Presenter Lubomir Bodnar
Authors L. Bodnar1, R. Stec1, M. Cichowicz2, S. Cierniak3, M. Smoter4, W. Kozłowski2, C. Szczylik1
  • 1Department Of Oncology, Military Institute of Medicine, 04-141 - Warsaw/PL
  • 2Department Of Pathology, Military Institute of Medicine, 04-141 - Warsaw/PL
  • 3Pathology, Military Institute of Medicine, 04-141 - warsaw/PL
  • 4Oncology, Military Institute of Medicine, 04-141 - Warsaw/PL

Abstract

Background

The phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway is involved in growth regulation, proliferation control and metabolism in renal cell carcinoma (RCC). In our prospective pilot study, we determined whether common genetic variations in the AKT/ PI3K, FRAP1 (encoding mTOR) are associated with clinical outcomes in RCC patients who underwent palliative therapy with everolimus.

Patients and methods

Our pilot study was designed to assess everolimus efficacy in RCC patients relapsed after TKI inhibitors (sunitinib and/or sorafenib). Patients were treated with everolimus 10 mg daily orally until disease progression. The genomic DNA was extracted from formalin-fixed, paraffin-embedded primary tumor RCC tissues. 12 potentially functional SNPs in 4 key genes (AKT1, AKT2, FRAP1, PIK3CA) were determined using a real-time PCR genotyping assay and analyzed for association with response to therapy, progression free survival (PFS) and overall survival (OS).

Results

Median age of 45 enrolled patients was 62 years (range, 41–78). At a median follow-up duration of 8,6 months, the 6-month PFS rate was 53.3%. Partial response was observed in 4,4% (2/45) of the patients. Median PFS was significantly prolonged in the PIK3CA rs6443624 for the CC genotype in comparison to the AA/AC genotype (8.9 months versus 5.5 months, log rank, p= 0.0157). In the multivariate analysis elevated corrected serum calcium and PIK3CA rs6443624 for the AA/AC genotype were unfavorable predictors of PFS (HR 5.25; 95% CI, 1.75–15.75 and HR 3.48; 95%CI, 1.47–8.25, respectively, p < 0.05). 1-year OS rate for patients with PIK3CA rs6443624 CC and AA/AC genotype was 86% and 51%, respectively (p = 0.0018). In multivariate analysis PIK3CA rs6443624 for the AA/AC genotype and elevated LDH serum level remained significant for OS (HR 18.7; 95% CI,2.70–129.38 and HR 9.7; 95% CI,2.18 – 43.07, respectively; p < 0.05).

Conclusion

These results suggest that PIK3CA rs6443624 genetic variation in PI3K/AKT/mTOR pathway may modulate clinical outcomes in patients with RCC who undergo chemotherapy with everolimus. Further clinical studies are needed to confirm these findings.

Disclosure

All authors have declared no conflicts of interest.