Association of an aurora kinase a (AURKA) gene polymorphism with progression-free survival in patients with advanced urothelial carcinoma treated with the selective aurora kinase a inhibitor alisertib.
Background and purpose Salvage therapies for urothelial carcinoma are needed. A single-arm trial in patients with advanced or metastatic urothelial carcinoma refractive to other therapies found that alisertib, a selective inhibitor of aurora kinase A, maintained stable disease in a few cases, despite a low objective response rate. To better understand why some patients benefited from alisertib, we genotyped the 22 patients of this pilot trial for two single nucleotide polymorphisms (rs2273535 and rs1047972) in AURKA, the gene encoding aurora kinase A, and looked for associations with survival and treatment response. Results Carrier status for the minor allele of rs2273535 (T91A, p. F31I) was a favorable prognostic factor for progression-free survival (HR = 0.18; 95% CI, 0.039-0.81; P = 0.026) but not for overall survival (HR = 0.88; 95% CI, 0.26-2.9; P = 0.83). These results were confirmed in multivariable analyses, adjusting for sex, age and hemoglobin, for both progression-free survival (HR = 0.11; 95% CI, 0.018-0.69; P = 0.018) and overall survival. No association was found between rs1047972 and survival. Moreover, neither SNP was associated with treatment response. Conclusion In patients who received alisertib for advanced or metastatic urothelial carcinoma, longer progression-free survival was observed in carriers of the minor allele A of rs2273535 in AURKA than in patients who were homozygous for the major allele T. This finding, based on a small pilot trial, warrants further investigation.
Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Andrea
A
Necchi
Department of Predictive and Preventive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G.A. Amadeo 42, I-20133, Milan, Italy.
Giulia
G
Pintarelli
Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Daniele
D
Raggi
Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Patrizia
P
Giannatempo
Department of Predictive and Preventive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G.A. Amadeo 42, I-20133, Milan, Italy. francesca.colombo@istitutotumori.mi.it.
Francesca
0000-0003-2015-4317
F
Colombo
D000328:Adult; D000368:Aged; D000483:Alleles; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors / Q000235:genetics*; D001381:Azepines / Q000627:therapeutic use*; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D014571:Urologic Neoplasms / Q000188:drug therapy / Q000235:genetics
D001381:Azepines; C550258:MLN 8237; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C576917:AURKA protein, human; D064096:Aurora Kinase A
Bladder cancer; MLN8237; NCT02109328; Serine/threonine kinase