TSC1-mutant bladder cancers had better responses to everolimus than TSC1-wild-type tumors.

  • Major finding: TSC1-mutant bladder cancers had better responses to everolimus than TSC1–wild-type tumors.

  • Clinical relevance: Sequencing the tumor genomes of outlier patients may uncover the basis of their drug response.

  • Impact: mTOR-targeted therapies may be especially effective in patients with somatic TSC1 mutations.

Even if an anticancer drug has significant activity in a small number of patients, it will be considered inactive and not developed further if most patients experience disease progression or if the median progression-free survival does not increase. Iyer and colleagues reasoned that the tumor genomes of outlier patients who responded to a “failed” drug might provide insight into drug sensitivity and guide patient selection for future trials. A recent phase II trial of the mTOR inhibitor everolimus in metastatic bladder cancer failed to achieve its endpoint of prolonging progression-free survival, but 1 patient who was enrolled in the trial experienced a durable and ongoing complete response lasting more than 2 years. The authors performed whole-genome sequencing of this patient's primary tumor and identified a somatic frameshift truncation mutation in tuberous sclerosis complex 1 (TSC1), which encodes a negative regulator of the mTOR pathway. Exon sequencing of 13 additional tumors from patients enrolled in the same trial revealed that 4 other tumors harbored TSC1 mutations. Of these patients with TSC1-mutant tumors, 3 experienced minor responses to everolimus therapy, whereas 8 of the 9 patients in this group that showed disease progression had TSC1–wild-type tumors. Furthermore, patients with TSC1-mutant tumors remained on everolimus significantly longer than patients with TSC1–wild-type tumors and had a significant improvement in time to recurrence. Although limited to a small group of patients, this approach demonstrates the feasibility of identifying biomarkers of drug sensitivity by sequencing the tumor genomes of responders and suggests an approach for the future clinical development of everolimus in a selected patient population.

Iyer G, Hanrahan AJ, Milowsky MI, Al-Ahmadie H, Scott SN, Janakiraman M, et al. Genome sequencing identifies a basis for everolimus sensitivity. Science 2012 Aug 23 [Epub ahead of print].

Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.

©2012 American Association for Cancer Research.
2012