Whole-genome sequencing finds a genetic basis for everolimus sensitivity
Genetic analysis of durable remission of progressive, metastatic bladder cancer treated with everolimus
- Date : 22 Oct 2012
- Topic : Genitourinary cancers
The lack of development of new therapeutic agents might partly account for the slow decrease of mortality rates in bladder cancer. In addition, this disease has the highest recurrence rate of all cancers and most patients suffering from it (50–70%) experience either recurrence or disease progression.
David Solit, Gopa Iyer and collaborators were intrigued by the results of a phase II clinical trial assessing the mTOR inhibitor everolimus, as a single agent in the treatment of progressive, metastatic bladder cancer, in which one patient showed a complete response to the drug within 1 year of treatment initiation. They hypothesized that a specific genetic lesion within this patient's tumour was responsible for such response.
To test their hypothesis the researchers used whole-genome sequencing of DNA derived from both tumour and peripheral blood from this patient. Of the 17,136 somatic mutations detected, they found a two base-pair deletion in TSC1 (tuberous sclerosis complex 1) - a gene already found to be mutated in bladder cancer in previous studies, and which is also known as a regulator of mTOR pathway activation. Knock down of TSC1 in bladder cancer cell lines resulted in enhanced sensitivity to mTOR inhibition.
The researchers sought to analyse tumours from more patients in the phase II everolimus study. Targeted sequencing revealed TSC1 mutations in about 8% of 109 additional bladder cancers examined, and TSC1 mutation correlated with everolimus sensitivity. Four patients with minor treatment responses harboured TSC1 alterations, whereas eight of nine patients with tumour progression harboured wild-type TSC1. Patients with TSC1 mutant tumours had a significant improvement in time to disease recurrence (4.1 versus 1.8 months).
The findings from this study are published in the Science. The results underline the importance of identifying the molecular profile of tumours and demonstrate the feasibility of using whole-genome sequencing in the clinical setting to identify previously occult biomarkers of drug sensitivity that can aid in the identification of patients most likely to respond to targeted anticancer drugs.
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