Re: Genome Sequencing Identifies a Basis for EverolimusSensitivity

Iyer G, Hanrahan AJ, Milowsky MI, et al.

Science 2012;338:221

Expert’s summary

Iyer et al. used whole-genome sequencing to investigate the

genetic basis of a durable remission of metastatic bladder

cancer in a patient treated with everolimus, a well-known

mammalian target of rapamycin (mTOR) inhibitor. They ob-

served a somatic mutation with loss of function in tuberous

sclerosis 1 (TSC1), a regulator of mTOR pathway activation.

TSC1 mutations were found in a minority (8%) of 109

additional bladder cancers examined but correlated with

everolimus sensitivity. The other mutation revealed by this

high-throughput technology was a loss-of-function mutation

in neurofibromin 2 (NF2), which is also amenable to mTOR

inhibition. The authors concluded that their results demon-

strate the feasibility of using whole-genome sequencing in the

clinical setting for personalized care.

Expert’s comments

Physicians treating cancer have always observed major differ-

ences in response to treatment among their patients. Many

‘‘failed’’ trials based on statistics analyzing an entire cohort of

patients treated ‘‘blindly’’ by a targeted therapy might have

yielded more positive results if only the subset of patients

likely to respond had been treated rather than using the ‘‘one

size fits all’’ paradigm. This is the concept of personalized or

precision medicine, namely, inducing dramatic responses using

cancer drugs in a small minority of patients likely to respond

rather than targeting all patients, thus stratifying patients and

their cancer into molecular subtypes and treating them with

subtype-specific targeted drugs.

Two approaches that complement each other as they take

advantage of our improved molecular and genetic under-

standing of cancer are gaining traction to improve drug

efficacy. One is drug ‘‘repositioning,’’ which aims to find new

uses for existing drugs, and the other is personalized

medicine, which aims to give the right therapy to the right

individual patient based on his or her tumor profiling.

Next-generation sequencing technologies have revolu-

tionized and accelerated our knowledge of genetic variation

among individuals and have dramatically broadened our

understanding of cancer. They represent a quantum

advance in our ability to decipher cancer at the genetic

level and have unraveled a previously unsuspected wealth

of information, helping to further grasp the complexity of

cancer biology and disease subsets.

The heterogeneity of genomic instability in human

cancers confers a broad range of advantageous growth and

invasive qualities. Somatic genomic alterations contribute to

cancer by altering the function of genes or pathways that are

important for tumor growth, metastasis, and resistance to

therapies. As such, mutation mapping has the potential to

unravel key genes involved in discriminating between

different tumor subsets and to unravel potential and, at

times, unsuspected therapeutic targets.

A report published in 2012 in the journal Science nicely

illustrates how retrospective genetic analysis of tumors

(ie, bladder cancer) from occasional responders in a clinical

trial can provide valuable information about the subset of

patients that can be effectively targeted by a specific drug.

Iyer and collaborators from the human oncology and

pathogenesis program group at Memorial Sloan-Kettering

Cancer Center, in collaboration with urologist Bernie

Bochner and medical oncologist Dean Bajorin, looked back

at the results of a phase 2 clinical trial assessing the mTOR

inhibitor everolimus as a single agent in the treatment of

progressive metastatic bladder cancer. Although the trial was

deemed a failure, they noticed that one patient presented

with a complete response to the drug. They hypothesized that

a specific genetic lesion within this patient’s tumor might

be responsible for such response.

They performed whole-genome DNA sequencing of the

tumor from this patient in this trial who had achieved a

complete response and maintained the response for >2 yr.

The massive parallel sequencing technology revealed loss-

of-function mutations in TSC1 and NF2. The TSC1 gene is

mutated in a minority of bladder tumors, and mutation of

NF2 is even more rare [1,2]. Mutations in these genes,

however, are of therapeutic interest because they have been

shown to inhibit mTOR signaling, suggesting that tumors

harboring these mutations might be sensitive to treatment

with mTOR-inhibiting agents like everolimus.

Analysis of tumors from additional patients treated in

this trial showed that the presence of these mutations was

associated with a longer time to disease recurrence. This

landmark paper demonstrates the importance of elucidat-

ing the genetic make-up of tumors for drug repositioning

and personalized care.

As Iyer et al. conclude, single-patient anecdotes are often

dismissed, but in the area of personalized medicine and

high-throughput technologies, we should start paying more

attention to the exception and the unusual rather than

always looking for the rule.

Conflicts of interest: The author has nothing to disclose.

References

[1] Platt FM, Hurst CD, Taylor CF, Gregory WM, Harnden P, Knowles

MA. Spectrum of phosphatidylinositol 3-kinase pathway gene

alterations in bladder cancer. Clin Cancer Res 2009;15:6008–17.

[2] Guo Y, Chekaluk Y, Zhang J, et al. TSC1 involvement in bladder cancer:

diverse effects and therapeutic implications. J Pathol 2013;230:

17–27.

Alexandre R. Zlotta

Division of Urology, Department of Surgery, University of Toronto,

Toronto, Canada

E-mail address: azlotta@mtsinai.on.ca.

http://dx.doi.org/10.1016/j.eururo.2013.06.031

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