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the UK without strong supportive evidence. In 2006, NICE recommended against bortezomib use in the UK based mainly on a lack of appropriate comparative trials and cost at that time; the drug was only approved 3 years later. To have an opportunity to gain access to ixazomib in the UK, appropriate comparator trials must be done to avoid a repetition of the 2006 NICE rejection of bortezomib. Guy Pratt School of Cancer Sciences, University of Birmingham, Edgbaston, Birmingham, UK; and Department of Haematology, Birmingham Heartlands Hospital, Birmingham, B9 5SS, UK [email protected]

I have served on a medical advisory board for Takeda UK Ltd. 1

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Kumar SK, Dispenzieri A, Lacy MQ, et al. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia 2014; 28: 455–73. Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood 2010; 116: 679–86. Kortuem KM, Stewart AK. Carfilzomib. Blood 2013; 121: 893–97. Kumar SK, Berdeja JG, Niesvizky R, et al. Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study. Lancet Oncol 2014; published online Nov 14. http://dx.doi.org/10.1016/S1470-2045(14)71125-8. Palumbo A, Bringhen S, Ludwig H, Dimopoulos MA, Blade J, Mateos MV, et al. Personalized therapy in multiple myeloma according to patient age and vulnerability: a report of the European Myeloma Network (EMN). Blood 2011; 118: 4519–29.

Living Art Enterprises/Science Photo Library

The mTOR inhibitor revolution rolls on

Published Online November 10, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)71101-5 See Articles page 1513

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In The Lancet Oncology, David Franz and colleagues1 report findings from the latest in a series of studies of mTOR inhibitors in individuals who have tuberous sclerosis complex (TSC). TSC is genetic, affecting 1 million people worldwide, and characterised by formation of hamartomatous growths throughout the body. Benign tumours in the brain result in seizures, developmental delay, and intellectual disability and a neuropsychiatric phenotype that incudes autism (roughly 50% of affected individuals), attention-deficit hyperactivity disorder, anxiety, and mood disorders. Outside the CNS, other morbidities are associated with renal tumours (angiomyolipomas) and cysts, and lung tumours (lymphangioleiomyomatosis).2 20 years ago, the underlying molecular abnormalities were unknown and, thus, the only available therapies treated symptoms. Once investigators discovered the causative genes (TSC1 and TSC2),3,4 an opportunity existed to establish their cellular function. In 2001, researchers working with drosophilia5,6 reported that tuberin and hamartin, the TSC2 and TSC2 gene products, respectively, form a dimeric protein complex so-called master switch, modulating the mTOR pathway to control cell growth and division. Franz and colleagues7 started the revolution in treatment of patients with TSC by reporting the first case series of successful treatment for TSC-associated brain tumours in 2006. The Article in The Lancet Oncology is an interim analysis of the extension phase of the first large randomised controlled trial (EXIST-1) in treatment of subependymal

giant cell astrocytomas (SEGA), which affect roughly 20% of patients with TSC.8 SEGAs can block the foramen of Monro, leading to hydrocephalus and herniation without intervention. Before mTOR inhibitors were developed, neurosurgery, with all of its inherent risks, was the only option for treatment. Findings from the primary report of EXIST-18 proved efficacy for mTOR inhibitors (everolimus), more than 35% of patients having at least a 50% reduction on SEGA volume after 9·6 months. However questions remained about longterm efficacy and side-effect profile, and whether its mechanism of action would have negative effects on growth in children who opt for medical rather than surgical treatment. The current Article by Franz and colleagues aimed to address these questions and showed that clinically meaningful reductions in SEGA volume are maintained over time—treatment at the time of the analysis had been continued for a median time of 28·3 months (IQR 19·3–33·0). Volume was reduced by 50% in 39 (37%) of 105 patients at 24 weeks and 36 (47%) of 76 patients at 96 weeks. Similarly, adverse events appeared to decrease over time. Lastly, the authors noted no growth issues in children. The investigators reported amenorrhoea in five (18%) of 28 women and girls aged 10−55 years treated with everolimus. This event has been reported in this and other trials and most commonly spontaneously resolves (only one case did not resolve in the trial). I personally remain uncertain as to the contribution made by mTOR inhibitors to this adverse event. The effects of www.thelancet.com/oncology Vol 15 December 2014

Comment

TSC on the endocrine system are not yet understood,9 and TSC might cause amenorrhea independently. This relationship needs to be assessed. Finally, the authors mention the benefits of oral mTOR inhibitors for patients with TSC that are not addressed by this analysis. mTOR inhibitors are efficacious for renal angiomyolipomas and lymphangioleimyomatosis,10,11 and there are continuing and completed studies in patients with TSC to assess oral mTOR inhibitors for intractable epilepsy (EXIST-3; NCT01713946) and cognition (TRON; NCT01954693) and topical mTOR inhibitors for disfiguring facial angiofibromas (TREATMENT; NCT01526356). Surgical interventions for SEGAs do not offer these positive sideeffects in the rest of the body. With the recent promise shown by mTOR inhibitors to help neural connectivity and the fairly minor negative side-effect profile, the drugs might soon be prescribed to patients with TSC for indications other than tumour shrinkage. The mTOR inhibitor revolution rolls on… Hope Northrup Division of Medical Genetics, Department of Pediatrics, The University of Texas Medical School at Houston, Houston, TX 77030, USA [email protected]

I declare honoraria and payment of travel expenses from Novartis for speaking at the TSC Days Conference in Dublin, Ireland; Sept 12–13, 2014. 1

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Franz DN, Belousova E, Sparagana S, et al. Everolimus for subependymal giant cell astrocytoma in patients with tuberous sclerosis complex: 2-year open-label extension of the randomised EXIST-1 study. Lancet Oncol 2014; published online Nov 10. http://dx.doi.org/10.1016/S14702045(14)70489-9. Northrup H, Koenig MK, Au KS. Tuberous sclerosis complex. In: Pagon RA, Bird TD, Dolan CR, et al, eds. GeneReviews. Medical Genetics Information Resource. Seattle: University of Washington, 2011. van Slegtenhorst M, de Hoogt R, Hermans C, et al. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 1997; 277: 805–08. The European Chromosome 16 Tuberous Sclerosis Consortium. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 1993; 75: 1305–15. Potter CJ, Huang H, Xu T. Drosophila Tsc1 functions with Tsc2 to antagonize insulin signaling in regulating cell growth, cell proliferation, and organ size. Cell 2001; 105: 357–68. Tapon N, Ito N, Dickson BJ, Treisman JE, Hariharan IK. The drosophila tuberous sclerosis complex gene homologs restrict cell growth and cell proliferation. Cell 2001; 105: 345–55. Franz DN, Leonard J, Tudor C, et al. Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann Neurol 2006; 59: 490–98. Franz DN, Belousova E, Sparagana S, et al. Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicenter, randomized, placebo-controlled phase 3 trial. Lancet 2013; 381: 125–32. Gabitzsch EK, Hashmi SS, Koenig MK, et al. Self-reported reproductive health in women with tuberous sclerosis complex. Genet Med 2013; 15: 966–71. Bissler JJ, McCormack FX, Young LR, et al. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med 2008; 358: 140–51. McCormack FX, Inoue Y, Moss J, et al, for the National Institutes of Health Rare Lung Diseases Consortium and the MILES Trial Group. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med 2011; 364: 1595–606.

In The Lancet Oncology, Emilie Lalonde and colleagues’ retrospective cohort analysis1 assesses genomics, genomic instability, and hypoxia as predictors of recurrence in men with localised prostate cancer. Recurrence was measured mainly on the basis of recurrence and progression of prostate-specific antigen by standard definitions after either radiotherapy or surgery. The investigators controlled for pretreatment prostate-specific antigen, Gleason score, and T stage. Their results suggest that genomic signatures or measures of genomic instability have independent value in prediction of biochemical (prostate-specific antigen) relapse and clinical metastasis in patients with localised prostate cancer. The addition of tumour hypoxia measures to genomic data refined prediction of www.thelancet.com/oncology Vol 15 December 2014

recurrence when the investigators controlled for clinical covariates. Hypoxia was not associated with a specific genomic signature, suggesting that it is caused by epigenetic factors that determine the microenvironment of a tumour. Although the mechanisms by which hypoxia leads to radiation resistance can be reasonably assumed, the mechanism for an association between hypoxia in tumour tissue and biochemical recurrence after surgery is far less clear. Genetic aberrations driving both hypoxia and cancer progression could be an explanation, but in this study there was no association between genomic alterations and hypoxia. As such, the work in Lalonde and colleagues’ study is novel in that it shows that cancer aggression is driven not only by genome instability and mutations, but also by tissue hypoxia.

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Chromoplexy and hypoxic microenvironment drives prostate cancer

Published Online November 13, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)71114-3 See Articles page 1521

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The mTOR inhibitor revolution rolls on.

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