Genome Sequencing Identifies a Basis for Everolimus Sensitivity

Iyer, Gopa; Hanrahan, Aphrothiti J.; Milowsky, Matthew I.; Al‐Ahmadie, Hikmat; Scott, Sasinya N.; Janakiraman, Manickam; Pirun, Mono; Sander, Chris; Socci, Nicholas D.; Ostrovnaya, Irina; Viale, Agnès; Heguy, Adriana; Peng, Luke; Chan, Timothy A.; Bochner, Bernard H.; Bajorin, Dean F.; Berger, Michael F.; Taylor, Barry S.; Solit, David B.

doi:10.1126/science.1226344

Cited by 650 publications

(439 citation statements)

References 18 publications

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“…[65][66][67][68] A recent study demonstrated the utility of cancer genomic profiling by linking such mutations in TSC2 to improved survival for UC patients under everolimus treatment. 69 Amplification of RAF1, which has been linked to high-grade tumor, advanced-stage tumor and poor survival in UC, [70][71][72] was also observed in the series, and can be targeted by kinase inhibitors such as Sorafenib, a multikinase inhibitor whose targets include the Raf1 protein (CRAF). Sorafenib has been approved for use in renal cell carcinoma and hepatocellular carcinoma and is under investigation in clinical trials in multiple solid tumor types.…”

Section: Discussionmentioning

confidence: 99%

Advanced urothelial carcinoma: next-generation sequencing reveals diverse genomic alterations and targets of therapy

Wang²,

et al. 2014

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Although urothelial carcinoma (UC) of the urinary bladder generally portends a favorable prognosis, metastatic tumors often follow an aggressive clinical course. DNA was extracted from 40 lm of formalin-fixed, paraffinembedded (FFPE) sections from 35 stage IV UCs that had relapsed and progressed after primary surgery and conventional chemotherapy. Next-generation sequencing (NGS) was performed on hybridization-captured, adaptor ligation-based libraries for 3320 exons of 182 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer to at an average sequencing depth of 1164 Â and evaluated for all classes of genomic alterations (GAs). Actionable GAs were defined as those impacting the selection of targeted anticancer therapies on the market or in registered clinical trials. A total of 139 GAs were identified, with an average of 4.0 GAs per tumor (range 0-10), of which 78 (56%) were considered actionable, with an average of 2.2 per tumor (range 0-7). Twenty-nine (83%) cases harbored at least one actionable GA including: PIK3CA (9 cases; 26%); CDKN2A/B (8 cases; 23%); CCND1 (5 cases; 14%); FGFR1 (5 cases; 14%); CCND3 (4 cases; 11%); FGFR3 (4 cases; 11%); MCL1 (4 cases; 11%); MDM2 (4 cases; 11%); EGFR (2 cases, 6%); ERBB2 (HER2/neu) (2 cases, 6%); NF1 (2 cases, 6%) and TSC1 (2 cases, 6%). Notable additional alterations included TP53 (19 cases, 54%) and RB1 (6 cases; 17%). Genes involved in chromatin modification were altered by nonsense mutation, splice site mutation or frameshift indel in a mutually exclusive manner in nearly half of all cases including KDM6A (10 cases; 29%) and ARID1A (7 cases; 20%). Comprehensive NGS of 35 UCs of the bladder revealed a diverse spectrum of actionable GAs in 83% of cases, which has the potential to inform treatment decisions for patients with relapsed and metastatic disease.

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Section: Discussionmentioning

confidence: 99%

Advanced urothelial carcinoma: next-generation sequencing reveals diverse genomic alterations and targets of therapy

Wang²,

et al. 2014

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“…In agreement with our findings, mutations in TSC1/2 as putative biomarkers that predict efficacy of mTORC1 inhibitors have emerged recently from whole-genome or -exome sequencing analyses of tumor samples from patients who had experienced extraordinary benefit from mTORC1 inhibitor treatments. Solit and colleagues showed that TSC1 loss-of-function mutations were present in one metastatic bladder cancer patient with a durable (>2 years) complete response and four with partial response or stable disease after receiving everolimus, but in only 1 of 9 patients with disease progression (36). Similarly, Voss and colleagues found inactivating mutations in TSC1 or TSC2, or activating mutations in MTOR, in 4 of 6 renal cell carcinoma patients who had durable response to either everolimus or temsirolimus, but not in patients who progressed rapidly on the same treatments (37).…”

Section: Discussionmentioning

confidence: 99%

Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus

Huynh

Hao²,

Chan

et al. 2015

Molecular Cancer Therapeutics

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Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide and hyperactivation of mTOR signaling plays a pivotal role in HCC tumorigenesis. Tuberous sclerosis complex (TSC), a heterodimer of TSC1 and TSC2, functions as a negative regulator of mTOR signaling. In the current study, we discovered that TSC2 loss-of-function is common in HCC. TSC2 loss was found in 4 of 8 HCC cell lines and 8 of 28 (28.6%) patient-derived HCC xenografts. TSC2 mutations and deletions are likely to be the underlying cause of TSC2 loss in HCC cell lines, xenografts, and primary tumors for most cases. We further demonstrated that TSC2-null HCC cell lines and xenografts had elevated mTOR signaling and, more importantly, were significantly more sensitive to RAD001/everolimus, an mTORC1 inhibitor. These preclinical findings led to the analysis of TSC2 status in HCC samples collected in the EVOLVE-1 clinical trial of everolimus using an optimized immunohistochemistry assay and identified 15 of 139 (10.8%) samples with low to undetectable levels of TSC2. Although the sample size is too small for formal statistical analysis, TSC2-null/low tumor patients who received everolimus tended to have longer overall survival than those who received placebo. Finally, we performed an epidemiology survey of more than 239 Asian HCC tumors and found the frequency of TSC2 loss to be approximately 20% in Asian HBV þ HCC. Taken together, our data strongly argue that TSC2 loss is a predictive biomarker for the response to everolimus in HCC patients. Mol Cancer Ther; 14(5); 1224-35. Ó2015 AACR.

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“…This drug failed a phase II trial for metastatic bladder cancer -but one patient's cancer went away and stayed away for more than two years. Researchers at the Memorial Sloan-Kettering Cancer Center in New York subsequently found that about 8% of people with bladder cancer carry a mutation that makes their tumour susceptible to the drug 6 . The US National Cancer Institute is now examining other reports of rare but significant drug responses through its Exceptional Responders programme, which might see some failed drugs put back into development.…”

Section: Disease Redefinedmentioning

confidence: 99%

Clinical trials: More trials, fewer tribulations

Eisenstein¹

2014

Nature

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Genome Sequencing Identifies a Basis for Everolimus Sensitivity

Abstract: Tumor genome sequencing reveals the molecular basis of a patient’s unexpected and dramatic response to a cancer drug.

Cited by 650 publications

References 18 publications

Advanced urothelial carcinoma: next-generation sequencing reveals diverse genomic alterations and targets of therapy

Advanced urothelial carcinoma: next-generation sequencing reveals diverse genomic alterations and targets of therapy

Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus

Clinical trials: More trials, fewer tribulations

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