Systematic Evaluation of the Prognostic Impact and Intratumour Heterogeneity of Clear Cell Renal Cell Carcinoma Biomarkers

Gulati, Sakshi; Martinez, Pierre; Joshi, Tejal; Birkbak, Nicolai J.; Santos, Cláudio R.; Rowan, Andrew; Pickering, Lisa; Gore, Martin; Larkin, James; Szállási, Zoltán; Bates, Paul A.; Swanton, Charles; Gerlinger, Marco

doi:10.1016/j.eururo.2014.06.053

Cited by 151 publications

(144 citation statements)

References 37 publications

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“…And if there is variability, it is unknown how it would influence clinical outcome. The use of miRNAs as predictive markers in ccRCC is further supported by the fact that an mRNA gene-expression signature affected by intratumor heterogeneity has been shown to outperform genetic biomarkers for the prediction of ccRCC cancer-specific survival and to add prognostic information to tumor stage and SSIGN prognostic model (42,43).…”

Section: Discussionmentioning

confidence: 94%

Deep sequencing reveals microRNAs predictive of antiangiogenic drug response

García-Donás¹,

Beuselinck²,

Inglada-Pérez³

et al. 2016

JCI Insight

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Section: Discussionmentioning

confidence: 94%

Deep sequencing reveals microRNAs predictive of antiangiogenic drug response

García-Donás¹,

Beuselinck²,

Inglada-Pérez³

et al. 2016

JCI Insight

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“…Although this makes intuitive sense, we recognize that therapeutically targeting a clonally dominant, truncal driver has not yet been shown to be a more effective drug development strategy ( 9 ). If important for treatment decisions, quantifi cation of this heterogeneity and clonality could have a major impact in the development of companion diagnostics for genotypespecifi c drugs ( 10 ). Of note, the Deciphering Anti-tumor Response With Intratumor Heterogeneity (DARWIN) trial will test whether targeting a clonally dominant driver event results in a better outcome compared with targeting the same driver mutation when present subclonally.…”

Section: See Related Article By Brastianos and Colleagues P 1164 (2)mentioning

confidence: 99%

Drug-Resistant Brain Metastases: A Role for Pharmacology, Tumor Evolution, and Too-Late Therapy

Stricker

Arteaga

2015

Cancer Discovery

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Summary :Two recent studies report deep molecular profi ling of matched brain metastases and primary tumors. In both studies, somatic alterations in the brain metastases were frequently discordant with those in the primary tumor, suggesting divergent evolution at metastatic sites and raising questions about the use of biomarkers in patients in clinical trials with targeted therapies. Cancer Discov; 5(11); 1124-6See related article by Brastianos and colleagues, p. 1164 (2).Brain metastases are one of the most deadly complications of malignancy, and their treatment remains diffi cult. Two recent articles in Cancer Discovery report deep molecular profi ling of matched brain metastases and primary tumors. The fi rst study by Paik and colleagues ( 1 ) of 79 stage IV squamous cell lung cancers (SqCLC) used exon capture/next-generation sequencing (NGS) and identifi ed two major subtypes: tumors with FGFR1 amplifi cation and tumors with alterations in the PI3K pathway, comprising PIK3CA mutations and loss of the tumor suppressor PTEN . In total, 61% of patients' tumors harbored a somatic alteration in either FGFR or the PI3K pathway, aberrations both potentially targetable with drugs in clinical development. Primary cancers that gave rise to brain metastases exhibited truncal loss of PTEN . There were no clonal differences in PTEN loss or PIK3CA mutations between primary tumors and brain metastases. Interestingly, patients with SqCLC with alterations in the PI3K pathway exhibited a higher metastatic burden and incidence of brain metastases and, importantly, a strikingly shorter overall survival compared with patients without these aberrations. In the second study, in this issue of Cancer Discovery , Brastianos and colleagues ( 2 ) performed whole-exome sequencing (WES) of 86 matched brain metastases and primary tumors, mainly breast, lung, and renal cell cancers. Fifty-three percent of brain metastases harbored somatic alterations not detected in the matched primary tumor, many of them associated with sensitivity to targeted therapies either approved or in development.Temporally and spatially distinct brain metastases from the same patients were genetically homogenous, whereas extracranial metastases were highly divergent from brain metastases. Using computational methods that integrate somatic mutations and copy-number alterations to estimate the cancer cell fraction harboring each mutation, the authors identifi ed branched evolution in all clonally related matched biopsies, where all metastatic and primary tumor sites share a common ancestor yet continue to evolve independently. Indeed, both of these studies showed that brain metastases and their matched primary tumor are clonally related, yet genetically diverse. In Paik and colleagues (1), trios (brain metastasis, primary tumor, and normal tissue) from 6 patients with SqCLC were subjected to WES. Brastianos and colleagues (2) interrogated DNA from 86 trios, also with WES. Mutations for the primary and metastases were identifi ed separately by comparison with the mat...

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“…12,13 This largely limits the utility of prognostic impact of biomarkers and, in addition, spatial variation in genetic and phenotypic properties poses a significant obstacle for optimal personalized treatment. 14 …”

Section: Intratumoral Heterogeneitymentioning

confidence: 99%

Moving beyond vascular endothelial growth factor-targeted therapy in renal cell cancer: latest evidence and therapeutic implications

Tsao

Liaw

et al. 2017

Ther Adv Med Oncol

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Renal cell cancer (RCC) continues to be among the most lethal malignancies in the USA. Introduction of anti-vascular epidermal growth factor receptor tyrosine kinase inhibitors over a decade ago resulted in improvement in disease outcomes, but further development of new therapies largely stagnated for many years. More recently, a better understanding of disease biology and treatment-resistance patterns has led to a second renaissance in drug development, with the anti-programmed cell death protein 1 immune checkpoint inhibitor, nivolumab, paving the way for additional therapies entering clinical trial testing in the treatment of RCC.

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Systematic Evaluation of the Prognostic Impact and Intratumour Heterogeneity of Clear Cell Renal Cell Carcinoma Biomarkers

Cited by 151 publications

References 37 publications

Deep sequencing reveals microRNAs predictive of antiangiogenic drug response

Deep sequencing reveals microRNAs predictive of antiangiogenic drug response

Drug-Resistant Brain Metastases: A Role for Pharmacology, Tumor Evolution, and Too-Late Therapy

Moving beyond vascular endothelial growth factor-targeted therapy in renal cell cancer: latest evidence and therapeutic implications

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