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Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients.

ABSTRACT: Tumor molecular profiling is a fundamental component of precision oncology, enabling the identification of genomic alterations in genes and pathways that can be targeted therapeutically. The existence of recurrent targetable alterations across distinct histologically defined tumor types, coupled with an expanding portfolio of molecularly targeted therapies, demands flexible and comprehensive approaches to profile clinically relevant genes across the full spectrum of cancers. We established a large-scale, prospective clinical sequencing initiative using a comprehensive assay, MSK-IMPACT, through which we have compiled tumor and matched normal sequence data from a unique cohort of more than 10,000 patients with advanced cancer and available pathological and clinical annotations. Using these data, we identified clinically relevant somatic mutations, novel noncoding alterations, and mutational signatures that were shared by common and rare tumor types. Patients were enrolled on genomically matched clinical trials at a rate of 11%. To enable discovery of novel biomarkers and deeper investigation into rare alterations and tumor types, all results are publicly accessible.

SUBMITTER: Zehir A

PROVIDER: S-EPMC5461196 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients.

Zehir Ahmet A Benayed Ryma R Shah Ronak H RH Syed Aijazuddin A Middha Sumit S Kim Hyunjae R HR Srinivasan Preethi P Gao Jianjiong J Chakravarty Debyani D Devlin Sean M SM Hellmann Matthew D MD Barron David A DA Schram Alison M AM Hameed Meera M Dogan Snjezana S Ross Dara S DS Hechtman Jaclyn F JF DeLair Deborah F DF Yao JinJuan J Mandelker Diana L DL Cheng Donavan T DT Chandramohan Raghu R Mohanty Abhinita S AS Ptashkin Ryan N RN Jayakumaran Gowtham G Prasad Meera M Syed Mustafa H MH Rema Anoop Balakrishnan AB Liu Zhen Y ZY Nafa Khedoudja K Borsu Laetitia L Sadowska Justyna J Casanova Jacklyn J Bacares Ruben R Kiecka Iwona J IJ Razumova Anna A Son Julie B JB Stewart Lisa L Baldi Tessara T Mullaney Kerry A KA Al-Ahmadie Hikmat H Vakiani Efsevia E Abeshouse Adam A AA Penson Alexander V AV Jonsson Philip P Camacho Niedzica N Chang Matthew T MT Won Helen H HH Gross Benjamin E BE Kundra Ritika R Heins Zachary J ZJ Chen Hsiao-Wei HW Phillips Sarah S Zhang Hongxin H Wang Jiaojiao J Ochoa Angelica A Wills Jonathan J Eubank Michael M Thomas Stacy B SB Gardos Stuart M SM Reales Dalicia N DN Galle Jesse J Durany Robert R Cambria Roy R Abida Wassim W Cercek Andrea A Feldman Darren R DR Gounder Mrinal M MM Hakimi A Ari AA Harding James J JJ Iyer Gopa G Janjigian Yelena Y YY Jordan Emmet J EJ Kelly Ciara M CM Lowery Maeve A MA Morris Luc G T LGT Omuro Antonio M AM Raj Nitya N Razavi Pedram P Shoushtari Alexander N AN Shukla Neerav N Soumerai Tara E TE Varghese Anna M AM Yaeger Rona R Coleman Jonathan J Bochner Bernard B Riely Gregory J GJ Saltz Leonard B LB Scher Howard I HI Sabbatini Paul J PJ Robson Mark E ME Klimstra David S DS Taylor Barry S BS Baselga Jose J Schultz Nikolaus N Hyman David M DM Arcila Maria E ME Solit David B DB Ladanyi Marc M Berger Michael F MF

Nature medicine 20170508 6

Tumor molecular profiling is a fundamental component of precision oncology, enabling the identification of genomic alterations in genes and pathways that can be targeted therapeutically. The existence of recurrent targetable alterations across distinct histologically defined tumor types, coupled with an expanding portfolio of molecularly targeted therapies, demands flexible and comprehensive approaches to profile clinically relevant genes across the full spectrum of cancers. We established a lar ...[more]

PMID: 28481359

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Project description:BackgroundEmerging data suggest that metastasis is a spectrum of disease burden rather than a binary state, and local therapies, such as radiation, might improve outcomes in oligometastasis. However, current definitions of oligometastasis are solely numerical.ObjectiveTo characterize the somatic mutational landscape across the disease spectrum of metastatic castration-sensitive prostate cancer (mCSPC) to elucidate a biological definition of oligometastatic CSPC.Design, setting, and participantsThis was a retrospective study of men with mCSPC who underwent clinical-grade sequencing of their tumors (269 primary tumor, 25 metastatic sites). Patients were classified as having biochemically recurrent (ie, micrometastatic), metachronous oligometastatic (≤5 lesions), metachronous polymetastatic (>5 lesions), or de novo metastatic (metastasis at diagnosis) disease.Outcome measurements and statistical analysisWe measured the frequency of driver mutations across metastatic classifications and the genomic associations with radiographic progression-free survival (rPFS) and time to castrate-resistant prostate cancer (CRPC).Results and limitationsThe frequency of driver mutations in TP53 (p = 0.01), WNT (p = 0.08), and cell cycle (p = 0.04) genes increased across the mCSPC spectrum. TP53 mutation was associated with shorter rPFS (26.7 vs 48.6 mo; p = 0.002), and time to CRPC (95.6 vs 155.8 mo; p = 0.02) in men with oligometastasis, and identified men with polymetastasis with better rPFS (TP53 wild-type, 42.7 mo; TP53 mutated, 18.5 mo; p = 0.01). Mutations in TP53 (incidence rate ratio [IRR] 1.45; p = 0.004) and DNA double-strand break repair (IRR 1.61; p < 0.001) were associated with a higher number of metastases. Mutations in TP53 were also independently associated with shorter rPFS (hazard ratio [HR] 1.59; p = 0.03) and the development of CRPC (HR 1.71; p = 0.01) on multivariable analysis. This study was limited by its retrospective nature, sample size, and the use of commercially available sequencing platforms, resulting in a limited predefined set of genes examined.ConclusionsSomatic mutational profiles reveal a spectrum of metastatic biology that helps in redefining oligometastasis beyond a simple binary state of lesion enumeration.Patient summaryOligometastatic prostate cancer is typically defined as less than three to five metastatic lesions and evidence suggests that using radiation or surgery to treat these sites improves clinical outcomes. As of now, treatment decisions for oligometastasis are solely defined according to the number of lesions. However, this study suggests that tumor mutational profiles can provide a biological definition of oligometastasis and complement currently used numerical definitions.

Dataset Information

Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients.

Publications

Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients.

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