Comprehensive Genomic Profiling of Carcinoma of Unknown Primary Site

Ross, Jeffrey S.; Wang, Kai; Otto, Geoff; White, Emily; Iwanik, Kiel; Palmer, Gary A.; Yelensky, Roman; Lipson, Doron; Chmielecki, Juliann; Erlich, Rachel; Rankin, Andrew; Ali, Siraj M.; Elvin, Julia A.; Morosini, Deborah; Miller, Vincent A.; Stephens, Philip J.

doi:10.1001/jamaoncol.2014.216

Cited by 215 publications

(252 citation statements)

References 56 publications

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“…The most frequent alterations were in the TP53 gene; these alterations were detected in 37.1% of cases, followed by aberrations in KRAS (18.6%), and PIK3CA (15.4%). These results are consistent with previous reports of approximate frequencies of gene alterations in tissue samples from CUP patients (15,16) (Supplemental Figure 6). …”

Section: Discussionsupporting

confidence: 93%

“…Further understanding of the underlying genomic alterations among patients with CUP may also prove useful. Previous studies using archival tumor tissues of CUP patients found that TP53 (38–55%), KRAS (18–20%), CDKN2A (19%), MYC (12%), ARID1A (11%) and PIK3CA (9–14%) were frequently altered as assessed by targeted next-generation sequencing (NGS) (15,16). Although genomic sequencing is generally done on archival cancer samples, limitations with the use of tissues include intra-tumor genomic heterogeneity (17) as well as the dynamic mutational processes that can occur along with therapeutic intervention (18).…”

Section: Introductionmentioning

confidence: 99%

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Utility of Genomic Analysis In Circulating Tumor DNA from Patients with Carcinoma of Unknown Primary

et al. 2017

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Carcinoma of unknown primary (CUP) is a rare and difficult-to-treat malignancy, the management of which might be improved by the identification of actionable driver mutations. We interrogated interrogated 54–70 genes in 442 patients with CUP using targeted clinical-grade, next-generation sequencing (NGS) of circulating tumor DNA (ctDNA). Overall, 80% of patients exhibited ctDNA alterations; 66%, ≥ 1 characterized alteration(s) excluding variants of unknown significance. TP53-associated genes were most commonly altered (37.8%) followed by genes involved in the MAPK pathway (31.2%), PI3K signaling (18.1%) and the cell cycle machinery (10.4%). Distinct genomic profiles were observed in 87.9% of CUP cases with 99.7% exhibiting potentially targetable alterations. An illustrative patient with dynamic changes in ctDNA content during therapy and a responder given a checkpoint inhibitor-based regimen because of a mismatch repair gene anomaly are presented. Our results demonstrate that ctDNA evaluation is feasible in CUP and that most patients harbor a unique somatic profile with pharmacologically actionable alterations, justifying the inclusion of non-invasive liquid biopsies in next-generation clinical trials.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Utility of Genomic Analysis In Circulating Tumor DNA from Patients with Carcinoma of Unknown Primary

et al. 2017

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“…Recent comprehensive genomic profiling of 200 CUP specimens revealed targetable genetic alterations presented in 96% of patients 9. The authors furthermore described two patients for whom targeted therapies selected on the basis of the tumour genomic profile—a MET amplification and EML4-ALK fusion, respectively—led to sustained complete responses on crizotinib.…”

Section: Discussionmentioning

confidence: 99%

Genomic characterisation of two cancers of unknown primary cases supports a kidney cancer origin

Wei

Chen

Hsieh³

2015

BMJ Case Reports

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Cancer of unknown primary (CUP) comprises of 3–5% of new cancer diagnoses in the USA. Diagnostic work up typically includes CT of the chest, abdomen and pelvis, and histopathological review of tissue specimens. These measures are neither sensitive nor specific in determining tissue of origin (ToO) of primary tumours and, therefore, are unable to guide therapy. We present two cases of CUP for which we utilised ultra-deep genomic sequencing to identify the candidate ToO and to propose treatment. Patient 1 presented with metastases involving the lung, lymph nodes and bone. Patient 2 presented with an acute pathological fracture of the T7 vertebral body and metastases involving the bone, lymph nodes and soft tissue. No primary renal mass was found. Sequencing revealed SETD2 and NF2 mutations, and heterozygous loss of the short arm of chromosome 3 (3p). Mutations in conjunction with clinicopathological features strongly support a diagnosis of renal cell carcinoma. Both patients initially responded to mTORC1 inhibition therapy.

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“…• Carcinoma escamocelular metastásico de cuello que frecuentemente se manifiesta con adenopatía cervical (2) HER2 (1, 2) EGFR, (2,21) C kit (1) PDGFR (1) BCL2 (2,8) KRAS (22) p53 (1,8,23) c-Met (1,24) pMAPK (25) Notch 3 (25), PTEN (22,25) pAKT, pRPS6 (25), p21 (25) TIMP-1,(2, 10), MMP2, 9 (1, 2, 10) E-cadherina (25) EMT (25) kiSS1 (2) VEGF (1, 2, 8, 10)…”

Section: Clasificaciónmentioning

confidence: 99%

Cáncer metastásico con primario desconocido. Una revisión

Rodríguez

Regino

Grosso

2018

Rev. Colomb. Gastroenterol.

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ResumenEl tumor metastásico no siempre tiene un origen evidente, hasta en un tercio de los casos nunca se encuentra el tumor primario. Este artículo es una guía de los avances más recientes para mejorar el enfoque diagnóstico y el manejo del paciente con este tumor fatal y frecuente. El objetivo de este artículo, además de ser una guía, es ayudar a evitar errores comunes y graves. Uno de los errores más importantes es no tener en cuenta el papel fundamental de la confirmación histológica, pues esta puede evitar investigaciones innecesarias.En el artículo también se detallan los componentes de la evaluación estándar, la clasificación según su pronóstico y las indicaciones de la evaluación secundaria, que incluye las indicaciones de la endoscopia alta y baja, los marcadores tumorales, la tomografía por emisión de positrones (TEP), el papel que ocupa el perfil genético, la epigenética y el ácido desoxirribonucleico (ADN) viral. Adicionalmente, se indica el momento en que se debe detener la investigación. Recientemente, el tratamiento se ha modificado, lo que parece cambiar la historia de estos pacientes y de sus contrapartes con primario conocido. Palabras claveTumor metastásico, primario desconocido, cáncer. AbstractMetastatic tumors do not always have obvious origins: in one third of these cases, the primary tumor is never found. This article is a guide to the most recent advances in diagnostic approaches and patient management of these fatal and frequent tumors. An additional objective of this article is to help avoid common and serious errors. One of the most important errors is not taking the fundamental role of histological confirmation into account since it can avoid unnecessary investigations.The article also details the components of a standard evaluation, classification according to prognosis and indications for a secondary evaluation. These include indications for upper and lower endoscopy, tumor markers, positron emission tomography, and the roles of genetic profiling, epigenetics and viral DNA. It also indicates the moment at which an investigation should be stopped. Recently, treatment has changed, and these changes seems to have changed the history of these patients and their counterparts with known primary tumors.

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Comprehensive Genomic Profiling of Carcinoma of Unknown Primary Site

Cited by 215 publications

References 56 publications

Utility of Genomic Analysis In Circulating Tumor DNA from Patients with Carcinoma of Unknown Primary

Utility of Genomic Analysis In Circulating Tumor DNA from Patients with Carcinoma of Unknown Primary

Genomic characterisation of two cancers of unknown primary cases supports a kidney cancer origin

Cáncer metastásico con primario desconocido. Una revisión

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