Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine.
Andrew J AguirreJonathan A NowakNicholas D CamardaRichard A MoffittArezou A GhazaniMehlika Hazar-RethinamSrivatsan RaghavanJaegil KimLauren K BraisDorisanne RagonMarisa W WelchEmma ReillyDevin McCabeLori MariniKristin AnderkaKarla HelvieNelly OliverAna BabicAnnacarolina Da SilvaBrandon NadresEmily E Van SeventerHeather A ShahzadeJoseph P St PierreKelly P BurkeThomas ClancyJames M ClearyLeona A DoyleKunal JajooNadine J McClearyJeffrey A MeyerhardtJanet E MurphyKimmie NgAnuj K PatelKimberly PerezMichael H RosenthalDouglas A RubinsonMarvin RyouGeoffrey I ShapiroEwa SicinskaStuart G SilvermanRebecca J NagyRichard B LanmanDeborah KnoerzerDean J WelschMatthew B YurgelunCharles S FuchsLevi A GarrawayGad GetzJason L HornickBruce E JohnsonMatthew H KulkeRobert J MayerJeffrey W MillerPaul B ShynDavid A TuvesonNikhil WagleJen Jen YehWilliam C HahnRyan B CorcoranScott L CarterBrian M WolpinPublished in: Cancer discovery (2018)
Clinically relevant subtypes exist for pancreatic ductal adenocarcinoma (PDAC), but molecular characterization is not yet standard in clinical care. We implemented a biopsy protocol to perform time-sensitive whole-exome sequencing and RNA sequencing for patients with advanced PDAC. Therapeutically relevant genomic alterations were identified in 48% (34/71) and pathogenic/likely pathogenic germline alterations in 18% (13/71) of patients. Overall, 30% (21/71) of enrolled patients experienced a change in clinical management as a result of genomic data. Twenty-six patients had germline and/or somatic alterations in DNA-damage repair genes, and 5 additional patients had mutational signatures of homologous recombination deficiency but no identified causal genomic alteration. Two patients had oncogenic in-frame BRAF deletions, and we report the first clinical evidence that this alteration confers sensitivity to MAPK pathway inhibition. Moreover, we identified tumor/stroma gene expression signatures with clinical relevance. Collectively, these data demonstrate the feasibility and value of real-time genomic characterization of advanced PDAC.Significance: Molecular analyses of metastatic PDAC tumors are challenging due to the heterogeneous cellular composition of biopsy specimens and rapid progression of the disease. Using an integrated multidisciplinary biopsy program, we demonstrate that real-time genomic characterization of advanced PDAC can identify clinically relevant alterations that inform management of this difficult disease. Cancer Discov; 8(9); 1096-111. ©2018 AACR.See related commentary by Collisson, p. 1062This article is highlighted in the In This Issue feature, p. 1047.
Keyphrases
- end stage renal disease
- gene expression
- dna damage
- ejection fraction
- chronic kidney disease
- newly diagnosed
- prognostic factors
- squamous cell carcinoma
- copy number
- randomized controlled trial
- dna repair
- small cell lung cancer
- dna methylation
- healthcare
- palliative care
- patient reported outcomes
- machine learning
- electronic health record
- quantum dots
- patient reported
- cell proliferation
- artificial intelligence