TY - JOUR
T1 - Clinical actionability of comprehensive genomic profiling for management of rare or refractory cancers
AU - Hirshfield, Kim M.
AU - Tolkunov, Denis
AU - Zhong, Hua
AU - Ali, Siraj M.
AU - Stein, Mark N.
AU - Murphy, Susan
AU - Vig, Hetal
AU - Vazquez, Alexei
AU - Glod, John
AU - Moss, Rebecca A.
AU - Belyi, Vladimir
AU - Chan, Chang S.
AU - Chen, Suzie
AU - Goodell, Lauri
AU - Foran, David
AU - Yelensky, Roman
AU - Palma, Norma A.
AU - Sun, James X.
AU - Miller, Vincent A.
AU - Stephens, Philip J.
AU - Ross, Jeffrey S.
AU - Kaufman, Howard
AU - Poplin, Elizabeth
AU - Mehnert, Janice
AU - Tan, Antoinette R.
AU - Bertino, Joseph R.
AU - Aisner, Joseph
AU - DiPaola, Robert S.
AU - Rodriguez-Rodriguez, Lorna
AU - Ganesan, Shridar
N1 - Publisher Copyright:
© AlphaMed Press 2016.
PY - 2016/11
Y1 - 2016/11
N2 - Background. The frequency with which targeted tumor sequencing results will lead to implemented change in care is unclear. Prospective assessment of the feasibility and limitations of using genomic sequencing is critically important. Methods. A prospective clinical study was conducted on 100 patients with diverse-histology, rare, or poor-prognosis cancers to evaluate the clinical actionability of a Clinical Laboratory Improvement Amendments (CLIA)-certified, comprehensive genomic profiling assay (FoundationOne), using formalin-fixed, paraffin-embedded tumors. The primary objectives were to assess utility, feasibility, and limitations of genomic sequencing for genomically guided therapy or other clinical purpose in the setting of a multidisciplinary molecular tumor board. Results. Of the tumors from the 92 patients with sufficient tissue,88(96%)hadat leastonegenomic alteration(average3.6, range 0–10). Commonly altered pathways included p53 (46%), RAS/RAF/MAPK(rat sarcoma; rapidly acceleratedfibrosarcoma; mitogen-activated protein kinase) (45%), receptor tyrosine kinases/ligand (44%), PI3K/AKT/mTOR (phosphatidylinositol- 4,5-bisphosphate 3-kinase; protein kinase B;mammalian target of rapamycin) (35%), transcriptionfactors/regulators (31%), and cell cycle regulators (30%). Many low frequency but potentially actionable alterationswere identifiedin diverse histologies. Use of comprehensive profiling led to implementable clinical action in 35% of tumors with genomic alterations, including genomically guided therapy, diagnostic modification, and trigger for germline genetic testing. Conclusion. Use of targeted next-generation sequencing in the setting of an institutional molecular tumor board led to implementable clinical action in more than one third of patients with rare and poor-prognosis cancers. Major barriers to implementation of genomically guided therapywereclinical statusof the patient and drug access. Early and serial sequencing in the clinical course and expanded access to genomically guided early-phase clinical trials and targeted agents may increase actionability.
AB - Background. The frequency with which targeted tumor sequencing results will lead to implemented change in care is unclear. Prospective assessment of the feasibility and limitations of using genomic sequencing is critically important. Methods. A prospective clinical study was conducted on 100 patients with diverse-histology, rare, or poor-prognosis cancers to evaluate the clinical actionability of a Clinical Laboratory Improvement Amendments (CLIA)-certified, comprehensive genomic profiling assay (FoundationOne), using formalin-fixed, paraffin-embedded tumors. The primary objectives were to assess utility, feasibility, and limitations of genomic sequencing for genomically guided therapy or other clinical purpose in the setting of a multidisciplinary molecular tumor board. Results. Of the tumors from the 92 patients with sufficient tissue,88(96%)hadat leastonegenomic alteration(average3.6, range 0–10). Commonly altered pathways included p53 (46%), RAS/RAF/MAPK(rat sarcoma; rapidly acceleratedfibrosarcoma; mitogen-activated protein kinase) (45%), receptor tyrosine kinases/ligand (44%), PI3K/AKT/mTOR (phosphatidylinositol- 4,5-bisphosphate 3-kinase; protein kinase B;mammalian target of rapamycin) (35%), transcriptionfactors/regulators (31%), and cell cycle regulators (30%). Many low frequency but potentially actionable alterationswere identifiedin diverse histologies. Use of comprehensive profiling led to implementable clinical action in 35% of tumors with genomic alterations, including genomically guided therapy, diagnostic modification, and trigger for germline genetic testing. Conclusion. Use of targeted next-generation sequencing in the setting of an institutional molecular tumor board led to implementable clinical action in more than one third of patients with rare and poor-prognosis cancers. Major barriers to implementation of genomically guided therapywereclinical statusof the patient and drug access. Early and serial sequencing in the clinical course and expanded access to genomically guided early-phase clinical trials and targeted agents may increase actionability.
KW - Cancer
KW - Molecular sequencing
KW - Molecular targeted therapy
KW - Mutation
KW - Tumor genomics
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U2 - 10.1634/theoncologist.2016-0049
DO - 10.1634/theoncologist.2016-0049
M3 - Article
AN - SCOPUS:84995526699
SN - 1083-7159
VL - 21
SP - 1315
EP - 1325
JO - Oncologist
JF - Oncologist
IS - 11
ER -