Clinical actionability of comprehensive genomic profiling for management of rare or refractory cancers

Kim M. Hirshfield, Denis Tolkunov, Hua Zhong, Siraj M. Ali, Mark N. Stein, Susan Murphy, Hetal Vig, Alexei Vazquez, John Glod, Rebecca A. Moss, Vladimir Belyi, Chang S. Chan, Suzie Chen, Lauri Goodell, David Foran, Roman Yelensky, Norma A. Palma, James X. Sun, Vincent A. Miller, Philip J. StephensJeffrey S. Ross, Howard Kaufman, Elizabeth Poplin, Janice Mehnert, Antoinette R. Tan, Joseph R. Bertino, Joseph Aisner, Robert S. DiPaola, Lorna Rodriguez-Rodriguez, Shridar Ganesan

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1315-1325
Number of pages11
JournalOncologist
Volume21
Issue number11
DOIs
StatePublished - Nov 2016

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Keywords

  • Cancer
  • Molecular sequencing
  • Molecular targeted therapy
  • Mutation
  • Tumor genomics

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