Testing ERBB2 p.L755S kinase domain mutation as a druggable target in a patient with advanced colorectal cancer.
Recent advances in molecular profiling technologies allow genetic driver events in individual tumors to be identified. The hypothesis behind this ongoing molecular profiling effort is that improvement in patients' clinical outcomes will be achieved by inhibiting these discovered genetic driver events with matched targeted drugs. This hypothesis is currently being tested in oncology clinics with variable early results. Herein, we present our experience with a case of advanced colorectal cancer (CRC) with an ERBB2 p.L755S kinase domain mutation, a BRAF p.N581S mutation, and an APC p.Q1429fs mutation, together with a brief review of the literature describing the biological and clinical significance of ERRB2 kinase domain mutations in CRC. The patient was treated with trastuzumab combined with infusional 5-fluorouracil and leucovorin based on the presence of ERBB2 p.L755S kinase mutation in the tumor and based on the available evidence at the time when standard treatment options had been exhausted. However, there was no therapeutic response illustrating the challenges we face in managing patients with potentially targetable mutations where results from functional in vitro and in vivo studies lag behind those of genomic sequencing studies. Also lagging behind are clinical utility data from oncology clinics, hampering rapid therapeutic advances. Our case also highlights the logistical barriers associated with getting the most optimal therapeutic agents to the right patient in this era of personalized therapeutics based on cancer genomics.
Drug Development Program, Division of Medical Oncology and Hematology; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5S 1A8, Canada;
Kyaw L
KL
Aung
Drug Development Program, Division of Medical Oncology and Hematology; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5S 1A8, Canada;; Laboratory Medicine Program, Department of Pathology, University Health Network, Toronto, Ontario M5G 2C4, Canada;; Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario M5S 1A8, Canada;
Tracy L
TL
Stockley
Drug Development Program, Division of Medical Oncology and Hematology; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5S 1A8, Canada;; Laboratory Medicine Program, Department of Pathology, University Health Network, Toronto, Ontario M5G 2C4, Canada;; Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario M5S 1A8, Canada;
Stefano
S
Serra
Drug Development Program, Division of Medical Oncology and Hematology; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5S 1A8, Canada;; Laboratory Medicine Program, Department of Pathology, University Health Network, Toronto, Ontario M5G 2C4, Canada;; Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario M5S 1A8, Canada;
Suzanne
S
Kamel-Reid
Drug Development Program, Division of Medical Oncology and Hematology; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5S 1A8, Canada;; Department of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Philippe L
PL
Bedard
Drug Development Program, Division of Medical Oncology and Hematology; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5S 1A8, Canada;; Department of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Lillian L
LL
Siu
neoplasm of the gastrointestinal tract