RT Book, Section
A1 Symeonides, Stefan
A1 Leahy, Michael
A2 Copson, Ellen R
A2 Hall, Peter
A2 Board, Ruth E
A2 Cook, Gordon
A2 Selby, Peter
SR Print(0)
ID 1152360825
T1 A Patient with an Advanced Gastrointestinal Stromal Tumour Tested for a KIT Mutation, with Important Drug-Drug Interactions
T2 Problem Solving Through Precision Oncology
YR 2018
FD 2018
PB Clinical Publishing
PP New York, NY
SN 9781846921117
LK hemonc.mhmedical.com/content.aspx?aid=1152360825
RD 2021/03/09
AB A  68-year-old  woman  presented  with  a  1  month  history  of  dysphagia.  Her  medical  history  included  hypertension,  a  pacemaker  and  a  previous  gastric  polyp.  Medications  included  simvastatin,  amlodipine  and  candesartan.  Endoscopy  revealed  a  3  cm  polypoid  submucosal  mass  with  ulcers.  Although  mucosa  from  the  original  biopsy  was  normal,  the  underlying  lesion  was  identified  on  re-biopsy  as  a  gastrointestinal  stromal  tumour  (GIST).  CT  staging  identified  a  4  cm  left  gastric  wall  soft  tissue  mass.  The  patient  proceeded  to  have  a  total  gastrectomy  with  Roux-en-Y  reconstruction.  Final  pathology  showed  a  51  mm  pleomorphic  (mixed  spindle  cell/epithelioid)  GIST  with  six  mitoses  per  50  high-powered  fields  (HPFs)  and  areas  of  necrosis.  Genetics  showed  the  tumour  to  have  an  exon  13  K642E  KIT  mutation.  The  GIST  multidisciplinary  team  recommended  adjuvant  imatinib,  which  the  patient  accepted.  After  completion  of  treatment,  there  was  no  evidence  of  recurrence  on  surveillance  imaging.There  were,  however,  complications  during  her  management.  Investigation  and  treatment  of  a  neck  nodule  (thyroidectomy  and  radioiodine  ablation  for  a  concurrent  papillary  thyroid  cancer)  led  to  identification  of  borderline  enlarged  mediastinal  lymph  nodes.  These  were  found  to  be  caseating  granulomas;  Mantoux/T-SPOT  testing,  along  with  a  history  of  exposure  to  an  infected  contact,  necessitated  treatment  for  tuberculosis  (TB).  This  required  combination  antimicrobial  therapy,  including  6  months  of  rifampicin,  a  strong  cytochrome  P450  (CYP)  3A4  inducer.  Although  the  interaction  with  her  simvastatin  is  well  recognized,  it  is  also  very  common  for  small  molecule  inhibitors  used  in  oncology  to  be  CYP3A4  substrates,  as  is  the  case  with  imatinib.  Mild  imatinib-related  gastrointestinal  toxicities  reduced  on  rifampicin  but  recurred  with  a  compensatory  50%  dose  increase  of  imatinib  to  600  mg.  The  dose  was  reduced  again  on  completion  of  rifampicin.A  potential  second  major  drug-drug  interaction  occurred  when  the  patient  developed  frequent  paroxysmal  atrial  fibrillation  (an  arrhythmia  not  corrected  by  pacemakers  such  as  hers).  Anticoagulation  was  recommended,  but  imatinib  interacts  with  warfarin  via  CYP2D6  (with  one  case  of  intracerebral  bleed  reported)  and  oral  Factor  Xa  inhibitors  via  CYP3A4  (guidance  cautions  against  these  combinations).  After  discussion,  anticoagulation  was  postponed  for  5  months  until  the  imatinib  course  was  completed.  The  patient  remains  clear  of  any  recurrence  of  cancer  or  TB  and  of  any  thromboembolic  event.Which  patients  are  likely  to  benefit  from  adjuvant  imatinib  and  what  duration  is  recommended?What  is  the  role  of  individualKIT(orPDGFRA)  mutations  in  diagnosis?What  is  the  role  of  individualKIT(orPDGFRA)  mutations  in  imatinib  sensitivity  and  dose?How  can  drug-drug  interactions  be  identified  and  managed?