Isocitrate dehydrogenase 1 (IDH1) mutation in breast adenocarcinoma is associated with elevated levels of serum and urine 2-hydroxyglutarate.
Mutations in the IDH1 and IDH2 (isocitrate dehydrogenase) genes have been discovered across a range of solid-organ and hematologic malignancies, including acute myeloid leukemia, glioma, chondrosarcoma, and cholangiocarcinoma. An intriguing aspect of IDH-mutant tumors is the aberrant production and accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), which may play a pivotal oncogenic role in these malignancies. We describe the first reported case of an IDH1 p.R132L mutation in a patient with hormone receptor-positive (HR+) breast adenocarcinoma. This patient was initially treated for locally advanced disease, but then suffered a relapse and metastasis, at which point an IDH1-R132 mutation was discovered in an affected lymph node. The mutation was subsequently found in the primary tumor tissue and all metastatic sites, but not in an uninvolved lymph node. In addition, the patient's serum and urine displayed marked elevations in the concentration of 2-HG, significantly higher than that measured in six other patients with metastatic HR+ breast carcinoma whose tumors were found to harbor wild-type IDH1. In summary, IDH1 mutations may impact a rare subgroup of patients with breast adenocarcinoma. This may suggest future avenues for disease monitoring through noninvasive measurement of 2-HG, as well as for the development and study of targeted therapies against the aberrant IDH1 enzyme.
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA; Agios Pharmaceuticals, Cambridge, Massachusetts, USA afathi@partners.org.
Amir T
AT
Fathi
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA; Agios Pharmaceuticals, Cambridge, Massachusetts, USA.
Hossein
H
Sadrzadeh
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA; Agios Pharmaceuticals, Cambridge, Massachusetts, USA.
Amy H
AH
Comander
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA; Agios Pharmaceuticals, Cambridge, Massachusetts, USA.
Michaela J
MJ
Higgins
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA; Agios Pharmaceuticals, Cambridge, Massachusetts, USA.
Aditya
A
Bardia
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA; Agios Pharmaceuticals, Cambridge, Massachusetts, USA.
Ashley
A
Perry
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA; Agios Pharmaceuticals, Cambridge, Massachusetts, USA.
Meghan
M
Burke
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA; Agios Pharmaceuticals, Cambridge, Massachusetts, USA.
Regina
R
Silver
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA; Agios Pharmaceuticals, Cambridge, Massachusetts, USA.
Christina R
CR
Matulis
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA; Agios Pharmaceuticals, Cambridge, Massachusetts, USA.
Kimberly S
KS
Straley
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA; Agios Pharmaceuticals, Cambridge, Massachusetts, USA.
Katharine E
KE
Yen
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA; Agios Pharmaceuticals, Cambridge, Massachusetts, USA.
Sam
S
Agresta
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA; Agios Pharmaceuticals, Cambridge, Massachusetts, USA.
Hyeryun
H
Kim
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA; Agios Pharmaceuticals, Cambridge, Massachusetts, USA.
David P
DP
Schenkein
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA; Agios Pharmaceuticals, Cambridge, Massachusetts, USA.
Darrell R
DR
Borger
D000230:Adenocarcinoma / Q000097:blood / Q000235:genetics* / Q000473:pathology / Q000652:urine; D001943:Breast Neoplasms / Q000097:blood / Q000235:genetics* / Q000473:pathology / Q000652:urine; D005260:Female; D005977:Glutarates / Q000097:blood / Q000652:urine; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009376:Neoplasms, Hormone-Dependent / Q000097:blood / Q000235:genetics* / Q000473:pathology / Q000652:urine
D005977:Glutarates; C019417:alpha-hydroxyglutarate; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human
2-Hydroxyglutarate; Breast adenocarcinoma; Isocitrate dehydrogenase 1; Targeted therapy