Endometrial K-ras mutations in postmenopausal breast cancer patients treated with adjuvant tamoxifen or toremifene.
OBJECTIVE
Long-term use of tamoxifen is associated with a two- to threefold increased risk of endometrial cancer in postmenopausal women. Toremifene is another triphenylethylene antiestrogen, which is as effective as tamoxifen in postmenopausal breast cancer. Thus far, its use has not been associated with an increased risk of endometrial cancer. K-ras codon 12 mutations seem to be important in endometrial carcinogenesis, and these mutations have been found in endometrial samples of patients on tamoxifen. The present study was undertaken to investigate if there is any difference in the frequency of endometrial K-ras mutations among patients treated with tamoxifen or toremifene.


METHODS
Endometrial samples were taken from 23 postmenopausal breast cancer patients (tamoxifen, n = 11; toremifene, n = 12) before and after 36 months of treatment. DNA was isolated from formalin-fixed paraffin-embedded samples using a routine proteinase K digestion protocol. K-ras mutations in codon 12 were screened using real-time PCR and melting curve analysis in LightCycler equipment. Wild-type PNA oligomer was used to increase the sensitivity of the assay.


RESULTS
All baseline samples contained wild-type K-ras, while 10/23 (43%) of the follow-up samples carried a codon 12 mutation. Mutations were identified in 3 of the 11 in the tamoxifen group and in 7 of the 12 in the toremifene group. Seven were transitions (G-->A), and three were transversions (two G-->T, one G-->C). One of the mutations in the toremifene group was associated with a polypoid endometrium. All the other mutations were found in an atrophic (n = 6) or proliferative (n = 3) endometrium.


CONCLUSIONS
Both tamoxifen and toremifene induce endometrial K-ras codon 12 mutations. The significance of this finding to endometrial carcinogenesis remains to be elucidated.
Wallén
Mika
M
Institute of Medical Technology, University of Tampere, Tampere, Finland.|The Centre for Laboratory Medicine, Tampere University Hospital, Tampere, Finland.
Tomás
Eija
E
Department of Obstetrics and Gynecology, Tampere University Hospital, 33521, Tampere, Finland.
Visakorpi
Tapio
T
Institute of Medical Technology, University of Tampere, Tampere, Finland.|The Centre for Laboratory Medicine, Tampere University Hospital, Tampere, Finland.
Holli
Kaija
K
Palliative Medicine, Tampere University Hospital, Tampere, Finland.|Medical School, University of Tampere, Tampere, Finland.
Mäenpää
Johanna
J
Department of Obstetrics and Gynecology, Tampere University Hospital, 33521, Tampere, Finland. johanna.maenpaa@pshp.fi.|Medical School, University of Tampere, Tampere, Finland. johanna.maenpaa@pshp.fi.
D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D004717:Endometrium / Q000187:drug effects*; D005260:Female; D011905:Genes, ras; D006801:Humans; D009154:Mutation; D017698:Postmenopause; D011446:Prospective Studies; D013629:Tamoxifen / Q000627:therapeutic use*; D017312:Toremifene / Q000627:therapeutic use*
D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen; D017312:Toremifene