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Endometrial K-ras mutations in postmenopausal breast cancer patients treated with adjuvant tamoxifen or toremifene

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Abstract

Purpose

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.

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Authors and Affiliations

  1. Institute of Medical Technology, University of Tampere, Tampere, Finland

    Mika Wallén & Tapio Visakorpi

  2. The Centre for Laboratory Medicine, Tampere University Hospital, Tampere, Finland

    Mika Wallén & Tapio Visakorpi

  3. Department of Obstetrics and Gynecology, Tampere University Hospital, 33521, Tampere, Finland

    Eija Tomás & Johanna Mäenpää

  4. Palliative Medicine, Tampere University Hospital, Tampere, Finland

    Kaija Holli

  5. Medical School, University of Tampere, Tampere, Finland

    Kaija Holli & Johanna Mäenpää

Authors
  1. Mika Wallén
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  2. Eija Tomás
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  3. Tapio Visakorpi
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  4. Kaija Holli
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  5. Johanna Mäenpää
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Corresponding author

Correspondence to Johanna Mäenpää.

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Wallén, M., Tomás, E., Visakorpi, T. et al. Endometrial K-ras mutations in postmenopausal breast cancer patients treated with adjuvant tamoxifen or toremifene. Cancer Chemother Pharmacol 55, 343–346 (2005). https://doi.org/10.1007/s00280-004-0923-x

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  • DOI: https://doi.org/10.1007/s00280-004-0923-x

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