Hot flashes are associated with CYP2D6 genotype in breast cancer survivors taking tamoxifen.

Abstract

Abstract Abstract #6045 Background: We have previously shown that participants in the Women's Healthy Eating and Living (WHEL) study comparison group who reported hot flashes after breast cancer treatment had more favorable disease-free survival than women who did not report hot flashes. However, this was not the case in the intervention group. The polymorphic CYP450 enzyme CYP2D6 catalyzes the conversion of tamoxifen (TAM) to one of its key active metabolites, endoxifen. Some studies have suggested that certain genetic variants of CYP2D6 are associated with a decreased likelihood of hot flashes, reduced endoxifen levels and an increased risk of disease recurrence in women receiving adjuvant TAM therapy. This analysis was performed to estimate the association between CYP2D6 genotype and hot flashes in early stage breast cancer survivors who took adjuvant TAM in the WHEL study.
 Methods: The WHEL study was a randomized trial of a dietary intervention in breast cancer survivors, who enrolled in the study within 4 years of diagnosis from 1995-2000. Participants self-reported TAM use, hot flash severity and menopausal status at study entry. Clinical characteristics (tumor stage, estrogen receptor status, chemotherapy) were extracted from medical records. Blood samples were obtained by venipuncture, separated and stored at -80 deg. DNA was extracted from stored buffy coat and analyzed using the Roche AmpliChip CYP450 Test. Women were classified according to their predicted CYP2D6 phenotype as Extensive (EM), Heterozygous Extensive (Het EM), Intermediate (IM), Poor (PM), or Ultrarapid (UM) Metabolizers.
 Results: Overall, 1434 WHEL participants had verified estrogen receptor-positive stage I or II breast cancers and reported taking TAM at baseline for at least 4 months. A total of 1411 women were successfully genotyped and their CYP2D6 phenotypes were classified as follows: 468 EM (33.2%); 665 Het EM(47.1%), 164 IM (11.6%), 86 PM (6.1%) and 28 UM (2.0%). In univariate analyses, there was a significant difference among CYP2D6 genotype in relation to hot flashes reported at baseline: 79.8% of EMs, 76.3% of Het EMs, 80.1% of IMs, 63.9% of PMs, and 75% of UMs reported hot flashes (χ2= 11.3, p=0.02). After controlling for age, menopausal status, and time since diagnosis, the PM group was half as likely to report hot flashes as the referent EM group (OR= 0.46; 95% CI= 0.28-0.78; p=0.003). Additional analyses of serum endoxifen levels and associations with disease outcome are underway.
 Conclusion: In the WHEL study, women who were classified as Poor Metabolizers of TAM, based on their CYP2D6 genotype, were half as likely as Extensive Metabolizers to report experiencing hot flashes while receiving adjuvant TAM treatment for early stage breast cancer. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6045.