TY - JOUR
T1 - Association of CYP2D6 genotype and tamoxifen metabolites with breast cancer recurrence in a low-dose trial
AU - DeCensi, Andrea
AU - Johansson, Harriet
AU - Helland, Thomas
AU - Puntoni, Matteo
AU - Macis, Debora
AU - Aristarco, Valentina
AU - Caviglia, Silvia
AU - Webber, Tania Buttiron
AU - Briata, Irene Maria
AU - D’Amico, Mauro
AU - Serrano, Davide
AU - Guerrieri-Gonzaga, Aliana
AU - Bifulco, Ersilia
AU - Hustad, Steinar
AU - Søiland, Håvard
AU - Boni, Luca
AU - Bonanni, Bernardo
AU - Mellgren, Gunnar
N1 - Funding Information:
The trial was supported by: Italian Ministry of Health RFPS-2006-1-339898, Italian Association for Cancer Research (AIRC) IG 2008 Grant no. 5611, and the Italian League against Cancer (LILT 7-08). This work was partially supported by the Italian Ministry of Health with Ricerca Corrente and 5×1000 funds. They had no role in the design and conduct of the study, collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - Low-dose tamoxifen halves recurrence in non-invasive breast cancer without significant adverse events. Some adjuvant trials with tamoxifen 20 mg/day had shown an association between low endoxifen levels (9–16 nM) and recurrence, but no association with CYP2D6 was shown in the NSABP P1 and P2 prevention trials. We studied the association of CYP2D6 genotype and tamoxifen metabolites with tumor biomarkers and recurrence in a randomized phase III trial of low-dose tamoxifen. Median (IQR) endoxifen levels at year 1 were 8.4 (5.3–11.4) in patients who recurred vs 7.5 (5.1–10.2) in those who did not recur (p = 0.60). Tamoxifen and metabolites significantly decreased C-reactive protein (CRP, p < 0.05), and a CRP increase after 3 years was associated with higher risk of recurrence (HR = 4.37, 95% CI, 1.14–16.73, P = 0.03). In conclusion, endoxifen is below 9 nM in most subjects treated with 5 mg/day despite strong efficacy and there is no association with recurrence, suggesting that the reason for tamoxifen failure is not poor drug metabolism. Trial registration: ClinicalTrials.gov, Identifier: NCT01357772.
AB - Low-dose tamoxifen halves recurrence in non-invasive breast cancer without significant adverse events. Some adjuvant trials with tamoxifen 20 mg/day had shown an association between low endoxifen levels (9–16 nM) and recurrence, but no association with CYP2D6 was shown in the NSABP P1 and P2 prevention trials. We studied the association of CYP2D6 genotype and tamoxifen metabolites with tumor biomarkers and recurrence in a randomized phase III trial of low-dose tamoxifen. Median (IQR) endoxifen levels at year 1 were 8.4 (5.3–11.4) in patients who recurred vs 7.5 (5.1–10.2) in those who did not recur (p = 0.60). Tamoxifen and metabolites significantly decreased C-reactive protein (CRP, p < 0.05), and a CRP increase after 3 years was associated with higher risk of recurrence (HR = 4.37, 95% CI, 1.14–16.73, P = 0.03). In conclusion, endoxifen is below 9 nM in most subjects treated with 5 mg/day despite strong efficacy and there is no association with recurrence, suggesting that the reason for tamoxifen failure is not poor drug metabolism. Trial registration: ClinicalTrials.gov, Identifier: NCT01357772.
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U2 - 10.1038/s41523-021-00236-6
DO - 10.1038/s41523-021-00236-6
M3 - Article
AN - SCOPUS:85103402254
VL - 7
JO - npj Breast Cancer
JF - npj Breast Cancer
SN - 2374-4677
IS - 1
M1 - 34
ER -