Abstract
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.
Highlights
Low-dose tamoxifen halves recurrence in non-invasive breast cancer without significant adverse events
Tamoxifen is the standard of care in women at high risk for breast cancer, including women with pre-invasive disorders, but toxicity, especially menopausal symptoms and rare serious adverse events such as endometrial cancer and venous thromboembolism have largely hampered its uptake in clinical practice[1]
Some retrospective studies with tamoxifen 20 mg/day have shown an association between poor CYP2D6 metabolizers or levels of the most potent metabolite endoxifen below 9 or 16 nM and higher risk of recurrence in the adjuvant setting[4,5,6], but the association with CYP2D6 has not been shown in the NSABP P1 and P2 tamoxifen prevention trials[7]
Summary
The study characteristics (EudraCT Number: 2007–007740–10; ClinicalTrials.gov Identifier: NCT01357772, first submitted date: May 17, 2011) and main clinical findings of the trial have previously been reported[2]. Women with high-grade or comedo/ necrosis DCIS received 50 grays adjuvant radiotherapy. All breast events occurring during the trial were centrally adjudicated by a clinical committee. The primary endpoint was the incidence of invasive breast cancer or DCIS. Toxicity was assessed by the NCI-CTCAE version 3 and patient-reported menopausal symptoms were recorded by the Breast Cancer Prevention Trial Symptom Scale[2]. All patients were informed of the objectives of the study and were invited to voluntarily participate. Patients who agreed to participate provided written consent before any study-specific procedure that could be withdrawn at any time without consequences for further treatment.
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