Effects of letrozole on serum estradiol and estrone in postmenopausal breast cancer patients and tolerability of treatment: a prospective trial using a highly sensitive LC–MS/MS (liquid chromatography–tandem mass spectrometry) method for estrogen measurement

PURPOSE: To analyze serum estradiol (E2) and estrone (E1) during letrozole treatment and their association to Quality of Life (QoL) and side-effects. METHODS: Postmenopausal breast cancer patients starting adjuvant letrozole were eligible. Serum samples were taken at baseline, three, and 12 months. E2 and FSH were measured with routine chemiluminescent immunoassays. E2 and E1 were analyzed after trial completion with a highly sensitive liquid chromatography-tandem mass spectrometry method (LC–MS/MS) with lower limits of quantification (LLOQ) of 5 pmol/L. QoL was measured at baseline and at 12 months with the EORTC QLQ-C30 and QLQ-BR23 and the Women’s Health questionnaires, and menopause-related symptoms with the modified Kupperman Index. RESULTS: Of 100 screened patients 90 completed the trial. Baseline mean LC–MS/MS E2 and E1 were 12 pmol/L (range < 5–57) and 66 pmol/L (< 5–226), respectively. E2 levels measured by immunoassay and LC–MS/MS showed no correlation. E2 and E1 were completely suppressed by letrozole except for one occasion (E1 11 pmol/L at 3 months). Pain, side effects of systemic therapy, vasomotor symptoms, joint and muscle aches, and vaginal dryness increased during letrozole treatment. A high baseline E2 was significantly associated with increased aching joints and muscles, but not with the other side effects. CONCLUSIONS: Letrozole supresses E2 and E1 completely below the LLOQ of the LC–MS/MS in postmenopausal women. High pre-treatment E2 levels were associated with more joint and muscle pain during letrozole. Automated immunoassays are unsuitable for E2 monitoring during letrozole therapy due to poor sensitivity. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10549-023-07054-3.