Abstract P1-07-06: Endoxifen exposure after 5 weeks of preoperative tamoxifen is predictive of long-term outcome of operable hormone receptor positive (HR+) HER2 - early breast cancer

Abstract Introduction: Endoxifen exposure, the most active metabolite of tamoxifen, may be a better predictor of tamoxifen efficacy, than CYP2D6 genotypes. However, conflicting results have been reported so far. We evaluated prospectively the impact of 5 weeks of pre-operative tamoxifen on Ki-67 levels in early-stage breast cancer (EBC) patients. We correlated CYP2D6 genotype, exposure of tamoxifen and its metabolites with long-term outcome. Patients and methods: TAM pre-op was an open-label, multicentre, phase 2 trial in which pre and postmenopausal women with WHO performance status 0-1 and HR+ HER2-, operable breast cancer were given tamoxifen (20mg per day orally) for 5 weeks before surgery. Adjuvant treatments were given as standard practice. CYP2D6 genotype was determined at initiation. Plasma concentrations of tamoxifen and its main metabolites (N-desmethyltamoxifen, Z-endoxifen, and Z-4-hydroxytamoxifen) were assessed at baseline (b), week 2 (w2) and week 5 (w5) of treatment, using a validated performed LC-MS/MS method. AUCs, used as marker of exposure, were computed with Monolix© (Lixoft, Antony, France). Tumour Ki-67 variations between baseline (Ki-67b) and w5 (Ki-67w5) were determined to assess the sensitivity to tamoxifen. We used a pre-defined 10% cut-off to dichotomize low versus high Ki-67. All these parameters were associated with disease free survival by Cox regression analyses. Results: Out of the 136 patients enrolled, 98 pts had paired Ki-67 values evaluable. With a median follow up of 78 months (IQR 58-95), 14/136 women had cancer recurrence (12 distant and 2 contralateral) with the proportion free from cancer recurrence at 5 years of 90% (95% CI 83-94). Ki-67b, Ki-67w5 and variations between baseline and week 5 were not associated with DFS. Endoxifen AUC was correlated with CYP2D6 genotype (normal/hyper metabolizer versus low metabolizer) but CYP2D6 genotype was not predictive for DFS (adjusted hazard ratio, 2.24; 95% CI, 0.29 to 17.37; P = 0.44). Endoxifen AUCs at w2 and w5 were similar in patients with low Ki67b and low Ki67w5 (low-low) (n=36), low Ki67b and high Ki67w5 (n=12), high Ki67b and low Ki67w5 (n=14) and high Ki67b and high Ki67w5 (n=30). However, low endoxifen AUC at w5 was a pejorative factor of disease free survival: 5 years PFS 81.8% vs 90.3% (HR 2.70, CI 95% [1.04-7.06], p=0.04). Conclusion: This prospective clinical study shows that endoxifen exposure at w5 of pre-operative tamoxifen is associated with DFS in patients with HR+/HER2- EBC. Translationnal studies are ongoing. N°EUDRACT 2008-007652-10. Citation Format: Jean-Sebastien Frenel, Loic Campion, Antonin Schmitt, Patricia De Cremoux, Elsa Rossignol, Celine Renaudeau, Marie Robert, Jean-Marie Bard, Christine Bobin-Dubigeon, Mario Campone. Endoxifen exposure after 5 weeks of preoperative tamoxifen is predictive of long-term outcome of operable hormone receptor positive (HR+) HER2 - early breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-07-06.