Impact of anti-HER2 therapy alone and in association with weekly paclitaxel on the ovarian reserve of young women with HER2-positive early breast cancer: Biomarker analysis of the NeoALTTO trial.
Authors: Lambertini Matteo , Ceppi Marcello , Anderson Richard , Cameron David A. , El-Abed Sarra , Wang Yingbo , Lecocq Christophe , Nuciforo Paolo , Rolyance Rebecca , Pusztai Lajos , Sohn Joohyuk , Arecco Luca , Del Mastro Lucia , Partridge Ann H. , Saura Cristina , Untch Michael , Piccart-Gebhart Martine J. , Di Cosimo Serena , de Azambuja Evandro , Demeestere Isabelle 
Published: June 2022

12084

Background: The potential gonadotoxicity of anti-HER2 agents remains largely unknown and limited conflicting evidence exists for taxanes. Anti-Mullerian hormone (AMH) is an established biomarker of ovarian reserve; its measurement during systemic therapies may aid in indicating gonadotoxicity, in the diagnosis and prediction of primary ovarian insufficiency (POI). The present analysis explored for the first time the impact of anti-HER2 therapy alone and then combined with weekly paclitaxel on ovarian reserve measured by AMH levels in breast cancer (BC) patients not previously exposed to anthracycline and cyclophosphamide. Methods: This biomarker analysis of the NeoALTTO (NCT00553358) randomized phase III neoadjuvant trial included premenopausal women aged ≤45 years at diagnosis of HER2-positive early BC with available frozen serum samples at baseline (i.e. before administering any anticancer treatment), at week 2 (i.e. “biological window” of anti-HER2 therapy alone) and/or at the time of surgery (i.e. after completion of paclitaxel plus anti-HER2 therapy and before starting adjuvant chemotherapy). Central AMH testing was performed with the Roche Elecsysâ AMH Plus assay (LoD = 0.01 ng/ml). AMH levels during anti-HER2 therapy alone and then combined with paclitaxel were assessed as a measure of treatment acute gonadotoxicity. The impact of different anti-HER2 agents, patients’ age, and baseline AMH levels on treatment gonadotoxicity were also investigated. Results: The present analysis included 130 patients with a median age of 38 years (IQR: 33-42 years). AMH values at the 3 time points differed significantly from each other (p < 0.001). At baseline, median AMH levels were 1.29 ng/mL (IQR 0.56 – 2.62 ng/mL). At week 2, a small but significant reduction in AMH levels was observed (median value: 1.10 ng/mL, IQR 0.45 – 2.09 ng/mL, p < 0.001). At surgery, there was a larger significant decline in AMH levels (median value: 0.01 ng/mL, IQR 0.01 – 0.03 ng/mL, p < 0.001). There was no significant difference between treatment arms (trastuzumab vs. lapatinib vs. trastuzumab plus lapatinib) in the degree of reduction in AMH levels at week 2 (p = 0.763) and at surgery (p = 0.700). Age and pre-treatment ovarian reserve had a major influence on treatment-induced gonadotoxicity risk, with older age and lower AMH levels at diagnosis being associated with a greater negative impact. Conclusions: This biomarker analysis of the NeoALTTO trial showed for the first time that anti-HER2 therapies alone had limited gonadotoxicity but the addition of weekly paclitaxel resulted in marked AMH decline which likely has implications for subsequent ovarian function and fertility. These data highlight the importance of oncofertility counselling among all premenopausal women with HER2-positive BC receiving systemic anticancer treatments. Clinical trial information: NCT00553358.