Adjuvant anti-HER2 therapy, treatment-induced amenorrhea (TIA) and survival in premenopausal patients (pts) with HER2-positive (HER2+) early breast cancer (EBC): Analysis from the ALTTO trial (BIG 2-06)

Abstract

Background: In premenopausal pts with HER2+ EBC, the prognostic effect of TIA is unknown and the gonadotoxicity of trastuzumab (T) and lapatinib (L) remains largely uncertain. We aimed to assess the prognostic effect of TIA and the impact of T and/or L on the risk of developing TIA in premenopausal pts with HER2+ EBC. Methods: ALTTO was an international, open‐label, randomised phase 3 trial in pts with HER2+ EBC. Pts were randomised in 4 adjuvant anti‐HER2 arms: T alone, L alone, a sequence of the 2 agents (T‐>L) and their combination (T+L). As per study protocol, menopausal status was collected in all pts at randomisation and at week 37. By selecting only premenopausal pts at randomisation, we investigated whether TIA in pts with hormone receptor‐positive (HR+) and negative (HR‐) EBC would impact on disease‐free (DFS) and overall survival (OS), and the risk factors for developing TIA. Landmark and time‐dependent modeling were used to account for guaranteed time bias. Results: Out of 8381 pts randomised in ALTTO, 2862 were included in this analysis. Median age was 43 years (range 38‐47); 1679 (59%) pts had HR+ EBC. Pts with HR+/ HER2+ EBC who experienced TIA had significant better DFS (hazard ratio [HR] 0.64; 95% confidence intervals [CI] 0.52‐0.79) and OS (HR 0.53; 95% CI 0.38‐0.74) than those who did not have TIA. By contrast, pts with HR‐/HER2+ EBC had similar DFS (HR 0.85; 95% CI 0.68‐1.07) and OS (HR 0.89; 95% CI 0.64‐1.25) regardless of whether they had TIA (interaction P for DFS=0.009 and for OS=0.002). A similar TIA rate was observed in the T (72.6%), L (74.0%), T‐>L (72.1%) and 74.8% (T+L) arms (p=0.644). Older age (p<0.001), addition of taxanes to anthracycline‐based chemotherapy (p<0.001), and use of adjuvant endocrine therapy (p<0.001) significantly increased the risk of TIA. Conclusions: In premenopausal pts with HR+/HER2+ EBC, TIA was associated with significant survival benefits. Anti‐HER2 agents did not impact the likelihood of developing TIA. These data are of great importance in oncofertility counseling and support the use of ovarian suppression as part of adjuvant endocrine therapy in premenopausal HR+/HER2+ EBC pts.