El-Abed, Sarra

Background: The potential gonadotoxicity of anti-HER2 agents remains largely unknown, and limited, conflicting evidence exists for taxanes. Antimüllerian hormone (AMH) is an established biomarker of ovarian reserve that may aid in quantifying anticancer treatment–induced gonadotoxicity. Patients and Methods: The present biomarker analysis of the randomized phase III neoadjuvant NeoALTTO trial included premenopausal women aged ≤45 years at diagnosis of HER2-positive early breast cancer with available frozen serum samples at baseline (ie, before anticancer treatments), at week 2 (ie, the “biological window” of anti-HER2 therapy alone), and/or at the time of surgery (ie, after completing paclitaxel + anti-HER2 therapy, before starting adjuvant chemotherapy). Results: The present analysis included 130 patients with a median age of 38 years (interquartile ratio [IQR], age 33–42 years). AMH values at the 3 time points differed significantly (P<.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, 1.10 ng/mL; IQR, 0.45–2.09 ng/mL; P<.001). At surgery, a larger significant decline in AMH levels was observed (median, 0.01 ng/mL; IQR, 0.01–0.03 ng/mL; P<.001). Although the type of anti-HER2 treatment (trastuzumab and/or lapatinib) did not seem to impact the results, age and pretreatment ovarian reserve had a major influence on treatment-induced gonadotoxicity risk. Conclusions: This NeoALTTO biomarker analysis showed that anti-HER2 therapies alone had limited gonadotoxicity but that the addition of weekly paclitaxel resulted in marked AMH decline with possible negative implications for subsequent ovarian function and fertility.

522 Background: Our preclinical findings suggest a role for the mevalonate pathway (MVA) in treatment resistance in HER2+ BC by providing alternative growth and survival signaling to bypass potent HER2 blockade, which could be overcome by the MVA inhibitors statins and nitrogen-containing bisphosphonates (NBs). Here we explored the effect of MVA inhibitors’ use on pts’ outcomes in the ALTTO trial (BIG2-06; NCT00490139). Methods: In the ALTTO trial, 8381 pts with HER2+ BC were randomized to 1 year of adjuvant lapatinib (L), trastuzumab (T), L+T, or T→L. All pts with documented treatment start with statins or NBs < 1 year after randomization were considered as MVA inhibitors users. Survival curves, with a median follow-up of 6.9 years, for disease-free survival (DFS), distant relapse-free interval (DRFI), BC-specific survival (BCSS), and overall survival (OS) according to MVA inhibitors use were estimated by the Kaplan Meier method and Log-rank test. All multivariate survival analyses employed a Cox proportional hazards regression model, adjusting for tumor size, nodal status, hormonal receptor (HoR), menopausal status, BMI, timing of chemo, and randomization arm. We considered interactions terms in Cox’s model between MVA inhibitors use and randomization arm, hormonal status, and BMI group. Results: Among the 8381 pts included in this study, 493 and 299 were statins or NBs users, respectively. Table 1 summarizes the significant differences in pts’ characteristics according to MVA inhibitors use ( P <.005). In multivariate survival analyses, only NBs use was associated independently with better BCSS (HR, 0.44; 95% CI, 0.23 - 0.84; P = 0.014). Statin use was not independently associated with prognosis but only in interaction with pts characteristics: worse DFS, BCSS and OS in pts treated with L+T, worse DRFI and OS in pts treated with HoR+ BC (respective interaction P-values <0.05 in the Cox’s model). Conclusions: NBs independently predicted improved BC-specific outcome in pts with HER2+ BC treated with adjuvant anti-HER2 therapy. Statin use was associated with an inferior outcome in pts with HoR+ disease and/or those treated with L+T. Whether this inferior association in statin users may reflect the underlying predisposition factors that can weaken the efficacy of anti-HER2 treatments and whether this effect was observed only in the L+T arm due to the more potent inhibition of the HER2 signaling pathway remain open questions. Further clinical investigations on the impact of MVA inhibitors on the outcome of pts with HER2+ BC are warranted. [Table: see text]

PURPOSE The PALLAS study investigated whether the addition of palbociclib, an oral CDK4/6 inhibitor, to adjuvant endocrine therapy (ET) improves invasive disease-free survival (iDFS) in early hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) breast cancer. In this analysis, we evaluated palbociclib exposure and discontinuation in PALLAS. METHODS Patients with stage II-III HR+, HER2– disease were randomly assigned to 2 years of palbociclib with adjuvant ET versus ET alone. The primary objective was to compare iDFS between arms. Continuous monitoring of toxicity, dose modifications, and early discontinuation was performed. Association of baseline covariates with time to palbociclib reduction and discontinuation was analyzed with multivariable competing risk models. Landmark and inverse probability weighted per-protocol analyses were performed to assess the impact of drug persistence and exposure on iDFS. RESULTS Of the 5,743 patient analysis population (2,840 initiating palbociclib), 1,199 (42.2%) stopped palbociclib before 2 years, the majority (772, 27.2%) for adverse effects, most commonly neutropenia and fatigue. Discontinuation of ET did not differ between arms. Discontinuations for non–protocol-defined reasons were greater in the first 3 months of palbociclib, and in the first calendar year of accrual, and declined over time. No significant relationship was seen between longer palbociclib duration or ≥ 70% exposure intensity and improved iDFS. In the weighted per-protocol analysis, no improvement in iDFS was observed in patients receiving palbociclib versus not (hazard ratio 0.89; 95% CI, 0.72 to 1.11). CONCLUSION Despite observed rates of discontinuation in PALLAS, analyses suggest that the lack of significant iDFS difference between arms was not directly related to inadequate palbociclib exposure. However, the discontinuation rate illustrates the challenge of introducing novel adjuvant treatments, and the need for interventions to improve persistence with oral cancer therapies.