Short-term risk of recurrence in patients (pts) with HR+/HER2− early breast cancer (EBC) treated with endocrine therapy (ET) in randomized clinical trials (RCTs): A meta-analysis.

Giuseppe Curigliano University of Milan and European Institute of Oncology, IRCCS, Milan, Italy info_outline Giuseppe Curigliano, Eva Ciruelos, Kevin Kalinsky, David Proudman, Dave Nellesen, Priscilla Lopez, Samantha Kaufhold, Olivia Shane, Adrienne Kwok, Vaidyanathan Ganapathy, Adaeze Q. Amefule, Agnes Lteif, Peter A. Fasching, Erika P. Hamilton

Authors Giuseppe Curigliano University of Milan and European Institute of Oncology, IRCCS, Milan, Italy info_outline Giuseppe Curigliano, Eva Ciruelos, Kevin Kalinsky, David Proudman, Dave Nellesen, Priscilla Lopez, Samantha Kaufhold, Olivia Shane, Adrienne Kwok, Vaidyanathan Ganapathy, Adaeze Q. Amefule, Agnes Lteif, Peter A. Fasching, Erika P. Hamilton Organizations University of Milan and European Institute of Oncology, IRCCS, Milan, Italy, Hospital 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre, Madrid, Spain, Winship Cancer Institute of Emory University, Atlanta, GA, Analysis Group, Inc., Menlo Park, CA, Analysis Group, New York, NY, Analysis Group, San Francisco, CA, Analysis Group, Inc., San Francisco, CA, Novartis Pharmaceuticals Corporation, East Hanover, NJ, University Hospital Erlangen, Erlangen, Germany, Sarah Cannon Research Institute, Nashville, TN Abstract Disclosures Research Funding No funding sources reported Background: ET ± chemotherapy (CT) has been standard of care for HR+/HER2− EBC for ≈20 yrs, yet pts continue to experience disease recurrences up to decades after completing adjuvant (adj) treatment (tx). There is little information on early recurrences (≤5 yrs) in the more recent tx landscape, which includes optimized local tx and improved systemic tx. This meta-analysis of ET arms in RCTs in pts with HR+/HER2− EBC seeks to fill this gap by evaluating 3- and 5-yr risk of recurrence (RoR). Methods: A systematic literature review identified RCTs that met study criteria: phase 3 trials that included pts with HR+/HER2− EBC who received 5 yrs of adj ET (aromatase inhibitors ± ovarian suppression or tamoxifen) ± CT with invasive disease-free survival (iDFS) or disease-free survival (DFS) reported at 3 and/or 5 yrs post tx randomization. Neoadj or extended ET trials were excluded. Survival curves were digitized for iDFS estimates. Meta-analysis of proportions, using a random-effects model with double arcsine transformation, was used to evaluate pooled 3-yr RoR (100 − iDFS/DFS rate) for all pts, by lymph node (LN) status (N0: 0, N1: 1-3, N+ any positive LN), and 5-yr RoR where available. The 3-yr RoR across ET arms in a subset of only adj cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) trials was evaluated given the recency of these RCTs. Results: RoR estimates were obtained from 14 trials (across 23 distinct ET-only arms), including 4 adj CDK4/6i trials that met study criteria; studies included pts with stage I-III disease ± nodal involvement. Pooled 3- and 5-yr RoR for the overall HR+/HER2− EBC pt population regardless of LN/stage were 7% and 12%, respectively. In trials with nodal status subgroups, pooled 3-yr RoR was 5% for N0, 6% for N1, and 13% for N+ pts. In a sensitivity analysis excluding cohorts with low to medium risk scores based on genomic testing, pooled 3-yr RoR estimates for N0 and N1 subgroups were 7% and 10%, respectively. Meta-analysis across ET arms of CDK4/6i trials revealed 3-yr RoR of 15% (all stage I-III) and 10% (N0). Conclusions: Despite the potential for late recurrence of HR+/HER2− EBC, short-term RoR is considerable and accumulates over time for these pts treated with ET ± CT in the adj setting. These findings highlight the unmet need for tolerable tx escalation among at-risk pts, including node-positive and select N0 pts with high-risk features.

Pre-clinical