LBA24 Multiparametric prognostic score in early HR+/HER2- breast cancer: Impact of recurrence score, clinical-pathological factors, gene mutations and histology

Several analyses have shown prognostic impact of clinical and IHC markers in addition to genomic signatures in HR+/HER2 EBC. However, it remains unclear whether histology (e.g. invasive lobular BC (ILC) or further factors provide additional information. We present outcome from the prospective WSG-ADAPT HR+/HER- trial combining both static and dynamic biomarkers to optimize adjuvant therapy in luminal EBC. pN0-1 with clinically high-risk HR+/HER2- EBC pts with RS0-11 OR RS12-25/Ki67postendocrine≤10% after 3 +/- of preoperative ET received ET alone; the remaining high-risk cohort was randomized to the CT trial. Prognostic scores containing clinical factors with and w/out mutational/copy number data were derived retrospectively after splitting the data into training- and validation sets. LASSO and cross validation methods were used to predict iDFS in therapy subgroups. Additionally, multivariate Cox models were adapted using a forward-backward selection approach to identify prognostic markers. 4491 pts were included (n=2246 ET- and n=2245 CT-treated). In the whole set, tumor and nodal (T/N) stage, RS and PR expression were prognostic for iDFS (Cox model). In ET-treated pts, only T-stage, RS and ER expression by RT-pCR were significant by Cox analysis, but prognostic score could not be determined. In CT-treated patients, T/N stage, G2-3 vs. G1, RS, ILC, and PR expression, but not IHC4 entered the model. In the CT cohort, a prognostic score consisting of T/N stage, age (≤50, >50), RS, ILC, PR expression and baseline and post-ET Ki67 yields a ROC AUC of 66% in the validation set. ILC was associated with lower RS than IDC (RS>25: 5.62% vs. 19.37%).High-risk CT-treated ILC had more frequently ERBB2 (11.6% vs. 2.5%) and a lower frequency of CDH1 mutations (60.5% vs 70.7%). Only CCND1 amplification was associated with worse iDFS in the NGS sub-cohort (n=584). Use of RS in combination with further clinical and genetic factors improves prognostic ability; however, there is no treatment-independent prognostic model for HR+ HER2- EBC pts. For the first time, we have shown worse prognosis of the ILC high-risk subgroup, associated with distinct biological features.