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

Background

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.

Methods

pN0-1 with clinically high-risk HR+/HER2- EBC pts with RS0-11 OR RS12-25/Ki67_{postendocrine}≤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.

Results

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).

Conclusions

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.

Clinical trial identification

NCT01779206.

Editorial acknowledgement

Legal entity responsible for the study

West German Study Group.

Funding

Exact Science.

Disclosure

O. Gluz: Financial Interests, Personal, Advisory Board: Roche, Lilly, Amgen, Novartis, Pierre Fabre, MSD, Celgene, Pfizer, Gilead, Molecular Health, Seagen, Agendia; Financial Interests, Personal, Invited Speaker: AstraZeneca, Exact Science; Financial Interests, Institutional, Coordinating PI: Roche, LIlly; Non-Financial Interests, Leadership Role: West German Study Group; Non-Financial Interests, Personal, Proprietary Information: West German Study Group. U.A. Nitz: Financial Interests, Personal, Advisory Board: Exact Science. S. Kummel: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Celgene, Daiichi Sankyo, Genomic Health/Exact Sciences, Lilly, MSD, Novartis, Seagen. Pfizer, pfm Medical, Roche, Somatex, Gilead. M. Braun: Financial Interests, Personal, Advisory Board: AstraZeneca, Exact Sciences, Novartis, Pfizer, Roche, Teva. B. Aktas: Financial Interests, Personal, Advisory Board: Pfizer, Roche Pharma, Merck Sharp & Dohme, onkowissen.de, Novartis Pharma, AstraZeneca, PharmaMar, Lilly, promedicis. R.F.L. Baehner: Financial Interests, Personal, Full or part-time Employment: Exact Science. M. Graeser: Financial Interests, Personal, Advisory Board: AstraZeneca. R. Würstlein: Financial Interests, Personal, Advisory Board: Agendia, Amgen, Apogheva, AstraZeneca, Daiichi Sankyo, Exact Sciences, Gilead, Lilly, MSD, Nanostring, Novartis, Pfizer, Pierre Fabre, Riemser, Roche, Sanofi Genzyme, Seagen, Stemline, Clinsol; Financial Interests, Personal, Invited Speaker: Aristo, Clovis Oncology, Eisai, Palleos, PINK, FOMF, Aurikamed, Pomme Med, medconcept, MCI; Financial Interests, Personal, Writing Engagement: Hexal; Financial Interests, Institutional, Funding: Lilly; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Coordinating PI: WSG, PINK; Financial Interests, Institutional, Local PI: BKFZ; Non-Financial Interests, Advisory Role: PINK, Brustkrebs Deutschland e.V., Junge Erwachsene Mit Krebs, AGO Kommission Mamma, AGSMO, DKG, TZM, CCC München, Mammamia. H. Kreipe: Financial Interests, Personal, Advisory Board: Roche Pharma, Novartis, Genomic Health, AstraZeneca, Lilly, Pfizer. N. Harbeck: Financial Interests, Personal, Invited Speaker: AstraZeneca, Daiichi Sankyo, Lilly, MSD, Novartis, Pierre Fabre, Roche, Seagen, Art Tempi, Onkowissen, Medscape, Gilead, Sanofi, Zuelligpharma, Viatris; Financial Interests, Personal, Other, IDMC: Roche; Financial Interests, Personal, Advisory Board: Sandoz-Hexal, Seagen, Aptitude Health, Pfizer, Gilead, Sanofi; Financial Interests, Personal, Other, Husband: WSG (Husband); Financial Interests, Personal, Ownership Interest: West German Study Group; Financial Interests, Institutional, Funding: AstraZeneca, BMS, Daiichi Sankyo, Lilly, MSD, Novartis, Pierre Fabre, Roche, Palleos, Seagen, TRIO, WSG; Non-Financial Interests, Member, Member German AGO Breast Guideline Committee: AGO Breast Committee; Non-Financial Interests, Member, Breast Cancer Educational Programs: ESO/ESCO; Other, Founding Editor: BreastCare Journal. All other authors have declared no conflicts of interest.