NACT is the standard treatment for eTNBC, yet, molecular phenotypes driving chemotherapy sensitivity are poorly understood. Whole transcriptome profiling of baseline tumor biopsies from the neoadjuvant WSG-ADAPT-TN phase II trial (NCT01815242) was performed to identify gene networks predictive and prognostic for pCR and survival.
Patients with cT1c-cT4c, cN+, centrally confirmed eTNBC were randomized to 12 weeks of nab-paclitaxel+gemcitabine (Arm A; n=182) or nab-paclitaxel+carboplatin (Arm B; n=154). The primary endpoint was pCR (ypT0/is, ypN0), secondary endpoints included survival and translational research. AmpliSeq RNA sequencing allowing simultaneous analysis of the expression of >20,000 genes was performed in 137 patients (Arm A/B: n=72/65). Differentially expressed genes were then evaluated in training (n=67) and validation (n=68) sets and two polygenic scores (PS) with a high diagnostic performance for prediction of pCR (PS:pCR) and invasive disease-free survival (PS:iDFS) were found.
49/135 (36.3%) patients had pCR; 30 iDFS events occurred during 60-month median follow-up. Genes and networks associated with immune recruitment, endogenous retroviral transcription, and viral defense were strongly associated with pCR and iDFS. PS:pCR achieved a high diagnostic accuracy (ROC AUC: 83%). In multivariate analysis (validation set) adjusted for clinical factors, pCR was associated with PS:pCR (OR 7.24; 95%CI 2.05, 25.58; p=0.002). Addition of PS:pCR to clinical factors increased ROC AUC for pCR from 0.707 to 0.887. iDFS was associated with PS:iDFS (HR 2.06; 95%CI 1.01, 4.20; p=0.046).
Polygenic scores based on immunomodulatory and anti-viral defense gene networks may have utility in predicting pCR and survival, and could represent an opportunity for selecting patients for de-escalated NACT in eTNBC. This transcriptome network analysis also identifies potential new targets for personalized medicine approaches for patients without response to chemotherapy.
NCT01815242.
West German Study Group GmbH.
Teva and Celgene funding the ADAPT TN trial.
M. Graeser: Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Other, Travel Support: Daiichi Sankyo. N. Harbeck: Financial Interests, Personal, Advisory Role: AstraZeneca, Daiichi Sankyo, Eli Lilly, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Sandoz, Seagen; Financial Interests, Institutional, Research Grant: Eli Lilly, MSD, Novartis, Pfizer, Roche. O. Gluz: Financial Interests, Personal, Advisory Role: Celgene, Genomic Health/Exact Sciences, Eli Lilly, MSD, Novartis, Pfizer, Roche, Seagen, Pierre Fabre, Gilead, Molecular health; Financial Interests, Personal, Expert Testimony: Genomic Health; Financial Interests, Personal, Other, travel support: Roche. U.A. Nitz: Financial Interests, Institutional, Research Grant: Agendia, Amgen, Celgene, Genomic Health, NanoString Technologies, Roche, Sanofi; Financial Interests, Personal, Advisory Role: Genomic Health , Roche; Financial Interests, Personal, Expert Testimony: Genomic Health; Financial Interests, Personal, Other, travel support: Genomic Health, Pfizer , Roche; Financial Interests, Personal, Advisory Board: Roche, Seagen, Exact Sciences. S. Kuemmel: Financial Interests, Institutional, Research Grant: Roche , Novartis; Financial Interests, Personal, Advisory Role: Amgen, AstraZeneca, Celgene, Daiichi Sankyo, Genomic Health/Exact Science, Lilly, MSD, Novartis, Seagen, Pfizer, pfm Medical, Roche, Somatex, Gilead; Financial Interests, Personal, Other, travel support: Roche , Daiichi Sankyo. H. Forstbauer: Financial Interests, Personal, Invited Speaker: Roche, iOMEDICO; Financial Interests, Personal, Invited Speaker, travel support: Celgene , Amgen. M. Braun: Financial Interests, Personal, Advisory Role: AstraZeneca, Exact Sciences, Novartis, Puma, Roche; Financial Interests, Personal, Invited Speaker, travel support: AstraZeneca, Celgene, Medac, Novartis, Roche, Daiichi Sankyo. C. Uleer: Financial Interests, Personal, Advisory Role: Tesaro, Novartis, Roche; Financial Interests, Institutional, Research Grant: Novartis, AstraZeneca, Tesaro, Palleos Healthcare Services GmbH, Pierre Fabre, AGO-Studiengrouppe, West German Study Group, German Breast Group; Financial Interests, Personal, Other, travel support: German Breast Group, West German Study Group, AGO-Studiengrouppe; Financial Interests, Personal, Speaker’s Bureau: Pfizer, Novartis, Roche, PharmaMar, AstraZeneca. B. Aktas: Financial Interests, Invited Speaker, Honoraria: Pfizer, Roche Pharma, MSD, Onkowissen, Novartis, AstraZeneca, PharmaMar, Lilly, Promedicis. R. Würstlein: Financial Interests, Personal, Advisory Role, and travel support: Agendia, Amgen, Aristo, AstraZeneca, Boeringer Ingelheim, Celgene, Daiichi Sankyo, Eisai, Exact Sciences/Genomic Health, Gilead, GSK, Hexal, Lilly, Medstrom Medical, MSD, Mundipharma, Mylan, Nanostring Technologies, Novartis, Odonate, Paxman, Palleos, Pfizer, Pierre Fabre, Puma, Riemser, Roche, Sandoz/Hexal, Sanofi Genzyme, Seattle Genetics/Seagen, Tesaro Bio, Teva, Veracyte , Viatris; Financial Interests, Personal, Advisory Role, and travel supportv: Carl Zeiss. H. Kreipe: Financial Interests, Personal, Invited Speaker: Roche , Novartis, Genomic Health, AstraZeneca, Lilly, Pfizer; Financial Interests, Personal, Advisory Board: Roche , Genomic Health, AstraZeneca. All other authors have declared no conflicts of interest.