Abstract 99P
Background
This exploratory biomarker analysis aimed to identify prognostic gene sets in the. T-DM1 and H arms of the phase III KATHERINE study (NCT01772472).
Methods
RNA sequencing was performed on post-NAT surgical samples. Genes and pathways associated with prognosis were identified using DGE, comparing pts with invasive disease-free survival (iDFS) events with censored pts at a 3-year cut-off, and gene set enrichment analysis (GSEA), using Hallmark, KEGG, xCell, and selected signatures. NMF was used to identify transcriptional subgroups; their association with iDFS was assessed by Cox regression. Association analyses were adjusted for tumour content (TC) and stratification factors.
Results
Eight hundred and fifteen samples were included in the analysis. GSEA showed that cell cycle, oxidative phosphorylation and DNA repair gene sets were associated with poor prognosis in both arms; in the H arm, metabolism-related signatures were associated with poor prognosis while immune signatures were associated with good prognosis; and in the T-DM1 arm, apoptosis and epithelial mesenchymal (EM) transition (EMT) gene sets and fibroblast, stroma and endothelial cell scores were associated with good prognosis. Trends were seen for poor prognosis with malignant-specific EM signatures in both arms. NMF clusters are described in the table.
Table: 99P
| Cluster, % prevalence | Gene and signature expression, TC and association with prognosis | iDFS hazard ratio,T-DM1 vs. H (95% confidence interval) |
| CL1, 24.0% | Cell cycle and DNA repair-related genes. High TC, higher HER2 and lower ESR1 levels vs. other clusters, poorest prognosis | 0.42 (0.24, 0.75) |
| CL2, 8.3% | Metabolism signatures and keratinisation-related genes | 0.58 (0.16, 2.19) |
| CL3, 40.6% | Focal adhesion, TGFβ, Wnt β catenin, EMT and extracellular matrix-related genes. Low TC, best prognosis | 0.25 (0.11, 0.57) |
| CL4, 18.5% | Oestrogen- and cilium assembly-related genes. High TC, highest ESR1 expression | 0.49 (0.22, 1.08) |
| CL5, 8.5% | Immune-related genes | 0.65 (0.18, 2.38) |
Conclusions
Both DGE and NMF approaches identified cell cycle pathway-related and DNA repair genes as associated with poor prognosis in both arms. Stromal genes and high stromal content were associated with good prognosis. The advantage of T-DM1 over H was seen across all NMF clusters.
Clinical trial identification
NCT01772472, January 21, 2013.
Editorial acknowledgement
Support for third-party writing assistance for this abstract, furnished by Brian Law, PhD, of Health Interactions, was provided by F. Hoffmann-La Roche Ltd., Basel, Switzerland.
Legal entity responsible for the study
F. Hoffmann-La Roche Ltd.
Funding
F. Hoffmann-La Roche Ltd.
Disclosure
C. Denkert: Financial Interests, Personal, Stocks/Shares: Sividon Diagnostics; Financial Interests, Personal, Advisory Board: Daiichi Sankyo, MSD Oncology; Financial Interests, Personal, Other: Novartis, F. Hoffmann-La Roche Ltd., AstraZeneca, Merck, Molecular Health; Non-Financial Interests, Personal, Other, Research funding: Support for third-party writing assistance from F. Hoffmann-La Roche Ltd.: F. Hoffmann-La Roche Ltd. M. Nowicka: Financial Interests, Personal, Full or part-time Employment: F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd.; Non-Financial Interests, Personal, Other, Research funding: Support for third-party writing assistance from F. Hoffmann-La Roche Ltd.: F. Hoffmann-La Roche Ltd. M. Basik: Financial Interests, Personal, Other, Honoraria: Roche Canada; Financial Interests, Personal, Funding, Research funding: LabCorp, Pfizer; Non-Financial Interests, Personal, Other, Research funding: Support for third-party writing assistance from F. Hoffmann-La Roche Ltd.: F. Hoffmann-La Roche Ltd. G. Lewis: Financial Interests, Personal, Full or part-time Employment: Genentech, Inc.; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd.; Non-Financial Interests, Personal, Other, Research funding: Support for third-party writing assistance from F. Hoffmann-La Roche Ltd.: F. Hoffmann-La Roche Ltd. P.A. Fasching: Financial Interests, Personal, Other, Honoraria: Agendia, AstraZeneca, Daiichi Sankyo, Eisai, Gilead Sciences, Hexal, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, F. Hoffmann-La Roche Ltd., Seattle Genetics; Financial Interests, Personal, Advisory Role: Agendia, AstraZeneca, Daiichi Sankyo, Eisai, Gilead Sciences, Hexal, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, F. Hoffmann-La Roche Ltd., Seattle Genetics; Financial Interests, Personal, Funding, Research funding: F. Hoffmann-La Roche Ltd.; Financial Interests, Institutional, Other, Honoraria: BioNTech, Cepheid; Financial Interests, Institutional, Funding, Research funding: BioNTech, Cepheid, Novartis; Non-Financial Interests, Personal, Other, Research funding: Support for third-party writing assistance from F. Hoffmann-La Roche Ltd.: F. Hoffmann-La Roche Ltd. P. Lucas: Financial Interests, Personal, Other, Honoraria (spouse): Schrodinger, Inc.; Financial Interests, Personal, Stocks/Shares: Amgen; Non-Financial Interests, Personal, Other, Research funding: Support for third-party writing assistance from F. Hoffmann-La Roche Ltd.: F. Hoffmann-La Roche Ltd. D. Eiger: Financial Interests, Personal, Full or part-time Employment: F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd.; Non-Financial Interests, Personal, Other, Research funding: Support for third-party writing assistance from F. Hoffmann-La Roche Ltd.: F. Hoffmann-La Roche Ltd. C.E. Geyer: Financial Interests, Personal, Funding, Research funding: Genentech Inc., F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Other, Honoraria: Athenex, Exact Sciences; Financial Interests, Personal, Other, Travel, accommodation, expenses: AbbVie, Daiichi Sankyo, Genentech Inc., F. Hoffmann-La Roche Ltd.; Non-Financial Interests, Personal, Other, Research funding: Support for third-party writing assistance from F. Hoffmann-La Roche Ltd.: F. Hoffmann-La Roche Ltd. S. Loibl: Financial Interests, Institutional, Funding, Research funding: AbbVie, AstraZeneca, Celgene, Daiichi Sankyo, Gilead Sciences, Novartis, Pfizer, F. Hoffmann-La Roche Ltd.; Financial Interests, Institutional, Speaker’s Bureau: AstraZeneca, Daiichi Sankyo Europe GmbH, Medscape, Novartis, Pfizer, Pierre Fabre, F. Hoffmann-La Roche Ltd., Samsung; Financial Interests, Institutional, Advisory Role: AbbVie, Amgen, AstraZeneca/MedImmune, Bayer, Bristol Myers Squibb, Celgene, Daiichi Sankyo, EirGenix, GlaxoSmithKline, Immunomedics, Lilly, Medscape, Merck KGaA, Novartis, Pfizer, Pierre Fabre, Puma Biotechnology, F. Hoffmann-La Roche Ltd., Seattle Genetic; Non-Financial Interests, Personal, Other, Research funding: Support for third-party writing assistance from F. Hoffmann-La Roche Ltd.: F. Hoffmann-La Roche Ltd. S. de Haas: Financial Interests, Personal, Full or part-time Employment: F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd.; Non-Financial Interests, Personal, Other, Research funding: Support for third-party writing assistance from F. Hoffmann-La Roche Ltd.: F. Hoffmann-La Roche Ltd. C. Lambertini: Financial Interests, Personal, Full or part-time Employment: F. Hoffmann-La Roche Ltd.; Non-Financial Interests, Personal, Other, Research funding: Support for third-party writing assistance from F. Hoffmann-La Roche Ltd.: F. Hoffmann-La Roche Ltd.