139MO - Identification of biologically-driven HER2-positive breast cancer subgroups associated with prognosis after adjuvant trastuzumab in the ALTTO trial

Background

Several tumor and microenvironment features impact HER2-positive breast cancer progression, portraying its heterogeneity. Here, we aimed to identify subgroups associated with prognosis in patients receiving adjuvant trastuzumab in the phase III ALTTO trial.

Methods

A case-control approach (1:2) was used to select from the trastuzumab arm 134 and 268 patients with and without a distant relapse, matched for clinicopathological characteristics. RNA was obtained from FFPE tumor cores from surgical samples. PAM50 subtypes were computed using Absolute Intrinsic Molecular Subtyping (AIMS). Uni- and multivariable (controlling for clinicopathological characteristics and PAM50 HER2-enriched [HER2-E] vs others) Cox proportional hazard models and Kaplan-Meier curves were used for distant relapse-free survival (DRFS) analysis. Clusters were identified using non-negative matrix factorization (NMF) and k-means clustering, and characterized with gene signatures.

Results

The case-control cohort includes higher proportions of >2cm, node positive and G3 tumors compared to the whole trastuzumab arm. RNA sequencing data were generated for 386/402 patients. Genes associated with DRFS (false discovery rate < 0.05, multivariable analysis) were selected for NMF to extract 4 factors. K-means clustering identified 4 groups with distinct prognosis: immune-enriched (N = 69; 91% 5-year DRFS), metabolic-enriched (N = 87; 51% 5-year DRFS), stroma-enriched (N = 76; 58% 5-year DRFS), and hormone receptor positive-enriched (N = 154; 78% 5-year DRFS) which could be divided into HER2-E and non-HER2-E (mainly Luminal A/B) tumors (N = 91 and 63; 72% and 87% 5-year DRFS, respectively). The robustness and prognostic value of the clusters were assessed via cross-validation of gene selection, NMF and k-means clustering.

Conclusions

A supervised top-down approach identified 4 biologically-driven clusters in HER2-positive breast cancer which can be integrated with PAM50. Our findings support the evaluation of de-escalation approaches in luminal and immune-enriched subgroups, presenting excellent prognosis with adjuvant trastuzumab alone in a high-risk population. Further validation is required.

Clinical trial identification

NCT00490139. First Posted: June 22, 2007.

Editorial acknowledgement

Legal entity responsible for the study

Novartis and NCI.

Funding

The conduct of the ALTTO study was funded by GSK and later Novartis. The RNA sequencing on which the analyses described in this abstract are based was funded by Breast Cancer Research Foundation (BCRF) and Fondation contre le Cancer.

Disclosure

S. El-Abed: Financial Interests, Personal, Other, Grant within the submitted work: Novartis; Financial Interests, Personal, Other, Grant outside the submitted work: Roche/Genentech, Pfizer. M.C. Liu: Financial Interests, Institutional, Other, Research support: Eisai, Exact Sciences, Genentech, Genomic Health, GRAIL, Menarini Silicon Biosystems, Merck, Novartis, Seattle Genetics, Tesaro; Financial Interests, Institutional, Advisory Board: AstraZeneca, Celgene, Roche/Genentech, Genomic Health, GRAIL, Ionis, Merck, Pfizer, Seattle Genetics, Syndax. S. Di Cosimo: Financial Interests, Personal, Other, Consulting fees: Pierre-Fabre, IQVIA, AstraZeneca; Financial Interests, Personal, Other, Grant reviewer compensations: Swiss Cancer League, Ellipses; Financial Interests, Personal, Other, Medical advisor fees: MEDSIR; Financial Interests, Institutional, Research Grant: Fondazione Associazione Italiana Ricerca contro il Cancro (AIRC); Non-Financial Interests, Personal, Other, Member of the steering committee: Neo-/ALTTO, Neo-Phoebe, Neo-Erubilin, NSABP-FB7, Parsifal, PHERGain; Non-Financial Interests, Personal, Member: ESMO EU Policy Committee, Regional Board of Associazione Italiana di Oncologia Medica, DIGICORE. M. Piccart: Financial Interests, Personal, Invited Speaker: Astra-Zeneca, Lilly, MSD, Novartis, Pfizer; Financial Interests, Personal, Other, Consultant: Camel-IDS/Precirix; Financial Interests, Personal, Advisory Board: Immunomedics, Menarini, Odonate, Seattle Genetics, Immutep, SeaGen, Gilead, NBE Therapeutics, Frame Therapeutics; Financial Interests, Personal, Advisory Board, Consultant and invited speaker: Roche-Genentech; Financial Interests, Personal, Invited Speaker, Scientific Board: Oncolytics; Financial Interests, Institutional, Research Grant: Astra-Zeneca, Immunomedics, Lilly; Financial Interests, Institutional, Funding: Menarini, MSD, Novartis, Pfizer, Radius, Roche-Genentech, Servier, Synthon. L. Pusztai: Financial Interests, Personal, Other, consulting fees and honoraria: Seagen, Pfizer, AstraZeneca, Merck, Novartis, Bristol-Myers Squibb, Genentech, Eisai, Pieris, Immunomedics, Clovis, Syndax, H3Bio, Radius Health, Personalis, Daiichi, Natera; Financial Interests, Institutional, Other, research funding: Seagen, AstraZeneca, Merck; Financial Interests, Institutional, Other, research: Pfizer, Bristol-Myers Squibb. S. Loi: Financial Interests, Institutional, Other, research funding: Novartis, Bristol Meyers Squibb, Merck, Puma Biotechnology, Eli Lilly, Nektar Therapeutics, AstraZeneca, Roche-Genentech, Seattle Genetics; Non-Financial Interests, Personal, Other, consultant: Seattle Genetics, Novartis, Bristol Meyers Squibb, Merck, AstraZeneca, Eli Lilly, Pfizer, Gilead Therapeutics, Roche-Genentech; Financial Interests, Institutional, Other, consultant: Aduro Biotech, Novartis, GlaxoSmithKline, Roche-Genentech, AstraZeneca, Silverback Therapeutics, G1 Therapeutics, PUMA Biotechnologies, Pfizer, Gilead Therapeutics, Seattle Genetics, Daiichi Sankyo, Merck, Amunix, Tallac Therapeutics, Eli Lilly, Bristol Meyers Squibb. R.F. Salgado: Non-Financial Interests, Personal, Other, non-financial support: Merck, Bristol Myers Squibb (BMS); Financial Interests, Personal, Other, research support: Merck, Puma Biotechnology, Roche; Financial Interests, Personal, Other, advisory board: Roche, Bristol Myers Squibb (BMS), Exact Sciences. G. Viale: Financial Interests, Personal, Other, Honoraria: MSD Oncology, Pfizer, Daiichi Sankyo Europe GmbH; Financial Interests, Personal, Advisory Role: Dako, Roche/Genentech, Novartis, Bayer, Daiichi Sankyo, MSD Oncology, Menarini; Financial Interests, Personal, Speaker’s Bureau: Roche/Genentech; Financial Interests, Personal, Other, Research Funding: Roche/Genentech; Financial Interests, Institutional, Other, Research Funding: Ventana Medical Systems, Dako/Agilent Technologies, Cepheid; Financial Interests, Personal, Invited Speaker, Travel, Accommodations, Expenses: Roche. C. Sotiriou: Financial Interests, Institutional, Advisory Board: Astellas, Vertex, Seattle Genetics, AMGEN, INC, Merck & Co; Financial Interests, Personal, Advisory Board: Cepheid, Puma; Financial Interests, Personal, Invited Speaker: Eisai, Prime oncology, Teva; Financial Interests, Institutional, Other, Travel: Roche; Financial Interests, Institutional, Other, Internal speaker: Genentech; Financial Interests, Personal, Other, Regional speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: Exact Sciences. All other authors have declared no conflicts of interest.