The spatially informed mFISHseq assay resolves biomarker discordance and predicts treatment response in breast cancer

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Evan D Paul - , MultiplexDX, Inc., MultiplexDX s.r.o., Slovakia (Author)
  • Barbora Huraiová - , MultiplexDX, Inc., MultiplexDX s.r.o., Slovakia (Author)
  • Natália Valková - , MultiplexDX, Inc., MultiplexDX s.r.o., Slovakia (Author)
  • Natalia Matyasovska - , MultiplexDX, Inc., MultiplexDX s.r.o., Slovakia, University of Hradec Kralove (Author)
  • Daniela Gábrišová - , MultiplexDX, Inc., MultiplexDX s.r.o., Slovakia (Author)
  • Soňa Gubová - , MultiplexDX, Inc., MultiplexDX s.r.o., Slovakia (Author)
  • Helena Ignačáková - , MultiplexDX, Inc., MultiplexDX s.r.o., Slovakia (Author)
  • Tomáš Ondris - , MultiplexDX, Inc., MultiplexDX s.r.o., Slovakia (Author)
  • Michal Gala - , MultiplexDX, Inc., MultiplexDX s.r.o., Slovakia (Author)
  • Liliane Barroso - , MultiplexDX, Inc., MultiplexDX s.r.o., Slovakia (Author)
  • Silvia Bendíková - , MultiplexDX, Inc., MultiplexDX s.r.o., Slovakia (Author)
  • Jarmila Bíla - , MultiplexDX, Inc., MultiplexDX s.r.o., Slovakia (Author)
  • Katarína Buranovská - , MultiplexDX, Inc., MultiplexDX s.r.o., Slovakia (Author)
  • Diana Drobná - , MultiplexDX, Inc., MultiplexDX s.r.o., Slovakia (Author)
  • Zuzana Krchňáková - , MultiplexDX, Inc., MultiplexDX s.r.o., Slovakia (Author)
  • Maryna Kryvokhyzha - , MultiplexDX, Inc., MultiplexDX s.r.o., Slovakia (Author)
  • Daniel Lovíšek - , MultiplexDX, Inc., MultiplexDX s.r.o., Slovakia (Author)
  • Viktoriia Mamoilyk - , MultiplexDX, Inc., MultiplexDX s.r.o., Slovakia (Author)
  • Veronika Mancikova - , MultiplexDX, Inc., MultiplexDX s.r.o., Slovakia (Author)
  • Nina Vojtaššáková - , MultiplexDX, Inc., MultiplexDX s.r.o., Slovakia (Author)
  • Michaela Ristová - , MultiplexDX, Inc., MultiplexDX s.r.o., Slovakia, University of Edinburgh (Author)
  • Iñaki Comino-Méndez - , Instituto de Investigación Biomédica de Málaga (IBIMA) (Author)
  • Igor Andrašina - , University of Pavol Jozef Safarik Kosice (Author)
  • Pavel Morozov - , Rockefeller University (Author)
  • Thomas Tuschl - , Rockefeller University (Author)
  • Fresia Pareja - , Memorial Sloan-Kettering Cancer Center (Author)
  • Jakob N Kather - , Department of Internal Medicine I, Else Kröner Fresenius Center for Digital Health, National Center for Tumor Diseases (NCT) Heidelberg (Author)
  • Pavol Čekan - , MultiplexDX, Inc., MultiplexDX s.r.o., Slovakia (Author)

Abstract

Current assays fail to address breast cancer's complex biology and accurately predict treatment response. On a retrospective cohort of 1082 female breast tissues, we develop and validate mFISHseq, which integrates multiplexed RNA fluorescent in situ hybridization with RNA-sequencing, guided by laser capture microdissection. This technique ensures tumor purity, unbiased whole transcriptome profiling, and explicitly quantifies intratumoral heterogeneity. Here we show mFISHseq has 93% accuracy compared to immunohistochemistry. Our consensus subtyping and risk groups mitigate single sample discordance, provide early and late prognostic information, and identify high risk patients with enriched immune signatures, which predict response to neoadjuvant immunotherapy in the multicenter, phase II, prospective I-SPY2 trial. We identify putative antibody-drug conjugate (ADC)-responsive patients, as evidenced by a 19-feature T-DM1 classifier, validated on I-SPY2. Deploying mFISHseq as a research-use only test on 48 patients demonstrates clinical feasibility, revealing insights into the efficacy of targeted therapies, like CDK4/6 inhibitors, immunotherapies, and ADCs.

Details

Original languageEnglish
Article number226
Pages (from-to)226
JournalNature communications
Volume16
Issue number1
Publication statusPublished - 2 Jan 2025
Peer-reviewedYes

External IDs

Scopus 85214031959

Keywords

Sustainable Development Goals

Keywords

  • Humans, Breast Neoplasms/genetics, Female, Biomarkers, Tumor/genetics, In Situ Hybridization, Fluorescence/methods, Retrospective Studies, Gene Expression Profiling/methods, Immunotherapy/methods, Prognosis, Sequence Analysis, RNA/methods, Middle Aged, Immunohistochemistry, Neoadjuvant Therapy, Treatment Outcome, Prospective Studies, Immunoconjugates/therapeutic use, Adult