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

Author

Listed:
  • Evan D. Paul

    (Comenius University Science Park
    Inc)

  • Barbora Huraiová

    (Comenius University Science Park
    Inc)

  • Natália Valková

    (Comenius University Science Park
    Inc)

  • Natalia Matyasovska

    (Comenius University Science Park
    Inc
    Charles University)

  • Daniela Gábrišová

    (Comenius University Science Park
    Inc)

  • Soňa Gubová

    (Comenius University Science Park
    Inc)

  • Helena Ignačáková

    (Comenius University Science Park
    Inc)

  • Tomáš Ondris

    (Comenius University Science Park
    Inc)

  • Michal Gala

    (Comenius University Science Park
    Inc)

  • Liliane Barroso

    (Comenius University Science Park
    Inc)

  • Silvia Bendíková

    (Comenius University Science Park
    Inc)

  • Jarmila Bíla

    (Comenius University Science Park
    Inc)

  • Katarína Buranovská

    (Comenius University Science Park
    Inc)

  • Diana Drobná

    (Comenius University Science Park
    Inc)

  • Zuzana Krchňáková

    (Comenius University Science Park
    Inc)

  • Maryna Kryvokhyzha

    (Comenius University Science Park
    Inc)

  • Daniel Lovíšek

    (Comenius University Science Park
    Inc)

  • Viktoriia Mamoilyk

    (Comenius University Science Park
    Inc)

  • Veronika Mancikova

    (Comenius University Science Park
    Inc)

  • Nina Vojtaššáková

    (Comenius University Science Park
    Inc)

  • Michaela Ristová

    (Comenius University Science Park
    Inc
    University of Edinburgh)

  • Iñaki Comino-Méndez

    (The Biomedical Research Institute of Málaga (IBIMA-CIMES-UMA))

  • Igor Andrašina

    (East Slovakia Institute of Oncology)

  • Pavel Morozov

    (The Rockefeller University)

  • Thomas Tuschl

    (The Rockefeller University)

  • Fresia Pareja

    (Memorial Sloan Kettering Cancer Center)

  • Jakob N. Kather

    (Technical University Dresden
    University Hospital Dresden
    University Hospital Heidelberg)

  • Pavol Čekan

    (Comenius University Science Park
    Inc)

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.

Suggested Citation

  • Evan D. Paul & Barbora Huraiová & Natália Valková & Natalia Matyasovska & Daniela Gábrišová & Soňa Gubová & Helena Ignačáková & Tomáš Ondris & Michal Gala & Liliane Barroso & Silvia Bendíková & Jarmil, 2025. "The spatially informed mFISHseq assay resolves biomarker discordance and predicts treatment response in breast cancer," Nature Communications, Nature, vol. 16(1), pages 1-22, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-55583-2
    DOI: 10.1038/s41467-024-55583-2
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    1. Charles M. Perou & Therese Sørlie & Michael B. Eisen & Matt van de Rijn & Stefanie S. Jeffrey & Christian A. Rees & Jonathan R. Pollack & Douglas T. Ross & Hilde Johnsen & Lars A. Akslen & Øystein Flu, 2000. "Molecular portraits of human breast tumours," Nature, Nature, vol. 406(6797), pages 747-752, August.
    2. Christina Curtis & Sohrab P. Shah & Suet-Feung Chin & Gulisa Turashvili & Oscar M. Rueda & Mark J. Dunning & Doug Speed & Andy G. Lynch & Shamith Samarajiwa & Yinyin Yuan & Stefan Gräf & Gavin Ha & Gh, 2012. "The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups," Nature, Nature, vol. 486(7403), pages 346-352, June.
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    Cited by:

    1. Kevin M. Boehm & Omar S. M. El Nahhas & Antonio Marra & Michele Waters & Justin Jee & Lior Braunstein & Nikolaus Schultz & Pier Selenica & Hannah Y. Wen & Britta Weigelt & Evan D. Paul & Pavol Cekan &, 2025. "Multimodal histopathologic models stratify hormone receptor-positive early breast cancer," Nature Communications, Nature, vol. 16(1), pages 1-14, December.

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