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

Evan D. Paul (), Barbora Huraiová, Natália Valková, Natalia Matyasovska, Daniela Gábrišová, Soňa Gubová, Helena Ignačáková, Tomáš Ondris, Michal Gala, Liliane Barroso, Silvia Bendíková, Jarmila Bíla, Katarína Buranovská, Diana Drobná, Zuzana Krchňáková, Maryna Kryvokhyzha, Daniel Lovíšek, Viktoriia Mamoilyk, Veronika Mancikova, Nina Vojtaššáková, Michaela Ristová, Iñaki Comino-Méndez, Igor Andrašina, Pavel Morozov, Thomas Tuschl, Fresia Pareja (), Jakob N. Kather () and Pavol Čekan ()
Additional contact information
Evan D. Paul: Comenius University Science Park
Barbora Huraiová: Comenius University Science Park
Natália Valková: Comenius University Science Park
Natalia Matyasovska: Comenius University Science Park
Daniela Gábrišová: Comenius University Science Park
Soňa Gubová: Comenius University Science Park
Helena Ignačáková: Comenius University Science Park
Tomáš Ondris: Comenius University Science Park
Michal Gala: Comenius University Science Park
Liliane Barroso: Comenius University Science Park
Silvia Bendíková: Comenius University Science Park
Jarmila Bíla: Comenius University Science Park
Katarína Buranovská: Comenius University Science Park
Diana Drobná: Comenius University Science Park
Zuzana Krchňáková: Comenius University Science Park
Maryna Kryvokhyzha: Comenius University Science Park
Daniel Lovíšek: Comenius University Science Park
Viktoriia Mamoilyk: Comenius University Science Park
Veronika Mancikova: Comenius University Science Park
Nina Vojtaššáková: Comenius University Science Park
Michaela Ristová: Comenius University Science Park
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
Pavol Čekan: Comenius University Science Park

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-024-55583-2

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