The spatially informed mFISHseq assay resolves biomarker discordance and predicts treatment response in breast cancer
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...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55583-2 |
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| author | 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 Pavol Čekan |
| author_facet | 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 Pavol Čekan |
| author_sort | Evan D. Paul |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-c4d81a72ac9647e79cbd452aed2f79e0 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-c4d81a72ac9647e79cbd452aed2f79e02025-01-05T12:39:47ZengNature PortfolioNature Communications2041-17232025-01-0116112210.1038/s41467-024-55583-2The spatially informed mFISHseq assay resolves biomarker discordance and predicts treatment response in breast cancerEvan D. Paul0Barbora Huraiová1Natália Valková2Natalia Matyasovska3Daniela Gábrišová4Soňa Gubová5Helena Ignačáková6Tomáš Ondris7Michal Gala8Liliane Barroso9Silvia Bendíková10Jarmila Bíla11Katarína Buranovská12Diana Drobná13Zuzana Krchňáková14Maryna Kryvokhyzha15Daniel Lovíšek16Viktoriia Mamoilyk17Veronika Mancikova18Nina Vojtaššáková19Michaela Ristová20Iñaki Comino-Méndez21Igor Andrašina22Pavel Morozov23Thomas Tuschl24Fresia Pareja25Jakob N. Kather26Pavol Čekan27MultiplexDX, s.r.o., Comenius University Science ParkMultiplexDX, s.r.o., Comenius University Science ParkMultiplexDX, s.r.o., Comenius University Science ParkMultiplexDX, s.r.o., Comenius University Science ParkMultiplexDX, s.r.o., Comenius University Science ParkMultiplexDX, s.r.o., Comenius University Science ParkMultiplexDX, s.r.o., Comenius University Science ParkMultiplexDX, s.r.o., Comenius University Science ParkMultiplexDX, s.r.o., Comenius University Science ParkMultiplexDX, s.r.o., Comenius University Science ParkMultiplexDX, s.r.o., Comenius University Science ParkMultiplexDX, s.r.o., Comenius University Science ParkMultiplexDX, s.r.o., Comenius University Science ParkMultiplexDX, s.r.o., Comenius University Science ParkMultiplexDX, s.r.o., Comenius University Science ParkMultiplexDX, s.r.o., Comenius University Science ParkMultiplexDX, s.r.o., Comenius University Science ParkMultiplexDX, s.r.o., Comenius University Science ParkMultiplexDX, s.r.o., Comenius University Science ParkMultiplexDX, s.r.o., Comenius University Science ParkMultiplexDX, s.r.o., Comenius University Science ParkHospital Universitario Virgen de la Victoria, The Biomedical Research Institute of Málaga (IBIMA-CIMES-UMA)Department of Radiotherapy and Oncology, East Slovakia Institute of OncologyLaboratory for RNA Molecular Biology, The Rockefeller UniversityLaboratory for RNA Molecular Biology, The Rockefeller UniversityDepartment of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer CenterElse Kroener Fresenius Center for Digital Health, Technical University DresdenMultiplexDX, s.r.o., Comenius University Science ParkAbstract 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.https://doi.org/10.1038/s41467-024-55583-2 |
| spellingShingle | 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 Pavol Čekan The spatially informed mFISHseq assay resolves biomarker discordance and predicts treatment response in breast cancer Nature Communications |
| title | The spatially informed mFISHseq assay resolves biomarker discordance and predicts treatment response in breast cancer |
| title_full | The spatially informed mFISHseq assay resolves biomarker discordance and predicts treatment response in breast cancer |
| title_fullStr | The spatially informed mFISHseq assay resolves biomarker discordance and predicts treatment response in breast cancer |
| title_full_unstemmed | The spatially informed mFISHseq assay resolves biomarker discordance and predicts treatment response in breast cancer |
| title_short | The spatially informed mFISHseq assay resolves biomarker discordance and predicts treatment response in breast cancer |
| title_sort | spatially informed mfishseq assay resolves biomarker discordance and predicts treatment response in breast cancer |
| url | https://doi.org/10.1038/s41467-024-55583-2 |
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