The spatially informed mFISHseq assay resolves biomarker discordance and predicts treatment response in breast cancer Journal Article
| Authors: | Paul, E. D.; Huraiová, B.; Valková, N.; Matyasovska, N.; Gábrišová, D.; Gubová, S.; Ignačáková, H.; Ondris, T.; Gala, M.; Barroso, L.; Bendíková, S.; Bíla, J.; Buranovská, K.; Drobná, D.; Krchňáková, Z.; Kryvokhyzha, M.; Lovíšek, D.; Mamoilyk, V.; Mancikova, V.; Vojtaššáková, N.; Ristová, M.; Comino-Méndez, I.; Andrašina, I.; Morozov, P.; Tuschl, T.; Pareja, F.; Kather, J. N.; Čekan, P. |
| Article Title: | 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 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. © The Author(s) 2025. |
| Keywords: | immunohistochemistry; adult; cancer survival; controlled study; human tissue; treatment outcome; treatment response; middle aged; retrospective studies; unclassified drug; major clinical study; overall survival; genetics; clinical feature; clinical trial; cancer combination chemotherapy; paclitaxel; comparative study; neoadjuvant therapy; diagnostic accuracy; prospective study; prospective studies; cd8 antigen; ki 67 antigen; cd8+ t lymphocyte; metabolism; in situ hybridization, fluorescence; cancer immunotherapy; phase 2 clinical trial; breast cancer; hepatocyte nuclear factor 3alpha; transcription factor gata 3; x box binding protein 1; gene expression profiling; image analysis; dendritic cell; tumor volume; epidermal growth factor receptor 2; cohort analysis; validation study; inhibitor; breast neoplasms; retrospective study; tumor marker; assay; prediction; high risk patient; molecular marker; fluorescence in situ hybridization; immunotherapy; biomarker; multicenter study; breast tumor; carcinoma in situ; innate immunity; multivariate analysis; eosin; hematoxylin; immunity; diagnostic test; monocyte; cancer classification; estrogen receptor; progesterone receptor; sequence analysis, rna; health risk; drug therapy; cyclin dependent kinase inhibitor; univariate analysis; cadherin; disease treatment; pertuzumab; descriptive research; pathological complete response; heterogeneity; triple negative breast cancer; atypical ductal hyperplasia; antibody conjugate; immunoconjugates; spatial analysis; laser capture microdissection; procedures; trastuzumab emtansine; low risk patient; cancer prognosis; invasive breast cancer; basal like breast cancer; cancer; humans; prognosis; human; female; article; rna sequencing; pembrolizumab; hormone receptor positive breast cancer; biomarkers, tumor; multispectral imaging; breast cancer molecular subtype; overlapping gene; antibody drug conjugate; cyclin dependent kinase inhibitor 4; cyclin dependent kinase inhibitor 6; ductal breast carcinoma in situ; invasive lobular breast carcinoma; multiplexed rna fluorescent in situ hybridization with rna sequencing assay |
| Journal Title: | Nature Communications |
| Volume: | 16 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2025-01-02 |
| Start Page: | 226 |
| Language: | English |
| DOI: | 10.1038/s41467-024-55583-2 |
| PUBMED: | 39747865 |
| PROVIDER: | scopus |
| PMCID: | PMC11696812 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Fresia Pareja -- Source: Scopus |
