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Outcome and biomarker supervised deep learning for survival prediction in two multicenter breast cancer series
Dmitrii Bychkov1, Heikki Joensuu2, Stig Nordling3, Aleksei Tiulpin4, Hakan Kücükel1, Mikael Lundin5, Harri Sihto3, Jorma Isola6, Tiina Lehtimäki7, Pirkko-Liisa Kellokumpu-Lehtinen8, Karl von Smitten9, Johan Lundin10, Nina Linder11
1 Institute for Molecular Medicine Finland (FIMM), University of Helsinki; iCAN Digital Precision Cancer Medicine Program, Helsinki, Finland
2 iCAN Digital Precision Cancer Medicine Program; Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
3 Department of Pathology, Medicum, University of Helsinki, Helsinki, Finland
4 Research Unit of Medical Imaging, Physics and Technology, University of Oulu; Department of Diagnostic Radiology, Oulu University Hospital; Ailean Technologies Oy, Oulu, Finland
5 Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
6 Department of Cancer Biology, BioMediTech, University of Tampere, Tampere, Finland
7 Helsinki University Hospital, Helsinki, Finland
8 Department of Oncology, Tampere University Hospital, Tampere, Finland
9 Eira Hospital, Helsinki, Finland
10 Institute for Molecular Medicine Finland (FIMM), University of Helsinki; iCAN Digital Precision Cancer Medicine Program, Helsinki, Finland; Department of Global Public Health, Karolinska Institutet, Stockholm, Sweden
11 Institute for Molecular Medicine Finland (FIMM), University of Helsinki; iCAN Digital Precision Cancer Medicine Program, Helsinki, Finland; Department of Women's and Children's Health, International Maternal and Child Health, Uppsala University, Uppsala, Sweden
Correspondence Address:
Mr. Dmitrii Bychkov
Institute for Molecular Medicine Finland FIMM, Nordic EMBL Partnership for Molecular Medicine, P. O. Box: 20, FI.00014 University of Helsinki, Helsinki; Biomedicum Helsinki 2U, Tukholmankatu 8, 00290 Helsinki
Finland
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/jpi.jpi_29_21
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Background: Prediction of clinical outcomes for individual cancer patients is an important step in the disease diagnosis and subsequently guides the treatment and patient counseling. In this work, we develop and evaluate a joint outcome and biomarker supervised (estrogen receptor expression and ERBB2 expression and gene amplification) multitask deep learning model for prediction of outcome in breast cancer patients in two nation-wide multicenter studies in Finland (the FinProg and FinHer studies). Our approach combines deep learning with expert knowledge to provide more accurate, robust, and integrated prediction of breast cancer outcomes. Materials and Methods: Using deep learning, we trained convolutional neural networks (CNNs) with digitized tissue microarray (TMA) samples of primary hematoxylin-eosin-stained breast cancer specimens from 693 patients in the FinProg series as input and breast cancer-specific survival as the endpoint. The trained algorithms were tested on 354 TMA patient samples in the same series. An independent set of whole-slide (WS) tumor samples from 674 patients in another multicenter study (FinHer) was used to validate and verify the generalization of the outcome prediction based on CNN models by Cox survival regression and concordance index (c-index). Visual cancer tissue characterization, i.e., number of mitoses, tubules, nuclear pleomorphism, tumor-infiltrating lymphocytes, and necrosis was performed on TMA samples in the FinProg test set by a pathologist and combined with deep learning-based outcome prediction in a multitask algorithm. Results: The multitask algorithm achieved a hazard ratio (HR) of 2.0 (95% confidence interval [CI] 1.30–3.00), P < 0.001, c-index of 0.59 on the 354 test set of FinProg patients, and an HR of 1.7 (95% CI 1.2–2.6), P = 0.003, c-index 0.57 on the WS tumor samples from 674 patients in the independent FinHer series. The multitask CNN remained a statistically independent predictor of survival in both test sets when adjusted for histological grade, tumor size, and axillary lymph node status in a multivariate Cox analyses. An improved accuracy (c-index 0.66) was achieved when deep learning was combined with the tissue characteristics assessed visually by a pathologist. Conclusions: A multitask deep learning algorithm supervised by both patient outcome and biomarker status learned features in basic tissue morphology predictive of survival in a nationwide, multicenter series of patients with breast cancer. The algorithms generalized to another independent multicenter patient series and whole-slide breast cancer samples and provide prognostic information complementary to that of a comprehensive series of established prognostic factors.
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