4P - Predicting triple-negative breast cancer molecular subtype from hematoxylin and eosin using deep neural networks

Background

Triple-negative breast cancer (TNBC) accounts for 15% to 20% of all breast cancer cases and is characterized by the absence of estrogen and progesterone receptor expression, as well as the lack of HER2 over-expression. TNBC is a heterogeneous disease, proving to be challenging in terms of disease therapy. RNA sequencing (RNA-Seq) analysis performed on TNBC samples has identified several molecular subtypes, namely: basal-like (BL), immunomodulatory (IM), luminal androgen receptor (LAR), mesenchymal (M), and mesenchymal stem-like (MSL), according to Bareche classification. Since RNA-Seq analysis is not routine practice, this classification is currently unavailable in the clinic. Our goal is to make it available to routine practice, by applying deep learning to Hematoxylin and Eosin (H&E) stained slides and predicting the TNBC molecular subtype.

Methods

We based this study on the IBCSG 22-00 trial. We selected 256 patients for which both digitalized H&E and bulk RNA-Seq were available. We use RNA-Seq to compute the TNBC molecular subtype. For each patient, we pre-process the Whole Slide Image (WSI) tiling the tissue in small patches. We then use the pre-trained UNI model to extract features from every tile. We then use CLAM, a multiple instance learning (MIL) model to predict the WSI-level TNBC subtype. As a starting point, we chose two classes that we consider easier to predict in terms of morphology: LAR and IM.

Results

We run a 10-fold cross-validation, performing a 60-20-20 split of the data. We measure the classification accuracy for each class in each fold, we report the average accuracy computed on the test set over 10 folds. The accuracies we obtain are 0.75 for LAR, 0.74 for IM, and 0.84 for other. We obtain 0.94 AUC (global).

Conclusions

Deep Learning can extract morphological information captured from H&E slides, and predict molecular subtype classification originally computed from bulk RNA-seq. We proved that it is possible to predict two out of five TNBC molecular subtypes from just H&E slides with high accuracy. We are confident that this can be extended to all of the five molecular subtypes, making this classification system available in clinic, bypassing expensive RNA-sequencing.

Editorial acknowledgement

Clinical trial identification

NCT00022516.

Legal entity responsible for the study

FNRS - Institute Jules Bordet.

Funding

FNRS Televie - Association Jules Bordet - BCRF.

Disclosure

M. Colleoni: Financial Interests, Institutional, Research Grant: Roche; Non-Financial Interests, Personal, Leadership Role, Co-Chair Scientific Committee: International Breast Cancer Study Group. S. Loi: Financial Interests, Institutional, Advisory Board, Consultant: AstraZeneca, Novartis, Roche Genentech; Financial Interests, Institutional, Expert Testimony, Consultant: BMS; Financial Interests, Institutional, Expert Testimony, consultant: Daiichi Sankyo, Eli Lilly, Gilead Sciences, Merck; Financial Interests, Personal, Expert Testimony: Novartis, AstraZeneca, BMS, Domain Therapeutics; Financial Interests, Personal, Advisory Board: Amaroq Therapeutics, Mersana Therapeutics; Financial Interests, Institutional, Funding, Research: Novartis, BMS, Merck, Puma Biotechnology, Eli Lilly, Nektar Therapeutics, AstraZeneca, Seattle Genetics, Roche - Genentech; Non-Financial Interests, Personal, Advisory Role, Consultant (Non remunerated): Seattle Genetics, Novartis, Bristol Myers Squibb, Merck, AstraZeneca, Roche Genentech; Non-Financial Interests, Personal, Advisory Role, consultant (not compensated): Eli Lilly, Gilead Therapeutics. G. Viale: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Daiichi Sankyo, MSD Oncology, Pfizer; Financial Interests, Personal, Other, Consulting fees: Agilent; Financial Interests, Personal, Invited Speaker: Gilead; Financial Interests, Personal, Other, Educational webinar: Medscape; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Research Grant: Roche. M. Regan: Financial Interests, Personal, Advisory Board, Also invited speaker: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board, Includes consulting: Tolmar Pharmaceuticals; Financial Interests, Personal, Advisory Board: AstraZeneca, Tersera Therapeutics; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, Bayer; Financial Interests, Institutional, Other, Director of IBCSG Statistical and Data Management Center for IBCSG investigator-initiated clinical trial supported by company: Novartis; Financial Interests, Institutional, Other, Director of IBCSG Statistical and Data Management Center for IBCSG investigator-initiated clinical trials supported by company: Pfizer, Ipsen, TerSera; Financial Interests, Institutional, Other, Director of IBCSG Statistical and Data Management Center for IBCSG investigator-initiated clinical trial drug supply from company: Roche; Financial Interests, Institutional, Other, Director of IBCSG Statistical and Data Management Center for IBCSG investigator-initiated clinical trials supported or drug supply from company: AstraZeneca; Financial Interests, Institutional, Other, Director of IBCSG Statistical and Data Management Center for IBCSG investigator-initiated clinical trials with funding from company: Debiopharm; Financial Interests, Institutional, Funding, IBCSG translational research collaboration: Biotheranostics; Non-Financial Interests, Personal, Advisory Role: Bristol Myers Squibb. E. Munzone: Financial Interests, Personal, Advisory Board: Eisai, Exact Science, MSD Oncology, Daiichi Sankyo/AstraZeneca, Pfizer, Seagen. B. Thürlimann: Financial Interests, Personal, Expert Testimony: Gilead; Financial Interests, Personal, Advisory Board: Pagetherapeutics; Financial Interests, Personal, Other, Expert Consultant Oncology: Innomedica; Financial Interests, Personal, Other, Expert Consultant: Enzymmanagement; Financial Interests, Personal, Invited Speaker, Med. Education Activities St. Gallen Breast Cancer Conference & Consensus: Medplus Honkong; Financial Interests, Personal, Member of Board of Directors: KFS, RTFCCR; Financial Interests, Personal, Other, Member QA Committee: donna-sg; Financial Interests, Personal, Other, Speaker in med. education activities St. Gallen Breast Cancer Conference & Consensus: Medplus Honkong; Financial Interests, Personal, Other, Co-Chair: SG Oncology Conferences; Financial Interests, Personal, Stocks/Shares: Novartis, Roche, Merck, Alcon, Sandoz, Innomedica, Organon; Non-Financial Interests, Personal, Member of Board of Directors: Hospiz St. Gallen. C. Sotiriou: Financial Interests, Institutional, Advisory Board: Astellas, Seattle Genetics, Amgen, Merck & Co.; Financial Interests, Personal, Advisory Board: Cepheid; Financial Interests, Institutional, Other, Travel: Roche; Financial Interests, Personal, Other, Travel: Pfizer; Financial Interests, Institutional, Invited Speaker: Exact Sciences; Financial Interests, Personal, Invited Speaker: Prime Oncology; Financial Interests, Personal, Advisory Board, Stock options: Signatur Biosciences; Financial Interests, Personal, Stocks/Shares, Stock: Signatur Biosciences. All other authors have declared no conflicts of interest.