Abstract
Oncotype DX (ODX) is a multi-gene expression signature designed for estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients to predict the recurrence score (RS) and chemotherapy (CT) benefit. The aim of our study is to develop a prediction tool for the three RS’s categories based on deep multi-layer perceptrons (DMLP) and using only the morphoimmunohistological variables. We performed a retrospective cohort of 320 patients who underwent ODX testing from three French hospitals. Clinico-pathological characteristics were recorded. We built a supervised machine learning classification model using Matlab software with 152 cases for the training and 168 cases for the testing. Three classifiers were used to learn the three risk categories of the ODX, namely the low, intermediate, and high risk. Experimental results provide the area under the curve (AUC), respectively, for the three risk categories: 0.63 [95% confidence interval: (0.5446, 0.7154), p < 0.001], 0.59 [95% confidence interval: (0.5031, 0.6769), p < 0.001], 0.75 [95% confidence interval: (0.6184, 0.8816), p < 0.001]. Concordance rate between actual RS and predicted RS ranged from 53 to 56% for each class between DMLP and ODX. The concordance rate of low and intermediate combined risk group was 85%.
We developed a predictive machine learning model that could help to define patient’s RS. Moreover, we integrated histopathological data and DMLP results to select tumor for ODX testing. Thus, this process allows more relevant use of histopathological data, and optimizes and enhances this information.
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References
Walsh S, de Jong EEC, van Timmeren JE, et al. Decision Support Systems in Oncology. JCO Clin Cancer Inform. 2019;3:1–9.
Cancer today. https://gco.iarc.fr/today/home. Accessed 27 Mar 2019
INCA—Les cancers en France. https://www.e-cancer.fr/ressources/cancers_en_france/#page=87. Accessed 17 Jul 2018
Senkus E, Kyriakides S, Ohno S, Penault-Llorca F, Poortmans P, Rutgers E, et al. Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26:v8–30.
Perou CM, Sørlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature. 2000;406:747–52.
Sorlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci. 2001;98:10869–74.
Sotiriou C, Neo S-Y, McShane LM, Korn EL, Long PM, Jazaeri A, et al. Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc Natl Acad Sci. 2003;100:10393–8.
Paik S, Shak S, Tang G, et al. A Multigene Assay to Predict Recurrence of Tamoxifen-Treated, Node-Negative Breast Cancer. N Engl J Med. 2004;351:2817–26.
Paik S, Tang G, Shak S, et al. Gene Expression and Benefit of Chemotherapy in Women With Node-Negative, Estrogen Receptor-Positive Breast Cancer. J Clin Oncol. 2006;24:3726–34.
Albain KS, Barlow WE, Shak S, et al. Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, estrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial. Lancet Oncol. 2010;11:55–65.
Sparano JA, Gray RJ, Makower DF, et al. Prospective Validation of a 21-Gene Expression Assay in Breast Cancer. N Engl J Med. 2015;373:2005–144.
Sparano JA, Gray RJ, Makower DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018;379:111–21.
Harris LN, Ismaila N, McShane LM, et al. Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2016;34:1134–50.
Gradishar WJ, Anderson BO, Balassanian R, et al. NCCN guidelines insights: breast cancer, version 1.2017. J Natl Compr Cancer Netw JNCCN. 2017;15:433–51.
Adjuvant therapy for early and locally advanced breast cancer - NICE Pathways. https://pathways.nice.org.uk/pathways/early-and-locally-advanced-breast-cancer/adjuvant-therapy-for-early-and-locally-advanced-breast-cancer. Accessed 17 Feb 2019
Coates AS, Winer EP, Goldhirsch A, Gelber RD, Gnant M, Piccart-Gebhart M, et al. Tailoring therapies—improving the management of early breast cancer: St Gallen International Expert Consensus on the primary therapy of early breast cancer 2015. Ann Oncol. 2015;26:1533–46.
Giuliano AE, Connolly JL, Edge SB, Mittendorf EA, Rugo HS, Solin LJ, et al. Breast Cancer-Major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. Updates to the AJCC Breast TNM Staging System. The 8th Edition. CA Cancer J Clin. 2017;67:290–303.
Klein ME, Dabbs DJ, Shuai Y, Brufsky AM, Jankowitz R, Puhalla SL, et al. Prediction of the Oncotype DX recurrence score: use of pathology-generated equations derived by linear regression analysis. Mod Pathol. 2013;26:658–64.
Hou Y, Tozbikian G, Zynger DL, Li Z. using the modified Magee equation to identify patients unlikely to benefit from the 21-Gene recurrence score assay (Oncotype DX Assay). Am J Clin Pathol. 2017;147:541–8.
Harowicz MR, Robinson TJ, Dinan MA, Saha A, Marks JR, Marcom PK, et al. Algorithms for prediction of the Oncotype DX recurrence score using clinicopathologic data: a review and comparison using an independent dataset. Breast Cancer Res Treat. 2017;162:1–10.
Sughayer M, Alaaraj R, Alsughayer A. Applying new Magee equations for predicting the Oncotype Dx recurrence score. Breast Cancer. 2018;25:597–604.
Yeo B, Zabaglo L, Hills M, Dodson A, Smith I, Dowsett M. Clinical utility of the IHC4+C score in estrogen receptor-positive early breast cancer: a prospective decision impact study. Br J Cancer. 2015;113:390–5.
Flanagan MB, Dabbs DJ, Brufsky AM, Beriwal S, Bhargava R. Histopathologic variables predict Oncotype DXTM Recurrence Score. Mod Pathol. 2008;21:1255–61.
Allison KH, Kandalaft PL, Sitlani CM, Dintzis SM, Gown AM. Routine pathologic parameters can predict Oncotype DXTM recurrence scores in subsets of ER positive patients: who does not always need testing? Breast Cancer Res Treat. 2012;131:413–24.
Tang P, Wang J, Hicks DG, et al. A lower allred score for progesterone receptor is strongly associated with a higher recurrence score of 21-Gene assay in breast cancer. Cancer Invest. 2010;28:978–82.
Wolff AC, Hammond MEH, Allison KH, et al. Human epidermal growth factor receptor 2 testing in breast cancer: american society of clinical oncology/college of american pathologists clinical practice guideline focused update. J Clin Oncol. 2018;36:2105–22.
Salgado R, Denkert C, Demaria S, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol. 2015;26:259–71.
Zemouri R, Omri N, Morello B, Devalland C, Arnould L, Zerhouni N, et al. Constructive deep neural network for breast cancer diagnosis. IFAC-Pap. 2018;51:98–103.
Zemouri R, Omri N, Devalland C, Arnould L, Morello B, Zerhouni N, et al. Breast cancer diagnosis based on joint variable selection and Constructive Deep Neural Network. 2018 IEEE 4th Middle East Conf. Tunis: Biomed. Eng. MECBME. IEEE; 2018. p. 159–164.
Zemouri R, Devalland C, Valmary-Degano S, Zerhouni N. Intelligence artificielle : quel avenir en anatomie pathologique ? Ann Pathol. 2019. https://doi.org/10.1016/j.annpat.2019.01.004.
van der Maaten L, Hinton G. Visualizing data using t-SNE. J Mach Learn Res. 2008;9:2579–605.
Khoury T, Huang X, Chen X, Wang D, Liu S, Opyrchal M. Comprehensive histologic scoring to maximize the predictability of pathology-generated equation of breast cancer oncotype DX Recurrence Score. Appl Immunohistochem Mol Morphol. 2016;24:703–11.
Turner BM, Skinner KA, Tang P, Jackson MC, Soukiazian N, Shayne M, et al. Use of modified Magee equations and histologic criteria to predict the Oncotype DX recurrence score. Mod Pathol. 2015;28:921–31.
Acs G, Esposito NN, Kiluk J, Loftus L, Laronga C. A mitotically active, cellular tumor stroma and/or inflammatory cells associated with tumor cells may contribute to intermediate or high Oncotype DX Recurrence Scores in low-grade invasive breast carcinomas. Mod Pathol. 2012;25:556–66.
Kim I, Choi HJ, Ryu JM, Lee SK, Yu JH, Kim SW, et al. A predictive model for high/low risk group according to oncotype DX recurrence score using machine learning. Eur J Surg Oncol. 2019;45:134–40.
Bhargava R, Clark BZ, Dabbs DJ. Breast cancers with Magee equation score of less than 18, or 18–25 and Mitosis score of 1, do not require Oncotype DX testing. Am J Clin Pathol. 2019;151:316–23.
Singh K, He X, Kalife ET, Ehdaivand S, Wang Y, Sung CJ. Relationship of histologic grade and histologic subtype with oncotype Dx recurrence score; retrospective review of 863 breast cancer oncotype Dx results. Breast Cancer Res Treat. 2018;168:29–34.
Penault-Llorca F, Radosevic-Robin N. Ki67 assessment in breast cancer: an update. Pathology (Phila). 2017;49:166–71.
Dumay A, Feugeas J-P, Wittmer E, et al. Distinct tumor protein p53 mutants in breast cancer subgroups. Int J Cancer. 2013;132:1227–311.
Lee SK, Bae SY, Lee JH, Lee H-C, Yi H, Kil WH, et al. Distinguishing low-risk luminal a breast cancer subtypes with Ki-67 and p53 is more predictive of long-term survival. PLoS ONE. 2015;10:e0124658.
Millar EKA, Graham PH, McNeil CM, et al. Prediction of outcome of early ER+ breast cancer is improved using a biomarker panel, which includes Ki-67 and p53. Br J Cancer. 2011;105:272–80.
Feeley LP, Mulligan AM, Pinnaduwage D, Bull SB, Andrulis IL. Distinguishing luminal breast cancer subtypes by Ki67, progesterone receptor or TP53 status provides prognostic information. Mod Pathol. 2014;27:554–61.
Litjens G, Kooi T, Bejnordi BE, Setio AA, Ciompi F, Ghafoorian M, et al. A survey on deep learning in medical image analysis. Med Image Anal. 2017;42:60–88.
Khan A, Sohail A, Zahoora U, Qureshi AS (2019) A Survey of the Recent Architectures of Deep Convolutional Neural Networks, preprint arXiv: 1901.06032
Khan A, Sohail A, Ali A (2018) A New Channel Boosted Convolutional Neural Network using Transfer Learning, preprint arXiv: 1804.08528
Zemouri R, Zerhouni N, Racoceanu D. Deep learning in the biomedical applications: recent and future status. Appl Sci. 2019;9:1526.
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AB, ZA, and CD contributed to the study design, data analysis, and drafting of the manuscript. AB collected the clinical, epidemiological and histological data, interpreted the results, and wrote the manuscript. LA contributed to the creation of the database. RZ conducted the model DMLP. ZA conducted the statistical analysis. AB, ZA, NZ and CD contributed to the study design and data analysis. All authors reviewed the manuscript and approved the final version.
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Baltres, A., Al Masry, Z., Zemouri, R. et al. Prediction of Oncotype DX recurrence score using deep multi-layer perceptrons in estrogen receptor-positive, HER2-negative breast cancer. Breast Cancer 27, 1007–1016 (2020). https://doi.org/10.1007/s12282-020-01100-4
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DOI: https://doi.org/10.1007/s12282-020-01100-4