Abstract
Personalized or precision medicine as a diagnostic and therapeutic paradigm was introduced some 10–15 years ago, with the advent of biomarker discovery as a mechanism for identifying prognostic and predictive attributes associated with treatment indication and outcome. While the concept is not new, the successful development and implementation of novel ‘companion diagnostics’, especially in oncology, continues to represent a significant challenge and is currently at the forefront of smart trial design and therapeutic choice. The ability to determine patient selection for a specific therapy has broad implications including better chances for a positive outcome, limited exposure to potentially toxic drugs and improved health economics. Importantly, a significant step in this paradigm is the role of predictive pathology or the accurate assessment of morphology at the microscopic level. In breast cancer, this has been most useful where histologic attributes such as the classification of tubular and cribriform carcinoma dictates surgery while neoadjuvant studies suggest that patients with lobular carcinoma are not likely to benefit from chemotherapy. The next level of ‘personalized pathology’ at the tissue-cellular level is the use of ‘protein biomarker panels’ to classify the disease process and ultimately drive tumor characterization and treatment. The following review article will focus on the evolution of predictive pathology from a subjective, ‘opinion-based’ approach to a quantitative science. In addition, we will discuss the individual components of the precise pathology platform including advanced image analysis, biomarker quantitation with mathematical modeling and the integration with fluid-based (i.e. blood, urine) analytics as drivers of next generation precise patient phenotyping.
Similar content being viewed by others
References
Hertz DL, Rae JM. Pharmacogenetic predictors of response. Adv Exp Med Biol. 2016;882:191–215.
Gleason DF. Classification of prostate carcinomas. Cancer Chemother Rep. 1966;50:125–8.
Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. The value of histologic grade in breast cancer: experience from a large study with long term follow-up. Histopathology. 1991;19:403.
Epstein JI, Egevad L, Amin MB, Delahunt B, Srigley JR, Humphrey PA, et al. The 2014 International Society of Urological Pathology (ISUP) consensus conference on Gleason grading of prostatic carcinoma: definition of grading patterns and proposal for a new grading system. Am J Surg Pathol. 2016;40:244–52.
Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129–39.
Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisingewr KR, Yatabe Y, et al. International association for the study of lung cancer/american thoracic society/European respoiroty society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol. 2011;6:244–85.
Prabhakar C. Epidermal growth factor receptor in non-small cell lung cancer. Transl Lung Cancer Res. 2015;4:110–8.
Servant N, Romejon J, Gestraud P, La Rosa P, Lucotte G, Lair S, et al. Bioinformatics for precision medicine in oncology: principles and application to the SHIVA clinical trial. Front Genet. 2014;5:152.
Lopez-Chavez A, Thomas A, Rajan A, Raffeld M, Morrow B, Kelly R. Molecular profiling and targeted therapy for advanced thoracic malignancies: a biomarker-derived, multiarm, multihistology phase II basket trial. J Clin Oncol. 2015;33:1000–7.
Ping Z, Xia Y, Shen T, Parekh Siegal G, Eltoum I-E, et al. A microscopic landscape of the invasive breast cancer genome. Sci Rep. 2016;6:27545.
Natrajan R, Sailem H, Mardakheh F, Garcia MA, Tape CJ, Dowsett M, et al. Microenvironmental heterogeneity parallels breast cancer progression: a histology–genomic integration analysis. PLoS Med. 2016;13:e1001961.
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–54.
Nanda R, Chow LQ, Dees EC, Berger R, Gupta S, Geva R, et al. Pembrolizumab in patients with advanced triple-negative breast cancer: phase 1b KEYNOTE—12 study. JCO. 2016;34:2460–7.
Vuong D, Simpson PT, Green B, Cummings MC, Lakhani SR. Molecular classification of breast cancer. Virchows Arch. 2014;465:1–14.
Cardoso F, van’t Veer LJ, Bogaerts J, Slaets L, Viale G, Delaloge S, et al. 70-gene signature as an aid to treatment decisions in early-stage breast cancer. N Engl J Med. 2016;8:717–29.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66:7–30.
Barbieri CE, Tomlins SA. The prostate cancer genome: perspectives and potential. Urol Oncol. 2014;32:53.e15–22.
Fraser M, Berlin A, Bristow RG, van der Kwast T. Genomic, pathological, and clinical heterogeneity as drivers of personalized medicine in prostate cancer. Urol Oncol. 2015;33:85–94.
Chatterjee P, Choudhary GS, Sharma A, Singh K, Heston WD, Ciezki J, et al. PARP inhibition sensitizes to low dose-rate radiation TMPRSS2-ERG fusion gene-expressing and PTEN-deficient prostate cancer cells. PLoS One. 2013;8:e60408.
Chen X, Rycaj K, Liu X, Tang DG. New insights into prostate cancer stem cells. Cell Cycle. 2013;12:579–86.
Domingo-Domenech J, Vidal SJ, Rodriguez-Bravo V, Castillo-Martin M, Quinn SA, Rodriguez-Barrueco R, et al. Suppression of acquired docetaxe resistance in prostate cancer through depletion of notch-and hedgehog-dependent tumor-initiating cells. Cancer Cell. 2012;22:373–88.
Kannan N, Nguyen LV, Eaves CJ. Integrin B3 links therapy resistance and cancer stem cell properties. Nat Cell Biol. 2014;16:397–9.
Vidal SJ, Rodriguez-Bravo V, Quinn SA, Rodriguez-Bravo R, Lujambio A, Williams E, et al. A targetable GATA-IGF2 axis confers aggressiveness in lethal prostate cancer. Cancer Cell. 2015;27:223–39.
Tsiatas M, Grivas P. Immunobiology and immunotherapy in genitourinary malignancies. Ann Transl Med. 2016;4:270.
Mountzios G, Linardou H, Kosmidis P. Immunotherapy in non-small cell lung cancer: the clinical impact of immune response and targeting. Ann Transl Med. 2016;4:268.
Cordon-Cardo C, Kotsianti A, Verbel DA, Teverovskiy M, Capodieci P, Hamann S, et al. Improved prediction of prostate cancer recurrence through systems pathology. J Clin Investig. 2007;117:1876–83.
Donovan MJ, Hamann S, Clayton M, Khan FM, Sapir M, Bayer-Zubek V, et al. Systems pathology approach for the prediction of prostate cancer progression after radical prostatectomy. J Clin Oncol. 2008;26:3923–9.
Donovan MJ, Kotsianti A, Bayer-Zubek V, Verbel D, Teverovskiy M, Cordon-Cardo C, et al. A systems pathology model for predicting overall survival in patients with refractory, advanced non-small cell lung cancer treated with gefitinib. Eur J Cancer. 2009;45:18–26.
Donovan MJ, Khan FM, Fernandez G, Mesa-Tejada R, Sapir M, Zubek VB, et al. Personalized prediction of tumor response and cancer progression on prostate needle biopsy. J Urol. 2009;182:125–32.
Donovan MJ, Khan F, Powell D, Fernandez G, Feliz A, Hansen T, et al. Previously developed systems-based model (Prostate Px+) identifies favorable-risk prostate cancer for men enrolled in an active surveillance program. J Urol. 2011;185:e517–8.
Kyi C, Sabado RL, Saenger YM, Marshall PR, Donovan M, Loging W, et al. In situ, therapeutic vaccination against refractory solid cancers with intratumoral Poly-ICLC: a phase I study. J Clin Oncol. 2016;34:suppl abstr 3086.
Ullal A, Peterson V, Agasti SS, Tuang S, Juric D, Castro CM, et al. Cancer cell profiling by barcoding allows multiplexed protein analysis in fine-needle aspirates. Sci Transl Med. 2014;6:219ra9.
Giesen C, Wang HA, Schapiro D, Zivanovic N, Jacob SA, Hattendorf B, et al. Highly multiplexed imaging of tumor tissues with subcellular resolution by mass cytometry. Nat Methods. 2014;11:417–22.
Wolf C, Jarutat T, Vega Harring S, Haupt K, Babitzki G, Bader K, et al. Determination of phosphorylated proteins in tissue specimens requires high-quality samples collected under stringent conditions. Histopathology. 2014;64:431–44.
Abel EJ, Bauman TM, Weiker M, Shi F, Downs TM, Jarrard DF, et al. Analysis and validation of tissue biomarkers for renal cell carcinoma using automated high-throughput evaluation of protein expression. Hum Pathol. 2014;45:1092–9.
Steurer S, Singer JM, Rink M, Chun F, Dahlem R, Simon R, et al. MALDI imaging-based identification of prognostically relevant signals in bladder cancer using large-scale tissue microarrays. Urol Oncol. 2014;32:1225–33.
Pereira LH, Reis IM, Reategui EP, Gordon C, Saint-Victor S, Duncan R, et al. Risk stratification system for oral cancer screening. Cancer Prev Res. 2016;9:445–55.
Strotman LN, Millner LM, Valides R Jr, Linder MW. Liquid biopsies in oncology and the current regulatory landscape. Mol Diagn Ther. 2016;20:429–36.
Jia S, Zocco D, Samuels MI, Chou MF, Chammas R, Skog J, et al. Emerging technologies in extracellular vesicle-based diagnostics. Expert Rev Mol Diagn. 2014;14:307–21.
Lianidou ES, Strati A, Markou A. Circulating tumor cells as promising novel biomarkers in solid cancers. Crit Rev Clin Lab Sci. 2014;51:160–7.
Kolbl AC, Jeschke U, Andergasses U. The significance of epithelial-to-mesenchymal transition for circulating tumor cells. Int J Mol Sci. 2016;17:E1308.
Antonarakis E, Lu C, Wang H, Luber B, Nakazawa M, Roeser J, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 2014;371:1028–38.
Nicolazzo C, Raimondi C, Mancini ML, Caponnetto S, Gradilone A, Gandini O, et al. Monitoring PD-L1 positive circulating tumor cells in non-small cell lung cancer patients treated with the PD-1 inhibitor Nivolumab. Sci Rep. 2016;6:31726.
Esposito A, Bardelli A, Criscitiello C, Colombo N, Gelao L, Fumagalli L, et al. Monitoring tumor-derived cell-free DNA in patients with solid tumors: clinical perspectives and research opportunities. Cancer Treat Rev. 2014;40:648–55.
Lewis JM, Heineck DP, Heller MJ. Detecting cancer biomarkers in blood: challenges for new molecular diagnostic and point-of-care tests using cell-free nucleic acids. Expert Rev Mol Diagn. 2015;15:1187–200.
Mok T, Wu YL, Lee JS, Yu CJ, Sriuranpong V, Sandoval-Tan J, et al. Detection and dynamic changes of EGFR mutations from circulating tumor DNA as a predictor of survival outcomes in NSCLC patients treated with first-line intercalated erlotinib and chemotherapy. Clin Cancer Res. 2015;21:3196–203.
Legendre C, Gooden GC, Johnson K, Martinez RA, Liang WS, Salhia B. Whole-genome bisulfite sequencing of cell-free DNA identifies signature associated with metastatic breast cancer. Clin Epigenet. 2015;7:100.
Skog J, Wurdinger T, van Rijn S, Meijer DH, Gainche L, Sena-Esteves M, et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol. 2008;10:1470–6.
Mizutani K, Terazawa R, Kameyama K, Kato T, Horie K, Tsuchiya T, et al. Isolation of prostate cancer-related exosomes. Anticancer Res. 2014;34:3419–23.
Donovan MJ, Noerholm M, Bentink S, Belzer S, Skog J, O’Neill V, et al. A molecular signature of PCA3 and ERG exosomal RNA from non-DRE urine is predictive of initial prostate biopsy result. Prostate Cancer Prostatic Dis. 2015;18:370–5.
McKiernan J, Donovan MJ, O’Neill V, Bentink S, Noerholm M, Belzer S, et al. A novel urine exosome gene expression assay to predict high-grade prostate cancer at initial biopsy. JAMA Oncol. 2016;2:882–9.
Montamedinia P, Scott AN, Bate KL, Sadeghi N, Salazar G, Shapiro E, et al. Urine exosomes for non-invasive assessment of gene expression and mutations of prostate cancer. PLoS One. 2016;11:e154507.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
MJD and CCC have no conflicts.
Funding
No funding was used in the preparation of this manuscript.
Rights and permissions
About this article
Cite this article
Donovan, M.J., Cordon-Cardo, C. Implementation of a Precision Pathology Program Focused on Oncology-Based Prognostic and Predictive Outcomes. Mol Diagn Ther 21, 115–123 (2017). https://doi.org/10.1007/s40291-016-0249-5
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40291-016-0249-5