PracticeUpdate: Haematology & Oncology

10 top advances in diagnostic and molecular pathology in breast cancer NEWS 4

O ver the last 2 decades there has been great advancement in the field of breast cancer molec- ular classification and prognostication, and in the understanding of the pathogenesis of this heterogeneous disease. Applications of high throughput molecular techniques coupled with state-of-the art bioinformatics approaches have generated vast amounts of data and opened avenues to refine breast cancer classification and identify novel therapeutic targets with a subse- quent move towards personalised therapy. Here are our 10 hot topics to watch.

Leading pathologists, Jane E. Dahlstrom*, Emad A.Rakha # , Sunil R. Lakhani†, Stuart J. Schnitt‡ and colleagues share their current ‘hot topics’ in the field of breast diagnostic and molecular pathology and the research to watch.

1 . Application of molecular techniques Rakha and Green 1 provide an update on the appli- cation of molecular techniques with regard to breast cancer diagnosis, prognosis and outcome prediction. They briefly highlight current contri- butions of this emerging technology towards our understanding of breast cancer, in addition to the essential role of immunohistochemistry and other molecular techniques in the diagnosis and differ- ential diagnosis of breast lesions. 2 . Molecular profiling Ross and Gay 2 present a review on the molecular profiling of advanced breast cancer and the role of comprehensive genomic sequencing technology. They discuss massive parallel sequencing and next generation sequencing (NGS) technology and its potential applications in breast cancer research and management, in particular identification of targetable, clinically relevant genomic alterations. 3 . Stromal-epithelial interactions McCuaig and colleagues 3 discuss the biological and clinical significance of stromal-epithelial interactions in breast cancer. In this review recent advances in our understanding of how cancer epithelial cells interact with their microenvironment and how this knowledge can be exploited clinically are presented. 4 . DNA damage Three main pathways play a major role in DNA repair in breast cancer. This article highlights how basic science can be translated into clinical bene- fit. For example, there is evidence to indicate the efficacy of targeting DNA damage repair mole- cules in BRCA-mutated breast cancer using PARP inhibitors. In contrast, the response to such therapy is lim- ited in sporadic cases, despite the presence of evidence of DNA repair defect suggesting differ- ent mechanisms other than BRCA gene mutation. The different mechanisms of DNA repair in breast cancer and the concept of synthetic lethality,

BRCAness and the therapeutic potential of some proteins involved in DNA repair are highlighted in the article by Ali et al. 4 5 . Ki67 use There is a continuous effort to identify new prog- nostic and predictive markers; however, there is also a need to refine, validate and further assess the clinical utility of existing variables. Although the prognostic value of Ki67 in breast cancer is well demonstrated and some authors have pro- vided evidence for its predictive value, at least in certain situations, its application in routine prac- tice remains less than what was initially expected. The issue of reproducibility of Ki67 staining and scoring, and the use of several cut-off points have resulted in a delay in its application in routine practice and some current international guidelines have recommended not to use Ki67 to guide treat- ment decisions. This topic and other issues related to Ki67 use in breast cancer are covered in the article by Penault-Llorca and Radosevic-Robin. 5 6 . Tumour infiltrating lymphocytes A topic which has gained a lot of attention fol- lowing a series of publications demonstrating its prognostic value and the emerging role of immuno- therapy is tumour infiltrating lymphocytes (TILs). Luen et al 6 provide a comprehensive review on TILs and the emerging role of immunotherapy in breast cancer. Although breast cancer has not previously been considered a highly immunogenic cancer, retrospective analysis of clinical trial sam- ples has demonstrated the potential role of host immunosurveillance in influencing the biology of at least certain subtypes of breast cancer; namely triple negative and HER2-positive classes. Evi- dence indicates that TILs are associated with improved pathological complete response and patient outcome. In their article they cover the existing methodologies of assessment of TILs in breast cancer and efforts to standardise TILs eval- uation, and discuss clinical relevance of TILs and ways to improve efficacy of immunotherapeutic approaches in breast cancer.

* ACT Pathology, The Canberra Hospital and ANU Medical School, Canberra, Australia; # Department of Cellular Pathology, University of Nottingham and Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham, United Kingdom; † Breast Pathology Group, The University of Queensland Centre for Clinical Research, Discipline of Molecular & Cellular Pathology, The University of Queensland School of Medicine and Pathology Queensland, Brisbane, Australia; ‡ Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States.

PRACTICEUPDATE HAEMATOLOGY & ONCOLOGY