Liquid biopsy - emergence of a new era in personalized cancer care

Abraham et al. Applied Cancer Research (2018) 38:4 DOI 10.1186/s41241-018-0053-0 Applied Cancer Research REVIEW Open Access Liquid biopsy - emergence of a new era in personalized cancer care Jessy Abraham1* , Sunita Singh2 and Shalaka Joshi3 Abstract The most successful treatment for cancer involves identifying druggable, biological markers for targeted therapy. In the clinical setting, surgical removal of tumors is the only procedure for identifying such targetable molecules. Shed from tumor cells, these markers are also present in circulating blood, albeit in very negligible amounts. Liquid biopsy is a procedure performed on a blood sample to look for such circulating cancer markers cells or pieces of nucleic acid from the tumor. The procedure shows promise in revolutionizing personalized cancer treatments. Here we briefly review the technique, characterization, and its utilization in clinics. Keywords: Liquid biopsy, Circulating tumor cells, Cell free DNA, Cell free RNA, Clinical utility Background Today, cancer remains the leading cause of premature deaths worldwide. Treatment relies on profiling a piece of biopsied tumor tissue. However, the ease of acquiring biopsy depends on patient condition and tumor accessibility. In the case of advanced or metastatic non-small cell lung cancers (NSCLC) as many as 31% of cases do not have accessible tissue [1]. Likewise, majority of patients with pancreatic cancer progress to either locally advanced or metastatic disease in the asymptomatic phase and as many as 80% presents late with metastasis at diagnosis [2]. Progress remains hindered also by diverse landscape of tumor and technical limitations involved in sampling of biopsied tissue. Following excision, biopsy samples are fixed and sections, similar to a bread loaf, are cut and the tddop most layers are sliced again for pathological staining. But tumors are characterized by intra-tumor heterogeneity arising from clonal evolution of individual tumor cells (Fig. 1) [3]. So, the technique may fail in capturing newly evolving, genetically distinct cells that do not lie on the surface of the bread-loaf section (Fig. 2). Similarly, primary tissue from pancreatic ductal adenocarcinoma patients is usually available only by fine-needle aspiration biopsies and there is a high chance of missing aggressive clones [4]. Besides, a standard protocol in cancer * Correspondence: 1 Department of Biochemistry, All India Institute of Medical Sciences, Raipur, Chhattisgarh 492099, India Full list of author information is available at the end of the article management involves periodic monitoring for progression and/or recurrence of the cancer. Because a tissue biopsy can be painful and expensive, most patients shy away from a repeat biopsy. And in most cases the physician does not know where to look for metastasis. Even, commonly used imaging techniques like ultrasonography, positron emission tomography (PET), computed tomography (CT) and magnetic resonance imaging (MRI) [5] cannot detect many early-stage cancers and very small metastases [6]. While challenges in obtaining adequate tumor tissue and issues of heterogeneity continue to hamper tissue profiling, minimally invasive technologies to capture genomic contents of tumor in various bodily fluids like blood, urine, saliva, sweat and tears combined with sensitive genotyping assays, have become available. “Liquid biopsy” is the term coined to describe such diagnostic procedures performed on cancer-derived material captured in a blood sample. Since, cancer cells that detach from solid tumors circulate in the peripheral blood, analyzing blood of patients with cancer holds the possibility for capture and molecular analysis of diverse tumor-derived materials. In normal, healthy individuals, cellular debris from apoptotic or necrotic cells is normally phagocytized by infiltrating macrophages and cleared from the circulation. However, this clearance mechanism does not proceed effectively in cells derived from tumor mass, leading to an accumulation of cellular debris including DNA, and its release into the circulation [7]. By and large, cellular components sampled © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Abraham et al. Applied Cancer Research (2018) 38:4 Page 2 of 17 Fig. 1 Snapshot of the evolving tumor landscape. Tumor cells undergo frequent mutations resulting in emergence of distinct sub clones. This leads to ever evolving/ changing landscape of tumor cells which are difficult to monitor by traditional standard biopsy. But with recent advances in single cell detection technologies, it has become possible to capture and characterize cells shed from these distinct sub clones into the blood. They are shed either by dying tumor cells or are tumor cells that have detached from parent primary tumor and have metastatic abilities from the blood of cancer patients is highly consistent with gene alteration patterns reported in traditional tumor tissue testing (https://www.cancer.gov/news-events/cancercurrents-blog/2016/asco-liquid-biopsy) [8, 9], which makes these circulating cancer-derived materials in the bloodstream an appealing alternative to overcoming some of the challenges described above. Because blood collection is simple and minimally invasive, this alternative method is currently being developed by many investigators, particularly with the aim of obtaining a complementary tool to tumor biopsy to predict what drugs will work for a patient and monitor how a tumor changes over time. Herein, we provide a brief overview of the various types of tumorderived material that can be sampled using liquid biopsies. Subsequently, we discuss the available technologies for extraction of molecular information from liquid biopsy Abraham et al. Applied Cancer Research (2018) 38:4 Page 3 of 17 Fig. 2 Conventional sectioning of tissues using the bread loaf sectioning technique. Standard tissue biopsy evaluation of excised tissues involve bread-loaf technique wherein vertical sections of the tissues are embedded in paraffin or frozen, sectioned with microtome and stained. As illustrated here, residual tumor or tumor extensions may not be found and may recur samples and their clinical use, focusing mostly on those associated to DNA derived from blood samples. Approaches to liquid biopsy Cancer at any stage can shed tumor cells as well as fragments of cancer-causing DNA into the blood sy (...truncated)