Deciphering the importance of biomarkers in colorectal and urothelial cancers in the era of precision oncology

Precision oncology is a rapidly evolving field in many different aspects. Taking this in mind and considering the central role of biomarkers in precision oncology, this thesis affords various important aspects regarding predictive and prognostic biomarkers in two important clinical scenarios. First, this thesis presents a systematic and comprehensive review on metastatic colorectal cancer that summarizes the most relevant milestones achieved in the field of predictive biomarkers to various treatments; analyzes and discusses methodological aspects, current trends, and future directions in this exciting area. Second, because of the lack of biomarkers in the context of mucinous colorectal cancer, this thesis affords the role of microRNAs from a biological and prognostic viewpoint in this specific colorectal cancer subtype. Lastly, this thesis presents a multicenter retrospective study in metastatic urothelial carcinoma patients, which investigates the safety and efficacy of immunotherapy, and explores pretreatment factors influencing therapeutic outcomes in daily clinical practice

Integrative analysis of the colorectal cancer proteome : potential clinical impact

Peer reviewedPostprin

Quantification and expert evaluation of evidence for chemopredictive biomarkers to personalize cancer treatment.

Predictive biomarkers have the potential to facilitate cancer precision medicine by guiding the optimal choice of therapies for patients. However, clinicians are faced with an enormous volume of often-contradictory evidence regarding the therapeutic context of chemopredictive biomarkers.We extensively surveyed public literature to systematically review the predictive effect of 7 biomarkers claimed to predict response to various chemotherapy drugs: ERCC1-platinums, RRM1-gemcitabine, TYMS-5-fluorouracil/Capecitabine, TUBB3-taxanes, MGMT-temozolomide, TOP1-irinotecan/topotecan, and TOP2A-anthracyclines. We focused on studies that investigated changes in gene or protein expression as predictors of drug sensitivity or resistance. We considered an evidence framework that ranked studies from high level I evidence for randomized controlled trials to low level IV evidence for pre-clinical studies and patient case studies.We found that further in-depth analysis will be required to explore methodological issues, inconsistencies between studies, and tumor specific effects present even within high evidence level studies. Some of these nuances will lend themselves to automation, others will require manual curation. However, the comprehensive cataloging and analysis of dispersed public data utilizing an evidence framework provides a high level perspective on clinical actionability of these protein biomarkers. This framework and perspective will ultimately facilitate clinical trial design as well as therapeutic decision-making for individual patients

The predictive and prognostic potential of plasma telomerase reverse transcriptase (TERT) RNA in rectal cancer patients

Background: Preoperative chemoradiotherapy (CRT) followed by surgery is the standard care for locally advanced rectal cancer, but tumour response to CRT and disease outcome are variable. The current study aimed to investigate the effectiveness of plasma telomerase reverse transcriptase (TERT) levels in predicting tumour response and clinical outcome. Methods: 176 rectal cancer patients were included. Plasma samples were collected at baseline (before CRT\ubcT0), 2 weeks after CRT was initiated (T1), post-CRT and before surgery (T2), and 4\u20138 months after surgery (T3) time points. Plasma TERT mRNA levels and total cell-free RNA were determined using real-time PCR. Results: Plasma levels of TERT were significantly lower at T2 (Po0.0001) in responders than in non-responders. Post-CRT TERT levels and the differences between pre- and post-CRT TERT levels independently predicted tumour response, and the prediction model had an area under curve of 0.80 (95% confidence interval (CI) 0.73\u20130.87). Multiple analysis demonstrated that patients with detectable TERT levels at T2 and T3 time points had a risk of disease progression 2.13 (95% CI 1.10\u20134.11)-fold and 4.55 (95% CI 1.48\u201313.95)-fold higher, respectively, than those with undetectable plasma TERT levels. Conclusions: Plasma TERT levels are independent markers of tumour response and are prognostic of disease progression in rectal cancer patients who undergo neoadjuvant therapy

The pathomorphologist’s role in the era of personalised therapy regarding the case of colorectal tumours

Colorectal cancer is one of the most common epithelial tumours amongst humans. Effective treatment requires a multidisciplinary approach and in some cases target therapy. In order to introduce treatment, both the clinical stage and pathomorphological diagnosis have to be taken into account. An analysis of the microscopic appearance as well as immunohistochemical and molecular tests are the basis of proper diagnosis. Biomarkers for diagnosis of colorectal cancer can be divided into two groups. The first one constitutes diagnostic and prognostic markers which are commonly used by pathologists. They are useful in the recognition of morphological and clinical features of tumours. The second group of biomarkers is used additionally and has predictive value. In an era of personalised therapy, the pathomrothologist’s role is to assess the prognostic and predictive biomarkers, in order to identify patients who will benefit from molecular targeted therapy. In the case of colorectal cancer mutations of genes: KRAS, NRAS and BRAF are clinically significant. A lack of the aforementioned mutations correlates with a better response to anti-EGRF therapy

A coordinate deregulation of microRNAs expressed in mucosa adjacent to tumor predicts relapse after resection in localized colon cancer

Up to 20% of colorectal cancer (CRC) node-negative patients develop loco-regional or distant recurrences within 5 years from surgery. No predictive biomarker able to identify the node-negative subjects at high risk of relapse after curative treatment is presently available.Forty-eight localized (i.e. stage I-II) colon cancer patients who underwent radical tumor resection were considered. The expression of five miRNAs, involved in CRC progression, was investigated by qRT-PCR in both tumor tissue and matched normal colon mucosa.Interestingly, we found that the coordinate deregulation of four miRNAs (i.e. miR-18a, miR-21, miR-182 and miR-183), evaluated in the normal mucosa adjacent to tumor, is predictive of relapse within 55 months from curative surgery.Our results, if confirmed in independent studies, may help to identify high-risk patients who could benefit most from adjuvant therapy. Moreover, this work highlights the importance of extending the search for tissue biomarkers also to the tumor-adjacent mucosa

EPMA position paper in cancer:current overview and future perspectives

At present, a radical shift in cancer treatment is occurring in terms of predictive, preventive, and personalized medicine (PPPM). Individual patients will participate in more aspects of their healthcare. During the development of PPPM, many rapid, specific, and sensitive new methods for earlier detection of cancer will result in more efficient management of the patient and hence a better quality of life. Coordination of the various activities among different healthcare professionals in primary, secondary, and tertiary care requires well-defined competencies, implementation of training and educational programs, sharing of data, and harmonized guidelines. In this position paper, the current knowledge to understand cancer predisposition and risk factors, the cellular biology of cancer, predictive markers and treatment outcome, the improvement in technologies in screening and diagnosis, and provision of better drug development solutions are discussed in the context of a better implementation of personalized medicine. Recognition of the major risk factors for cancer initiation is the key for preventive strategies (EPMA J. 4(1):6, 2013). Of interest, cancer predisposing syndromes in particular the monogenic subtypes that lead to cancer progression are well defined and one should focus on implementation strategies to identify individuals at risk to allow preventive measures and early screening/diagnosis. Implementation of such measures is disturbed by improper use of the data, with breach of data protection as one of the risks to be heavily controlled. Population screening requires in depth cost-benefit analysis to justify healthcare costs, and the parameters screened should provide information that allow an actionable and deliverable solution, for better healthcare provision

The expression and prognostic significance of retinoic acid metabolising enzymes in colorectal cancer

Peer reviewedPublisher PD

Functional imaging and circulating biomarkers of response to regorafenib in treatment-refractory metastatic colorectal cancer patients in a prospective phase II study

open32Regorafenib demonstrated efficacy in patients with metastatic colorectal cancer (mCRC). Lack of predictive biomarkers, potential toxicities and cost-effectiveness concerns highlight the unmet need for better patient selection.openKhan, Khurum; Rata, Mihaela; Cunningham, David; Koh, Dow-Mu; Tunariu, Nina; Hahne, Jens C; Vlachogiannis, George; Hedayat, Somaieh; Marchetti, Silvia; Lampis, Andrea; Damavandi, Mahnaz Darvish; Lote, Hazel; Rana, Isma; Williams, Anja; Eccles, Suzanne A; Fontana, Elisa; Collins, David; Eltahir, Zakaria; Rao, Sheela; Watkins, David; Starling, Naureen; Thomas, Jan; Kalaitzaki, Eleftheria; Fotiadis, Nicos; Begum, Ruwaida; Bali, Maria; Rugge, Massimo; Temple, Eleanor; Fassan, Matteo; Chau, Ian; Braconi, Chiara; Valeri, NicolaKhan, Khurum; Rata, Mihaela; Cunningham, David; Koh, Dow-Mu; Tunariu, Nina; Hahne, Jens C; Vlachogiannis, George; Hedayat, Somaieh; Marchetti, Silvia; Lampis, Andrea; Damavandi, Mahnaz Darvish; Lote, Hazel; Rana, Isma; Williams, Anja; Eccles, Suzanne A; Fontana, Elisa; Collins, David; Eltahir, Zakaria; Rao, Sheela; Watkins, David; Starling, Naureen; Thomas, Jan; Kalaitzaki, Eleftheria; Fotiadis, Nicos; Begum, Ruwaida; Bali, Maria; Rugge, Massimo; Temple, Eleanor; Fassan, Matteo; Chau, Ian; Braconi, Chiara; Valeri, Nicol