Expert in the field of circulating biomarkers for GI tumors

Background: The management of locally advanced rectal cancer (RC) is an evolving clinical field where the multidisciplinary approach can reach its best and liquid biopsy for obtaining tumor-derived component such as circulating tumor DNA (ctDNA) might provide complementary informations. Methods: A systematic review of studies available in literature of liquid biopsy in non-metastatic RC has been performed according to PRISMA criteria to assess the role of ctDNA as a diagnostic, predictive and prognostic biomarker in this setting. Results: Twenty-five publications have been retrieved, of which 8 fulltext articles, 7 abstracts and 10 clinical trials. Results have been categorized into three groups: diagnostic, predictive and prognostic. Few but promising data are available about the use of liquid biopsy for early diagnosis of RC, with the main limitation of sensitivity due to low concentrations of ctDNA in this setting. In terms of prediction of response to chemoradiation, still inconclusive data are available about the utility of a pre-treatment liquid biopsy, whereas some studies report a positive correlation with a dynamic (pre/post-treatment) monitoring. The presence of minimal residual disease by ctDNA was consistently associated with worse prognosis across studies. Conclusions: The use of liquid biopsy for monitoring response to chemoradiation and assess the risk of disease recurrence are the most advanced potential applications for liquid biopsy in RC, with implications also in the context of non-operative management strategies. Suggested Reviewers: Ludovic Barault Istituto di Candiolo Fondazione del Piemonte per l'Oncologia ludovic.barault@ircc.it Expert in the field of circulating biomarkers for GI tumors Giuseppe Curigliano European Institute of Oncology, Milan giuseppe.curigliano@ieo.it Expert in the field of precision oncology Fernando Lopez-Rios Hospital Universitario Madrid Sanchinarro, Universidad San Pablo‐CEU, Madrid flopezrios@hospitaldemadrid.com Pathologist with broad experience in the field of cancer biomarkers Dipartimento di Ematologia ed Oncologia Struttura Complessa Oncologia Falck Direttore: Dr. Salvatore Siena Direzione e Segreteria 02 6444.2291 Degenza 02 6444.2290 Ambulatorio (appuntamenti) 800 638 638 Day Hospital 02 6444.2367 Sperimentazioni Oncologiche 02 6444.3695 Fax 02 6444.2957 Email oncologia@ospedaleniguarda.it Web cancercenter.ospedaleniguarda.it August 19th, 2019 N. Pavlidis Professor of Medical Oncology, Department of Medical Oncology, School of Medicine, University of Ioannina, 451 Ioannina, Greece, Email: npavlid@cc.uoi. gr R.A. Stahel Laboratory for Molecular Oncology, Department of Oncology, University Hospital Zuerich, Haeldeliweg 4, CH-8044 Zuerich, Switzerland, Email: rolf.stahel@usz.ch Editors-in-Chief, Cancer Treatment Reviews Dear Professors Pavlidis and Stahel, We would like to submit to your attention the manuscript entitled “Liquid biopsy for rectal cancer: a systematic review” for publication in Cancer Treatment Reviews. The management of locally advanced rectal cancer is an evolving clinical field where the multidisciplinary approach can reach its best and liquid biopsy for obtaining tumor-derived component such as circulating tumor DNA (ctDNA) might provide important complementary pieces of information. While there are many reviews available in the literature concerning the broad applications of liquid biopsy in cancer treatment, including a few about colorectal cancer as a whole, no systematic review has been performed with the focus of this specific tumor type, that has distinctive clinical features and different treatment modalities as compared to colon cancer. We performed a systematic review categorizing results into three groups: diagnostic, predictive and prognostic applications of liquid biopsy for rectal cancer. We found interesting potential application of this diagnostic tool with implications also in the context of the emerging approach of non-operative management strategies, making overall the topic of very up to date according to the latest developments in this type of cancer. We therefore would like to submit our systematic review to the Journal for consideration since we feel that Cancer Treatment Reviews can offer proper dissemination to pathologists and oncologists. Thank You very much indeed for your attention and collaboration. Kindest regards, Prof. Andrea Sartore-Bianchi, M.D Department of Hematology & Oncology Università degli Studi di Milano and Niguarda Cancer Center Grande Ospedale Metropolitano Niguarda Piazza Ospedale Maggiore, 3, 20162 Milano Phone +39 02 6444 2291 email: andrea.sartorebianchi@unimi.it Cover Letter