Zie ook de literatuurlijst niet-toxische middelen en behandelingen specifiek bij darmkanker van arts-bioloog drs. Engelbert Valstar

25 juli 2023: Bron: Front. Oncol., 30 January 2023 Sec. Surgical Oncology Volume 13 - 2023

Het regelmatig meten van in bloed circulerend tumor DNA (ctDNA) bij patiënten die behandeld worden voor endeldarmkanker - rectumkanker blijkt een uitstekende biomarker voor een wel of niet optredend recidief na een operatie of tijdens en na de behandeling met meestal chemotherapie. Dat blijkt uit een meta-analyse uitgevoerd bij 19 studies waarvan er 7 overbleven om geanalyseerd te worden wat betreft de relatie tussen het gemeten circulerend tumor DNA (ctDNA) en een optredend recidief.

Resultaten uit het abstract vertaald :

In totaal werden 291 unieke studies gescreend, waarvan 261 originele publicaties en 30 lopende studies. Negentien originele publicaties werden beoordeeld en besproken, waarvan er zeven voldoende gegevens leverden voor meta-analyses over het verband tussen de aanwezigheid van ctDNA na de behandeling en optredend recidief (RFS).
De resultaten van de meta-analyses toonden aan dat ctDNA-analyse kan worden gebruikt om patiënten te stratificeren in zeer hoge en lage risicogroepen voor recidief, vooral wanneer gedetecteerd na neoadjuvante behandeling (HR voor RFS: 9,3 [4,6 – 18,8]) en na chirurgie (HR voor RFS: 15,5 [8,2 – 29,3]).
Studies onderzochten verschillende soorten assays en gebruikten verschillende technieken voor de detectie en kwantificering van ctDNA.

In Nederland wordt bij vormen van darmkanker waaronder endeldarmkanker en ook slokdarmkanker al enkele jaren bij geselecteerde patiënten circulerend tumor DNA (ctDNA) toegepast. Maar uit verhalen van patiënten blijkt het heel lastig om daarvoor in aanmerking te komen.

De MIRACLE studie in Erasmus MC gebruikt circulerend tumor DNA (ctDNA) om leveruiitzaaiingen bij vormen van darmkanker te traceren en daarmee wellicht te voorkomen met aangepaste behandeling:

Colorectal cancer patients often develop surgically removable liver metastases. We aim to develop a test to identify patients in need of additional treatment.

Een andere studie die ctDNA metingen gebruikt bij vormen van darmkanker is de DOLPHIN studie:

DOLPHIN (DNA-testing Of Liquid biopsies for Patient care close to Home In the Netherlands)

Het abstract van de meta-analyse is dit. Als u op de titel klikt krijgt u het volledige studierapport:

SYSTEMATIC REVIEW article

Front. Oncol., 30 January 2023
Sec. Surgical Oncology
Volume 13 - 2023 | https://doi.org/10.3389/fonc.2023.1083285

This article is part of the Research Topic

Innovations in Surgical Oncology

View all 19 Articles

Circulating tumour DNA as biomarker for rectal cancer: A systematic review and meta-analyses

Jan M. van Rees1*

Lissa Wullaert1

Alexander A. J. Grüter2

Yassmina Derraze2

Pieter J. Tanis1

Henk M. W. Verheul3

John W. M. Martens3

Saskia M. Wilting3

Geraldine Vink4,5

Jeroen L. A. van Vugt1

Nick Beije3

Cornelis Verhoef1

1Department of Surgical Oncology and Gastrointestinal Surgery, Erasmus MC Cancer Institute, Rotterdam, Netherlands
2Department of Surgery, Amsterdam University Medical Centres (UMC), Vrije Universiteit Amsterdam, Department of Surgery, Cancer Center Amsterdam, Amsterdam, Netherlands
3Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, Netherlands
4Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
5Department of Research and Development, Netherlands Comprehensive Cancer Organisation, Utrecht, Netherlands

Background: Circulating tumour DNA (ctDNA) has been established as a promising (prognostic) biomarker with the potential to personalise treatment in cancer patients. The objective of this systematic review is to provide an overview of the current literature and the future perspectives of ctDNA in non-metastatic rectal cancer.

Methods: A comprehensive search for studies published prior to the 4th of October 2022 was conducted in Embase, Medline, Cochrane, Google scholar, and Web of Science. Only peer-reviewed original articles and ongoing clinical trials investigating the association between ctDNA and oncological outcomes in non-metastatic rectal cancer patients were included. Meta-analyses were performed to pool hazard ratios (HR) for recurrence-free survival (RFS).

Results: A total of 291 unique records were screened, of which 261 were original publications and 30 ongoing trials. Nineteen original publications were reviewed and discussed, of which seven provided sufficient data for meta-analyses on the association between the presence of post-treatment ctDNA and RFS. Results of the meta-analyses demonstrated that ctDNA analysis can be used to stratify patients into very high and low risk groups for recurrence, especially when detected after neoadjuvant treatment (HR for RFS: 9.3 [4.6 – 18.8]) and after surgery (HR for RFS: 15.5 [8.2 – 29.3]). Studies investigated different types of assays and used various techniques for the detection and quantification of ctDNA.

Conclusions: This literature overview and meta-analyses provide evidence for the strong association between ctDNA and recurrent disease. Future research should focus on the feasibility of ctDNA-guided treatment and follow-up strategies in rectal cancer. A blueprint for agreed-upon timing, preprocessing, and assay techniques is needed to empower adaptation of ctDNA into daily practice.

Discussion

The aim of this literature review was to provide an overview of the current evidence and ongoing trials in the field of ctDNA in non-metastatic rectal cancer. Studies have consistently shown the strong association between detectable ctDNA after treatment and unfavourable prognosis. It can be concluded from these results that ctDNA analysis from peripheral blood samples, especially detected after surgery with curative intent, stratifies patients into two groups: one with a very high risk for recurrence, another with a low risk for recurrence. Thus far, there are no rectal cancer trials published, that have investigated ctDNA-guided adjuvant treatment in a randomised setting.

Based on our systematic search, this systematic review is the first to pool long-term oncological survival outcomes in a meta-analysis. A systematic review by Boyson et al. included nine single arm studies with a total of 615 patients undergoing chemoradiation for rectal cancer and investigated the relation between ctDNA and clinical outcomes (15). Eight of the nine studies showed some degree of correlation between ctDNA and either response to chemoradiation, risk of recurrence or disease-free survival. A second systematic review also included nine studies and investigated the association between clinical outcomes and ctDNA at different time points (at diagnosis, after chemoradiation, and after surgery) (38). No association was found between treatment response and ctDNA status at baseline. Studies reporting the prognostic impact of ctDNA after chemoradiation and before surgery showed varying results. All five studies reporting outcomes of detectable ctDNA postoperative and clinical outcomes, found an association between ctDNA positivity after surgery and worse survival. This review demonstrated that post-operative ctDNA is the most predictive prognostic factor of all investigated time points. A third systematic review investigating different ctDNA measurement techniques on predictive and prognostic outcomes in LARC patients, concluded that detection of ctDNA at different time points of treatment was consistently associated with worse prognosis, but that the ideal method and timing for the liquid biopsy still needed to be defined (39).

Although all studies found a positive correlation between ctDNA and treatment and oncological outcomes, various methods to analyse ctDNA were used, including those with quantitative (e.g. absolute cfDNA concentration) and qualitative (tumour-specific somatic mutations) measurements. Articles that utilized quantitative analyses were generally published between 2008-2018, and were considered relatively inferior because quantitative tests do not have the ability to discriminate tumour DNA from physiological circulating DNA from non-cancerous cells. More recent studies often used qualitative techniques that are able to specifically detect tumour-specific cfDNA. These mutation-specific analyses are nowadays considered as technique of choice, and are acceptable in terms of costs (40). Differences in qualitative analyses exist as well, as was shown as shown by Liu et al. (22) This study revealed that minor differences in the sensitivity of ctDNA are observed when different gene panels and techniques for ctDNA quantification are used, in which a personalised assay targeting tumour-informed mutations was suggested to yield the best performance. However, tumour-informed assays are more expensive and labour-intensive as they require sequencing of the tumour and subsequent design of tumour-specific assays. This can be challenging, especially in a setting where the turnaround time for clinical decision-making needs to be short and will be accompanied by higher costs. A tumour-agnostic method is likely to have a faster turnaround time, as it is easier to conduct, and is accompanied by lower costs. Currently, well-powered studies in a real-world setting comparing all assays with regard to its sensitivity, specificity and turnaround time are lacking.

Another controversy in ctDNA analysis is the optimal timing of measurement to detect MRD after surgery, as it has been suggested that an abundance of surgery‐induced cfDNA fragments could hamper the detection of ctDNA from the tumour (41). In a study by Hendriksen et al., it was shown that cfDNA levels in patients with colorectal cancer were increased by threefold during the first week after surgery (median 3.6‐fold increase, mean: 4.0, 95% CI 2.90–5.37, P = 0.0005), and slowly decreased over the next 3 weeks. Notably, it was assumed that in five of the eight patients, ctDNA was falsely measured as being negative, as these patients were ctDNA positive in all other measurements in which ctDNA surgery‐induced cfDNA fragments were not increased. Therefore, to maximize sensitivity of the measurement, one could argue to only measure ctDNA at least four weeks after surgery. On the other hand, when the results of the ctDNA analyses have clinical consequences, e.g. ctDNA-based adjuvant therapy, results ought to be known within the timeframe that consolidation treatment will still be sufficient. Typically, most ctDNA assays are accompanied by an additional four weeks turnover time from blood withdrawal to definite results (42), so the typical timeframe of a maximum of 8 or 12 weeks from surgery to start with adjuvant treatment could be endangered when delaying the ctDNA result too long (43–45). A balance between test sensitivity, and considerations regarding turnaround times inherent to different methods, should be considered for each clinical implication and setting.

Precision biomarkers to predict postoperative outcomes, such as ctDNA, could contribute to the ongoing debate whether additional treatment should be considered after rectal cancer surgery. The role of adjuvant systemic treatment in rectal cancer has not been established globally; practice differs between Europe and the USA, and between European countries as well. In the Netherlands, adjuvant chemotherapy is not recommended for any stage (46). There are only a few randomised controlled trials on adjuvant chemotherapy for rectal cancer available, which yielded conflicting results (47). The fact that the benefit of adjuvant chemotherapy has not yet been demonstrated, is likely related to a dilution effect, and it might very well be true that a subgroup of patients will benefit from additional treatment. Therefore, it would certainly be of interest to explore whether high-risk patients based on ctDNA detected in postoperative peripheral blood samples might benefit from adjuvant treatment. A trial randomising patients with detectable ctDNA into an adjuvant treatment group and a follow-up group is warranted. Such a trial should be able to answer the important question whether ctDNA-guided adjuvant treatment is beneficial in rectal cancer.

Another potential opportunity of ctDNA-guided treatment is the ability to tailor follow-up strategies based on patients’ individual risk of recurrence. As intensive follow-up does not appear to improve overall and cancer-specific survival and quality of life in colorectal cancer, there seems to be an incentive to reduce surveillance after curative surgery (46, 48, 49). Studies have demonstrated that ctDNA outperforms CEA in (colo)rectal cancer patients to detect relapsing disease (5, 25, 31, 50). Therefore, ctDNA-based risk prediction for recurrence may very well be an excellent biomarker to stratify patients without detectable DNA into a less intensive and decentralised surveillance programme in the home environment or even earlier discharge of standard follow-up. This could eventually improve health-related quality of life, cause a reduction in health-related and societal costs as well as anxiety in cancer patients, without compromising oncological outcomes. Further research would be needed to investigate whether this ctDNA-guided follow-up approach is feasible in rectal cancer.

Finally, novel technical advances highlight the promise of several tumour-agnostic ways to detect ctDNA (i.e. without prior tissue-based information) in the future. For example, recent results highlight the merit of circulating cell free (cf)DNA methylation analyses for both detection and classification of many cancer types, including colorectal cancer (51–54). Next to methylation profiling, recently discovered “fragmentomics” also shows great promise for the sensitive detection of cancer using cfDNA (55–57). Both cfDNA methylation profiling and fragmentomics capture information from a much broader spectrum of the circulating tumour genome, theoretically enabling a higher analytical sensitivity for the detection of minute traces of ctDNA in case of MRD. Supporting this notion, combining features from different molecular levels was shown to have complementary value for MRD detection in colorectal cancer (58).

In conclusion, in rectal cancer patients treated with neoadjuvant treatment and surgery, a very strong association was found between post-treatment detectable ctDNA and recurrent disease as well as overall survival. Randomised controlled trials are needed to investigate whether this ctDNA-informed risk classification could be used during clinical decision making for the purpose of patient-tailored treatment.

Data availability statement

The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.

Author contributions

All authors have significantly contributed to this work. JR, LW, AG, YD, CV, NB were involved in writing the introduction, the systematic search, and the article selection process. JR, LW, NB, JV, SW conducted the quality assessment of the included articles and methodology. GV, PT, HV, JM, CV were part of the writing committee. The manuscript was drafted by JM, LW, AG, YD, and corrected by NB, JV, SW, GV, PT, HV, JM, CV. Supervision was provided by SW, NB and CV. All authors contributed to the article and approved the submitted version.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2023.1083285/full#supplementary-material

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Keywords: Ctdna (circulating tumour DNA), cfDNA (circulating free DNA), rectal cancer, minimal residual disease (MRD), liquid biopsy

Citation: van Rees JM, Wullaert L, Grüter AAJ, Derraze Y, Tanis PJ, Verheul HMW, Martens JWM, Wilting SM, Vink G, van Vugt JLA, Beije N and Verhoef C (2023) Circulating tumour DNA as biomarker for rectal cancer: A systematic review and meta-analyses. Front. Oncol. 13:1083285. doi: 10.3389/fonc.2023.1083285

Received: 28 October 2022; Accepted: 09 January 2023;
Published: 30 January 2023.

Edited by:

Marek Minarik, Elphogene, s.r.o, Czechia

Reviewed by:

Manuela Gariboldi, Fondazione IRCCS Istituto Nazionale Tumori, Italy
Dalong Pang, Georgetown University, United States

Copyright © 2023 van Rees, Wullaert, Grüter, Derraze, Tanis, Verheul, Martens, Wilting, Vink, van Vugt, Beije and Verhoef. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Jan M. van Rees, j.vanrees@erasmusmc.nl

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

ctDNA, circulerend tumor-DNA, endeldarmkanker, rectumkanker, voorspellende waarde, recidief, operatie, biomarker