7 oktober 2023: lees ook dit artikel: https://kanker-actueel.nl/ctdna-analyse-bij-patienten-met-hrher2-gevorderde-borstkanker-behandeld-in-de-monaleesa-studies-met-ribociclib-plus-endocriene-therapie-toont-specifieke-genmutaties-die-positief-en-negatief-reageerden-op-ribociclib.html

8 april 2023: zie ook dit artikel: https://kanker-actueel.nl/ctdna-een-bloedtest-op-circulerend-dna-geeft-98-procent-betrouwbaarheid-bij-borstkankerpatienten-en-bewijst-effectiviteit-van-gebruik-in-de-klinische-praktijk-bij-studie-met-350-patienten.html

8 april 2023: Bron: N Engl J Med 2013; 368:1199-1209

Al in 2013 werd deze studie gepubliceerd. Dus tien jaar geleden bewees het meten van Circulerend tumor-DNA (ctDNA) al bij borstkankerpatiënten of een behandeling effectief was of niet. En nog steeds wordt dit niet algemeen gedaan bij kankerpatiënten terwijl dit een manier van meten is die weinig belastend is voor kankerpatiënten. Wel zijn er inmiddels Liquid biopsie centra / laboratoria in Nederland en België in nagenoeg alle academische ziekenhuizen.  Een van de bekendste is in het Erasmus Rotterdam. Of in Amsterdam.

In een kleinschalige studie werd Circulerend tumor-DNA (ctDNA) met succes gedetecteerd bij 29 van de 30 vrouwen (97%) bij wie somatische genomische veranderingen werden geïdentificeerd; CA 15-3 en circulerende tumorcellen werden gedetecteerd bij respectievelijk 21 van de 27 vrouwen (78%) en 26 van de 30 vrouwen (87%).

Circulerende tumor-DNA-waarden vertoonden een groter dynamisch bereik en een grotere correlatie met veranderingen in tumorbelasting dan CA 15-3 of circulerende tumorcellen.de geteste maatregelen leverde circulerend tumor-DNA het eerste meting resultaat voor de respons op de behandeling bij 10 van de 19 vrouwen (53%).

Circulerende DNA-fragmenten met tumorspecifieke sequentieveranderingen (circulerend tumor-DNA) worden aangetroffen in de celvrije fractie van bloed, die een variabel en over het algemeen klein deel van het totale circulerende DNA vertegenwoordigen. (ref. 11,12). 
Vooruitgang in sequentietechnologieën heeft de snelle identificatie mogelijk gemaakt van somatische genomische veranderingen in individuele tumoren en deze kunnen worden gebruikt om gepersonaliseerde assays te ontwerpen voor het monitoren van circulerend tumor-DNA. Studies hebben de haalbaarheid aangetoond van het gebruik van circulerend tumor-DNA om de tumordynamiek te monitoren bij een beperkt aantal patiënten met diverse solide kankers, maar er zijn weinig gevallen van borstkanker geanalyseerd. (ref. 13-20 ).

In een kleinschalige studie geven de onderzoekers een directe vergelijking tussen circulerend tumor-DNA en andere circulerende biomarkers (CA 15-3 en circulerende tumorcellen) en medische beeldvorming voor de niet-invasieve monitoring van uitgezaaide borstkanker.




Figure 1. Enrollment of Patients and Collection of Clinical Samples.

In the 30 women who were found to have somatic mutations, structural variants (SVs), or both, the genomic alterations were determined through targeted deep sequencing or whole-genome paired-end sequencing of tumor-tissue specimens and matched normal-tissue specimens. CA 15-3 denotes cancer antigen 15-3.

En in deze grafiek zie je de effecten van de ctDNA meting op de behandeling:




Figure 4. Comparison of Circulating Biomarkers to Monitor Tumor Dynamics and Predict Survival.

Panels A, B, C, and D show serial circulating tumor DNA (ctDNA) levels (number of copies per milliliter of plasma), circulating tumor cell (CTC) numbers (per 7.5 ml of whole blood), CA 15-3 levels (U per milliliter), and disease status as ascertained on computed tomography (vertical dashed lines) for four patients (one in each panel). Details of endocrine or cytotoxic therapy are indicated by colored shading. The orange dashed line indicates the threshold of 5 CTCs per 7.5 ml of whole blood. The green dashed line indicates the CA 15-3 threshold of 32.4 U per milliliter. ND denotes not detected, PD progressive disease, PR partial response, and SD stable disease. Panel E shows the results of a Cox regression model, which identified an inverse relationship between quantiles (quant.) of ctDNA (indicated in copies per milliliter of plasma) and overall survival, with increasing levels significantly associated with poor overall survival (P<0.001). At 200, 400, and 600 days, a total of 23, 8, and 3 patients were at risk, respectively. Panel F shows that increasing ctDNA levels (copies per milliliter), as indicated on the bottom x axis, and increasing numbers of CTCs (per 7.5 ml of whole blood), as indicated on the top x axis, were associated with an increased log e relative hazard. The prognostic discrimination power of circulating tumor DNA level was greatest with levels up to 2000 copies per milliliter. Patients with levels of more than 2000 copies per milliliter were uniformly found to have the worst prognosis. The prognostic power of CTCs increased according to the number of cells. Dashed lines represent 95% confidence intervals.


Het volledige studieverslag is gratis in te zien of te downloaden. Klik daarvoor op de titel van het abstract:

Analysis of Circulating Tumor DNA to Monitor Metastatic Breast Cancer

List of authors.
  • Sarah-Jane Dawson, F.R.A.C.P., Ph.D., 
  • Dana W.Y. Tsui, Ph.D., 
  • Muhammed Murtaza, M.B., B.S., 
  • Heather Biggs, M.A., 
  • Oscar M. Rueda, Ph.D., 
  • Suet-Feung Chin, Ph.D., 
  • Mark J. Dunning, Ph.D., 
  • Davina Gale, B.Sc., 
  • Tim Forshew, Ph.D., 
  • Betania Mahler-Araujo, M.D., 
  • Sabrina Rajan, M.D., 
  • Sean Humphray, B.Sc., 
March 28, 2013
N Engl J Med 2013; 368:1199-1209
DOI: 10.1056/NEJMoa1213261

Abstract

BACKGROUND

The management of metastatic breast cancer requires monitoring of the tumor burden to determine the response to treatment, and improved biomarkers are needed. Biomarkers such as cancer antigen 15-3 (CA 15-3) and circulating tumor cells have been widely studied. However, circulating cell-free DNA carrying tumor-specific alterations (circulating tumor DNA) has not been extensively investigated or compared with other circulating biomarkers in breast cancer.

METHODS

We compared the radiographic imaging of tumors with the assay of circulating tumor DNA, CA 15-3, and circulating tumor cells in 30 women with metastatic breast cancer who were receiving systemic therapy. We used targeted or whole-genome sequencing to identify somatic genomic alterations and designed personalized assays to quantify circulating tumor DNA in serially collected plasma specimens. CA 15-3 levels and numbers of circulating tumor cells were measured at identical time points.

RESULTS

Circulating tumor DNA was successfully detected in 29 of the 30 women (97%) in whom somatic genomic alterations were identified; CA 15-3 and circulating tumor cells were detected in 21 of 27 women (78%) and 26 of 30 women (87%), respectively. Circulating tumor DNA levels showed a greater dynamic range, and greater correlation with changes in tumor burden, than did CA 15-3 or circulating tumor cells. Among the measures tested, circulating tumor DNA provided the earliest measure of treatment response in 10 of 19 women (53%).

CONCLUSIONS

This proof-of-concept analysis showed that circulating tumor DNA is an informative, inherently specific, and highly sensitive biomarker of metastatic breast cancer. (Funded by Cancer Research UK and others.)

Discussion

In the detection of metastatic breast cancer, circulating tumor DNA shows superior sensitivity to that of other circulating biomarkers and has a greater dynamic range that correlates with changes in tumor burden. Circulating tumor DNA often provides the earliest measure of treatment response, as has been supported by recent analyses of circulating tumor DNA in other solid cancers.20,32

The monitoring of circulating tumor DNA levels requires the identification of somatic alterations in individual patients. Future developments will reduce the cost of whole-genome paired-end sequencing, and targeted sequencing can be readily expanded to include other genes, in addition to PIK3CA and TP53, known to be recurrently mutated in breast cancer.33-35 Here we have demonstrated the use of two strategies to quantify circulating tumor DNA: digital PCR assay and targeted deep sequencing. Digital PCR assay provides high accuracy and sensitivity but requires the design of personalized assays, an expensive and rate-limiting step. Targeted deep sequencing of plasma DNA provides a cost-effective alternative for high-throughput analysis and may overcome limitations of initial tumor-tissue assessment by virtue of allowing for the direct identification of mutations in plasma.22 However, our findings on circulating tumor DNA are not limited to these molecular platforms. Other methods for the identification of somatic mutations (such as exome sequencing33) or for the quantification of circulating tumor DNA (e.g., BEAMing [beads, emulsions, amplification, and magnetics] technology13 or Safe-SeqS [Safe-Sequencing System]36) may be applied with even greater sensitivity. Recent studies have also shown the feasibility of performing genomewide analysis of tumor-associated copy-number changes and mutations in plasma.37-39

Our expanding knowledge of the genetic mechanisms underpinning breast cancer now provides a framework to better stratify patients.30,33-35,40,41 The analysis of circulating tumor DNA represents a unique opportunity to integrate this knowledge into the clinical arena. Although the acquisition of tumor-tissue specimens will continue to be important, the use of biopsy specimens is limited, since such material may not capture tumor heterogeneity; in addition, repeated biopsy is impractical. Circulating tumor DNA represents a “liquid biopsy” alternative, allowing for sensitive and specific serial sampling to be performed during the course of treatment.

Supported by grants from Cancer Research UK, and the Experimental Cancer Medicine Centre and National Institute for Health Research Cambridge Biomedical Research Centre, and by an Australian National Health and Medical Research Council–R.G. Menzies Early Career Fellowship (to Dr. Dawson).

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Drs. Dawson and Tsui and Drs. Caldas and Rosenfeld contributed equally to this article.

This article was published on March 13, 2013, at NEJM.org.

We thank Linda Jones and Susan Richardson for recruiting patients into the study; all the medical and ancillary staff in the breast-cancer clinic and the patients for consenting to participate; Sonia Bradbury from the Department of Clinical Biochemistry and Immunology, Addenbrooke's Hospital, for assistance with the CA 15-3 analysis; the Genomics, Histopathology, Bioinformatic, and Biorepository Core Facilities at the Cancer Research UK Cambridge Institute; the Addenbrooke's Human Research Tissue Bank (supported by the National Institute for Health Research Cambridge Biomedical Research Centre); and Sarah Dawson and Sarah Vowler for their contribution to the statistical analysis.

Author Affiliations

From the Department of Oncology, University of Cambridge and Cancer Research UK Cambridge Institute, Li Ka Shing Centre (S.-J.D., D.W.Y.T., M.M., O.M.R., S.-F.C., M.J.D., D.G., T.F., C.C., N.R.), the Departments of Histopathology (B.M.-A.), Radiology (S.R., M.W.), and Clinical Biochemistry and Immunology (D.H.) and the Cambridge Breast Unit (S.-J.D., H.B., B.M.-A., S.R., M.W., C.C.), Addenbrooke's Hospital, Cambridge University Hospital National Health Service Foundation Trust and National Institute for Health Research Cambridge Biomedical Research Centre, and the Cambridge Experimental Cancer Medicine Centre (C.C.), Cambridge; and Illumina, Little Chesterford (S.H., J.B., D.B.) — all in the United Kingdom; and the Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia (S.-J.D.).

Address reprint requests to Dr. Rosenfeld or Dr. Caldas at Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, United Kingdom, or at .

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