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ctDNA-Response evaluation criteria in solid tumors – a new measure in medical oncology

  • Anders K.M. Jakobsen
    Affiliations
    Institute of Regional Health Services, University of Southern Denmark, Department of Oncology, Vejle University Hospital, 7100, Vejle, Denmark
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  • Karen-Lise G. Spindler
    Correspondence
    Corresponding author: Department of Oncology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark.
    Affiliations
    Department of Oncology, Aarhus University Hospital, Denmark

    Department of Clinical Medicine, Aarhus University, Denmark
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Open AccessPublished:January 05, 2023DOI:https://doi.org/10.1016/j.ejca.2022.11.039

      Highlights

      • Early changes in ctDNA during treatment has clinical potential in solid tumours.
      • CtDNA response can become a useful surrogate for oncological outcome.
      • Standardisation of criteria for ctDNA response evaluations are mandatory.
      • We propose the ctDNA Response Evaluation Criteria in Solid Tumor similar to RECIST.
      • The clinical utility of ctDNA-RECIST must be validated in carefully designed trial.

      Abstract

      In the metastatic setting, most decisions during systemic palliative therapies are based on the imaging-based Response Evaluation Criteria in Solid Tumors (RECIST), which is, however, known to be a suboptimal surrogate marker for the clinical outcome overall survival. Over the past decade, research has brought focus to the potential of circulating tumour DNA in cancer. However, at present, there is no generally accepted classification of quantitative changes during the treatment course, and prospective investigations can therefore not be validated. We here propose, for the first time, a response classification based on circulating tumour DNA measurements and its confidence intervals, a “ctDNA-RECIST” that has proven valuable in retrospective studies and goes along with the conventional RECIST classification. We aim to raise the topic for discussion and to encourage analyses of ctDNA data along this line.

      Keywords

      1. Current perspectives

      Systemic treatment with chemo- or immunotherapy is a cornerstone in the management of metastatic cancer. The approach is characterised by a high level of toxicity and a low curative potential, which calls for careful consideration of its benefits and harms. A valid measure of the treatment effect is therefore an absolute condition. Overall survival (OS) is the ultimate end-point of a new treatment, but it often has a perspective of several years, which may delay important progress in the development of treatment and introduction of new drugs. Finding reliable surrogate end-points for OS therefore ranks high.

      2. Surrogate end-points

      A surrogate end-point must be validated before it can be used in daily practice. Careful methodological consideration with respect to trial design and statistics are therefore imperative. Buyse et al. have suggested a two-step procedure [
      • Buyse M.
      • Molenberghs G.
      Criteria for the validation of surrogate endpoints in randomized experiments.
      ]. An individual level of surrogacy requires a correlation between the surrogate and the clinical end-point. The trial level must demonstrate an association between treatment effect and the two end-points.
      Traditionally, response according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria has been used as an early measure of treatment effect. It has rather wide limits of measurement uncertainty, which implies that major changes are needed for it to qualify as a true response measure, and the correlation with OS is poor. A recent meta-analysis including 32 trials reported a low correlation with OS in 91% of the trials [
      • Haslam A.
      • Hey S.P.
      • Gill J.
      • et al.
      A systematic review of trial-level meta-analyses measuring the strength of association between surrogate end-points and overall survival in oncology.
      ]. Despite shortcomings, response has been basis of FDA approval of several new drugs [
      • Chen E.Y.
      • Raghunathan V.
      • Prasad V.
      An overview of cancer drugs approved by the US food and drug administration based on the surrogate end point of response rate.
      ], but better measures are urgently warranted.
      Measurement of circulating tumour DNA (ctDNA) holds many inherent advantages being readily accessible for repeated measurement with little discomfort to the patient. It also seems to overcome intratumoural heterogeneity and reflect important biological characteristics. It has passed the steps from discovery to analytical validity and several studies have documented its clinical validity, but its clinical utility in the metastatic setting remains to be proven. This concept, however, is not too clearly defined, and it is used differently by different authors. According to the evaluation of genomic applications in practice and prevention (EGAPP) initiative [
      • Teutsch S.M.
      • Bradley L.A.
      • Palomaki G.E.
      • et al.
      The evaluation of genomic applications in practice and prevention (EGAPP) initiative: methods of the EGAPP working group.
      ] the clinical utility of a marker defines “the balance of benefit and harm associated with use of the test.” It is important to underline that clinical validity does not necessarily imply clinical utility.
      A considerable literature indicates that ctDNA may serve as a prognostic marker [
      • Reichert Z.R.
      • Morgan T.M.
      • Li G.
      • et al.
      Prognostic value of plasma circulating tumor DNA fraction across four common cancer types: a real-world outcomes study.
      ]. Generally, a high level of ctDNA reflects a high tumour burden and a poor prognosis, but ctDNA is not merely a measure of tumour volume. The transition of ctDNA from the tumour into the circulation is a multifactorial process not yet clarified in detail. There are few studies systematically dealing with ctDNA in treatment monitoring, and so far, there is no level I evidence of clinical utility in the metastatic setting, whereas changes in the molecular characteristics of tumour DNA (i.e., appearance or clearance of specific tumour mutations) during therapy are widely investigated in different solid tumours, and the use of ctDNA concentration as a quantitative measure is less elucidated.
      Another problem is the diversity in reporting of results [
      • Brenner Thomsen C.
      • Dandanell Juul A.
      • Lefèvre A.C.
      • et al.
      Reporting on circulating tumor DNA monitoring in metastatic cancer-From clinical validity to clinical utility.
      ]. Most studies find that a decrease of ctDNA during treatment implies a better survival compared to non-decreasing ctDNA, but there is no agreement as to a quantitative definition of the decrease to qualify it as ctDNA response. Some authors argue that a relative decrease to a low value would suffice, while others report an undetectable level as a response criterion. The same problem appears in the outlining of a ctDNA increase and a definition of ctDNA progression. The diversity in studies is illustrated in a recent systematic review and meta-analysis of ctDNA in metastatic colorectal cancer [
      • Callesen L.B.
      • Hamfjord J.
      • Boysen A.K.
      • et al.
      Circulating tumour DNA and its clinical utility in predicting treatment response or survival in patients with metastatic colorectal cancer: a systematic review and meta-analysis.
      ]. Even in this widely investigated disease, only a limited number of studies reported on the role of early dynamics of ctDNA, and the review revealed a high level of heterogeneity in the use of measurements, time points and definition of response.

      3. ctDNA-RECIST

      As discussed above, objective response evaluation based on imaging is a poor surrogate end-point with only marginal correlation with OS. It is therefore relevant to explore new markers for early evaluation of response and surrogate end-points for outcome.
      Indeed, in a retrospective analysis of ctDNA, complete response was shown to be a much better candidate than imaging-based evaluations [
      • Jakobsen A.
      • Andersen R.F.
      • Hansen T.F.
      • et al.
      Early ctDNA response to chemotherapy. A potential surrogate marker for overall survival.
      ], and other trials point to the same direction [
      • Vega D.M.
      • Nishimura K.K.
      • Zariffa N.
      • et al.
      Changes in circulating tumor DNA reflect clinical benefit across multiple studies of patients with non-small-cell lung cancer treated with immune checkpoint inhibitors.
      ]. On the other hand, a rapid increase in ctDNA correlates with a poor prognosis [
      • Faaborg L.
      • Andersen R.F.
      • Waldstrøm M.
      • et al.
      Prognostic impact of circulating methylated homeobox A9 DNA in patients undergoing treatment for recurrent ovarian cancer.
      ]. ctDNA seems to fulfil the first criterion of a surrogate end-point as suggested by Buyse et al. [
      • Buyse M.
      • Molenberghs G.
      Criteria for the validation of surrogate endpoints in randomized experiments.
      ]. Therefore, it is rational to define and directly compare ctDNA-RECIST with the standard RECIST criteria in a prospective, randomised trial to investigate its value as a surrogate end-point. For this purpose, a clear definition of the quantitative changes in ctDNA must be presented and validated.
      A generally accepted measure of an analyte is its mean value with a 95% confidence interval (CI) assuming a normal distribution. The principle of droplet digital polymerase chain reaction, which is a common method for ctDNA analysis, is based on a Poisson distribution. With 20,000 or more droplets analysed, its form is close to a normal distribution even with a small fraction of ctDNA in the sample. Therefore, it seems reasonable to base the classification of ctDNA levels on the measured values with their CI's and use this approach for establishment of a ctDNA response scale, ctDNA-RECIST. Hence, we propose to define ctDNA-RECIST as follows:
      • ctDNA-RECIST progression is an increase of ctDNA above the previous value with no overlap of the two CI's.
      • Stable ctDNA-RECIST is a value within the CI of the previous value. The category also includes samples with both the previous and present value being 0 (undetectable).
      • ctDNA-RECIST partial response implies a decrease below the previous value with no overlap of the two CI'S, but the lower CI does not overlap 0.
      • ctDNA-RECIST complete response is a decreasing value to an undetectable level, whereas a near complete ctDNA-RECIST response can be defines as when the value below the previous value with the lower CI overlapping 0. These can be combined and termed ctDNA-RECIST maximal response.
      The ctDNA-RECIST criteria are compared to objective RECIST in Table 1. Of note, the two classifications systems seem compliant except for near complete response, which is not included in the standard RECIST criteria. The major part of this small subgroup will have no ctDNA and be complete responders, but it is probably semantically misleading to classify samples with a signal as complete responders.
      Table 1Comparison of criteria for response evaluation by standard RECIST and ctDNA-RECIST.
      Standard RECIST v1.1 (Imaging)ctDNA -RECIST
      ProgressionAt least a 20% increase in the sum of diameters of target lesionsAn increase of ctDNA above the previous value with no overlap of the two CI's
      Stable diseaseNeither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.A value within CI of the previous value. The category also includes samples with both previous and present value being 0 (undetectable).
      Partial ResponseAt least a 30% decrease in the sum of diameters of target lesionsA decrease below the previous value with no overlap of the two CI'S but the lower CI does not overlap 0.
      Complete Response
      Complete and near complete response can be combined and classified as maximal responders.
      Disappearance of all target lesionsDecreasing value to an undetectable level
      Near complete response
      Complete and near complete response can be combined and classified as maximal responders.
      Has no corresponding standard RECIST value.A decrease below the previous value with no overlap of the two CI'S and with the lower CI overlapping 0
      Complete and near complete response can be combined and classified as maximal responders.
      a Complete and near complete response can be combined and classified as maximal responders.

      4. Perspectives

      Objective response is currently used as the first measure of efficacy, and the treatment continues until objective progression. This approach implies that a certain fraction of the patients over a period of time receive an ineffective treatment with considerable toxicity. Recent studies have documented patients with an early increase of ctDNA to have a poor prognosis and should be spared further treatment with the current regimen. The ctDNA-RECIST approach holds promise as to a more rational use of systemic treatment.
      Following phase I trials, the next step in the approval of new drugs is usually phase II trials with objective response rate as the primary end-point. ctDNA-RECIST may serve as an end-point highly correlated with OS as well as a tool for early rejection of ineffective drugs. The concept may be a step forward in the development of new drugs.

      5. Conclusion

      ctDNA is on the doorstep to clinical utility. Classification into increase/decrease of ctDNA according to a system similar to that of objective response seems to be a relevant tool for further clinical application. The ctDNA-RECIST classification has the advantage of using a well-known terminology familiar to any department of oncology.

      Author contributions

      Professor Jakobsen and Professor Garm Spindler contributed equally to the concepts and design of the commentary and wrote the manuscript together.

      Conflict of interest statement

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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