Proposing Response Evaluation Criteria in Solid Tumors Based on Genomic
Profiling or Genomic RECIST: A Retrospective Study on the Liquid Biopsy
Results of 29 Cancer Patients
Junichi TAGUCHI, Khin Zay YAR MYINT, Masamori SHIMABUKU,
Kenichi KASHIHARA, Ruriko HORIO, Munehisa KANEDA, Yoko SHIMIZU
Center for Advanced Medical Science and Technology
at Tokyo Midtown, Minato-ku, Tokyo, Japan.

Introduction
Assessment of Tumor Burden

Rationale➢ Overall survival is the most preferable end of therapeutic efficacy in cancer research.
➢ However, the tumor response to treatment and time to disease progression can also
evaluate the effectiveness of certain cancer treatments.
➢ The first standardized assessment tool was developed by the World Health Organization(WHO) in 1981.
➢ To address some pitfalls in WHO criteria, simple and standardized guidelines for theevaluation of therapeutic efficacy were developed in 2000 and called Response Evaluation
Criteria in Solid Tumors (RECIST), which was again revised in 2009 with additionalfeatures for assessment.
➢ Using radiological technologies, anatomical size and changes were categorized into four (a) complete response, (b) partial response, (c) stable disease, and (d) progressive
disease.

➢ Sum of the products ofdiameters (SPDs) andits changes frombaseline during
treatment

WHO Criteria
1981➢ Longest diameter of thetumor, number of lesions
to follow, definitions of theminimum size ofmeasurable lesions, andprogressive disease, spiral
CT guidelines➢ Additional features assessment of lymph nodes
and guidance on
multidetector CT andmagnetic resonance (MR)imaging.

Response Evaluation
Criteria in Solid Tumors(RECIST)

Circulating tumor DNA (ctDNA)

Imaging technologies forassessing tumor burden• Assess gross tumor shrinkage
only, no other responses• Evaluate efficacy of cytotoxic
drug• Takes time to evaluate• Detects molecular level changes andclonal evolution• Evaluates efficacy of more advanced,
targeted and personalized treatment
methods (molecular-targeted therapies,locoregional therapies or immunotherapies,etc.)• Enables timely and continuous monitoringfor prompt actions to be taken

Objectives

RECIST 1.1
2009

1. To examine the quantity and composition of ctDNA results of 29 cancer patients
before and after undergoing dendritic cell (DC) immunotherapy with or without
chemotherapy and/or radiotherapy
2. To develop criteria to evaluate the molecular response to treatment based on ctDNA
results

2000

Methods
Study population and measures• Retrospective observational study of genomic profiling results in 29 cancer patients who
had undergone dendritic cell immunotherapy at the Department of Advanced Medical
Science and Technology, Tokyo Midtown Medical Center.
• Blood specimens for liquid biopsy were taken from the patients immediately before andafter completion of one course of DC immunotherapy.
• We used GenoDive (GenoDive Pharma, Atsugi, Kanagawa, Japan) assays for genomic
profiling of cancer patients in this study.
• Changes in the quantity and composition of circulating tumor DNA (ctDNA) levels were firstcompared among patients who had received different treatment regimens while
undergoing DC immunotherapy.
• These changes were also compared among those diagnosed with different clinical stages
after dendritic cell immunotherapy.
Statistical methods• All continuous variables were expressed as means and standard deviations.
• All categorical variables were expressed as numbers and proportions.
• The calculations and figure generation were performed using Microsoft Excel (MicrosoftCorporation, 2018) and R software (R 4.1.0, R Core Team, 2021).
* Calculation: The change in total ctDNA was calculated as the percent of total ctDNA after
the treatment (LB2) as the numerator and the percent of total ctDNA at baseline (LB1) as
the denominator. The percentage of total ctDNA was the titer of ctDNA divided by that ofcell-free DNA (cfDNA). Baseline ctDNA must be at least 0.1% to be eligible for this calculation.

Setting genomic RECIST with reference to RECIST 1.1
RECIST 1.1
GenomicRECIST

Total ctDNAchanges*(LB2/LB1ratio)

Complete Response (CR): Disappearance of all targetlesions. Any pathological lymph nodes (whether target ornontarget) must have reduction in short axis to <10 mm.

gCR

<0.01

Partial Response (PR): At least a 30% decrease in the sumof diameters of target lesions, taking as reference thebaseline sum diameters.

gPR

0.01-0.69

Stable Disease (SD): Neither sufficient shrinkage to qualify
for PR nor sufficient increase to qualify for PD, taking asreference the smallest sum diameters while on study.

gSD

0.7-1.2

Progressive Disease (PD): At least a 20% increase in thesum of diameters of target lesions, taking as reference thesmallest sum on study (this includes the baseline sum ifthat is the smallest on study). In addition to the relative
increase of 20%, the sum must also demonstrate anabsolute increase of at least 5 mm.

gPD

>1.2

Results
Figure 2. Comparison of clinical andgenomic RECIST

Figure 1. Types of cancer in thestudy cohort

Figure 3. Clonal evolution results in genomic RECIST
Newly formed ctDNAlevels can be the mostprognostic parameter intumor progression ortreatment response,while ctDNA clearance
and the decline or rise inexisting ctDNA did notchange significantly ingenomic response
categories (gRECIST).

Gastroenterological cancers such as pancreatic,colorectal, stomach, and biliary cancers
constituted more than half of the participants.

Even those who are clinically evaluated as having agood response might harbor unfavorable tumor
responses at the molecular level.

Figure 4. Changes in ctDNA with regards to treatment regimens

Figure 4. Changes in ctDNA with regards to clinical response
Even in clinicallystable cases, there
could be highctDNA due to newly
formed ctDNA. A
significantly
increasing trend in
existing ctDNA wasobserved as thediseases progressedclinically.

The patients who
received bothchemotherapy andradiotherapy during DC
immunotherapy had
the highest percent
changes in total ctDNAand newly formed
ctDNA. Patients who
underwent DC
immunotherapy alone
had the least decreasein ctDNA.

Discussions and conclusions
Discussions• Not only ctDNA clearance but also newly formed ctDNA levels can be prognostic in tumor
progression or treatment response.
• In gPR category, approximately 30% of newly formed ctDNA was noted, reflecting thedynamic state of tumor evolution.
• Those clinically evaluated as good response might have unfavorable molecular response.
For example, even in clinically stable cases, ctDNA can be high because of newly formed
ctDNA, although the existing ctDNA level decreases.
• Close monitoring of ctDNA titter and composition can assess more precise tumor
response.
• Hence, monitoring ctDNA is critical in cancer prognosis and should be incorporated in theclinical monitoring of cancer patients.

Conclusions➢ This is the first and only to propose using genomic RECIST and liquid biopsy resultsin various tumors after DC immunotherapy with standard cancer treatments.
➢ Our study showed that genomic RECIST could be useful to monitor the treatment
response, disease progression, and the selection of potential effective treatment incancer patients.
➢ Additionally, our study highlighted that more delicate and precise assessment wasfeasible by prospectively monitoring ctDNA values.
➢ Although generalizability remains an issue, these findings have opened up further
potential for real-world data and evidence to support the clinical use of ctDNA in
precision oncology and personalized cancer treatment.
References: