2021 ASH big coffee talks about Professor Zhang Yizhu: the application of circulating tumor DNA in childhood lymphoma

The 63rd Annual Meeting of the American Society of Hematology (ASH) was successfully held on December 11-14, 2021
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Professor Zhang Yizhu from the Cancer Center of Sun Yat-sen University and his team explored the analysis of circulating tumor DNA (ctDNA) in children with mature B-cell non-Hodgkin lymphoma (B-NHL) and were selected for this year's ASH poster presentation
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Yimaitong invited Professor Zhang Yizhuo to accept an interview to talk about the application of ctDNA detection technology in children with lymphoma
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Yimaitong: ctDNA liquid biopsy has become an emerging technology, and most of these studies are based on adult lymphoma research data
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Could you please introduce the current status, importance and necessity of its application in the field of childhood lymphoma? Professor Zhang Yizhuo in recent years, with the continuous development of detection technology, ctDNA liquid biopsy has become an emerging technology.
Compared with tissue biopsy, liquid biopsy has the advantages of overcoming tumor heterogeneity and convenient sampling (plasma, cerebrospinal fluid, pleural and ascites, etc.
) urine, etc.
) and other advantages, can be detected and include different types of mutations, gene rearrangements, mutations in copy number variation and the like
.

At present, more research data has been accumulated in the research of adult lymphoma
.

For intravascular large B-cell lymphoma and primary central lymphoma, which are subtypes of lymphoma that are difficult to obtain biopsy tissue samples, ctDNA testing can be used to assist in the diagnosis
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A study on liquid biopsy of adult diffuse large B-cell lymphoma (DLBCL) showed that compared with the tissue gold standard, the sensitivity of plasma ctDNA to detect mutations was as high as 82.
8%
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Compared with imaging examinations, ctDNA's high-sensitivity detection can detect recurrence, minimal residual disease (MRD) monitoring and the exploration of drug resistance mechanisms in advance
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Another study conducted dynamic detection of ctDNA on the plasma samples of 217 adult DLBCL patients and found that the earlier the early molecular response (EMR) or the major molecular response (MMR) patient’s event-free survival (EFS) and overall survival The better the period (OS), indicating that the ctDNA test can prompt the prognosis
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In addition, for patients with PCNSL, the use of cerebrospinal fluid ctDNA for testing can help clinicians identify patients with central violations in advance
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The pathogenesis and pathological types of lymphoma in children and adolescents are different from those in adult lymphoma.
In the British Journal of Haematology in 2016, there is a review summarizing that molecular genetic abnormalities are common in non-Hodgkin’s lymphoma (NHL).
It is related to the classification, prognosis and treatment of tumor pathogenesis
.

However, most of the molecular genetic studies of B-NHL and T-NHL are conducted on adult patient samples, and whether many of the results are the same in children and adolescents NHL remains to be confirmed
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For example, double-hit or triple-hit lymphoma is a poor prognostic factor in adult lymphoma and rarely occurs in childhood lymphoma; non-GCB subtypes have a poor prognosis in adult DLBCL, while children's non-GCB subtypes and GCB subtypes DLBCL There is no difference in the prognosis
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The article emphasized the genetic characteristics of young NHL patients, and pointed out that there are still gaps with adult NHL research.
More research is still needed to help predict the prognosis of young NHL patients and guide future treatment
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At present, ctDNA detection has preliminary results in children’s lymphoma.
International studies have explored the value of plasma ctDNA detection in the pathogenesis of children’s classic Hodgkin’s lymphoma (HL) and monitoring treatment response.
In 72 cases The results of identifying gene variants derived from tumor cells in patients’ peripheral blood samples showed that the SOCS1 gene was the most common, and the JAK/STAT, NFkB, and PI3K signaling pathways were mainly abnormal
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Although the OS rate of childhood HL and childhood NHL can be as high as 80%-90% after standard treatment, the overall prognosis is good, but there are still some patients with relapse/refractory, and most patients with relapsed and refractory lymphoma have a poor prognosis
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At present, there are few research data of ctDNA in childhood lymphoma at home and abroad, and the feasibility and clinical value of ctDNA detection in childhood lymphoma have not been clarified
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There is no mutation map data for Chinese children’s lymphoma; the value of ctDNA in judging the curative effect of children’s lymphoma, whether the use of ctDNA detection technology can identify relapsed and refractory patients earlier than imaging examinations, and carry out early intervention treatment to further improve relapse and refractory treatment The prognosis of patients; whether ctDNA monitoring can detect drug resistance mechanisms; and whether ctDNA testing can help children with lymphoma to better prognosis stratification, etc.
, all need to be confirmed by prospective clinical studies
.

Based on this
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The Cancer Center of Sun Yat-sen University carried out a prospective study on the dynamic monitoring of ctDNA in children with lymphoma, and explored the practical application value of ctNDA in children with lymphoma in China by including more children with lymphoma
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Yimaitong: The multi-center and prospective study of children's mature B-NHL ctDNA dynamic monitoring conducted by you and your team was selected for the poster presentation of this year's ASH annual meeting.
Could you please introduce the results and significance of this study? Professor Zhang Yizhuo Sun Yat-sen University Cancer Center has started to carry out clinical research on the dynamic monitoring of ctDNA in childhood lymphoma (NCT4957901) in 2019.
At present, there are more than a dozen centers and more than 160 children with lymphoma patients have been enrolled, mainly including Burkitt.
lymphoma, DLBCL, lymphoblastic lymphoma, in addition to between a few large cell lymphoma, NK / T cell lymphoma, and the like of HL
.

The study selected for the 2021 ASH conference poster presentation included 53 newly diagnosed children with mature B-NHL patients, including 35 cases of Burkitt lymphoma, 18 cases of DLBCL or high-grade B-cell lymphoma (DLBCL/HGBCL)
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Collect the paraffin-embedded tissue (FFPE) of the newly diagnosed patients and the plasma samples before, during and after the treatment, and use a large panel of 475 genes to dynamically monitor the blood samples of newly diagnosed childhood lymphoma
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This study explored the genetic profile of childhood mature B-cell lymphoma.
The top5 genes detected in 38 baseline tissues and 31 baseline plasma samples were MYC (71%), DDX3X (45%), and ID3 (42%).
, TP53 (40%), SMARCA4 (29%) and MYC (52%), DDX3X (45%), ID3 (42%), TP53 (36%), GNA13 (23%)
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Studies have found that in plasma, genes with higher mutation abundance are MYC, DDX3X, ID3, TP53, SMARCA4, ARID1A, indicating that these genes may be the origin of early tumors, and ctDNA high-frequency mutation genes are highly consistent with tissue samples, suggesting that plasma samples It can reflect the mutation characteristics of mature B-NHL in children
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This study showed that the positive rate of baseline plasma detection is high, and 100% of tumor-specific mutations can be detected in baseline plasma of untreated patients.
The abundance of ctDNA is significantly related to clinical factors (stage, risk stratification, LDH level)
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ctDNA dynamic monitoring was basically consistent with tumor burden and clinical efficacy.
6 patients who underwent surgical resection of the lesion at the first diagnosis received baseline ctDNA testing, and 4 patients had negative ctDNA results (3 patients showed no residual tumor after PET/CT, and 1 patient) The patient’s PET/CT suspected a little residual tumor), suggesting that the ctDNA results at the first diagnosis can reflect the surgical resection of the lesion
.

The study also conducted clinical follow-up and ctDNA analysis of 37 mature B-NHL patients.
The median follow-up was 182 days.
33 patients completed anti-tumor therapy, and 27 patients underwent PET-CT after the treatment, 20 of which were The patients undergo ctDNA testing simultaneously
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Among the 20 patients, 4 patients showed residual tumors by PET/CT, and no mutation was detected in ctDNA of these 4 patients
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Three of the 4 patients underwent biopsy of residual lesions.
No tumor was found in pathology.
Another patient could not undergo surgery or biopsy for residual lesions.
Regular follow-up was performed.
Tumor recurred after 1 month
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As of the last follow-up, all 53 patients were alive
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The results of this study suggest that in children with mature B-NHL, dynamic monitoring of plasma ctDNA can reflect the mutation characteristics of children with mature B-NHL, and can find undetected gene mutations in the tissues, which can be used as a supplement to tissue samples
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The mutation abundance of ctDNA is related to tumor burden, clinical stage and risk
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In monitoring residual tumor foci, ctDNA results are consistent with the pathological results of residual foci, which is of higher value in judging tumor residual
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The study is still in the enrollment follow-up stage, and we look forward to more research data to further explore the prognostic value of ctDNA dynamic monitoring in childhood lymphoma, the mechanism of relapse and resistance, and improve the molecular characteristics of Chinese childhood lymphoma, hoping to further from the molecular level Refine the prognostic stratification of childhood lymphoma to promote more precise and individualized treatment
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Yimaitong: What are the current deficiencies in ctDNA detection technology? What are your expectations for its future development and application prospects? From the current research data and clinical practice, Professor Zhang Yizhuo shows that ctDNA-based liquid biopsy has a wide range of applications in tumor diagnosis and treatment.
ctDNA detection technologies including RT-PCR, ddPCR, and NGS have become the mainstream technologies in current research
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With the advantages of high sensitivity, high specificity and high throughput, NGS technology is increasingly used in tumor genome mutations including ctDNA detection
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With the deepening of research, some shortcomings have also been exposed
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The first is whether it can provide better sensitivity, especially in tumor MRD research
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At the technical level, increasing the depth of sequencing to improve the sensitivity of the technology will also bring a lot of background noise.
How to identify the mutation of the tumor source from this noise is the current technical difficulty
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Second, how to exclude clonal hematopoietic mutations
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As we age, physiologically healthy tissues such as skin, colon, esophagus, and blood will accumulate cancer-related gene mutations
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In the blood, this phenomenon is called clonal hematopoiesis
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These mutations will also be detected in cfDNA, and how to distinguish them is also an urgent problem to be solved
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The current research is mostly observational research.
Although extensive research and discussion have been conducted on the clinical application prospects of ctDNA, clinical research on drugs in lung cancer has drug-guided research based on ctDNA test results, which is not inferior to the guiding role of tissue test results.
There are also research reports that based on ctDNA results can increase the screening time of clinical trials and increase the enrollment rate, but there is still a lack of interventional research results in the field of lymphoma
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In addition, ctDNA detection is a collection of information at the DNA level, which can detect mutation, amplification, fusion, mutation and other information, but does not have information on expression, modification, and transcription
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I hope that in the future, ctDNA and related tests such as expression, modification, and transcription can be integrated to better serve the precise diagnosis and treatment of patients
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Professor Zhang Yizhuo, Director, Department of Pediatric Oncology, Sun Yat-sen University Cancer Prevention and Treatment Center, South China State Key Laboratory of Oncology Group Leader, Chinese Anti-Cancer Association Hematological Transformation Research Professional Committee Vice Chairman CSCO China Anti-Lymphoma Alliance Standing Committee CSCO China Anti-Lymphoma Alliance Standing Deputy Leader of the Pediatrics and Adolescents Group Member of the Standing Committee of the Pediatric Oncology Professional Committee of the Chinese Research Hospital Association Member of the Pediatric Oncology Professional Committee of the Chinese Anti-Cancer Association Member of the Standing Committee of the Hematological Oncology Professional Committee of the Chinese Anti-Cancer Association (fourth and fifth) stamp "Read the original text", We make progress together