*For medical professionals reading reference only
Professor Zhang Xiaotian will take you to learn about the new progress of gastric cancer liquid biopsy!
Liquid biopsy refers to the detection of blood samples to find circulating tumor cells or tumor cell DNA fragments in the blood. Liquid biopsy can be used to help detect cancer early, guide treatment, detect cancer recurrence, etc. Compared with tissue biopsy technology, liquid biopsy is relatively non-invasive, and through the detection of blood samples at multiple time points, it can monitor and dynamically reflect the patient's tumor burden and tumor mutation in real time, which has great clinical application value. Among a variety of liquid biopsy technologies, circulating tumor DNA (ctDNA) is one of the most widely used technologies.
On November 9, 2022, at the 25th National Clinical Oncology Conference and 2022 CSCO Academic Annual Meeting, Professor Zhang Xiaotian from Peking University Cancer Hospital gave a wonderful speech on the topic of "The Application and Breakthrough of ctDNA in the Diagnosis and Treatment of Gastric Cancer". Let's learn together!
Figure 1 Professor Zhang Xiaotian’s academic lecture at the CSCO conference
HER2 positive gastric cancer ctDNA detection
ctDNA HER2 detection can be an effective supplement to tissue HER2 detection.
Guardant360 clinical trial evidence shows that the consistency of gastric cancer ctDNA NGS and tissue HER2 status (IHC/FISH) is 61% (17/28), the sensitivity is 58% (15/26), and the specificity is 100% (2/2). The consistency of HER2 amplification was detected by colorectal cancer blood NGS and tissue (FISH or NGS), 83% (62/75), PPA was 82% (32/39), and NPA was 83% (30/36).
Professor Zhang Xiaotian introduced that IHC/FISH technology is the gold standard for tissue HER2 detection, but gastric cancer HER2 positive detection still faces the dilemma of heterogeneity and tissue accessibility: HER2 molecules have spatiotemporal heterogeneity, and the detection results of tumor tissue sampling may not reflect the overall tumor, and IHC testing for only major lesions may affect the treatment decisions of some patients.
. Using ctDNA detection can reflect the HER2 status of tumor tissues and even the entire genome status, comprehensively predict and guide the treatment of HER2-positive gastric cancer, replace biopsy again, and evaluate the efficacy of the drug.
ctDNA can detect efficacy and prognosis during the treatment of advanced gastric cancer against HER2 in the treatment of advanced gastric cancer
Clinical evidence shows that ctDNA NGS was tested for blood samples from 40 advanced gastric cancer patients receiving anti-HER2 treatment, and at the time of disease progression. By analyzing the abundance of TP53 and HER2 mutations, 40% of patients can predict disease progression before CT evaluation, and disease progression trends can be detected on average 38.4 days ahead of schedule compared with CT.
In terms of prognostic detection, 46 patients with advanced gastric cancer treated with PD-1 monoclonal antibody were tested for NGS for blood sample ctDNA. The maximum somatic variant allelic frequency (maxVAF) decreased by 25% compared with those without decreases PFS (7.3 months vs 3.6 months), and more effective (53.3% vs 13.3%, p=0.06). The mutation status of TGFBR2, RHOA and PREX2 affects the PFS of immunotherapy (p0.05), and patients with CEBPA, FGFR4, MET or KMT2Bs variants are highly likely to have immune-related adverse events (P=0.09).
ctDNA helps explore biomarkers related to the efficacy of immunotherapy combined with anti-HER2 treatment
Figure 2. ctDNA gene enrichment diagram of gastric cancer patients
. ctDNA detection analysis of blood samples of gastric cancer patients receiving immunotherapy combined with anti-HER2 treatment found that HER2 amplification and POLE variants were significantly enriched in the group of patients with optimal efficacy evaluation as partial remission and complete remission. The "immune-related negative gene set" variants included in the signaling pathway RTK/RAS, PI3K, p53, cell cycle, WNT, and ICI_neg_genes are significantly enriched in the group of patients with stable disease and progression of disease.
POLE common mutations are p.P286R, V411L, S297F, A456P and S459F, indicating a positive correlation with immunotherapy efficacy. However, the clinical guiding significance of some uncommon variants is still unclear. The above study further proposes that Polyphen-2 predicts harmful variants: p.Y766F, p.K733N, p.L1766M and p.A546Sp.A2262S.
patients with ctDNA carrying POLE wild-type genes have higher ORR.The variant carrying "immune-related negative gene set" of ctDNA is significantly related to the poor efficacy of combined treatment. The variant of ctDNA's "immune-related negative gene set" can be used as an independent predictor of "immune therapy + anti-HER2 combination therapy".
ctDNA-positive gastric cancer patients should be more active after surgery
In patients with gastric cancer undergoing surgical treatment, the detection of micro-residual lesions is very limited in the prediction data for recurrence risk, and ctDNA can effectively predict the recurrence of gastroesophageal cancer patients. In a clinical study of
, 269 patients with stage I-IV gastroesophageal cancer (esophageal cancer N=79, gastroesophageal junction cancer N=73, gastroesophageal cancer N=117), the customized PCR detection method was used to detect ctDNA in the blood samples of patients. In the postoperative testing cohort of stage I-III patients, the prognosis of ctDNA positive patients was worse than that of ctDNA negative patients (HR-9.0, p6.S0e-12), suggesting that patients with ctDNA positive need more active treatment.
Compared with traditional imaging, ctDNA can detect disease recurrence about 6 months earlier. In a clinical study of 46 patients with gastric cancer who underwent surgical resection in stage I-III, the variant detected in tissues was defined as ctDNA positive, and the detection rate of ctDNA in preoperative blood was 45%. Among them, the ctDNA detection rate in stage III patients was 68% (15/22), and the ctDNA detection rate in stage I-II patients was 21% (4/9).
Figure 3. ctDNA detection can detect cancer recurrence early
Compared with imaging, ctDNA can detect recurrence 179 days earlier. Professor Zhang Xiaotian mentioned that if ctDNA detection technology is used earlier than imaging technology to detect disease recurrence, whether intervention measures are needed in advance are also a question we need to think about. Application of
ctDNA in gastric cancer metastasis
PANGEN study analyzed the molecular variation maps of primary and metastases of gastric cancer. About 35% of gastric cancer patients (28/80) were inconsistent, and the proportions of primary foci FGFR2 and MET amp were 1.25% and 5% respectively; the proportions of corresponding metastases were 5% and 11%. In 16 HER2-positive patients, 12.5% (2/16) turned to HER2-negative patients; 3.1% (2/64) turned to HER2-positive patients, indicating that the HER2 status of tumor tissues in patients with gastric cancer also changed dynamically during the treatment process.
Figure 4. Genomic heterogeneity in PANGEA clinical trials with molecular-driven treatment
For patients with gastric cancer metastasis, ctDNA can effectively reflect the genomic characteristics of metastatic foci. The primary foci and metastatic foci of 28 metastatic gastroesophageal gland patients were detected with cell free DNA (cfDNA). There were significant differences in the genomes of primary foci and metastatic foci in 36% (10/28) of patients. The treatment plan of 9 patients was adjusted accordingly. In terms of target gene amplification of
, 85% (17/20) patients had metastatic lesions and cfDNA results; among patients whose genome changes were inconsistent with the primary lesions and metastatic lesions, 87.5% (7/8) patients had consistent metastatic lesions and cfDNA results suggest that compared with the primary lesions sequencing guidance, metastatic lesions or cfDNA sequencing has more effective guiding significance.
1. In HER2-positive gastric cancer, ctDNA HER2 detection can be used as an effective supplement to tissue HER2 detection. ctDNA can detect efficacy and prognosis in the anti-HER2 treatment process of advanced gastric cancer. ctDNA can also help explore the biomarker related to the efficacy of immunotherapy combined with anti-HER2 treatment.
2. In patients with gastric cancer who undergo surgery, ctDNA can detect cancer recurrence about 6 months earlier than imaging.
3. For patients with gastric cancer metastasis, ctDNA can effectively respond to the genomic characteristics of metastasis.
This article is first published: Medical community tumor channel
Author: Zhu Ziqing
Editor: Sweet
Copyright statement
Original article If you need to reprint, please contact the authorization
- End -
* The medical community strives to ensure the accuracy and reliability of the published content when it is approved, but does not make any commitments and guarantees for the timeliness of the published content, as well as the accuracy and completeness of the cited materials (if any), and does not assume any responsibility arising from the outdated content, the possible inaccuracy or incompleteness of the cited materials. Please check separately when using this or using it as the basis for decision-making.
