IMBDX

Our Solution

Early detection of cancer.

Presentations

게시물 목록
NO YEAR SUBJECT JOURNAL NAME LINK
8 2024

Pairwise analysis of plasma cell-free DNA before and after paclitaxel plus ramucirumab treatment in patients with metastatic gastric cancer

Abstract Background Plasma cell-free DNA (cfDNA) analysis has emerged as an appealing alternative to detect somatic mutations. This study compared cfDNA at baseline (baseline-cfDNA) and progressive disease (PD-cfDNA) and tumor tissue DNA (ttDNA) in patients with metastatic gastric cancer who underwent palliative second-line paclitaxel+ramucirumab treatment.   Methods We conducted targeted sequencing of 106 cancer-related genes using germline DNA, baseline-cfDNA, and PD-cfDNA samples. The results were then compared with conventional cancer panel results using ttDNA.   Results Of 76 consecutively enrolled patients who received paclitaxel+ramucirumab treatment, 46 patients (27 males; median age 57.5 [range, 32-73] years) with access to all three samples were analyzed along with their ttDNA data. A total of 138, 145, and 80 mutations were detected in baseline-cfDNA, PD-cfDNA, and ttDNA respectively. Combined analysis of baseline-cfDNA and ttDNA revealed that TP53 (56.5%) was the most frequently mutated gene, followed by CDH1 (26.1%), KRAS (21.7%), and APC (13.5%). For the top four genes, the sensitivity and positive predictive value of baseline-cfDNA compared with ttDNA were 71.8% and 51.9%, respectively. Compared with ttDNA alone, 32 patients (70.0%) benefited fr|om baseline-cfDNA in detecting novel mutations. When combined with baseline-cfDNA and PD-cfDNA, novel mutations were discovered in 34 patients (73.9%). Of note, PD-cfDNA analysis detected 9 novel pathogenic mutations in TP53, APC, PIK3CA, CDH1, RNF43, CTNNB1, and BRCA2 genes in 8 patients (17.4%) after treatment. In baseline-cfDNA, patients with a circulating ttDNA fraction concentration at 110-160 bp of >4.3777 ng/µL had significantly shorter progression-free survival (PFS) (median 3.5 vs. 5.3 months, P=0.016). In addition, maximal variant allele frequency (VAF) values of >0.1045 (median 3.4 vs. 5.2 months, P=0.022) and the sum of VAF values of >0.2071 (median 3.4 vs. 5.2 months, P=0.028) were significantly associated with shorter PFS. In patients with TP53 mutations, those with TP53 VAF values of >0.1014 significantly had worse PFS (median 4.6 vs. 6.4 months, P=0.022).   Conclusions Although cfDNA could not entirely take over the role of ttDNA, cfDNA analysis identified additional somatic mutations that were otherwise missed by ttDNA alone. Moreover, PD-cfDNA analysis detected novel pathogenic mutations that developed during treatment, implicating the clonal evolution of cancer. In addition, baseline cfDNA predicted PFS of patients receiving paclitaxel+ramucirumab therapy.

Pairwise analysis of plasma cell-free DNA before and after paclitaxel plus ramucirumab treatment in patients with metastatic gastric cancer

KSMO
7 2024

High circulating tumor DNA (ctDNA) concentration was associated with shorter progression free survival in patients with metastatic breast cancer

Abstract   Background Metastatic breast cancer can be classified into different subtypes depending on hormone receptor (HR) and HER2 status. The subtype can change during tumor progression, and repeated biopsy is needed to deliver the most appropriate treatment every time a new lesion is found. It is not always possible to get a new biopsy fr|om metastatic sites, and therefore liquid biopsy using circulating tumor DNA (ctDNA) is suggested as an alternative method to replace conventional biopsy.   Methods We performed a prospective serial collection of 65 ctDNA samples fr|om 17 patients with metastatic breast cancer (mBC) at Seoul National University Hospital fr|om October 2020 to March 2022. We used IMBdx AlphaLiquid®100 method to detect the genetic changes and analyzed the correlation with clinical outcomes.   Results Median age was 45 (range 32 – 62). Fifteen patients (88.2%) were relapsed mBC and most of the patients (14/17: 82.4%) were HR-positive and HER2-negative. Most of the patients had their ctDNA examined at baseline and at the time of maximal response and/or at progression. Fifteen patients (88.2%) received systemic therapy including hormone therapy, anti-HER2 therapy, and cytotoxic chemotherapy. Eight patients (47.1%) were on the first-line treatment for mBC, and 7 patients (41.2%) were on the second or later lines for mBC at the time of baseline sampling. The concentration of ctDNA and the sum of mutated allelic frequency was calculated for each sample. The ctDNA concentration ranged fr|om 0.71 to 1386.00 ng/mL, and the median value was 5.37 ng/mL. We dichotomized these samples into two groups, with ctDNA concentration either higher or lower than the median value. Then we analyzed progression free survival (PFS) of each group. Patients with higher ctDNA concentration showed shorter PFS (7 mo. vs. not reached, p< 0.001). The sum of mutated allelic frequency ranged fr|om 0.00% to 223.46% and the median value was 6.36%. Patients with higher mutated allelic frequency showed shorter PFS (6 mo. vs. 22 mo., p< 0.001). In addition, the PFS was significantly worse in patients who had mutated PIK3CA (5 mo vs. 22 mo, p< 0.001). The patients with mutated TP53 also showed shorter PFS (6 mo vs. 17 mo, p< 0.001) in univariate analysis. High estrogen receptor positivity in immunohistochemistry was correlated with lower mutated allelic frequency in ctDNA (p=0.003) but had no impact on the concentration of ctDNA (p=0.165). The concentration of ctDNA differed by metastatic sites. Patients with metastases to bones (p=0.007), liver (p< 0.001), soft tissue or lymph nodes (p=0.002) were more likely to have higher concentrations of ctDNA, while patients with brain metastases had significantly lower ctDNA concentration (p=0.006). When the sum of mutated allelic frequency of ctDNA and metastatic sites was analyzed, bone (p=0.001), liver (p< 0.001), and soft tissue or lymph node (p< 0.001) metastases had a positive correlation, while brain had negative correlation (p=0.017). Lung or pleural metastases had no significant correlation with ctDNA, neither concentration (p=0.271) nor mutated allelic frequency (p=0.965).   Conclusion Patients with mBC with higher concentrations of ctDNA or higher mutated allelic frequency of ctDNA at baseline showed significantly shorter PFS. PIK3CAmt and TP53mt detected by liquid biopsy could be used as a poor prognostic biomarkers for mBC patients.

High circulating tumor DNA (ctDNA) concentration was associated with shorter progression free survival in patients with metastatic breast cancer

AACR

LINK _VIEW
6 2024

Multi-feature cell free DNA analysis and ensemble machine learning for early detection of cancer

Background Early cancer detection is crucial for reducing mortality rates, but current screening methods vary widely in age, intervals, and invasiveness. Unfortunately, over 50% of cancer deaths occur in types without recommended screening tests. Non-invasive multi-cancer early detection (MCED) technology could provide a solution.   Methods We enrolled both healthy individuals (398) and patients diagnosed with stage I-IV colon (107), liver (113), lung (213), prostate cancer (92), gastric (100), pancreatic (113), breast (74), and ovarian (87) cancers for the development of the Multi-Cancer Early Detection (MCED) test. Whole-genome methylation sequencing was performed on tumor and normal tissues at 15X coverage for marker selection, while cell-free DNA was sequenced at 30X coverage to construct the machine learning model. We calculated three genome-wide features: methylation, copy number variation, and fragment-based patterns. For the training set, which comprised 60% of the samples, support vector machine (SVM) algorithms were applied to these features, and ensemble logistic regression was employed to identify cancer signals and tissue-of-origin (TOO) based on scores fr|om the single-feature models. To determine the minimum yield that maintains equivalent performance, we downsampled a 50% fraction of reads fr|om each cfDNA sequencing dataset.   Results The overall sensitivity of the cancer detection model was 85.7% at the specificity of 95.6%, and TOO accuracy was 81.1%. The sensitivity performance for cancers without recommended screening tests previously, such as pancreatic (83.9%) and ovarian (79.7%) cancer, has also been maintained at a high sensitivity level. In-silico analysis confirmed that reducing coverage to 15X, half of the original, maintains high performance in sensitivity and specificity, significantly lowering data processing requirements. Conclusions Proposed MCED method for eight types of cancer, including pancreatic, and ovarian cancer, which were previously difficult to diagnose early, performs with high sensitivity. The reduced coverage of 15X can lower sequencing costs and increase patient accessibility.  

Multi-feature cell free DNA analysis and ensemble machine learning for early detection of cancer

ESMO

LINK _VIEW
5 2024

ctDNA as a biomarker in phase II study of tepotinib in advanced solid cancers with MET exon 14 skipping mutation or amplification (KCSG AL19-17).

Abstract Background Tepotinib consistently demonstrated antitumor activity in patients with MET exon 14 skipping mutation (METex14) and promising activity in various cancers with MET amplification, according to previous reports. We assessed plasma ctDNA as a potential biomarker in MET-dysregulated advanced cancer patients with tepotinib treatment.    Methods KM-08 (KCSG AL19-17, NCT04647838) was a phase 2, multicenter study with tepotinib treatment for patients with advanced or metastatic solid cancers harboring either METex14 or MET amplification detected in tissue-based next-generation sequencing (NGS). For exploratory analyses, we analyzed the genetic profile using liquid-based NGS testing with AlphaLiquid-100 panel (IMBdx Inc. Seoul, KR) at baseline (T0), after six weeks during treatment (T1), and at the time of disease progression (T2).    Results Baseline ctDNA NGS data was available in 28 (80%) out of 35 patients enrolled in the trial. Among them, METex14 or MET amplification was detected in 18 patients, with a sensitivity of 64.3%. The most commonly co-mutated gene was TP53, followed by PIK3CA, ATM, MYCN, and KRAS. The objective response rate (ORR) in plasma MET positive (PM+) patients was higher (81.2%) than the ORR in plasma MET negative (PM−) patients’ group (30.0%). In contrast, PM− group had a longer progression-free survival (PFS) and overall survival (OS) than PM+ group. PFS was 11.0 months (95% CI 8.1, 13.9) vs 6.0 months (95% CI 3.6, 8.3) and OS was NR vs 14.0 months (95% CI 4.7, 23.3), respectively. The molecular responder (MR, MET alteration variant allele frequency [VAF] T1/T0 <50%) was 80.0% (12/15 patients), and the molecular non-responder (MNR, METVAF T1/T0≥50%) was 20.0% (3/15 patients). ORR was higher in the MR group (91.7%) than in the MNR group (33.3%). PFS and OS were longer in the MR group than in the MNR group, 6.0 months (95% CI 0.0, 14.5) vs 3.0 months (95% CI 1.4, 4.6) with P= 0.114 and NR vs 4.0 months (95% CI 2.4, 5.6) with P= 0.067, respectively. Out of the 20 patients with samples available at T2, one had an on-target mutation on MET (D1228N, and Y1230H) while two had off-target emerging oncogenic alterations in KRAS, BRAF, and ERBB2 genes.    Conclusions In the liquid biomarker analysis in the MET-dysregulated cancer patients who were treated with tepotinib, the presence of ctDNA METalteration at baseline was associated with a higher response rate but shorter PFS and OS. The molecular response was well correlated with the radiological response and associated with better outcomes. (Funded by Merck KGaA, Darmstadt, Germany, ClinicalTrials.gov number, NCT04647838.)

ctDNA as a biomarker in phase II study of tepotinib in advanced solid cancers with MET exon 14 skipping mutation or amplification (KCSG AL19-17).

ASCO

LINK _VIEW
4 2024

Pairwise analysis of plasma cell-free DNA before and after paclitaxel plus ramucirumab treatment in patients with metastatic gastric cancer

Abstract Background Plasma cell-free DNA (cfDNA) analysis has emerged as an appealing alternative to detect somatic mutations. This study compared cfDNA at baseline (baseline-cfDNA) and progressive disease (PD-cfDNA) and tumor tissue DNA (ttDNA) in patients with metastatic gastric cancer who underwent palliative second-line paclitaxel+ramucirumab treatment.   Methods We conducted targeted sequencing of 106 cancer-related genes using germline DNA, baseline-cfDNA, and PD-cfDNA samples. The results were then compared with conventional cancer panel results using ttDNA.   Results Of 76 consecutively enrolled patients who received paclitaxel+ramucirumab treatment, 46 patients (27 males; median age 57.5 [range, 32-73] years) with access to all three samples were analyzed along with their ttDNA data. A total of 138, 145, and 80 mutations were detected in baseline-cfDNA, PD-cfDNA, and ttDNA respectively. Combined analysis of baseline-cfDNA and ttDNA revealed that TP53 (56.5%) was the most frequently mutated gene, followed by CDH1 (26.1%), KRAS (21.7%), and APC (13.5%). For the top four genes, the sensitivity and positive predictive value of baseline-cfDNA compared with ttDNA were 71.8% and 51.9%, respectively. Compared with ttDNA alone, 32 patients (70.0%) benefited fr|om baseline-cfDNA in detecting novel mutations. When combined with baseline-cfDNA and PD-cfDNA, novel mutations were discovered in 34 patients (73.9%). Of note, PD-cfDNA analysis detected 9 novel pathogenic mutations in TP53, APC, PIK3CA, CDH1, RNF43, CTNNB1, and BRCA2 genes in 8 patients (17.4%) after treatment. In baseline-cfDNA, patients with a circulating ttDNA fraction concentration at 110-160 bp of >4.3777 ng/µL had significantly shorter progression-free survival (PFS) (median 3.5 vs. 5.3 months, P=0.016). In addition, maximal variant allele frequency (VAF) values of >0.1045 (median 3.4 vs. 5.2 months, P=0.022) and the sum of VAF values of >0.2071 (median 3.4 vs. 5.2 months, P=0.028) were significantly associated with shorter PFS. In patients with TP53 mutations, those with TP53 VAF values of >0.1014 significantly had worse PFS (median 4.6 vs. 6.4 months, P=0.022).   Conclusions Although cfDNA could not entirely take over the role of ttDNA, cfDNA analysis identified additional somatic mutations that were otherwise missed by ttDNA alone. Moreover, PD-cfDNA analysis detected novel pathogenic mutations that developed during treatment, implicating the clonal evolution of cancer. In addition, baseline cfDNA predicted PFS of patients receiving paclitaxel+ramucirumab therapy.

Pairwise analysis of plasma cell-free DNA before and after paclitaxel plus ramucirumab treatment in patients with metastatic gastric cancer

AACR

LINK _VIEW