| 6 |
2025 |
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ASCO |
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| 5 |
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.
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| 4 |
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.)
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| 3 |
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.
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| 2 |
2024 |
Assessing the clinical value of ctDNA sequencing for initial tumor profiling in metastatic colorectal cancer patients with sufficient tumor tissue
Abstract
Introduction Tumor profiling including RAS, BRAF, HER2, and MSI/MMR status, is required to determine the treatment for patients with metastatic colorectal cancer (mCRC) at the time of diagnosis. While comprehensive tumor profiling using tissue-based next-generation sequencing (NGS) is increasingly adopted for initial profiling in mCRC, the role of circulating tumor DNA (ctDNA) NGS as initial testing in patients with sufficient tumor tissue is not clearly understood. We assessed the clinical value of ctDNA sequencing compared to tumor NGS in patients with newly diagnosed mCRC who have sufficient tumor specimens.
Methods
We prospectively enrolled consecutive patients with newly diagnosed mCRC at the National Cancer Center Korea. As per the institutional protocol for mCRC, initial tumor profiling was performed on primary tumor tissue using an in-house NGS panel (NCC PCP ver.3), which included 525 genes. For ctDNA sequencing, patients were evaluated using the AlphaLiquid®100 comprehensive cancer panel (IMBdx, Inc.), which included 118 genes, before the initiation of chemotherapy. Additionally, immunohistochemical (IHC) testing for HER2 and polymerase chain reaction (PCR)/IHC testing for MSI and/or MMR were performed to assess the accuracy of HER2 and MSI/MMR status.
Results
A total of 188 patients were enrolled. In 139 eligible patients, 275 potentially actionable mutations were found in 12 selected CRC-related genes (APC, TP53, KRAS, NRAS, BRAF, FBXW7, PIK3CA, ERBB2, SMAD4, NF1, EGFR, MET). Of these, 32% were found both in ctDNA and tissue; 54% were found in ctDNA only; 12% in tissue only, and 2% were discordant. For RAS/BRAF mutations, which are required for anti-EGFR treatment decisions, the concordance rate between ctDNA and tissue NGS was 83.1%, and the concordance was higher in patients with higher ctDNA concentrations. For 9 patients with potentially actionable copy number variations (CNV) in EGFR, HER2, MET, and FGFR1, 3 cases were found by both assays; 4 were found by ctDNA only, and 2 were found by tissue only. ctDNA NGS correctly predicted MSI/MMR status in 2 out of 4 patients with MSI-H/dMMR; in the 2 other patients, the MSI and MMR statuses were different, suggesting potential false positivity. In addition, the fold changes in ctDNA dynamics during treatment significantly correlated with changes in tumor size and CEA levels, as well as with droplet digital PCR copy number fold changes. In a patient with MET amplification, ctDNA NGS identified MET Y1230H as a potential acquired resistance mutation after crizotinib treatment, which responded to cabozantinib but not to capmatinib.
Conclusions
Initial tumor profiling using ctDNA NGS yielded outcomes comparable to those of tumor tissue NGS in guiding treatment for patients with newly diagnosed mCRC, thereby suggesting its utility as an initial profiling method in mCRC.
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