| 25 |
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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AACR |
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| 24 |
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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AACR |
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| 23 |
2024 |
A phase II study of tepotinib in patients with advanced solid cancers harboring MET exon 14 skipping mutations or amplification (KCSG AL19-17)
Abstract
Background
We evaluated the efficacy and safety of tepotinib in patients with various solid cancers harboring MET exon 14 skipping mutation (METex14) or MET gene amplification.
Patients and methods
A phase II, multicenter study was conducted in patients with advanced or metastatic solid cancers who progressed after standard treatment, harboring either METex14 or MET amplification detected in tissue-based next-generation sequencing (NGS). The primary endpoint was objective response rate (ORR). For exploratory analyses, we analyzed the gene profiles using plasma NGS test.
Results
Thirty-five patients were enrolled. The ORR was 57.6% for all patients, 52.2% for those with METex14, and 70% for those with MET amplification. Median progression-free survival (PFS) was 8 months [95% confidence interval (CI) 4.5-11.5 months] and median overall survival (OS) was 14 months (95% CI 7.8-20.2 months) in all patients. For patients with non-small-cell lung cancer with METex14, the median PFS was 9 months (95% CI 4.7-13.4 months) and the median OS was 17 months [95% CI not applicable (NA)-NA]. For patients with MET amplification, the median PFS was 7 months (95% CI 1.5-12.5 months) and the median OS was 10 months (95% CI 5.8-14.2 months). The ORR of patients with MET dysregulation detected by plasma NGS was 72.2%, whereas the ORR was 30% in those without detection. The most common adverse events were peripheral edema, asthenia, transaminase elevation, and anorexia, mostly grade 1 or 2.
Conclusions
Tepotinib demonstrated consistent antitumor activity in patients with METex14, and promising antitumor activity in various cancers with MET amplification. Detection of MET dysregulation by plasma NGS may predict the response to tepotinib.
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ESMO Open |
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| 22 |
2024 |
Varlitinib and Paclitaxel for EGFR/HER2 Co-expressing Advanced Gastric Cancer: A Multicenter Phase Ib/II Study (K-MASTER-13)
Abstract
Purpose
Varlitinib is a
pan-human epidermal growth factor receptor (HER) inhibitor targeting epidermal
growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2),
and HER4. We present a phase Ib/II study of a combination of varlitinib and weekly
paclitaxel as a second-line treatment for patients with EGFR/HER2 co-expressing
advanced gastric cancer (AGC).
Materials and
Methods
Patients whose
tumors with EGFR and HER2 overexpression by immunohistochemistry (≥ 1+) were
enrolled. Varlitinib and paclitaxel were investigated every 4 weeks. After
determining the recommended phase II dose (RP2D) in phase Ib, a phase II study
was conducted to evaluate the antitumor activity.
Results
RP2D was treated
with a combination of varlitinib (300 mg twice daily) and paclitaxel. Among 27
patients treated with RP2D, the median progression-free survival and overall
survival (OS) were 3.3 months (95% confidence interval [CI], 1.7 to 4.9) and
7.9 months (95% CI, 5.0 to 10.8), respectively, with a median follow-up of 15.7
months. Among 16 patients with measurable disease, the objective response rate
(ORR) and disease control rate were 31% and 88%, respectively. Patients with
strong HER2 expression (n=8) had a higher ORR and longer OS, whereas those with
strong EGFR expression (n=3) had poorer outcomes. The most common adverse
events (AEs) of any grade were neutropenia (52%), diarrhea (27%), aspartate
aminotransferase/alanine transaminase elevation (22%), and nausea (19%). No
treatment-related deaths or unexpected AEs resulting fr|om treatment cessation
were observed in patients with RP2D.
Conclusion
A combination of
varlitinib and paclitaxel displayed manageable toxicity and modest antitumor
activity in patients with EGFR/HER2 co-expressing AGC who progressed after
first-line chemotherapy.
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Cancer Research and Treatment |
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| 21 |
2024 |
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Annals of Laboratory Medicine |
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