Mechanisms of Acquired Resistance to Savolitinib, a Selective MET Inhibitor in MET-Amplified Gastric Cancer

PURPOSE Some gastric cancers harbor MET gene amplifications that can be targeted by selective MET inhibitors to achieve tumor responses, but resistance eventually develops. Savolitinib, a selective MET inhibitor, is beneficial for treating patients with MET-driven gastric cancer. Understanding the resistance mechanisms is important for optimizing postfailure treatment options. PATIENTS AND METHODS Here, we identified the mechanisms of acquired resistance to savolitinib in 3 patients with gastric cancer and MET-amplified tumors who showed a clinical response and then cancer progression. Longitudinal circulating tumor DNA (ctDNA) is useful for monitoring resistance during treatment and progression when rebiopsy cannot be performed. RESULTS Using a next-generation sequencing 100-gene panel, we identified the target mechanisms of resistance MET D1228V/N/H and Y1230C mutations or high copy number MET gene amplifications that emerge when resistance to savolitinib develops in patients with MET-amplified gastric cancer. CONCLUSION We demonstrated the utility of ctDNA in gastric cancer and confirmed this approach using baseline tumor tissue or rebiopsy.

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Circulating tumor DNA profiling by next generation sequencing reveals heterogeneity of crizotinib resistance mechanisms in a gastric cancer patient with MET amplification

Oncotarget ◽

10.18632/oncotarget.15457 ◽

2017 ◽

Vol 8 (16) ◽

pp. 26281-26287 ◽

Cited By ~ 13

Author(s):

Juan Du ◽

Xue Wu ◽

Xiaoling Tong ◽

Xiaonan Wang ◽

Jia Wei ◽

...

Keyword(s):

Gastric Cancer ◽

Next Generation Sequencing ◽

Cancer Patient ◽

Gastric Cancer Patient ◽

Circulating Tumor Dna ◽

Resistance Mechanisms ◽

Next Generation ◽

Met Amplification ◽

Tumor Dna ◽

Generation Sequencing

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Plasma ctDNA is a tumor tissue surrogate and enables clinical-genomic stratification of metastatic bladder cancer

Nature Communications ◽

10.1038/s41467-020-20493-6 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Gillian Vandekerkhove ◽

Jean-Michel Lavoie ◽

Matti Annala ◽

Andrew J. Murtha ◽

Nora Sundahl ◽

...

Keyword(s):

Tumor Tissue ◽

Treatment Options ◽

Circulating Tumor Dna ◽

Molecular Stratification ◽

Clinical Biomarkers ◽

Surgery Patient ◽

Metastatic Urothelial Carcinoma ◽

Ctdna Analysis ◽

Clinical Genomic ◽

Tumor Dna

AbstractMolecular stratification can improve the management of advanced cancers, but requires relevant tumor samples. Metastatic urothelial carcinoma (mUC) is poised to benefit given a recent expansion of treatment options and its high genomic heterogeneity. We profile minimally-invasive plasma circulating tumor DNA (ctDNA) samples from 104 mUC patients, and compare to same-patient tumor tissue obtained during invasive surgery. Patient ctDNA abundance is independently prognostic for overall survival in patients initiating first-line systemic therapy. Importantly, ctDNA analysis reproduces the somatic driver genome as described from tissue-based cohorts. Furthermore, mutation concordance between ctDNA and matched tumor tissue is 83.4%, enabling benchmarking of proposed clinical biomarkers. While 90% of mutations are identified across serial ctDNA samples, concordance for serial tumor tissue is significantly lower. Overall, our exploratory analysis demonstrates that genomic profiling of ctDNA in mUC is reliable and practical, and mitigates against disease undersampling inherent to studying archival primary tumor foci. We urge the incorporation of cell-free DNA profiling into molecularly-guided clinical trials for mUC.

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Genomic analysis of circulating tumor DNA in 3,334 patients with advanced prostate cancer to identify targetable BRCA alterations and AR resistance mechanisms.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.25 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. 25-25

Author(s):

Hanna Tukachinsky ◽

Russell Madison ◽

Jon Chung ◽

Lucas Dennis ◽

Bernard Fendler ◽

...

Keyword(s):

Prostate Cancer ◽

Advanced Prostate Cancer ◽

Acquired Resistance ◽

Genomic Analysis ◽

Circulating Tumor Dna ◽

Resistance Mechanisms ◽

Cancer Tissue ◽

Castration Resistant Prostate Cancer ◽

High Level ◽

Tumor Dna

25 Background: Comprehensive genomic profiling (CGP) by next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) from plasma provides a minimally invasive method to identify targetable genomic alterations (GAs) and resistance mechanisms in patients with metastatic castration-resistant prostate cancer (mCRPC). The circulating tumor fraction in patients with mCRPC and the clinical validity of GAs detected in plasma remain unknown. We evaluated the landscape of GAs using ctDNA-based CGP and assessed concordance with tissue-based CGP. Methods: Plasma from 3,334 patients with advanced prostate cancer (including 1,674 mCRPC screening samples from the TRITON2/3 trials and 1,660 samples from routine clinical CGP) was analyzed using hybrid-capture-based gene panel NGS assays. Results were compared with CGP of 2,006 metastatic prostate cancer tissue biopsies. Concordance was evaluated in 837 patients with both tissue (archival or contemporaneous) and plasma NGS results. Results: 3,127 patients [94%] had detectable ctDNA. BRCA1/2 were mutated in 295 patients [8.8%]. In concordance analysis, 72/837 [8.6%] patients had BRCA1/2 mutations detected in tissue, 67 [93%] of whom were also identified by ctDNA, and 20 patients were identified using ctDNA but not tissue [23% of all patients identified using ctDNA]. ctDNA detected subclonal BRCA1/2 reversions in 10 of 1,660 [0.6%] routine clinical CGP samples. AR alterations, including amplifications and hotspot mutations, which were detected in 940/2,213 patients [42%]. Rare AR compound mutations, rearrangements, and novel in-frame deletions were identified. Altered pathways included PI3K/AKT/mTOR [14%], WNT/β-catenin [17%], and RAS/RAF/MEK [5%]. Microsatellite instability was detected in 31/2,213 patients [1.4%]. Conclusions: In the largest study of mCRPC plasma samples conducted to date, CGP of ctDNA recapitulated the genomic landscape detected in tissue biopsies, with a high level of agreement in detection of BRCA1/2 alterations. It also identified patients who may have gained somatic BRCA1/2 alterations since archival tissue was collected. ctDNA detected more acquired resistance GAs than tissue, including novel AR-activating variants. The large percentage of patients with rich genomic signal from ctDNA, and the sensitive, specific detection of BRCA1/2 alterations position liquid biopsy as a compelling clinical complement to tissue CGP for patients with mCRPC.

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Correlation of genomic alterations between tumor tissue and circulating tumor DNA by next-generation sequencing

Journal of Cancer Research and Clinical Oncology ◽

10.1007/s00432-018-2747-9 ◽

2018 ◽

Vol 144 (11) ◽

pp. 2167-2175 ◽

Cited By ~ 5

Author(s):

Ya-Sian Chang ◽

Hsin-Yuan Fang ◽

Yao-Ching Hung ◽

Tao-Wei Ke ◽

Chieh-Min Chang ◽

...

Keyword(s):

Next Generation Sequencing ◽

Tumor Tissue ◽

Circulating Tumor Dna ◽

Next Generation ◽

Genomic Alterations ◽

Tumor Dna ◽

Generation Sequencing

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Abstract P1-07-15: Detection of molecular alterations in breast cancer through next generation sequencing of both tumor tissue and circulating tumor DNA: The UC San Diego Moores Cancer Center experience

10.1158/1538-7445.sabcs16-p1-07-15 ◽

2017 ◽

Author(s):

RA Shatsky ◽

BA Parker ◽

R Schwab ◽

T Helsten ◽

SG Boles ◽

...

Keyword(s):

Breast Cancer ◽

Next Generation Sequencing ◽

San Diego ◽

Tumor Tissue ◽

Circulating Tumor Dna ◽

Cancer Center ◽

Next Generation ◽

Molecular Alterations ◽

Tumor Dna ◽

Generation Sequencing

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Comparison of tissue DNA to circulating tumor DNA in patients with brain metastases.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e13546 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e13546-e13546 ◽

Cited By ~ 1

Author(s):

Tyler A. Lanman ◽

Santosh Kesari ◽

Sandip Pravin Patel ◽

Lyudmila Bazhenova ◽

Barbara A. Parker ◽

...

Keyword(s):

Brain Metastases ◽

Tumor Tissue ◽

Late Complication ◽

Median Number ◽

Circulating Tumor Dna ◽

Molecular Alterations ◽

Dna Sampling ◽

Next Generation Sequencing Ngs ◽

Tumor Dna ◽

Generation Sequencing

e13546 Background: Brain metastases are often a late complication of cancer, not easily amenable to biopsy, and may contain additional molecular alterations not found in the original tumor. We sought to analyze the concordance between tissue DNA and cell-free circulating tumor DNA (ctDNA) in patients who developed brain metastases, and determine how the ctDNA profile changed with time. Methods: We retrospectively analyzed 31 patients with brain metastases who underwent next-generation sequencing (NGS) from both ctDNA and tumor tissue DNA. Breast, lung, ovarian, renal, melanoma, and colon primaries were included (42, 32, 13, 7, 3, and 3%, respectively). Tissue DNA was from primary tumor, systemic metastasis or brain (39, 39, and 7%, respectively). A median number of five alterations was found in each tissue group. Alterations in ctDNA were compared to tumor DNA and analyzed for relative frequencies, concordance, and novel alterations. Overall survival (OS) and time between DNA sample collections was analyzed. Results: All 31 patients had detectable mutations in tumor tissue. 25 patients (80.6%) had detectable ctDNA alterations and 14 patients (45.2%) had at least one identical ctDNA alteration that was concordant with tissue DNA. The most commonly altered genes (in both ctDNA and tissue DNA) were TP53 and EGFR. Breast cancer had both the highest proportion of patients with ≥ 1 ctDNA alterations (92.3%) and the highest proportion of patients who had ≥ 1 alterations in common with tissue DNA (61.5%). 23 of the 25 patients (92%) with detectable ctDNA alterations had additional alterations not found in tissue DNA, which increased with time from tumor DNA sampling. Median time between ctDNA extraction and tissue biopsy was 6.5 months for cases with common alterations, and 12.4 months for those without common alterations. There was trend to decreased OS with increasing ctDNA burden. Conclusions: We found that ctDNA is comparable with tissue DNA sequencing in patients with brain metastases. This concordance decreases with increasing time from tissue diagnosis, reflecting the changing nature of tumor genetics and highlighting the utility of ctDNA as a feasible way to monitor changes and identify additional potentially targetable alterations.

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