Dataset Information

Liquid Biopsy as a Tool Exploring in Real-Time Both Genomic Perturbation and Resistance to EGFR Antagonists in Colorectal Cancer.

ABSTRACT: The treatment of metastatic colorectal cancer (mCRC) has improved since the introduction of the epithelial growth factor receptor (EGFR) inhibitors as cetuximab and panitumumab. However, only patients with peculiar genomic profiles benefit from these targeting therapies. In fact, the molecular integrity of RAS genes is a predominant factor conditioning both primary and acquired resistance in non-responders although additional molecular derangements induced by selective anti-EGFR pressure may concur to the failure of those disease treatment, liquid biopsy (LB) appears as a surrogate of tissue biopsy, provides the genomic information to reveal tumor resistance to anti-EGFR agents, the detection of minimal residual disease before adjuvant therapies, and the discovery of tumor molecular status suitable for rechallenging treatments with EGFR antagonists. LB investigates circulating tumor cells (CTCs), cell-free tumor DNA (ctDNA), and tumor-derived exosomes. In mCRC, ctDNA analysis has been demonstrated as a useful method in the mutational tracking of defined genes as well as on tumor burden and detection of molecular alterations driving the resistance to anti-EGFR targeting treatments. However, despite their efficiency in molecular diagnosis and prognostic evaluation of mCRC, the affordability of these procedures is prevalently restricted to research centers, and the lack of consensus validation prevents their translation to clinical practice. Here, we revisit the major mechanisms responsible for resistance to EGFR blockade and review the different methods of LB potentially useful for treatment options in mCRC.

SUBMITTER: Interno V

PROVIDER: S-EPMC7546030 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Liquid Biopsy as a Tool Exploring in Real-Time Both Genomic Perturbation and Resistance to EGFR Antagonists in Colorectal Cancer.

Internò Valeria V Tucci Marco M Pezzicoli Gaetano G Silvestris Franco F Porta Camillo C Mannavola Francesco F

Frontiers in oncology 20200925

The treatment of metastatic colorectal cancer (mCRC) has improved since the introduction of the epithelial growth factor receptor (EGFR) inhibitors as cetuximab and panitumumab. However, only patients with peculiar genomic profiles benefit from these targeting therapies. In fact, the molecular integrity of <i>RAS</i> genes is a predominant factor conditioning both primary and acquired resistance in non-responders although additional molecular derangements induced by selective anti-EGFR pressure ...[more]

PMID: 33102237

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Project description:BackgroundAbout 15% of non-small cell lung cancers (NSCLCs) harbor epidermal growth factor receptor (EGFR) mutations. Upfront treatment with first and second generation EGFR tyrosine kinase inhibitors (1-2gen TKIs) is superior to chemotherapy. The most frequent resistance mechanism to 1-2gen TKIs is EGFR T790M mutation, which is targeted by osimertinib. T790M mutation can be revealed by liquid biopsy (LB) or by tissue rebiopsy (TB). LB is easily feasible but less sensitive than TB. We focused on repeated LBs and analyzed clinical features associated with EGFR T790M detection.MethodsThis is a retrospective multicenter observational study including EGFR-mutant NSCLC consecutive patients with disease progression (PD) after 1-2gen TKIs and with a first EGFR LB negative for T790M mutation, referred between 2016 and 2019. Aims of the study were to determine the prevalence of T790M mutation using LB in a real-life setting and the prevalence of T790M mutation by repeated LBs. We explored the association of T790M with clinical-pathological features and, through a survey, we evaluated the decision-making process behind LB request. Data on TBs were also collected.ResultsOne hundred and ten patients were included in the study, for a total of 326 LBs. Median number of LB per patient was 3.0. The T790M prevalence through LB was 34.5%. Over time, significantly more LBs were requested "at clinical and radiological PD" and "at radiological PD" compared to "arbitrarily". The probability of finding the T790M mutation for a patient across each subsequent LB did not significantly change. Liver and lymph node PD were significantly correlated to T790M positivity. Notably, "at PD" compared to "arbitrarily" LB request and liver, bone or lymph node PD were correlated to the detection of any EGFR mutation in cfDNA. TB was performed in 59.7% of patients with a T790M negative LB and 18.8% of them were T790M positive. In most cases, TB was not feasible due to anatomical reasons. In our study population, the overall T790M prevalence-detected with both LB and TB-was 42.7%.ConclusionsRepeated LB testing can be useful in a real-life scenario to detect EGFR T790M mutation.

Project description:Simple Summary There are some challenges to improve the clinical outcome of colorectal cancers (CRCs) by implementing new technologies, such as early detection of recurrence/relapse and selection of appropriate drugs based on the genomic profiles of tumors. For example, the genomic characteristics of tumors can be analyzed by blood-based tests, namely ‘liquid biopsies’, which are minimally-invasive and can be performed repeatedly during the treatment course. Hence, liquid biopsies are considered to hold great promise to fill these gaps in clinical routines. In this review, we addressed clinical usefulness of liquid biopsies in the clinical management of CRC patients, including cancer screening, detection of minimal residual disease, selection of appropriate molecular-targeted drugs, monitoring of the treatment responsiveness, and very early detection of recurrence/relapse of the disease. Furthermore, we discussed the possibility of adoptive T cell therapies and a future personalized immunotherapy based on tumor genome information. Abstract In the field of colorectal cancer (CRC) treatment, diagnostic modalities and chemotherapy regimens have progressed remarkably in the last two decades. However, it is still difficult to identify minimal residual disease (MRD) necessary for early detection of recurrence/relapse of tumors and to select and provide appropriate drugs timely before a tumor becomes multi-drug-resistant and more aggressive. We consider the leveraging of in-depth genomic profiles of tumors as a significant breakthrough to further improve the overall prognosis of CRC patients. With the recent technological advances in methodologies and bioinformatics, the genomic profiles can be analyzed profoundly without delay by blood-based tests—‘liquid biopsies’. From a clinical point of view, a minimally-invasive liquid biopsy is thought to be a promising method and can be implemented in routine clinical settings in order to meet unmet clinical needs. In this review, we highlighted clinical usefulness of liquid biopsies in the clinical management of CRC patients, including cancer screening, detection of MRD, selection of appropriate molecular-targeted drugs, monitoring of the treatment responsiveness, and very early detection of recurrence/relapse of the disease. In addition, we addressed a possibility of adoptive T cell therapies and a future personalized immunotherapy based on tumor genome information.

Dataset Information

Liquid Biopsy as a Tool Exploring in Real-Time Both Genomic Perturbation and Resistance to EGFR Antagonists in Colorectal Cancer.

Publications

Liquid Biopsy as a Tool Exploring in Real-Time Both Genomic Perturbation and Resistance to EGFR Antagonists in Colorectal Cancer.

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