Prediction of response to anti-EGFR antibody-based therapies by multigene sequencing in colorectal cancer patients

Lupini, Laura; Bassi, Cristian; Mlčochová, Jitka; Musa, Gentian; Russo, Mara; Vychytilova-Faltejskova, Petra; Svoboda, Marek; Sabbioni, Silvia; Němeček, Radim; Slabý, Ondřej; Negrini, Massimo

doi:10.1186/s12885-015-1752-5

Cited by 53 publications

(47 citation statements)

References 31 publications

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“…The exon 1 mutation we detected in CTC was very infrequent, and its importance and function remain incompletely understood. As for other genes, mutations in FBXW7 and SMAD4 were frequently detected, and these mutations, which are located in the same domain as the mutation we reported in this study, are involved in acquired resistance to anti–EGFR therapy . Our data, which were obtained from a relatively small number of samples, showed that further study is needed to determine whether genetic information for CRC cells obtained from liquid biopsy of patients resistant to anti–EGFR therapy could enhance efforts to overcome drug resistance.…”

Section: Discussionsupporting

confidence: 65%

Monitoring of cancer patients via next‐generation sequencing of patient‐derived circulating tumor cells and tumor DNA

Onidani

Shoji²,

Kakizaki³

et al. 2019

Cancer Science

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Liquid biopsy of circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) is gaining attention as a method for real‐time monitoring in cancer patients. Conventional methods based upon epithelial cell adhesion molecule (EpCAM) expression have a risk of missing the most aggressive CTC subpopulations due to epithelial‐mesenchymal transition and may, thus, underestimate the total number of actual CTC present in the bloodstream. Techniques utilizing a label‐free inertial microfluidics approach (LFIMA) enable efficient capture of CTC without the need for EpCAM expression. In this study, we optimized a method for analyzing genetic alterations using next‐generation sequencing (NGS) of extracted ctDNA and CTC enriched using an LFIMA as a first‐phase examination of 30 patients with head and neck cancer, esophageal cancer, gastric cancer and colorectal cancer (CRC). Seven patients with advanced CRC were enrolled in the second‐phase examination to monitor the emergence of alterations occurring during treatment with epidermal growth factor receptor (EGFR)‐specific antibodies. Using LFIMA, we effectively captured CTC (median number of CTC, 14.5 cells/mL) from several types of cancer and detected missense mutations via NGS of CTC and ctDNA. We also detected time‐dependent genetic alterations that appeared during anti–EGFR therapy in CTC and ctDNA from CRC patients. The results of NGS analyses indicated that alterations in the genomic profile revealed by the liquid biopsy could be expanded by using a combination of assays with CTC and ctDNA. The study was registered with the University Hospital Medical Information Network Clinical Trials Registry (ID: UMIN000014095).

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Section: Discussionsupporting

confidence: 65%

Monitoring of cancer patients via next‐generation sequencing of patient‐derived circulating tumor cells and tumor DNA

Onidani

Shoji²,

Kakizaki³

et al. 2019

Cancer Science

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“…Indeed, SMAD4, ErBB4 and FBXW7 mutations appear to confer treatment resistance to Cetuximab [5]. However, this association was not seen in our study, with e.g.…”

Section: Discussioncontrasting

confidence: 68%

“…Indeed, predictive markers further to RAS were first suggested to be found within the EGFR downstream signaling pathways, including alterations of - for example - BRAF, PIK3CA and PTEN [5, 6]. Of these, PIK3CA and associated kinases - as key regulators of the PI3K/AKT pathway - are highly attractive predictive and, in fact, also potentially actionable candidates: PIK3CA is a proto-oncogene encoding phosphatidylinositol 3-kinase (PI3K), the signal inducer of the PI3K-AKT pathway and is mutated in about 10-30% of CRC, mostly in sequence hotspots in exons 9 and 20 [7, 8].…”

Section: Introductionmentioning

confidence: 99%

ATM mutations and E-cadherin expression define sensitivity to EGFR-targeted therapy in colorectal cancer

et al. 2017

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EGFR-targeted therapy is a key treatment approach in patients with RAS wildtype metastatic colorectal cancers (CRC). Still, also RAS wildtype CRC may be resistant to EGFR-targeted therapy, with few predictive markers available for improved stratification of patients. Here, we investigated response of 7 CRC cell lines (Caco-2, DLD1, HCT116, HT29, LS174T, RKO, SW480) to Cetuximab and correlated this to NGS-based mutation profiles, EGFR promoter methylation and EGFR expression status as well as to E-cadherin expression. Moreover, tissue specimens of primary and/or recurrent tumors as well as liver and/or lung metastases of 25 CRC patients having received Cetuximab and/or Panitumumab were examined for the same molecular markers. In vitro and in situ analyses showed that EGFR promoter methylation and EGFR expression as well as the MSI and or CIMP-type status did not guide treatment responses. In fact, EGFR-targeted treatment responses were also observed in RAS exon 2 p.G13 mutated CRC cell lines or CRC cases and were further linked to PIK3CA exon 9 mutations. In contrast, non-response to EGFR-targeted treatment was associated with ATM mutations and low E-cadherin expression. Moreover, down-regulation of E-cadherin by siRNA in otherwise Cetuximab responding E-cadherin positive cells abrogated their response. Hence, we here identify ATM and E-cadherin expression as potential novel supportive predictive markers for EGFR-targeted therapy.

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“…One should not forget that despite fragmentation and subclassification of histologic diagnoses in oncology on a genotypic level to assign the best treatment (e.g., KRAS, NRAS, or BRAF, in mutated CRC [58]), the majority of these are captured under the umbrella of a few blood based TMs on a phenotypic level (e.g., CEA and CA19-9 in CRC). Simply put, that means one biomarker can be used for many molecularly distinct diseases to tell us whether tumor cells are being killed or not.…”

Section: Role Of Tms In Current Clinical Practicementioning

confidence: 99%

Clinically Meaningful Use of Blood Tumor Markers in Oncology

Holdenrieder

Pagliaro

Morgenstern

et al. 2016

BioMed Research International

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Before the introduction of modern imaging techniques and the recent developments in molecular diagnosis, tumor markers (TMs) were among the few available diagnostic tools for the management of cancer patients. Easily obtained from serum or plasma samples, TMs are minimally invasive and convenient, and the associated costs are low. Single TMs were traditionally used but these have come under scrutiny due to their low sensitivity and specificity when used, for example, in a screening setting. However, recent research has shown superior performance using a combination of multiple TMs as a panel for assessment, or as part of validated algorithms that also incorporate other clinical factors. In addition, newer TMs have been discovered that have an increased sensitivity and specificity profile for defined malignancies. The aim of this review is to provide a concise overview of the appropriate uses of both traditional and newer TMs and their roles in diagnosis, prognosis, and the monitoring of patients in current clinical practice. We also look at the future direction of TMs and their integration with other diagnostic modalities and other emerging serum based biomarkers, such as circulating nucleic acids, to ultimately advance diagnostic performance and improve patient management.

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Prediction of response to anti-EGFR antibody-based therapies by multigene sequencing in colorectal cancer patients

Cited by 53 publications

References 31 publications

Monitoring of cancer patients via next‐generation sequencing of patient‐derived circulating tumor cells and tumor DNA

Monitoring of cancer patients via next‐generation sequencing of patient‐derived circulating tumor cells and tumor DNA

ATM mutations and E-cadherin expression define sensitivity to EGFR-targeted therapy in colorectal cancer

Clinically Meaningful Use of Blood Tumor Markers in Oncology

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