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Transient Disappearance of RAS Mutant Clones in Plasma: A Counterintuitive Clinical Use of EGFR Inhibitors in RAS Mutant Metastatic Colorectal Cancer

1
Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, V.le Regina Elena 324, 00161 Rome, Italy
2
Department of Molecular Medicine, Sapienza University of Rome, V.le Regina Elena 324, 00161 Rome, Italy
3
Institut Pasteur—Cenci Bolognetti Foundation, V.le Regina Elena 291, 00161 Rome, Italy
*
Author to whom correspondence should be addressed.
These authors contributed equally (co-first).
These authors contributed equally (co-senior).
Cancers 2019, 11(1), 42; https://doi.org/10.3390/cancers11010042
Received: 12 December 2018 / Revised: 27 December 2018 / Accepted: 28 December 2018 / Published: 4 January 2019
(This article belongs to the Special Issue Liquid Biopsy for Cancer)
Genomic studies performed through liquid biopsies widely elucidated the evolutionary trajectory of RAS mutant clones under the selective pressure of EGFR inhibitors in patients with wild type RAS primary colorectal tumors. Similarly, the disappearance of RAS mutant clones in plasma has been more recently reported in some patients with primary RAS mutant cancers, supporting for the first time an unexpected negative selection of RAS mutations during the clonal evolution of mCRC. To date, the extent of conversion to RAS wild type disease at the time of progression has not been clarified yet. As a proof of concept, we prospectively enrolled mCRC patients progressing under anti-VEGF based treatments. Idylla™ system was used to screen RAS mutations in plasma and the wild type status of RAS was further confirmed through IT-PGM (Ion Torrent Personal Genome Machine) sequencing. RAS was found mutant in 55% of cases, retaining the same plasma mutation as in the primary tumor at diagnosis, while it was found wild-type in 45%. Four patients testing negative for RAS mutations in plasma at the time of progression of disease (PD) were considered eligible for treatment with EGFR inhibitors and treated accordingly, achieving a clinical benefit. We here propose a hypothetical algorithm that accounts for the transient disappearance of RAS mutant clones over time, which might extend the continuum of care of mutant RAS colorectal cancer patients through the delivery of a further line of therapy. View Full-Text
Keywords: metastatic colorectal cancer; circulating tumor DNA; RAS; EGFR inhibitors metastatic colorectal cancer; circulating tumor DNA; RAS; EGFR inhibitors
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Raimondi, C.; Nicolazzo, C.; Belardinilli, F.; Loreni, F.; Gradilone, A.; Mahdavian, Y.; Gelibter, A.; Giannini, G.; Cortesi, E.; Gazzaniga, P. Transient Disappearance of RAS Mutant Clones in Plasma: A Counterintuitive Clinical Use of EGFR Inhibitors in RAS Mutant Metastatic Colorectal Cancer. Cancers 2019, 11, 42.

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