Research Papers:

Occurence of RAS reversion in metastatic colorectal cancer patients treated with bevacizumab

Samantha Epistolio _, Marco Cefalì, Paolo Spina, Francesca Molinari, Alessandra Movilia, Massimiliano Cergnul, Luca Mazzucchelli, Sara De Dosso, Milo Frattini and Piercarlo Saletti

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Oncotarget. 2021; 12:1046-1056. https://doi.org/10.18632/oncotarget.27965

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Samantha Epistolio1,*, Marco Cefalì2,*, Paolo Spina1,3, Francesca Molinari1, Alessandra Movilia4, Massimiliano Cergnul5, Luca Mazzucchelli1, Sara De Dosso2, Milo Frattini1,# and Piercarlo Saletti2,6,#

1 Institute of Pathology, EOC, Locarno, Switzerland

2 Oncology Institute of Southern Switzerland, EOC, Bellinzona, Switzerland

3 Department of Health Sciences, University of Eastern Piedmont, Novara, Italy

4 Department of Pathology, ASST Ovest Milanese, Ospedale di Legnano, Legnano, Italy

5 Department of Medical Oncology, ASST Ovest Milanese, Ospedale di Legnano, Legnano, Italy

6 Current address: Department of Medical Oncology, Clinica Luganese Moncucco, Lugano, Switzerland

* These authors are Joined First Authors

# These authors are Joint Senior Authors

Correspondence to:

Samantha Epistolio,email: [email protected]

Keywords: RAS mutations; bevacizumab; metastatic colorectal cancer; next-generation sequencing

Received: March 23, 2021     Accepted: May 03, 2021     Published: May 25, 2021

Copyright: © 2021 Epistolio et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Background: A disappearance of RAS mutations in the plasma of about 50% of mCRCs (metastatic colorectal cancers) treated with bevacizumab-based chemotherapy has been reported. Our aim was to evaluate the same issue at tissue level.

Materials and Methods: Using next-generation sequencing and real-time PCR approaches, we characterized the primary tumor (PT) and paired liver metastases in 28 RAS mutant mCRCs. Patients were subdivided into 3 treatment groups: 1) bevacizumab plus chemotherapy; 2) chemotherapy alone; 3) any systemic therapy (control group). In groups 1 and 2, liver metastases were resected after removal of PT and subsequent neoadjuvant systemic therapy.

Results: RAS mutant alleles are at the same percentage in PT and liver metastases in the control group, while a significant reduction of the level of RAS mutations was detected in 57.1% of cases in group 1 and in 8.3% of cases in group 2. Differences among groups are statistically significant (p = 0.038).

Conclusions: Most of mCRC patients treated with bevacizumab-containing regimens experience a strong reduction of RAS mutant cells, suggesting bevacizumab as particularly active against RAS mutant cells. This finding might have potential therapeutic implications, as anti-EGFR could be reconsidered in primarily RAS mutant patients reverted to a wild-type status after bevacizumab exposure.

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