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. 2021 May 25;12(11):1046-1056.
doi: 10.18632/oncotarget.27965.

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

Samantha Epistolio  1   2 , Marco Cefalì  3   2 , Paolo Spina  1   4 , Francesca Molinari  1 , Alessandra Movilia  5 , Massimiliano Cergnul  6 , Luca Mazzucchelli  1 , Sara De Dosso  3 , Milo Frattini  1   7 , Piercarlo Saletti  3   8   7
Affiliations

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

Samantha Epistolio et al. Oncotarget. .

Abstract

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.

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

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Conflict of interest statement

CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1. Real-time PCR (SensiScreen™) amplification curves of patient 1 (group 1).
X-axis reports real-time PCR cycles and Y-axis reports relative fluorescence unit (RFU). In red is represented the amplification of the reference gene and in blue the amplification of the specific mutation (G12C). (A) Curves obtained from amplification of DNA extracted from sample 1PT; (B) Curves obtained from amplification of DNA extracted from sample 1LM1. Abbreviations: 1LM1, liver metastasis sample (patient 1); 1PT, primary tumor sample (patient 1); RFU, relative fluorescence unit.
Figure 2
Figure 2. Real-time PCR (SensiScreen™) amplification curves of patient 8 (group 2).
X-axis reports real-time PCR cycles and Y-axis reports relative fluorescence unit (RFU). In red is represented the amplification of the reference gene and in blue the amplification of the specific mutation (G13D). (A) Curves obtained from amplification of DNA extracted from sample 8PT; (B) Curves obtained from amplification of DNA extracted from sample 8LM1. Abbreviations: 8LM1, liver metastasis sample (patient 8); 8PT, primary tumor sample (patient 8); RFU, relative fluorescence unit.
See this image and copyright information in PMC

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