<abstract xmlns="http://www.w3.org/1999/xhtml">

<sec id="j_raon-2019-0013_s_006">
<h3>Background</h3>
<p>Histological parameters of primary tumour and nodal metastases are prognostic factors for survival of operable colorectal (CRC) patients, but not predictive for response rate of systemic therapy. <italic>KRAS</italic> mutations in codons 12 and 13 were first recognized as a predictive factor for resistance to anti-EGFR monoclonal antibodies. Not all patients with wild-type <italic>KRAS</italic> (wt<italic>KRAS</italic>) respond to anti-EGFR antibody treatment. Additional mechanisms of resistance may activate mutations of the other main EGFR effectors pathway, such as other mutations in RAS gene, mutations in P13K and PTEN expression.</p></sec>
<sec id="j_raon-2019-0013_s_007">
<h3>Patients and methods</h3>
<p>In the prospective study prognostic and predictive impact of histological parameters of primary tumour, <italic>KRAS</italic> and <italic>BRAF</italic> mutations on overall survival (OS) and objective response (OR) rate of metastatic CRC (mCRC) patients treated with 1<sup>st</sup> line systemic therapy were analysed. We additionally retrospectively analysed other mutations in RAS genes and their impact on survival and time to progression.</p></sec>
<sec id="j_raon-2019-0013_s_008">
<h3>Results</h3>
<p>From November 2010 to December 2012, we enrolled 154 patients in the study, 95 men and 59 women. Mutations in <italic>KRAS</italic> gene and <italic>V600E BRAF</italic> gene were found in 42% and in 3% of patients, respectively. Median OS of the patients with T1, T2 and T3 tumour was 65.4 months (95% CI, 55.7–75.6) while in patients with T4 tumour, lymphangiosis, vascular and perineural invasion it has not been reached yet. Median OS of the patients with G1, G2 and G3 of tumour differentiation was 65.6 (95% CI, 53.7–77.5) and 25.3 months (95% CI, 16.6–34.1), respectively. Median OS of the patients with stage N0, N1 and N2 was 65.6 (95% CI, 56.4–74.8) and 58.0 months (95% CI, 21.9–94.2), respectively. Median OS of wt<italic>KRAS</italic> and mutated <italic>KRAS</italic> patients was 56.5 (95% CI, 48.2–64.9) and 58 months (95% CI, 52.6–63.4), respectively. Median OS of mutated codon 12 and codon 13 patients was 57 (95% CI, 50.9–64.4) and 44 months (95% CI, 40.1–48.4), respectively. Median OS of wt<italic>BRAF</italic> and of mutated <italic>BRAF</italic> patients was 59.2 (95% CI, 52.5–65.9) and 27.6 months (95% CI, 12.6–42.5), respectively. wt<italic>KRAS</italic> significantly affected the response to the first systemic therapy (p = 0.028), while other parameters did not affected it, p= 0.07. In 14 patients (17%), additional mutations in <italic>NRAS</italic> gene, codon 61 and codon 146 were found. Median OS of wt<italic>NRAS</italic>, codon 61 and 146 patients was 67.1 months (50.3–67.6) while median OS of mutated <italic>NRAS</italic> patients has not been reached yet (p = 0.072). Median time to progression of wt<italic>NRAS</italic>, codon 61 and 146 patients was 11.7 months (10.4–14.5) while median time to progression of mutated <italic>NRAS</italic> patients was 7.9 months (6.1–11.0), (p = 0.025).</p></sec>
<sec id="j_raon-2019-0013_s_009">
<h3>Conclusions</h3>
<p>Mutated <italic>BRAF</italic>, N2 and G3 of primary tumour were poor prognostic factors for OS in mCRC patients. wt<italic>KRAS</italic> significantly affected the response to the first line systemic therapy. Histological parameters included in the analysis and mutated <italic>BRAF</italic> did not affect significantly the efficacy of 1<sup>st</sup> line systemic therapy in mCRC patients.</p></sec>
</abstract>

Background
Histological parameters of primary tumour and nodal metastases are prognostic factors for survival of operable colorectal (CRC) patients, but not predictive for response rate of systemic therapy. KRAS mutations in codons 12 and 13 were first recognized as a predictive factor for resistance to anti-EGFR monoclonal antibodies. Not all patients with wild-type KRAS (wtKRAS) respond to anti-EGFR antibody treatment. Additional mechanisms of resistance may activate mutations of the other main EGFR effectors pathway, such as other mutations in RAS gene, mutations in P13K and PTEN expression.

Patients and methods
In the prospective study prognostic and predictive impact of histological parameters of primary tumour, KRAS and BRAF mutations on overall survival (OS) and objective response (OR) rate of metastatic CRC (mCRC) patients treated with 1st line systemic therapy were analysed. We additionally retrospectively analysed other mutations in RAS genes and their impact on survival and time to progression.

Results
From November 2010 to December 2012, we enrolled 154 patients in the study, 95 men and 59 women. Mutations in KRAS gene and V600E BRAF gene were found in 42% and in 3% of patients, respectively. Median OS of the patients with T1, T2 and T3 tumour was 65.4 months (95% CI, 55.7–75.6) while in patients with T4 tumour, lymphangiosis, vascular and perineural invasion it has not been reached yet. Median OS of the patients with G1, G2 and G3 of tumour differentiation was 65.6 (95% CI, 53.7–77.5) and 25.3 months (95% CI, 16.6–34.1), respectively. Median OS of the patients with stage N0, N1 and N2 was 65.6 (95% CI, 56.4–74.8) and 58.0 months (95% CI, 21.9–94.2), respectively. Median OS of wtKRAS and mutated KRAS patients was 56.5 (95% CI, 48.2–64.9) and 58 months (95% CI, 52.6–63.4), respectively. Median OS of mutated codon 12 and codon 13 patients was 57 (95% CI, 50.9–64.4) and 44 months (95% CI, 40.1–48.4), respectively. Median OS of wtBRAF and of mutated BRAF patients was 59.2 (95% CI, 52.5–65.9) and 27.6 months (95% CI, 12.6–42.5), respectively. wtKRAS significantly affected the response to the first systemic therapy (p = 0.028), while other parameters did not affected it, p= 0.07. In 14 patients (17%), additional mutations in NRAS gene, codon 61 and codon 146 were found. Median OS of wtNRAS, codon 61 and 146 patients was 67.1 months (50.3–67.6) while median OS of mutated NRAS patients has not been reached yet (p = 0.072). Median time to progression of wtNRAS, codon 61 and 146 patients was 11.7 months (10.4–14.5) while median time to progression of mutated NRAS patients was 7.9 months (6.1–11.0), (p = 0.025).

Conclusions
Mutated BRAF, N2 and G3 of primary tumour were poor prognostic factors for OS in mCRC patients. wtKRAS significantly affected the response to the first line systemic therapy. Histological parameters included in the analysis and mutated BRAF did not affect significantly the efficacy of 1st line systemic therapy in mCRC patients.

Molecular biomarkers and histological parameters impact on survival and response to first- line systemic therapy of metastatic colorectal cancer patients

Radiology and Oncology

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Background
Histological parameters of primary tumour and nodal metastases are prognostic factors for survival of operable colorectal (CRC) patients, but not...

Molecular biomarkers and histological parameters impact on survival and response to first- line systemic therapy of metastatic colorectal cancer patients

Article Category: Research Article

Published Online: Mar 03, 2019

Page range: 85 - 95

Received: Aug 30, 2018

Accepted: Sep 20, 2018

DOI: https://doi.org/10.2478/raon-2019-0013

© 2019 Martina Rebersek, Tanja Mesti, Marko Boc, Janja Ocvirk, published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.