Study Probes Links Between Mutations, Metastasis in mCRC in China

Researchers sought to gain a better understanding of the relationship between genetic mutations in metastatic colon cancer (mCRC), advanced disease, and locations of primary tumors.

Colorectal cancer (CRC) is the fourth most frequent cause of cancer-related mortality worldwide, and in China, it is on the rise due to an improved economy, which has led to Westernized diets.

Cancer researchers there sought to define correlations between gene mutations and clinicopathological features in metastatic CRC (mCRC) in the Chinese population, hoping that their findings would be useful for prognosis and also for choosing individualized therapy.

It is already known that patients with KRAS, NRAS or BRAF gene mutations likely gain resistance to treatments targeting mutations in the epidermal growth factor receptor (EGFR) gene, and that they may have poorer outcomes. In addition, it is becoming known that “sidedness” in CRC has prognostic implications, with right-sided tumors having higher incidence of BRAF and KRAS mutations, a worse outcome, and a different response to therapy.

Next-generation sequencing (NGS) was used in a retrospective study to analyze the genetic status of KRAS, NRAS, and BRAF in mCRC in a Chinese population to explore whether there is a connection between clinicopathological characteristics and gene mutations, when compared with all wild type, with a particular interest in the location of the primary tumor and where it has spread.

Using NGS, researchers analyzed tissue samples from 200 newly diagnosed patients who were therapy-naïve with synchronous mCRC and had undergone primary lesion resection or endoscopic biopsy. Medical records were used to obtain clinicopathological data. The 3 main areas for primary tumor locations were the right-sided colon (ascending colon, hepatic flexure, and transverse colon); left-sided colon (splenic flexure, descending and sigmoid colon); and the rectum, defined as the large bowel up to the edge of 16 cm from the dentate line.

Patient median age was 59 years and 62.4% were men. By side, 61 (31.4%) had right-sided colon tumors, 80 (41.2%) had left-sided colon tumors, and 53 (27.3%) patients’ tumors were located in the rectum.

The distribution frequency of gene mutation was 41% KRAS, 4% NRAS, 11.5% BRAF, and 0.5% both KRAS and BRAF.

The right side was more likely to harbor tumors with any gene mutations (any gene mutations in KRAS/NRAS/BRAF), KRAS, and KRAS codon 12 mutation (P = .007; P = .008; and P = .026, respectively).

By site of spread, tumors with any gene mutations, KRAS, and KRAS codon 12 mutations were significantly correlated with peritoneal metastasis (P = .019; P = .017; and P = .014, respectively); liver-peritoneum metastases (P = .004; P = .003; and P = .002, respectively), and multiorgan metastases (P = .002; P = .008; and P = .001, respectively).

Tumors with all wild type were significantly correlated with distant lymph node-only metastasis. No statistically significant differences were found between clinicopathological characteristics and KRAS codon 13 and NRAS mutations.


"After stratification, KRAS codon 12 mutation, but not codon 13 mutation, was remarkably associated with peritoneal metastasis, liver-peritoneum metastases, and multi-organ metastases compared to all wild type," the researchers wrote.

They said a future study will include survival outcomes and choice of therapy regimens.

Reference

He K, Wang Y, Zhong Y, Pan X, Si L, Lu J. KRAS codon 12 mutation is associated with more aggressive invasiveness in synchronous metastatic colorectal cancer (mCRC): retrospective research. Onco Targets Ther. Published online December 8, 2020. doi: 10.2147/OTT.S279312