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KRAS mutation status concordance between the primary tumor and the corresponding metastasis in patients with rectal
Peter Jo1, Markus Bernhardt1, Manuel Nietert2
1Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, Goettingen, Germany.
Introduction:
Oncogenic mutation within the KRAS gene represents a negative predictor for treatment response to anti-epidermal growth factor receptor (EGFR) in patients with colorectal cancer. Recently, we have shown no relevant heterogeneity for KRAS mutation status within and between pre- and posttherapeutic samples from the primary tumor in patients with locally advanced rectal cancer. The aim of this study was to evaluate the intertumoral heterogeneity of KRAS mutation status between the primary tumor and the corresponding metastasis or local recurrence in the similar cohort and to evaluate the ideal representative tissue for KRAS mutation testing.
Materials And Methods:
KRAS mutation status was analyzed from 47 patients with locally advanced rectal cancer, which were enrolled in the CAO/ARO/AIO-94 or CAO/ARO/AIO-04 trial. Mutations in KRAS codons 12, 13, and 61 were analyzed by using the KRAS RGQ PCR Kit (therascreen® KRAS test). Six patients needed to be excluded due to incomplete follow up data. 11 patients showed a relapse of the disease during the follow up presented by distant metastases or local recurrence. DNA from representative areas of metastatic tissue was obtained from formalin-fixed paraffin-embedded specimens.
Results:
The mean patient age was 64.13 ± 10.64 years. In total, 19 patients showed a KRAS mutation (46.34%) in the primary tumor. Of the eleven patients with a metastatic disease or local recurrence, five patients showed a KRAS mutation whereas six patients had a KRAS wildtype status. Metastatic localizations included the liver (n = 2), lung (n = 4), local recurrence (n = 1), liver + lung (n = 3), lung + local recurrence (n = 1). For these eleven patients with paired data available for the primary tumor and metastatic tissue, a significant KRAS mutation status concordance was detected in 81.18% (9/11) of the patients (p = 0.03271). Only two patients showed intertumoral heterogeneity, which harbored in one patient a KRAS G12C mutation status in the primary tumor, but a G12V KRAS mutation status in the corresponding lung lesion, and in the other patient a G12A mutation in the primary lesion and a WT in the lung metastasis.
Conclusions:
We show a significant concordance of the KRAS mutation status between tumor samples obtained from the primary tumor and the corresponding metastasis and/ or local recurrence in patients with rectal cancer indicating no relevant intertumoral heterogeneity. Our data suggest that sampling either the primary (pre- or posttherapeutical tumor tissue) or metastatic lesion may be valid for the initial evaluation of KRAS mutation status predicting the response to anti-EGFR treatment and guiding clinical decisions.
Insights
KRAS mutation status is consistent between primary rectal tumors and metastases, suggesting either can guide anti-EGFR treatment decisions. This finding minimizes concerns about intertumoral heterogeneity in KRAS testing.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- KRAS mutations predict response to anti-EGFR therapy in colorectal cancer.
- Intertumoral heterogeneity of KRAS status is a concern for treatment selection.
- Previous studies showed KRAS stability within primary tumors.
Purpose of the Study:
- To assess KRAS mutation status heterogeneity between primary rectal tumors and metastases/local recurrences.
- To determine the ideal tissue for KRAS mutation testing in locally advanced rectal cancer.
Main Methods:
- KRAS mutation analysis (codons 12, 13, 61) using PCR in 47 patients with locally advanced rectal cancer.
- Paired analysis of primary tumor and metastatic/recurrent tissue DNA.
- therascreen® KRAS test utilized for mutation detection.
Main Results:
- 19 out of 47 patients (46.34%) had KRAS mutations in the primary tumor.
- High concordance (81.18%, 9/11) in KRAS mutation status between primary tumors and metastases/recurrences.
- Only two cases exhibited intertumoral heterogeneity in KRAS mutation status.
Conclusions:
- Significant concordance of KRAS mutation status between primary and metastatic/recurrent lesions in rectal cancer.
- No relevant intertumoral heterogeneity observed, supporting KRAS stability.
- Sampling either primary or metastatic tissue is valid for KRAS testing to guide anti-EGFR treatment.
