Analysis of the Concordance in the EGFR Pathway Status Between Primary Tumors and Related Metastases of Colorectal Cancer Patients:Implications for Cancer Therapy

Abstract

Patients with metastatic Colorectal Cancer (mCRC), in which primary tumors are KRAS mutated, have no response to anti-EGFR therapy. However, less than half of mCRC patients with KRAS wild-type primary tumors respond to anti-EGFR therapy. Other downstream effectors of the EGFR pathway are being analyzed to fine-tune KRAS predictive value. However, as the primary tumor is the tissue of analysis that determines the use of anti-EGFR therapy in advanced disease, a high concordance in the status of these effectors between primary tumors and related metastases is required. We analyzed the concordances of downstream EGFR effectors in tumoral pairs of primaries and related metastases in a series of KRAS wild-type patients. One hundred seventeen tumoral pairs from patients with CRC were tested for KRAS mutational status. The level of concordance in the presence of KRAS mutations was 91% between the primary tumor and related metastases. The 70 pairs with KRAS wild-type primary tumors were further analyzed for BRAF and PIK3CA mutational status and for EGFR, PTEN and pAKT expression, and the number of concordant pairs was 70 (100%), 66 (94%), 43 (61%), 46 (66%) and 36 (54%), respectively. Our findings suggest that the mutational status of KRAS, BRAF and PIK3CA in the primary tumor is an adequate surrogate marker of the status in the metastatic disease. On the other hand, the immunohistochemical analysis of EGFR, PTEN and pAKT showed a much higher degree of discordance between primaries and related metastases.

Molecular Biomarkers for the Evaluation of Colorectal Cancer: Guideline From the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology

“…101,102 In the study by Lee et al, analysis of KRAS mutation in primary and recurrent tumors after radical resection showed 20.3% discordance. 103 This recommendation was supported by two retrospective cohort studies 101,102 that were obtained in the systematic review. Both of these studies compared results within a single cohort.…”

“…Table 12 shows the summary of two subsequent studies where KRAS, NRAS, BRAF, and PIK3CA mutation and PTEN expression were compared in paired primary versus metastatic tumor lesions. 101,102 Overall concordance rates between primary and metastatic lesions were high with more than 90% concordance (Table 12). 101,102 In the study by Lee et al, analysis of KRAS mutation in primary and recurrent tumors after radical resection showed 20.3% discordance.…”

“…101,102 Overall concordance rates between primary and metastatic lesions were high with more than 90% concordance (Table 12). 101,102 In the study by Lee et al, analysis of KRAS mutation in primary and recurrent tumors after radical resection showed 20.3% discordance. 103 This recommendation was supported by two retrospective cohort studies 101,102 that were obtained in the systematic review.…”

“…The study reported by Cejas et al 101 reported at least partial industry funding, and the study reported by Vakiani et al 102 did not report the source of funding, if any. The study by Cejas et al 101 was deemed to have a low to moderate risk of bias, and the study by Vakiani et al 102 was deemed to be low. 101 In the study by Cejas et al, 101 metastases were synchronous or metachronous.…”

“…The study by Cejas et al 101 was deemed to have a low to moderate risk of bias, and the study by Vakiani et al 102 was deemed to be low. 101 In the study by Cejas et al, 101 metastases were synchronous or metachronous. DNA was extracted from formalin-fixed, paraffin-embedded tissue, and mutational analysis was performed with a polymerase chain reaction-direct sequencing assay.…”