BRAF, PIK3CA, and HER2 Oncogenic Alterations According to KRAS Mutation Status in Advanced Colorectal Cancers with Distant Metastasis

Abstract

BackgroundAnti-EGFR antibody–based treatment is an important therapeutic strategy for advanced colorectal cancer (CRC); despite this, several mutations—including KRAS, BRAF, and PIK3CA mutations, and HER2 amplification—are associated with the mechanisms underlying the development of resistance to anti-EGFR therapy. The aim of our study was to investigate the frequencies and clinical implications of these genetic alterations in advanced CRC.MethodsKRAS, BRAF, and PIK3CA mutations were determined by Cobas real-time polymerase chain reaction (PCR) in 191 advanced CRC patients with distant metastasis. Microsatellite instability (MSI) status was determined by a fragmentation assay and HER2 amplification was assessed by silver in situ hybridization. In addition, KRAS mutations were investigated by the Sanger sequencing method in 97 of 191 CRC cases.ResultsMutations in KRAS, BRAF, and PIK3CA were found in 104 (54.5%), 6 (3.1%), and 25 (13.1%) cases of advanced CRC, respectively. MSI-high status and HER2 amplification were observed in 3 (1.6%) and 16 (8.4%) cases, respectively. PIK3CA mutations were more frequently found in KRAS mutant type (18.3%) than KRAS wild type (6.9%) (P = 0.020). In contrast, HER2 amplifications and BRAF mutations were associated with KRAS wild type with borderline significance (P = 0.052 and 0.094, respectively). In combined analyses with KRAS, BRAF and HER2 status, BRAF mutations or HER2 amplifications were associated with the worst prognosis in the wild type KRAS group (P = 0.004). When comparing the efficacy of detection methods, the results of real time PCR analysis revealed 56 of 97 (57.7%) CRC cases with KRAS mutations, whereas Sanger sequencing revealed 49 cases (50.5%).ConclusionsKRAS mutations were found in 54.5% of advanced CRC patients. Our results support that subgrouping using PIK3CA and BRAF mutation or HER2 amplification status, in addition to KRAS mutation status, is helpful for managing advanced CRC patients.

HER2 Positivity Predicts Unresponsiveness to EGFR-Targeted Treatment in Metastatic Colorectal Cancer

“…Our data suggest that right-sided tumors are less likely to be HER2 positive, in line with previous reports showing that chromosomal regions hosting receptor tyrosine kinases are more often amplified in distal than in proximal carcinomas [21,22]. On one hand, however, this should not preclude testing for HER2 based on sidedness, as some positive cases might be missed; on the other hand, the predominant presence of HER2 positivity in the left colon carries therapeutic implications by mitigating the clinical paradigm according to which left-sided CRCs as a whole are more sensitive to EGFR-targeted treatment [23].…”

Targeting HER2 in colorectal cancer: The landscape of amplification and short variant mutations in ERBB2 and ERBB3

“…81,83,84 Mutations in KRAS are widely accepted as predictors of resistance to anti-EGFR antibody therapies in patients with mCRC. 85 In the current study and previous reports, 34,86 ERBB2 amplification strongly correlated with a lack of RAS and BRAF alterations. In addition, although we did not observe a difference between rectal and colonic tumors in terms of frequency of ERBB2 amplifications, other studies have demonstrated a strong correlation between ERBB2 amplification and left colonic tumors.…”

LRIG1 expression and colorectal cancer prognosis

“…Some studies showed that distal and proximal colon cancers differ in terms of molecular, pathological, and clinical features [26,27]. The present data revealed that there was not any correlation between LRIG1 expression and bilateral and peritoneal CRC metastasis (P > 0.05) and also with age, synchronous or metachronous CRC or primary tumor location (P > 0.05).…”