Epidermal growth factor receptor pathway mutation and expression profiles in cervical squamous cell carcinoma: Therapeutic implications

Background: Cervical squamous cell carcinoma (CSCC) is a major cause of female mortality worldwide. This study has examined epidermal growth factor receptor (EGFR) pathway markers that represent actionable pharmacological targets. Methods: HPV16 positive CSCCs (n=105 patients) from Madhya Pradesh, India were screened for KRAS and PIK3CA mutations by PNA-clamp real-time PCR. Immunohistochemistry (IHC) was performed for EGFR, PIK3CA, PTEN, phospho-AKT, phospho-mTOR and phospho-44/42 MAPK (ERK1/2). Results: KRAS mutations were detected in 0/91 (0%) and PIK3CA mutations in 19/95 (20.0%) informative specimens: exon 9, E542 (n=3) and E545 (n=15); exon 20, H1047R (n=1). PIK3CA mutation detection was associated with older mean patient age [48.2 vs. 56.6 years (P=0.007)] and with post-menopausal age: 5/45 (11.1%) patients <50years vs. 14/50 (28.0%) patients ≥50years (P=0.045; OR=3.11). EGFR expression was present in 60/101 (59.4%) CSCCs and was associated with PIK3CA mutation detection (P<0.05) but not age (P>0.05). EGFR and phospho-AKT staining showed associations with tumor grade and/or lymph node status (P<0.05). Significant associations were not found for the other study markers (P>0.05). Conclusion: These data show that PIK3CA mutation acquisition is related to patient age and EGFR expression. The absence of KRAS mutations supports the potential of anti-EGFR therapies for CSCC treatment. The relatively high PIK3CA mutation rates indicate that PI3K may be a therapeutic target for a significant subset of CSCC patients. Qualitatively distinct IHC staining profiles for the marker panel were noted patient to patient; however, across patients, consistent linear relationships between up- and downstream pathway markers were not observed. Evaluation of the expression status of potential cancer pathway targets may be of value in addition to molecular profiling for choosing among therapeutic options.