PTEN loss as a predictive biomarker in head and neck squamous cell cancer (HNSCC) patients treated with cetuximab (C).

Abstract

e17520 Background: No biomarker of C resistance has been identified in HNSCC. PTEN loss is present in approximately 30% of HNSCC. Biomarker analysis of the E5397 study suggested that addition of C to cisplatin in R/M HNSCC improves PFS in PTEN high/PIK3CA wild type patients but not those with PTEN loss or PIK3CA mutation. We hypothesized that PTEN testing may aid patient (pt.) selection for C therapy in HNSCC. Methods: MCC15780 was a phase II randomized trial of C plus sorafenib or C plus placebo in R/M HNSCC. 52/56 pts. in this study received C. PTEN analysis using AQUA as previously described was performed on tumor from 38 pts. Automated image capture was performed with HistoRx PM-2000 using the AQUAsition software. AQUA PTEN cut off determined as 1177 based on the first tertile.Fisher’s exact test used to compare low and high expression group. Event-time distributions estimated by Kaplan-Meier and compared using log-rank. Stratified Cox proportional hazards models used to estimate hazard ratios (HR) and test for significance for OS and PFS. All p-values are two-sided. A level of p < 0.05 is considered statistically significant. Results: 12/37 (32%) tumors were PTEN low. There was statistically significant improvement in PFS in PTEN high tumors compared to PTEN low tumors (HR (high/low) =0.33, 95% CI= (0.14, 0.75), p=0.008); and this remains significant after adjusting for age, sex, race, and ethnicity (HR (high/low) =0.27, 95% CI= (0.11, 0.67), p=0.004). Conclusions: PFS is significantly longer in PTEN high tumors compared to PTEN low tumors (HR=0.33, 95% CI= (0.14-0.75), p=0.008) in patients with R/M HNSCC treated with C. This finding remains significant after adjusting for age, sex, race, and ethnicity (HR=0.27, 95% CI= (0.11-0.67), p=0.004).This warrants PTEN analysis of specimens from larger cetuximab-based RCT. [Table: see text]

Molecular and Clinical Activity of CDX-3379, an Anti-ErbB3 Monoclonal Antibody, in Head and Neck Squamous Cell Carcinoma Patients

“…Comparison of NRG1, NRG2 and ErbB3 expression data with changes in pErbB3, Ki-67 or tumor measurements did not reveal significant correlations, although we may be limited by the small sample size and brief duration of treatment (Supplementary Figure S3). Two patients with PTEN loss showed some of the largest pErbB3 reduction changes and measurable tumor shrinkage, which is of potential interest considering that PTEN loss has previously been associated with resistance to cetuximab [14]. Consistent with previous data, we observed that the majority of HNSCC tumors express NRG1 but not NRG2.…”

Personalized biomarker-based treatment strategy for patients with squamous cell carcinoma of the head and neck: EORTC position and approach

“…Median PFS favored afatinib in patients with p16-negative, EGFR-amplified (defined as 50% of cells with 4 copies, or 1 cell with 8 copies), HER3-low (defined as H-score 50), and PTEN-high (defined as H-score >150) tumors. In the MCC15780 trial where 38 SCCHN patients were treated with cetuximab [42], PFS was also significantly increased in PTEN-high tumors compared with PTEN-low tumors [43]. The fact that afatinib seemed to be more active in case of HER3-low and PTEN-high disease suggests that pan-HER inhibitors could be more active when the PI3K pathway is not or less activated.…”