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Cetuximab (CTX) is an anti-EGFR monoclonal antibody and demonstrated to improve survival with respect to radiotherapy (RT) alone in patients (pts) with head and neck squamous cell carcinoma (HNSCC). RT+CTX resulted inferior in comparison to standard chemoradiation (CRT) in HPV+ pts and represents an option for HNSCC pts who are unfit to standard CRT with curative intent. Biomarkers of efficacy are lacking, resulting in many pts treated with disappointing results and unnecessary toxicities. MicroRNA (miR) expression is altered in tumors, and their deregulation is a useful tool to predict oncologic outcome. In HNSCC, several miRs are differentially expressed with respect to the normal/peritumoral mucosa and we found that a four-miR signature (miR-1, -9, -133, and -150) efficiently identifies HNSCC pts at high risk of loco-regional recurrence. This study aims to evaluate the role of miR-9 as biomarker of efficacy of RT+CTX in terms of relapse free survival (RFS). 

We reviewed retrospectively 35 pts with HNSCC treated at our Institutions between 2012 and 2017. Inclusion criteria were: histologic proof of HNSCC, primary tumor originating from oropharynx (OP), hypopharynx (HP) and larynx (L), pts treated with curative intent with a total RT dose of 70 Gray with concomitant CTX. Induction chemotherapy and surgery were allowed. Recurrent or metastatic pts were excluded. For all pts, miR-9 was evaluated on Paraffin-embedded samples using Droplet Digital PCR Assay (ddPCR). To evaluate the impact of miR-9 on survival, the median of expression level was used as cut off. After treatment, follow up was performed every 3 months with clinical examination, fibrolaryngoscopy, and radiologic/metabolic imaging. RFS was evaluated with Kaplan Meyer method.

Median age of the 35 pts was 65 years (range 44-81 years). Twenty-six out of 35 pts were male (74%). Current smokers and former smokers were 14 (40%) and 9 (26%), respectively. Alcohol abuse was found in 17 (48%) pts. HNSCC originated from OP, HP and L in 30 (86%), 1 (3%) and 4 (11%), respectively. HPV status was detected in 16 out of 35 pts and resulted HPV+ in only 5 pts. TNM stage was III and IV in 14 (39%) and 21 (61%) pts, respectively. Pts treated with RT+CTX and RT+CTX+other were 26 (74%) and 9 (26%), respectively. The cut-off of miR-9 expression was 75,819 reads: 18 (58%) showed high levels of miR-9 expression. Complete response, Partial response and progressive disease was assessed in 18 (48%), 11 (26%) and 6 (26%) pts, respectively. Pts with higher miR-9 expression experienced worse PFS (p=0,0382) with respect to pts with low miR-9 expression (fig. 1). 

Our preliminary data suggest that high expression of miR-9 identifies a subset of HNSCC pts with decreased PFS after RT+CTX. Further evaluations are ongoing, in particular to evaluate the impact of miR-9 on overall survival in this cohort and in the subgroup of  pts unfit for chemotherapy and treated with radical RT+CTX.