913P - Characterisation of genomic biomarkers of response to cetuximab versus cisplatin in concomitance with radiotherapy in locally advanced squamous head and neck cancer

Background

Treatment of unresectable locally advanced head and neck squamous cell carcinoma (LA-HNSCC) is based on chemoradiotherapy (CRT). The standard being concomitant cisplatin, as other drugs have not improved the results of platinum despite better toxicity profiles. The aim was to characterise genomic biomarkers associated with response for personalisation of LA-HNSCC treatment.

Methods

An analysis of samples from the TTCC-2007-01 trial, which studied the non-inferiority of RT with cetuximab (CET/RT) vs cisplatin (CDDP/RT) after induction chemotherapy, was conducted. Patients subclassified according to response: Complete or partial response “CR/PR” and stabilisation or progression “SD/PD”. After DNA extraction, it was processed with the OncoScan platform to determine copy number alterations (CNAs). A mutational analysis was conducted using massive targeted sequencing (TruSight panel) and a functional analysis of the results.

Results

142 samples were analysed: 70 patients received CET/RT (n=55; 76% CR/RP), and 72 received CDDP/RT (n=53; 76% CR/RP). Mean age was 57 [29–73] years, with a predominance of males (127, 89.4%). CDDP/RT group associated the response with 11p- and 11q- alterations (49% vs. 17.65%; p<.05). Focal gains in 3q11.2 (SD/PD 76.5%) and deletions in 9p22.1 (SD/PD 88.24%) were associated with non-response. Alterations in 17q21.23 or BRCA1 (CR/PR 29.4%) and 12q24.33 or POLE (CR/PR 29.4%) were associated with worse response (p<.05). The functional analysis showed involvement of ATM and PI3KCA pathways in response. In CET/RT, 2p+ and 2q+ alterations were associated with poor response (58.8% vs. 29.1%; p<.05). Gene alterations present on 1p36.11 (ARID1A) and 5p15.33 (TERT) were found in non-responders (p<.05). Functionally CET/RT-associated response to epigenetic and cellular immortalisation-associated pathways.

Conclusions

Somatic genomic alterations in genes such as ARID1A or TERT were associated with resistance to CET/RT, with the response being associated with epigenetic control pathways and cell immortality. These alterations may constitute genomic biomarkers predictive of response that could be used to implement precision medicine.

Clinical trial identification

TTCC-2007-01 trial (NCT0071639122). Year of publication: 2014.

Editorial acknowledgement

Funding

This work was supported by grants PI18/01476 from Instituto de Salud Carlos III.

Disclosure

All authors have declared no conflicts of interest.