Inferring optimal detection of homozygous loss (homozygous deletion) in head and neck cancer: Associations with HPV status, primary disease site, and clinical outcomes.

6071 Background: Validated detection of homozygous loss is becoming increasingly important in clinical practice. Examples include targeting the AKT pathway in breast cancer with PTEN loss and ongoing multi-tumor trials of PRMT5 and MAT2A inhibitors, with MTAP loss serving as a key biomarker. Homozygous losses are challenging to detect and require intentional next-generation sequencing assay design and validation. We evaluated the prevalence of the most common homozygous losses in advanced head and neck squamous cell carcinoma (HNSCC) and their associations with HPV status, primary site, and clinical outcomes on standard first-line (1L) therapies. Methods: This study used the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine head and neck cancer clinico-genomic database (FH-FMI CGDB), originating from approximately 280 US cancer clinics (~800 sites of care). Patients with advanced HNSCC who underwent tissue-based genomic profiling with FoundationOneCDx were included. First-line therapy included chemotherapy alone or in combination with cetuximab or immune checkpoint inhibitors (ICIs). Logistic regression assessed the associations of prior treatment, HPV status, and primary disease site with homozygous losses. Clinical outcomes were evaluated with Cox proportional hazards models. Results: Among 969 HNSCC specimens, homozygous losses were most frequent in CDKN2A (22.1%), CDKN2B (17.8%), MTAP (9.4%), and PTEN (5.3%). CDKN2A, CDKN2B and MTAP losses were enriched in tumors arising from the larynx and hypopharynx compared with the oral cavity and oropharynx and were largely mutually exclusive with HPV positivity. PTEN loss was most common in the oropharynx and was enriched in HPV-positive tumors and in metastatic liver biopsies. In univariable analysis, homozygous losses were not associated with outcomes after 1L therapy. In multivariable analysis, HPV negativity and higher ECOG scoring, but not PD-L1 status, were independently associated with worse overall survival. Conclusions: Using an assay that is FDA-approved to detect and report copy-number (CN) losses, homozygous losses of CDKN2A , CDKN2B , MTAP , and PTEN were frequently observed in HNSCC. These alterations were not directly associated with outcomes following 1L therapy. Similar to CDKN2A/B loss , MTAP loss was enriched in HPV-negative tumors and defines a clinically relevant subset of HNSCC (~10%) potentially eligible for emerging MTAP-targeted therapies.