## 4 Discussion
### HNSCC HPV Positive PI3 CA and FGFR Positive  
[PERSON] et al., evaluated the genetic differences between HPV-positive and HPV-negative HNSCC, by sequencing carried out at the Institute for Genomics and Systems Biology, University of Chicago. The authors found that HPV-positive tumors showed unique mutations in DDX3X, FGFR2/3, and aberrations in PIK3 CA and KRAS. The mutation of the FGFR and PI3K genes were considered by the authors targetable genes fortherapy [50]. As fibroblast growth factor receptor family member proteins (FGFR1-4) have been identified as promising novel therapeutic targets and prognostic markers in a wide spectrum of solid tumors, researchers from the Netherlands Cancer Institute analyzed the protein expression of FGFR1-4 by immunohistochemistry, on tissue microarrays. FGFR proteins were highly expressed in oral cavity (39-64%) and oropharyngeal squamous cell carcinoma (63-79%); therefore, the authors considered that FGFRs may be potential targets for therapy, in order to optimize the survival of this category of HNSCC patients [51]. Even though the therapeutic benefit of FGFR inhibitors is already known, the appearance of resistance is also a known possibility. The same research team from the Netherlands evaluated, one year later, the possibility to avoid or delay resistance, by using AZD4547 and gefitinib in FGFR inhibitor resistant HNSCC patients [52]. [PERSON] et al. from Karolinska Institute analyzed by NGS, HPV+ TSCC/BOTSSCC and HPV+ HNSCCUP and HPV\(-\)TSCC/BOTSCC samples. The authors found that the mutation of PIK3 CA was most frequently observed in HPV-positive tumors, and FGFR3 mutation was associated with severe prognosis [53]. Researchers from Korea also studied HNSCC and their correspondent blood samples by NGS, and they found that the most frequent mutations were for TP53, CDKN2A, CCND1, and PIK3 CA. This team concluded that the implementation of precision medicine in HNSCC is feasible and requires clinical trials to assess the efficiency of molecular targeted agents [54]. [PERSON] et al. developed a special assay to detect FGFR mutation, Competitive Allele-Specific Taqman PCR (CAST-PCR). This method was cost efficient, in comparison to the previous NGS and useful to correlate the expression of FGFR3 with disease free survival [20]. [PERSON] et al. tested by Real Time PCR 42 genes coding for major druggable proteins, from selected HNSCC patients. The authors identified that the most significantly overexpressed genes involved cell cycle regulation tyrosine kinase receptors, angiogenesis, and immune system and PIK3 CA expression, and they considered that these genes are druggable [55]. Similar research studies have also been made by other authors regarding molecular profiling of HNSCC: [PERSON] et al. identified TP53 and PIK3 CA mutations among HPV-positive or HPV-negative patients [56]; and [PERSON] et al. detected ZNF750, PIK3 CA, and EP300 mutations as candidate driver events in HPV-positive cancers [57]. Understanding the mutational landscape of HNSCC has opened the path of evaluating optimized therapeutic approaches to manage this group of diseases. Additional insight into the molecular subtypes of HNSCC and its specific subsites will further drive improved strategies to stratify and treat patients with this debilitating disease [58]. Given these detected gene mutations in HNSCC, some authors evaluated targeted therapy in corresponding cell lines, such as, for example, evaluating the sensitivity of TSC/BOTSCC cell lines to PIK3 CA. Food and Drug Administration (FDA) approved the drugs' algebils (BYL719) and eradifitinib (JNJ-42756493) alone and in combination with cisplatin or docetaxel [59; 60]. BYL719 was tested by other authors in HNSCC cell lines therapy [61]. As a logical continuation after these preclinical studies, a two-phase II clinical trials were carried out regarding deintesification of CRT for PIK3 CA mutations in HPV-associated OPSCC patients.