“…In addition, mutational profiles that notably differ between HPV-positive and HPV-negative patients may be explored, as they could suggest multiple avenues for the investigation of targeted therapies in anal SCC ( 59 ). Also, hyperthermia could be considered as a potential means of increasing the sensitivity of cancer cells to therapeutic agents, inducing direct cytotoxicity, triggering anticancer immune responses and improving drug delivery, as supported by previous studies ( 60 , 61 ). Hypoxia-sensitizing methods may also be explored, particularly in radioresistant HPV-negative or p16-negative subgroups, as in the DAHANCA 5 trials ( 46 , 62 ).…”