Second primary squamous cell cancers in the HPV de-escalation Quarterback Trials.
Authors: Posner Marshall R. , Westra William , Roof Scott , Bakst Richard Lorne , Sindhu Kunal K. , Genden Eric Michael , Chen Thomas , Ahn Seungjun , Misiukiewicz Krzystof 
Published: July 2024

e18049 Background: Patients with HPV oropharyngeal cancer (HPVOPC) have a cure rate approaching 90%, and will live for decades with the sequelae of therapy. Trials evaluating treatments for HPVOPC select patients by p16 status rather than using more accurate molecular testing; a fraction of these patients, approaching 5%, are HPV16 negative. Recurrent cancers are often not tested molecularly and may not be tested for p16. Applying molecular diagnostics for HPV at diagnosis and relapse can avoid significant mis-assignment, mistreatment, and inaccurate results in clinical trials. We reviewed and report results from the Quarterback Trials (QT) where molecular testing confirmed HPV status at diagnosis and recurrence. Methods: Patients entered on the QT were required to have < 20 py smoking history, not be active smokers, have non-metastatic locally advanced disease, and have a molecularly confirmed HPV status, including genotype (PCR based DNA Sequencing). Subjects were treated with TPF chemotherapy for 3 cycles and patients with an adequate response were eligible for de-escalation of chemoradiotherapy (CRT) to 5600 cGy (RD). The first 20 patients were randomized to standard dose (SD) 7000 cGy (8) or RD (12). Patients who withdrew from the study or had an inadequate response to TPF, were treated with SD. Patients were monitored for recurrent disease by routine surveillance with physical examination and PET scan. Recurrences were confirmed with tissue biopsy. We performed a retrospective analysis of 2nd in-field primaries (SP) and compared them to local regional recurrences (LRF) in the entire eligible population. Results: 62 patients were consented on to the QTs. 2 patients failed screening and are not considered any further. 14 patients received 7000 cGy: 8/14 were randomized to SD, 5/14 had an inadequate response to TPF and 1/14 patient withdrew consent. One patient randomized to SD withdrew consent and stopped CRT at 5200cGy. There were 7 HPV+ LRF: (1 SD and 6 RD); and 4 molecularly documented in-field non-HPV SP squamous cell cancers: 2/14 SD (14%) and 2/46 RD (4%). 1 of 4 SP tumors was p16+; all were molecularly negative for HPV and had documented p53 mutations. Median time to LRF was 8 mo. (4-49) and 66 mo. (35-84) for SP. Median survival after LRF is 11 (4-72+) and after SP 18+ (3-36+). 4/11 (36%) of post treatment local regional squamous cancer events were not HPV related. Conclusions: Non-HPV SP SCC were not rare events in this documented HPV+, non-smoking population. SP were more common in the SD than the RD treated patients suggesting an RT dose dependency and causality, although other biologic explanations are possible. SP will increase and be a major cause of mortality in this population indicating a need for awareness during surveillance. p16 is inaccurate for determining HPV16 status at diagnosis and recurrence in HPV critical clinical trials and in-field cancer events should be molecularly assessed to determine if they are LRF or SP.