Risk patterns for second primary malignancies among human papillomavirus (HPV)–associated first primary cancer survivors in the United States.

10516 Background: Previous studies have shown an increased risk of second primary malignancies (SPMs) among human papillomavirus (HPV)-associated first primary cancer (FPC) survivors; however, this has not been comprehensively examined by cancer site and patient’s sex. We utilized a large population-based database to examine disparities in SPM risk by site of HPV-associated first and second cancers. Methods: From 17 United States population-based Surveillance, Epidemiology and End Results (SEER) program cancer registry areas, we identified 124,802 ≥12-month survivors of HPV-associated invasive FPCs (including oropharynx, anus, vulva, vagina, cervix and penis) diagnosed between 2000-2021. Standardized incidence ratios (SIRs) and accompanying 95% confidence intervals (CIs) quantified SPM risk by cancer site compared with the general population. Excess SPM risks were calculated based on SIRs and excess absolute risks (EARs) per 10,000 person-years at risk (PYR). Results: Overall, we observed 13,431 SPMs after HPV-associated FPCs representing a 1.6-fold significantly increased risk (95% Confidence Interval [CI] = 1.61-1.67) compared to the general population and an excess of 68 cases per 10,000 PYR. All index HPV-associated FPCs showed statistically significant increased SPM risk compared to the general population. SIRs varied significantly by FPC site with female survivors of vulvar, oropharyngeal and vaginal cancers resulting in higher SPM risk (SIR vulva = 2.46; CI = 2.33-2.58; EAR = 166, SIR oropharynx-female = 2.02; CI = 1.90-2.14; EAR = 121 and SIR vagina = 1.81; CI = 1.56-2.08; EAR = 96) compared to other sites (p < 0.001). Analyses by patient’s sex revealed significantly increased SPM risk among female survivors of oropharyngeal cancer compared to the males (SIR oropharynx-male = 1.66; CI = 1.61-1.70; p < 0.01) but not after anal cancer (p > 0.05). Results from SPM site specific analyses revealed significantly higher SIRs for second solid cancers compared to hematological malignancies (SIR solidSPM = 1.69; CI = 1.66-1.72; SIR hematSPM = 1.03; CI = 0.96-1.11; p < 0.001). Among the solid SPMs, the risk of developing a HPV-associated SPM was significantly higher than that of developing a non-HPV-associated SPM (SIR HPV-SPM = 8.89; CI = 8.59-9.21 versus SIR non-HPV-SPM = 1.33; CI = 1.30-1.35; p-heterogeneity < 0.001); and the difference was more pronounced in females than the males. Strikingly increased SIRs were observed for penile (SIR = 17.61), vulvar (SIR = 27.83) and vaginal (SIR = 32.09) SPMs. Conclusions: Using a large-scale population-based data, we observed remarkable similarity in SPM risk by FPC site suggesting a potential role of shared HPV-associated etiology between the two malignancies. SPMs have emerged as an important challenge for cancer survivors, therefore, further research to understand drivers of the observed patterns is warranted.