HPV Serum Antibodies as Predictors of Survival and Disease Progression in Patients with HPV-Positive Squamous Cell Carcinoma of the Oropharynx

Dahlstrom, Kristina R.; Anderson, Karen S.; Cheng, Julia N.; Chowell, Diego; Li, Guojun; Posner, Marshall R.

doi:10.1158/1078-0432.ccr-14-3323

Cited by 59 publications

(70 citation statements)

References 25 publications

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“…1; Table 3), although not statistically significant. These findings are in contrast with a recent report from MD Anderson which noted lower median antibody levels among 8 patients with recurrence than 23 patients without recurrence [20]; (Supplemental Table 4). …”

Section: Discussioncontrasting

confidence: 99%

Human papillomavirus (HPV) 16 antibodies at diagnosis of HPV-related oropharyngeal cancer and antibody trajectories after treatment

et al. 2017

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Objectives Despite the fact that HPV-driven oropharyngeal cancer (HPV-OPC) has relatively low recurrence rates, intensive post-therapy monitoring remains the standard of care. Post-treatment biomarkers are needed to risk stratify HPV-OPC patients for more individualized surveillance intensity and which remain at higher recurrence risk. Materials and Methods 115 HPV-OPC patients (ascertained by p16 immunohistochemistry and/or in-situ hybridization) from a multicenter prospective case study (HOTSPOT) had blood collected at diagnosis, and 64 of these also had blood collected at post-treatment follow-up visits for up to two years. Samples were centrally tested for antibodies to the L1, E1, E2, E4, E6, and E7 proteins of HPV16. Results At diagnosis, most HPV-OPC cases were seropositive to HPV16 E6 (85%). In post therapeutic samples, HPV16 antibody level decreased slowly over time, but only 3 (of 51 cases seropositive at enrollment) dropped low enough to be classified as seronegative. At 3 years after diagnosis, cumulative risk of recurrence was 10.2% and 0% in HPV16 E6 seropositive and E6 seronegative HPV-OPC cases, respectively (p = 0.18). Risk of recurrence was increased, although not statistically significant, in those with higher HPV16 E6 antibody levels at diagnosis (per log antibody level, hazard ratio [HR] = 1.81, 95%CI = 0.47–6.92). Conclusion This study confirms the high seroprevalence of HPV oncogenic antibodies at diagnosis of HPV-OPC. HPV16 E6 antibody levels decrease after treatment, but most cases remain seropositive for up to two years. HPV16 E6 antibody levels at diagnosis did not appear to be a strong predictor of recurrence.

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Section: Discussioncontrasting

confidence: 99%

Human papillomavirus (HPV) 16 antibodies at diagnosis of HPV-related oropharyngeal cancer and antibody trajectories after treatment

et al. 2017

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“…In contrast to the findings of the current study, the median antibody levels of individuals who recurred or did not recur were statistically similar and appeared to be (non-significantly) lower for patients who recurred. Of note, consistent with our findings, a decline in median antibody levels is apparent graphically when comparing pre-treatment and post-treatment levels (25). …”

Section: Discussionsupporting

confidence: 90%

“…Indeed other head and neck cancers which are not HPV-related are not expected to be HPV seropositive (24), and therefore any associations observed may be driven by the majority seronegative and low levels of antibodies. A similar approach of restricting to HPV-positive OPCs (determined by PCR) was recently used to demonstrate that the presence of HPV E6 serum antibodies at diagnosis was significantly associated with improved overall and progression-free survival (25). In contrast to the findings of the current study, the median antibody levels of individuals who recurred or did not recur were statistically similar and appeared to be (non-significantly) lower for patients who recurred.…”

Section: Discussionmentioning

confidence: 99%

Serum Antibodies to HPV16 Early Proteins Warrant Investigation as Potential Biomarkers for Risk Stratification and Recurrence of HPV-Associated Oropharyngeal Cancer

Fakhry

Qualliotine

Zhang

et al. 2016

Cancer Prevention Research

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Human papillomavirus (HPV) is responsible for increasing incidence of oropharyngeal cancer (OPC). At present, there are no biomarkers in the surveillance algorithm for HPV-positive oropharyngeal cancer (HPV-OPC). HPV16 E6 antibody precedes OPC diagnosis. If HPV16 E6 indeed precedes primary diagnosis, it is similarly expected to precede disease recurrence and may have a potential role as a biomarker for surveillance of HPV-OPC. To determine whether HPV antibody titers have a potential role as early markers of disease recurrence or prognosis a retrospective pilot study was designed to determine whether HPV16 early antibody titers E6, E7, E1 and E2 decrease after treatment of HPV16-positive OPC. Trends in pre-treatment, early- (≤6 months after treatment) and late- post treatment (>6 months after treatment) HPV16 antibody titers were examined. There were 43, 34 and 52 subjects with serum samples available for pre-treatment, early- and late- post treatment intervals. Mean pre-treatment antibody levels were higher than post-treatment antibody levels. Average antibody levels decreased significantly over time for E6 (p-trend=0.001) and E7 (p-trend<0.001). 6 disease recurrences were observed during the follow-up period (median 4.4 years). In univariate analysis, a log unit increase in pre-treatment E6 titer was significantly associated with increased risk of disease recurrence (HR 5.42, 95%CI 1.1–25.7, p=0.03). Therefore, levels of antibodies to HPV16 early oncoproteins decline after therapy. Higher E6 titers at diagnosis are associated with significant increases in risk of recurrence. These data support the prospective evaluation of HPV16 antibodies as markers of surveillance and for risk stratification at diagnosis.

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“…[22] The examination of post-treatment oral rinses by Rettig et al [23] has specific merit, as this study showed the ability to detect HPV16 DNA in the oral rinses of 5 patients who developed recurrence of their cancer. They showed high specificity for local disease recurrence (median time from earliest post-treatment detection to recurrence: 7 months), suggesting that this biomarker be used in subsequent surveillance protocols.…”

Section: Discussionmentioning

confidence: 99%

E6 and E7 Antibody Levels Are Potential Biomarkers of Recurrence in Patients with Advanced-Stage Human Papillomavirus–Positive Oropharyngeal Squamous Cell Carcinoma

Spector

Sacco

Bellile

et al. 2017

Clinical Cancer Research

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Background There is a paucity of biomarkers to predict failure in human papilloma-virus positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) following curative therapy. E6/E7 viral oncoproteins are constitutively expressed in HPV+ tumors and highly immunogenic, resulting in readily detected serum antibodies. The purpose of this study is to determine if serum E6 and E7 antibody levels can potentially serve as a biomarker of recurrence in patients with HPV+OPSCC. Methods We evaluated E6/E7 antibody levels in patients with previously untreated, advanced stage (III, IVa-b), HPV+OPSCC receiving definitive chemoradiation under a uniform protocol from 2003-2010. Baseline and longitudinal serum samples were obtained from our archived repository. E6/E7 serum levels were measured using a glutathione-S-transferase capture ELISA and quantified by approximating the area under the dilution curve, and were analyzed using ANOVA and linear mixed model for longitudinal analysis. Results We compared 22 HPV+OPSCC patients who developed recurrence to 30 patients who remained disease-free. There were no differences in T classification, N classification, disease subsite or smoking status between the groups. In a longitudinal analysis, recurrent patients had significantly higher E6 and E7 serum antibody levels than the non-recurrent patients over the follow-up period (p=0.02 and p=0.002, respectively). Patients who recurred had a lower clearance of E7 antibody than patients who remained disease free (p=0.0016). Conclusion Patients with HPV+OPSCC whose disease recurs have a lower clearance of E6 and E7 antibodies than patients who do not recur. The ratio of E7 antibody at disease recurrence compared to baseline is potentially a clinically significant measurement of disease status in HPV+OPSCC.

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HPV Serum Antibodies as Predictors of Survival and Disease Progression in Patients with HPV-Positive Squamous Cell Carcinoma of the Oropharynx

Cited by 59 publications

References 25 publications

Human papillomavirus (HPV) 16 antibodies at diagnosis of HPV-related oropharyngeal cancer and antibody trajectories after treatment

Human papillomavirus (HPV) 16 antibodies at diagnosis of HPV-related oropharyngeal cancer and antibody trajectories after treatment

Serum Antibodies to HPV16 Early Proteins Warrant Investigation as Potential Biomarkers for Risk Stratification and Recurrence of HPV-Associated Oropharyngeal Cancer

E6 and E7 Antibody Levels Are Potential Biomarkers of Recurrence in Patients with Advanced-Stage Human Papillomavirus–Positive Oropharyngeal Squamous Cell Carcinoma

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