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Trending Anti-E7 Serology Predicts Mortality and Recurrence of HPV-Associated Cancers of the Oropharynx

Trending Anti-E7 Serology Predicts Mortality and Recurrence of HPV-Associated Cancers of the... Hindawi Journal of Oncology Volume 2022, Article ID 3107990, 6 pages https://doi.org/10.1155/2022/3107990 Research Article Trending Anti-E7 Serology Predicts Mortality and Recurrence of HPV-Associated Cancers of the Oropharynx 1 2 2 1 1 Luke Johnson , Dat T. Ha , Melissa B. Hall, Gregory Shoemaker , Paul A. Bevins , 3 4,5 1,2 1,2 John Strickley , Shadmehr Demehri , Rebecca A. Redman , and Joongho Joh Department of Medicine, University of Louisville School of Medicine, KY 40202, USA Brown Cancer Center, University of Louisville School of Medicine, KY 40202, USA John T Milliken Department of Internal Medicine, Washington University School of Medicine in St. Louis, MO 63110, USA Center for Cancer Immunology, Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA Correspondence should be addressed to Joongho Joh; joongho.joh@louisville.edu Received 23 June 2022; Revised 22 August 2022; Accepted 5 September 2022; Published 26 September 2022 Academic Editor: Xiaosheng Wang Copyright © 2022 Luke Johnson et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. High-risk human papillomavirus (HPV) is among the most common causes of head and neck cancer (HNC) with increasing incidence. HPV-associated HNC patients’ clinical response to treatment varies drastically, which has made treatment de- escalation clinical trials challenging. To address the need for noninvasive biomarkers that differentiate patient outcomes, serum antibodies to E7 oncoprotein levels were evaluated in serial serum specimens from HPV-positive HNC patients (n =48). We have found that increasing antibodies to E7 throughout treatment correlates with increased cancer recurrence or progression to mortality (p = :004) with 100% specificity as a predictive test. 1. Introduction [4]. HPV positivity may guide the treatment strategies as T-cell-specific therapies have been reported to be more effec- Head and neck cancer (HNC) is estimated to affect over 4 tive in HPV-positive patients [5–7]. Current clinical guide- million people worldwide and is the seventh most common lines for HNC patients outline an initial p16 test with a follow-up HPV DNA test [8]. However, p16 immunohisto- cancer type [1–3]. Human papillomavirus (HPV)-associated HNC has been on the rise for the last 3 decades and sur- chemistry has been widely accepted as a surrogate marker passed cervical cancer as the most prolific cause of HPV- for HPV essentially replacing HPV in situ hybridization associated cancer in the United States [1–3]. Although it is (ISH) in clinical settings [9]. The reason for this is that diagnosed at a median age of 60 years, a recent rise in HPV ISH is not done routinely in practice and sometimes HPV-associated HNC has increased the HNC incidence in includes low-risk HPV subtypes. Therefore, because of the younger patients [2, 3]. availability of p16 data for each patient, this marker was The most common type of HNC is squamous cell carci- used to identify HPV-associated cancers in this manuscript. noma (HNSCC). The risk factors for HNSCC include smok- Although the benefit of identifying p16 status is evident, ing and high-risk HPV [4]. Although smoking prevalence there is significant heterogeneity within HPV-associated has been on the decline for the past half century, HPV- HNC and patients’ treatment response varies drastically associated HNC remains a significant threat [4]. 50% of [10]. There are currently limited molecular tools for differ- HNC patients have detectable oncogenic HPV DNA, with entiating between treatment responders and treatment the highest proportion of HPV positivity in non-smokers non-responders. Multiple recent clinical trial investigation 2 Journal of Oncology Table 1: E7 antibody trend predicts mortality in head and neck cancer. Number of patients No Mortality P -value (%) mortality Overall 48 Lost to follow-up 5 Patients available for mortality analysis 43 9 34 <60 24 (56) 6 18 Age ≥60 19 (44) 3 16 .677 (NS) Male 37 (86) 7 30 Sex Female 6 (14) 2 4 .589 (NS) White 41 (95) 8 33 Race African American 2 (5) 1 1 .378 (NS) 1 1 (2) 1 0 2 3 (7) 0 3 Stage at diagnosis 3 6 (14) 4 2 4 33 (77) 4 29 .006(∗∗) Yes 39 (91) 8 31 P16 + No (control) 4 (9) 1 3 1 (NS) Positive with increasing 4 (10) 4 0 trend E7 antibody trend among P16 positive Positive with decreasing 19 (50) 3 16 patients trend .0007(∗∗∗ Negative 16 (40) 1 15 Contingency tables of patient demographics at the time of diagnosis, stage, HPV relevant markers, and E7 trend are shown to compare HNC patients with mortality and patients with no mortality. The Fisher’s exact test is used for the 2×2 contingency tables, and the Fisher’s exact test with Freeman-Halton extension is added to the larger contingency table to show the significance level of observed differences (NS = not significant, ∗∗ = p ≤ :01, ∗∗∗ = p ≤ :001). Table 2: E7 antibody trend predicts cancer recurrence or progression to mortality among HPV-associated HNC patients. Number of Cancer recurrence or No cancer recurrence or P-value patients (%) progression to mortality progression to mortality p16+ HNC patients 39 11 27 Positive with 4 (10) 4 0 increasing trend E7 antibody trend among Positive with 19 (50) 5 14 p16 positive patients decreasing trend P = :004 Negative 16 (40) 2 14 (∗∗) Contingency table of HPV-associated HNC patients’ immune response trend in consecutive clinical visits throughout the treatment. The Fisher’s exact test with Freeman-Halton extension is used for significance testing (∗∗ = p ≤ :01). This presence of E7 in the blood stream when cancer is de-escalation treatment strategies have failed to meaning- fully change clinical practice [10]. active is due to one of the following mechanisms: cancer cells Therefore, this study sought to identify molecular markers floating in the blood are transcriptionally active, tumors, for squamous cell head and neck cancer (HNSCC) that can be release oncoproteins directly into tumor vascular beds used to tailor cancer treatment to individual patient needs. because of necrosis, or tumor cells are secreting exosomes Our research has been particularly interested in two potential of viral oncoproteins [14–17]. Therefore, measuring anti- prognostic markers: oncoproteins E6 and E7, which inactivate bodies to E7 via liquid biopsy throughout the treatment the tumor suppressors p53 and RB, respectively [11]. P16, the course provides a potential marker for predicting cancer HPV-associated HNC marker used in this paper, is upregu- outcome and activity. Here, we aim to further examine the lated by E7’s suppression of RB [12, 13]. activity of E7 throughout cancer, the potential of E7 Journal of Oncology 3 HPV18 HPV16 antibodies to be used to monitor cancer, and its potential as 513 a noninvasive prognostic marker. 2.0 2. Methods 1.8 The study was reviewed and approved by the Institutional 1.6 Review Board at the University of Louisville (IRB# 08.0388, 15.0582) in compliance with the Declaration of Helsinki. 1.4 De-identified patient sera and clinical information were obtained from the Clinical Trials Office Biorepository of 1.2 the Brown Cancer Center. Blood was drawn for serum anal- ysis prior to treatment and every 3 months thereafter for 2 1.0 years. All serum specimens were obtained by collecting blood into nonadditive vacutainers, processed by centrifuga- 0.8 tion after a 30-minute clot, aliquoted, and stored at 4 C until analyzed. 0.6 Human E7 oncoprotein was created from a viral plasmid (pQE30) in bacterial cell culture from the manufacturer 0.4 (Qiagen). The production of E7 oncoprotein was confirmed via gel electrophoresis and Western Blot. This same process 0.2 of E7 antigen production is described in more detail in our 12345678 12345678 previous manuscript [18]. The ELISA 96 plates (Immulon 2HB) were purchased from the manufacturer (Thermo Visits Sci). The ELISA tray was coated with E7 oncoprotein at Figure 1: Heat map of anti-E7 ELISA values at consecutive clinical 1:200 ratio with PBS for 1 hour and washed with ×3. Patient visits for HPV-18 and HPV-16 E7 antibodies. All patients with serum at a 1:50 ratio with PBS was added to the ELISA tray increasing trends on ELISA (patients 610, 619, 625, and 864) overnight. In the morning, the tray was washed ×3. Second- correlated with patient mortality. The p16 negative controls ary mouse anti-human antibodies with alkaline phosphatase (patients 705, 865, and 872) are all seronegative for anti-E7 as conjugate (Sigma) were added at a 1:2000 ratio for 1 hour predicted. Note that HPV-18 and HPV-16 were used to generate and then washed with ×3. The signal was developed in the the E7 antigens but are not specific for these subtypes of HPV but ELISA tray by adding alkaline phosphatase per ELISA man- rather indicative or reactivity to high-risk HPV E7 protein. ufacturer instructions. The ELISA assays were then read via Synergy HT (BioTek) at time intervals 30, 50, and 70 minutes. 50 minutes was used as the reporting data as it pro- vided the clearest signal differentiation between test and controls. HPV-associated HNC patients were identified with p16 50 immunohistochemistry. All patients had cancers of the oro- pharynx with exception of patients 881 and 891. Patient 881 had a cancer of the larynx, and patient 891 had cancer of the oral tongue. Anti-E7 positive patients were identified with the standard ELISA cutoff procedure: at least one visit where the mean ELISA value was more than the mean of the neg- 0 1000 2000 3000 ative control value +3 standard deviations (.545 for HPV-16 Days elapsed anti-E7 and .423 for HPV-18 anti-E7) which was established in our p16 negative patients (750, 865, 872, and 1002). If the Positive for anti-E7 with increasing trend patient did not meet this criterion, they were classified as negative. Increasing trends were identified as at least 1 Positive for anti-E7 with decreasing trend increasing trend line throughout the study period for high- Negative for anti-E7 risk anti-E7. Decreasing trending patients were defined as having no increasing trend and at least 1 decreasing trend Figure 2: Survival data of patients differentiated by anti-E7 trend. for high-risk anti-E7. The percent survival in each group following treatment is shown. The data was analyzed utilizing the Microsoft Excel, Positive for anti-E7 with increasing trend n =4, positive for anti- Prism, and MedCalc statistical software. The analysis of sig- E7 with decreasing trend n =19, negative for anti-E7 n =25. Two nificance was done via FISHER’s exact testing of contin- of four patients suffered recurrence, and all four patients suffered gency tables as the cohort was too small for a chi-square mortality in the positive for anti-E7 with increasing trend group analysis to be accurate. For contingency tables larger than by day 2035. 2×2, a Freeman-Halton extension was added to the FISH- ER’s exact test. Percent (%) survival Patients 4 Journal of Oncology Patient 610 Patient 619 0.8 1.0 0.9 0.6 0.8 0.4 0.7 0.2 0.6 0.0 0.5 0 12345 0 2468 Visit number Visit number Patient 625 Patient 864 1.1 0.80 0.75 1.0 0.70 0.9 0.65 0.8 0.60 0.7 0.55 0 246 0 14 23 Visit number Visit number Figure 3: HPV-16 anti-E7 ELISA trends in patients with increasing ELISA values. All patients suffered mortality following treatment, and patients 610 and 625 suffered relapse following treatment. Note that HPV-16 was used to generate the E7 antigen but is not specific for this subtype of HPV but rather indicative or reactivity to high-risk HPV E7 protein. 3. Results positive trending high-risk anti-E7 throughout the study were more likely to have worse clinical outcome with relapse Of the 48 patients in this study, our ELISA results indicate of cancer or progression to mortality (p = :004). Of the 4 that 45.8% are positive for high-risk anti-E7 at one or more patients with an increasing anti-E7 trend, all had cancers collection time points during the study period with positivity progressing to mortality and 2 had cancer that recurred. A positive trending anti-E7 panel as a predictive test of recur- being defined as +3 standard deviations above the mean of the p16 negative patients ELISA values. Of the 43 patients rence or progression to mortality among p16+ HNC patients available for follow-up, 56% were aged less than 60, 86% confers a 36.36% (95% CI 10.93% to 69.21%) sensitivity, were male, 95% were white, and 5% were African American. 100% specificity (95% CI 88.06% to 100%), positive predic- The majority (91%) of patients were stage 3 or 4 at diagnosis. tive value of 100%, and negative predictive value of 83.3% The demographic and clinical characteristics of the patients (72.60% to 86.62%). can be seen in supplementary table 1. Treatments underwent by patients primarily were comprised of surgery followed by 4. Discussion immunotherapy, chemotherapy, and radiation. Specific treatments chosen for each patient can be seen in The presence of serum antibodies to E7 at the first clinical supplementary table 2. Eight patients had relapse of cancer visit of HNSCC patients were measured for the first time with metastasis to various sites including the lungs, recently and suggested that E7 may be a marker of cancer pericardium, lymph nodes, brain, bone, and liver. Nine recurrence [19]. Additionally, it has been reported that E6 patients suffered mortality, and 8 patients suffered cancer and E7 positivity correlates with better survival but worse recurrence. The patients suffering recurrence and mortality tumor grade and stage [14]. However, no study to our are shown and separated by HPV anti-E7 trend status in knowledge has yet identified oncoprotein titer variation supplementary table 3. Interestingly, two of the four throughout the disease course to be useful for predicting patients included in this study without p16 positivity HPV HNC clinical outcome [19–22]. (patients 750, 865, 872, and 1002) had cancer recurrence Our data did not demonstrate the same trend of E7 and 1 of 4 had cancer-associated mortality. Three of four oncoprotein positivity at the first visit to be useful to predict of these patients had negative anti-E7 values as predicted recurrence and survival (p =1). This is likely because our by the lack of high-risk HPV infection. study population was known HPV-associated HNC who E7 oncoprotein positivity at the first visit was not useful should have elevated E7 in the bloodstream before undergo- to predict recurrence and survival (p =1). Patients who had ing extensive treatment rather than the study population of HPV-16 anti-E7 ELISA value HPV-16 anti-E7 ELISA value HPV-16 anti-E7 ELISA value HPV-16 anti-E7 ELISA value Journal of Oncology 5 cer recurrence or fatal disease course, thus guiding head and all HNC patients used in previous studies where HPV- associated HNC confers better survival. For the HPV- neck cancer therapy. associated HNC population, our data demonstrates that an increasing anti-E7 trend throughout the course of treatment Data Availability predicts mortality (p = :0007) and recurrence or progression The clinical data of HNC patients used to support the find- to mortality (p = :004) with 100% specificity. The increasing ings of this study are included within the supplementary anti-E7 trend for patients experiencing relapse and mortality information file. is illustrated by the contingency tables (Tables 1 and 2), the heat map (Figure 1), and relapsed patients 610 and 625 (Figures 2 and 3). Conflicts of Interest Our ELISA is not specific enough to distinguish between All authors have no conflicts of interest. subtypes of high-risk HPV accurately because of cross- reactivity between other high-risk HPV E7 proteins present Authors’ Contributions in the sera due to sequence similarity. HPV-18 and HPV- 16 were used to produce E7 antigens because these are com- RAR and JJJ conceived and designed the experiments. LJ, mon subtypes of high-risk HPV; however, we have denoted DTH, MBH, GS, PAB, JS, and JJJ performed the experi- throughout the paper that the reactivity is against high-risk ments. LJ, JS, SD, and JJJ analyzed the data. LJ, DTH, HPV E7 instead of specific subtypes of HPV. Furthermore, MBH, JS, SD, RAR, and JJJ contributed to the writing of patients positive for both anti-E7 HPV 18 and anti-E7 the manuscript. HPV 16 do not necessarily indicate true positivity for both antibodies because the antigens have over 40% sequence Acknowledgments similarity. Although this data is not representative of specific sub- This study was supported by a fund from Dr. Alfred B Jen- types of HPV E7 present in the sera, as a predictive test for son for Head and Neck Cancer Research, the James Graham clinical relapse or progression to mortality trending high- Brown Cancer Center, University of Louisville, and NIH risk anti-E7 among HPV+ HNC patients may have utility NCI fund (1R01CA251755-01, Immunity to commensal as a specificity of 100% makes the test ideal for ruling in papillomaviruses for cancer therapy). the possibility of relapse and cancer mortality. This test may allow increased disease activity to be identified, and Supplementary Materials patients may benefit from more aggressive treatment. The sensitivity of 36.36% is relatively low and makes this a poor Supplementary Table 1. The demographic and clinical char- screening test, especially for patients without high-risk acteristics of head and neck cancer patients. The patient HPV-associated cancer. identification number, age at diagnosis, cancer description, This novel trend will be useful to future studies that p16 status, stage at diagnosis, sex, race, survival status, and expand the sample size to introduce more biologic variabil- overall survival days are shown. All patients had cancers of ity. Because of the ability of anti-E7 to predict clinical out- the oropharynx apart from patients 881 and 891 which were come and thus guide treatment, it should be considered as denoted as having non-oropharynx cancers specifically. If a target for high-risk HPV-associated HNC patient monitor- the patient was alive at the time of data collection the sur- ing. Previous data is limited regarding direct ELISA or E7 in vival days are shown up to that interval. Supplementary sera, although the clinical impact of a noninvasive test for Table 2. Treatment. Patient study identification number, stratifying outcomes is large. The use of novel biomarkers therapy type, therapy details, and day from day of diagnosis like E7 in conjunction with classical cancer staging tech- are shown. Supplementary Table 3. Patient mortality and niques is critical to deliver high-quality tailored care. Further recurrence by E7 trend following treatment. Patients entirely research comparing the prognostic efficacy of circulating E7 negative for anti-E7 HPV-16 and HPV-18, Patients with at nucleic acid at sequential clinical visits with E7 antibodies least one increasing anti-E7 trend for HPV-16 or HPV-18, would be impactful. This data is important to further our and Patients with at least one decreasing anti-E7 trend for understanding of HPV serology, non-invasively monitor HPV-16 or HPV-18 is shown following treatment. High- persistent or occult tumors, and will help to create personal- lighted in red are patients suffering from cancer recurrence, ized cancer treatments in the future. purple font is indicative of patients that suffered from mor- tality, and patients denoted with (∗) is indicative of p16 neg- ative status. Note that HPV-18 and HPV-16 was used to 5. Conclusion generate the E7 antigens but are not specific for these sub- types of HPV but rather indicative or reactivity to high- High-risk human papillomavirus-associated head and neck risk HPV E7 protein. (Supplementary Materials) cancer is an increasing issue with significant clinical out- come heterogeneity. Trending anti-E7 via liquid biopsy is References strongly predictive of cancer recurrence or progression with mortality (p = :004). Measuring E7 oncoprotein at consecu- [1] Y. Huang and X. 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Trending Anti-E7 Serology Predicts Mortality and Recurrence of HPV-Associated Cancers of the Oropharynx

Trending Anti-E7 Serology Predicts Mortality and Recurrence of HPV-Associated Cancers of the Oropharynx

Abstract

High-risk human papillomavirus (HPV) is among the most common causes of head and neck cancer (HNC) with increasing incidence. HPV-associated HNC patients’ clinical response to treatment varies drastically, which has made treatment de-escalation clinical trials challenging. To address the need for noninvasive biomarkers that differentiate patient outcomes, serum antibodies to E7 oncoprotein levels were evaluated in serial serum specimens from HPV-positive HNC patients (<span class="inline_break"><svg xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg" width="17.789pt" style="vertical-align:-0.2063904pt" id="M1" height="8.55521pt" version="1.1" viewBox="-0.0498162 -8.34882 17.789 8.55521"><g transform="matrix(.013,0,0,-0.013,0,0)"><path id="g113-111" d="M495 86L479 114C446 82 419 66 409 66C401 66 401 72 406 97C420 166 436 231 453 297C489 435 454 448 428 448C406 448 384 439 354 422C305 394 222 327 161 247H159L183 345C200 415 194 448 173 448C143 448 82 410 23 351L38 325C64 349 95 371 105 371C111 371 116 365 109 336L25 -4L31 -12C50 -4 77 3 107 9C119 69 132 122 145 168C197 254 321 381 370 381C387 381 393 374 378 305L329 95C309 17 320 -12 345 -12C372 -12 430 19 495 86Z"/></g><g transform="matrix(.013,0,0,-0.013,10.158,0)"><path id="g117-34" d="M535 323V373H52V323H535ZM535 138V188H52V138H535Z"/></g></svg><span class="irelop"/><span class="nowrap"><svg xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg" width="12.679pt" style="vertical-align:-0.2063904pt" height="8.55521pt" version="1.1" viewBox="21.3711838 -8.34882 12.679 8.55521"><g transform="matrix(.013,0,0,-0.013,21.421,0)"><path id="g113-53" d="M456 178V225H360V632H320C217 496 115 347 20 206V178H280V106C280 40 276 34 189 27V0H445V27C364 34 360 39 360 106V178H456ZM280 225H82C149 335 214 431 278 520H280V225Z"/></g><g transform="matrix(.013,0,0,-0.013,27.661,0)"><path id="g113-57" d="M249 635C141 635 70 555 70 471C70 401 114 353 179 316C143 294 106 267 90 252C68 231 45 202 45 157C45 50 130 -12 237 -12C322 -12 435 52 435 169C435 256 372 304 303 343C349 374 375 398 383 407C401 429 411 458 411 487C411 569 344 635 249 635ZM238 603C285 603 337 567 337 482C337 422 310 385 276 358C205 393 145 426 145 500C145 552 179 603 238 603ZM248 20C183 20 125 70 125 163C125 218 158 268 206 300C284 261 355 217 355 143C355 66 308 20 248 20Z"/></g></svg>).</span></span> We have found that increasing antibodies to E7 throughout treatment correlates with increased cancer recurrence or progression to mortality (<span class="inline_break"><svg xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg" width="18.973pt" style="vertical-align:-3.42938pt" id="M2" height="11.7782pt" version="1.1" viewBox="-0.0498162 -8.34882 18.973 11.7782"><g transform="matrix(.013,0,0,-0.013,0,0)"><path id="g113-113" d="M570 304C570 398 525 448 414 448C385 448 343 445 312 434L329 511L321 518C297 504 262 482 244 460L233 411C195 397 159 381 128 358L135 332C160 347 189 360 224 373L111 -147C97 -210 84 -218 17 -231L13 -257L254 -247L259 -218L233 -216C183 -212 177 -202 189 -142L218 -1C238 -10 266 -12 283 -12C351 3 429 48 483 105C543 168 570 242 570 304ZM482 289C482 161 380 33 304 33C278 33 248 51 233 69L303 396C326 400 352 403 369 403C428 403 482 380 482 289Z"/></g><g transform="matrix(.013,0,0,-0.013,11.342,0)"><use xlink:href="#g117-34"/></g></svg><span class="irelop"/><span class="nowrap"><svg xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg" width="21.921pt" style="vertical-align:-3.42938pt" height="11.7782pt" version="1.1" viewBox="22.555183800000002 -8.34882 21.921 11.7782"><g transform="matrix(.013,0,0,-0.013,22.605,0)"><path id="g113-47" d="M113 -12C146 -12 170 11 170 46C170 78 146 103 114 103S58 78 58 46C58 11 82 -12 113 -12Z"/></g><g transform="matrix(.013,0,0,-0.013,25.569,0)"><path id="g113-49" d="M241 635C89 635 35 457 35 312C35 153 89 -12 240 -12C390 -12 443 166 443 312C443 466 390 635 241 635ZM238 602C329 602 354 454 354 312C354 172 330 22 240 22C152 22 124 173 124 313S148 602 238 602Z"/></g><g transform="matrix(.013,0,0,-0.013,31.809,0)"><use xlink:href="#g113-49"/></g><g transform="matrix(.013,0,0,-0.013,38.049,0)"><use xlink:href="#g113-53"/></g></svg>)</span></span> with 100% specificity as a predictive test.

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Abstract

Hindawi Journal of Oncology Volume 2022, Article ID 3107990, 6 pages https://doi.org/10.1155/2022/3107990 Research Article Trending Anti-E7 Serology Predicts Mortality and Recurrence of HPV-Associated Cancers of the Oropharynx 1 2 2 1 1 Luke Johnson , Dat T. Ha , Melissa B. Hall, Gregory Shoemaker , Paul A. Bevins , 3 4,5 1,2 1,2 John Strickley , Shadmehr Demehri , Rebecca A. Redman , and Joongho Joh Department of Medicine, University of Louisville School of Medicine, KY 40202, USA Brown Cancer Center, University of Louisville School of Medicine, KY 40202, USA John T Milliken Department of Internal Medicine, Washington University School of Medicine in St. Louis, MO 63110, USA Center for Cancer Immunology, Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA Correspondence should be addressed to Joongho Joh; joongho.joh@louisville.edu Received 23 June 2022; Revised 22 August 2022; Accepted 5 September 2022; Published 26 September 2022 Academic Editor: Xiaosheng Wang Copyright © 2022 Luke Johnson et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. High-risk human papillomavirus (HPV) is among the most common causes of head and neck cancer (HNC) with increasing incidence. HPV-associated HNC patients’ clinical response to treatment varies drastically, which has made treatment de- escalation clinical trials challenging. To address the need for noninvasive biomarkers that differentiate patient outcomes, serum antibodies to E7 oncoprotein levels were evaluated in serial serum specimens from HPV-positive HNC patients (n =48). We have found that increasing antibodies to E7 throughout treatment correlates with increased cancer recurrence or progression to mortality (p = :004) with 100% specificity as a predictive test. 1. Introduction [4]. HPV positivity may guide the treatment strategies as T-cell-specific therapies have been reported to be more effec- Head and neck cancer (HNC) is estimated to affect over 4 tive in HPV-positive patients [5–7]. Current clinical guide- million people worldwide and is the seventh most common lines for HNC patients outline an initial p16 test with a follow-up HPV DNA test [8]. However, p16 immunohisto- cancer type [1–3]. Human papillomavirus (HPV)-associated HNC has been on the rise for the last 3 decades and sur- chemistry has been widely accepted as a surrogate marker passed cervical cancer as the most prolific cause of HPV- for HPV essentially replacing HPV in situ hybridization associated cancer in the United States [1–3]. Although it is (ISH) in clinical settings [9]. The reason for this is that diagnosed at a median age of 60 years, a recent rise in HPV ISH is not done routinely in practice and sometimes HPV-associated HNC has increased the HNC incidence in includes low-risk HPV subtypes. Therefore, because of the younger patients [2, 3]. availability of p16 data for each patient, this marker was The most common type of HNC is squamous cell carci- used to identify HPV-associated cancers in this manuscript. noma (HNSCC). The risk factors for HNSCC include smok- Although the benefit of identifying p16 status is evident, ing and high-risk HPV [4]. Although smoking prevalence there is significant heterogeneity within HPV-associated has been on the decline for the past half century, HPV- HNC and patients’ treatment response varies drastically associated HNC remains a significant threat [4]. 50% of [10]. There are currently limited molecular tools for differ- HNC patients have detectable oncogenic HPV DNA, with entiating between treatment responders and treatment the highest proportion of HPV positivity in non-smokers non-responders. Multiple recent clinical trial investigation 2 Journal of Oncology Table 1: E7 antibody trend predicts mortality in head and neck cancer. Number of patients No Mortality P -value (%) mortality Overall 48 Lost to follow-up 5 Patients available for mortality analysis 43 9 34 <60 24 (56) 6 18 Age ≥60 19 (44) 3 16 .677 (NS) Male 37 (86) 7 30 Sex Female 6 (14) 2 4 .589 (NS) White 41 (95) 8 33 Race African American 2 (5) 1 1 .378 (NS) 1 1 (2) 1 0 2 3 (7) 0 3 Stage at diagnosis 3 6 (14) 4 2 4 33 (77) 4 29 .006(∗∗) Yes 39 (91) 8 31 P16 + No (control) 4 (9) 1 3 1 (NS) Positive with increasing 4 (10) 4 0 trend E7 antibody trend among P16 positive Positive with decreasing 19 (50) 3 16 patients trend .0007(∗∗∗ Negative 16 (40) 1 15 Contingency tables of patient demographics at the time of diagnosis, stage, HPV relevant markers, and E7 trend are shown to compare HNC patients with mortality and patients with no mortality. The Fisher’s exact test is used for the 2×2 contingency tables, and the Fisher’s exact test with Freeman-Halton extension is added to the larger contingency table to show the significance level of observed differences (NS = not significant, ∗∗ = p ≤ :01, ∗∗∗ = p ≤ :001). Table 2: E7 antibody trend predicts cancer recurrence or progression to mortality among HPV-associated HNC patients. Number of Cancer recurrence or No cancer recurrence or P-value patients (%) progression to mortality progression to mortality p16+ HNC patients 39 11 27 Positive with 4 (10) 4 0 increasing trend E7 antibody trend among Positive with 19 (50) 5 14 p16 positive patients decreasing trend P = :004 Negative 16 (40) 2 14 (∗∗) Contingency table of HPV-associated HNC patients’ immune response trend in consecutive clinical visits throughout the treatment. The Fisher’s exact test with Freeman-Halton extension is used for significance testing (∗∗ = p ≤ :01). This presence of E7 in the blood stream when cancer is de-escalation treatment strategies have failed to meaning- fully change clinical practice [10]. active is due to one of the following mechanisms: cancer cells Therefore, this study sought to identify molecular markers floating in the blood are transcriptionally active, tumors, for squamous cell head and neck cancer (HNSCC) that can be release oncoproteins directly into tumor vascular beds used to tailor cancer treatment to individual patient needs. because of necrosis, or tumor cells are secreting exosomes Our research has been particularly interested in two potential of viral oncoproteins [14–17]. Therefore, measuring anti- prognostic markers: oncoproteins E6 and E7, which inactivate bodies to E7 via liquid biopsy throughout the treatment the tumor suppressors p53 and RB, respectively [11]. P16, the course provides a potential marker for predicting cancer HPV-associated HNC marker used in this paper, is upregu- outcome and activity. Here, we aim to further examine the lated by E7’s suppression of RB [12, 13]. activity of E7 throughout cancer, the potential of E7 Journal of Oncology 3 HPV18 HPV16 antibodies to be used to monitor cancer, and its potential as 513 a noninvasive prognostic marker. 2.0 2. Methods 1.8 The study was reviewed and approved by the Institutional 1.6 Review Board at the University of Louisville (IRB# 08.0388, 15.0582) in compliance with the Declaration of Helsinki. 1.4 De-identified patient sera and clinical information were obtained from the Clinical Trials Office Biorepository of 1.2 the Brown Cancer Center. Blood was drawn for serum anal- ysis prior to treatment and every 3 months thereafter for 2 1.0 years. All serum specimens were obtained by collecting blood into nonadditive vacutainers, processed by centrifuga- 0.8 tion after a 30-minute clot, aliquoted, and stored at 4 C until analyzed. 0.6 Human E7 oncoprotein was created from a viral plasmid (pQE30) in bacterial cell culture from the manufacturer 0.4 (Qiagen). The production of E7 oncoprotein was confirmed via gel electrophoresis and Western Blot. This same process 0.2 of E7 antigen production is described in more detail in our 12345678 12345678 previous manuscript [18]. The ELISA 96 plates (Immulon 2HB) were purchased from the manufacturer (Thermo Visits Sci). The ELISA tray was coated with E7 oncoprotein at Figure 1: Heat map of anti-E7 ELISA values at consecutive clinical 1:200 ratio with PBS for 1 hour and washed with ×3. Patient visits for HPV-18 and HPV-16 E7 antibodies. All patients with serum at a 1:50 ratio with PBS was added to the ELISA tray increasing trends on ELISA (patients 610, 619, 625, and 864) overnight. In the morning, the tray was washed ×3. Second- correlated with patient mortality. The p16 negative controls ary mouse anti-human antibodies with alkaline phosphatase (patients 705, 865, and 872) are all seronegative for anti-E7 as conjugate (Sigma) were added at a 1:2000 ratio for 1 hour predicted. Note that HPV-18 and HPV-16 were used to generate and then washed with ×3. The signal was developed in the the E7 antigens but are not specific for these subtypes of HPV but ELISA tray by adding alkaline phosphatase per ELISA man- rather indicative or reactivity to high-risk HPV E7 protein. ufacturer instructions. The ELISA assays were then read via Synergy HT (BioTek) at time intervals 30, 50, and 70 minutes. 50 minutes was used as the reporting data as it pro- vided the clearest signal differentiation between test and controls. HPV-associated HNC patients were identified with p16 50 immunohistochemistry. All patients had cancers of the oro- pharynx with exception of patients 881 and 891. Patient 881 had a cancer of the larynx, and patient 891 had cancer of the oral tongue. Anti-E7 positive patients were identified with the standard ELISA cutoff procedure: at least one visit where the mean ELISA value was more than the mean of the neg- 0 1000 2000 3000 ative control value +3 standard deviations (.545 for HPV-16 Days elapsed anti-E7 and .423 for HPV-18 anti-E7) which was established in our p16 negative patients (750, 865, 872, and 1002). If the Positive for anti-E7 with increasing trend patient did not meet this criterion, they were classified as negative. Increasing trends were identified as at least 1 Positive for anti-E7 with decreasing trend increasing trend line throughout the study period for high- Negative for anti-E7 risk anti-E7. Decreasing trending patients were defined as having no increasing trend and at least 1 decreasing trend Figure 2: Survival data of patients differentiated by anti-E7 trend. for high-risk anti-E7. The percent survival in each group following treatment is shown. The data was analyzed utilizing the Microsoft Excel, Positive for anti-E7 with increasing trend n =4, positive for anti- Prism, and MedCalc statistical software. The analysis of sig- E7 with decreasing trend n =19, negative for anti-E7 n =25. Two nificance was done via FISHER’s exact testing of contin- of four patients suffered recurrence, and all four patients suffered gency tables as the cohort was too small for a chi-square mortality in the positive for anti-E7 with increasing trend group analysis to be accurate. For contingency tables larger than by day 2035. 2×2, a Freeman-Halton extension was added to the FISH- ER’s exact test. Percent (%) survival Patients 4 Journal of Oncology Patient 610 Patient 619 0.8 1.0 0.9 0.6 0.8 0.4 0.7 0.2 0.6 0.0 0.5 0 12345 0 2468 Visit number Visit number Patient 625 Patient 864 1.1 0.80 0.75 1.0 0.70 0.9 0.65 0.8 0.60 0.7 0.55 0 246 0 14 23 Visit number Visit number Figure 3: HPV-16 anti-E7 ELISA trends in patients with increasing ELISA values. All patients suffered mortality following treatment, and patients 610 and 625 suffered relapse following treatment. Note that HPV-16 was used to generate the E7 antigen but is not specific for this subtype of HPV but rather indicative or reactivity to high-risk HPV E7 protein. 3. Results positive trending high-risk anti-E7 throughout the study were more likely to have worse clinical outcome with relapse Of the 48 patients in this study, our ELISA results indicate of cancer or progression to mortality (p = :004). Of the 4 that 45.8% are positive for high-risk anti-E7 at one or more patients with an increasing anti-E7 trend, all had cancers collection time points during the study period with positivity progressing to mortality and 2 had cancer that recurred. A positive trending anti-E7 panel as a predictive test of recur- being defined as +3 standard deviations above the mean of the p16 negative patients ELISA values. Of the 43 patients rence or progression to mortality among p16+ HNC patients available for follow-up, 56% were aged less than 60, 86% confers a 36.36% (95% CI 10.93% to 69.21%) sensitivity, were male, 95% were white, and 5% were African American. 100% specificity (95% CI 88.06% to 100%), positive predic- The majority (91%) of patients were stage 3 or 4 at diagnosis. tive value of 100%, and negative predictive value of 83.3% The demographic and clinical characteristics of the patients (72.60% to 86.62%). can be seen in supplementary table 1. Treatments underwent by patients primarily were comprised of surgery followed by 4. Discussion immunotherapy, chemotherapy, and radiation. Specific treatments chosen for each patient can be seen in The presence of serum antibodies to E7 at the first clinical supplementary table 2. Eight patients had relapse of cancer visit of HNSCC patients were measured for the first time with metastasis to various sites including the lungs, recently and suggested that E7 may be a marker of cancer pericardium, lymph nodes, brain, bone, and liver. Nine recurrence [19]. Additionally, it has been reported that E6 patients suffered mortality, and 8 patients suffered cancer and E7 positivity correlates with better survival but worse recurrence. The patients suffering recurrence and mortality tumor grade and stage [14]. However, no study to our are shown and separated by HPV anti-E7 trend status in knowledge has yet identified oncoprotein titer variation supplementary table 3. Interestingly, two of the four throughout the disease course to be useful for predicting patients included in this study without p16 positivity HPV HNC clinical outcome [19–22]. (patients 750, 865, 872, and 1002) had cancer recurrence Our data did not demonstrate the same trend of E7 and 1 of 4 had cancer-associated mortality. Three of four oncoprotein positivity at the first visit to be useful to predict of these patients had negative anti-E7 values as predicted recurrence and survival (p =1). This is likely because our by the lack of high-risk HPV infection. study population was known HPV-associated HNC who E7 oncoprotein positivity at the first visit was not useful should have elevated E7 in the bloodstream before undergo- to predict recurrence and survival (p =1). Patients who had ing extensive treatment rather than the study population of HPV-16 anti-E7 ELISA value HPV-16 anti-E7 ELISA value HPV-16 anti-E7 ELISA value HPV-16 anti-E7 ELISA value Journal of Oncology 5 cer recurrence or fatal disease course, thus guiding head and all HNC patients used in previous studies where HPV- associated HNC confers better survival. For the HPV- neck cancer therapy. associated HNC population, our data demonstrates that an increasing anti-E7 trend throughout the course of treatment Data Availability predicts mortality (p = :0007) and recurrence or progression The clinical data of HNC patients used to support the find- to mortality (p = :004) with 100% specificity. The increasing ings of this study are included within the supplementary anti-E7 trend for patients experiencing relapse and mortality information file. is illustrated by the contingency tables (Tables 1 and 2), the heat map (Figure 1), and relapsed patients 610 and 625 (Figures 2 and 3). Conflicts of Interest Our ELISA is not specific enough to distinguish between All authors have no conflicts of interest. subtypes of high-risk HPV accurately because of cross- reactivity between other high-risk HPV E7 proteins present Authors’ Contributions in the sera due to sequence similarity. HPV-18 and HPV- 16 were used to produce E7 antigens because these are com- RAR and JJJ conceived and designed the experiments. LJ, mon subtypes of high-risk HPV; however, we have denoted DTH, MBH, GS, PAB, JS, and JJJ performed the experi- throughout the paper that the reactivity is against high-risk ments. LJ, JS, SD, and JJJ analyzed the data. LJ, DTH, HPV E7 instead of specific subtypes of HPV. Furthermore, MBH, JS, SD, RAR, and JJJ contributed to the writing of patients positive for both anti-E7 HPV 18 and anti-E7 the manuscript. HPV 16 do not necessarily indicate true positivity for both antibodies because the antigens have over 40% sequence Acknowledgments similarity. Although this data is not representative of specific sub- This study was supported by a fund from Dr. Alfred B Jen- types of HPV E7 present in the sera, as a predictive test for son for Head and Neck Cancer Research, the James Graham clinical relapse or progression to mortality trending high- Brown Cancer Center, University of Louisville, and NIH risk anti-E7 among HPV+ HNC patients may have utility NCI fund (1R01CA251755-01, Immunity to commensal as a specificity of 100% makes the test ideal for ruling in papillomaviruses for cancer therapy). the possibility of relapse and cancer mortality. This test may allow increased disease activity to be identified, and Supplementary Materials patients may benefit from more aggressive treatment. The sensitivity of 36.36% is relatively low and makes this a poor Supplementary Table 1. The demographic and clinical char- screening test, especially for patients without high-risk acteristics of head and neck cancer patients. The patient HPV-associated cancer. identification number, age at diagnosis, cancer description, This novel trend will be useful to future studies that p16 status, stage at diagnosis, sex, race, survival status, and expand the sample size to introduce more biologic variabil- overall survival days are shown. All patients had cancers of ity. Because of the ability of anti-E7 to predict clinical out- the oropharynx apart from patients 881 and 891 which were come and thus guide treatment, it should be considered as denoted as having non-oropharynx cancers specifically. If a target for high-risk HPV-associated HNC patient monitor- the patient was alive at the time of data collection the sur- ing. Previous data is limited regarding direct ELISA or E7 in vival days are shown up to that interval. Supplementary sera, although the clinical impact of a noninvasive test for Table 2. Treatment. Patient study identification number, stratifying outcomes is large. The use of novel biomarkers therapy type, therapy details, and day from day of diagnosis like E7 in conjunction with classical cancer staging tech- are shown. Supplementary Table 3. Patient mortality and niques is critical to deliver high-quality tailored care. Further recurrence by E7 trend following treatment. Patients entirely research comparing the prognostic efficacy of circulating E7 negative for anti-E7 HPV-16 and HPV-18, Patients with at nucleic acid at sequential clinical visits with E7 antibodies least one increasing anti-E7 trend for HPV-16 or HPV-18, would be impactful. This data is important to further our and Patients with at least one decreasing anti-E7 trend for understanding of HPV serology, non-invasively monitor HPV-16 or HPV-18 is shown following treatment. High- persistent or occult tumors, and will help to create personal- lighted in red are patients suffering from cancer recurrence, ized cancer treatments in the future. purple font is indicative of patients that suffered from mor- tality, and patients denoted with (∗) is indicative of p16 neg- ative status. Note that HPV-18 and HPV-16 was used to 5. Conclusion generate the E7 antigens but are not specific for these sub- types of HPV but rather indicative or reactivity to high- High-risk human papillomavirus-associated head and neck risk HPV E7 protein. (Supplementary Materials) cancer is an increasing issue with significant clinical out- come heterogeneity. Trending anti-E7 via liquid biopsy is References strongly predictive of cancer recurrence or progression with mortality (p = :004). Measuring E7 oncoprotein at consecu- [1] Y. Huang and X. 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