HPV-negative Cancers Research Articles

CENPM upregulation by E5 oncoprotein of human papillomavirus promotes radiosensitivity in head and neck squamous cell carcinoma

ObjectivesThis study aims to investigate how human papillomavirus (HPV) affects the key gene in the biological behaviors of head and neck squamous cell carcinoma (HNSCC) that leads to better response to radiotherapy. Materials and MethodsThe expression of key gene CENPM was analyzed using The Cancer Genome Atlas (TCGA) HNSCC data and HPV positive and HPV negative HNSCC tumors and cells. Assays with siRNAs, CRISPR/Cas9-based models, Western blot, qRT-PCR, ChIP, etc., were used to explore how HPV affects CENPM and response to radiotherapy for HNSCC. ResultsCENPM occupies the hub in the HPV-related gene network. HPV-positive HNSCC showed higher level of CENPM expression comparing with HPV-negative HNSCC. HPV E5 has the most pronounced impact on CENPM (R = 0.44, p = 0.00081). This might result from the binding of transcription factor E2F1 to CENPM. We further found that inhibition of CENPM expression in HPV-positive HNSCC cell line SCC47 increased resistance to X-ray radiation by approximately 59% under 2 Gy irradiation, which may be resulted from a reduced proportion of mitotic cells. ConclusionHPV E5 enhances CENPM expression by transcription factor E2F1 in HNSCC, which results in a radiosensitive profile in cell cycle redistribution of HNSCC. Thus, HPV infection in HNSCC provides profound evidence that underscores the magnitude of E2F1 control of CENPM expression illustrating the potential clinical benefit of CENPM examination for difficult-to-treat HPV-negative cancers.

YAP1 activation by human papillomavirus E7 promotes basal cell identity in squamous epithelia.

Persistent human papillomavirus (HPV) infection of stratified squamous epithelial cells causes nearly 5% of cancer cases worldwide. HPV-positive oropharyngeal cancers harbor few mutations in the Hippo signaling pathway compared to HPV-negative cancers at the same anatomical site, prompting the hypothesis that an HPV-encoded protein inactivates the Hippo pathway and activates the Hippo effector yes-associated protein (YAP1). The HPV E7 oncoprotein is required for HPV infection and for HPV-mediated oncogenic transformation. We investigated the effects of HPV oncoproteins on YAP1 and found that E7 activates YAP1, promoting YAP1 nuclear localization in basal epithelial cells. YAP1 activation by HPV E7 required that E7 binds and degrades the tumor suppressor protein tyrosine phosphatase non-receptor type 14 (PTPN14). E7 required YAP1 transcriptional activity to extend the lifespan of primary keratinocytes, indicating that YAP1 activation contributes to E7 carcinogenic activity. Maintaining infection in basal cells is critical for HPV persistence, and here we demonstrate that YAP1 activation causes HPV E7 expressing cells to be retained in the basal compartment of stratified epithelia. We propose that YAP1 activation resulting from PTPN14 inactivation is an essential, targetable activity of the HPV E7 oncoprotein relevant to HPV infection and carcinogenesis.

Identification of differentially expressed genes and pathways for risk stratification in HPV-associated cancers governing different anatomical sites.

Human papillomavirus (HPV) is the major cause of cervical cancer (CC) etiology; its contribution to head and neck cancer (HNC) incidence is steadily increasing. As individual patients' response to the treatment of HPV-associated cancer is variable, there is a pressing need for the identification of biomarkers for risk stratification that can help determine the intensity of treatment. We have previously reported a novel prognostic and predictive indicator (HPPI) scoring system in HPV-associated cancers regardless of anatomical location by analyzing The Cancer Genome Atlas and Gene Expression Omnibus databases. In the present study, we comprehensively investigated the association of group-specific expression patterns of common differentially expressed genes (DEGs) between high- and low-risk groups in HPV-associated CC and HNC, identifying molecular biomarkers and pathways for risk stratification. Among the 174 identified DEGs, the expression of genes associated with extracellular matrix (ECM)-receptor interaction pathway (ITGA5, ITGB1, LAMB1, and LAMC1) was increased in high-risk groups in both HPV-associated CC and HNC, while the expression of genes associated with T-cell immunity (CD3D, CD3E, CD8B, LCK, and ZAP70) was decreased and vice versa. The individual genes showed significant prognostic impact on HPV-associated cancers but not on HPV-negative cancers. The expression levels of identified genes were similar between HPV-negative and HPV-associated high-risk groups with distinct expression patterns only in HPV-associated low-risk groups. Each group of genes showed negative correlations and distinct patterns of immune cell infiltration in tumor microenvironments. These results allowed us to identify molecular biomarkers and pathways for risk stratification in HPV-associated cancers regardless of anatomical location. The identified targets were found to be selectively working in only HPV-associated cancers and not in HPV-negative cancers, indicating the possibility of selective targets governing HPV-infective tumor microenvironments.

Induction chemoimmunotherapy followed by CD8+ immune cell-based patient selection for chemotherapy-free radioimmunotherapy in locally advanced head and neck cancer

PurposeThe first aim of the trial is to study feasibility of combined programmed death protein ligand 1/cytotoxic T-lymphocyte-associated protein 4 inhibition concomitant to radiotherapy. In addition, efficacy of the entire...

Molecular Pathology of Human Papilloma Virus-Negative Cervical Cancers

Simple SummaryAlthough cervical cancer is mainly caused by infection with human papillomavirus (HPV), some cervical cancers test negative for HPV. As these HPV-negative cervical cancers are often diagnosed at an advanced stage and have a poor prognosis, it is important to understand their molecular pathology. Here, we provide an overview of the potential causes of false-negative HPV tests, as well as the histology, genetic profile, and pathogenesis of HPV-negative cancers.Cervical cancer is the fourth most common cancer in women worldwide and is predominantly caused by infection with human papillomavirus (HPV). However, a small subset of cervical cancers tests negative for HPV, including true HPV-independent cancers and false-negative cases. True HPV-negative cancers appear to be more prevalent in certain pathological adenocarcinoma subtypes, such as gastric- and clear-cell-type adenocarcinomas. Moreover, HPV-negative cervical cancers have proven to be a biologically distinct tumor subset that follows a different pathogenetic pathway to HPV-associated cervical cancers. HPV-negative cervical cancers are often diagnosed at an advanced stage with a poor prognosis and are expected to persist in the post-HPV vaccination era; therefore, it is important to understand HPV-negative cancers. In this review, we provide a concise overview of the molecular pathology of HPV-negative cervical cancers, with a focus on their definitions, the potential causes of false-negative HPV tests, and the histology, genetic profiles, and pathogenesis of HPV-negative cancers.

Metabolic rewiring is associated with HPV-specific profiles in cervical cancer cell lines

Both HPV-positive and HPV-negative cervical cancers are associated with aberrant metabolism, although the oncogenic drivers remain elusive. Here we show the assessment of the metabolomic profiles of four distinct cervical cell lines, a normal and three cancer cell lines, one HPV-negative (C33A) and two HPV-positive (SiHa HPV16+, HeLa HPV18+), employing an ultra performance liquid chromatography and a high resolution mass spectrometry. Out of the total 462 metabolites, 248 to 326 exhibited statistically significant differences, while Random Forests analysis identified unique molecules for each cell line. The two HPV+ cell lines exhibited features of Warburg metabolism, consistent with the role of the HPV E6 protein. SiHa and HeLa cells displayed purine salvage pathway activity, while C33A cells revealed synthesis of cytidine, via a novel mechanism. These data document a highly dynamic HPV-specific rewiring of metabolic pathways occurring in cervical cancer. Therefore, this approach can eventually provide novel mechanistic insights into cervical carcinogenesis.

Prognostic Markers and Driver Genes and Options for Targeted Therapy in Human-Papillomavirus-Positive Tonsillar and Base-of-Tongue Squamous Cell Carcinoma.

The incidence of Human-papillomavirus-positive (HPV+) tonsillar and base-of-tongue squamous cell carcinoma (TSCC and BOTSCC, respectively) is increasing epidemically, but they have better prognosis than equivalent HPV-negative (HPV−) cancers, with roughly 80% vs. 50% 3-year disease-free survival, respectively. The majority of HPV+ TSCC and BOTSCC patients therefore most likely do not require the intensified chemoradiotherapy given today to head and neck cancer patients and would with de-escalated therapy avoid several severe side effects. Moreover, for those with poor prognosis, survival has not improved, so better-tailored alternatives are urgently needed. In line with refined personalized medicine, recent studies have focused on identifying predictive markers and driver cancer genes useful for better stratifying patient treatment as well as for targeted therapy. This review presents some of these endeavors and briefly describes some recent experimental progress and some clinical trials with targeted therapy.

HPV73 in cervical cancer and distribution of HPV73 variants in cervical dysplasia.

HPV73 is classified as possibly oncogenic and is not recognized by most commercial primary HPV screening platforms. The aim was to determine the prevalence of HPV73 among invasive cervical cancers, formalin-fixed paraffin embedded (FFPE) samples (N = 69), from southern Sweden during 2009 to 2010. Another aim was to determine proportions of HPV73 among Aptima HPV assay negative cervical cancers (N = 9, out of 206 cancers) and of high-grade cytological cervical diagnosis (N = 75, out of 5807 high grade lesions) in liquid-based cytology (LBC) samples collected between 2016 and 2019. We also investigated the distribution of HPV73 variants A1, A2 and B among HPV73-positive cases. HPV73 was detected by multiplex MGP-PCR and Luminex, and HPV73 variants were identified by sequencing PCR amplicons. HPV73 was detected in 2.9% (2/69, 95% CI: 0.18-9.9) of the FFPE cervical cancer series. Among the Aptima HPV-negative LBC samples, HPV73 was present in 55.5% (5/9) of the cancers and 29.3% (22/75) of the different grades of cervical diagnosis. The A1, A2 and B variants were present in 6.9% (2/29), 82.7% (24/29) and 10.3% (3/29) of the HPV73-positive women, respectively. Among the seven HPV73 cancer cases (two FFPE samples and five LBC samples), six A2 and one A1 isolate were detected. In summary, the A2 variant of HPV73 was most common in our region. In addition, the observed prevalence of HPV73 (2.9%) in cervical cancers and its relative high occurrence (55.5%) among Aptima HPV-negative cancers urge that detection of HPV73 should be included in future primary HPV screening programs.

Independent association of marijuana use and poor oral hygiene with HPV-negative but not HPV-positive head and neck squamous cell carcinomas.

Sexual behavior is associated with human papillomavirus (HPV)-positive head and neck cancer, whereas tobacco and alcohol use are associated with HPV-negative cancer. A case-control study was designed to investigate additional demographic and behavioral factors independently associated with these distinct oral cancers. From 2011 to 2014, 249 newly diagnosed oral cavity and oropharyngeal squamous cell carcinoma (OSCC) cases were matched (1:2) on age, gender, and self-identified race to 498 controls without a cancer history attending the outpatient otolaryngology clinic at The Ohio State University in Columbus. Cases were stratified by detection of high-risk HPV DNA and RNA in tumors. Demographic and behavioral data were collected using an audio computer-assisted self-interview, and associations with HPV-positive versus HPV-negative OSCCs were investigated by use of univariable and multivariable conditional logistic regression models. After adjustment for oral sexual behavior, the odds of HPV-positive cancer decreased with the patient's years of education. Annual income, tobacco smoking, alcohol drinking, marijuana smoking, and poor oral hygiene were not associated with HPV-positive OSCC. In contrast, the odds of HPV-negative OSCC increased independently with decreased annual income, decreased with a high number of marijuana hit-years, and increased with fewer than annual dental visits after adjustment for lifetime tobacco and alcohol use. Sexual behavior and education were not associated with HPV-negative OSCC. The distinct risk-factor profiles for HPV-positive and HPV-negative OSCC are confirmed and extended in this case-control study, thus supporting 2 principal etiological pathways for OSCC development. Sexually acquired human papillomavirus (HPV) infection is an established cause of tonsil and base of tongue cancers. This study compared and contrasted risk factors for HPV-positive and HPV-negative oral cancers. Low number of years of education and sexual behavior are associated with HPV-positive cancer. In contrast, low annual income, infrequent dental visits, and tobacco and alcohol use are associated with HPV-negative cancers. Long-term marijuana use appears protective for HPV-negative cancer. Public health efforts to address these modifiable risk factors may prevent oral cancer.

Human Papillomavirus-Negative Cervical Cancer: A Comprehensive Review.

Human papillomavirus (HPV) has been the leading cause of cervical cancer for over 25 years. Approximately 5.5–11% of all cervical cancers are reported to be HPV-negative, which can be attributed to truly negative and false-negative results. The truly HPV-negative cervical cancers are almost all cervical adenocarcinomas with unclear etiology. False HPV negativity can arise from histological misclassification, latent HPV infection, disruption of the targeting fragment, non-high risk HPV infection, and HPV testing methods. HPV-negative cervical cancers are often diagnosed at an advanced FIGO stage and have a poor prognosis; thus, the management of these cases requires greater attention.

EGFR/PI3K/Akt/mTOR pathway in head and neck squamous cell carcinoma patients with different HPV status.

The aim of the study was to compare prognostic potential of PIK3CA mutations and expression of proteins involved in or regulate EGFR/PI3K/Akt/mTOR signaling in HPV16 positive and HPV negative head and neck squamous cell carcinoma (HNSCC) patients. The expression of proteins (EGFR, Akt, pAkt(Ser473), pAkt(Thr308), mTOR, PTEN, pPTEN, APOBEC3B) were assessed immunohistochemically and PIK3CA mutations (p.E542K, p.E545K, p.H1047R) by qPCR. Significantly more HPV16 positive tumors (89.29%) with low EGFR expression were found as compared to HPV negative ones (58.82%). PIK3CA mutations were detected in 7.14% of HPV16 positive and 2.5% of HPV negative cancers. In HPV16 positive patients survival analysis has shown that positive prognostic potential for disease free survival (DFS) had low expression of APOBEC3B. In HPV negative patients prognostic significance for DFS had APOBEC3B, Akt and pAkt(Thr308) levels, and for overall survival (OS) - pAkt(Thr308) only. Independent favorable prognostic factors in the whole group of patients were: low T stage, low pAkt(Thr308) expression, active HPV16 infection (for OS and DFS) and female gender (for OS). Obtained results suggest the existence of significant differences in expression and prognostic potential of proteins involved in EGFR/PI3K/Akt/mTOR signaling between HPV16 positive and HPV negative HNSCC patients.

Therapeutic strategies of different HPV status in Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is the 9th most common malignant tumor in the world. Based on the etiology, HNSCC has two main subtypes: human papillomavirus (HPV) -related and HPV-unrelated. HPV-positive HNSCC is more sensitive to treatment with favorable survival. Due to the different biological behaviors, individual therapy is necessary and urgently required to deduce the therapeutic intensity of HPV-positive disease and look for a more effective and toxicity-acceptable regimen for HPV-negative disease. EGFR amplification and PI3K/AKT/mTOR pathway aberrant activation are quite common in HPV-positive HNSCC. Besides, HPV infection alters immune cell infiltrating in HNSCC and encompasses a diverse and heterogeneous landscape with more immune infiltration. On the other hand, the chance of HPV-negative cancers harboring mutation on the P53 gene is significantly higher than that of HPV-positive disease. This review focuses on the updated preclinical and clinical data of HPV-positive and HPV-negative HNSCC and discusses the therapeutic strategies of different HPV status in HNSCC.

Treatment of Early Stage Tonsil Cancer in the Age of Human Papillomavirus-Associated Malignancies.

To investigate the patterns of care and outcomes of treatment of early stage tonsil cancers, controlling for human papillomavirus (HPV) status. Historical cohort study. National Cancer Database (NCDB). Review of the NCDB between 2010 and 2017 for all T1-2N0M0 tonsillar squamous cell carcinoma (SCC). Demographics, clinical characteristics, HPV status, treatment regimens, and survival were analyzed. A total of 4720 patients were identified with early stage SCC of the tonsil. Most were tested for HPV (2759 [58.5%]). Among tested patients, 1758 (63.7%) were positive for HPV and 1001 (36.3%) were negative for HPV. HPV-positive patients had higher 3-year survival compared to HPV-negative patients (93.2% vs 77.8%, P < .001). Among HPV-positive patients, there was no significant difference in survival between treatment cohorts. However, in the HPV-negative cohort, 3-year survival was higher in both bimodality surgical-based settings (tonsillectomy + neck dissection + radiotherapy, 86.0% vs chemoradiotherapy, 69.6%, P = .01) and for all surgical-based treatments when compared to nonsurgical management (84.6% vs 69.3%, P < .001). This difference was maintained in multivariable regression controlling for age, sex, comorbidities, clinical T stage, and treatments. In a subpopulation of HPV-negative patients propensity score matched by all factors significant in multivariable analysis, 3-year survival remained higher in the surgically treated group compared to the nonsurgically treated cohort (84.9% vs 67.1%, P < .001). Surgical- or radiation-based treatment resulted in similar survival in early stage HPV-positive tonsil cancer. Surgical-based treatments were associated with longer survival in HPV-negative cancers. These findings should be further investigated in a randomized prospective trial.

Awareness of Human papilloma Virus (HPV) and its Toxicity

Human Papilloma Virus (HPV) lead to epidemiologically and clinically distinct form of Orpharyngeal Squamous Cell Carcinoma (OPSCC). HPV-positive OPSCCs have risk factors related to sexual behaviour whereas HPV-negative cancers strongly co-related with tobacco and alcohol usage. In addition HPV-positive patients have substantially better survival than compared with HPV-negative patients.

Abstract PO-006: Single cell transcriptomic analysis of primary head and neck cancer stem cells

Abstract Despite advances in treatment modalities for head and neck squamous cell carcinoma (HNSCC) survival rates remain unchanged. Tumor heterogeneity within HNSCC as well as within the tumor microenvironment (TME) has been shown to be a major driver of treatment failure and poor outcomes. A key component of the TME and a potential key to deciphering tumor heterogeneity are cancer stem cells. While numerous studies have demonstrated the tumorigenicity and malignant potential of these cells, few studies have investigated their expression profiles. The aim of this study is to leverage single cell technology to investigate the expression profile of primary HNSCC cancer stem cells. We performed single cell sequencing of five primary HPV-negative head and neck cancers and two HNSCC cell lines that were presorted into the CSC (CD44high/ALDH+) and non-CSC (CD44low/ALDH-) phenotype. We are able to characterize an expression profile of the CSC TME niche and a novel CSC expression profile (DCN, C110rf96, KLF4, MEG3 and NR4A1) relative to non-CSC. We confirm this CSC profile is conserved across all five primary tumors. Together these data provide some of the first insights into CSC transcriptome, further define the CSC-TME niche, and identify conserved targets within HNSCC CSC as a means to decipher the challenges inherent to tumor heterogeneity. Citation Format: Molly E. Heft Neal, Stephanie The, John Henry J. Owen, Clifford Chang, Mark E.P. Prince, Arvind Rao, Steven B. Chinn. Single cell transcriptomic analysis of primary head and neck cancer stem cells [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-006.

Implementation of primary HPV testing in Japan.

Cervical cancer screening has been shifting from primary cytology to primary HPV testing worldwide as primary HPV testing is more sensitive than primary cytology. To the best of our knowledge, the current study is the first in Japan to examine the feasibility of primary HPV testing. One of the disadvantages of this shift is that hrHPV-/≥LSIL/CIN2+ (high-risk HPV negative cancers or pre-cancerous lesions with abnormal cytology results) can be missed. The objectives of the present study are to clarify in detail CIN2+ missed by this shift and to evaluate the feasibility of primary HPV testing in Japan. Data from 115,273 women who underwent co-testing with cytology and HPV testing in cancer screening were used in the current study. The cases with hrHPV-/≥LSIL (‘hrHPV-/≥L-SIL’ include CIN2-, in contrast, ‘hrHPV-/≥L-SIL/CIN2+’ doesn't include CIN2-) were analysed in detail. Women with hrHPV-/≥LSIL comprised 0.3% of the total. The prevalence of CIN2, CIN3, SCC or cervical adenocarcinomas in the lesions with HPV-/≥LSIL was 0.03% in the cancer screening group. Only one case of 14 cervical adenocarcinomas in ≥LSIL was hrHPV-. The prevalence of cancer missed by the shift in patients >50 years of age was significantly higher compared with patients younger than 49 years. In conclusion, the prevalence of CIN2+, which might be missed by the shift from primary cytology to primary HPV testing, was remarkably low in this Japanese cancer screening. The data indicated that primary HPV testing, which was more sensitive for CIN2+ than primary cytology, was a feasible method that can be used in Japan. In particular, primary HPV testing should be introduced for women <50 years old.

EGFR Activation is Suppressed by High Doses of Folic Acid in HPV Negative Cervical Cancer Cells

Cervical cancer is one of the leading causes of death due to cancer in women. Human Papilloma Virus infection is the primary risk factor for developing cervical cancer, however very little is known about HPV negative cervical cancers. Folate fortification of flour for prevention of neural tube defects has been mandatory in North America since 1998; and folate supplementation is recommended during pregnancy. Folate fortification is not mandated in all countries, however, due to concerns about possible adverse effects on cancer incidence or prognosis. There is evidence that folate intake can reduce risk of developing tumors but other contradictory studies indicate that supraphysiologic doses of folate can actually lead to disease progression. Folate receptor alpha is known to be expressed in many cancer cell lines, including HPV positive cervical cancer. There is some evidence that folic acid can promote methylation of the EGFR, leading to a decrease in EGFR expression, and that EGFR might be active in some HPV positive cervical cancers. The purpose of this study is to determine if EGFR plays a role in HPV negative cervical cancer cell growth, and the effects of folic acid on EGFR protein expression and activation. Two HPV negative cervical cancer cell lines were used for this study: C33A and DoTc2‐4510. High doses of folic acid caused a decrease in both C33A and DoTc cell proliferation. Interestingly, qPCR and western blotting analysis indicate that only the DoTc2‐4510 cells expressed EGFR. The DoTc2‐4510 cells were sensitive to the EGFR inhibitor, gefinitib, with an IC50 of 0.01 uM. There was no change in EGFR expression upon folic acid treatment, but interestingly high doses of folic acid did inhibit EGFR activation. Taken together this data indicates that EGFR may be a target for a subset of HPV negative cervical cancers, and that high doses of folic acid may help prevent EGFR positive HPV negative cervical cancer cell growth.

Nimotuzumab-cisplatin-radiation versus cisplatin-radiation in HPV negative oropharyngeal cancer

Background: Addition of nimotuzumab to weekly cisplatin and radiation improves outcomes in head and neck cancer. HPV negative oropharyngeal cancer has unsatisfactory treatment outcomes and is a candidate for escalation of treatment. We wanted to determine whether the addition of nimotuzumab to cisplatin-radiation could improve outcomes in these poor-risk tumors.Methods: This was a subgroup analysis of a phase 3 randomized study. In this study, locally advanced head and neck cancer patients undergoing definitive chemoradiation were randomly allocated to weekly cisplatin (30 mg/m2 IV)- radiation (66–70 Gy) {CRT arm} or nimotuzumab (200 mg weekly) -weekly cisplatin (30 mg/m2)-radiation (66–70 Gy) {NCRT arm}. The data of HPV negative oropharyngeal cancer was extracted from the database of this study for the analysis. HPV testing was done with p16 immunohistochemistry (IHC) staining and reported according to the CAP criteria. The outcomes assessed were progression-free survival (PFS), disease-free survival (DFS), locoregional control, and overall survival (OS). Interaction test was performed between the study arms and HPV status prior to doing any HPV specific analysis for each of the studied outcomes. Kaplan Meier estimates for 2 year OS with 95%CI was calculated. The hazard ratio was obtained using COX regression analysis.Results: We had 187 HPV negative oropharyngeal cancers, 91 in the CRT arm and 96 in NCRT arm. The interaction test was significant for PFS (p = 0.000), locoregional control (p = 0.007) and overall survival (p = 0.002) but not for DFS (p = 0.072). The 2- year PFS was 31.5% (95%CI 21.5–42) in CRT arm versus 57.2% (95%CI 45.8–67.1) in NCRT arm (HR -0.54; 95%CI 0.36–0.79, p = 0.002). The 2-year LRC was 41.4% (95%CI 29.8–52.6) in the CRT arm versus in 60.4% (95%CI 48.7–70.2) in the NCRT arm (HR -0.61; 95%CI 0.4–0.94, p = 0.024). The addition of nimotuzumab also lead to an improvement in 2-year OS from 39.0% (95%CI 28.4–49.6) to 57.6% (95%CI 46.3–67.4) (HR-0.63, 95%CI 0.43–0.92, p = 0.018).Conclusions: The addition of nimotuzumab to weekly cisplatin-radiation improves outcomes inclusive of OS in HPV negative oropharyngeal cancers.

Therapeutic Outcomes of HPV Positive and HPV Negative Oropharyngeal Squamous Cell Carcinomas

Background & Objectives: HPV associated (HPV+) oropharyngeal cancers, compared with HPV non-associated ones (HPV?) have different characters and significantly better outcomes. HPV and cancer characteristics differ among countries and few data is available in Indian population regarding this issue. Thus, we attempted to determine the treatment response and survival rates between HPV+ versus HPV negative oropharyngeal cancers in Indian population. Methods: This prospective observational study was conducted from December 2016 - October 2018 in patients with stage III/IV oropharyngeal squamous cell carcinomas (SCC) (n = 65). The patients received induction chemotherapy with Docetaxel, Cisplatin, 5-Fluorouracil × 3 cycles, followed by concurrent chemoradiation 66 Gy as 33 fractions along with cisplatin 40 mg/m2 weekly. The primary outcome was treatment response rate, which was defined as per Response Evaluation Criteria in Solid Tumours (RECIST) criteria. Secondary outcomes were clinico-pathological differences between two groups, overall survival (OS), progression free survival (PFS). Results: Of the 65 patients included in the study, 17 were HPV positive and 48 patients were HPV negative. Median age in HPV positive arm is 48 years and HPV negative arm is 59 years. HPV positive patients presented with early T stage and advanced nodal (N) stage. Most common histopathology in both arms was moderately differentiated squamous cell carcinomas followed by well differentiated squamous cell carcinomas. HPV+ vs HPV? showed the following, treatment response 82.4% vs 52.1% (p-0.029). 1 year progression free survival (PFS) of 76.5% vs 52.1% in HPV negative arm (p-0.08) & 1 year overall survival was 82.4% vs 70.8% (p-0.353). Grade 3 or 4 toxicities did not differ significantly between HPV positive and HPV negative arms. Conclusion: HPV positive oropharyngeal SCC patients showed significantly better treatment response than HPV negative ones. Progression free survival, overall survival and toxicity profile did not differ significantly between the two groups. Although due to small size, we did not compare data stratified by the cancer characteristics, the data is worthy to further characterize this tumour especially as HPV positive versus HPV negative.

Biological and clinical aspects of HPV-related cancers.

Cancer-related diseases represent the second overall cause of death worldwide. Human papilloma virus (HPV) is an infectious agent which is mainly sexually transmitted and may lead to HPV-associated cancers in both men and women. Almost all cervical cancers are HPV-associated, however, an increasing number of head and neck cancers (HNCs), especially oropharyngeal cancer, can be linked to HPV infection. Moreover, anogenital cancers, including vaginal, vulvar, penial, and anal cancers, represent a subset of HPV-related cancers. Whereas testing and prevention of cervical cancer have significantly improved over past decades, anogenital cancers remain more difficult to confirm. Current clinical trials including patients with HPV-related cancers focus on finding proper testing for all HPV-associated cancers as well as improve the currently applied treatments. The HPV viral oncoproteins, E6 and E7, lead to degradation of, respectively, p53 and pRb resulting in entering the S phase without G1 arrest. These high-risk HPV viral oncogenes alter numerous cellular processes, including DNA repair, angiogenesis, and/or apoptosis, which eventually result in carcinogenesis. Additionally, a comprehensive analysis of gene expression and alteration among a panel of DNA double strand breaks (DSB) repair genes in HPV-negative and HPV-positive HNC cancers reveals differences pointing to HPV-dependent modifications of DNA repair processes in these cancers. In this review, we discuss the current knowledge regarding HPV-related cancers, current screening, and treatment options as well as DNA damage response-related biological aspects of the HPV infection and clinical trials.