Key differences between HPV-positive and HPV-negative head and neck squamous cell carcinomas (HNSCC)

Head and neck squamous cell carcinomas (HNSCC) develop from the mucosal epithelium in the oral cavity, pharynx, and larynx and are the most common malignancies that arise in the head and neck.1 Increasingly, tumors in the oropharynx are linked to prior infection with oncogenic strains of human papillomavirus (HPV), primarily HPV-16 and, to a lesser extent HPV-18 and others.2,3 HNSCCs of the oral cavity and larynx are primarily associated with tobacco-derived carcinogens, excessive alcohol consumption, or both, and are collectively referred to as HPV-negative HNSCC.4 The median age of diagnosis for non-virally associated HNSCC is 66 years, whereas the median age of diagnosis for HPV-associated oropharyngeal cancer is about 53 years.5

HPV-positive and HPV-negative HNSCC are two distinct diseases with different sites of origin, etiological agents, risk factors, and contributions to the development of oropharyngeal squamous cell carcinoma (OPSCC). The demographics, cause, and prevalence of HPV-positive and NPV-negative cancers are summarized in Table 1.

Table 1: Demographics, Cause, and Prevalence of HNSCC.

Whereas the incidence of smoking-related HNSCC continues to decline worldwide, that of HPV-positive HNSCC is on the rise.6 During 2007-2016, HPV-associated cancers increased by 2.1% per year on average, whereas cancers not associated with HPV decreased by 0.4% per year on average.6

HPV-positive and HPV-negative HNSCCs present with different molecular characteristics, immune landscapes, and clinical prognosis (Table 2) and lead to two fundamentally different diseases with distinct pathogenesis in terms of gene expression, tumor microenvironment (TME), and mutational burden.

Table 2. Pathology and Disease Signature in HNSCC.

Genomic and epigenetic analyses reveal extremely high heterogeneity in HNSCC in terms of characteristic mutations, molecular signature, cellular phenotype, composition of TME, and immune landscape (Table 3).

Table 3. Characteristic mutations in HPV-positive and HPV-negative HNSCC.

Various promising vaccine targets have been identified and treatment options employed for the treatment of HPV-positive and HPV-negative cancers with varying degrees of success (Table 4).

Table 4. Treatment options and targets.
Treatment personalization and de-escalation

According to Dr. Nishant Agrawal, Chief of Otolaryngology-Head & Neck Surgery UChicago Medicine, “We have seen a significant increase in the incidence of HPV-associated oropharyngeal cancer in relatively younger patients, with the median age of diagnosis in the 50s, even patients in their 30s.”32 He added that “Even at 2 years after radiation therapy, 15% of patients had grade 2 swallowing dysfunction and 8% had progressive dysphagia, so their swallowing is going to continue to get worse. Patients may also have chronic xerostomia. The dry mouth improves but it never gets back to 100%.”33 In contrast to patients with HPV-negative HNSCC, who have a five-year survival rate of about 25%-40%, patients with HPV-positive HNSCC fare much better with a disease-free survival rate of 85%-90% over five years. According to Dr. Agrawal, the better prognosis for HPV-positive patients suggests a need to de-escalate treatment while preserving survival.

References

  1. Stein, A.P. et al. (2015) Prevalence of human papillomavirus in oropharyngeal cancer: a systematic review. Cancer J. (21);138-46.
  2. Isayeva, T. et al. (2012) Human papillomavirus in non-oropharyngeal head and neck cancers: a systematic literature review. Head Neck Pathol. (6);S104-20.
  3. Michaud, D.S. et al. (2014) High-risk HPV types and head and neck cancer. Int J Cancer. (135);1653-61.
  4. https://pubmed.ncbi.nlm.nih.gov/33243986/  
  5. Windon, M.J. et al. (2018) Increasing prevalence of human papillomavirus-positive oropharyngeal cancers among older adults. Cancer (124);2993-99.
  6. Ellington, T.D. et al. (2020) Trends in incidence of cancers of the oral cavity and pharynx – United States 2007-2016. Morb Morta Wkly Rep. (69);433-38.
  7. https://www.cancer.org/cancer/oral-cavity-and-oropharyngeal-cancer/causes-risks-prevention/risk-factors.html  
  8. https://pubmed.ncbi.nlm.nih.gov/33243986/  
  9. Gillison, M.L. et al. (2015) Epidemiology of human papillomavirus positive head and neck squamous cell carcinoma. J Clin Oncol. (33);3235-42.
  10. Mahal, B.A. et al. (2019) Incidence and Demographic Burden of HPV-Associated Oropharyngeal Head and Neck Cancers in the United States. Cancer Epidemiol Biomark Prev. 28(10);1660-67.
  11. Kazuhiro, K. et al. (2018) A Review of HPV-Related Head and Neck Cancer. J Clin Med Sep. 7(9);241.
  12. https://bmccancer.biomedcentral.com/articles/10.1186/s12885-022-09407-5 
  13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5486734
  14. Canning, M. et al. (2019) Heterogeneity of the Head and Neck Squamous Cell Carcinoma Immune Landscape and Its Impact on Immunotherapy. Front Cell Dev Bio.l vol7. https://doi.org/10.3389/fcell.2019.00052
  15. Fakhry, C. et al. (2017) The prognostic role of sex, race, and human papillomavirus in oropharyngeal and nonoropharyngeal head and neck squamous cell cancer. Cancer (123);1566-75. Doi: 10.1002/cncr.30353.
  16. Pai, S.I. et al. (2009) Molecular pathology of head and neck cancer: implications for diagnosis, prognosis, and treatment. Annu Rev Pathol. (4);49-70.
  17. Keck, M.K. et al. (2015) Integrative analysis of head and neck cancer identifies two biologically distinct HPV and three non-HPV subtypes. Clin Cancer Res. (21);870-81. Doi: 10.1158/1078-0432.CCR-14-2481.
  18. Hanna, G.J. et al. (2018) Frameshift events predict anti-PD-1/L1 response in head and neck cancer. JCI Insight 3:98811. Doi: 10.1172/jci.insight.98811.
  19. Elpek, K.G. et al. (2014) The tumor microenvironment shapes lineage, transcriptional, and functional diversity of infiltrating myeloid cells. Cancer Immunol Res. (2);655-67. Doi: 10.1158/2326-6066.CIR-13-0209.
  20. Mandal, R. et al. (2016) The head and neck cancer immune landscape and its immunotherapeutic implications. JCI Insight 1: e89829. Doi: 10.1172/jci.insight.89829.
  21. Badoual, C. et al. (2013) PD-1-expressing tumor-infiltrating T cells are a favorable prognostic biomarker in HPV-associated head and neck cancer. Cancer Res. (73);128-38. Doi: 10.1158/0008-5472.CAN-12-2606.
  22. Hanna, G.J. et al. (2017) Defining an inflamed tumor immunophenotype in recurrent, metastatic squamous cell carcinoma of the head and neck. Oral Oncol. (67);61-69.
  23. Taberna, M. et al. (2017) Human papillomavirus-related oropharyngeal cancer. Ann Oncol. (28);2386-98.
  24. Coca-Pelaz, A. et al. (2020) The risk of second primary tumors in head and neck cancer: a systematic review. Head Neck. (42);456-66.
  25. Tomaic, V. (2016) Functional roles of E6 and E7 oncoproteins in HPV-induced malignancies at diverse anatomical sites. Cancers (8);95.
  26. Johnson, D.E. et al. (2020) Head and neck squamous cell carcinoma. Nat Rev Dis Primers. (6);92.
  27. The Cancer Genome Atlas Network [TCGA]. (2015) Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature (517) 576-82.
  28. Beck, T.N. et al. (2016) EGFR and RB1 as Dual Biomarkers in HPV-Negative Head and Neck Cancer. Mol Cancer Ther. 15(10);2486-97.
  29. Schreiber, R.D. et al. (2011) Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331;1565-70.
  30. Skeate, J.G., et al. (2016) Current therapeutic vaccination and immunotherapy strategies for HPV-related diseases. Hum Vaccin Immunother. (12);1418-29.
  31. Seiwert, T.Y. et al. (2016) Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol. (17);956-65.
  32. Dr. Nishant Agrawal, Chief of Otolaryngology-Head & Neck Surgery UChicago Medicine. Personal interview on 3/25/22.
  33. https:\\ascopost.com\\issues\\april-25-2017\\deintensifiying-treatment-of-hpv-positive-oropharyngeal-cancer-could-reduce-toxicity-while-maintaining-function-and-survival

Sysmex Inostics & QIAGEN Highlight Cancer Companion Diagnostics Alliance at ASCO 2022

Two poster presentations utilizing Sysmex Inostics technology to be featured

Baltimore, MD, June 2, 2022 – Sysmex Inostics, Inc. and QIAGEN N.V. will co-exhibit at the 2022 ASCO Annual Meeting, the world’s largest clinical cancer research meeting, held June 3, 2022, through June 7, 2022, in Chicago.

QIAGEN, the leading global provider of sample to insight solutions for molecular testing, and Sysmex Inostics combined forces in July 2021 to accelerate global companion diagnostic access. QIAGEN provides unparalleled global custom cancer companion diagnostics (CDx) development and commercialization capabilities utilizing Sysmex Inostics ultra-sensitive NGS liquid biopsy technology. The goal of the alliance is to promote early clinical implementation of Sysmex Inostics’ technology to expedite clinical trial timelines for pharmaceutical companies that develop molecularly targeted drugs for cancer.

“Sysmex Inostics is focused on developing tools to support the fight against cancer and other devastating diseases. By partnering with industry leaders like QIAGEN we can help accelerate the fight to help patients with these diseases,” said Shinichi Sato, CEO of Sysmex Inostics, Inc. “We look forward to highlighting our partnership with QIAGEN at ASCO 2022.”

“Through our partnership with Sysmex, we can develop ultrasensitive blood-based NGS panels to the specific requirements of our pharma partners for their clinical trials,” stated Jonathan Arnold, Vice President, Head of Oncology and Precision Diagnostics of QIAGEN. Arnold added, “If and when a CDx is required, QIAGEN will lead IVD submission, manufacturing, and global commercialization as a kitted product.”

Sysmex and QIAGEN will highlight their alliance at ASCO booth 8149, Saturday, June 4, 2022, through Monday, June 6, 2022, 9:00 AM – 5:00 PM CDT each day.

Poster Presentations Utilizing Sysmex Inostics’ Technology
Yoshinori Kagawa MD, PhD, Department of Gastroenterological Surgery, Osaka General Medical Center, Osaka, Japan, will present the poster “Plasma RAS dynamics and anti-EGFR rechallenge efficacy in patients with RAS/BRAF wild-type metastatic colorectal cancer: REMARRY and PURSUIT trials.” Circulating tumor DNA (ctDNA) was analyzed and monitored using the Sysmex Inostics OncoBEAMTM RAS CRC Kit. Dr. Kagawa will present poster 3518 during the Gastrointestinal Cancer—Colorectal and Anal session on Saturday, June 4, 2022, 3:00 PM-4:30 PM CDT.

Linda (Yilin) Cao, MD, Department of Radiation Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, will present the poster “Dynamic cell free HPV DNA is an early measure of treatment responsiveness in patients receiving induction chemotherapy for HPV-related head and neck cancer.” Findings add to the breadth of ongoing clinical studies using HPV-SEQ to investigate de-escalation of HPV-positive patients from unnecessary and potentially harmful head and neck squamous cell carcinomas (HNSCC) treatments. HPV-SEQ is an ultrasensitive test for the detection of HPV16/18 DNA from blood and is CLIA validated to detect as few as five HPV DNA molecules from two tubes of blood.1 See here for additional study information. Dr. Cao will present poster 6062 during the Head and Neck Cancer session on Monday, June 6, 2022, 1:15 PM- 4:15 PM CDT.

Posters will be available after each presentation here:
Plasma RAS dynamics and anti-EGFR rechallenge efficacy
Dynamic cell free HPV DNA is an early measure of treatment responsiveness

About QIAGEN
QIAGEN N.V., a Netherlands-based holding company, is the leading global provider of Sample to Insight solutions that enable customers to gain valuable molecular insights from samples containing the building blocks of life. Our sample technologies isolate and process DNA, RNA and proteins from blood, tissue and other materials. Assay technologies make these biomolecules visible and ready for analysis. Bioinformatics software and knowledge bases interpret data to report relevant, actionable insights. Automation solutions tie these together in seamless and cost-effective workflows. QIAGEN provides solutions to more than 500,000 customers around the world in Molecular Diagnostics (human healthcare), Applied Testing (primarily forensics), Pharma (pharma and biotech companies) and Academia (life sciences research). As of March 31, 2022, QIAGEN employed more than 6,000 people in over 35 locations worldwide. Further information can be found at http://www.qiagen.com.

About Sysmex Inostics
Sysmex Inostics, Inc., a US-based Sysmex Corporation subsidiary, empowers discoveries in oncology by providing investigators ultra-sensitive quantitative liquid biopsy solutions.

Developed by experts at Johns Hopkins with the philosophy of “no molecule left behind,” these technologies are optimized to ensure the detection of low-frequency mutant molecules (0.03%-0.05% MAF) with a high degree of specificity. Focused and flexible genomic coverage allows for superior sensitivity and reduced costs.

As forerunners of blood-based circulating tumor DNA (ctDNA) mutation detection, Sysmex Inostics has provided custom assays and CLIA-certified lab services to leading BioPharma companies over the last ten years to help monitor progression, identify targetable resistance alterations, and detect MRD throughout the clinical trial process.

Sysmex Inostics offers a portfolio of highly sensitive NGS panels through its CLIA-certified laboratory in Baltimore, Maryland.

For more information, refer to www.sysmex-inostics.com or email info@sysmex-inostics.com.

Contact:
Tracy Vandenbroek
Senior Director, Marketing & Strategy
Sysmex Inostics
+1.512.791.2899
vandenbroek.tracy@sysmex-inostics.com

Reference

  1. Internal validation data on file, Sysmex Inostics 2022

New Ultra-Sensitive Leukemia Blood Test Delivered by Sysmex Inostics

New Tool for Detection of Minimal Residual Disease in Acute Myeloid Leukemia to Better Help in Fight Against Cancer

Baltimore, MD, October 20, 2021 – Sysmex Inostics has developed a new CLIA-validated liquid biopsy test for the detection of Minimal Residual Disease (MRD) in Acute Myeloid Leukemia (AML). A global leader and pioneer in blood-based, ultra-sensitive molecular testing for oncology, the company’s new test uses a targeted Next Generation Sequencing (NGS) panel.

“The new test, AML-MRD-SEQ, offers clinical trial sponsors, and eventually physicians and patients, an early signal for the presence of cancer cells following initial therapy. This new liquid biopsy solution is a major step in developing treatment strategies to support the fight against a devastating disease,” said Shinichi Sato, CEO of Sysmex Inostics, Inc.

This new test, AML-MRD-SEQ, adds to the portfolio of ultra-sensitive Plasma-Safe-SeqS technology NGS tests available through Sysmex Inostics’ CLIA lab services in Baltimore, Maryland.

Previous generations of AML MRD tests were only able to detect a limited number of mutations that have an established therapeutic indication. AML-MRD-SEQ offers a more expansive panel covering 68 regions across 20 genes, including established MRD markers such as NPM1, and demonstrating significant potential for use as an investigational tool for other markers with prognostic values that are not yet well-established. The new highly sensitive AML-MRD-SEQ test with broader genomic coverage offers the opportunity for early intervention and clinical trial enrollment.

“Sysmex Inostics’ mission is to develop new innovative tools and expand partnerships with top-tier global biopharmaceutical companies to further advance drug development and treatments for the benefit of oncology patients worldwide,” Sato concluded.

AML-MRD-SEQ offers reliable detection of molecular MRD with 50 to 100 times greater sensitivity versus other currently available NGS pan-heme tests.1,2 Such ultra-sensitive detection of low-level mutant molecules allows clinical trial sponsors to execute on clinical development timelines more efficiently.

AML is one of the deadliest blood cancers, resulting in more than 10,000 lives lost in the U.S. each year.3 Because AML relapses usually result in a poor prognosis, it is necessary to test patients for MRD after initial treatment as a prognostic indicator of therapeutic effectiveness and relapse risk. Applying Sysmex Inostics’ ultra-sensitive liquid biopsy NGS technology, Plasma-Safe-SeqS, to the detection of gene mutations associated with AML MRD enables accelerated clinical development timelines, cost savings, and improved outcomes throughout the clinical trial process.

A recent market research report states that the liquid biopsy market is estimated to achieve an annual growth rate of more than 35% over the next few years, reaching $4 billion by 2024.4 The analysis notes that an increasing focus on personalized medicine for cancer care is driving the tremendous growth.

About Sysmex Inostics
Sysmex Inostics, Inc., a US-based Sysmex Corporation subsidiary, empowers discoveries in oncology by providing investigators cost-effective and ultra-sensitive quantitative liquid biopsy solutions.

Developed by experts at Johns Hopkins with the philosophy of “no molecule left behind,” these technologies are optimized to ensure the detection of low-frequency mutant molecules (<0.05% MAF) with a high degree of specificity. Focused and flexible genomic coverage allows for superior sensitivity and reduced costs.

As pioneers in blood-based circulating tumor DNA (ctDNA) mutation detection, Sysmex Inostics has provided custom assays and CLIA-certified lab services to leading BioPharma companies over the last ten years to help monitor progression, identify targetable resistance alterations, and detect MRD throughout the clinical trial process.

In July 2021, Sysmex Corporation announced a global strategic alliance with QIAGEN to provide custom cancer companion diagnostics (CDx) utilizing Plasma-Safe-SeqS technology. The alliance is intended to promote early clinical implementation of Sysmex Inostic’s technology to expedite clinical trial timelines for pharmaceutical companies that develop molecularly targeted drugs for cancer.

Sysmex Inostics offers a portfolio of highly sensitive NGS panels through its CLIA-certified laboratory in Baltimore, Maryland.

For more information, refer to www.sysmex-inostics.com or email info@sysmex-inostics.com.

Contact:
Tracy Vandenbroek
Director, Marketing
Sysmex Inostics
+1.512.791.2899
vandenbroek.tracy@sysmex-inostics.com

References:

  1. https://www.illumina.com/content/dam/illumina-marketing/documents/products/datasheets/datasheet-trusight-myeloid.pdf
  2. https://assets.ctfassets.net/w98cd481qyp0/42r1cTE8VR4137CaHrsaen/baf91080cb3d78a52ada10c6358fa130/FoundationOne_Heme_Technical_Specifications.pdf
  3. https://www.cancer.net/cancer-types/leukemia-acute-myeloid-aml/statistics
  4. Global Liquid Biopsy Market 2020-2024 (Sept. 2020) https://www.cancer.net/cancer-types/leukemia-acute-myeloid-aml/statistics

New ASCO 2021 poster highlights HPV-SEQ test’s ultra-sensitive detection of HPV 16/18 in plasma

Download our new poster, presented at the recent ASCO 2021 Annual Meeting: “Ultra-sensitive detection and quantification of human papillomavirus (HPV) DNA in the plasma of patients with oropharyngeal squamous cell carcinoma (OPSCC) enrolled in the OPTIMA 2 treatment de-escalation trial”.

About HPV-SEQ

As patients with HPV-driven tumors often have a good prognosis, clinical investigators have recently explored new strategies for treatment de-escalation to avoid unnecessary side-effects caused by overtreatment.  Important clinical data for HPV-SEQ was generated while investigating induction chemoimmunotherapy followed by risk/response stratified de-escalated locoregional therapy for patients with HPV+ OPSCC. During the trial, HPV-SEQ was employed to evaluate levels of cfHPV-DNA alongside patients’ radiographic response to therapy to assess the future utility in guiding treatment de-escalation strategies. HPV-SEQ showed robust quantitative detection of HPV 16/18 across a broad dynamic range over five orders of magnitude with low quantitative variability. Importantly, a high correlation was observed between dynamic changes in patients’ cfHPV DNA levels and radiographic responses following induction therapy.