Novel plasma Human Papillomavirus DNA assay as a predictor of residual disease after chemo-radiotherapy for locally advanced head and neck cancer

我们正在计划一项多中心生物样本收集研究，以验证循环人类乳头瘤病毒（HPV） DNA作为HPV阳性口咽癌潜在治愈治疗后残留疾病的标志物。人乳头瘤病毒（HPV）影响皮肤和粘膜。粘膜是覆盖在身体某些部位（如口腔和喉咙）内部的湿润膜。人乳头瘤病毒感染是非常常见的，已经确定了100多种不同类型的人乳头瘤病毒。虽然HPV会增加患某些类型癌症的风险，但大多数感染HPV的人不会患上癌症。在英国，每年大约有2000名患者被诊断为由HPV感染引起的口咽癌。这类癌症的标准治疗方法是预先化疗，然后手术切除任何残留的癌症。手术是根据18F-FDG PET-CT的扫描结果进行的。然而，在接受手术的患者中，只有20%的患者在显微病理检查中有存活的残留癌。因此，这些患者（每年300人）接受了不必要的外科手术。大约25%接受手术的患者在手术后立即出现严重的并发症，并且所有患者都遭受严重的永久性副作用，如疼痛，肩部功能障碍和生活质量改变。因此，需要一种更可靠的放化疗后残留肿瘤的标志物来指导治疗决策，避免不必要的外科手术。此外，患HPV相关咽喉癌的患者都很年轻（47-65岁）。平均年龄55岁)，并且由于目前治疗方法的良好治疗结果（5年生存率为90%），预计将终生承受治疗相关毒性的负担。口咽癌是由HPV从肿瘤中释放物质（含有HPV DNA）进入血流引起的。血液中存在HPV DNA可以作为残留（剩余）癌症的潜在标记。我们已经开发了一种超敏感和特异性的检测方法“HPV检测”，这是一种非侵入性的方法，可以通过简单的血液测试来测量化疗后的HPV DNA水平，以帮助指导管理决策并避免任何不必要的外科手术。hpv检测测试是由癌症研究所的一组研究人员在一项试点研究中开发和验证的。该初步研究包括测试组和盲法验证组，并证明hpv检测测试具有超过90%的敏感性和特异性。该研究还表明，血浆HPV DNA水平与化疗后的病理反应（即没有活跃的癌细胞存在）相关。目前的提案旨在通过一项大型前瞻性多中心研究来验证该测试在患者护理（临床效用）中的相关性和有用性，以确定其预测残余疾病消失的潜力。为了证明至少85%的特异性，需要招募143名接受化疗的HPV+口咽癌患者和48名HPV阴性患者作为阴性对照。血浆HPV DNA水平将使用HPV检测来测量，并在治疗后12周与18F-FDG PET-CT结果相关联。实验室测试将不包括HPV状态和临床数据。在与伦敦帝国理工学院的新冠病毒诊断证据合作组织合作进行验证研究的同时，我们将研究采用该测试的障碍以及如何解决这些障碍。我们还将进行详细的健康经济分析，以研究在英国医疗保健系统中实施该测试的成本效益。

We are planning a multicentre biological sample collection study to validate circulating human papilloma virus (HPV) DNA as a marker of residual disease following potentially curative treatment in HPV positive oropharyngeal (throat) cancer.Human papilloma virus (or HPV) affects the skin and the mucosa. The mucosa is the moist membrane that lines the inside of certain body parts eg mouth and throat. HPV infection is very common and over 100 different types of HPV have been identified. Although HPV can increase the risk of developing some types of cancer, most people who have HPV won't develop cancer.Approximately 2000 patients are diagnosed with oropharyngeal (throat) cancer caused by HPV infection every year in the UK. The standard treatment for this type of cancer is up-front chemo-radiotherapy followed by surgical removal of any cancer left behind. The surgery is undertaken based on the results of a scan known as an 18F-FDG PET-CT. However, of the patients who undergo surgery, only 20% have viable residual cancer on microscopic pathological examination.Therefore these patients (300 every year) undergo unnecessary surgical procedures. Approximately 25% of patients proceeding to surgery have severe complications immediately after surgery and all of them suffer with significant permanent side effects such as pain, shoulder dysfunction with altered quality of life. Therefore a more reliable marker of presence of residual cancer after chemo-radiotherapy is required to guide management decisions and avoid unnecessary surgical procedures. Furthermore, patients who develop HPV related throat cancer are young (range 47-65 yrs. Average age 55) and due to the excellent treatment outcomes with the current treatments (>90% 5 year survival) are expected to carry the burden of treatment related toxicity for life.Oropharyngeal cancers caused by HPV release material from the tumour (containing the HPV DNA) in to the blood stream. Presence of HPV DNA in the blood stream can serve as a potential marker of the residual (remaining) cancer. We have developed an ultra-sensitive and specific assay 'HPV-detect', which is a non-invasive way to measure the HPV DNA levels after chemo-radiotherapy using a simple blood test to help guide management decisions and avoid any unnecessary surgical procedures.The HPV-detect test was developed and validated in a pilot study carried out by a team of researchers at the Institute of Cancer Research. The pilot study comprised test and blinded validation groups and demonstrated that the HPV-detect test had a sensitivity and specificity in excess of 90%. The research also showed that the plasma HPV DNA levels correlated with the pathological response (ie no active cancer cells present) as assessed following chemo-radiotherapy.The current proposal is designed to validate the relevance and usefulness of the test in patient care (clinical utility) in a large prospective multi-centre study, in order to establish its potential to predict the absence of residual disease.To prove specificity of at least 85% will require the recruitment of 143 HPV+ oropharyngeal cancer patients undergoing chemo-radiotherapy and 48 HPV negative patients as negative controls.Plasma HPV DNA levels will be measured using HPV-detect and at 12 weeks following treatment will be correlated with the 18F-FDG PET-CT results. Laboratory tests will be blinded to HPV status and clinical data. In parallel with the validation study in collaboration with the NHR-Diagnostic Evidence Cooperative at Imperial College London, we will study barriers to adoption of the test and how to address these. We will also undertake a detailed health economic analysis to study the cost benefits of implementing the test in the UK healthcare system.