A Novel Postoperative Prognostic Liquid Biopsy: Tumor-Associated cfDNA and Leukocyte Analysis in Oropharyngeal Cancer Surgical Drain Fluid
一种新型术后预后液体活检:口咽癌手术引流液中肿瘤相关 cfDNA 和白细胞分析
基本信息
- 批准号:10678080
- 负责人:
- 金额:$ 3.36万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-05-01 至 2026-04-30
- 项目状态:未结题
- 来源:
- 关键词:AdjuvantAdjuvant TherapyAftercareAlcoholsBenchmarkingBiological AssayBiological MarkersBiopsyCD8-Positive T-LymphocytesCellsCervicalCisplatinClinicalClinical TrialsClinical assessmentsCodeCytometryDNADNA analysisDataDecision MakingDetectionDiseaseDoseEffector CellEnsureEnvironmentEquationExcisionExtranodalFutureGene ExpressionGene FrequencyGoalsHPV-High RiskHPV-negative head and neck cancerHomingHourHuman PapillomavirusImageImmuneImmune Response GenesImmunophenotypingIncidenceIndividualInfiltrationInflammatoryKineticsLacerationLengthLeukocytesLiquid substanceLymphLymphatic SystemMalignant NeoplasmsMeasuresMetastatic Neoplasm to Lymph NodesMicrometastasisMolecularMorbidity - disease rateMutationNeck DissectionNodalOperative Surgical ProceduresOropharyngeal Squamous Cell CarcinomaPathologicPathologyPatient riskPatient-Focused OutcomesPatientsPatternPlasmaPopulationPostoperative PeriodPrimary NeoplasmProxyQuality of lifeRadiation Dose UnitRecurrenceRecurrent diseaseRegimenResidual NeoplasmRiskRisk AssessmentRisk MarkerSalivaSamplingSignal TransductionSiteSurgical PathologySurvival RateTobaccoTreatment outcomeTreatment-related toxicityTumor stageUrineVariantanti-tumor immune responsecancer cellcancer surgerycandidate selectioncell free DNAchemoradiationclinical diagnosticscomorbiditydigitalexome sequencinggenetic varianthigh riskhuman papilloma virus oropharyngeal squamous cell carcinomaimprovedleukocyte activationliquid biopsylymph nodesmalignant oropharynx neoplasmminimally invasivemutantneoplastic cellnext generation sequencingnovelpatient stratificationprognosticprospectiverelapse predictionrisk stratificationsalivary assayside effectsuccesstooltraffickingtreatment responsetumortumor DNAtumor microenvironmenttumor-immune system interactionswound bed
项目摘要
PROJECT SUMMARY/ABSTRACT
The incidence of oropharyngeal squamous cell carcinoma (OPC) driven by high-risk (HR) HPV strains
continues to rise. As HPV (+) disease is prognostic for good post-treatment outcomes and arises in relatively
young patients with fewer co-morbidities, clinicians now recognize it as a distinct clinical entity from tobacco-
associated HPV (-) disease. But despite improved survival following surgery and adjuvant chemoradiation
(CRT), many HPV (+) OPC patients suffer prolonged morbidity from severe treatment-associated toxicities.
This has led to many treatment de-intensification clinical trials, which seek to reduce toxic side effects while
maintaining historic survival rates. Ideally, high-risk patients would remain on standard regimens while low to
intermediate-risk patients would receive de-escalated therapy. However, there is a great clinical need for an
objective biomarker of risk to aid the subjective clinical assessments: pre-treatment imaging and postoperative
pathology. Liquid biopsies can offer such objectivity; they quantify cell-free DNA (cfDNA) shed by cancer cells,
called circulating tumor DNA (ctDNA), in biofluids like saliva or plasma. Further, in HPV (+) OPC, cell-free HPV
DNA (cf-HPV) parallels ctDNA as a measure of minimal residual disease (MRD). But plasma and saliva assays
lack sensitivity to detect this cf-HPV MRD after surgery. To this clinical challenge, we offer our novel liquid
biopsy assay of Jackson Pratt (JP) surgical drain fluid (SDF). We believe SDF will be enriched with cf-HPV
compared to plasma because it's more proximal to the primary tumor resection site and to the lymph nodes,
where locoregional micrometastases are seeded. Additionally, because the JP drains also capture lymph fluid
from the lacerated cervical lymphatic system, we also believe the SDF contains informative effector leukocytes
that were in transit to the tumor microenvironments (TMEs) of metastatic nodes and the primary tumor. To
begin to elucidate the prognostic potential of SDF, we have collected paired SDF, plasma, tumor biopsy, and
metastatic lymph node samples. First, using PCR and next-generation sequencing approaches we will quantify
the cf-HPV burden in paired plasma and SDF samples. Then we will compare cf-HPV in each sample type
individually to histopathological markers of risk (extranodal extension and tumor stage) and recurrences. We
will then track tumor-informed variants on ctDNA, isolated from plasma and SDF, to show that ctDNA levels
align with cf-HPV and further validate that cf-HPV is a good proxy for MRD. Lastly, we will use digital cytometry
tools and mass cytometry to immunophenotype the immune cells within the SDF to determine if they reflect
immune response gene expression levels in paired metastatic nodes and tumors. If confirmed, our study has
the potential to demonstrate that tri-biomarker analysis (immune cell, cf-HPV, and ctDNA) in a novel liquid
analyte (SDF) can provide precision risk-stratification to aid subjective clinical diagnostics.
项目概要/摘要
高危 (HR) HPV 毒株导致口咽鳞状细胞癌 (OPC) 的发病率
继续上升。由于 HPV (+) 疾病可预示良好的治疗后结果,并且发生率相对较高
由于年轻患者的合并症较少,临床医生现在将其视为与烟草不同的临床实体。
相关 HPV (-) 疾病。但尽管手术和辅助放化疗后生存率有所提高
(CRT),许多 HPV (+) OPC 患者因严重的治疗相关毒性而长期发病。
这导致了许多治疗去强化临床试验,这些试验旨在减少毒副作用,同时
维持历史存活率。理想情况下,高风险患者应继续采用标准治疗方案,而低风险患者应继续接受标准治疗方案。
中危患者将接受降级治疗。然而,临床上有很大的需求
客观的风险生物标志物有助于主观临床评估:治疗前成像和术后
病理。液体活检可以提供这样的客观性;他们量化癌细胞脱落的游离 DNA (cfDNA),
称为循环肿瘤 DNA (ctDNA),存在于唾液或血浆等生物体液中。此外,在HPV (+) OPC中,无细胞HPV
DNA (cf-HPV) 与 ctDNA 类似,可作为微小残留病 (MRD) 的衡量标准。但血浆和唾液检测
手术后缺乏检测 cf-HPV MRD 的敏感性。针对这一临床挑战,我们提供了新型液体
Jackson Pratt (JP) 手术引流液 (SDF) 的活检分析。我们相信 SDF 将富含 cf-HPV
与血浆相比,因为它更接近原发肿瘤切除部位和淋巴结,
局部微转移的播种处。此外,由于 JP 引流管还捕获淋巴液
来自撕裂的颈部淋巴系统,我们还相信 SDF 含有信息效应白细胞
正在转移至转移淋巴结和原发肿瘤的肿瘤微环境(TME)。到
为了开始阐明 SDF 的预后潜力,我们收集了配对的 SDF、血浆、肿瘤活检和
转移淋巴结样本。首先,我们将使用 PCR 和下一代测序方法来量化
配对血浆和 SDF 样本中的 cf-HPV 负荷。然后我们将比较每个样本类型中的 cf-HPV
分别针对风险(结外扩散和肿瘤分期)和复发的组织病理学标志物。我们
然后将追踪从血浆和 SDF 中分离出的 ctDNA 上的肿瘤相关变异,以显示 ctDNA 水平
与 cf-HPV 保持一致,并进一步验证 cf-HPV 是 MRD 的良好替代指标。最后,我们将使用数字细胞术
工具和质谱流式分析仪对 SDF 内的免疫细胞进行免疫表型分析,以确定它们是否反映
配对转移淋巴结和肿瘤中的免疫反应基因表达水平。如果得到证实,我们的研究
证明新型液体中的三生物标志物分析(免疫细胞、cf-HPV 和 ctDNA)的潜力
分析物 (SDF) 可以提供精确的风险分层,以帮助主观临床诊断。
项目成果
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