Dabbs David, Mittal Karuna, Heineman Scott, Whitworth Pat, Shah Chirag, Savala Jess, Shivers Steven C, Bremer Troy
PreludeDx, Laguna Hills, CA, United States.
University of Tennessee, Knoxville, TN, United States.
Front Oncol. 2023 May 19;13:1069059. doi: 10.3389/fonc.2023.1069059. eCollection 2023.
Ductal carcinoma (DCIS), is a noninvasive breast cancer, representing 20-25% of breast cancer diagnoses in the USA. Current treatment options for DCIS include mastectomy or breast-conserving surgery (BCS) with or without radiation therapy (RT), but optimal risk-adjusted treatment selection remains a challenge. Findings from past and recent clinical trials have failed to identify a 'low risk' group of patients who do not benefit significantly from RT after BCS. To address this unmet need, a DCIS biosignature, DCISionRT (PreludeDx, Laguna Hills, CA), was developed and validated in multiple cohorts. DCISionRT is a molecular assay with an algorithm reporting a recurrence risk score for patients diagnosed with DCIS intended to guide DCIS treatment. In this study, we present results from analytical validity, performance assessment, and clinical performance validation and clinical utility for the DCISionRT test comprised of multianalyte assays with algorithmic analysis.
The analytical validation of each molecular assay was performed based on the Clinical and Laboratory Standards Institute (CLSI) guidelines Quality Assurance for Design Control and Implementation of Immunohistochemistry Assays and the College of American Pathologists/American Society of Clinical Oncology (CAP/ASCO) recommendations for analytic validation of immunohistochemical assays.
The analytic validation showed that the molecular assays that are part of DCISionRT test have high sensitivity, specificity, and accuracy/reproducibility (≥95%). The analytic precision of the molecular assays under controlled non-standard conditions had a total standard deviation of 6.6 (100-point scale), where the analytic variables (Lot, Machine, Run) each contributed <1% of the total variance. Additionally, the precision in the DCISionRT test result (DS) had a 95%CI ≤0.4 DS units under controlled non-standard conditions (Day, Lot, and Machine) for molecular assays over a wide range of clinicopathologic factor values. Clinical validation showed that the test identified 37% of patients in a low-risk group with a 10-year invasive IBR rate of ~3% and an absolute risk reduction (ARR) from RT of 1% (number needed to treat, NNT=100), while remaining patients with higher DS scores (elevated-risk) had an ARR for RT of 9% (NNT=11) and 96% clinical sensitivity for RT benefit.
The analytical performance of the PreludeDx DCISionRT molecular assays was high in representative formalin-fixed, paraffin-embedded breast tumor specimens. The DCISionRT test has been analytically validated and has been clinically validated in multiple peer-reviewed published studies.
导管原位癌（DCIS）是一种非侵袭性乳腺癌，在美国乳腺癌诊断病例中占20%-25%。DCIS目前的治疗选择包括乳房切除术或保乳手术（BCS），可联合或不联合放射治疗（RT），但最佳的风险调整治疗选择仍然是一项挑战。过去和近期临床试验的结果未能确定一组“低风险”患者，这些患者在BCS后不会从RT中显著获益。为满足这一未被满足的需求，一种DCIS生物标志物DCISionRT（PreludeDx，加利福尼亚州拉古纳希尔斯）被开发出来，并在多个队列中得到验证。DCISionRT是一种分子检测方法，其算法可为诊断为DCIS的患者报告复发风险评分，旨在指导DCIS的治疗。在本研究中，我们展示了DCISionRT检测的分析有效性、性能评估、临床性能验证及临床实用性的结果，该检测由多分析物检测和算法分析组成。
每项分子检测的分析验证均基于临床和实验室标准协会（CLSI）的指南《免疫组织化学检测的设计、控制和实施的质量保证》以及美国病理学家学会/美国临床肿瘤学会（CAP/ASCO）关于免疫组织化学检测分析验证的建议进行。
分析验证表明，作为DCISionRT检测一部分的分子检测具有高灵敏度、特异性和准确性/可重复性（≥95%）。在受控的非标准条件下，分子检测的分析精密度的总标准差为6.6（100分制），其中分析变量（批次、仪器、运行）各自对总方差的贡献<1%。此外，在广泛的临床病理因素值范围内，在受控的非标准条件（日期、批次和仪器）下，DCISionRT检测结果（DS）的精密度在95%置信区间内≤0.4 DS单位。临床验证表明，该检测在低风险组中识别出37%的患者，其10年侵袭性同侧乳房肿瘤复发率约为3%，RT带来的绝对风险降低（ARR）为1%（需治疗人数，NNT = 100），而其余DS评分较高（高风险）的患者RT的ARR为9%（NNT = 11），且对RT获益的临床敏感性为96%。
在代表性的福尔马林固定、石蜡包埋的乳腺肿瘤标本中，PreludeDx DCISionRT分子检测的分析性能很高。DCISionRT检测已通过分析验证，并在多项同行评审的已发表研究中得到临床验证。
