Molecularly-based outcome and toxicity prediction after radiotherapy for lung cancer

项目概要/摘要 PI：马克西米利安Diehn，医学博士/博士& Ash Alizadeh，医学博士/博士 非小细胞肺癌（NSCLC）是美国最常见的癌症， 癌症相关死亡的原因。放射治疗（RT）在治疗中起着至关重要的作用， 非小细胞肺癌，无论是在治愈和姑息治疗的环境。虽然肿瘤成像和 在过去几十年中的放射递送技术已经显著地改善了RT， 对肿瘤的基因组和分子理解的进展在很大程度上未能影响 因此，“精确放射”的发展， “肿瘤学”的方法，定义为使用分子生物标志物来个性化RT，仍然是一种 未满足的重大需求。此外，预测哪些患者会出现RT诱导的毒性仍然是一个难题。 这是一个挑战，并防止在症状出现之前进行早期干预。 我们的长期目标是开发新的、基于分子的精确放射肿瘤学 我们的中心假设是，新的生物标志物， ctDNA和基因图谱分析可用于早期预测 治疗结果的影响。我们将通过三个方面来检验我们的假设。 具体目的：（1）建立治疗中期ctDNA变化预测最终疗效的能力 RT治疗局部晚期NSCLC患者的结果，（2）开发新的， 个性化的风险模型，整合分子和临床因素，可以准确预测 复发的风险，和（3）为了检验假设，一种新的液体活检方法，我们有 最近开发的一种新方法可以预测哪些患者会发生有症状的放射性肺炎。 如果成功，我们的项目将导致新的方法来个性化治疗当地先进的 非小细胞肺癌患者接受RT治疗。我们的创新方法，我们将采用基于血液的 开发了肿瘤基因分型、疾病监测和毒性预测的方法 将为旨在降低治疗失败风险的研究奠定基础， 我们设想我们的方法将使未来的试验， 实施分子驱动的精确放射肿瘤学的设计， 复发风险最高的患者的治疗递增，复发风险最低的患者的治疗递减 风险此外，我们的工作将作为一种方法的原理证明， 应用于放射肿瘤学的其他领域。

PROJECT SUMMARY/ABSTRACT PIs: Maximilian Diehn, M.D./Ph.D. & Ash Alizadeh, M.D./Ph.D. Non-small cell lung cancer (NSCLC) is the most common cancer in the U.S. and the number one cause of cancer-related deaths. Radiation therapy (RT) plays a critical role in the treatment of NSCLC, both in the curative and palliative settings. While advances in tumor imaging and radiation delivery techniques over the past several decades have significantly improved RT, advances in genomic and molecular understanding of tumors have largely failed to impact management of patients treated with RT. Therefore, development of “precision radiation oncology” approaches, defined as the use of molecular biomarkers to personalize RT, remains a major unmet need. Additionally, predicting which patients will develop RT-induced toxicity remains a challenge and prevents early intervention prior to onset of symptoms. Our long-term goal is to develop novel, molecularly-based precision radiation oncology approaches for NSCLC patients treated with RT. Our central hypothesis is that novel biomarkers of recurrence risk, such as analysis of ctDNA and genetic profiling, can be used for early prediction of treatment outcomes while a patient is still on therapy. We will test our hypothesis via three specific aims: (1) To establish the ability of mid-treatment ctDNA changes to predict ultimate outcomes in locally advanced NSCLC patients treated with RT, (2) To develop novel, personalized risk models that integrate molecular and clinical factors and can accurately predict the risk of recurrence, and (3) To test the hypothesis that a novel liquid biopsy approach we have recently developed can predict which patients will develop symptomatic radiation pneumonitis. If successful, our project will lead to novel ways to personalize therapy for locally advanced NSCLC patients treated with RT. Our innovative approach, in which we will employ blood-based methods for tumor genotyping, disease monitoring, and toxicity prediction that were developed by our group, will lay the foundation for studies aimed at reducing risk of treatment failure and toxicity in NSCLC patients treated with RT. We envision that our approach will enable future trial designs that implement molecularly-driven precision radiation oncology and will facilitate treatment escalation for patients at highest risk of recurrence and de-escalation for those at lowest risk. Additionally, our work will serve as proof-of-principle for an approach that could also be applied to other areas of radiation oncology.