Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA.
Center for Cancer Genomics, National Cancer Institute, Bethesda, MD, USA.
J Natl Cancer Inst. 2021 Jan 4;113(1):27-37. doi: 10.1093/jnci/djaa061.
Tumor molecular profiling from patients experiencing exceptional responses to systemic therapy may provide insights into cancer biology and improve treatment tailoring. This pilot study evaluates the feasibility of identifying exceptional responders retrospectively, obtaining pre-exceptional response treatment tumor tissues, and analyzing them with state-of-the-art molecular analysis tools to identify potential molecular explanations for responses.
Exceptional response was defined as partial (PR) or complete (CR) response to a systemic treatment with population PR or CR rate less than 10% or an unusually long response (eg, duration >3 times published median). Cases proposed by patients' clinicians were reviewed by clinical and translational experts. Tumor and normal tissue (if possible) were profiled with whole exome sequencing and, if possible, targeted deep sequencing, RNA sequencing, methylation arrays, and immunohistochemistry. Potential germline mutations were tracked for relevance to disease.
Cases reflected a variety of tumors and standard and investigational treatments. Of 520 cases, 476 (91.5%) were accepted for further review, and 222 of 476 (46.6%) proposed cases met requirements as exceptional responders. Clinical data were obtained from 168 of 222 cases (75.7%). Tumor was provided from 130 of 168 cases (77.4%). Of 117 of the 130 (90.0%) cases with sufficient nucleic acids, 109 (93.2%) were successfully analyzed; 6 patients had potentially actionable germline mutations.
Exceptional responses occur with standard and investigational treatment. Retrospective identification of exceptional responders, accessioning, and sequencing of pretreatment archived tissue is feasible. Data from molecular analyses of tumors, particularly when combining results from patients who received similar treatments, may elucidate molecular bases for exceptional responses.
从对全身治疗有显著反应的患者中获取肿瘤分子谱，可能有助于了解癌症生物学并改善治疗方案。本研究旨在评估通过回顾性识别、获取治疗前肿瘤组织，并利用最先进的分子分析工具进行分析，从而识别潜在分子解释反应的可能性。
将显著缓解定义为全身治疗后部分缓解（PR）或完全缓解（CR），其中人群缓解率低于 10%或缓解时间异常长（如，持续时间> 3 倍于发表的中位数）。由患者的临床医生提出的病例由临床和转化专家进行审查。对肿瘤和正常组织（如果可能）进行全外显子组测序，如果可能，还进行靶向深度测序、RNA 测序、甲基化阵列和免疫组化分析。对潜在的种系突变进行相关性分析，以确定其与疾病的关系。
所纳入的病例反映了各种肿瘤和标准及研究性治疗。在 520 例病例中，476 例（91.5%）接受进一步审查，其中 222 例（46.6%）符合显著缓解标准。168 例（75.7%）病例获得了临床数据，130 例（77.4%）提供了肿瘤组织。在 117 例（93.2%）有足够核酸的病例中，有 109 例（93.2%）成功进行了分析；6 例患者存在潜在可治疗的种系突变。
标准和研究性治疗均可出现显著缓解。回顾性识别、获取和测序治疗前的存档组织是可行的。对肿瘤进行分子分析的数据，特别是当将接受类似治疗的患者的结果结合起来时，可能阐明显著缓解的分子基础。
