Abstract

Background

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.

Methods

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.

Results

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.

Conclusion

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.

中文翻译：

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特殊响应者倡议：国家癌症研究所试点研究的可行性。

摘要

背景

对全身治疗反应异常的患者的肿瘤分子谱分析可能会提供对癌症生物学的见解并改进治疗方案。这项试点研究评估了回顾性识别异常反应者的可行性，获得异常反应治疗前的肿瘤组织，并使用最先进的分子分析工具对其进行分析，以确定反应的潜在分子解释。

方法

异常反应被定义为对全身治疗的部分（PR）或完全（CR）反应，人群PR或CR率低于10％或异常长的反应（例如，持续时间> 3倍公布的中位数）。患者临床医生提出的病例由临床和转化专家审查。肿瘤和正常组织（如果可能）通过全外显子组测序进行分析，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织化学。跟踪潜在的种系突变与疾病的相关性。

结果

病例反映了各种肿瘤以及标准和研究性治疗。在 520 例中，476 例（91.5%）被接受进一步审查，476 例中的 222 例（46.6%）符合特殊响应者的要求。临床数据来自 222 例中的 168 例 (75.7%)。168 例中的 130 例 (77.4%) 提供了肿瘤。在 130 例（90.0%）核酸充足的病例中，117 例（90.0%）成功分析了 109 例（93.2%）；6 名患者有潜在可操作的种系突变。

结论

标准和研究性治疗会出现异常反应。对特殊反应者的回顾性鉴定、加入和预处理存档组织的测序是可行的。来自肿瘤分子分析的数据，特别是结合接受类似治疗的患者的结果时，可能会阐明特殊反应的分子基础。