Clonal hematopoiesis and therapy-emergent myeloid neoplasms in patients with ovarian cancer

摘要 大多数被诊断患有卵巢癌的女性都接受了多轮化疗， 通常需要数年的口服PARP抑制剂药物进行“维持”治疗。这些疗法已 延长了转移性卵巢癌妇女的生命，但代价是增加了毒性。 一种长期毒性是白血病或其他血液疾病的发展，通常被称为 治疗相关性髓样瘤形成（TMN）。这些继发性恶性肿瘤是已知的风险， 化疗，卵巢癌幸存者有一个最高的利率TMN的任何组 癌症幸存者。TMN的诊断通常是致命的，生存时间以月为单位。 TMN在癌前状态几乎总是可检测到的，作为血细胞的克隆扩增 在临床诊断前几年。白色血细胞的非恶性克隆性扩增通常 克隆性造血（ClonalHematopoiesis of Indeterminate Potential，CHIP）。CHIP和 血液癌症的发展是多年，提供了一个机会，以更好地了解 TMN的自然发展，可能是干预和预防的窗口。克隆 造血（CH）也可以在正常衰老过程中出现，但只有一小部分进展到 血癌更好地了解CH在卵巢癌中的自然进展 需要幸存者量身定制安全有效的卵巢癌治疗方法。我们的团队由 卵巢癌遗传学和血液恶性肿瘤专家，将招收2000名 全国各地的卵巢癌幸存者，包括200名CH。我们将跟踪这些 每6个月进行一次连续抽血至少3年的CH患者， 定义CH进展为TMN的风险因素。对于获得以下疾病的患者子集， 在研究过程中，我们将评估克隆动态和遗传和染色体 随着时间的推移，在单细胞水平上的变化，这将提供新的数据的变化， 发生在响应细胞毒性治疗的骨髓细胞的恶性转化中。在这 通过这种方式，我们将了解谁处于TMN的风险之中，并制定监控策略， 预防这种致命的长期治疗毒性。这些研究将改善 卵巢癌患者，也将适用于幸存者或许多癌症类型， TMN也有风险。

ABSTRACT Most women diagnosed with ovarian cancer are treated with many rounds of chemotherapy and often years of a an oral PARP inhibitor drug for “maintenance” therapy. These therapies have extended life for women with metastatic ovarian cancer, but at the cost of increased toxicity. One long term toxicity is the development of leukemia or other blood disorders, often called therapy related myeloid neoplasia (TMN). These secondary malignancies are a known risk of chemotherapy, and ovarian cancer survivors have one of the highest rates of TMN of any group of cancer survivors. The diagnosis of TMN is usually fatal, with survival measured in months. TMN is nearly always detectable in a pre-malignant state as a clonal expansion of blood cells years before a clinical diagnosis. Non-malignant clonal expansion of white blood cells is often termed clonal hematopoiesis of indeterminate potential (CHIP). The interval between CHIP and development of blood cancers is many years, providing an opportunity to better understand the natural progression of TMN and perhaps a window for intervention and prevention. Clonal hematopoiesis (CH) can also arise during normal aging, but only a small fraction progress to a blood cancer. A better understanding of the natural progression of CH in ovarian cancer survivors is needed to tailor safe and effective ovarian cancer therapies. Our team is co-led by experts in ovarian cancer genetics and hematological malignancies and will enroll 2000 survivors across the country with ovarian cancer, including 200 with CH. We will follow these individuals with CH with serial blood draws obtained every 6 months for at least 3 years to define risk factors for progression of CH to TMN. For a subset of patients with acquisition of TMN during the study, we will evaluate clonal dynamics and genetic and chromosomal alterations over time at the single cell level, which will provide novel data on the changes that occur in the malignant transformation of myeloid cells in response to cytotoxic therapy. In this way, we will learn who is at risk of TMN and develop strategies for the monitoring and prevention of this deadly long-term treatment toxicity. These studies will improve outcomes for patients with ovarian cancer and also will be applicable to survivors or many cancer types, who are also at risk for TMN.