公元前695年，中国古代四大名医扁鹊见蔡桓公时，疾病早期诊断只能达到腠理水平。现代，疾病早期诊断已经达到分子水平。虽然现有的治疗手段可以治愈大多数早期乳腺癌患者，但是需要更好的检测技术确定哪些患者存在复发风险。肿瘤临床复发之前，可能向血液循环释放微乎其微的脱氧核糖核酸DNA分子，这为监测早期乳腺癌分子水平复发提供了理论基础。
2019年8月1日，《美国医学会杂志》在线发表英国伦敦大学癌症研究院、皇家马斯登医院拉夫劳伦乳腺癌研究中心、欣琴布鲁克医院、普尔综合医院、皇家伯恩茅斯医院、皇家康沃尔医院的研究报告，探讨了利用血液循环肿瘤DNA分析技术检测早期乳腺癌分子水平复发的临床有效性。
该多中心前瞻样本采集验证研究于2011年11月24日～2016年10月18日从5个英国医疗中心入组无论激素受体和HER2状态如何的早期乳腺癌患者170例（术前新辅助化疗140例、术后辅助化疗30例），对原发肿瘤进行测序以确定体细胞突变，并采用个体化肿瘤特异性数字化聚合酶链反应法，监测第一年每3个月、随后每6个月连续采集的血浆样本突变，其中101例突变患者（平均年龄：54±11岁）组成主要队列，并与既往理论验证研究已被分析的43例患者组成144例患者联合队列进行二次分析。主要终点为无复发生存，通过多因素比例风险回归模型进行分析。
结果，主要队列中位随访35.5个月（四分位：27.9～43.0个月）期间，检出与未检出血液循环肿瘤DNA的患者相比，复发风险高25.2倍（95%置信区间：6.7～95.6，P<0.001）。诊断时、任何治疗前，检出与未检出血液循环肿瘤DNA的患者相比，复发风险高5.8倍（95%置信区间：1.2～27.1，P=0.01）。
联合队列检出血液循环肿瘤DNA至临床复发中位10.7个月（95%置信区间：8.1～19.1个月）并与所有乳腺癌亚型复发相关。远处颅外转移复发患者23例，其中22例（96%）检出血液循环肿瘤DNA。仅脑转移患者6例，其中1例（17%）检出血液循环肿瘤DNA，表明该复发部位不易被血液循环肿瘤DNA分析检出，可能需要其他监测手段。
因此，该研究结果表明，早期乳腺癌术后随访期间检出血液循环肿瘤DNA与将来复发高风险相关，临床有效性较高，故有必要开展前瞻研究对分子水平复发检测指导术后辅助治疗的潜力进行评定，而非等到无法治愈的临床转移发生以后才开始治疗。
对此，美国霍普金斯大学医学院西德尼金梅尔综合癌症中心、范德堡大学医学中心英格拉姆癌症中心发表特邀评论：血液循环肿瘤DNA作为早期乳腺癌疾病复发的标志——坏血液。
JAMA Oncol. 2019 Aug 1. [Epub ahead of print]
Assessment of Molecular Relapse Detection in Early-Stage Breast Cancer.
Isaac Garcia-Murillas, Neha Chopra, Inaki Comino-Méndez, Matthew Beaney, Holly Tovey, Rosalind J. Cutts, Claire Swift, Divya Kriplani, Maria Afentakis, Sarah Hrebien, Giselle Walsh-Crestani, Peter Barry, Stephen R. D. Johnston, Alistair Ring, Judith Bliss, Simon Russell, Abigail Evans, Anthony Skene, Duncan Wheatley, Mitch Dowsett, Ian E. Smith, Nicholas C. Turner.
The Institute of Cancer Research, London, UK; Ralph Lauren Centre for Breast Cancer Research, London, UK; Royal Marsden Hospital, London, UK; Hinchingbrooke Hospital, Huntingdon, UK; Poole General Hospital, Dorset, UK; Royal Bournemouth Hospital, Bournemouth, UK; Royal Cornwall Hospitals National Health Service Trust, Truro, UK.
This validation study assesses the clinical validity of molecular relapse detection with circulating tumor DNA analysis in early-stage breast cancer.
QUESTION: What is the clinical validity of molecular relapse detection with circulating tumor DNA analysis in early-stage breast cancer?
FINDINGS: This independent, prospective, multicenter, validation study of 101 women early-stage breast cancer assessed circulating tumor DNA mutation tracking and found that detection of circulating tumor DNA during follow-up had a median lead time of 10.7 months compared with clinical relapse, anticipating relapse in all major breast cancer subtypes. Brain-only metastasis was detected less frequently by circulating tumor DNA analysis, potentially requiring alternative surveillance.
MEANING: The findings suggest that molecular relapse detection has high levels of clinical validity, and clinical trials of treatment initiated at molecular relapse without waiting for incurable metastatic disease to develop are needed.
IMPORTANCE: Current treatment cures most cases of early-stage, primary breast cancer. However, better techniques are required to identify which patients are at risk of relapse.
OBJECTIVE: To assess the clinical validity of molecular relapse detection with circulating tumor DNA (ctDNA) analysis in early-stage breast cancer.
DESIGN, SETTING, AND PARTICIPANTS: This prospective, multicenter, sample collection, validation study conducted at 5 United Kingdom medical centers from November 24, 2011, to October 18, 2016, assessed patients with early-stage breast cancer irrespective of hormone receptor and ERBB2 (formerly HER2 or HER2/neu) status who were receiving neoadjuvant chemotherapy followed by surgery or surgery before adjuvant chemotherapy. The study recruited 170 women, with mutations identified in 101 patients forming the main cohort. Secondary analyses were conducted on a combined cohort of 144 patients, including 43 patients previously analyzed in a proof of principle study.
INTERVENTIONS: Primary tumor was sequenced to identify somatic mutations, and personalized tumor-specific digital polymerase chain reaction assays were used to monitor these mutations in serial plasma samples taken every 3 months for the first year of follow-up and subsequently every 6 months.
MAIN OUTCOMES AND MEASURES: The primary end point was relapse-free survival analyzed with Cox proportional hazards regression models.
RESULTS: In the main cohort of 101 female patients (mean [SD] age, 54 [11] years) with a median follow-up of 35.5 months (interquartile range, 27.9-43.0 months), detection of ctDNA during follow-up was associated with relapse (hazard ratio, 25.2; 95% CI, 6.7-95.6; P<0.001). Detection of ctDNA at diagnosis, before any treatment, was also associated with relapse-free survival (hazard ratio, 5.8; 95% CI, 1.2-27.1; P=0.01). In the combined cohort, ctDNA detection had a median lead time of 10.7 months (95% CI, 8.1-19.1 months) compared with clinical relapse and was associated with relapse in all breast cancer subtypes. Distant extracranial metastatic relapse was detected by ctDNA in 22 of 23 patients (96%). Brain-only metastasis was less commonly detected by ctDNA (1 of 6 patients [17%]), suggesting relapse sites less readily detectable by ctDNA analysis.
CONCLUSIONS AND RELEVANCE: The findings suggest that detection of ctDNA during follow-up is associated with a high risk of future relapse of early-stage breast cancer. Prospective studies are needed to assess the potential of molecular relapse detection to guide adjuvant therapy.
DOI: 10.1001/jamaoncol.2019.1838
JAMA Oncol. 2019 Aug 1. [Epub ahead of print]
Circulating Tumor DNA as a Marker for Disease Relapse in Early-Stage Breast Cancer—Bad Blood.
Swathi Karthikeyan, Ben Ho Park.
The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
DOI: 10.1001/jamaoncol.2019.2047
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