Bettegowda Chetan, Sausen Mark, Leary Rebecca J, Kinde Isaac, Wang Yuxuan, Agrawal Nishant, Bartlett Bjarne R, Wang Hao, Luber Brandon, Alani Rhoda M, Antonarakis Emmanuel S, Azad Nilofer S, Bardelli Alberto, Brem Henry, Cameron John L, Lee Clarence C, Fecher Leslie A, Gallia Gary L, Gibbs Peter, Le Dung, Giuntoli Robert L, Goggins Michael, Hogarty Michael D, Holdhoff Matthias, Hong Seung-Mo, Jiao Yuchen, Juhl Hartmut H, Kim Jenny J, Siravegna Giulia, Laheru Daniel A, Lauricella Calogero, Lim Michael, Lipson Evan J, Marie Suely Kazue Nagahashi, Netto George J, Oliner Kelly S, Olivi Alessandro, Olsson Louise, Riggins Gregory J, Sartore-Bianchi Andrea, Schmidt Kerstin, Shih le-Ming, Oba-Shinjo Sueli Mieko, Siena Salvatore, Theodorescu Dan, Tie Jeanne, Harkins Timothy T, Veronese Silvio, Wang Tian-Li, Weingart Jon D, Wolfgang Christopher L, Wood Laura D, Xing Dongmei, Hruban Ralph H, Wu Jian, Allen Peter J, Schmidt C Max, Choti Michael A, Velculescu Victor E, Kinzler Kenneth W, Vogelstein Bert, Papadopoulos Nickolas, Diaz Luis A
Ludwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA.
Sci Transl Med. 2014 Feb 19;6(224):224ra24. doi: 10.1126/scitranslmed.3007094.
The development of noninvasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital polymerase chain reaction-based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. We found that ctDNA was detectable in >75% of patients with advanced pancreatic, ovarian, colorectal, bladder, gastroesophageal, breast, melanoma, hepatocellular, and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. In patients with localized tumors, ctDNA was detected in 73, 57, 48, and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively. ctDNA was often present in patients without detectable circulating tumor cells, suggesting that these two biomarkers are distinct entities. In a separate panel of 206 patients with metastatic colorectal cancers, we showed that the sensitivity of ctDNA for detection of clinically relevant KRAS gene mutations was 87.2% and its specificity was 99.2%. Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor blockade in 24 patients who objectively responded to therapy but subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase pathway. Together, these data suggest that ctDNA is a broadly applicable, sensitive, and specific biomarker that can be used for a variety of clinical and research purposes in patients with multiple different types of cancer.
开发用于检测和监测肿瘤的非侵入性方法仍然是肿瘤学中的一项重大挑战。我们使用基于数字聚合酶链反应的技术来评估循环肿瘤DNA（ctDNA）在640例患有各种癌症类型的患者中检测肿瘤的能力。我们发现，在晚期胰腺癌、卵巢癌、结直肠癌、膀胱癌、胃食管癌、乳腺癌、黑色素瘤、肝细胞癌和头颈癌患者中，超过75%的患者可检测到ctDNA，但在原发性脑癌、肾癌、前列腺癌或甲状腺癌患者中，这一比例不到50%。在患有局限性肿瘤的患者中，分别有73%、57%、48%和50%的结直肠癌、胃食管癌、胰腺癌和乳腺腺癌患者检测到ctDNA。ctDNA经常出现在没有可检测到的循环肿瘤细胞的患者中，这表明这两种生物标志物是不同的实体。在另一组206例转移性结直肠癌患者中，我们表明ctDNA检测临床相关KRAS基因突变的敏感性为87.2%，特异性为99.2%。最后，我们评估了ctDNA是否能为24例对治疗有客观反应但随后复发的患者提供有关表皮生长因子受体阻断耐药机制的线索。这些患者中有23例（96%）在丝裂原活化蛋白激酶途径相关基因中发生了一个或多个突变。总之，这些数据表明ctDNA是一种广泛适用、敏感且特异的生物标志物，可用于多种不同类型癌症患者的各种临床和研究目的。
