Circulating tumor DNA in neoadjuvant-treated breast cancer reflects response and survival

作者：Mark Jesus M. Magbanua, Lamorna Brown Swigart, H.-T. Wu, Gillian L. Hirst, Christina Yau, Denise M. Wolf, Aung Soe Tin, Raheleh Salari, Svetlana Shchegrova, H. Pawar, Amy L. Delson, Angela DeMichele, M.C. Liu, A. Jo Chien, Debu Tripathy, Smita Asare, C-HJ Lin, Paul R. Billings, Alexey Aleshin, Himanshu Sethi, Maggie C. Louie, Bernhard Zimmermann, Laura J. Esserman, Laura van ‘t Veer · 发表于：Annals of Oncology · 年份：2020 · DOI：10.1016/j.annonc.2020.11.007 · 被引用次数：463 · 研究领域：Cancer Genomics and Diagnostics、Breast Cancer Treatment Studies、Cancer Cells and Metastasis

BACKGROUND: Pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) is strongly associated with favorable outcome. We examined the utility of serial circulating tumor DNA (ctDNA) testing for predicting pCR and risk of metastatic recurrence. PATIENTS AND METHODS: Cell-free DNA (cfDNA) was isolated from 291 plasma samples of 84 high-risk early breast cancer patients treated in the neoadjuvant I-SPY 2 TRIAL with standard NAC alone or combined with MK-2206 (AKT inhibitor) treatment. Blood was collected at pretreatment (T0), 3 weeks after initiation of paclitaxel (T1), between paclitaxel and anthracycline regimens (T2), or prior to surgery (T3). A personalized ctDNA test was designed to detect up to 16 patient-specific mutations (from whole-exome sequencing of pretreatment tumor) in cfDNA by ultra-deep sequencing. The median follow-up time for survival analysis was 4.8 years. RESULTS: At T0, 61 of 84 (73%) patients were ctDNA positive, which decreased over time (T1: 35%; T2: 14%; and T3: 9%). Patients who remained ctDNA positive at T1 were significantly more likely to have residual disease after NAC (83% non-pCR) compared with those who cleared ctDNA (52% non-pCR; odds ratio 4.33, P = 0.012). After NAC, all patients who achieved pCR were ctDNA negative (n = 17, 100%). For those who did not achieve pCR (n = 43), ctDNA-positive patients (14%) had a significantly increased risk of metastatic recurrence [hazard ratio (HR) 10.4; 95% confidence interval (CI) 2.3-46.6]; inte...