TBCRC 030 研究中三阴性乳腺癌新辅助化疗后循环肿瘤 DNA 与残留癌负荷的相关性
Circulating tumor DNA association with residual cancer burden after neoadjuvant chemotherapy in triple-negative breast cancer in TBCRC 030.
机构信息
Medical Oncology, Dana-Farber Cancer Institute, Boston; Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston; Harvard Medical School, Boston.
Broad Institute of MIT and Harvard, Cambridge.
出版信息
Ann Oncol. 2023 Oct;34(10):899-906. doi: 10.1016/j.annonc.2023.08.004. Epub 2023 Aug 18.
BACKGROUND
We aimed to examine circulating tumor DNA (ctDNA) and its association with residual cancer burden (RCB) using an ultrasensitive assay in patients with triple-negative breast cancer (TNBC) receiving neoadjuvant chemotherapy.
PATIENTS AND METHODS
We identified responders (RCB 0/1) and matched non-responders (RCB 2/3) from the phase II TBCRC 030 prospective study of neoadjuvant paclitaxel versus cisplatin in TNBC. We collected plasma samples at baseline, 3 weeks and 12 weeks (end of therapy). We created personalized ctDNA assays utilizing MAESTRO mutation enrichment sequencing. We explored associations between ctDNA and RCB status and disease recurrence.
RESULTS
Of 139 patients, 68 had complete samples and no additional neoadjuvant chemotherapy. Twenty-two were responders and 19 of those had sufficient tissue for whole-genome sequencing. We identified an additional 19 non-responders for a matched case-control analysis of 38 patients using a MAESTRO ctDNA assay tracking 319-1000 variants (median 1000 variants) to 114 plasma samples from 3 timepoints. Overall, ctDNA positivity was 100% at baseline, 79% at week 3 and 55% at week 12. Median tumor fraction (TFx) was 3.7 × 10 (range 7.9 × 10-4.9 × 10). TFx decreased 285-fold from baseline to week 3 in responders and 24-fold in non-responders. Week 12 ctDNA clearance correlated with RCB: clearance was observed in 10 of 11 patients with RCB 0, 3 of 8 with RCB 1, 4 of 15 with RCB 2 and 0 of 4 with RCB 3. Among six patients with known recurrence, five had persistent ctDNA at week 12.
CONCLUSIONS
Neoadjuvant chemotherapy for TNBC reduced ctDNA TFx by 285-fold in responders and 24-fold in non-responders. In 58% (22/38) of patients, ctDNA TFx dropped below the detection level of a commercially available test, emphasizing the need for sensitive tests. Additional studies will determine whether ctDNA-guided approaches can improve outcomes.
背景
我们旨在使用超敏检测方法，检测接受新辅助化疗的三阴性乳腺癌（TNBC）患者的循环肿瘤 DNA（ctDNA）及其与残留肿瘤负担（RCB）的关联。
患者和方法
我们从 II 期 TBCRC 030 前瞻性研究中确定了新辅助紫杉醇与顺铂治疗 TNBC 的应答者（RCB0/1）和匹配的无应答者（RCB2/3）。我们在基线、3 周和 12 周（治疗结束时）采集血浆样本。我们利用 MAESTRO 突变富集测序创建了个性化的 ctDNA 检测。我们探讨了 ctDNA 与 RCB 状态和疾病复发之间的关联。
结果
在 139 名患者中，有 68 名患者有完整的样本且未接受额外的新辅助化疗。22 名患者为应答者，其中 22 名患者有足够的组织进行全基因组测序。我们使用 MAESTRO ctDNA 检测方法鉴定了另外 19 名无应答者，该检测方法在 38 名患者中进行了匹配的病例对照分析，共检测了 319-1000 个变体（中位数 1000 个变体）的 114 个血浆样本，来自 3 个时间点。总体而言，基线时 ctDNA 阳性率为 100%，第 3 周为 79%，第 12 周为 55%。中位肿瘤分数（TFx）为 3.7×10（范围 7.9×10-4.9×10）。在应答者中，TFx 从基线下降了 285 倍，在无应答者中下降了 24 倍。第 12 周时 ctDNA 清除与 RCB 相关：RCB0 的 11 名患者中有 10 名清除，RCB1 的 8 名患者中有 3 名清除，RCB2 的 15 名患者中有 4 名清除，RCB3 的 4 名患者中无一例清除。在 6 名已知复发的患者中，5 名患者在第 12 周时仍有持续的 ctDNA。
结论
新辅助化疗使 TNBC 患者的 ctDNA TFx 降低了 285 倍（应答者）和 24 倍（无应答者）。在 58%（22/38）的患者中，ctDNA TFx 降至商业上可用检测方法的检测水平以下，这强调了需要使用敏感的检测方法。进一步的研究将确定 ctDNA 指导方法是否可以改善结局。
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