新辅助治疗乳腺癌患者循环肿瘤 DNA 可反映治疗应答和生存情况。
Circulating tumor DNA in neoadjuvant-treated breast cancer reflects response and survival.
机构信息
Department of Laboratory Medicine, University of California San Francisco, San Francisco, USA.
Department of Laboratory Medicine, University of California San Francisco, San Francisco, USA.
出版信息
Ann Oncol. 2021 Feb;32(2):229-239. doi: 10.1016/j.annonc.2020.11.007. Epub 2020 Nov 21.
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]; interestingly, patients who did not achieve pCR but were ctDNA negative (86%) had excellent outcome, similar to those who achieved pCR (HR 1.4; 95% CI 0.15-13.5).
CONCLUSIONS
Lack of ctDNA clearance was a significant predictor of poor response and metastatic recurrence, while clearance was associated with improved survival even in patients who did not achieve pCR. Personalized monitoring of ctDNA during NAC of high-risk early breast cancer may aid in real-time assessment of treatment response and help fine-tune pCR as a surrogate endpoint of survival.
背景
新辅助化疗（NAC）后的病理完全缓解（pCR）与良好的预后密切相关。我们研究了连续循环肿瘤 DNA（ctDNA）检测在预测 pCR 和转移性复发风险方面的效用。
方法
84 例高危早期乳腺癌患者在新辅助 I-SPY 2 试验中接受标准 NAC 或联合 MK-2206（AKT 抑制剂）治疗，共采集 291 份血浆样本中的无细胞 DNA（cfDNA）。血液采集于预处理（T0）、紫杉醇治疗开始后 3 周（T1）、紫杉醇和蒽环类药物治疗之间（T2）或手术前（T3）。设计了一种个性化 ctDNA 检测方法，通过超深度测序检测 cfDNA 中多达 16 种患者特异性突变（来自预处理肿瘤的全外显子组测序）。生存分析的中位随访时间为 4.8 年。
结果
在 T0，84 例患者中有 61 例（73%）ctDNA 阳性，且随时间推移逐渐降低（T1：35%；T2：14%；T3：9%）。T1 时仍为 ctDNA 阳性的患者在 NAC 后残留疾病的可能性明显高于清除 ctDNA 的患者（非 pCR 为 83%，而非 pCR 为 52%；优势比 4.33，P=0.012）。在 NAC 后，所有达到 pCR 的患者均为 ctDNA 阴性（n=17，100%）。对于未达到 pCR 的患者（n=43），ctDNA 阳性患者（14%）发生转移性复发的风险显著增加[风险比（HR）10.4；95%置信区间（CI）2.3-46.6]；有趣的是，未达到 pCR 但 ctDNA 阴性的患者（86%）预后良好，与达到 pCR 的患者相似（HR 1.4；95%CI 0.15-13.5）。
结论
ctDNA 清除不足是不良反应和转移性复发的显著预测因子，而清除与改善生存相关，即使在未达到 pCR 的患者中也是如此。在高危早期乳腺癌的 NAC 期间对 ctDNA 进行个体化监测可能有助于实时评估治疗反应，并有助于微调 pCR 作为生存的替代终点。
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