来源：肿瘤资讯
Palbociclib联合氟维司群（P+F）治疗转移性乳腺癌的疗效与循环肿瘤DNA（ctDNA）中ESR1的分析
摘要编号：512
Citation: J Clin Oncol 34, 2016 (suppl; abstr 512)
背景：PALOMA-3是一项随机、双盲、III期临床研究，观察palbociclib联合氟维司群对照氟维司群联合安慰剂治疗经内分泌治疗进展后的绝经前、绝经后HR+/HER2–转移性乳腺癌。近期研究提示ESR1突变是转移性乳腺癌获得性耐药的机制之一。血清ctDNA检测是肿瘤组织基因检测的替代方法之一。由此，我们评估了ctDNA ESR1突变状态与palobciclib敏感性的相关性，及ctDNA检测ESR1的可重复性。
方法：从521例入组PALOMA-3的患者中收集396例患者基线时血清样本，并获得患者知情同意。采用QIAamp Circulating Nucleic Acid Kit 从2mL中抽提DNA，采用Sysmex Inostics分析位于外显子5，7，8的12个ESR1配体结合域的突变。为了验证ESR1突变检测的可重复性，采用droplet digital PCR重复检测。
结果：395例血清样本中检测出106例（26.8%）ESR1突变，大部分为D538G（14.1%）, E380Q（8.1%）, Y537S（7.3%），Y537N（4.5%）。10.1%患者为多克隆突变。所有106例ESR1突变的患者既往接受过芳香化酶抑制剂的治疗，仅接受他莫西芬治疗的患者未发现ESR1突变。总体而言，ESR1突变者的中位无进展生存期（PFS）为5.7个月（95%CI：3.7-9.4），无ESR1突变者为9.2个月（95%CI：0.31-0.62，双侧p=0.0572）。无论ESR1突变状态，P+F组中位PFS均较F+安慰剂组显著延长，无ESR1突变（9.5 vs 3.8 mos; HR = 0.44 [95% CI: 0.31‒0.62], 1-sided P< 0.0001），存在ESR1突变（9.4 vs 4.1 mos; HR = 0.52 [95% CI: 0.32‒0.87], 1-sided P= 0.0052）。采用droplet digital PCR方法独立检测的标本中（353/395），两种检测方法的一致性达94.1%（Kappa = 0.84）。
结论：HR+转移性乳腺癌通过血清ctDNA检测发现存在高比例的ESR1突变，提示ESR1突变与内分泌治疗耐药相关。不论是否存在ESR1突变，转移性乳腺癌患者都能从P+F的治疗中获益。临床研究信息：NCT01942135
Efficacy of palbociclib plus fulvestrant (P+F) in patients (pts) with metastatic breast cancer (MBC) and ESR1 mutations (mus) in circulating tumor DNA (ctDNA).
Abstract No:
512
Citation: J Clin Oncol 34, 2016 (suppl; abstr 512)
Background: PALOMA-3 is a randomized, double-blind, phase III study comparing P+F with fulvestrant plus placebo (F+Pla) in pre- and postmenopausal women with HR+/HER2– MBC that progressed on prior endocrine therapy. Recent studies have implicated ESR1 mu as a mechanism for acquired endocrine resistance in MBC. ctDNA assessed in plasma is a potential surrogate for a tumor’s genetic profile. Here, we assess the relationship between ctDNA ESR1 mu status and palbociclib sensitivity, and the reproducibility of ESR1 ctDNA analysis.
Methods: 396 baseline plasma samples from 521 pts enrolled in PALOMA-3 were collected and consented for use in this study. DNA was extracted from 2 mL aliquots using the QIAamp Circulating Nucleic Acid Kit and 12 ESR1 ligand-binding domain mus were analyzed in exons 5, 7, and 8 by Sysmex Inostics. To assess reproducibility of ESR1 mu analysis, separate samples were analysed by droplet digital PCR.
Results:ESR1 mus were detected in 106 (26.8%) of the 395 plasma samples tested, most frequently D538G (14.1%), E380Q (8.1%), Y537S (7.3%), and Y537N (4.5%). Mus were poly-clonal in 10.1% of pts. All 106 pts with ESR1 mus were previously treated with an aromatase inhibitor; no ESR1 mus were identified in pts previously treated with tamoxifen only. Overall, median progression-free survival (PFS) was 5.7 months (mos) (95% confidence interval [CI]: 3.7–9.4) for pts with ESR1 mus versus 9.2 mos (95% CI: 7.5–10.9) for pts without ESR1 mus (hazard ratio [HR] = 1.33 [95% CI: 0.99–1.80]; 2-sided P= 0.0572). Median PFS was significantly longer in the P+F group compared with the F+Pla group both in pts without a detectable ESR1 mu (9.5 vs 3.8 mos; HR = 0.44 [95% CI: 0.31‒0.62], 1-sided P< 0.0001) and in pts with an ESR1 mu (9.4 vs 4.1 mos; HR = 0.52 [95% CI: 0.32‒0.87], 1-sided P= 0.0052). In samples independently tested by droplet digital PCR (353/395), the concordance between the two assays was 94.1% (Kappa = 0.84).
Conclusions:ESR1 mus, detected in plasma ctDNA, were identified in a high percentage of pts with HR+ MBC confirming an important role in endocrine-resistance. P+F treatment provided significant benefit for MBC pts with and without ESR1 mus. Clinical trial information: NCT01942135
Link：http://abstracts.asco.org/176/AbstView_176_165547.html
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