BRCA-1 methylation and TP53 mutation in triple-negative breast cancer patients without pathological complete response to taxane-based neoadjuvant chemotherapy
BRCA-1 methylation and TP53 mutation in triple-negative breast cancer patients without pathological complete response to taxane-based neoadjuvant chemotherapy
复制标题
DOI：
10.1007/s00280-014-2404-1
复制
发表时间：
2014-04-01
影响因子：
3
通讯作者：
Bartsch, Rupert
中科院分区：
文献类型：
--
作者：
Foedermayr, Mathilde;Sebesta, Miriam;Bartsch, Rupert
引言新辅助化疗无病理完全缓解（pCR）的三阴性乳腺癌（TNBC）患者预后不良。携带BRCA-1生殖系突变的TNBC可能对紫杉烷类药物的反应较低，而对DNA损伤剂的敏感性保留。在具有表观遗传BRCA-1沉默的肿瘤中观察到类似的效果。对新辅助化疗（包括表阿霉素加多西他赛）无pCR的患者在我们中心常规接受术后CMF。在这里，我们研究了辅助CMF在有或没有BRCA-1甲基化或TP 53突变的患者中的作用。为了确定BRCA-1甲基化状态，进行定量甲基化特异性PCR。结果24例乳腺癌患者BRCA-1甲基化率为41.7%，TP 53突变率为66.7%。在中位随访27.5个月时，20%的BRCA-1甲基化患者发生无病生存（DFS）事件，而非甲基化组为64.3%（p = 0.0472）。非甲基化组的中位DFS为16个月，甲基化组未达到（n.s.）。TP 53突变状态与临床outcome. ConclusionadjuvantCMF在紫杉烷类新辅助化疗难治的TNBC中活性有限。在该人群中，BRCA-1甲基化与DFS事件的显著减少相关，表明预后更好，DNA损伤剂的活性可能保留。
Introduction Triple-negative breast cancer (TNBC) patients without pathological complete response (pCR) to neoadjuvant chemotherapy have an unfavourable prognosis. TNBC harbouring BRCA-1 germline mutations may be less responsive to taxanes, while sensitivity to DNA-damaging agents is retained. A similar effect was seen in tumours with epigenetic BRCA-1 silencing. Patients without pCR to neoadjuvant chemotherapy consisting of epirubicin plus docetaxel routinely received post-operative CMF at our centre. Here, we investigated the effect of adjuvant CMF in patients with or without BRCA-1 methylation or TP53 mutation.Methods DNA was extracted from formalin-fixed paraffin-embedded tissue. For determining BRCA-1 methylation status, quantitative methylation-specific PCR was performed. For the investigation of TP53 mutation status, DNA was PCR amplified and sequenced by Sanger sequencing.Results Twenty-four patients were included; BRCA-1 methylation was present in 41.7 %, while TP53 mutations were observed in 66.7 %. At a median follow-up of 27.5 months, 20 % of patients with BRCA-1 methylation had a disease-free survival (DFS) event, as compared to 64.3 % in the non-methylated group (p = 0.0472). Median DFS in the non-methylated group was 16 months and was not reached in the methylated group (n.s.). No association TP53 mutation status with clinical outcome was observed.Conclusions Adjuvant CMF is of limited activity in TNBC refractory to taxane-based neoadjuvant chemotherapy. In this population, BRCA-1 methylation was associated with a significant decrease in DFS events suggesting a better prognosis and potentially retained activity of DNA damaging agents.