乳腺癌干细胞突变提示转移风险高

《美国医学会杂志-外科学》(JAMA Surgery)7月24日在线发表的一项研究显示，乳腺癌干细胞和祖细胞存在PI3/Akt信号传导缺陷的乳腺癌患者面临更高的淋巴结转移风险(JAMA Surg. 2013 July 17 [doi:10.1001/jamasurg.2013.3028])。

在这项研究中，俄勒冈健康与科学大学的Cory A. Donovan医生及其同事评估了30份新鲜导管型乳腺癌手术样本的恶性和良性细胞。在10份存在乳腺癌干细胞和祖细胞(BCSC)突变的样本中，9份与腋窝淋巴结微转移或巨转移相关。在20份无突变的肿瘤样本中，仅4份与腋窝淋巴结转移相关。

这些肿瘤样本采集自通过细胞分选的ⅠA至ⅢB期癌症患者。研究者对肿瘤样本进行全基因组扩增，然后筛查有无致癌基因突变。结果显示，10份BCSC缺陷肿瘤样本具有AKT1、HRAS或PIK3CA突变。在PIK3CA中检出3种不同突变(E545k、N345k和H1047R)，在AKT1中检出1种突变，在HRAS中检出1种突变。

有和无突变的BCSC的CD44阳性率无差异。BCSC突变与诊断年龄、肿瘤大小、肿瘤组织学级别、雌激素受体表达、孕激素受体表达和ERBB2状态无统计学关联。然而，BCSC突变的存在与腋窝淋巴结转移之间有显著关联，在纳入微转移疾病的情况下，其显著性进一步加强。

平均随访29个月，10例BCSC突变患者中有3例在治疗后出现进展，2例死于疾病，1例发生脑转移。相反，平均随访19个月，在BCSC无突变的患者中未观察到疾病征象。

由于无BCSC突变的患者中有20%发生腋窝淋巴结转移，因此BCSC中的PI3K/Akt突变似乎并非发生转移的必要因素，但该研究观察到的PI3K与转移潜在性之间的关联提示，具有PI3K/Akt突变的微转移可能伴随不同的远端转移性疾病风险。研究者表示，延长随访时间及增加样本量将可确定此亚组患者的风险是否增高，以及是否可受益于专门的辅助化疗。

虽然该研究的BCSC结果与其他研究一致，即乳腺癌PIK3CA和AKT突变与提示预后不良和生存降低的因素有关，但另外一些研究在具有PIK3CA突变的肿瘤患者中观察到生存改善、肿瘤级别降低及雌激素受体阳性率增加。这些矛盾的结果可能归因于突变的变异性、肿瘤的异质性和PI3K/Akt信号传导通路的复杂性。

研究者表示，该研究结果表明，消除这些争议的关键在于识别BCSC中的突变及总体肿瘤中的突变，因此有必要进行BCSC评估和总体乳腺癌评估。通过分析BCSC可获得单纯分析肿瘤后代细胞所无法获得的有关肿瘤生长和转移潜在性的特异性信息。同时进行肿瘤和BCSC的分子分析可更好地识别那些可从特定治疗方案获益的患者。单纯进行肿瘤分析可能会遗漏一些可能从治疗获益的患者，同时进行BCSC和肿瘤分析可增加此类获益患者的数量。P13K/Akt信号传导通路抑制剂目前正处于临床试验阶段，此类抑制剂可能有效治疗BCSC突变患者，甚至对无PIK/Akt突变的患者也是如此。BCSC特异性和肿瘤靶向化疗药物的应用可能互相具有协同作用，这为患者提供了新的治疗方法。

该研究获Janet E. Bowen基金会资助。研究者声明无经济利益冲突。

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Stem cell mutations in breast cancer may confer metastatic risk

By: SHARON WORCESTER, Ob.Gyn. News Digital Network

The likelihood of nodal metastases is increased in breast cancer patients whose tumors have breast cancer stem and progenitor cells with defects in PI3/Akt signaling.

The findings, drawn from an analysis of surgical specimens, "support embarking on a new way of approaching breast cancer diagnosis and treatment planning" and have potential implications for targeted treatment with PI3/Akt inhibitors currently being tested in clinical trials, Dr. Cory A. Donovan and his colleagues at the Oregon Health and Science University, Portland reported online July 24 in JAMA Surgery.

The researchers evaluated malignant and benign stem cells from 30 fresh surgical specimens of ductal breast cancers. Nine of the 10 specimens with mutations in breast cancer stem and progenitor cells (BCSCs) were associated with axillary lymph node micro- or macrometastases. Just 4 of the 20 tumors without mutations were associated with axillary lymph node metastases, the investigators said (JAMA Surg. 2013 July 17 [doi:10.1001/jamasurg.2013.3028]).

The tumor specimens were collected from patients with stage IA through IIIB cancers via cell sorting and were subjected to whole genomic amplification and subsequent screening for oncogene mutations. The 10 tumors with BCSC defects had AKT1, HRAS, or PIK3CA mutations.

"Three different mutations (E545k, N345k, and H1047R) were detected in PIK3CA, a single mutation was detected in AKT1, and a single mutation was detected in HRAS," the investigators wrote.

No difference in CD44 positivity was observed between BCSCs with and without mutations.

"When the presence of any BCSC mutation correlated with patient and breast cancer characteristics, no statistically significant correlations were found with patient age at diagnosis, tumor size, tumor histologic grade, estrogen receptor expression, progesterone receptor expression, or ERBB2 status. However, a statistically significant correlation was observed between the presence of BCSC mutations and axillary lymph node metastases. This significance was more pronounced when micrometastatic disease was included," they said.

At a mean follow-up of 29 months, disease had progressed after treatment in 3 of the 10 patients with BCSC mutations. Two patients died of disease; one had brain metastases. Conversely, there was no evidence of disease at a mean follow-up of 19 months in the patients with BCSCs without mutations.

Since 20% of patients without BCSC mutations had axillary lymph node metastases, it appears that a PI3K/Akt mutation in BCSC is not a requirement for metastases, but the link between PI3K and metastatic potential demonstrated in this study suggests that "micrometastases harboring PI3K/Akt mutations may carry a different risk for distant metastatic disease," Dr. Donovan and his associates noted.

"Longer patient follow-up periods and a larger sample size will determine if this subset of patients demonstrates an increased risk and may benefit from specifically designed use of adjuvant chemotherapy," the researchers added.

The existing evidence regarding the prognostic significance of specific PI3K/Akt signaling pathway mutations is conflicting, likely because of the variability of the mutations, the heterogeneity of the tumors, and the complexity of the pathway. Although the findings in BCSCs in the current study are consistent with others showing that PIK3CA and AKT mutations in breast cancers are associated with factors that may indicate poor prognosis and decreased survival, other studies have demonstrated improved survival, lower tumor grades, and increased rates of estrogen receptor positivity in patients with tumors that have PIK3CA mutations, they said.

"Our study findings indicate that the answer to this controversy may lie in identifying mutations in BCSCs, as well as mutations in the tumor as a whole," they said, adding that the findings support an evaluation of BCSCs along with overall breast cancer assessment.

"The analysis of BCSCs can generate specific information about tumor growth and metastatic potential that may not be obtained from analysis of the tumor progeny cells alone. Simultaneous molecular analyses of both the tumor and BCSCs may better identify patients who are likely to benefit from specific therapeutic regimens. Similarly, simultaneous BCSC and tumor analysis may increase the number of patients who might benefit from treatment but be missed by tumor analysis alone," Dr. Donovan and his coworkers said.

P13K/Akt signaling pathway inhibitors are currently being evaluated in clinical trials and could prove useful for the treatment of patients with BCSC mutations, they noted, adding that this may be true even in cases without PIK/Akt mutation.

"The use of BCSC-specific and tumor-targeted chemotherapeutic agents may prove to be synergistic with each other, providing a novel therapeutic approach," they said.

This study was supported by a grant from the Janet E. Bowen Foundation. The authors reported having no disclosures.