Department of Pathology, University of Texas Southwestern, Dallas, TX 75390.
J Natl Cancer Inst. 2012 Dec 5;104(23):1825-36. doi: 10.1093/jnci/djs446. Epub 2012 Nov 28.
A subset of patients with ductal carcinoma in situ (DCIS) will progress to invasive breast cancer. However, there are currently no markers to differentiate women at high risk from those at lower risk of developing invasive disease.
The association of two major tumor suppressor genes, retinoblastoma (RB) and phosphatase and tensin homolog (PTEN), with risk of any ipsilateral breast event (IBE) or progression to invasive breast cancer (IBC) was analyzed using data from 236 DCIS patients treated with breast conserving surgery with long-term follow-up. RB and PTEN expression was assessed with immunohistochemistry. The functional effects of RB and/or PTEN loss were modeled in MCF10A cells. Hazard ratios (HRs) were estimated with univariate and multivariable Cox regression models. All statistical tests were two-sided.
Loss of RB immunoreactivity in DCIS was strongly associated with risk of IBE occurrence (HR = 2.64; 95% confidence interval [CI] = 1.64 to 4.25) and IBC recurrence (HR = 4.66; 95% CI = 2.19 to 9.93). The prognostic power of RB loss remained statistically significant in multivariable analyses. PTEN loss occurred frequently in DCIS but was not associated with recurrence or progression. However, patients with DCIS lesions that were both RB and PTEN deficient were at further increased risk for IBEs (HR = 3.39; 95% CI = 1.92 to 5.99) and IBC recurrence (HR = 6.1, 95% CI = 2.5 to 14.76). Preclinical modeling in MCF10A cells demonstrated that loss of RB and PTEN impacted proliferation, motility, and invasive properties.
These studies indicate that RB and PTEN together have prognostic utility and could be used to target aggressive treatment for patients with the greatest probability of benefit.
一小部分导管原位癌（DCIS）患者会进展为浸润性乳腺癌。然而，目前尚无标记物能够区分高风险和低风险的女性患者，以预测其是否会发生浸润性疾病。
我们分析了 236 例接受保乳手术治疗且长期随访的 DCIS 患者的数据，研究了两种主要肿瘤抑制基因视网膜母细胞瘤（RB）和磷酸酶张力蛋白同源物（PTEN）与同侧乳腺事件（IBE）或进展为浸润性乳腺癌（IBC）的风险之间的关联。使用免疫组织化学检测 RB 和/或 PTEN 表达缺失。在 MCF10A 细胞中模拟 RB 和/或 PTEN 缺失的功能效应。使用单变量和多变量 Cox 回归模型估计风险比（HR）。所有统计检验均为双侧检验。
DCIS 中 RB 免疫反应性缺失与 IBE 发生（HR=2.64；95%置信区间[CI]为 1.64 至 4.25）和 IBC 复发（HR=4.66；95%CI 为 2.19 至 9.93）风险密切相关。多变量分析显示 RB 缺失的预后作用仍具有统计学意义。PTEN 缺失在 DCIS 中经常发生，但与复发或进展无关。然而，RB 和 PTEN 均缺失的 DCIS 病变患者发生 IBE（HR=3.39；95%CI 为 1.92 至 5.99）和 IBC 复发（HR=6.1，95%CI 为 2.5 至 14.76）的风险进一步增加。MCF10A 细胞的临床前模型表明，RB 和 PTEN 的缺失会影响增殖、运动性和侵袭性。
这些研究表明，RB 和 PTEN 一起具有预后价值，可用于针对最有可能受益的患者进行强化治疗。
