Institute of Pathology, Hannover Medical School, Hannover, Germany.
Genes Chromosomes Cancer. 2013 Jan;52(1):69-80. doi: 10.1002/gcc.22007. Epub 2012 Sep 21.
Infiltrating lobular breast cancer (ILBC) is a tumor-biologically distinct breast cancer subtype. A high frequency of oncogenic PIK3CA mutations has been reported in ILBC, which may allow for targeted therapy with newly developed PI3K inhibitors. This is of particular clinical relevance for ILBC patients, who have failed to respond to current treatment regimes and suffer from tumor recurrence or dissemination. In anticipation of this therapeutic strategy, we investigated PIK3CA mutations in ILBC with special reference to late stage tumor progression. A total of 88 ILBCs from 73 patients, including primary tumors (PTs, n = 43), ipsilateral locally recurrent tumors (LRTs, n = 15), and distant organ metastases (DOMs, n = 30), were compiled on tissue microarrays. Established ILBC marker proteins were evaluated by immunohistochemistry and PIK3CA hot spot mutations in exons 9 and 20 by direct sequencing. Matched PT/LRT, PT/DOM, and DOM/DOM cases were characterized on a patient-by-patient basis. Following correction for redundant patient representations, mutation frequencies were compared in PTs versus LRTs or DOMs. Nearly all specimens were E-cadherin-negative (99%), estrogen receptor (ER)-positive (91%), and lacked basal epithelial markers (100%), demonstrating correct ILBC classification. PIK3CA mutations were detected in 32/88 (36%) specimens. The mutation rate was similar in PTs (33%) and DOMs (26%, P = 0.769), but approximately two-fold increased in LRTs (69%, P = 0.022). Consistently, matched PT/LRT and LRT/DOM cases showed additional PIK3CA mutations in LRTs. Intriguingly, these findings imply that PIK3CA mutations are positively selected for during ILBC progression to local recurrence but not distant metastasis, which may have clinical implications for PI3K inhibitor-based therapy.
浸润性小叶乳腺癌（ILBC）是一种肿瘤生物学上独特的乳腺癌亚型。已经报道在 ILBC 中存在高频的致癌 PIK3CA 突变，这可能允许使用新开发的 PI3K 抑制剂进行靶向治疗。对于 ILBC 患者来说，这具有特别的临床意义，他们对当前的治疗方案没有反应，并且患有肿瘤复发或扩散。预计这种治疗策略会对 ILBC 患者产生影响，我们特别研究了 PIK3CA 突变与晚期肿瘤进展的关系。总共收集了 73 名患者的 88 例 ILBC 组织，包括原发性肿瘤（PT，n=43）、同侧局部复发性肿瘤（LRT，n=15）和远处器官转移（DOM，n=30），并将其编制在组织微阵列上。通过免疫组织化学评估了已建立的 ILBC 标志物蛋白，并通过直接测序检测了外显子 9 和 20 中的 PIK3CA 热点突变。对每例患者的 PT/LRT、PT/DOM 和 DOM/DOM 病例进行了特征描述。在对冗余患者表示进行校正后，比较了 PT 与 LRT 或 DOM 之间的突变频率。几乎所有标本的 E-钙黏蛋白均为阴性（99%），雌激素受体（ER）阳性（91%），缺乏基底上皮标志物（100%），表明正确的 ILBC 分类。在 88 例标本中，检测到 32 例（36%）标本存在 PIK3CA 突变。PT 中的突变率与 DOM 中的相似（33%）（P=0.769），但 LRT 中的突变率约为两倍（69%）（P=0.022）。一致的是，在 LRT 中，匹配的 PT/LRT 和 LRT/DOM 病例中也发现了额外的 PIK3CA 突变。有趣的是，这些发现表明，PIK3CA 突变在 ILBC 向局部复发进展过程中被积极选择，但在远处转移中未被选择，这可能对基于 PI3K 抑制剂的治疗具有临床意义。
