Department of Cancer Diagnosis, Research Institute for Clinical Oncology, Saitama Cancer Center, 818 Komuro, Ina, Saitama, 362-0806, Japan.
BMC Cancer. 2013 May 16;13:241. doi: 10.1186/1471-2407-13-241.
Chemotherapy with trastuzumab is widely used for patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer, but a significant number of patients with the tumor fail to respond, or relapse. The mechanisms of recurrence and biomarkers that indicate the response to the chemotherapy and outcome are not fully investigated.
Genomic alterations were analyzed using single-nucleotide polymorphism arrays in 46 HER2 immunohistochemistry (IHC) 3+ or 2+/fluorescent in situ hybridization (FISH)+ breast cancers that were treated with neoadjuvant chemotherapy with paclitaxel, cyclophosphamid, epirubicin, fluorouracil, and trastuzumab. Patients were classified into two groups based on presence or absence of alterations of 65 cancer-associated genes, and the two groups were further classified into four groups based on genomic HER2 copy numbers or hormone receptor status (HR+/-). Pathological complete response (pCR) and relapse-free survival (RFS) rates were compared between any two of the groups.
The pCR rate was 54% in 37 patients, and the RFS rate at 3 years was 72% (95% CI, 0.55-0.89) in 42 patients. The analysis disclosed 8 tumors with nonamplified HER2 and 38 tumors with HER2 amplification, indicating the presence of discordance in tumors diagnosed using current HER2 testing. The 8 patients showed more difficulty in achieving pCR (P=0.019), more frequent relapse (P=0.018), and more frequent alterations of genes in the PI3K pathway (P=0.009) than the patients with HER2 amplification. The alterations of the PI3K and estrogen receptor (ER) pathway genes generally indicated worse RFS rates. The prognostic significance of the alterations was shown in patients with a HR+ tumor, but not in patients with a HR- tumor when divided. Alterations of the PI3K and ER pathway genes found in patients with a HR+ tumor with poor outcome suggested that crosstalk between the two pathways may be involved in resistance to the current chemotherapy with trastuzumab.
We recommend FISH analysis as a primary HER2 testing because patients with IHC 2+/3+ and nonamplified HER2 had poor outcome. We also support concurrent use of trastuzumab, lapatinib, and cytotoxic and anti-hormonal agents for patients having HR+ tumors with alterations of the PI3K and ER pathway genes.
曲妥珠单抗化疗广泛用于人表皮生长因子受体 2 阳性（HER2+）乳腺癌患者，但相当数量的肿瘤患者对化疗无反应或复发。复发的机制和预测化疗反应及结果的生物标志物尚未完全研究清楚。
采用单核苷酸多态性微阵列分析 46 例经紫杉醇、环磷酰胺、表柔比星、氟尿嘧啶和曲妥珠单抗新辅助化疗的 HER2 免疫组化（IHC）3+或 2+/荧光原位杂交（FISH）+乳腺癌患者的基因组改变。根据 65 个癌症相关基因的改变情况，将患者分为两组，并根据基因组 HER2 拷贝数或激素受体状态（HR+/ -）将两组进一步分为四组。比较任意两组之间的病理完全缓解（pCR）率和无复发生存率（RFS）。
37 例患者的 pCR 率为 54%，42 例患者的 3 年 RFS 率为 72%（95%CI，0.55-0.89）。分析显示 8 例患者存在非扩增 HER2，38 例患者存在 HER2 扩增，表明当前 HER2 检测诊断的肿瘤存在不一致性。8 例患者 pCR 难度较大（P=0.019），复发频率较高（P=0.018），PI3K 通路基因改变频率较高（P=0.009），较 HER2 扩增患者更差。PI3K 和雌激素受体（ER）通路基因的改变通常预示着 RFS 率较差。当按 HR+肿瘤和 HR-肿瘤进行分组时，这些改变的预后意义仅在 HR+肿瘤患者中可见。在预后不良的 HR+肿瘤患者中发现 PI3K 和 ER 通路基因的改变提示这两个通路之间的相互作用可能与当前曲妥珠单抗化疗的耐药性有关。
我们建议采用 FISH 分析作为 HER2 的主要检测方法，因为 IHC 2+/3+和非扩增 HER2 的患者预后较差。我们还支持对存在 PI3K 和 ER 通路基因改变的 HR+肿瘤患者联合使用曲妥珠单抗、拉帕替尼、细胞毒性药物和抗激素药物。
