JCO：PTEN状态不影响乳腺癌患者从曲妥珠单抗治疗中获益

PTEN染色图
A：0，无染色；B：1+，弱染色；C：2+，中度染色；D：3+，强染色

治疗组DFS曲线
A：阴性；B：阳性(1,2,3+)；C：阴性(0,1+);D:阳性(2,3+)；AC, 多柔比星 60 mg/m2 联合环磷酰胺 600 mg/m2 每三周一次共4周;T, 紫杉醇 80 mg/m2/wk共12 周；H, 曲妥珠单抗4 mg/kg 起始，  2 mg/kg/wk 共52 周

10号染色体缺失与张力蛋白同源物磷酸酯酶基因(PTEN)为PI3K/AKT信号通路的一种负调节因子，有证据显示，PTEN与肿瘤对曲妥珠单抗的敏感性有关。在2013年5月6日在线出版的《临床肿瘤学杂志》(Journal of Clinical Oncology)上，美国梅奥诊所的Edith A. Perez博士等人发表了美国中北部肿瘤治疗组(NCCTG) N9831研究，即早期人表皮生长因子受体2 (HER2)阳性临床III期临床试验(NCT00898898)的一项结果，该文对肿瘤PTEN蛋白表达与患者无病生存期(DFS)间的关系进行了考察，在试验中，参试患者经随机分配后，接受单纯的化疗(A组)或化疗联合序贯(B组)或同步(C组)曲妥珠单抗治疗。

研究人员针对各区组中含有3个核心片区(n = 1,286)或全部组织片区(WS; n = 516)的组织芯片，通过常规免疫组化方法(138G6 单克隆抗体)，得到经细胞质PTEN染色确定的侵犯细胞密集度及比例。如任何核心片区或WS显示存在≥ 1+染色的侵犯细胞，则认为PTEN阳性肿瘤(PTEN-positive) 。该研究中位随访时间为6.0年。

在该分析所包括的1,802例(N9831试验共有3,505例登记患者)患者中，1,342例(74%)患者为PTEN阳性肿瘤。研究显示，PTEN阳性与阴性激素受体状态(χ2 P < .001)及阳性淋巴结(χ2 P = .04)有关。PETN并未对各组患者的DFS产生影响。对CA两组间DFS进行比较后发现，PTEN阳性与PTEN阴性肿瘤的风险比(HR)分别为0.65 (P = .003) 及0.47 (P = .005，相互作用P = .16)。CA两组间比较后发现，PTEN阳性与PTEN阴性肿瘤的HR分别为0.70 (P = .009) 及0.85 (P = .44，相互作用P = .47)

尽管某些进行筛选后的临床前研究和数量有限的临床研究认为，PTEN阴性肿瘤患者对曲妥珠单抗的敏感性降低，但与之相反，此项研究结果表明，无论阳性HER2乳腺癌患者肿瘤PTEN状态如何，通过曲妥珠单抗辅助治疗都会取得临床获益。

Impact of PTEN Protein Expression on Benefit From Adjuvant Trastuzumab in Early-Stage Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer in the North Central Cancer Treatment Group N9831 Trial.
Abstract
PURPOSEIt has been suggested that PTEN, a negative regulator of PI3K/AKT signaling, is involved in tumor sensitivity to trastuzumab. We investigated the association between tumor PTEN protein expression and disease-free survival (DFS) of patients randomly assigned to receive chemotherapy alone (arm A) or chemotherapy with sequential (arm B) or concurrent trastuzumab (arm C) in the phase III early-stage human epidermal growth factor receptor 2 (HER2) -positive trial-North Central Cancer Treatment Group (NCCTG) N9831. PATIENTS AND METHODSThe intensity and percentage of invasive cells with cytoplasmic PTEN staining were determined in tissue microarray sections containing three cores per block (n = 1,286) or in whole tissue sections (WS; n = 516) by using standard immunohistochemistry (138G6 monoclonal antibody). Tumors were considered positive for PTEN (PTEN-positive) if any core or WS had any invasive cells with ≥ 1+ staining. Median follow-up was 6.0 years.ResultsOf 1,802 patients included in this analysis (of 3,505 patients registered to N9831), 1,342 (74%) had PTEN-positive tumors. PTEN positivity was associated with hormone receptor negativity (χ2 P < .001) and nodal positivity (χ2 P = .04). PTEN did not have an impact on DFS within the various arms. Comparing DFS of arm C to arm A, patients with PTEN-positive and PTEN-negative tumors had hazard ratios (HRs) of 0.65 (P = .003) and 0.47 (P = .005), respectively (interaction P = .16). For arm B versus arm A, patients with PTEN-positive and PTEN-negative tumors had HRs of 0.70 (P = .009) and 0.85 (P = .44), respectively (interaction P = .47). CONCLUSIONIn contrast to selected preclinical and limited clinical studies suggesting a decrease in trastuzumab sensitivity in patients with PTEN-negative tumors, our data show benefit of adjuvant trastuzumab for patients with HER2-positive breast cancer, independent of tumor PTEN status.