Ahern Thomas P, Cronin-Fenton Deirdre P, Lash Timothy L, Sørensen Henrik Toft, Ording Anne Gulbech, Hamilton-Dutoit Stephen J, Hellberg Ylva
a Department of Surgery , University of Vermont College of Medicine , Burlington , Vermont , USA ;
b Department of Clinical Epidemiology , Aarhus University Hospital , Aarhus , Denmark ;
Acta Oncol. 2016 Jun;55(6):734-41. doi: 10.3109/0284186X.2016.1150606. Epub 2016 Apr 8.
Background Adjuvant tamoxifen therapy approximately halves the risk of estrogen receptor-positive (ER+) breast cancer recurrence, but many women do not respond to therapy. Observational studies nested in clinical trial populations suggest that overexpression or nuclear localization of p21-activated kinase 1 (Pak1) in primary tumors predicts tamoxifen failure. Material and methods We measured the association between Pak1 expression and breast cancer recurrence in a Danish population-based case-control study. Pak1 cytoplasmic expression level and nuclear positivity were determined by immunohistochemical staining of primary breast tumors from recurrence cases and matched controls from two breast cancer populations; women diagnosed with ER-positive tumors who received at least one year of tamoxifen therapy (ER+/TAM+), and women diagnosed with ER-negative tumors who survived for at least one year (ER-/TAM-). Pak1 staining was assessed by a single, blinded pathologist, and associations were estimated with conditional logistic regression models. Results We included 541 recurrence cases and 1:1 matched controls from the ER+/TAM + group and 300 recurrence cases and 1:1 matched controls from the ER-/TAM - group. Pak1 cytoplasmic intensity was not associated with breast cancer recurrence in either group (ER+/TAM + ORadj for strong vs. no cytoplasmic staining = 0.91, 95% CI 0.57, 1.5; ER-/TAM - ORadj for strong vs. no cytoplasmic staining = 0.74, 95% CI 0.39, 1.4). Associations between Pak1 nuclear positivity and breast cancer recurrence were similarly near null in both groups. Conclusion Pak1 positivity in primary breast tumors was neither predictive nor prognostic in this prospective, population-based study.
辅助性他莫昔芬治疗可使雌激素受体阳性（ER+）乳腺癌复发风险降低约一半，但许多女性对该治疗无反应。纳入临床试验人群的观察性研究表明，原发性肿瘤中p21激活激酶1（Pak1）的过表达或核定位预示着他莫昔芬治疗失败。材料与方法：在一项基于丹麦人群的病例对照研究中，我们测量了Pak1表达与乳腺癌复发之间的关联。通过对来自两个乳腺癌人群的复发病例的原发性乳腺肿瘤以及匹配对照进行免疫组织化学染色，确定Pak1的细胞质表达水平和核阳性情况；这些人群包括接受至少一年他莫昔芬治疗的ER阳性肿瘤女性（ER+/TAM+），以及存活至少一年的ER阴性肿瘤女性（ER-/TAM-）。由一名单盲病理学家评估Pak1染色情况，并使用条件逻辑回归模型估计关联。结果：我们纳入了ER+/TAM+组的541例复发病例和1:1匹配对照，以及ER-/TAM-组的300例复发病例和1:1匹配对照。在两组中，Pak1的细胞质强度均与乳腺癌复发无关（ER+/TAM+组中，强细胞质染色与无细胞质染色相比的调整后OR=0.91，95%CI为0.57,1.5；ER-/TAM-组中，强细胞质染色与无细胞质染色相比的调整后OR=0.74，95%CI为0.39,1.4）。两组中Pak1核阳性与乳腺癌复发之间的关联同样接近无效。结论：在这项基于人群的前瞻性研究中，原发性乳腺肿瘤中Pak1阳性既无预测性也无预后性。
