Tokunaga Eriko, Kataoka Akemi, Kimura Yasue, Oki Eiji, Mashino Kojiro, Nishida Kojiro, Koga Tadashi, Morita Masaru, Kakeji Yoshihiro, Baba Hideo, Ohno Shinji, Maehara Yoshihiko
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan.
Eur J Cancer. 2006 Mar;42(5):629-35. doi: 10.1016/j.ejca.2005.11.025. Epub 2006 Feb 7.
In this retrospective study, the relationship between Akt activation and the efficacy of endocrine therapy for metastatic breast cancer was investigated. Thirty-six metastatic breast cancer patients, treated with endocrine therapy, were evaluated for the activation of Akt by an immunohistochemical assessment of the expression of phosphorylated Akt at Ser 473 (pAkt). The relationship between the efficacy of endocrine therapy and Akt activation, HER2 status and hormone receptor expression was also investigated. Of these 36 cases, 12 cases (33.4%) were considered to show a positive pAkt expression. In the pAkt-positive patients, endocrine therapy demonstrated a worse efficacy than in pAkt-negative patients (P<0.01). pAkt positivity was also associated with a poorer objective response (P<0.05). The clinical benefit rate was lower in HER2 positive groups than in HER2 negative group (P<0.05). In addition, the clinical benefit was the smallest in both the HER2 and pAkt-positive patients (P<0.01). Regarding the endocrine agents, the clinical benefit of estrogen deprivation therapy with aromatase inhibitor or luteinising hormone-releasing hormone agosists was significantly lower in the pAkt-positive patients than that in the pAkt-negative ones (P<0.05). In addition, there was a tendency for clinical benefit of selective estrogen receptor modulator to be smaller in the pAkt-positive patients (P=0.09). These findings, therefore, suggest that Akt activation induces endocrine resistance in metastatic breast cancer, irrespective of the kind of endocrine agents that were administered. Our findings suggest that the activation of Akt in the downstream pathway of HER2 plays an important role in the resistance to endocrine therapy for breast cancer. Although our study was small in scope and retrospective in design, our findings suggest that pAkt may be a useful predictor of resistance to endocrine therapy for breast cancer, while also suggesting that the inhibition of Akt may increase the efficacy of endocrine therapy.
在这项回顾性研究中，研究了Akt激活与转移性乳腺癌内分泌治疗疗效之间的关系。对36例接受内分泌治疗的转移性乳腺癌患者，通过免疫组织化学评估Ser 473位点磷酸化Akt（pAkt）的表达来评价Akt的激活情况。还研究了内分泌治疗疗效与Akt激活、HER2状态及激素受体表达之间的关系。在这36例病例中，12例（33.4%）被认为pAkt表达呈阳性。在pAkt阳性患者中，内分泌治疗的疗效比pAkt阴性患者差（P<0.01）。pAkt阳性也与较差的客观缓解率相关（P<0.05）。HER2阳性组的临床获益率低于HER2阴性组（P<0.05）。此外，HER2和pAkt均阳性的患者临床获益最小（P<0.01）。关于内分泌药物，在pAkt阳性患者中，使用芳香化酶抑制剂或促黄体生成素释放激素激动剂进行雌激素剥夺治疗的临床获益明显低于pAkt阴性患者（P<0.05）。此外，pAkt阳性患者中选择性雌激素受体调节剂的临床获益有变小的趋势（P=0.09）。因此，这些发现表明，无论所给予的内分泌药物种类如何，Akt激活均会诱导转移性乳腺癌的内分泌抵抗。我们的发现表明，HER2下游通路中Akt的激活在乳腺癌内分泌治疗抵抗中起重要作用。尽管我们的研究规模较小且为回顾性设计，但我们的发现表明pAkt可能是乳腺癌内分泌治疗抵抗的有用预测指标，同时也表明抑制Akt可能会提高内分泌治疗的疗效。
