曲妥珠单抗耐药乳腺癌患者新靶标

　　虽然曲妥珠单抗是HER2阳性乳腺癌的有效治疗方法，但是最终可能发生耐药。由于雄激素受体表达和免疫细胞浸润被认为与曲妥珠单抗效果相关，故有可能成为HER2阳性乳腺癌治疗新靶标而备受关注。

　　2018年9月9日，欧洲癌症治疗研究组织、欧洲癌症组织、欧洲乳腺癌专科学会《欧洲癌症杂志》在线发表荷兰格罗宁根马提尼医院、格罗宁根大学医学中心、茲沃勒艾瑟拉医院、中国汕头大学医学院附属肿瘤医院的研究报告，分析了HER2阳性乳腺癌的雄激素受体表达和免疫细胞浸润。

　　该研究选择221例曲妥珠单抗治疗原发肿瘤转移病变患者，HER2状态得到集中确认。通过免疫组织化学染色法检测雄激素受体、T淋巴细胞（CD3和CD8）、程序性细胞死亡蛋白1（PD-1）和PD-1配体1（PD-L1），通过免疫荧光法检测肿瘤相关巨噬细胞M2（CD68和CD163）。通过苏木精伊红染色法检测肿瘤浸润淋巴细胞。

　　结果从150例患者获得足够的肿瘤标本供检测，雌激素受体、雄激素受体分别表达于51.3%、81.3%的肿瘤。

　　雄激素受体表达水平与以下细胞浸润水平成反比：

• 肿瘤相关巨噬细胞M2（r=-0.361，P<0.001）

• CD3阳性T淋巴细胞（r=-0.199，P<0.030）

• CD8阳性T淋巴细胞（r=-0.212，P<0.021）

　　聚类分析（群组分析）表明：

• 雄激素受体低表达肿瘤的免疫细胞浸润水平高

• 雄激素受体高表达肿瘤的免疫细胞浸润水平低

　　因此，雄激素受体表达与HER2阳性乳腺癌免疫细胞浸润成反比，其中肿瘤相关巨噬细胞M2的反比关系最强。免疫细胞低浸润和雄激素受体高表达可以作为曲妥珠单抗耐药乳腺癌患者新靶标。

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Eur J Cancer. 2018 Sep 9;103:52-60.

Androgen receptor expression inversely correlates with immune cell infiltration in human epidermal growth factor receptor 2-positive breast cancer.

Johan M. van Rooijen, Si-Qi Qiu, Hetty Timmer-Bosscha, Bert van der Vegt, James E. Boers, Carolien P. Schroder, Elisabeth G.E. de Vries.

Martini Hospital Groningen, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Cancer Hospital of Shantou University Medical College, Guangdong, China; Isala Clinics, Zwolle, The Netherlands.

HIGHLIGHTS

• Androgen receptor (AR) expression was studied in human epidermal growth factor receptor 2-positive advanced breast cancer.

• AR expression was negatively correlated with immune cell infiltration.

• The strongest negative correlation with immune cell infiltration was with M2 tumour-associated macrophages.

• A subgroup was identified with low immune cell infiltration and high AR expression.

INTRODUCTION: Although targeting human epidermal growth factor receptor 2 (HER2) is a meaningful treatment in HER2-positive breast cancer, ultimately resistance develops. Androgen receptor (AR) expression and immune cell infiltration are thought to be involved in trastuzumab response and may, therefore, be of interest as additional targets for therapy in HER2-positive breast cancer.

AIM: To improve insights into the presence among AR expression, immune cell infiltration and HER2, we analysed HER2-positive breast tumours.

METHODS: Primary tumours of 221 patients treated with trastuzumab for metastatic disease were selected. HER2 status was centrally confirmed. AR, T-cells (CD3 and CD8), programmed cell death protein 1 (PD-1) and PD-1 ligand 1 immunohistochemical staining and M2 tumour-associated macrophages (TAMs; CD68 and CD163) immunofluorescence were performed. Tumour-infiltrating lymphocytes were evaluated by haematoxylin and eosin staining.

RESULTS: Sufficient tumour material was available for 150 patients. Oestrogen receptor was expressed in 51.3% of the tumours and AR in 81.3% of the tumours. AR expression was inversely correlated with M2 TAM (Pearson's r = -0.361, P < 0.001), CD3+ (r = -0.199, P < 0.030) and CD8+ (r = -0.212, P < 0.021) T-cell infiltration. Clustering analysis showed high immune cell infiltration in AR low-expressing tumours, and low immune cell infiltration in AR-high expressing tumours.

CONCLUSION: AR expression inversely correlates with immune cell infiltration in HER2-positive breast cancer.

KEYWORDS: Androgen receptor expression, HER2-positive metastatic breast cancer, Immune cell infiltration, Trastuzumab resistance

DOI: 10.1016/j.ejca.2018.08.001