Mountzios Giannis, Aivazi Dimitra, Kostopoulos Ioannis, Kourea Helen P, Kouvatseas George, Timotheadou Eleni, Zebekakis Pantelis, Efstratiou Ioannis, Gogas Helen, Vamvouka Chrisanthi, Chrisafi Sofia, Stofas Anastasios, Pentheroudakis George, Koutras Angelos, Galani Eleni, Bafaloukos Dimitrios, Fountzilas George
Department of Medical Oncology, 251 Airforce General Hospital, Athens, Greece.
Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
PLoS One. 2014 Mar 17;9(3):e91407. doi: 10.1371/journal.pone.0091407. eCollection 2014.
We sought to determine the level of protein expression of the critical components of the insulin-like growth factor receptor (IGFR) pathway and to evaluate their prognostic significance across the different early breast cancer subtypes.
Archival tumor tissue from 1,021 women with early, node positive breast cancer, who were prospectively evaluated within two randomized clinical trials, was used to construct tissue microarrays that were stained for hormone receptors (HR), Ki67, HER2, epidermal growth factor receptor (EGFR) and cytokeratins 5/6, to classify tumors into five immunophenotypical subgroups. Immunohistochemical (IHC) expression of IGF1R-alpha and beta subunits, IGF2R and IGF-binding protein 2 (IGFBP2) was assessed using the immunoreactive score (IRS). Repeated internal cross-validation was performed to examine the statistical validity of the cut off points for all biomarkers.
After a median follow-up time of 105.4 months, overall 370 women (36.2%) had relapsed and 270 (26.4%) had died. Tumors expressing IGF1R-alpha above the median IRS were significantly more frequently HR positive (luminal A+B+HER2), as compared to HER2-enriched and triple negative ones (p<0.001 for both comparisons). IGF2R was overexpressed significantly more frequently in HR negative tumors (p = 0.001) and had an inverse correlation with all other biomarkers. Patients with luminal A and B tumors with high IGF1R-alpha and negative EGFR expression (N = 190) had significantly higher 4-year survival rates, as compared to the rest (log-rank p = 0.046), as did patients with luminal A and B tumors with high IGF1R-alpha and low IGF2R expression, as compared to the rest (N = 91), (log-rank p = 0.035). After adjustment for significant variables, patients in the latter group had a relative 45% reduction in the risk of death, as compared to the rest (p = 0.035).
Aberrant expression of components of the IGF1R pathway is associated with better clinical outcomes in women with luminal A and B, node positive, early breast cancer.
我们试图确定胰岛素样生长因子受体（IGFR）通路关键组分的蛋白表达水平，并评估其在不同早期乳腺癌亚型中的预后意义。
来自1021例早期、淋巴结阳性乳腺癌女性患者的存档肿瘤组织用于构建组织微阵列，这些患者在两项随机临床试验中接受了前瞻性评估。该组织微阵列进行了激素受体（HR）、Ki67、HER2、表皮生长因子受体（EGFR）和细胞角蛋白5/6染色，以将肿瘤分为五个免疫表型亚组。使用免疫反应评分（IRS）评估IGF1R-α和-β亚基、IGF2R和胰岛素样生长因子结合蛋白2（IGFBP2）的免疫组织化学（IHC）表达。进行重复内部交叉验证以检验所有生物标志物截断点的统计有效性。
中位随访时间为105.4个月后，共有370例女性（36.2%）复发，270例（26.4%）死亡。与HER2富集型和三阴性肿瘤相比，IRS中位数以上表达IGF1R-α的肿瘤HR阳性（管腔A+B+HER2）更为常见（两项比较均p<0.001）。IGF2R在HR阴性肿瘤中过表达更为频繁（p = 0.001），且与所有其他生物标志物呈负相关。与其余患者相比，IGF1R-α高表达且EGFR阴性的管腔A和B肿瘤患者（N = 190）4年生存率显著更高（对数秩检验p = 0.046），与其余患者相比，IGF1R-α高表达且IGF2R低表达的管腔A和B肿瘤患者（N = 91）也是如此（对数秩检验p = 0.035）。在对显著变量进行调整后，与其余患者相比，后一组患者死亡风险相对降低45%（p = 0.035）。
IGF1R通路组分的异常表达与管腔A和B、淋巴结阳性、早期乳腺癌女性更好的临床结局相关。
