Levva Sofia, Kotoula Vassiliki, Kostopoulos Ioannis, Manousou Kyriaki, Papadimitriou Christos, Papadopoulou Kyriaki, Lakis Sotiris, Koukoulias Kyriakos, Karavasilis Vasilios, Pentheroudakis George, Balassi Eufemia, Zagouri Flora, Kaklamanos Ioannis G, Pectasides Dimitrios, Razis Evangelia, Aravantinos Gerasimos, Papakostas Pavlos, Bafaloukos Dimitrios, Rallis Grigorios, Gogas Helen, Fountzilas George
Department of Medical Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine, Thessaloniki, Greece
Department of Pathology, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine, Thessaloniki, Greece.
Cancer Genomics Proteomics. 2017 May-Jun;14(3):181-195. doi: 10.21873/cgp.20030.
Epidermal growth factor receptor (EGFR) aberrations have been implicated in the pathogenesis of triple-negative breast cancer (TNBC) but their impact on prognosis and, therefore, druggability, remain controversial. Herein, we studied EGFR aberrations at different molecular levels and assessed their prognostic impact in patients with operable TNBC treated with adjuvant anthracycline-based chemotherapy.
We evaluated the prognostic impact of EGFR gene status by fluorescent in situ hybridization (FISH), EGFR coding mutations by Sanger and next-generation sequencing, relative EGFR messenger RNA (mRNA) levels by qPCR (upper quartile) and EGFR and p53 protein expression by immunohistochemistry (IHC), in 352 centrally-assessed tumors from an equal number of TNBC patients.
Approximately 53.5% of the tumors expressed EGFR, 59.3% p53 and 35.9% both EGFR and p53 proteins; 4.1% showed EGFR gene amplification and 4.4% carried EGFR mutations. The latter were located outside the druggable kinase domain region and presented at low frequencies. Amplification and mutations overlapped only in one case of glycogen-rich carcinoma. EGFR and CEN7 copies were higher in tumors from older patients (p=0.002 and p=0.003, respectively). Patients with amplified tumors (n=11) had excellent prognosis (0 relapses and deaths). Upon multivariate analysis, high EGFR copies conferred significantly favorable disease-free survival (HR=0.57, 95% CI 0.36-0.90, Wald's p=0.017) and high CEN7 copies favorable overall survival (HR=0.49, 95% CI=0.29-0.83, Wald's p=0.008). Patients with EGFR-/p53+ and EGFR+/p53- tumors had significantly higher risk for relapse than those with EGFR-/p53- and EGFR+/p53+ tumors (HR=1.73, 95% CI=1.12-2.67, Wald's p=0.013).
EGFR gene amplification and mutations are rare in TNBC, the latter of no apparent clinical relevance. Surrogate markers of EGFR-related chromosomal aberrations and combined EGFR/p53 IHC phenotypes appear to be associated with favorable prognosis in patients with operable TNBC receiving conventional adjuvant chemotherapy.
表皮生长因子受体（EGFR）异常与三阴性乳腺癌（TNBC）的发病机制有关，但其对预后的影响以及因此对药物可及性的影响仍存在争议。在此，我们研究了不同分子水平下的EGFR异常，并评估了其对接受蒽环类辅助化疗的可手术TNBC患者预后的影响。
我们通过荧光原位杂交（FISH）评估EGFR基因状态的预后影响，通过桑格测序和二代测序检测EGFR编码突变，通过定量PCR（上四分位数）检测EGFR信使核糖核酸（mRNA）相对水平，通过免疫组织化学（IHC）检测EGFR和p53蛋白表达，研究对象为来自同等数量TNBC患者的352例经中心评估的肿瘤。
约53.5%的肿瘤表达EGFR，59.3%表达p53，35.9%同时表达EGFR和p53蛋白；4.1%显示EGFR基因扩增，4.4%携带EGFR突变。后者位于药物可及的激酶结构域区域之外，且频率较低。扩增和突变仅在1例富含糖原的癌中重叠。老年患者肿瘤中的EGFR和7号染色体着丝粒（CEN7）拷贝数更高（分别为p = 0.002和p = 0.003）。肿瘤扩增患者（n = 11）预后良好（无复发和死亡）。多因素分析显示，高EGFR拷贝数赋予显著良好的无病生存期（HR = 0.57，95%CI 0.36 - 0.90，Wald检验p = 0.017），高CEN7拷贝数赋予良好的总生存期（HR = 0.49，95%CI = 0.29 - 0.83，Wald检验p = 0.008）。EGFR - /p53 +和EGFR + /p53 -肿瘤患者的复发风险显著高于EGFR - /p53 -和EGFR + /p53 +肿瘤患者（HR = 1.73，95%CI = 1.12 - 2.67，Wald检验p = 0.013）。
EGFR基因扩增和突变在TNBC中罕见，后者无明显临床相关性。EGFR相关染色体异常的替代标志物以及EGFR/p53联合免疫组化表型似乎与接受传统辅助化疗的可手术TNBC患者的良好预后相关。
