Jacot William, Mollevi Caroline, Fina Frédéric, Lopez-Crapez Evelyne, Martin Pierre-Marie, Colombo Pierre-Emmanuel, Bibeau Frédéric, Romieu Gilles, Lamy Pierre-Jean
Department of Medical Oncology, Montpellier Cancer Institute Val d'Aurelle, 208, rue des Apothicaires, Montpellier, F-34298, France.
Translationnal Research Unit, Montpellier Cancer Institute Val d'Aurelle, 208, rue des Apothicaires, Montpellier, F-34298, France.
BMC Cancer. 2015 Dec 18;15:986. doi: 10.1186/s12885-015-1977-3.
Triple negative breast cancers (TNBC) are a more aggressive subset of breast cancer. A better understanding of its biology could allow the rational development of targeted therapies.
We extensively analyzed the EGFR/PI3K/PTEN axis in a large, homogeneous population of TNBC to help defining the putative role of anti-EGFR and -PI3K targeted therapies in this setting. EGFR gene amplification, EGFR protein expression, PIK3CA and PTEN gene alterations (two members of EGFR downstream pathways) and their clinicopathological and prognostic implications were analyzed in 204 TNBC samples from European patients.
EGFR amplification was detected in 18 of the 204 TNBC specimens (8.9 %) and was significantly associated with higher EGFR protein levels. Fourteen PIK3CA mutations were identified in exon 9 (6.7 %), and 17 in exon 20 (8.3 %). PIK3CA mutations, especially in exon 9, were significantly associated with grade I-II tumors. PTEN deletions were detected in 43 samples (21.50 %) and were significantly associated with grade III tumors (p < 0.001). Univariate analysis showed a significant association between relapse-free survival (RFS), T and N stage and exon 9 PIK3CA mutations. Overall survival was significantly associated with T stage, N stage and adjuvant chemotherapy, which was administered to 70.3 % of patients. In multivariate analyses, T stage, N stage, presence of exon 9 PIK3CA mutations and high EGFR protein level were independent poor prognostic factors for RFS, while adjuvant chemotherapy was associated with a better outcome.
High EGFR protein expression and exon 9 PIK3CA activating mutations are independent prognostic factors in TNBC. The efficacy of anti-PI3K targeted therapies needs to be evaluated in this setting.
三阴性乳腺癌（TNBC）是乳腺癌中侵袭性更强的一个亚型。更好地了解其生物学特性有助于合理开发靶向治疗方法。
我们在大量同质化的TNBC人群中广泛分析了EGFR/PI3K/PTEN轴，以帮助确定抗EGFR和抗PI3K靶向治疗在此情况下的假定作用。对来自欧洲患者的204份TNBC样本分析了EGFR基因扩增、EGFR蛋白表达、PIK3CA和PTEN基因改变（EGFR下游通路的两个成员）及其临床病理和预后意义。
在204份TNBC标本中有18份检测到EGFR扩增（8.9%），且与更高的EGFR蛋白水平显著相关。在第9外显子中鉴定出14个PIK3CA突变（6.7%），在第20外显子中鉴定出17个（8.3%）。PIK3CA突变，尤其是第9外显子中的突变，与I-II级肿瘤显著相关。在43个样本（21.50%）中检测到PTEN缺失，且与III级肿瘤显著相关（p<0.001）。单因素分析显示无复发生存期（RFS）、T和N分期与第9外显子PIK3CA突变之间存在显著关联。总生存期与T分期、N分期及辅助化疗显著相关，70.3%的患者接受了辅助化疗。在多因素分析中, T分期、N分期、第9外显子PIK3CA突变的存在及高EGFR蛋白水平是RFS的独立不良预后因素，而辅助化疗与更好的预后相关。
高EGFR蛋白表达和第9外显子PIK3CA激活突变是TNBC的独立预后因素。在此情况下需要评估抗PI3K靶向治疗的疗效。
