Ogino Shuji, Meyerhardt Jeffrey A, Cantor Mami, Brahmandam Mohan, Clark Jeffrey W, Namgyal Chungdak, Kawasaki Takako, Kinsella Kate, Michelini Ann L, Enzinger Peter C, Kulke Matthew H, Ryan David P, Loda Massimo, Fuchs Charles S
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Clin Cancer Res. 2005 Sep 15;11(18):6650-6. doi: 10.1158/1078-0432.CCR-05-0738.
Recently, activating mutations of the epidermal growth factor receptor (EGFR) gene were discovered in non-small cell lung cancers sensitive to gefitinib (ZD1839, an EGFR tyrosine kinase inhibitor) but not in gefitinib-resistant cancers. Abnormalities of EGFR and related pathways may have an effect on responsiveness of advanced colorectal cancer to combination chemotherapy with gefitinib.
We examined patients with previously untreated metastatic colorectal cancer, who were enrolled into two phase I/II trials of combination chemotherapy (irinotecan, leucovorin, and 5-fluorouracil) and daily oral gefitinib. We obtained paraffin tissue blocks of primary tumors from 31 patients, sequenced the EGFR, KRAS, and BRAF genes, and did immunohistochemistry for EGFR, phosphorylated AKT1, p53, p21, and p27.
Twelve (39%) of the 31 patients experienced a partial objective response to the therapy. A novel EGFR mutation in exon 18 (c.2170G>A, p.Gly724Ser) was identified in only one patient who did not experience an objective tumor response. EGFR immunohistochemistry was not predictive of responsiveness. In contrast, loss of p21 was associated with a higher response rate to therapy (P = 0.05). Moreover, the response rate among patients whose tumors maintained p21 expression and possessed a mutation in p53 was only 9% (1 of 11, P = 0.005). Overexpression of phosphorylated AKT1 also seemed to predict a trend towards resistance to the therapy.
p21 expression in colorectal cancer, especially in combination with p53 mutation, is a predictor of resistance to the combination chemotherapy with gefitinib. Activating EGFR mutations are rare in colorectal cancer and do not seem to confer sensitivity to gefitinib and chemotherapy.
最近，在对吉非替尼（ZD1839，一种表皮生长因子受体酪氨酸激酶抑制剂）敏感的非小细胞肺癌中发现了表皮生长因子受体（EGFR）基因的激活突变，但在吉非替尼耐药的癌症中未发现。EGFR及相关通路的异常可能会影响晚期结直肠癌对吉非替尼联合化疗的反应性。
我们研究了先前未经治疗的转移性结直肠癌患者，这些患者参加了两项关于联合化疗（伊立替康、亚叶酸钙和5-氟尿嘧啶）及每日口服吉非替尼的I/II期试验。我们从31例患者的原发性肿瘤中获取石蜡组织块，对EGFR、KRAS和BRAF基因进行测序，并对EGFR、磷酸化AKT1、p53、p21和p27进行免疫组织化学检测。
31例患者中有12例（39%）对治疗有部分客观反应。仅在1例未出现客观肿瘤反应的患者中发现了外显子18中的一种新型EGFR突变（c.2170G>A，p.Gly724Ser）。EGFR免疫组织化学检测不能预测反应性。相反，p21缺失与更高的治疗反应率相关（P = 0.05）。此外，肿瘤维持p21表达且存在p53突变的患者的反应率仅为9%（11例中的1例，P = 0.005）。磷酸化AKT1的过表达似乎也预示着对治疗耐药的趋势。
结直肠癌中p21的表达，尤其是与p53突变相结合时，是对吉非替尼联合化疗耐药的一个预测指标。激活的EGFR突变在结直肠癌中很少见，似乎不会使肿瘤对吉非替尼和化疗敏感。
