Khan Sajid A, Zeng Zhaoshi, Shia Jinru, Paty Philip B
Department of Surgery, Section of Surgical Oncology, Yale University School of Medicine, 310 Cedar Street, FMB 130, New Haven, CT, 06520, USA.
Colorectal Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Pathol Oncol Res. 2017 Jul;23(3):673-677. doi: 10.1007/s12253-016-0166-2. Epub 2016 Dec 26.
Genetic variability in KRAS and EGFR predicts response to cetuximab in irinotecan refractory colorectal cancer. Whether these markers or others remain predictive in combination biologic therapies including bevacizumab is unknown. We identified predictive biomarkers from patients with irinotecan refractory metastatic colorectal cancer treated with cetuximab plus bevacizumab. Patients who received cetuximab plus bevacizumab for irinotecan refractory colorectal cancer in either of two Phase II trials conducted were identified. Tumor tissue was available for 33 patients. Genomic DNA was extracted and used for mutational analysis of KRAS, BRAF, and p53 genes. Fluorescence in situ hybridization was performed to assess EGFR copy number. The status of single genes and various combinations were tested for association with response. Seven of 33 patients responded to treatment. KRAS mutations were found in 14/33 cases, and 0 responded to treatment (p = 0.01). EGFR gene amplification was seen in 3/33 of tumors and in every case was associated with response to treatment (p < 0.001). TP53 and BRAF mutations were found in 18/33 and 0/33 tumors, respectively, and there were no associations with response to either gene. EGFR gene amplification and KRAS mutations are predictive markers for patients receiving combination biologic therapy of cetuximab plus bevacizumab for metastatic colorectal cancer. One marker or the other is present in the tumor of half of all patients allowing treatment response to be predicted with a high degree of certainty. The role for molecular markers in combination biologic therapy seems promising.
KRAS和EGFR的基因变异性可预测伊立替康难治性结直肠癌对西妥昔单抗的反应。在包括贝伐单抗在内的联合生物疗法中，这些标志物或其他标志物是否仍具有预测性尚不清楚。我们从接受西妥昔单抗联合贝伐单抗治疗的伊立替康难治性转移性结直肠癌患者中确定了预测性生物标志物。确定了在两项进行的II期试验中任何一项接受西妥昔单抗联合贝伐单抗治疗伊立替康难治性结直肠癌的患者。33例患者有肿瘤组织可用。提取基因组DNA并用于KRAS、BRAF和p53基因的突变分析。进行荧光原位杂交以评估EGFR拷贝数。测试单个基因的状态和各种组合与反应的相关性。33例患者中有7例对治疗有反应。在14/33例中发现KRAS突变，0例对治疗有反应（p = 0.01）。在3/33的肿瘤中观察到EGFR基因扩增，并且在每种情况下均与治疗反应相关（p < 0.001）。分别在18/33和0/33的肿瘤中发现TP53和BRAF突变，且与任一基因的反应均无关联。EGFR基因扩增和KRAS突变是接受西妥昔单抗联合贝伐单抗治疗转移性结直肠癌的联合生物疗法患者的预测性标志物。所有患者中有一半的肿瘤中存在一种或另一种标志物，从而可以高度确定地预测治疗反应。分子标志物在联合生物疗法中的作用似乎很有前景。
