BACKGROUND: Oral squamous cell carcinoma (OSCC) is a prevalent type of cancer with a high mortality rate in its late stages. One of the major challenges in OSCC treatment is the resistance to epidermal growth factor receptor (EGFR) inhibitors. Therefore, it is imperative to elucidate the mechanism underlying drug resistance and develop appropriate precision therapy strategies to enhance clinical efficacy. METHODS: To evaluate the efficacy of the combination of the Ca 2+ /calmodulin-dependent protein kinase II (CAMK2) inhibitor KN93 and EGFR inhibitors, we performed in vitro and in vivo experiments using two FAT atypical cadherin 1 ( FAT1 )-deficient (SCC9 and SCC25) and two FAT1 wild-type (SCC47 and HN12) OSCC cell lines. We assessed the effects of EGFR inhibitors (afatinib or cetuximab), KN93, or their combination on the malignant phenotype of OSCC in vivo and in vitro . The alterations in protein expression levels of members of the EGFR signaling pathway and SRY-box transcription factor 2 (SOX2) were analyzed. Changes in the yes-associated protein 1 (YAP1) protein were characterized. Moreover, we analyzed mitochondrial dysfunction. Besides, the effects of combination therapy on mitochondrial dynamics were also evaluated. RESULTS: OSCC with FAT1 mutations exhibited resistance to EGFR inhibitors treatment. The combination of KN93 and EGFR inhibitors significantly inhibited the proliferation, survival, and migration of FAT1 -mutated OSCC cells and suppressed tumor growth in vivo . Mechanistically, combination therapy enhanced the therapeutic sensitivity of FAT1 -mutated OSCC cells to EGFR inhibitors by modulating the EGFR pathway and downregulated tumor stemness-related proteins. Furthermore, combination therapy induced reactive oxygen species (ROS)-mediated mitochondrial dysfunction and disrupted mitochondrial dynamics, ultimately resulting in tumor suppression. CONCLUSION Combination therapy with EGFR inhibitors and KN93 could be a novel precision therapeutic strategy and a potential clinical solution for EGFR-resistant OSCC patients with FAT1 mutations.
Humans ; ErbB Receptors/metabolism* ; Mouth Neoplasms/metabolism* ; Cell Line, Tumor ; Animals ; Drug Resistance, Neoplasm/genetics* ; Cadherins/metabolism* ; Carcinoma, Squamous Cell/metabolism* ; Mice ; Mutation/genetics* ; Mice, Nude ; Protein Kinase Inhibitors/therapeutic use* ; Cetuximab/pharmacology* ; Afatinib/therapeutic use* ; Cell Proliferation/drug effects* ; Signal Transduction/drug effects*

Head and neck squamous cell carcinoma （HNSCC） is one of the ten most common cancers worldwide and is one of the refractory cancers with a poor prognosis in otorhinolaryngology-head and neck surgery. Cetuximab is widely used in the clinical treatment of HNSCC and has been approved by the FDA as a first-line chemotherapeutic agent. However, its efficacy varies significantly among different individuals. Therefore, exploring the resistance mechanisms of cetuximab in the treatment of HNSCC and screening for sensitive populations are essential for the precision treatment of head and neck cancer. This article summarizes the research progress on cetuximab resistance mechanisms in HNSCC, and the main aspects include: alterations in epidermal growth factor receptor （EGFR） and its ligands, changes in downstream effectors of EGFR, bypass activation and crosstalk, epithelial-mesenchymal transition, epigenetic modifications, and immunosuppression in the tumor microenvironment.
Humans ; Cetuximab/therapeutic use* ; Drug Resistance, Neoplasm ; Squamous Cell Carcinoma of Head and Neck/drug therapy* ; Head and Neck Neoplasms/drug therapy* ; ErbB Receptors/metabolism* ; Tumor Microenvironment ; Epithelial-Mesenchymal Transition ; Molecular Targeted Therapy ; Antineoplastic Agents, Immunological/therapeutic use*

Objective:To analyze the risk factors that affect the prognosis of patients with hypopharyngeal squamous cell carcinoma（HPSCC） and to compare the efficacy of surgical resection followed by adjuvant radiotherapy（SR） with that of neoadjuvant therapy consisting of platinum-based chemotherapy and fluorouracil combined with either cetuximab or nimotuzumab, followed by SR. The study also aimed to evaluate the overall survival（OS） of patients, their postoperative eating function, tracheostomy decannulation rate, and tumor response to the two neoadjuvant chemotherapies. Methods:A retrospective analysis was performed on the medical records of HPSCC patients who received SR or neoadjuvant therapy followed by SR treatment at the Shanghai General Hospital from 2012 to 2019 and had not undergone any prior treatment. The prognostic factors were analyzed, and the survival analysis of patients who underwent SR treatment with two neoadjuvant chemotherapy regimens was performed. Results:A total of 108 patients were included in the study. The results of the univariate analysis showed that gender（P=0.850） had no significant correlation with the survival rate of HPSCC patients who underwent SR. However, age, smoking history, alcohol consumption history, platelet-to-lymphocyte ratio（PLR）, neutrophil-to-lymphocyte ratio（NLR）, T stage, N stage, neoadjuvant therapy with either cetuximab or nimotuzumab combined with platinum-based chemotherapy and fluorouracil, and histological grade were significantly associated with prognosis（P<0.05）. The multivariate analysis revealed that smoking history, histological grade, and neoadjuvant therapy with either cetuximab or nimotuzumab combined with platinum-based chemotherapy and fluorouracil were independent risk factors affecting the prognosis of HPSCC（P<0.05）. Patients who received neoadjuvant therapy had longer OS than those who underwent SR only（P<0.001）. There was no significant difference in tumor response to the two neoadjuvant therapies and in OS（P>0.05）, and there was no significant difference in the rate of oral feeding and tracheostomy decannulation among the three treatment groups（P>0.05）. Conclusion:Univariate analysis showed that age at tumor onset, smoking history, alcohol consumption history, NLR, PLR, T stage, N stage, whether receiving neoadjuvant chemotherapy, and pathological grade were associated with the prognosis of HPSCC patients receiving SR treatment. Multivariate analysis showed that smoking history, pathological grade, and neoadjuvant chemotherapy were independent risk factors affecting the prognosis. Neoadjuvant chemotherapy with cetuximab or nimotuzumab can prolong the OS of patients, providing a certain basis and reference for the treatment of HPSCC.
Humans ; Neoadjuvant Therapy ; Squamous Cell Carcinoma of Head and Neck ; Cetuximab/therapeutic use* ; Retrospective Studies ; China ; Prognosis ; Fluorouracil ; Head and Neck Neoplasms

PURPOSE: Rearrangement of the proto-oncogene rearranged during transfection (RET) has been newly identified potential driver mutation in lung adenocarcinoma. Clinically available tyrosine kinase inhibitors (TKIs) target RET kinase activity, which suggests that patients with RET fusion genes may be treatable with a kinase inhibitor. Nevertheless, the mechanisms of resistance to these agents remain largely unknown. Thus, the present study aimed to determine whether epidermal growth factor (EGF) and hepatocyte growth factor (HGF) trigger RET inhibitor resistance in LC-2/ad cells with CCDC6-RET fusion genes. MATERIALS AND METHODS: The effects of EGF and HGF on the susceptibility of a CCDC6-RET lung cancer cell line to RET inhibitors (sunitinib, E7080, vandetanib, and sorafenib) were examined. RESULTS: CCDC6-RET lung cancer cells were highly sensitive to RET inhibitors. EGF activated epidermal growth factor receptor (EGFR) and triggered resistance to sunitinib, E7080, vandetanib, and sorafenib by transducing bypass survival signaling through ERK and AKT. Reversible EGFR-TKI (gefitinib) resensitized cancer cells to RET inhibitors, even in the presence of EGF. Endothelial cells, which are known to produce EGF, decreased the sensitivity of CCDC6-RET lung cancer cells to RET inhibitors, an effect that was inhibited by EGFR small interfering RNA (siRNA), anti-EGFR antibody (cetuximab), and EGFR-TKI (Iressa). HGF had relatively little effect on the sensitivity to RET inhibitors. CONCLUSION: EGF could trigger resistance to RET inhibition in CCDC6-RET lung cancer cells, and endothelial cells may confer resistance to RET inhibitors by EGF. E7080 and other RET inhibitors may provide therapeutic benefits in the treatment of RET-positive lung cancer patients.
Adenocarcinoma/drug therapy/*genetics ; Cell Line, Tumor ; Cetuximab/pharmacology ; Drug Resistance, Neoplasm/drug effects/*genetics ; Epidermal Growth Factor/metabolism/*pharmacology ; *Gene Rearrangement ; Hepatocyte Growth Factor/*pharmacology ; Humans ; Indoles/pharmacology ; Lung Neoplasms/drug therapy/*genetics ; MAP Kinase Signaling System ; *Mutation ; Niacinamide/analogs & derivatives/pharmacology ; Phenylurea Compounds/pharmacology ; Piperidines/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Proto-Oncogene Proteins c-ret/*antagonists & inhibitors/genetics ; Pyrroles/pharmacology ; Quinazolines/pharmacology ; RNA, Small Interfering/pharmacology ; Receptor, Epidermal Growth Factor/genetics/metabolism ; Signal Transduction/drug effects ; fms-Like Tyrosine Kinase 3/metabolism

The NCCN has recently released its 2017 version 1.0 guideline for colorectal cancer. There are several updates from this new version guideline which are believed to change the current clinical practice. Update one, low-dose aspirin is recommended for patients with colorectal cancer after colectomy for secondary chemoprevention. Update two, biological agents are removed from the neoadjuvant treatment regimen for resectable metastatic colorectal cancer (mCRC). This update is based on lack of evidence to support benefits of biological agents including bevacizumab and cetuximab in the neoadjuvant setting. Both technical criteria and prognostic information should be considered for decision-making. Currently biological agents may not be excluded from the neoadjuvant setting for patients with resectable but poor prognostic disease. Update three, panitumumab and cetuximab combination therapy is only recommended for left-sided tumors in the first line therapy. The location of the primary tumor can be both prognostic and predictive in response to EGFR inhibitors in metastatic colorectal cancer. Cetuximab and panitumumab confer little benefit to patients with metastatic colorectal cancer in the primary tumor originated on the right side. On the other hand, EGFR inhibitors provide significant benefit compared with bevacizumab-containing therapy or chemotherapy alone for patients with left primary tumor. Update four, PD-1 immune checkpoint inhibitors including pembrolizumab or nivolumab are recommended as treatment options in patients with metastatic deficient mismatch repair (dMMR) colorectal cancer in second- or third-line therapy. dMMR tumors contain thousands of mutations, which can encode mutant proteins with the potential to be recognized and targeted by the immune system. It has therefore been hypothesized that dMMR tumors may be sensitive to PD-1 inhibitors.
Antibodies, Monoclonal ; pharmacology ; therapeutic use ; Antibodies, Monoclonal, Humanized ; therapeutic use ; Antineoplastic Agents ; therapeutic use ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Aspirin ; administration & dosage ; therapeutic use ; Bevacizumab ; therapeutic use ; Biological Products ; therapeutic use ; Brain Neoplasms ; drug therapy ; genetics ; Cetuximab ; therapeutic use ; Clinical Decision-Making ; methods ; Colorectal Neoplasms ; drug therapy ; genetics ; pathology ; prevention & control ; therapy ; Contraindications ; Humans ; Mutation ; physiology ; Neoadjuvant Therapy ; standards ; Neoplasm Metastasis ; drug therapy ; Neoplastic Syndromes, Hereditary ; drug therapy ; genetics ; Practice Guidelines as Topic ; Prognosis ; Secondary Prevention ; methods ; standards

Preoperative chemoradiotherapy (CRT) has become an important component of comprehensive treatment for rectal cancer. Although local recurrent risk has been remarkably reduced by CRT, distant metastasis remains the main cause of therapeutic failure. Therefore, more and more studies focused on controlling distant metastasis in order to prolong long-term survival. Recently, CRT has achieved certain progression in rectal cancer: (1)Patients with stage T3 should be classified into specific subgroups to formulate individualized treatment regimen. For stage T3a, it is feasible to perform surgery alone or administrate low intensity preoperative CRT; for stage T3b and T3c, conventional preoperative CRT should be performed in order to reduce the risk of recurrence postoperatively. (2)With regard to combined regimen for chemotherapy, oral capecitabine superiors to intravenous bolus 5-fluorouracil (5-FU) and is comparable to continuous intravenous infusion 5-FU with a better safety. Therefore, capecitabine is recommended for older patients and those with poor tolerance to chemotherapy. Compared to single 5-FU concurrent CRT, addition of oxaliplatin into preoperative CRT may result in a higher survival benefit in Chinese patients. As to the application of irinotecan, bevacizumab or cetuximab, unless there are more evidence to confirm their efficacy and safety from randomized controlled trial, they should not be recommended for adding to preoperative CRT routinely. (3)On the optimization in CRT pattern, the application values of induction chemotherapy before concurrent CRT, consolidation chemotherapy after concurrent CRT, neoadjuvant sandwich CRT, neoadjuvant chemotherapy alone and short-course preoperative radiotherapy remain further exploration. (4)On the treatment strategy for clinical complete response (cCR) after CRT, whether "wait and see" strategy is able to be adopted, it is still a hot topic with controversy.
Antineoplastic Agents ; therapeutic use ; Bevacizumab ; therapeutic use ; Camptothecin ; analogs & derivatives ; therapeutic use ; Capecitabine ; therapeutic use ; Cetuximab ; therapeutic use ; Chemoradiotherapy ; Deoxycytidine ; Fluorouracil ; therapeutic use ; Humans ; Neoadjuvant Therapy ; Neoplasm Recurrence, Local ; Neoplasm Staging ; Organoplatinum Compounds ; therapeutic use ; Preoperative Care ; Rectal Neoplasms ; surgery ; therapy

OBJECTIVE: To-evaluate the role and clinical value of cetuximab in the treatment of head and neck squamous cell carcinoma (HNSCC), and figure out its effectiveness and application, so as to develop evidence-based recommendations for treatment. METHOD: We comprehensively searched the CBM, Pubmed, EMBASE, and the Cochrane databases to identify published studies on the effect of cetuximab in HNSCC patients. Primary outcomes included overall survival (OS), progression-free survival(PFS) and overall response rate(ORR). Secondary outcomes included serious adverse events, such as neutropenia, anemia, thrombocytopenia, skin reactions, hypokalemia, vomiting, asthenia, hypomagnesemia, dyspnea and sepsis. Results were dispalyed as risk ratio (RR), odds ratio (OR), mean difference (MD) and 95% CI. RESULT: A Meta-analysis was conducted on 4 randomized controlled trials, including 2 trials comprising 1,319 patients with locally advanced HNSCC and 2 trails comprising 559 patients with recurrent or metastatic HNSCC. For locally advanced HNSCC, the 2 year PFS and OS showed no significant differences in patients received cetuximab or not (PFS fixed effect: RR=1.02, 95%CI 0.92-1.12, P>0.05; OS fixed effect: RR=1.06, 95%CI 1.00-1.13, P>0.05, respectively). Grade 3-4 dysphagia was also similar in patients treated with cetuximab or no cetuximab (dysphagia: fixed effect: RR = 0.92; 95% CI 0.84-1.02, P>0. 05). Only grade 3-4 mucositis and skin reaction showed statistical significance between patients treated with cetuximab and patients with no cetuximab (mucositis: fixed effect: RR=1.21; 95%CI 1.07-1. 36, P<0. 05; skin reaction: fixed effect: RR=1.99; 95%CI 1.39-2.85, P<0.05, respectively). For recurrent or metastatic HNSCC, the OS overall mean difference was 2.41 (95% CI 0.96-3.86, P<0.05), the PFS overall mean difference was 2. 06 (95% CI 1.34 - 2.77, P<0.05), and the ORR overall Odds ratio was 2.38 (95% CI 1.60-3.54,P<0.05), suggesting significant effect of cetuximab in improving the prognosis of R/M HNSCC. Owing to small number of trials it was not possible to assess the presence of publication bias. Of note, the 1 year survival overall Odds ratio was 1.39 (95% CI 0.98-1.97, P>0.05). The grade 3 or 4 adverse effects were described in 83. 4% of patients in cetuximab group and 75. 5% of patients in no cetuximab group. The overall side effects risk ratio suggested statistically significant difference between patients treated with cetuximab and pa- tients with no cetuximab (RR=1.11, 95% CI 1.01-1.20, P<0.05, P =47%). CONCLUSION The 2 year progression-free survival and overall survival were similar between cetuximab group and no cetuximab group in patients with locally advanced head and neck squamous cell cancer. Data are limited and the benefits of cetuximab on this outcome remain uncertain. Impact of grade 3-4 dysphagia was similar in both groups, however, the incidence of grade 3-4 mucositis and skin reaction were lower in patients treated with cetuximab. Existing randomized controlled trials provided a scientific evidence for the use of cetuximab in R/M HNSCC. The conclusion of the study is based on limited number of RCT, so further investigation is still needed before firm recommendations of cetuximab can be made in the treatment of HNSCC.
Antibodies, Monoclonal, Humanized ; therapeutic use ; Antineoplastic Agents ; therapeutic use ; Carcinoma, Squamous Cell ; drug therapy ; Cetuximab ; Disease-Free Survival ; Head and Neck Neoplasms ; drug therapy ; Humans ; Squamous Cell Carcinoma of Head and Neck

OBJECTIVETo investigate the treatment outcome of loco-regionally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) after been treated with multi-modality approach since 2005 in our hospital and to explore the prognostic factors for treatment outcomes.

METHODSClinical data of 125 postoperative LA-SCCHN patients treated in our department with radiotherapy/chemoradiotherapy from May 2005 to December 2011 were collected and reviewed in this study. The radiotherapy technique was intensity-modulated radiotherapy (IMRT) (93.6%) and a minority of patients received 3D-conformal radiotherapy (3D-CRT).

RESULTSUp to January 6th, 2013, 124 patients were followed up with a median follow-up duration of 25 months. The 3-year overall survival (OS), disease-free survival (DFS), loco-regional control (LRC), distant metastasis-free survival (DMFS) were 69.7%, 56.1%, 80.8%, and 73.1%, respectively. A total of 37 patients died during the follow-up period. Among the 43 patients presented with treatment failure, 13 patients had loco-regional relapse, 20 patients had distant metastasis and 10 patients presented with both loco-regional and distant relapses. Distant metastasis accounted for the predominant cause of death. Lung and mediastinal lymph nodes are the most common sites involved by distant metastasis.Univariate analysis indicated that patients who underwent non-radical surgery, with larger size of invaded lymph nodes, higher N stage (N2b and above) and vascular tumor embolism had a lower OS (P = 0.001, 0.000, 0.032, 0.007, respectively). Patients who underwent neck dissection only, or those with higher N stage (N2b and above) or higher TNM stage or vascular tumor thrombi had higher distant metastasis rates (P = 0.017, 0.002, 0.008, 0.001, respectively). The multivariate analysis showed that non-radical surgery was an independent prognostic factor for OS (P = 0.001), larger size of invaded lymph nodes was an independent prognostic factor for poorer LRC (P = 0.001); higher N stage (N2b and above) or T4 stage and vascular tumor thrombi were independent prognostic factors for poorer distant metastasis-free survival (P = 0.035, 0.008 and 0.050, respectively).

CONCLUSIONSOur results indicate that multi-modality treatment for LA-SCCHN has achieved better outcome than before. Distant metastasis has become the predominant pattern of failure as well as the primary cause of death instead of loco-regional relapse as a result of improved local control modality. More efforts should be made to decrease the rate of distant metastasis in the future.

Adult ; Aged ; Antibodies, Monoclonal, Humanized ; therapeutic use ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Carcinoma, Squamous Cell ; pathology ; secondary ; therapy ; Cetuximab ; Cisplatin ; therapeutic use ; Combined Modality Therapy ; Disease-Free Survival ; Female ; Fluorouracil ; therapeutic use ; Follow-Up Studies ; Head and Neck Neoplasms ; pathology ; secondary ; therapy ; Humans ; Lymphatic Metastasis ; Male ; Middle Aged ; Neck Dissection ; Neoplasm Metastasis ; Neoplasm Recurrence, Local ; Neoplasm Staging ; Neoplastic Cells, Circulating ; Radiotherapy, Conformal ; Radiotherapy, Intensity-Modulated ; Survival Rate ; Taxoids ; therapeutic use

OBJECTIVEThe aim of this study was to investigate the effects of combination of icotinib and cetuximab on the acquired drug resistance caused by T790M mutation of EGFR in NSCLC, and provide experimental evidence for rational treatment of NSCLC.

METHODSThe effects of these two agents on cell proliferation, apoptosis, and EGFR-dependent signaling were evaluated using 3-(4, 5-dimethylthiazol-2-yl)- 5-diphenyltetrazolium bromide (MTT) assay, annexin V staining, and Western blotting. The expression of molecular markers of tumor proliferation PCNA and Ki-67 protein was further examined by immunohistochemistry, and the expression of EGFR-signaling-related proteins in tissue sections taken from H1975 tumor xenografts was assessed by Western blot assay. Sensitivity to EGFR inhibitors was detected in human H1975 tumor xenograft in nude mice.

RESULTSThe in vitro experiment showed that the proliferative ability of H1975 cells was inhibited in a dose-dependent manner, along with the increasing doses of cetuximab and icotinib, and the combination of cetuximab with icotinib resulted in a more pronounced growth inhibition of the H1975 cells. The apoptosis rate of H1975 cells after treatment with 0.5 µmol/L icotinib and 1 µg/ml cetuximab was (22.03 ± 2.41)% and that after treatment with 5 µmol/L icotinib and 10 µg/ml cetuximab was (42.75 ± 2.49)%, both were significantly higher than that after treatment with the same dose of icotinib or cetuximab alone (P < 0.05). The nude mouse experiment showed that the transplanted tumor was growing to (614.5 ± 10.8) mm(3) in the blank control group and to (611.2 ± 8.7) mm(3) at 28 days after icotinib treatment, but (30.8 ± 2.0) mm(3) in the cetuximab treatment group and 0 mm(3) in the cetuximab combined with icotinib group. There was a significantly decreased expression of Ki-67 and PCNA proteins and down-regulation of phosphorylation of EGFR signaling-related proteins in the cetuximab combined with icotinib group.

CONCLUSIONSThe combination of icotinib with cetuximab can exert synergistic inhibitory effect on the acquired drug resistance caused by T790M mutation of EGFR in NSCLC H1975 cells, interrupts the EGFR-downstream signaling pathway, and enhances the anticancer activity of chemotherapeutic drugs. Our results provide further experimental evidence for the clinical studies of combination of icotinib with cetuximab in the treatment of NSCLC patients associated with secondary drug resistance caused by T790M mutation of EGFR.

Animals ; Antibodies, Monoclonal, Humanized ; administration & dosage ; therapeutic use ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Apoptosis ; Carcinoma, Non-Small-Cell Lung ; drug therapy ; genetics ; Cell Line, Tumor ; Cell Proliferation ; Cetuximab ; Crown Ethers ; administration & dosage ; therapeutic use ; Down-Regulation ; Drug Resistance, Neoplasm ; genetics ; Genes, erbB-1 ; genetics ; Humans ; Lung Neoplasms ; drug therapy ; Mice ; Mice, Nude ; Mutation ; Quinazolines ; administration & dosage ; therapeutic use ; Receptor, Epidermal Growth Factor ; Signal Transduction

OBJECTIVETo detect K-ras gene mutations in plasma free DNA by peptide nucleic acid clamp PCR assay (PNA-PCR) and nested primer PCR, and to analyze the correlation between K-ras mutations and prognosis in patients with metastatic colorectal cancer (mCRC).

METHODSPeripheral blood was collected and free DNA was extracted from plasma in 106 patients with mCRC. Nested primer PCR and PNA-PCR were used to detect K-ras gene mutation in the plasma free DNA. The patients were divided into three groups by K-ras status: wild-type group (wild-type determined by both methods), low mutation group (mutation by PNA-PCR method, wild-type by nested primer PCR method) and high mutation group (mutation by two methods). The correlation between K-ras mutations and prognosis was analyzed.

RESULTSThe mutation rate of K-ras in tumor tissues of the 106 patients was 40.6%. The Mutation rate of K-ras in plasma free DNA detected by PNA-PCR was 31.1%, significantly higher than that of 15.1% detected by nested primer PCR (P = 0.006). The consistent rate of the K-ras status in plasma free DNA detected by PNA-PCR and that in tumor tissue detected by traditional method was up to 83.0%. The median overall survival (OS) of patients of the wild type, low mutation and high mutation groups was 23.5 months, 17.3 months and 13.9 months, respectively (P = 0.002). The median progression-free survival (PFS) of the K-ras wild-type, low mutation and high mutation groups with first-line chemotherapy was 6.8 months, 6.1 months and 3.2 months, respectively (P = 0.002), and the median OS of them were 23.0 months, 15.5 months and 13.9 months, respectively (P = 0.036). The overall response rate (ORR) was improved in the K-ras wide-type patients who received cetuximab combined with chemotherapy as first-line therapy (75.0% vs. 23.4%, P = 0.058). Cetuximab combined with in second-line therapy chemotherapy led to a significant improvement in disease control rate (DCR) ( 100% vs. 35.7%, P < 0.001) as compared with those of chemotherapy alone. COX regression model showed that K-ras status detected by PNA-PCR, ECOG PS, number of surgery and initially metastatic site were independent factors for prognosis.

CONCLUSIONSPNA-PCR for the detection of K-ras mutation in plasma free DNA can be used to substitute the traditional method for detection of K-ras mutation in tumor tissues. The abundance of K-ras mutation in plasma free DNA is an independent prognostic factor for patients with metastatic colorectal cancer.

Adult ; Aged ; Antibodies, Monoclonal, Humanized ; therapeutic use ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Cetuximab ; Colorectal Neoplasms ; genetics ; metabolism ; pathology ; DNA ; blood ; Disease-Free Survival ; Female ; Follow-Up Studies ; Genes, ras ; Humans ; Liver Neoplasms ; secondary ; Lung Neoplasms ; secondary ; Male ; Middle Aged ; Mutation ; Peptide Nucleic Acids ; Polymerase Chain Reaction ; Remission Induction ; Retrospective Studies ; Survival Rate ; Young Adult ; ras Proteins ; genetics ; metabolism