1 文献来源
Hecht JR，Mitchell E，Chidiac T，et al．A randomized phase Ⅲ B trial of chemotherapy, Bevacizumab, and Panitumumab compared with chemotherapy and Bevacizumab alone for metastatic colorectal cancer [J]. J ...1 文献来源
Hecht JR，Mitchell E，Chidiac T，et al．A randomized phase Ⅲ B trial of chemotherapy, Bevacizumab, and Panitumumab compared with chemotherapy and Bevacizumab alone for metastatic colorectal cancer [J]. J Clin Oncol, 2009, 27（5）： 672-680.展开更多
Cetuximab and panitumumab,as the highly effective antibodies targeting epidermal growth factor receptor(EGFR),have clinical activity in the patients with metastatic colorectal cancer(mCRC).These agents have good curat...Cetuximab and panitumumab,as the highly effective antibodies targeting epidermal growth factor receptor(EGFR),have clinical activity in the patients with metastatic colorectal cancer(mCRC).These agents have good curative efficacy,but drug resistance also exists at the same time.The effects of KRAS,NRAS,and BRAF mutations and HER2 amplification on the treatment of refractory mCRC have been elucidated and the corresponding countermeasures have been put forward.However,the changes in EGFR and its ligands,the mutations or amplifications of PIK3CA,PTEN,TP53,MET,HER3,IRS2,FGFR1,and MAP2K1,the overexpression of insulin growth factor-1,the low expression of Bcl-2-interacting mediator of cell death,mismatch repair-deficient,and epigenetic instability may also lead to drug resistance in mCRC.Although the emergence of drug resistance has genetic or epigenetic heterogeneity,most of these molecular changes relating to it are focused on the key signaling pathways,such as the RAS/RAF/mitogen-activated protein kinase or phosphatidylinositol 3-kinase/Akt/mammalian target of the rapamycin pathway.Accordingly,numerous efforts to target these signaling pathways and develop the novel therapeutic regimens have been carried out.Herein,we have reviewed the underlying mechanisms of the resistance to anti-EGFR therapy and the possible implications in clinical practice.展开更多
Colorectal cancer(CRC) is a significant cause of cancer-related morbidity and mortality all over the world.Improvements of cytotoxic and biologic agents have prolonged the survival in metastatic CRC(mC RC),with a medi...Colorectal cancer(CRC) is a significant cause of cancer-related morbidity and mortality all over the world.Improvements of cytotoxic and biologic agents have prolonged the survival in metastatic CRC(mC RC),with a median overall survival of approximately 2 years and more in the past two decades.The biologic agents that have proven clinical benefits in m CRC mainly target vascular endothelial growth factor(VEGF) and epidermal growth factor receptor(EGFR).In particular,bevacizumab targeting VEGF and cetuximab and panitumumab targeting EGFR have demonstrated sig-nificant survival benefits in combination with cytotoxic chemotherapy in the first-line,second-line,or salvage setting.Aflibercept,ramucirumab,and regorafenib are also used in second-line or salvage therapy.Recent retrospective analyses have shown that KRAS or NRAS mutations were negative predictive markers for anti-EGFR therapy.Based on the evidence from large rand-omized clinical trials,personalized therapy is necessary for patients with m CRC according to their tumor biology and characteristics.The aim of this paper was to summarize the results of the major randomized clinical trials and highlight the benefits of the molecular targeted agents in patients with mC RC.展开更多
Monoclonal antibodies against epidermal growth factor receptor(EGFR) are used in the treatment of advanced colorectal cancer. However, these agents can induce severe dermatological side effects that discourage their a...Monoclonal antibodies against epidermal growth factor receptor(EGFR) are used in the treatment of advanced colorectal cancer. However, these agents can induce severe dermatological side effects that discourage their administration in patients with chronic dermatological disease. EGFR plays a key role in normal skin development and immunological function, and is expressed in various tissues and organs, although contrarily, it is overexpressed in psoriasis-related skin lesions. Thus, discussion is ongoing regarding the putative pathological role and therapeutic potential of this protein. We herein report on a patient with advanced colon cancer and concomitant long-standing psoriasis vulgaris who received antiEGFR antibody monotherapy as a third-line treatment for metastatic disease. One week after the initiation of treatment, the patient's skin lesions dramatically subsided and the improvement was sustained during therapy. Based on this case, we propose that anti-EGFR antibody therapy is not necessarily contraindicated in patients with psoriasis vulgaris. Moreover, the findings reaffirmed that EGFR is an important molecule in the pathology of psoriasis.展开更多
BACKGROUND Hyperbilirubinemia with hepatic metastases is a common complication and a poor prognostic factor for colorectal cancer(CRC).Effective drainage is often im-possible before initiating systemic chemotherapy,ow...BACKGROUND Hyperbilirubinemia with hepatic metastases is a common complication and a poor prognostic factor for colorectal cancer(CRC).Effective drainage is often im-possible before initiating systemic chemotherapy,owing to the liver’s diffuse metastatic involvement.Moreover,an appropriate chemotherapeutic approach for the treatment of hyperbilirubinemia is currently unavailable.CASE SUMMARY The patient,a man in his 50s,presented with progressive fatigue and severe jaundice.Computed tomography revealed multiple hepatic masses with thick-ened walls in the sigmoid colon,which was pathologically confirmed as a well-differentiated adenocarcinoma.No RAS or BRAF mutations were detected.The Eastern Cooperative Oncology Group(ECOG)performance status(PS)score was 2.Biliary drainage was impossible due to the absence of a dilated bile duct,and panitumumab monotherapy was promptly initiated.Subsequently,the bilirubin level decreased and then normalized,and the patient’s PS improved to zero ECOG score after four cycles of therapy without significant adverse events.CONCLUSION Anti-EGFR antibody monotherapy is a safe and effective treatment for RAS wild-type CRC and hepatic metastases with severe hyperbilirubinemia.展开更多
Epidermal growth factor receptor(EGFR) has been an attractive target for treatment of epithelial cancers, including colorectal cancer(CRC). Evidence from clinical trials indicates that cetuximab and panitumumab(antiEG...Epidermal growth factor receptor(EGFR) has been an attractive target for treatment of epithelial cancers, including colorectal cancer(CRC). Evidence from clinical trials indicates that cetuximab and panitumumab(antiEGFR monoclonal antibodies) have clinical activity in patients with metastatic CRC. The discovery of intrinsic EGFR blockade resistance in Kirsten RAS(KRAS)-mutant patients led to the restriction of anti-EGFR antibodies to KRAS wild-type patients by Food and Drug Administration and European Medicine Agency. Studies have since focused on the evaluation of biomarkers to identify appropriate patient populations that may benefit from EGFR blockade. Accumulating evidence suggests that patients with mutations in EGFR downstream signaling pathways including KRAS, BRAF, PIK3CA and PTEN could be intrinsically resistant to EGFR blockade. Recent whole genome studies also suggest that dynamic alterations in signaling pathways downstream of EGFR leads to distinct oncogenic signatures and subclones which might have some impact on emerging resistance in KRAS wild-type patients. While anti-EGFR monoclonal antibodies have a clear potential in the management of a subset of patients with metastatic CRC, further studies are warranted to uncover exact mechanisms related to acquired resistance to EGFR blockade.展开更多
Molecularly targeted therapeutic agents are constantly being developed and have been shown to be effective in various clinical trials. One group of representative targeted oncogenic kinases, the receptor tyrosine kina...Molecularly targeted therapeutic agents are constantly being developed and have been shown to be effective in various clinical trials. One group of representative targeted oncogenic kinases, the receptor tyrosine kinases (RTKs), has been associated with gastric cancer development. Trastuzumab, an inhibitor of ERBB2, has been approved for the treatment of gastric cancer, although other receptor tyrosine kinases, such as epidermal growth factor receptor, vascular endothelial growth factor, platelet-derived growth factor receptor, c-Met, IGF-1R and fibroblast growth factor receptor 2, are also activated in gastric cancer. The promising results of the trastuzumab clinical trial for gastric cancer resulted in the approval of trastuzumab-based therapy as a first-line treatment for human epidermal growth factor receptor 2-positive patients. On the other hand, the trial examining bevacizumab in combination with conventional chemotherapy did not meet its primary goal of increasing the overall survival time of gastric cancer patients; however, a significantly higher response rate and a longer progression-free survival were observed in the bevacizumab arm of the trial. Other clinical trials, especially phase III trials that have tested drugs targeting RTKs, such as cetuximab, panitumumab, gefitinib, erlotinib, figitumumab, sorafenib, sunitinib and lapatinib, have shown that these drugs have modest effects against gastric cancer. This review summarizes the recent results from the clinical trials of molecularly targeted drugs and suggests that further improvements in the treatment of advanced gastric cancer can be achieved through the combination of conventional drugs with the new molecularly targeted therapies.展开更多
Colorectal cancer(CRC)has high incidence and mortality worldwide.In 2012,CRC was the second most prevalent cancer among males(9%)and the third among females(8%).In recent decades,standard chemotherapies protocols comb...Colorectal cancer(CRC)has high incidence and mortality worldwide.In 2012,CRC was the second most prevalent cancer among males(9%)and the third among females(8%).In recent decades,standard chemotherapies protocols combining 5-fluorouracil,leucovorin,irinotecan and oxaliplatin were important for improve survival in this set of patients.Further,biological drugs throughout epidermal growth factor receptor(EGFR)pathways showed interesting results in metastatic disease(mCRC)control when in association to standard chemotherapy regimens.Cetuximab and panitumumab are two cornerstones for mCRC treatment and are both approved in Europe and United States based on previous results phaseⅢtrials.This paper will briefly summarize those anti-EGFR therapies framework in mCRC and discusses some issues in this regard.展开更多
Human epidermal growth factor receptor 2(HER2) signaling pathway activation has been identified as a contributor to de novo or acquired resistance to epidermal growth factor receptor(EGFR) inhibitors in a small subset...Human epidermal growth factor receptor 2(HER2) signaling pathway activation has been identified as a contributor to de novo or acquired resistance to epidermal growth factor receptor(EGFR) inhibitors in a small subset of patients with metastatic colorectal cancer(mCRC). Dual anti-HER2-targeted treatment exhibits strong antitumor activity in preclinical models of HER2-positive mCRC, supporting its testing in clinical trials. The HERACLES trial at four Italian academic cancer centers has confirmed the effectiveness of dual blockage of HER2 with trastuzumab plus lapatinib in patients with heavily pretreated HER2-positive mCRC, refractory to the anti-EGFR antibodies cetuximab or panitumumab. Here, we reviewed the preclinical studies exploring the role of HER2 signaling in the development of anti-EGFR therapy resistance and discussed the status of clinical trials assessing the activity of HER2 inhibitors in this setting.展开更多
文摘1 文献来源
Hecht JR，Mitchell E，Chidiac T，et al．A randomized phase Ⅲ B trial of chemotherapy, Bevacizumab, and Panitumumab compared with chemotherapy and Bevacizumab alone for metastatic colorectal cancer [J]. J Clin Oncol, 2009, 27（5）： 672-680.
基金supported by the National Natural Science Foundation of China[81871994 and 81701834]the Guangdong Natural Science Foundation[2019B151502063]the Guangdong Science and Technology Planning Program[20190202018].
文摘Cetuximab and panitumumab,as the highly effective antibodies targeting epidermal growth factor receptor(EGFR),have clinical activity in the patients with metastatic colorectal cancer(mCRC).These agents have good curative efficacy,but drug resistance also exists at the same time.The effects of KRAS,NRAS,and BRAF mutations and HER2 amplification on the treatment of refractory mCRC have been elucidated and the corresponding countermeasures have been put forward.However,the changes in EGFR and its ligands,the mutations or amplifications of PIK3CA,PTEN,TP53,MET,HER3,IRS2,FGFR1,and MAP2K1,the overexpression of insulin growth factor-1,the low expression of Bcl-2-interacting mediator of cell death,mismatch repair-deficient,and epigenetic instability may also lead to drug resistance in mCRC.Although the emergence of drug resistance has genetic or epigenetic heterogeneity,most of these molecular changes relating to it are focused on the key signaling pathways,such as the RAS/RAF/mitogen-activated protein kinase or phosphatidylinositol 3-kinase/Akt/mammalian target of the rapamycin pathway.Accordingly,numerous efforts to target these signaling pathways and develop the novel therapeutic regimens have been carried out.Herein,we have reviewed the underlying mechanisms of the resistance to anti-EGFR therapy and the possible implications in clinical practice.
文摘Colorectal cancer(CRC) is a significant cause of cancer-related morbidity and mortality all over the world.Improvements of cytotoxic and biologic agents have prolonged the survival in metastatic CRC(mC RC),with a median overall survival of approximately 2 years and more in the past two decades.The biologic agents that have proven clinical benefits in m CRC mainly target vascular endothelial growth factor(VEGF) and epidermal growth factor receptor(EGFR).In particular,bevacizumab targeting VEGF and cetuximab and panitumumab targeting EGFR have demonstrated sig-nificant survival benefits in combination with cytotoxic chemotherapy in the first-line,second-line,or salvage setting.Aflibercept,ramucirumab,and regorafenib are also used in second-line or salvage therapy.Recent retrospective analyses have shown that KRAS or NRAS mutations were negative predictive markers for anti-EGFR therapy.Based on the evidence from large rand-omized clinical trials,personalized therapy is necessary for patients with m CRC according to their tumor biology and characteristics.The aim of this paper was to summarize the results of the major randomized clinical trials and highlight the benefits of the molecular targeted agents in patients with mC RC.
文摘Monoclonal antibodies against epidermal growth factor receptor(EGFR) are used in the treatment of advanced colorectal cancer. However, these agents can induce severe dermatological side effects that discourage their administration in patients with chronic dermatological disease. EGFR plays a key role in normal skin development and immunological function, and is expressed in various tissues and organs, although contrarily, it is overexpressed in psoriasis-related skin lesions. Thus, discussion is ongoing regarding the putative pathological role and therapeutic potential of this protein. We herein report on a patient with advanced colon cancer and concomitant long-standing psoriasis vulgaris who received antiEGFR antibody monotherapy as a third-line treatment for metastatic disease. One week after the initiation of treatment, the patient's skin lesions dramatically subsided and the improvement was sustained during therapy. Based on this case, we propose that anti-EGFR antibody therapy is not necessarily contraindicated in patients with psoriasis vulgaris. Moreover, the findings reaffirmed that EGFR is an important molecule in the pathology of psoriasis.
文摘BACKGROUND Hyperbilirubinemia with hepatic metastases is a common complication and a poor prognostic factor for colorectal cancer(CRC).Effective drainage is often im-possible before initiating systemic chemotherapy,owing to the liver’s diffuse metastatic involvement.Moreover,an appropriate chemotherapeutic approach for the treatment of hyperbilirubinemia is currently unavailable.CASE SUMMARY The patient,a man in his 50s,presented with progressive fatigue and severe jaundice.Computed tomography revealed multiple hepatic masses with thick-ened walls in the sigmoid colon,which was pathologically confirmed as a well-differentiated adenocarcinoma.No RAS or BRAF mutations were detected.The Eastern Cooperative Oncology Group(ECOG)performance status(PS)score was 2.Biliary drainage was impossible due to the absence of a dilated bile duct,and panitumumab monotherapy was promptly initiated.Subsequently,the bilirubin level decreased and then normalized,and the patient’s PS improved to zero ECOG score after four cycles of therapy without significant adverse events.CONCLUSION Anti-EGFR antibody monotherapy is a safe and effective treatment for RAS wild-type CRC and hepatic metastases with severe hyperbilirubinemia.
文摘Epidermal growth factor receptor(EGFR) has been an attractive target for treatment of epithelial cancers, including colorectal cancer(CRC). Evidence from clinical trials indicates that cetuximab and panitumumab(antiEGFR monoclonal antibodies) have clinical activity in patients with metastatic CRC. The discovery of intrinsic EGFR blockade resistance in Kirsten RAS(KRAS)-mutant patients led to the restriction of anti-EGFR antibodies to KRAS wild-type patients by Food and Drug Administration and European Medicine Agency. Studies have since focused on the evaluation of biomarkers to identify appropriate patient populations that may benefit from EGFR blockade. Accumulating evidence suggests that patients with mutations in EGFR downstream signaling pathways including KRAS, BRAF, PIK3CA and PTEN could be intrinsically resistant to EGFR blockade. Recent whole genome studies also suggest that dynamic alterations in signaling pathways downstream of EGFR leads to distinct oncogenic signatures and subclones which might have some impact on emerging resistance in KRAS wild-type patients. While anti-EGFR monoclonal antibodies have a clear potential in the management of a subset of patients with metastatic CRC, further studies are warranted to uncover exact mechanisms related to acquired resistance to EGFR blockade.
基金Supported by Grant-in-Aid for Scientific Research(C)from the Ministry of Education,Culture,Sports,Science and Technology of Japan to Masaki T,No.25460998
文摘Molecularly targeted therapeutic agents are constantly being developed and have been shown to be effective in various clinical trials. One group of representative targeted oncogenic kinases, the receptor tyrosine kinases (RTKs), has been associated with gastric cancer development. Trastuzumab, an inhibitor of ERBB2, has been approved for the treatment of gastric cancer, although other receptor tyrosine kinases, such as epidermal growth factor receptor, vascular endothelial growth factor, platelet-derived growth factor receptor, c-Met, IGF-1R and fibroblast growth factor receptor 2, are also activated in gastric cancer. The promising results of the trastuzumab clinical trial for gastric cancer resulted in the approval of trastuzumab-based therapy as a first-line treatment for human epidermal growth factor receptor 2-positive patients. On the other hand, the trial examining bevacizumab in combination with conventional chemotherapy did not meet its primary goal of increasing the overall survival time of gastric cancer patients; however, a significantly higher response rate and a longer progression-free survival were observed in the bevacizumab arm of the trial. Other clinical trials, especially phase III trials that have tested drugs targeting RTKs, such as cetuximab, panitumumab, gefitinib, erlotinib, figitumumab, sorafenib, sunitinib and lapatinib, have shown that these drugs have modest effects against gastric cancer. This review summarizes the recent results from the clinical trials of molecularly targeted drugs and suggests that further improvements in the treatment of advanced gastric cancer can be achieved through the combination of conventional drugs with the new molecularly targeted therapies.
文摘Colorectal cancer(CRC)has high incidence and mortality worldwide.In 2012,CRC was the second most prevalent cancer among males(9%)and the third among females(8%).In recent decades,standard chemotherapies protocols combining 5-fluorouracil,leucovorin,irinotecan and oxaliplatin were important for improve survival in this set of patients.Further,biological drugs throughout epidermal growth factor receptor(EGFR)pathways showed interesting results in metastatic disease(mCRC)control when in association to standard chemotherapy regimens.Cetuximab and panitumumab are two cornerstones for mCRC treatment and are both approved in Europe and United States based on previous results phaseⅢtrials.This paper will briefly summarize those anti-EGFR therapies framework in mCRC and discusses some issues in this regard.
文摘Human epidermal growth factor receptor 2(HER2) signaling pathway activation has been identified as a contributor to de novo or acquired resistance to epidermal growth factor receptor(EGFR) inhibitors in a small subset of patients with metastatic colorectal cancer(mCRC). Dual anti-HER2-targeted treatment exhibits strong antitumor activity in preclinical models of HER2-positive mCRC, supporting its testing in clinical trials. The HERACLES trial at four Italian academic cancer centers has confirmed the effectiveness of dual blockage of HER2 with trastuzumab plus lapatinib in patients with heavily pretreated HER2-positive mCRC, refractory to the anti-EGFR antibodies cetuximab or panitumumab. Here, we reviewed the preclinical studies exploring the role of HER2 signaling in the development of anti-EGFR therapy resistance and discussed the status of clinical trials assessing the activity of HER2 inhibitors in this setting.
