BACKGROUND Although chemotherapy is effective for treating advanced gastric carcinoma(aGC),it may lead to an adverse prognosis.Establishing a highly effective and low-toxicity chemotherapy regimen is necessary for imp...BACKGROUND Although chemotherapy is effective for treating advanced gastric carcinoma(aGC),it may lead to an adverse prognosis.Establishing a highly effective and low-toxicity chemotherapy regimen is necessary for improving efficacy and outcomes in aGC patients.AIM To determine the efficacy and safety of cetuximab(CET)combined with the FOLFOX4 regimen(infusional fluorouracil,folinic acid,and oxaliplatin)as firstline therapy for patients with aGC,who received evidence-based care(EBC).METHODS A total of 117 aGC patients who received EBC from March 2019 to March 2022 were enrolled.Of these,60 in the research group(RG)received CET+FOLFOX4 as first-line therapy,whereas 57 in the control group(CG)received FOLFOX4.The efficacy[clinical response rate(RR)and disease control rate(DCR)],safety(liver and kidney dysfunction,leukopenia,thrombocytopenia,rash,and diarrhea),serum tumor marker expression[STMs;carbohydrate antigen(CA)19-9,CA72-4,and carcinoembryonic antigen(CEA)],inflammatory indicators[interleukin(IL)-2 and IL-10],and quality of life(QOL)of the two groups were compared.RESULTS A markedly higher RR and DCR were observed in the RG compared with the CG,with an equivalent safety profile between the two groups.RG exhibited notably reduced CA19-9,CA72-4,CEA,and IL-2 levels following treatment,which were lower than the pre-treatment levels and those in the CG.Post-treatment IL-10 was statistically increased in RG,higher than the pre-treatment level and the CG.Moreover,a significantly improved QOL was evident in the RG.CONCLUSION The CET+FOLFOX4 regimen is highly effective as first-line treatment for aGC patients receiving EBC.It facilitates the suppression of STMs,ameliorates the serum inflammatory microenvironment,and enhances QOL,without increased adverse drug effects.展开更多
BACKGROUND Multiple primary carcinomas(MPCs)are defined as two or more independent primary cancers that occur simultaneously or sequentially in the same individual.Synchronous MPCs are rarer than solitary cancers or m...BACKGROUND Multiple primary carcinomas(MPCs)are defined as two or more independent primary cancers that occur simultaneously or sequentially in the same individual.Synchronous MPCs are rarer than solitary cancers or metachronous MPCs.Accurate diagnoses of synchronous MPCs and the choice of treatment are critical for successful outcomes in these cases.CASE SUMMARY A 64-year-old patient presented with dysphagia,without obvious cause.A diagnosis of synchronous esophageal squamous cell carcinoma and colon adenocarcinoma with liver metastasis was confirmed based on examination and laboratory results.After multi-disciplinary consultations,combination chemotherapy(a 3-wk cycle with oxaliplatin 212 mg administered on day 1 and capecitabine 1.5 g twice daily on days 1-14)and esophageal cancer radiotherapy were initiated.Based on the results of genetic testing,we switched to a regimen of leucovorin+fluorouracil+oxaliplatin and cetuximab regimen for 8 cycles.Subsequently,capecitabine and bevacizumab were administered until the most recent follow-up,at which the tumor remained stable.CONCLUSION Successful cetuximab chemotherapy treatment provides a reference for the nonoperative and homogeneous treatment of different pathological types of synchronous MCPs.展开更多
BACKGROUND Metastatic colorectal cancer(mCRC)treatment has been evolving and increasingly driven by tumor biology and gene expression analysis.Rechallenge with epidermal growth factor receptor(EGFR)inhibitors(anti-EGF...BACKGROUND Metastatic colorectal cancer(mCRC)treatment has been evolving and increasingly driven by tumor biology and gene expression analysis.Rechallenge with epidermal growth factor receptor(EGFR)inhibitors(anti-EGFR)represents a promising strategy for patients with RAS wild-type(RAS-wt)mCRC and circulating tumor DNA has emerged as a potential selection strategy.Herein,we report the case of a RAS-wt mCRC patient who had a successful response to cetuximab rechallenge.CASE SUMMARY Our patient was diagnosed with stage IV RAS-wt,microsatellite-stable rectosigmoid junction adenocarcinoma.He was started on first-line treatment with FOLFIRI and cetuximab and achieved partial response,allowing for a left hepatectomy(R0),followed by post-operative chemotherapy and an anterior resection;progression-free survival(PFS)of 16 months was obtained.Due to hepatic and nodal relapse,second-line treatment with FOLFOX and bevacizumab was started with partial response;metastasectomy was performed(R0),achieving a PFS of 11 months.After a 15 months anti-EGFR-free interval,FOLFIRI and cetuximab were reintroduced upon disease progression,again with partial response and a PFS of 16 months.Following extensive hepatic relapse,cetuximab was reintroduced and a marked clinical and analytical improvement was seen,after only one cycle.RASwt status was confirmed on circulating tumor DNA.The patient’s overall survival exceeded 5 years.CONCLUSION Our case provides real-world data to support cetuximab rechallenge in later lines of RAS-wt mCRC treatment.展开更多
AIM:To investigate the prognostic value of KRAS mutation,and phosphatase and tensin (PTEN) expression in Chinese metastatic colorectal cancer metastatic colorectal cancer (mCRC) patients treated with cetuximab.METHODS...AIM:To investigate the prognostic value of KRAS mutation,and phosphatase and tensin (PTEN) expression in Chinese metastatic colorectal cancer metastatic colorectal cancer (mCRC) patients treated with cetuximab.METHODS:Ninety Chinese mCRC patients treated with cetuximab were evaluated for KRAS mutation and PTEN protein expression by DNA sequencing of codons 12 and 13 and immunohistochemistry,respectively.We then selected 61 patients treated with cetuximab,either in combination with chemotherapy,or alone as a second-line or third-line regimen to assess whether KRAS mutation or PTEN protein expression is associated with the response and the survival time of mCRC patients treated with cetuximab.RESULTS:KRAS mutation was found in 30 (33.3%) tumor samples from the 90 patients,and positive PTEN expression was detected in 58 (64.4%) of the 90 patients.Among the 61 patients who were treated with cetuximab as a second-line or third-line regimen,the resistance to cetuximab was found in 22 patients with KRAS mutation and in 39 patients without KRAS mutation,with a response rate of 4.5% and 46.1% respectively (P=0.001),a shorter median progression-free survival (PFS) time of 14 ± 1.3 wk and 32 ± 2.5 wk respectively (P < 0.001),a median overall survival (OS) time of 11 ± 1.2 mo and 19 ± 1.8 mo respectively (P < 0.001),as well as in 24 patients with negative PTEN expression and in 37 patients with positive PTEN expression respectively (P < 0.001),with a responsive rate of 4.2% and 48.6% respectively,a shorter median PFS survival time of 17 ± 2.0 wk and 28 ± 1.9 wk respectively (P=0.07),and a median OS time of 11 ± 1.3 mo and 18 ± 1.9 mo respectively (P=0.004).Combined KRAS mutation and PTEN expression analysis showed that the PFS and OS time of patients with two favorable prognostic factors were longer than those of patients with one favorable prognostic factor or no favorable prognostic factor (P < 0.001).CONCLUSION:KRAS mutation and PTEN protein expression are significantly correlated with the response rate and survival time of Chinese mCRC patients treated with cetuximab.展开更多
AIM: To investigate efficacy and safety of cetuximab combined with two chemotherapy regimens in patients with unresectable metastatic colorectal cancer (mCRC). METHODS: Randomized patients received cetuximab with 5-fl...AIM: To investigate efficacy and safety of cetuximab combined with two chemotherapy regimens in patients with unresectable metastatic colorectal cancer (mCRC). METHODS: Randomized patients received cetuximab with 5-fluorouracil (5-FU), folinic acid (FA) and oxaliplatin (FOLFOX) 6 (arm A, n = 74) or 5-FU, FA and irinotecan (FOLFIRI) (arm B, n = 77). KRAS mutation status was determined retrospectively in a subset of tumors (n = 117). RESULTS: No significant difference was found between treatment arms A and B in the progression-free survival (PFS) rate at 9 mo, 45% vs 34%; median PFS, 8.6 mo vs 8.3 mo [hazard ratio (HR) = 1.06]; overall response rate (ORR) 43% vs 45% [odds ratio (OR) = 0.93] and median overall survival (OS), 17.4 mo vs 18.9 mo (HR = 0.98). Patients with KRAS wild-type tumors demonstrated improved PFS (HR = 0.55, P = 0.0051), OS, (HR = 0.62, P = 0.0296) and ORR (53% vs 36%) and in arm A, improved PFS (HR = 0.49, P = 0.0196), OS (HR = 0.48, P = 0.0201) and ORR (56%vs 30%), compared with patients with KRAS mutated tumors. In arm B no significant differences were found in efficacy by KRAS mutation status. Treatment in arms A and B was generally well tolerated. CONCLUSION: This study confirms that combinations of cetuximab with FOLFOX6 or FOLFIRI are effective and significantly improve clinical outcome in KRAS wild-type compared with KRAS mutated mCRC.展开更多
AIM: To review and assess the evidence related to cetuximab treatment in metastatic colorectal cancer(mCRC) with regard to KRAS status.METHODS: PubMed, EMBASE, Cochrane database and American Society of Clinical Oncolo...AIM: To review and assess the evidence related to cetuximab treatment in metastatic colorectal cancer(mCRC) with regard to KRAS status.METHODS: PubMed, EMBASE, Cochrane database and American Society of Clinical Oncology meeting abstracts were searched for randomized controlled trials(RCTs) reporting the effect of KRAS status on efficacy of chemotherapy regimen with or without cetuximab in mCRC. Baseline information such as sex and age was summarized from the included studies.Hazard ratios of progression-free survival(PFS) and overall survival(OS) as well as objective response based on KRAS status were extracted for analysis.RESULTS: A total of 8 RCTs with 6780 patients were included. The combined analysis showed that cetuximab failed to improve the OS and PFS in patients with mCRC.However, in subgroup analysis, the pooled data showed that addition of cetuximab to irinotecan containing chemotherapy regimen was sufficient to improve OS and PFS in wild-type KRAS mCRC patients, but not in patients with mutant-type KRAS. The addition of cetuximab increased the incidence of adverse events such as diarrhea, rash, skin toxicity/rash, and nausea and vomiting. There was no significant publication bias existing in the included studies.CONCLUSION: The clinical benefit of cetuximab was only confirmed in patients with wild-type KRAS. KRAS status could be considered a biomarker of efficacy of cetuximab.展开更多
The treatment of metastatic colorectal cancer(mCRC)has evolved considerably in the last decade,currently allowing most mCRC patients to live more than two years.Monoclonal antibodies targeting the epidermal growth fac...The treatment of metastatic colorectal cancer(mCRC)has evolved considerably in the last decade,currently allowing most mCRC patients to live more than two years.Monoclonal antibodies targeting the epidermal growth factor receptor(EGFR)and vascular endothelial growth factor play an important role in the current treatment of these patients.However,only antibodies directed against EGFR have a predictive marker of response,which is the mutation status of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog(KRAS).Cetuximab has been shown to be effective in patients with KRAS wild-type mCRC.The CRYSTAL study showed that adding cetuximab to FOLFIRI(regimen of irinotecan,infusional fluorouracil and leucovorin)significantly improved results in the first-line treatment of KRAS wildtype mCRC.However,results that evaluate the efficacy of cetuximab in combination with oxaliplatin-based chemotherapy in this setting are contradictory.On the other hand,recent advances in the management of colorectal liver metastases have improved survival in these patients.Adding cetuximab to standard chemotherapy increases the response rate in patients with wild-type KRAS and can thus increase the resectability rate of liver metastases in this group of patients.In this paper we review the different studies assessing the efficacy of cetuximab in the first-line treatment of mCRC.展开更多
BACKGROUND Colorectal cancer(CRC) is one of the main causes of cancer-related deaths in China and around the world. Advanced CRC(ACRC) patients suffer from a low cure rate though treated with targeted therapies. The r...BACKGROUND Colorectal cancer(CRC) is one of the main causes of cancer-related deaths in China and around the world. Advanced CRC(ACRC) patients suffer from a low cure rate though treated with targeted therapies. The response rate is about 50% to chemotherapy and cetuximab, a monoclonal antibody targeting epidermal growth factor receptor(EGFR) and used for ACRC with wild-type KRAS. It is important to identify more predictors of cetuximab efficacy to further improve precise treatment. Autophagy, showing a key role in the cancer progression, is influenced by the EGFR pathway. Whether autophagy can predict cetuximab efficacy in ACRC is an interesting topic.AIM To investigate the effect of autophagy on the efficacy of cetuximab in colon cancer cells and ACRC patients with wild-type KRAS.METHODS ACRC patients treated with cetuximab plus chemotherapy, with detailed data and tumor tissue, at Sun Yat-sen University Cancer Center from January 1, 2005,to October 1, 2015, were studied. Expression of autophagy-related proteins[Beclin1, microtubule-associated protein 1 A/B-light chain 3(LC3), and 4 Ebinding protein 1(4 E-BP1)] was examined by Western blot in CRC cells and by immunohistochemistry in cancerous and normal tissues. The effect of autophagy on cetuximab-treated cancer cells was confirmed by MTT assay. The associations between Beclin1, LC3, and 4 E-BP1 expression in tumor tissue and the efficacy of cetuximab-based therapy were analyzed.RESULTS In CACO-2 cells exposed to cetuximab, LC3 and 4 E-BP1 were upregulated, and P62 was downregulated. Autophagosome formation was observed, and autophagy increased the efficacy of cetuximab. In 68 ACRC patients,immunohistochemistry showed that Beclin1 levels were significantly correlated with those of LC3(0.657, P < 0.001) and 4 E-BP1(0.211, P = 0.042) in ACRC tissues.LC3 was significantly overexpressed in tumor tissues compared to normal tissues(P < 0.001). In 45 patients with wild-type KRAS, the expression levels of these three proteins were not related to progression-free survival; however, the expression levels of Beclin1(P = 0.010) and 4 E-BP1(P = 0.005), pathological grade(P = 0.002), and T stage(P = 0.004) were independent prognostic factors for overall survival(OS).CONCLUSION The effect of cetuximab on colon cancer cells might be improved by autophagy.LC3 is overexpressed in tumor tissues, and Beclin1 and 4 E-BP1 could be significant predictors of OS in ACRC patients treated with cetuximab.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
AIM:To investigate the prognostic role of invariant natural killer T(iNKT) cells and antibody-dependent cell-mediated cytotoxicity(ADCC) in wild type KRAS metastatic colorectal cancer(mC RC) patients treated with cetu...AIM:To investigate the prognostic role of invariant natural killer T(iNKT) cells and antibody-dependent cell-mediated cytotoxicity(ADCC) in wild type KRAS metastatic colorectal cancer(mC RC) patients treated with cetuximab.METHODS: Forty-one KRAS wt mC RC patients,treated with cetuximab and irinotecan-based chemotherapy in Ⅱ and Ⅲ lines were analyzed. Genotyping of single nucleotide polymorphism(SNP)s in the FCGR2A,FCGR3A and in the 3' untranslated regions of KRAS and mutational analysis for KRAS,BRAF and NRAS genes was determined either by sequencing or allelic discrimination assays. Enriched NK cells were obtained from lymphoprepperipheral blood mononuclear cell and iN KT cells were defined by co-expression of CD3,TCRVα24,TCRVβ11. ADCC was evaluated as ex vivo NK-dependent activity,measuring lactate dehydrogenase release.RESULTS: At basal,mCRC patients performing ADCC activity above the median level(71%) showed an improved overall survival(OS) compared to patients with ADCC below(median 16 vs 8 mo;P=0.026). We did not find any significant correlation of iN KT cells with OS(P=0.19),albeit we observed a trend to a longer survival after 10 mo in patients with iN KT above median basal level(0.382 cells/microliter). Correlation of OS and progression-free survival(PFS) with interesting SNPs involved in ADCC ability revealed not to be significant. Patients carrying alleles both with A in FCGR2 A and TT in FCGR3A presented a trend of longer PFS(median 9 vs 5 mo;P=0.064). Chemotherapy impacted both iN KT cells and ADCC activity. Their prognostic values get lost when we analysed them after 2 and 4 mo of treatment.CONCLUSION: Our results suggest a link between iN KT cells,basal ADCC activity,genotypes in FCGR2A and FCGR3A,and efficacy of cetuximab in KRAS wt mC RC patients.展开更多
AIM:To investigate the utility of Beclin-1 and LC3,two autophagy-related proteins,in predicting the cetuximab efficacy in advanced colorectal cancer(ACRC) . METHODS:The data of 85 patients with ACRC treated at the Sun...AIM:To investigate the utility of Beclin-1 and LC3,two autophagy-related proteins,in predicting the cetuximab efficacy in advanced colorectal cancer(ACRC) . METHODS:The data of 85 patients with ACRC treated at the Sun Yat-sen University Cancer Center from March 1,2005 to December 31,2008 were studied,including 45 cases treated with cetuximab-containing chemotherapy and 40 cases treated with non-cetuximab-containing chemotherapy.Beclin-1 and LC3 expression was evaluated by immunohistochemistry,and KRAS status was evaluated by polymerase chain reaction. RESULTS:Beclin-1 and LC3 expression in ACRC wassignificantly correlated(r=0.44,P<0.01);however,LC3 was more highly expressed in cancerous tissues than in normal tissues(Z=-2.63,P<0.01) .In the cetuximab-containing chemotherapy group,patients with low LC3 expression had higher objective response rates(ORRs) than those with high LC3 expression(52.9%vs 17.9%,P=0.01) ,and patients with low Beclin-1 expression had a longer median progressionfree survival(PFS) than their counterparts with higher Beclin-1 expression(9.0 mo vs 3.0 mo,P=0.01) . However,neither of these predictive relationships was detected in the group treated with non-cetuximabcontaining chemotherapy.Patients with wild-type KRAS had higher ORRs(42.3%vs 9.1%,P=0.049) and disease control rates(DCRs)(73.1%vs 36.4%,P= 0.035) ,and longer median PFS(5.5 mo vs 2.5 mo,P= 0.02) than those with mutant KRAS in the cetuximabcontaining chemotherapy group.Neither Beclin-1(P= 0.52) nor LC3(P=0.32) expression was significantly correlated with KRAS status. CONCLUSION:Patients with low Beclin-1 expression had a longer PFS than those with high Beclin-1 expression,and patients with low LC3 expression had a higher ORR in ACRC patients treated with cetuximab-containing chemotherapy.展开更多
BACKGROUND Cetuximab in combination with oral fluoropyrimidine(FP)remains controversial in metastatic colorectal cancer(mCRC).In view of the regional variation in the tolerability of FP,we conducted a retrospective an...BACKGROUND Cetuximab in combination with oral fluoropyrimidine(FP)remains controversial in metastatic colorectal cancer(mCRC).In view of the regional variation in the tolerability of FP,we conducted a retrospective analysis to compare oral FP with infusional FP in combination with cetuximab in Chinese population.AIM To compare the efficacy and safety profile of cetuximab in combination with oral FP and infusional FP in Chinese population in the real-world setting.METHODS A retrospective cohort study was done to analyse consecutive patients with Kras wild-type mCRC who received first-line treatment with cetuximab and FP-based chemotherapy in our unit from January 2010 to December 2015.Ninety-five eligible patients were included.The median follow-up of our cohort was 65.0 mo.RESULTS The median progression-free survival(mPFS)and median overall survival(mOS)of the entire cohort were 9.66 mo(95%CI:7.72–12.5)and 25.8 mo(95%CI:18.7–35.6),respectively.Between oral FP and infusional FP,there was no statistical significant difference in the mPFS[9.79 mo(95%CI:7.49–12.7)vs 9.63 mo(95%CI:6.34–13.4);P=0.72]and mOS[25.8 mo(95%CI:15.2–35.6)vs 26.3 mo(95%CI:18.7–41.2);P=0.63].Grade 3 or above adverse events were reported in 28.4%of patients,being similar with oral and infusional FP,and included 10.5%of neutropenia and 2.1%of diarrhoea events.CONCLUSION The current analysis demonstrates comparable efficacy and safety profiles of cetuximab in combination with oral and infusional FP in Chinese population.The results expand treatment options for Chinese patients and invite revision of existing treatment guidelines to incorporate oral FP-based chemotherapy plus cetuximab.展开更多
文摘BACKGROUND Although chemotherapy is effective for treating advanced gastric carcinoma(aGC),it may lead to an adverse prognosis.Establishing a highly effective and low-toxicity chemotherapy regimen is necessary for improving efficacy and outcomes in aGC patients.AIM To determine the efficacy and safety of cetuximab(CET)combined with the FOLFOX4 regimen(infusional fluorouracil,folinic acid,and oxaliplatin)as firstline therapy for patients with aGC,who received evidence-based care(EBC).METHODS A total of 117 aGC patients who received EBC from March 2019 to March 2022 were enrolled.Of these,60 in the research group(RG)received CET+FOLFOX4 as first-line therapy,whereas 57 in the control group(CG)received FOLFOX4.The efficacy[clinical response rate(RR)and disease control rate(DCR)],safety(liver and kidney dysfunction,leukopenia,thrombocytopenia,rash,and diarrhea),serum tumor marker expression[STMs;carbohydrate antigen(CA)19-9,CA72-4,and carcinoembryonic antigen(CEA)],inflammatory indicators[interleukin(IL)-2 and IL-10],and quality of life(QOL)of the two groups were compared.RESULTS A markedly higher RR and DCR were observed in the RG compared with the CG,with an equivalent safety profile between the two groups.RG exhibited notably reduced CA19-9,CA72-4,CEA,and IL-2 levels following treatment,which were lower than the pre-treatment levels and those in the CG.Post-treatment IL-10 was statistically increased in RG,higher than the pre-treatment level and the CG.Moreover,a significantly improved QOL was evident in the RG.CONCLUSION The CET+FOLFOX4 regimen is highly effective as first-line treatment for aGC patients receiving EBC.It facilitates the suppression of STMs,ameliorates the serum inflammatory microenvironment,and enhances QOL,without increased adverse drug effects.
文摘BACKGROUND Multiple primary carcinomas(MPCs)are defined as two or more independent primary cancers that occur simultaneously or sequentially in the same individual.Synchronous MPCs are rarer than solitary cancers or metachronous MPCs.Accurate diagnoses of synchronous MPCs and the choice of treatment are critical for successful outcomes in these cases.CASE SUMMARY A 64-year-old patient presented with dysphagia,without obvious cause.A diagnosis of synchronous esophageal squamous cell carcinoma and colon adenocarcinoma with liver metastasis was confirmed based on examination and laboratory results.After multi-disciplinary consultations,combination chemotherapy(a 3-wk cycle with oxaliplatin 212 mg administered on day 1 and capecitabine 1.5 g twice daily on days 1-14)and esophageal cancer radiotherapy were initiated.Based on the results of genetic testing,we switched to a regimen of leucovorin+fluorouracil+oxaliplatin and cetuximab regimen for 8 cycles.Subsequently,capecitabine and bevacizumab were administered until the most recent follow-up,at which the tumor remained stable.CONCLUSION Successful cetuximab chemotherapy treatment provides a reference for the nonoperative and homogeneous treatment of different pathological types of synchronous MCPs.
文摘BACKGROUND Metastatic colorectal cancer(mCRC)treatment has been evolving and increasingly driven by tumor biology and gene expression analysis.Rechallenge with epidermal growth factor receptor(EGFR)inhibitors(anti-EGFR)represents a promising strategy for patients with RAS wild-type(RAS-wt)mCRC and circulating tumor DNA has emerged as a potential selection strategy.Herein,we report the case of a RAS-wt mCRC patient who had a successful response to cetuximab rechallenge.CASE SUMMARY Our patient was diagnosed with stage IV RAS-wt,microsatellite-stable rectosigmoid junction adenocarcinoma.He was started on first-line treatment with FOLFIRI and cetuximab and achieved partial response,allowing for a left hepatectomy(R0),followed by post-operative chemotherapy and an anterior resection;progression-free survival(PFS)of 16 months was obtained.Due to hepatic and nodal relapse,second-line treatment with FOLFOX and bevacizumab was started with partial response;metastasectomy was performed(R0),achieving a PFS of 11 months.After a 15 months anti-EGFR-free interval,FOLFIRI and cetuximab were reintroduced upon disease progression,again with partial response and a PFS of 16 months.Following extensive hepatic relapse,cetuximab was reintroduced and a marked clinical and analytical improvement was seen,after only one cycle.RASwt status was confirmed on circulating tumor DNA.The patient’s overall survival exceeded 5 years.CONCLUSION Our case provides real-world data to support cetuximab rechallenge in later lines of RAS-wt mCRC treatment.
基金Supported by Program for New Century Excellent Talents in University
文摘AIM:To investigate the prognostic value of KRAS mutation,and phosphatase and tensin (PTEN) expression in Chinese metastatic colorectal cancer metastatic colorectal cancer (mCRC) patients treated with cetuximab.METHODS:Ninety Chinese mCRC patients treated with cetuximab were evaluated for KRAS mutation and PTEN protein expression by DNA sequencing of codons 12 and 13 and immunohistochemistry,respectively.We then selected 61 patients treated with cetuximab,either in combination with chemotherapy,or alone as a second-line or third-line regimen to assess whether KRAS mutation or PTEN protein expression is associated with the response and the survival time of mCRC patients treated with cetuximab.RESULTS:KRAS mutation was found in 30 (33.3%) tumor samples from the 90 patients,and positive PTEN expression was detected in 58 (64.4%) of the 90 patients.Among the 61 patients who were treated with cetuximab as a second-line or third-line regimen,the resistance to cetuximab was found in 22 patients with KRAS mutation and in 39 patients without KRAS mutation,with a response rate of 4.5% and 46.1% respectively (P=0.001),a shorter median progression-free survival (PFS) time of 14 ± 1.3 wk and 32 ± 2.5 wk respectively (P < 0.001),a median overall survival (OS) time of 11 ± 1.2 mo and 19 ± 1.8 mo respectively (P < 0.001),as well as in 24 patients with negative PTEN expression and in 37 patients with positive PTEN expression respectively (P < 0.001),with a responsive rate of 4.2% and 48.6% respectively,a shorter median PFS survival time of 17 ± 2.0 wk and 28 ± 1.9 wk respectively (P=0.07),and a median OS time of 11 ± 1.3 mo and 18 ± 1.9 mo respectively (P=0.004).Combined KRAS mutation and PTEN expression analysis showed that the PFS and OS time of patients with two favorable prognostic factors were longer than those of patients with one favorable prognostic factor or no favorable prognostic factor (P < 0.001).CONCLUSION:KRAS mutation and PTEN protein expression are significantly correlated with the response rate and survival time of Chinese mCRC patients treated with cetuximab.
文摘AIM: To investigate efficacy and safety of cetuximab combined with two chemotherapy regimens in patients with unresectable metastatic colorectal cancer (mCRC). METHODS: Randomized patients received cetuximab with 5-fluorouracil (5-FU), folinic acid (FA) and oxaliplatin (FOLFOX) 6 (arm A, n = 74) or 5-FU, FA and irinotecan (FOLFIRI) (arm B, n = 77). KRAS mutation status was determined retrospectively in a subset of tumors (n = 117). RESULTS: No significant difference was found between treatment arms A and B in the progression-free survival (PFS) rate at 9 mo, 45% vs 34%; median PFS, 8.6 mo vs 8.3 mo [hazard ratio (HR) = 1.06]; overall response rate (ORR) 43% vs 45% [odds ratio (OR) = 0.93] and median overall survival (OS), 17.4 mo vs 18.9 mo (HR = 0.98). Patients with KRAS wild-type tumors demonstrated improved PFS (HR = 0.55, P = 0.0051), OS, (HR = 0.62, P = 0.0296) and ORR (53% vs 36%) and in arm A, improved PFS (HR = 0.49, P = 0.0196), OS (HR = 0.48, P = 0.0201) and ORR (56%vs 30%), compared with patients with KRAS mutated tumors. In arm B no significant differences were found in efficacy by KRAS mutation status. Treatment in arms A and B was generally well tolerated. CONCLUSION: This study confirms that combinations of cetuximab with FOLFOX6 or FOLFIRI are effective and significantly improve clinical outcome in KRAS wild-type compared with KRAS mutated mCRC.
文摘AIM: To review and assess the evidence related to cetuximab treatment in metastatic colorectal cancer(mCRC) with regard to KRAS status.METHODS: PubMed, EMBASE, Cochrane database and American Society of Clinical Oncology meeting abstracts were searched for randomized controlled trials(RCTs) reporting the effect of KRAS status on efficacy of chemotherapy regimen with or without cetuximab in mCRC. Baseline information such as sex and age was summarized from the included studies.Hazard ratios of progression-free survival(PFS) and overall survival(OS) as well as objective response based on KRAS status were extracted for analysis.RESULTS: A total of 8 RCTs with 6780 patients were included. The combined analysis showed that cetuximab failed to improve the OS and PFS in patients with mCRC.However, in subgroup analysis, the pooled data showed that addition of cetuximab to irinotecan containing chemotherapy regimen was sufficient to improve OS and PFS in wild-type KRAS mCRC patients, but not in patients with mutant-type KRAS. The addition of cetuximab increased the incidence of adverse events such as diarrhea, rash, skin toxicity/rash, and nausea and vomiting. There was no significant publication bias existing in the included studies.CONCLUSION: The clinical benefit of cetuximab was only confirmed in patients with wild-type KRAS. KRAS status could be considered a biomarker of efficacy of cetuximab.
文摘The treatment of metastatic colorectal cancer(mCRC)has evolved considerably in the last decade,currently allowing most mCRC patients to live more than two years.Monoclonal antibodies targeting the epidermal growth factor receptor(EGFR)and vascular endothelial growth factor play an important role in the current treatment of these patients.However,only antibodies directed against EGFR have a predictive marker of response,which is the mutation status of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog(KRAS).Cetuximab has been shown to be effective in patients with KRAS wild-type mCRC.The CRYSTAL study showed that adding cetuximab to FOLFIRI(regimen of irinotecan,infusional fluorouracil and leucovorin)significantly improved results in the first-line treatment of KRAS wildtype mCRC.However,results that evaluate the efficacy of cetuximab in combination with oxaliplatin-based chemotherapy in this setting are contradictory.On the other hand,recent advances in the management of colorectal liver metastases have improved survival in these patients.Adding cetuximab to standard chemotherapy increases the response rate in patients with wild-type KRAS and can thus increase the resectability rate of liver metastases in this group of patients.In this paper we review the different studies assessing the efficacy of cetuximab in the first-line treatment of mCRC.
文摘BACKGROUND Colorectal cancer(CRC) is one of the main causes of cancer-related deaths in China and around the world. Advanced CRC(ACRC) patients suffer from a low cure rate though treated with targeted therapies. The response rate is about 50% to chemotherapy and cetuximab, a monoclonal antibody targeting epidermal growth factor receptor(EGFR) and used for ACRC with wild-type KRAS. It is important to identify more predictors of cetuximab efficacy to further improve precise treatment. Autophagy, showing a key role in the cancer progression, is influenced by the EGFR pathway. Whether autophagy can predict cetuximab efficacy in ACRC is an interesting topic.AIM To investigate the effect of autophagy on the efficacy of cetuximab in colon cancer cells and ACRC patients with wild-type KRAS.METHODS ACRC patients treated with cetuximab plus chemotherapy, with detailed data and tumor tissue, at Sun Yat-sen University Cancer Center from January 1, 2005,to October 1, 2015, were studied. Expression of autophagy-related proteins[Beclin1, microtubule-associated protein 1 A/B-light chain 3(LC3), and 4 Ebinding protein 1(4 E-BP1)] was examined by Western blot in CRC cells and by immunohistochemistry in cancerous and normal tissues. The effect of autophagy on cetuximab-treated cancer cells was confirmed by MTT assay. The associations between Beclin1, LC3, and 4 E-BP1 expression in tumor tissue and the efficacy of cetuximab-based therapy were analyzed.RESULTS In CACO-2 cells exposed to cetuximab, LC3 and 4 E-BP1 were upregulated, and P62 was downregulated. Autophagosome formation was observed, and autophagy increased the efficacy of cetuximab. In 68 ACRC patients,immunohistochemistry showed that Beclin1 levels were significantly correlated with those of LC3(0.657, P < 0.001) and 4 E-BP1(0.211, P = 0.042) in ACRC tissues.LC3 was significantly overexpressed in tumor tissues compared to normal tissues(P < 0.001). In 45 patients with wild-type KRAS, the expression levels of these three proteins were not related to progression-free survival; however, the expression levels of Beclin1(P = 0.010) and 4 E-BP1(P = 0.005), pathological grade(P = 0.002), and T stage(P = 0.004) were independent prognostic factors for overall survival(OS).CONCLUSION The effect of cetuximab on colon cancer cells might be improved by autophagy.LC3 is overexpressed in tumor tissues, and Beclin1 and 4 E-BP1 could be significant predictors of OS in ACRC patients treated with cetuximab.
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.
基金the Fondazione Veronesi that granted Daniela Vivenza and Martino Monteverde with PostDoctoral Fellowship Veronesithe Fondazione Cassa Risparmio of Cuneo for partially supporting the study
文摘AIM:To investigate the prognostic role of invariant natural killer T(iNKT) cells and antibody-dependent cell-mediated cytotoxicity(ADCC) in wild type KRAS metastatic colorectal cancer(mC RC) patients treated with cetuximab.METHODS: Forty-one KRAS wt mC RC patients,treated with cetuximab and irinotecan-based chemotherapy in Ⅱ and Ⅲ lines were analyzed. Genotyping of single nucleotide polymorphism(SNP)s in the FCGR2A,FCGR3A and in the 3' untranslated regions of KRAS and mutational analysis for KRAS,BRAF and NRAS genes was determined either by sequencing or allelic discrimination assays. Enriched NK cells were obtained from lymphoprepperipheral blood mononuclear cell and iN KT cells were defined by co-expression of CD3,TCRVα24,TCRVβ11. ADCC was evaluated as ex vivo NK-dependent activity,measuring lactate dehydrogenase release.RESULTS: At basal,mCRC patients performing ADCC activity above the median level(71%) showed an improved overall survival(OS) compared to patients with ADCC below(median 16 vs 8 mo;P=0.026). We did not find any significant correlation of iN KT cells with OS(P=0.19),albeit we observed a trend to a longer survival after 10 mo in patients with iN KT above median basal level(0.382 cells/microliter). Correlation of OS and progression-free survival(PFS) with interesting SNPs involved in ADCC ability revealed not to be significant. Patients carrying alleles both with A in FCGR2 A and TT in FCGR3A presented a trend of longer PFS(median 9 vs 5 mo;P=0.064). Chemotherapy impacted both iN KT cells and ADCC activity. Their prognostic values get lost when we analysed them after 2 and 4 mo of treatment.CONCLUSION: Our results suggest a link between iN KT cells,basal ADCC activity,genotypes in FCGR2A and FCGR3A,and efficacy of cetuximab in KRAS wt mC RC patients.
基金Supported by Grants from Science and Technology Planning Project of Guangdong Province,China,No.2010B031600317Administration of Traditional Chinese Medicine of Guangdong Province,China,No.20111169National Natural Science Foun-dation of China,No.81071872
文摘AIM:To investigate the utility of Beclin-1 and LC3,two autophagy-related proteins,in predicting the cetuximab efficacy in advanced colorectal cancer(ACRC) . METHODS:The data of 85 patients with ACRC treated at the Sun Yat-sen University Cancer Center from March 1,2005 to December 31,2008 were studied,including 45 cases treated with cetuximab-containing chemotherapy and 40 cases treated with non-cetuximab-containing chemotherapy.Beclin-1 and LC3 expression was evaluated by immunohistochemistry,and KRAS status was evaluated by polymerase chain reaction. RESULTS:Beclin-1 and LC3 expression in ACRC wassignificantly correlated(r=0.44,P<0.01);however,LC3 was more highly expressed in cancerous tissues than in normal tissues(Z=-2.63,P<0.01) .In the cetuximab-containing chemotherapy group,patients with low LC3 expression had higher objective response rates(ORRs) than those with high LC3 expression(52.9%vs 17.9%,P=0.01) ,and patients with low Beclin-1 expression had a longer median progressionfree survival(PFS) than their counterparts with higher Beclin-1 expression(9.0 mo vs 3.0 mo,P=0.01) . However,neither of these predictive relationships was detected in the group treated with non-cetuximabcontaining chemotherapy.Patients with wild-type KRAS had higher ORRs(42.3%vs 9.1%,P=0.049) and disease control rates(DCRs)(73.1%vs 36.4%,P= 0.035) ,and longer median PFS(5.5 mo vs 2.5 mo,P= 0.02) than those with mutant KRAS in the cetuximabcontaining chemotherapy group.Neither Beclin-1(P= 0.52) nor LC3(P=0.32) expression was significantly correlated with KRAS status. CONCLUSION:Patients with low Beclin-1 expression had a longer PFS than those with high Beclin-1 expression,and patients with low LC3 expression had a higher ORR in ACRC patients treated with cetuximab-containing chemotherapy.
文摘BACKGROUND Cetuximab in combination with oral fluoropyrimidine(FP)remains controversial in metastatic colorectal cancer(mCRC).In view of the regional variation in the tolerability of FP,we conducted a retrospective analysis to compare oral FP with infusional FP in combination with cetuximab in Chinese population.AIM To compare the efficacy and safety profile of cetuximab in combination with oral FP and infusional FP in Chinese population in the real-world setting.METHODS A retrospective cohort study was done to analyse consecutive patients with Kras wild-type mCRC who received first-line treatment with cetuximab and FP-based chemotherapy in our unit from January 2010 to December 2015.Ninety-five eligible patients were included.The median follow-up of our cohort was 65.0 mo.RESULTS The median progression-free survival(mPFS)and median overall survival(mOS)of the entire cohort were 9.66 mo(95%CI:7.72–12.5)and 25.8 mo(95%CI:18.7–35.6),respectively.Between oral FP and infusional FP,there was no statistical significant difference in the mPFS[9.79 mo(95%CI:7.49–12.7)vs 9.63 mo(95%CI:6.34–13.4);P=0.72]and mOS[25.8 mo(95%CI:15.2–35.6)vs 26.3 mo(95%CI:18.7–41.2);P=0.63].Grade 3 or above adverse events were reported in 28.4%of patients,being similar with oral and infusional FP,and included 10.5%of neutropenia and 2.1%of diarrhoea events.CONCLUSION The current analysis demonstrates comparable efficacy and safety profiles of cetuximab in combination with oral and infusional FP in Chinese population.The results expand treatment options for Chinese patients and invite revision of existing treatment guidelines to incorporate oral FP-based chemotherapy plus cetuximab.
