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Purpose: To investigate circulating tumor DNA (ctDNA) RAS mutant (MT) incidence before salvage-line treatment and the clinicopathological features and molecular biological factors associated with the efficacy of anti-epithelial growth factor receptor (EGFR) monoclonal antibody (mAb) rechallenge for tissue RAS/BRAF wild type (WT) metastatic colorectal cancer (mCRC). Methods: This multi-institutional retrospective observational study included 74 patients with mCRC with tissue RAS/BRAF WT refractory to first-line chemotherapy containing anti-EGFR mAb. ctDNA RAS status was assessed using the OncoBEAM™ RAS CRC Kit. We explored the clinicopathological features associated with ctDNA RAS status and the factors related to anti-EGFR mAb rechallenge efficacy in multivariate Cox proportional hazard regression. Results: The incidence of RAS MT in ctDNA was 40.5% (30/74), which was associated with primary tumor resection (P = 0.016), liver metastasis (P < 0.001), and high tumor marker levels (P < 0.001). Among the 39 patients treated with anti-EGFR mAb rechallenge, those with ctDNA RAS WT showed significantly longer progression-free survival (PFS) than those with ctDNA RAS MT (median 4.1 vs. 2.7 months, hazard ratio [HR] = 0.39, P = 0.045). Patients who responded to first-line anti-EGFR mAb showed significantly longer PFS (HR = 0.21, P = 0.0026) and overall survival (OS) (HR = 0.23, P = 0.026) than those with stable disease. Conclusions: The incidence of ctDNA RAS MT mCRC was 40.5%, which was associated with liver metastases and high tumor volumes. Anti-EGFR mAb rechallenge may be effective for patients with mCRC who responded to first-line chemotherapy containing anti-EGFR mAb. No patients with RAS MT in ctDNA responded to anti-EGFR mAb rechallenge. [ABSTRACT FROM AUTHOR]

Background: Spatial and temporal heterogeneities of RAS and other molecular genes should be considered in the treatment of metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs); acquired RAS mutation is sometimes observed at disease progression of treatment with the anti-EGFR mAb. At the same time, discrepancy of RAS status from tissues and circulating tumor DNA (ctDNA) in the same patient is sometimes observed. Based on this, we commenced two observational studies to clarify these heterogeneities of RAS and BRAF in mCRC, using next generation sequencing from liquid biopsy. Methods/Design: RAS-trace study is an observational study to monitor ctDNA RAS/BRAF/PIK3CA status every 4-12 weeks using the Plasma-SeqSensei™ CRC RUO Kit (Sysmex Inostics GmbH) in mCRC with RAS/BRAF wild-type (wt) on tumor tissue. The primary endpoint was the time to the acquired RAS mutations. A total of 42 patients has been accrued. RAS-trace-2 study is also an observational study aimed at comparing the efficacy of the anti-EGFR mAb in ctDNA RAS/BRAF wt with ctDNA RAS or BRAF mutant mCRC patients, whose RAS/BRAF are wt in tumor tissue. The primary endpoint was progression-free survival in patients with ctDNA RAS/BRAF wt and RAS or BRAF mutant. A total of 240 patients will be accrued over 2 years. Discussion: These trials will help us understanding the clinical significance of spatial and temporal heterogeneities of RAS, BRAF and other genes, while optimizing the anti-EGFR mAb treatment strategies in mCRC.

Abstract Background RAS mutations affect prognosis in patients with metastatic colorectal cancer (mCRC) and have been identified as strong negative predictive markers for anti-epidermal growth factor receptor monoclonal antibody (anti-EGFR mAb) therapy, but many tumors containing wild-type RAS genes still do not respond to these therapies. Some additional biomarkers may have prognostic or predictive roles, but conclusions remain controversial. Methods We performed a meta-analysis and systematic review of randomized controlled trials comparing anti-EGFR mAb therapy with alternative therapy that investigated the prognostic and predictive impact of additional biomarkers in RAS wild-type (wt) mCRC patients. Hazard ratios (HRs) and 95% confidence intervals (CIs) for progression-free survival (PFS) and overall survival (OS) and odds ratios (ORs) for objective response rate (ORR) were calculated. The prognostic value of biomarkers was investigated by separately pooling HR and OR for different treatment groups in an individual study. The predictive value was assessed by pooling study interactions between treatment effects and biomarker subgroups. Results Thirty publications reporting on eighteen trials were selected, including a total of 13,507 patients. In prognostic analysis, BRAF mutations were associated with poorer PFS [HRs = 3.76 (2.47–5.73) and 2.69 (1.82–3.98)] and OS [HRs = 2.66 (1.95–3.65) and 2.45 (1.55–3.88)] in both the experimental and control arms; low miR-31-3p expression appeared to have longer PFS and OS. In terms of predictive effect, a lack of response to anti-EGFR therapy was observed in patients with BRAF mutant tumors (P interaction

Background: RAS mutations affect prognosis in patients with metastatic colorectal cancer (mCRC) and have been identified as strong negative predictive markers for anti-epidermal growth factor receptor monoclonal antibody (anti-EGFR mAb) therapy, but many tumors containing wild-type RAS genes still do not respond to these therapies. Some additional biomarkers may have prognostic or predictive roles, but conclusions remain controversial. Methods: We performed a meta-analysis and systematic review of randomized controlled trials comparing anti-EGFR mAb therapy with alternative therapy that investigated the prognostic and predictive impact of additional biomarkers in RAS wild-type (wt) mCRC patients. Hazard ratios (HRs) and 95% confidence intervals (CIs) for progression-free survival (PFS) and overall survival (OS) and odds ratios (ORs) for objective response rate (ORR) were calculated. The prognostic value of biomarkers was investigated by separately pooling HR and OR for different treatment groups in an individual study. The predictive value was assessed by pooling study interactions between treatment effects and biomarker subgroups. Results: Thirty publications reporting on eighteen trials were selected, including a total of 13,507 patients. In prognostic analysis, BRAF mutations were associated with poorer PFS [HRs = 3.76 (2.47–5.73) and 2.69 (1.82–3.98)] and OS [HRs = 2.66 (1.95–3.65) and 2.45 (1.55–3.88)] in both the experimental and control arms; low miR-31-3p expression appeared to have longer PFS and OS. In terms of predictive effect, a lack of response to anti-EGFR therapy was observed in patients with BRAF mutant tumors (Pinteraction < 0.01 for PFS). Patients with tumors with any mutation in the KRAS/NRAS/BRAF/PIK3CA gene also showed similar results compared with all wild-type tumors (Pinteraction for PFS, OS, and ORR were < 0.01, < 0.01 and 0.01, respectively). While low miR-31-3p expression could predict PFS (Pinteraction = 0.01) and OS (Pinteraction = 0.04) benefit. The prognostic and predictive value regarding PIK3CA mutations, PTEN mutations or deletions, EGFR, EREG/AREG, HER2, HER3, and HER4 expression remains uncertain. Conclusions: In RAS wt mCRC patients receiving EGFR-targeted therapy, BRAF mutation is a powerful prognostic and therapy-predictive biomarker, with no effect found for PIK3CA mutation, PTEN mutation or deletion, but the combined biomarker KRAS/NRAS/BRAF/PIK3CA mutations predict resistance to anti-EGFR therapy. Low miR-31-3p expression may have positive prognostic and therapy predictive effects. Evidence on the prognostic and predictive roles of EGFR and its ligands, and HER2/3/4 is insufficient. [ABSTRACT FROM AUTHOR]

Squamous cell carcinoma of the head and neck (SCCHN) is the most common head and neck tumor. Patients are generally diagnosed with advanced stage attributed to no clinically evident symptom at the early stage. For locally advanced SCCHN, cisplatin-based concurrent chemoradiotherapy (CRT) is the standard non-surgical treatment. However, the tolerance to high-dose cisplatin is poor owing to the high prevalence of comorbidities in patients with SCCHN. There are also concerns on the acute and late toxicities of CRT. Epidermal growth factor receptor (EGFR) is proved to be overexpressed in most SCCHN and it is associated with resistance to cytotoxic agents and radiotherapy leading to poor prognosis. Anti-EGFR antibody, which competes with EGFR ligands, can lead to receptor internalization, antibody-receptor complex down-regulation and tumor death. In addition, anti-EGFR antibody can play a role in radiosensitization by affecting cell cycle, DNA damage repair and angiogenesis. Radiotherapy combined with anti-EGFR antibody was demonstrated to improve survival when compared to radiotherapy alone, while consensus on anti-EGFR antibody delivery in the eligible patients, optimal intervention time and the management of adverse effects when combined with radiotherapy are yet warranted. According to the current recommendations, all patients with locally advanced SCCHN should be assessed for the tolerance of standard dose cisplatin prior to CRT. Radiotherapy with cetuximab is an alternative for patients who cannot tolerate. For those who received induction chemotherapy with the purpose of tumor downstaging or organ preservation, the standard regimen is TPF (docetaxel+cisplatin+5-fluorouracil) scheme. TPE scheme, using cetuximab as a substitution for fluorouracil, is an option for toxicities reducing. Managements of skin reactions, oral mucositis and radiation dermatitis are proposed.

BRAF non-V600 mutations are a distinct molecular subset of colorectal cancer (CRC) that has little to no clinical similarity to the BRAF V600 mutations. It is generally considered that the BRAF non-V600 mutations correlate with better survival of CRC patients. In this report, we present an unusual case of that a midlife female patient who was initially diagnosed with stage IIIC colon cancer, and multiple metastases were found 25 months after radical surgery. Nextgeneration sequencing (NGS) revealed the BRAF p.N581I (c.1742A>T) mutation. She received chemotherapy, targeted therapy, and immunotherapy. However, the disease progressed rapidly with rare metastasis of the bone and cerebellum. This case highlights that the BRAF non-V600 mutations, such as BRAF p.N581I mutant, may lead to resistance to epidermal growth factor receptor (EGFR) inhibitors and result in a rapid course in colorectal cancer. The role of BRAF p.N581I mutation in colorectal cancer demands more attention. [ABSTRACT FROM AUTHOR]

Abstract Anti-epidermal-growth-factor-receptor (EGFR) monoclonal antibodies (mAbs) are of great significance for RAS and BRAF wild-type metastatic colorectal cancer (mCRC) patients. However, the generation of primary and secondary resistance to anti-EGFR mAbs has become an important factor restricting its efficacy. Recent studies have revealed that non-coding RNAs (ncRNAs), especially long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), are implicated in anti-EGFR antibodies resistance, affecting the sensitivity of CRC cells to Cetuximab and Panitumumab. This paper briefly reviewed the research advance of the expression, signaling network and functional mechanism of ncRNAs related to anti-EGFR mAbs resistance in CRC, as well as their relationship with clinical prognosis and the possibility of therapeutic targets. In addition, some ncRNAs that are involved in the regulation of signaling pathways or genes related to anti-EGFR resistance, but need to be further verified by resistance experiments were also included in this review, thereby providing more ideas and basis for ncRNAs as CRC prognostic markers and anti-EGFR therapy sensitizers. Video Abstract

Background: Epidermal growth factor receptor (EGFR) is a well-known target for cancer treatment. However, the authorized anti-EGFR monoclonal antibodies generally cause several toxic effects, especially severe cutaneous toxicities as well as infusion reactions, and the clinical indications are limited. Here we developed Ametumumab, a fully human recombinant anti-EGFR monoclonal antibody. Objectives: To assess the safety, tolerability, pharmacokinetics (PK), and immunogenicity of Ametumumab. Design: A first-in-human phase Ia dose escalation study of Ametumumab in patients with advanced solid malignancies. Methods: An open-label, first-in-human dose escalation study was done in 22 patients with advanced malignancies who received six ascending dosages ranging from 75 to 750 mg/m2. Following a single dosage and a 28-day dose-limiting toxicity (DLT) monitoring period, patients were given repeated doses weekly. Blood samples were taken to determine the PK parameters of Ametumumab and anti-drug antibody concentrations. Every 8 weeks, radiographic tumor evaluations were conducted. Results: In this trial, no DLT was observed, and the maximum tolerated dose was not reached at doses up to 750 mg/m2. There were no severe adverse events but mild and moderate adverse effects, such as headache, proteinuria, and rash. Single-dose PK results demonstrated a straightforward linear relationship with dosage escalation. The medication concentrations accumulated and attained steady-state after four rounds of injections. It was calculated that 10 patients with disease control would be observed in the 22 evaluable patients. The disease control rate was 45.5%. Conclusion: The Ametumumab was well tolerated and safe in patients with advanced solid malignancies, exhibiting minimal immunogenicity, a long half-life, high levels of drug exposure in the blood, and preliminary effectiveness. Registration: The trial was registered with CTR20170343 on 10 April 2017, The China Center for Drug Evaluation. [ABSTRACT FROM AUTHOR]

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Defeng Qing,1,* Yuying Wu,2,* Xu Liu,1,* Hailan Jiang,1,* Chaohua Zhu,1,* Pei Liu,3 Junming Dang,4 Xianglong Li,1 Zhaohong Chen,1 Xianfeng Long,1 Qiang Pang,1 Luxing Peng,1 Shan Deng,1 Junzhao Gu,1 Renfeng Zhao,2 Changyi Chen,2 Heming Lu1 1Department of Radiation Oncology, People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning 530021, People’s Republic of China; 2Department of Gynecology, People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning 530021, People’s Republic of China; 3Department of Radiation Oncology, Youjiang Medical University for Nationalities, Baise 533000, People’s Republic of China; 4Department of Oncology, Guangxi University of Chinese Medicine, Nanning 530001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Heming LuDepartment of Radiation Oncology, People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning City 530021, People’s Republic of ChinaTel +86-771-218-6504Email luhming3632@163.comPurpose: We aimed to evaluate the long-term survival outcomes of concurrent chemoradiotherapy (CCRT) combined with nimotuzumab followed by surgery in patients with locally advanced cervical cancer (LACC).Patients and Methods: Patients received whole pelvic intensity-modulated radiation therapy (IMRT) and concomitantly with weekly cisplatin (40 mg/m2) or nedaplatin (30 mg/m2) and weekly nimotuzumab (200 mg). After assessment of the treatment response, patients then underwent radical surgery.Results: Between June 2013 and July 2016, 33 patients with FIGO IB2–IIIB cervical cancer were recruited. Clinical complete response and partial response were observed in 8 (24.3%) and 23 patients (69.7%), respectively. Twenty-seven patients (81.8%) were successfully treated with radical hysterectomy and pelvic lymphadenectomy: 9 (33.3%) showed pathological complete response; 10 (37.1%) showed partial response and 8 (29.6%) presented with persistent macroscopic/microscopic residual carcinoma. For the intention-to-treat population, the median follow-up time was 53.7 months. Locoregional recurrence and distant metastases were observed in three and seven patients, respectively. The 5-year overall survival, progression-free survival, locoregional recurrence-free survival, and distant metastasis-free survival were 81.5%, 72.7%, 90.9%, and 78.3%, respectively. Both acute and late toxicities were manageable and mainly limited to grade 1 or 2.Conclusion: Concurrent chemoradiotherapy combined with nimotuzumab followed by surgery for patients with LACC is safe and results in excellent long-term treatment outcomes. Further randomized controlled studies are warranted to confirm the findings.Keywords: locally advanced cervical cancer, neoadjuvant chemotherapy, intensity-modulated radiotherapy, anti-EGFR monoclonal antibody, radical surgery

BackgroundClose to one third of colorectal cancer (CRC) patients are diagnosed with metastatic CRC (mCRC). Patients with wild-type RAS and BRAF usually receive anti-EGFR monoclonal antibody therapy containing cetuximab. Overall, 30–50% of mCRC patients are reported to harbor RAS mutations, and RAS mutation status should be assessed when considering EGFR inhibitor treatment according to mCRC biomarker guidelines. Of note, 0.67–2% of patients with CRC harbored a KRAS amplification. Here we reported a case of advanced rectal cancer with wild-type RAS and BRAF in a male patient who harbored a KRAS amplification during anti-EGFR treatment.Case PresentationA 46-year-old man was diagnosed with rectal adenocarcinoma with liver metastases (cT3NxM1a, stage IVA). After receiving first-line irinotecan- fluorouracil chemotherapy (FOLFIRI) plus cetuximab, second-line capecitabine- oxaliplatin chemotherapy (XELOX) plus bevacizumab, and third-line regorafenib, he rechallenged FOLFIRI and cetuximab for seven cycles, achieving a prolonged survival of at least 5 months. The KRAS copy number of circulating tumor DNA (ctDNA) was assessed during treatment. Notably, apart from serum carbohydrate antigen 199 (CA199) and carcinoembryonic antigen (CEA), the change of plasm Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) copy number appeared to strongly correlate with treatment response.ConclusionOur findings suggest that the dynamic change of KRAS copy number on ctDNA during treatment might be a negative predictive biomarker. Additionally, RAS and BRAF wild-type mCRC patients who are resistant to first-line FOLFIRI plus cetuximab therapy may respond well to the FOLFIRI plus cetuximab “rechallenged” strategy.

Mutations in KRAS (codon 12/13), NRAS, BRAFV600E, and amplification of ERBB2 and MET account for 70–80% of anti-epidermal growth factor receptor (EGFR) monoclonal antibody primary resistance. However, the list of anti-EGFR monoclonal antibody primary resistance biomarkers is still incomplete. Herein, we report a case of wild-type RAS/BRAF metastatic colorectal cancer (CRC) with resistance to anti-EGFR monoclonal antibody and chemotherapy. Initially, mutation detection in postoperative tumor tissue by using amplification-refractory mutation system polymerase chain reaction indicated wild-type RAS/BRAF without point mutations, insertion deletions, or fusion mutations. Therefore, we recommended combined therapy of cetuximab and FOLFIRI after failure of platinum-based adjuvant chemotherapy, but the disease continued to progress. Next generation sequencing analysis of the postoperative tumor tissue revealed that KRAS copy number was increased and detected SMAD4, RNF43, and PREX2 mutations. This is the first case of advanced CRC with increased copy numbers of KRAS resistant to cetuximab and chemotherapy, which results in poor patient survival, and other mutated genes may be associated with the outcomes. Our findings indicate KRAS copy number alterations should also be examined, especially with anti-EGFR monoclonal antibody therapy in CRC, since it may be related with the primary resistance to these drugs.

Mutations in KRAS (codon 12/13), NRAS, BRAF V600E, and amplification of ERBB2 and MET account for 70–80% of anti-epidermal growth factor receptor (EGFR) monoclonal antibody primary resistance. However, the list of anti-EGFR monoclonal antibody primary resistance biomarkers is still incomplete. Herein, we report a case of wild-type RAS/BRAF metastatic colorectal cancer (CRC) with resistance to anti-EGFR monoclonal antibody and chemotherapy. Initially, mutation detection in postoperative tumor tissue by using amplification-refractory mutation system polymerase chain reaction indicated wild-type RAS/BRAF without point mutations, insertion deletions, or fusion mutations. Therefore, we recommended combined therapy of cetuximab and FOLFIRI after failure of platinum-based adjuvant chemotherapy, but the disease continued to progress. Next generation sequencing analysis of the postoperative tumor tissue revealed that KRAS copy number was increased and detected SMAD4 , RNF43 , and PREX2 mutations. This is the first case of advanced CRC with increased copy numbers of KRAS resistant to cetuximab and chemotherapy, which results in poor patient survival, and other mutated genes may be associated with the outcomes. Our findings indicate KRAS copy number alterations should also be examined, especially with anti-EGFR monoclonal antibody therapy in CRC, since it may be related with the primary resistance to these drugs. [ABSTRACT FROM AUTHOR]

Cancer treatment with epidermal growth factor receptor inhibitors (EGFRIs) often induces severe xerotic dermatitis. Various irritants facilitate development of dermatitis in xerotic skin. As zinc deficiency plays a role in the development of irritant dermatitis, we measured serum zinc levels in 25 patients with xerotic dermatitis due to treatment with EGFRIs. Of these patients, nine were treated with EGFR tyrosine kinase inhibitors and 16 were treated with anti‐EGFR antibody alone or in combination with other anticancer agents. Serum zinc levels of all patients were lower than the normal range of >80 μg/dL, with a mean ± SD serum zinc level of 56.4 ± 11.7 μg/dL. These were correlated with serum magnesium levels in patients. As the serum magnesium level is known to be reduced by the inhibition of EGFR, a similar mechanism may also be involved in decreasing the serum zinc level. Among 21 patients treated with zinc supplementation for more than 2 months, xerotic dermatitis markedly improved, with an increase of serum zinc levels in 16 patients. The other five patients exhibited no significant improvement in their skin condition, and insufficient and unstable increase in serum zinc levels. In conclusion, zinc supplementation may be beneficial in supportive care for patients with EGFRI‐induced xerotic dermatitis. [ABSTRACT FROM AUTHOR]

Abstract Background Systemic cancer therapies may induce infusion reactions (IRs) or hypersensitivities. Metastatic colorectal cancer (mCRC) patients treated with anti‐EGFR therapies, including cetuximab and panitumumab, may be subject to these reactions. We conducted a meta‐analysis to estimate the IR incidence in this population and identify variations in this incidence by patient or study characteristics. Methods A systematic review was conducted to identify observational studies or clinical trials of mCRC patients treated with anti‐EGFR therapies that reported occurrences of IRs, hypersensitivity, or allergy/anaphylaxis. The objective of the study was to estimate the incidence of IRs. Random effects models were used to meta‐analyze the incidence of IRs overall and stratified by therapy type, study design, geographic location, RAS or KRAS mutation status, grade of reaction severity, and terminology used to describe the reaction. Results The pooled estimate for IR incidence was 4.9% (95% confidence interval: 3.6%‐6.5%). Lower‐grade reactions were more common than higher‐grade reactions overall and the incidence of reactions among cetuximab patients was nearly four times that of panitumumab patients (6.1% vs 1.6%). Conclusions IRs occur in approximately 5% of mCRC patients treated with anti‐EGFR therapies, and the incidence varies significantly by grade of severity and therapy type. Studies evaluating these outcomes should consider investigating survival outcomes by IR status to determine its prognostic relevance.

Background and Objectives: Seasonal climatic changes may affect the development of the rash that is characteristic of treatment with anti-epidermal growth factor receptor (EGFR) antibodies. We evaluated the association between seasons and rash incidence among patients with cancer. Materials and Methods: Data from patients with colorectal or head and neck cancer treated with cetuximab or panitumumab during summer (S group; n = 34) or winter (W group; n = 37) between June 2014 and February 2019 were collected to retrospectively examine patient characteristics and rash incidence ≤ 8 weeks after treatment initiation. Results: Rashes were observed in 73.5% (n = 25) and 78.4% (n = 29) and grade 3 rashes were observed in 17.6% (n = 6) and 2.7% (n = 1) of the patients in the S and W groups, respectively. The incidence of grade ≥ 2 rashes in males in the S group was higher than that in the rest of the patient groups (p < 0.01). Conclusions: The higher incidence of skin rashes in males during summer might be attributed to the effects of ultraviolet light, lack of skincare, male hormones, and secretion of anti-EGFR antibodies in sweat. These findings highlight the need for research on preventive measures for such rashes. [ABSTRACT FROM AUTHOR]

Background: Systemic cancer therapies may induce infusion reactions (IRs) or hypersensitivities. Metastatic colorectal cancer (mCRC) patients treated with anti‐EGFR therapies, including cetuximab and panitumumab, may be subject to these reactions. We conducted a meta‐analysis to estimate the IR incidence in this population and identify variations in this incidence by patient or study characteristics. Methods: A systematic review was conducted to identify observational studies or clinical trials of mCRC patients treated with anti‐EGFR therapies that reported occurrences of IRs, hypersensitivity, or allergy/anaphylaxis. The objective of the study was to estimate the incidence of IRs. Random effects models were used to meta‐analyze the incidence of IRs overall and stratified by therapy type, study design, geographic location, RAS or KRAS mutation status, grade of reaction severity, and terminology used to describe the reaction. Results: The pooled estimate for IR incidence was 4.9% (95% confidence interval: 3.6%‐6.5%). Lower‐grade reactions were more common than higher‐grade reactions overall and the incidence of reactions among cetuximab patients was nearly four times that of panitumumab patients (6.1% vs 1.6%). Conclusions: IRs occur in approximately 5% of mCRC patients treated with anti‐EGFR therapies, and the incidence varies significantly by grade of severity and therapy type. Studies evaluating these outcomes should consider investigating survival outcomes by IR status to determine its prognostic relevance. [ABSTRACT FROM AUTHOR]

Background: To investigate the efficacy and safety of neoadjuvant chemoradiotherapy plus anti-epidermal growth factor receptor monoclonal antibody followed by surgery for locally advanced cervical cancer (LACC). Patients and methods: Patients with histologically proven LACC were enrolled into this prospective study. All patients received intensity-modulated radiation therapy with conventional fractionation. Weekly cisplatin or nedaplatin was administered concurrently with intensity-modulated radiation therapy. Nimotuzumab, a humanized anti-epidermal growth factor receptor monoclonal antibody, was given at a dose of 200 mg per week for 6 cycles. Approximately 1 month after the completion of neoadjuvant treatment, the patients were assessed for clinical tumor response and operability based on MRI and gynecological examination. For those who were considered to be candidates for surgery, radical hysterectomy, and pelvic lymph node dissection were performed 5–6 weeks after the completion of neoadjuvant therapy. Results: Twenty-eight patients were enrolled. Clinical complete response and partial response were found in 8 (28.5%) and 20 (71.5%) patients, respectively. Four patients were not eligible for surgery and 2 patients refused surgery although they were assessed as surgical candidates. They were not included in this analysis. Radical hysterectomy and pelvic lymph node dissection were performed for the remaining 22 patients. Among them, 8 (36.4%) had complete pathology response, 9 (40.9%) presented with persistent atypical cells or cervical intraepithelial neoplasia, and 5 (22.7%) presented with macroscopic and/or microscopic residual disease, according to the pathological evaluation. Median follow-up time was 22 months (range, 5–39 months). The 2-year locoregional control rate, progression-free survival rate, distant metastasis-free survival rate, and overall survival rate were 95.0%, 85.2%, 84.0%, and 90.0%, respectively. Acute toxicities were mild in general and easily manageable. Chronic toxicities were mainly limited to grade 1. No severe late toxicities were observed. Conclusion: Concurrent chemoradiotherapy plus nimotuzumab followed by surgery is highly effective and safe in LACC. Further studies are warranted to confirm the findings. [ABSTRACT FROM AUTHOR]

Purpose: Anti-EGFR monoclonal antibody is effective for KRAS wild-type metastatic colorectal cancer (mCRC), but frequently causes several adverse reactions, including hypomagnesemia and skin disorders. The present study was designed to investigate the relationship between the incidence of adverse reactions and therapeutic effects in mCRC patients receiving anti-EGFR monoclonal antibody in combination with first-line chemotherapy. Methods: Forty-three mCRC patients who received cetuximab or panitumumab between April 2012 and December 2015 were the subjects of the present study. All patients were pretreated with oral minocycline in combination with skin treatment using moisturizer for prevention of skin rash. Hypomagnesemia and acneiform rash were graded according to the Common Terminology Criteria for Adverse Events, version 3.0. Overall response rate (ORR) and time to treatment failure (TTF) were compared between patients with and without these adverse events. Results: The incidence rates of hypomagnesemia and acneiform rash were 32.6 % (grade 1: 20.9 %, grade 2: 11.6 %) and 93.0 % (grade 1: 41.9 %, grade 2: 41.9 %, grade 3: 9.3 %), respectively. ORR was significantly higher in patients with hypomagnesemia than in those without it (71.4 vs 34.5 %, P = 0.048). Median TTF tended to be longer, though not significantly, in patients with hypomagnesemia than in those without it. However, no significant difference in both ORR and median TTF was observed between patients with and without acneiform rash. Conclusion: Hypomagnesemia may become a predicting factor for therapeutic effects of anti-EGFR monoclonal antibody in mCRC patients. [ABSTRACT FROM AUTHOR]

Background Clinical trials have reported a substantial variation in the risk of infection related to anti-EGFR monoclonal antibodies (mAbs) cetuximab and panitumumab. We performed a systematic review and meta-analysis to assess the infection risk in cancer patients treated with anti-EGFR mAbs. Patients and methods We searched PubMed and the ASCO online database of meeting abstracts up to January 2014 for relevant clinical trials. Eligible studies included randomized controlled trials (RCTs) of cetuximab and panitumumab that reported adequate safety data for grade 3–4 infection or febrile neutropenia (FN). The summary incidence, relative risk (RR) and 95% confidence intervals (CIs) were calculated. Results A total of 14,957 patients from 28 trials were included. Treatment with anti-EGFR mAbs was associated with an increased risk of high-grade infection (RR, 1.49; 95% CI, 1.33–1.66; P < 0.001) and FN (RR, 1.27; 95% CI, 1.09–1.48; P = 0.002). The incidence of high-grade infection and FN due to anti-EGFR mAbs was 9.3% (95% CI, 7.2–12.0%) and 5.3% (95% CI, 3.3–8.3%), respectively. A significantly increased risk of high-grade infection was observed in all subgroups analyses (type of anti-EGFR mAb, therapy of control arm and duration of treatment) except for tumor type (only colorectal cancer and non-small cell lung cancer (NSCLC) groups had the increased risk). Subgroup analyses revealed a significantly increased risk of FN in the following subgroups: cetuximab, NSCLC and treatment duration longer than the median of all trials (3.1 months). Conclusions The use of anti-EGFR mAbs is associated with a significantly higher risk of high-grade infection and febrile neutropenia. [ABSTRACT FROM AUTHOR]

Background Anti-epidermal growth factor receptor (EGFR)-monoclonal antibodies (MoAbs) have been widely used in a variety of malignancies. Severe infections (⩾grade 3) are potentially lifethreatening adverse events with these drugs. However, the contribution of anti-EGFR MoAbs to infections is still unknown. We performed this meta-analysis to determine the overall incidence and risk of severe infections in cancer patients treated with these drugs. Methods The databases of PubMed and abstracts presented at oncology conferences and published in the proceedings were searched for relevant studies from January 2000 to May 2014. Summary incidences, relative risks (RRs) and 95% confidence intervals (CIs) were calculated by using either random effects or fixed effect models according to the heterogeneity of included studies. Results A total of 14,066 patients from 26 randomized controlled trials (RCTs) were included. The use of anti-EGFR-MoAbs significantly increased the risk of developing severe infections (RR 1.34, 95%CI: 1.10 to 1.62, P =0.003) in cancer patients, but not for fatal infections (RR 1.62, 95%CI: 0.81 to 3.26, P =0.18). Meta-regression indicated the infections might possibly occur early in the treatment with anti-EGFR MoAbs. On sub-group analysis, the risk of severe infections significantly varied with tumor type (P =0.001). When stratified by specific anti- EGFR MoAbs, a significantly increased risk of infections with cetuximab was observed (P <0.001), but not for panitumumab (P =0.98). Additionally, the use of anti-EGFR MoAbs significantly increased the risk of severe infections when used in conjunction with cisplatin (RR 1.48, 95% CI 1.22 to 1.79, P <0.001) or irinotecan (RR 1.53, 95% CI 1.12 to 2.10, P =0.008).When stratified by specific infectious events, anti-EGFR-MoAbs significantly increased the risk of developing severe sepsis (RR 4.30, 95%CI: 1.80 to 10.27; P =0.001). Conclusions Anti-EGFR MoAbs treatment significantly increases the risk of developing severe infectious events in cancer patients. The risk may vary with tumor types. Clinicians should be aware of the risks of severe infections with the administration of these drugs in cancer patients. [ABSTRACT FROM AUTHOR]

The identification of KRAS mutations as a predictive marker of resistance to anti-EGFR antibodies has been considered as a major step in the personalized treatment of metastatic colorectal cancer. Recently, other mutations in genes of the RAS family have demonstrated their role in identifying patients who may benefit from anti-EGFR. Meanwhile, more fundamental works have led to better understand the mechanisms of secondary resistance to anti-EGFR antibodies and also to consider the possibility to a rapid research of KRAS or RAS mutations in peripheral blood. [ABSTRACT FROM AUTHOR]

Inhibition of the EGFR signaling pathway is one of the attractive therapeutic targets for pancreatic cancer as recent studies demonstrated that EGFR is over-expressed in pancreatic cancer. In this article we have demonstrated the design of targeted drug delivery system containing Bovine Serum Albumin (BSA) microspheres as delivery vehicle, gemcitabine as anticancer drug and anti-EGFR (epidermal growth factor receptor) monoclonal antibody as targeting agent. The conjugated BSA microspheres were characterized by several physico-chemical techniques such as scanning electron microscope, optical microscopy, fluorescent microscopy etc. Administration of these BSA microspheres containing gemcitabine and anti-EGFR (BSA-Gem-EGFR) shows significant inhibition of pancreatic cancer cells (AsPC1) compared to the cells treated with only BSA microspheres, BSA with gemcitabine (BSA-Gem), and free gemcitabine. This strategy could be used as a generalized approach for the treatment of pancreatic cancer along with other cancers which overexpress EGFR on cell surface. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Purpose: To comparatively evaluate whether metastatic colorectal cancer (mCRC) patients with KRAS codon 13 mutations (codon 13 muts) can benefit from anti-EGFR treatment. Methods: We performed a meta-analysis of relevant studies. Systematic searches of the PubMed, Embase, and Cochrane databases, as well as ASCO conference papers up to July 30, 2012, were retrieved, and the authors of included studies were contacted to obtain more individual data. Fixed effects meta-analytical models were used where indicated, and between-study heterogeneity was assessed. The primary study end points were the overall response rate (ORR). Secondary end points were progress-free survival (PFS) and overall survival (OS). Results: A total of 7 studies were included in the final meta-analysis, consisting of 2,802 mCRC patients, 1,679 of whom were treated with anti-EGFR monoclonal antibodies. The ORR of mCRC patients with codon 13 mutation was 25.2 % (29/115), compared to 17.6 % (98/558) for other KRAS mutations (other mut) and 42.6 % (429/1,006) for KRAS WT patients. The overall pooled RR for ORRs of codon 13 mut versus other mut was 1.52 (95 % CI 1.10-2.09, P = 0.003), whereas the pooled RR for codon 13 mut versus WT was 0.61 (95 % CI 0.45-0.83, P = 0.002). The pooled progression-free survival (PFS) times were 6.4 months for codon 13 mut, 4.1 months for other mut, and 6.6 months for WT, whereas the pooled OS durations were 14.6, 11.8, and 17.3 months, respectively. Subgroup analysis was conducted on the basis of the line of treatment, anti-EGFR drug, study design, and detection method, respectively. The results implicated that KRAS codon 13 mut patients gain more benefit from Cetuximab in further line treatment. Conclusions: Metastatic colorectal cancer patients with KRAS codon 13 mutations demonstrate a greater clinical response to anti-EGFR treatment than patients with other KRAS mutations. [ABSTRACT FROM AUTHOR]

Background: Epidermal growth factor receptor (EGFR) overexpression is associated with several key features of cancer development and growth. Therefore, EGFR is a very promising biological target for tumor diagnosis and anticancer therapy. Characterization of EGFR expression is important for clinicians to select patients for EGFR-targeted therapy and evaluate therapeutic effects. Purpose: To investigate whether near-infrared (NIR) fluorescent dye Cy5.5-labeled anti-EGFR monoclonal antibody Erbitux can characterize EGFR expression level in MDA-MB-231 and MCF-7 breast cancer xenografts using an in vivo NIR imaging method. Material and Methods: A fluorochrome probe was designed by coupling Cy5.5 to Erbitux through acidylation, and the fluorescence property of the Erbitux-Cy5.5 conjugate was characterized by fluorospectroscopy. Flow cytometry and laser confocal microscopy were used to test the EGFR specificity of the antibody probe in vitro. Erbitux-Cy5.5 was also injected intravenously into immune-deficient mice bearing MDA-MB-231 or MCF-7 tumors. Whole-body and region-of-interest fluorescence images were acquired and analyzed. The EGFR expression was also analyzed and confirmed by immunohistochemical assay. Results: The maximum excitation/emission wavelength for the Erbitux-Cy5.5 probe was 674/697 nm, similar to that of free Cy5.5 (674/712 nm). Confocal microscopy confirmed receptor-specific uptake in MDA-MB-231 and MCF-7 cells. In flow cytometry probe specificity assay, Erbitux-Cy5.5 showed a 9.32-fold higher affinity for MDA-MB-231 than MCF-7 cells. In vivo NIR imaging also indicated specific uptake in EGFR-positive tumors. Probe uptake rate and maximum intake dose in MDA-MB-231 were significantly higher than those in MCF-7 xenografts ( P < 0.001). Immunohistochemical staining confirmed the in vivo imaging results, showing differentiated EGFR expression in MDA-MB-231 (+ + +) and MCF-7 (+) tumor tissues. Conclusion: Erbitux-Cy5.5 may be used as a specific NIR contrast agent for the noninvasive characterization of EGFR expression level in breast cancer xenografts. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To evaluate systematically the efficacy and safety of anti-epidermal growth factor receptor (EGFR) monoclonal antibody added to a chemotherapeutic regimen in the treatment of patients with metastatic colorectal cancer (mCRC). METHODS: Eligible articles were identified by searching electronic databases. All randomized trials comparing the arm with an anti-EGFR monoclonal antibody to the arm without an anti-EGFR monoclonal antibody during the treatment of mCRC were included. A statistical analysis was performed with Review Manager 4.2.8. RESULTS: Seven randomized trials ( n= 4186) were identified. The pooled response rates were 25.4% and 17.6% by intention-to-treat analyses for patients with or without an anti-EGFR monoclonal antibody, respectively, the OR was 3.36 (95% CI 1.42–7.95); the incidence of grades 3–4 adverse events were 71.2% and 54.3% for two groups, respectively, the OR was 2.23 (95% CI 1.74–2.86). The incidence of diarrhea, skin toxicity, hypomagnesemia was 62.3% versus 55.7%; 79.3% versus 19.7%; 27.2% versus 5.6%; and the summary OR was 1.36 (95% CI 1.03–1.80); 33.47 (95% CI 14.81–75.61); 6.73 (95% CI 3.84–11.82), respectively. CONCLUSION: Our results confirmed that monoclonal antibody targeted to EGFR could be effective in increasing response rates and could be a key therapeutic agent in the optimal treatment of mCRC, despite a moderate increase in grades 3–4 adverse events. [ABSTRACT FROM AUTHOR]