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In this case report, we describe a patient who remains in complete remission two years after the discontinuation of anti-EGFR monotherapy as a third-line treatment, accompanied by persistent severe hypomagnesemia. A 45-year-old Caucasian woman with mCRC started chemotherapy with weekly cetuximab. After ten months of treatment, the therapy was stopped because the patient had persistent grade III hypomagnesemia despite amiloride, oral, and intravenous magnesium. A month later, the patient was switched to panitumumab 6 mg/kg every two weeks for four additional months to avoid weekly visits to the clinic. Following discontinuation of panitumumab, PET scans remain negative to this day, two years after anti-EGFR therapy discontinuation. No factor has been identified to explain the complete and sustained response experienced by this patient. Hypomagnesemia is a common adverse effect of anti-EGFR therapy that can lead to treatment interruption and discontinuation if severe. This case highlights the importance of pursuing anti-EGFR therapy when a response is observed in spite of severe hypomagnesemia. It also provides preliminary information that anti-EGFR therapy could be stopped after a complete response is obtained. [ABSTRACT FROM AUTHOR]

Introduction: Concurrent platinum-based chemoradiation currently represents the standard treatment for advanced head and neck cancer (HNC), but it induces a significant toxicity, in particular among elderly patients. Elderly and unfit patients have been underrepresented in clinical trials and there is a need for tailored guidelines. Methods: A retrospective review of clinical data of HNC patients treated at the Operative Oncology Unit of the San Giovanni di Dio Hospital in Frattamaggiore (Naples, Italy) was performed. At study entry, a comprehensive assessment including absolute contraindications for cisplatin use, as well as comorbidities, socioeconomic status, BMI, and weight loss, was performed. The treatment included high-dose radiotherapy plus weekly cetuximab (initially at a dose of 400 mg/m2of body surface area and thereafter at 250 mg weekly during the whole radiotherapy). The aim of this study was to evaluate the activity and toxicity of this schedule in a series of patients aged older than 69 years. Results: Between May 30, 2013, and March 30, 2015, sixty-four patients (age range, 69–87 years; median age, 73.7 years; male/female ratio, 46/18) were treated. The overall response rate was 67% in this series of patients. The disease control rate was 76%. Disease progression was recorded in 25% of the patients. The median duration of loco-regional control was 17 months (range, 15.8–17.7 months). PFS was 14.8 months (range, 13.9–15.5 months). The overall survival was 34 months, with a median follow-up of 41.0 months (range, 31.1–36.8 months). The main grade 3/4 adverse events were acne rash in 52% and radiation dermatitis in 32% of the cases. Conclusion: Cetuximab plus radiotherapy appears to be feasible and active in elderly patients unsuitable for cisplatin treatment. The treatment was supported by a favorable toxicity profile. [ABSTRACT FROM AUTHOR]

EGFR-antibodies are associated with significant skin toxicity, including acneiform rash and folliculitis. It remains impossible to predict the occurrence of severe skin toxicity due to the lack of predictive markers. Here, we present the first genome-wide association study (GWAS) to find single nucleotide polymorphisms (SNPs) associated with EGFR inhibitor-induced skin toxicity using data of the multicentre randomized phase III CAIRO2 trial (clinicaltrials.gov NCT00208546). In this study, advanced or metastatic colorectal cancer patients were treated with capecitabine, oxaliplatin and bevacizumab with or without cetuximab. Germline DNA was available in 282 of the 368 patients in the cetuximab arm. Mild skin toxicity occurred in 195 patients (i.e. CTC grade 1 or 2, respectively 91 and 104 patients) and severe skin toxicity (i.e. grade 3) in 36 patients. Grade 4 skin toxicity did not occur. None of the SNPs reached the formal genome wide threshold for significance of 5x10-8, though SNPs of at least 8 loci did show moderate association (p-value between 5x10-7 and 5x10-5) with the occurrence of grade 3 (severe) skin toxicity. These SNPs did not overlap with SNPs associated with cetuximab efficacy as found in a previous GWAS in the same CAIRO2 cohort. If formally proven by replication, the SNPs associated with severe EGFR induced skin toxicity may be helpful to predict the occurrence and severity of skin toxicity in patients that will receive cetuximab and allow for adequate information on the risk of skin toxicity and prophylactic measurements. [ABSTRACT FROM AUTHOR]

Pathological complete response is achievable with mFOLFOX6 plus cetuximab therapy for unresectable colorectal cancer with multiple paraaortic lymph node metastases (mCRC) despite right-sided colonic origin. A 62-year-old woman with synchronous paraaortic lymph node metastases of transverse colon cancer was treated with mFOLFOX6 plus cetuximab as first-line therapy. The tumor size was markedly decreased following 6 courses of chemotherapy, and all lymph node metastases had disappeared. The patient then underwent conventional right hemicolectomy with D3 lymph node dissection plus sampling excision of the paraaortic lymph nodes. The pathological diagnosis was a complete response. The patient is currently alive 5 years after surgery with no signs of recurrence. The present study reported the apparent effectiveness of conversion therapy (surgery) with combination treatment with mFOLFOX6 plus cetuximab and radical surgery. We hypothesized that patients with different types of mCRC of right-sided colon origin may be effectively treated with anti-EGFR monoclonal antibodies. [ABSTRACT FROM AUTHOR]

Objective: To evaluate cost‐effectiveness – from a local perspective – of cetuximab when it is added to conventional chemotherapy for the treatment of metastatic colon cancer. Methods: A Markov model was structured based on the systematic review of the evidence and the opinion of local experts. The economic model consists of three health states: (a) progression free survival (PFS), (b) progressive disease (PD) and (c) death. The basic measure to determine the effectiveness of the intervention was the Quality Adjusted Life Year (QALY); however, other intermediate outcomes of impact on survival were considered, such as 'R0 metastases resections' and 'early tumour shrinkage' (ETS). Quarterly cycles were considered with a time horizon of 19 quarters (approximately 5 years). The analysis perspective was based on the Ministry of Health (MoH). Key findings: The cost per quality adjusted life year (cost/QALY) for chemotherapy + cetuximab treatment (CT/Cet) with respect to the baseline strategy approaches S/. 20 078 (equivalent to 1 Gross Domestic Product per capita [GDP‐pc]). The probabilistic analysis of the ICER (Incremental Cost‐Effectiveness Ratio) shows that, in all the cases, the CT/Cet strategy becomes more cost‐effective with a payment threshold of S/. 30 000 (1.5 GDP‐pc). Likewise, the acceptability curves showed that, from a threshold of S/. 20 000, the intervention with cetuximab becomes more cost‐effective than chemotherapy alone (CT). Conclusions: The cost/QALY was S/. 20 078 (1 local GDP‐pc) for the intervention with CT plus cetuximab. Other results of clinical relevance, such as 'additional R0‐resections', 'additional ETS cases', 'disease progressions avoided' and 'deaths avoided' also favour the combination treatment. [ABSTRACT FROM AUTHOR]

Background: Two germ line Fc‐γ receptor (FCGR) polymorphisms, rs1801274 [FCGR2A; His(H)131Arg(R)] and rs396991 [FCGR3A; Phe(F)158Val(V)], produce altered proteins through amino acid substitutions. We previously reported that the FCGR2A H/H genotype was associated with longer overall survival (OS) in cetuximab‐treated chemotherapy‐refractory patients with metastatic colorectal cancer. Here, we aimed to replicate and extend this finding in the Canadian Clinical Trials Group CO.20 trial. Methods: After germ line DNA genotyping, polymorphic relationships with survival were assessed using log‐rank tests and hazard ratios (HR) from Cox proportional hazard models, adjusting for known prognostic factors. The dominant genetic inheritance model was used for the main analysis. Results: Of 592 wild‐type KRAS patients treated with cetuximab, those with the FCGR2A H/H genotype (n = 165, 28%) had improved OS (HR: 0.66, P < 0.001; median absolute benefit, 1.3 months) compared to those with R/‐ genotype (n = 427, 72%). Patients with H/R had intermediate results under a codominant genetic inheritance model (HR: 0.72, P = 0.003). No significant associations were found between FCGR3A genotype and OS. In an exploratory analysis, patients with the combination of FCGR2A H/H + FCGR3A F/F genotype had significantly better OS (HR: 0.33, P = 0.003; median absolute benefit, 12.5 months) than patients with the combination of double‐variant R/R + V/V genotype. Progression‐free survival results were similar to OS. Toxicity rates were not associated with either polymorphism. Conclusions: The FCGR2A genotype was associated with efficacy but not with toxicity in wild‐type KRAS, cetuximab‐treated colorectal cancer patients. FCGR3A genotype may modulate the relationship between FCGR2A polymorphism and outcome. FCGR2A is a promising biomarker for clinical management for these patients. FCGR2A genotype was associated with efficacy but not with toxicity in wild‐type KRAS, cetuximab‐treated colorectal cancer patients. FCGR2A is a promising biomarker for clinical management for these patients. [ABSTRACT FROM AUTHOR]

Background: Cetuximab combined with chemoradiotherapy chemotherapy is the standard therapy for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). However, survival benefit is limited. The purpose of this study was to investigate the expression of epiregulin (EREG) and amphiregulin (AREG), as predictive prognostic markers for the efficacy of cetuximab combined with chemotherapy in R/M HNSCC. Methods: We conducted a retrospective analysis of 37 patients diagnosed with R/M HNSCC. Tumor samples were analyzed for EREG and AREG mRNA gene expression, and clinical outcomes evaluated. Results: Values of EREG and AREG were associated with significantly longer overall survival (OS) (P =.03 and P =.01, respectively), as well as progression‐free survival (PFS) (P =.04 and P =.04, respectively). Multivariate analysis revealed that AREG expression was significantly associated with OS and PFS. Conclusions: Patients with recurrent/metastatic HNSCC with higher EREG and AREG gene expression appear to benefit more from cetuximab combined with chemoradiotherapy chemotherapy than those with lower expression. [ABSTRACT FROM AUTHOR]

Colorectal cancer is the second most common cancer, representing 13% of all diagnosed cancers. Cetuximab is a recombinant chimeric monoclonal IgG1 antibody and epidermal growth factor receptor (EGFR) inhibitor. Cetuximab is approved for the first-line treatment in combination with chemotherapy or as a single agent in patients who have failed or are intolerant to chemotherapy in patients with EGFR-expressing, RAS wild-type metastatic colorectal cancer. Cetuximab efficacy emerged from studies that were conducted to approve the drug. Cetuximab is well tolerated; its toxicities are caused by its mechanism of action and the most common adverse reaction is skin toxicity. The main purpose of this manuscript is to present an update on the evidence-based summary of efficacy and safety and on the cost-effectiveness of cetuximab. Furthermore, it suggests a management of adverse drug reactions to improve the tolerability of the drug. [ABSTRACT FROM AUTHOR]

Purpose of Review: During the past few years, several important clinical and molecular differences have been observed simply based on anatomic tumor location of colorectal cancer. With this review, we aimed to give an updated overview of the recent findings on tumor location as a surrogate of embryological, molecular, and clinical differences that have a direct impact on our daily clinical practice.Recent Findings: Increasing evidence has demonstrated a role for the microbiota in shaping inflammatory environments and promoting CRC growth and spread, and now we know that bacterial phylotypes vary depending on the primary tumor location. Compelling evidence has shown that tumor sidedness has both a strong prognostic and predictive value. In fact, right-sided colon cancers display a markedly worse prognosis compared to left-sided tumors; moreover, it seems that right-sided RAS wild-type metastatic colorectal cancer benefits from bevacizumab-based therapy while left-sided tumors have better outcomes with cetuximab-based treatment in the first-line setting. Since the underlying reasons of these differences are yet unknown, further investigations are warranted in this expanding and relevant field.Summary: In this review, we summarize the actual knowledge on the clinical, microbiome, and molecular differences observed between right- and left-sided colon cancers. We also present an overview of the existing data on the prognostic and predictive impact of tumor sidedness on metastatic colorectal cancer patient outcome. [ABSTRACT FROM AUTHOR]

Abstract: A prospective trial has not been performed to investigate associations between quality of life (QOL), adverse events (AEs), and overall survival (OS) in the first‐line treatment with cetuximab plus standard chemotherapy for advanced/metastatic colorectal cancer (mCRC). Associations between patient outcome and health‐related QOL (HRQOL) together with skin toxicity‐related QOL were prospectively evaluated using EORTC QLQ‐C30 and DLQI questionnaires. One hundred and forty mCRC patients were analyzed in this study, and 87.8% received pre‐emptive skin treatment. Skin toxicity had no clinical impact on HRQOL or skin‐related QOL during the first 8 weeks and throughout the study period. An early skin reaction with a grade ≥2 at 8 weeks was significantly associated with a favorable OS compared with a grade of ≤1 (HR, 0.50; 95% CI, 0.24‐0.95; P = .035) and was confirmed to be an independent predictor of OS (HR, 0.48; 95% CI, 0.21‐0.97; P = .040). Patients symptomatic at baseline who responded to treatment had improved HRQOL compared to nonresponding patients. Severe mucositis/stomatitis had a statistically significant and clinically meaningful negative impact on HRQOL (mean changes from baseline throughout the study period in global health status were −12.64 for a grade of ≥2 vs −0.35 for a grade of 0 or 1 (P = .005)). In conclusion, severe early skin reactions predict favorable OS for patients treated with cetuximab plus chemotherapy without impairing QOL. In addition, mucositis/stomatitis was the most substantial AE compromising both QOL and treatment compliance. [ABSTRACT FROM AUTHOR]

Dual-specificity phosphatase-2 (DUSP2), a negative regulator of extracellular-regulated kinase activity, has been identified as an important kinase with emerging roles in cancer. However, the clinical significance of DUSP2 in colorectal cancer (CRC) remains to be fully elucidated. In the present study, the expression of DUSP2 was investigated using immunohistochemistry in 96 patients with CRC. Cell viability was estimated using a cell counting kit-8 assay, and cell apoptosis by flow cytometry. The relationship between DUSP2 expression and patient characteristics, including overall survival, were studied retrospectively in these patients. It was found that DUSP2 was differentially expressed between left-sided colon carcinoma (LSCC) and right-sided colon carcinoma (RSCC). It was also found that decreased expression of DUSP2 was correlated with significantly shorter overall survival (P=0.001) and short distant-metastasis-free survival (P=0.002). In univariate comparisons, the decreased expression of DUSP2 was found to be an independent risk factor for poor survival rate (HR 3.55, CI 1.092-9.896; P=0.002). It was also found that the enforced overexpression of DUSP2 sensitized CRC cells to cetuximab. In conclusion, the findings demonstrated that DUSP2 was differentially expressed between RSCC and LSCC, and that the overexpression of DUSP2 increased the inhibitory effect of cetuximab in CRC, suggesting that DUSP2 may be a novel biomarker and therapeutic target in CRC therapy. [ABSTRACT FROM AUTHOR]

Background: Over the last few years only one large randomized phase III study has tried to prospectively assess the safety of cetuximab and panitumumab in a head-to-head comparison. Despite the similar overall toxicity profile, cetuximab and panitumumab retain peculiar safety characteristics that deserve to be deeply investigated. Methods: We conducted a systematic review for randomized trials in PubMed, the Cochrane Central Register of Controlled Trials, SCOPUS, Web of Science, and EMBASE using the terms (“cetuximab” or “panitumumab”) AND (“colorectal cancer” OR “colorectal carcinoma”). Data of adverse events were aggregated to obtain pooled incidence rates of prespecified adverse events. Incidence of skin toxicities was the primary outcome. A χ2 test was used for comparisons of proportions and an odds ratio (OR) was calculated for comparison. Results: A total of 38 studies were included for analysis. Cetuximab was associated with fewer G3–4 skin toxicities (OR = 0.62, 95% CI 0.53–0.62; p < 0.001), slightly more frequent G3–4 acne-like rash (OR = 1.24, 95% CI 1.04–1.48; p = 0.04), and paronychia (OR 1.36, 95% CI 1.1–1.7), but fewer cases of skin fissures (OR = 0.64, 95% CI 0.44–0.93; p = 0.02) and pruritus (OR = 0.45, 95% CI 0.35–0.58; p < 0.001) than PANI. Conclusions: In conclusion, this meta-analysis shows that cetuximab- and panitumumab-based chemotherapy have different toxicity profiles in terms of the rate of severe adverse events. [ABSTRACT FROM AUTHOR]

Background: In metastatic colorectal cancer, the location of the primary tumor has been suggested to have biological significance. In this study, we investigated whether primary tumor location affects cetuximab efficacy in patients with RAS wild-type metastatic colorectal cancer.Methods: Genotyping by the SequenomMassARRAY technology platform (OncoMap) targeting KRAS, NRAS, PIK3CA, and BRAF was performed in tumors from 307 patients who had been given cetuximab as salvage treatment. Tumors with mutated RAS (KRAS or NRAS; n = 127) and those with multiple primary location (n = 10) were excluded. Right colon cancer was defined as a tumor located in the proximal part to splenic flexure.Results: A total of 170 patients were included in the study (right versus left, 23 and 147, respectively). Patients with right colon cancer showed more mutated BRAF (39.1% vs. 5.4%), mutated PIK3CA (13% vs. 1.4%), poorly differentiated tumor (17.4% vs. 3.4%), and peritoneal involvement (26.1% vs. 8.8%) than those with left colon and rectal cancer. Right colon cancer showed poorer progression-free survival (2.0 vs.5.0 months, P = 0.002) and overall survival (4.1 months and 13.0 months, P < 0.001) than the left colon and rectal cancer. By multivariable analysis, BRAF mutation, right colon primary, poorly differentiated histology, and peritoneal involvement were associated with risk of death.Conclusions: In RAS wild-type colon cancer treated with cetuximab as salvage treatment, right colon primary was associated with poorer survival outcomes than left colon and rectal cancer. [ABSTRACT FROM AUTHOR]

Aim Metastatic colorectal cancer has a large burden of disease in Australia. Medical therapy is fundamental to extending survival and improving quality of life. The benefits of two costly medicines, bevacizumab and cetuximab, used in Australia remain unclear. The aim of this study was to retrospectively examine the use of these two medicines in metastatic colorectal cancer across five public hospitals in south east Queensland and to compare clinical outcomes to those of published clinical trials. Methods We extracted data from the chemotherapy prescribing database for patients planned for bevacizumab or cetuximab therapy between 2009 and 2013. Median overall survival was estimated using Kaplan-Meier methods. Results There were 490 bevacizumab-containing protocols planned and 292 patients received at least one dose of bevacizumab. Median overall survival was 17.2 months (95% confidence interval [CI], 15.4-19.3). Of 208 planned cetuximab-containing protocols, 134 patients received at least one dose of cetuximab. Median overall survival was 9.1 months (95% CI, 7.6-12.0). Thirty-day mortality rates from date of first dose were 0.7% for bevacizumab and 7.5% for cetuximab. Conclusion Overall survival of patients receiving bevacizumab and cetuximab was consistent with clinical trials, providing some assurance that benefits seen in trials are observed in usual practice. This study provides a methodology of using routinely collected health data for clinical monitoring and research. Because of the high cost of these medicines and the lack of toxicity data in this study, further analysis in the postmarketing setting should be explored. [ABSTRACT FROM AUTHOR]

Aims: Limited data regarding the objective evaluation of skin exsiccation caused by epidermal growth factor receptor (EGFR) inhibitors exist. Objective indices were applied to evaluate the usefulness of a moisturizer against skin exsiccation associated with the use of EGFR inhibitors in cancer patients. Patients and methods: Patients with either colorectal or head and neck cancer treated with either cetuximab or panitumumab were randomly assigned 1:2 to the prophylactic-treatment arm, where participants received prophylactical moisturizer treatment (heparinoid preparation, Hirudoid®), or to the symptomatic-treatment arm, where moisturizer was applied after the onset of cutaneous symptoms. Patients were observed for 6 weeks after the start of the administration of EGFR inhibitor. Results: A total of 15 patients were included and assessed: 6 in the prophylactic treatment group and 9 in the symptomatic treatment group. We evaluated the effect of EGFR inhibitors on the physiologic function of the skin. Administration of EGFR inhibitors resulted in a continued reduction in the moisture content of the horny layer and a decrease in cutaneous sebum levels. Skin observation revealed frequent development of an acneiform rash and significantly higher exsiccation and exfoliation scores. Administration of EGFR inhibitor was associated with a decrease in the horny layer moisture content and lower cutaneous sebum levels in the symptomatic treatment group. In contrast, levels of both the indicators were increased in the prophylactic treatment group. Moreover, the EGFR inhibitor-associated increase in exsiccation and exfoliation scores were minimized in the prophylactic treatment group relative to the symptomatic treatment group. Conclusion: Application of a moisturizer is effective against dry skin induced by the administration of an EGFR inhibitor. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to evaluate the efficacy and safety of combining irinotecan, bevacizumab and cetuximab/ panitumumab as a 4th-line treatment in patients with metastatic colorectal cancer. Methods: All patients had KRAS wild-type metastatic colorectal cancer and had previously received fluoropyrimidine, oxaliplatin, irinotecan and cetuximab/panitumumab in a 1st, 2nd and 3rd line setting. Most patients had previously received bevacizumab as well. All patients had progressed within 3 months after the last given treatment before starting the triple combination therapy every second week. Results: Sixty-three patients were evaluated. The triple combination therapy was well tolerated. The median progression-free survival was 6.1 months and the median overall survival was 11.9 months. Four patients (6%) obtained a partial response and 40 (63%) had stable disease. Conclusion: The combination of irinotecan, bevacizumab and cetuximab/panitumumab is safe and shows a toxicity profile corresponding to what is expected from the agents alone. The results indicate that the combination in the 4th line may result in a high rate of disease control in heavily pretreated patients with metastatic colorectal cancer. [ABSTRACT FROM AUTHOR]

Recently, the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) recommended that patients with epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer could be treated with anti-EGFR monoclonal antibodies (mAbs) cetuximab and panitumumab only in absence of Rat-Sarcoma (RAS) mutations. In addition to the previously established biomarker Kirsten rat sarcoma viral oncogene homolog (KRAS) exon 2, cumulative evidence also shows that patients whose tumors harbor KRAS exons 3 or 4 and neuroblastoma rat-sarcoma viral oncogene homolog (NRAS) exons 2, 3, and 4 mutations are found unlikely to benefit from anti-EGFR treatment. In line with the resistance of RAS mutated (mt) tumors, treatment response in BRAFmt tumors may also be altered given their important role in the EGFR signaling pathway. However, BRAF is not recommended as predictive biomarker yet because the evidence for the impact of BRAF mutations on treatment outcome is considered insufficient. This article summarizes the evidence for the impact of BRAF mutations on treatment outcome of anti-EGFR mAbs. Based on a review of literature, eight meta-analyses were included that consistently show that patients with BRAF mutations have a lack of treatment benefit of anti-EGFR mAbs. After discussing the quality and quantity of available evidence, we conclude that evidence is stronger than suggested by ESMO and ASCO. Additionally, we highlight that the quality of evidence for BRAF is even higher than for extended RAS as a biomarker. We therefore advise ESMO and ASCO to reconsider BRAF status as a predictive biomarker for response. [ABSTRACT FROM AUTHOR]

Aim Cetuximab improves the prognosis for wild-type KRAS metastatic colorectal cancer ( MCRC). We evaluated the safety and efficacy of cetuximab in combination with irinotecan in Japanese patients with wild-type KRAS MCRC refractory to irinotecan, oxaliplatin and fluoropyrimidines. Methods Cetuximab was administered initially at a dose of 400 mg/m2, followed by weekly infusions at 250 mg/m2. Irinotecan was administered every 2 weeks at 150 mg/m2. Primary endpoint was the incidence of grade 3/4 adverse events; secondary endpoints included overall survival ( OS), progression-free survival ( PFS), response rate ( RR), time to treatment failure ( TTF), and TTF for irinotecan. Results Thirty-four patients were enrolled. Grade 3 or 4 toxicities were leucopenia (11.8%), neutropenia (23.5%), anemia (11.8%), fatigue (2.9%), anorexia (2.9%), diarrhea (14.7%) and hypomagnesemia (5.9%). Skin toxicities were as follows (any grade/grade 3): acne (94.2/8.8%), rash (55.9/0%), nail changes (75.5/8.8%) and hand-foot syndrome (55.9/5.9%). Median PFS was 6.0 months (95% CI; 4.7-7.4). Median OS was 12.9 months (95% CI; 10.0-15.9). RR was 26.4%. Median TTF was 5.1 months and median TTF for irinotecan was 5.0 months (95% CI; 4.3-5.6). Conclusion Cetuximab with irinotecan therapy was well tolerated in Japanese patients with wild-type KRAS colorectal cancer refractory to irinotecan, oxaliplatin and fluoropyrimidine, thus demonstrating the feasibility of their usage. [ABSTRACT FROM AUTHOR]

In clinic, cetuximab, an anti-EGFR antibody, improves treatment outcomes in colorectal cancer (CRC). KRAS-mutant CRC is generally resistant to cetuximab, although difference of the sensitivity among KRAS-mutants has not been studied in detail. We previously developed the cancer tissue-originated spheroid (CTOS) method, a primary culture method for cancer cells. We applied CTOS method to investigate whether ex vivo cetuximab sensitivity assays reflect the difference in sensitivity in the xenografts. Firstly, in vivo cetuximab treatment was performed with xenografts derived from 10 CTOS lines (3 KRAS-wildtype and 7 KRAS mutants). All two CTOS lines which exhibited tumor regression were KRAS-wildtype, meanwhile all KRAS-mutant CTOS lines grew more than the initial size: were resistant to cetuximab according to the clinical evaluation criteria, although the sensitivity was quite diverse. We divided KRAS-mutants into two groups; partially responsive group in which cetuximab had a substantial growth inhibitory effect, and resistant group which exhibited no effect. The ex vivo signaling assay with EGF stimulation revealed that the partially responsive group, but not the resistant group, exhibited suppressed ERK phosphorylation ex vivo. Furthermore, two lines from the partially responsive group, but none of the lines in the resistant group, exhibited a combinatory effect of cetuximab and trametinib, a MEK inhibitor, ex vivo and in vivo. Taken together, the results indicate that ex vivo signaling assay reflects the difference in sensitivity in vivo and stratifies KRAS mutant CTOS lines by sensitivity. Therefore, coupling the in vivo and ex vivo assays with CTOS can be a useful platform for understanding the mechanism of diversity in drug sensitivity. [ABSTRACT FROM AUTHOR]

Background: To evaluate the efficacy of cetuximab combined with modified FOLFIRI (mFOLFIRI) as a second-line treatment in metastatic gastric cancer patients and to identify potential biomarkers of clinical outcomes.Methods: All 61 patients received an initial intravenous (IV) dose of cetuximab (400 mg/m2) and weekly doses (250 mg/m2) thereafter, starting on day 1. On day 2 of each 14-day period, patients received IV irinotecan (180 mg/m2), leucovorin (200 mg/m2), and an IV bolus dose of 5-FU (400 mg/m2) followed by a continuous infusion of 5-FU (2400 mg/m2) for 46 h. The primary endpoint was time-to-progression (TTP).Results: The response rate (RR) was 33.3% among 54 evaluable patients. In the intention-to-treat analysis, median TTP was 4.6 months (95% confidential interval [CI]: 3.6-5.6 months) and median overall survival (OS) was 8.6 months (95% CI: 7.3-9.9 months). In univariate analyses, plasma vascular endothelial growth factor (VEGF) levels were correlated with clinical outcome. In patients with low (≤12.6 pg/ml) and high (>12.6 pg/ml) baseline plasma VEGF levels, RR values were 55.0% and 5.3%, respectively (P = 0.001); median TTP values were 6.9 months and 2.8 months, respectively (P = 0.0005); and median OS values were 12 months and 5 months, respectively (P <0.0001). None of these patients exhibited KRAS, BRAF, or PIK3CA mutations.Conclusions: Combination therapy comprising cetuximab and mFOLFIRI was well tolerated and active as a second-line treatment for patients with metastatic gastric cancer. Patients with low baseline plasma VEGF levels were associated with better clinical outcomes.Trial Registration: ClinicalTrials.gov. NCT00699881 . Registered 17 June 2008 (retrospectively registered). [ABSTRACT FROM AUTHOR]

Background Despite improved survival by the addition of a monoclonal antibody against epidermal growth factor receptor (EGFR), cetuximab, to chemotherapy or radiotherapy for squamous cell carcinoma of the head and neck (SCCHN), cetuximab by itself is not a potent antiproliferative agent against SCCHN. We aimed to elucidate working mechanism of cetuximab in SCCHN. Methods The effect of cetuximab on the proliferation, migration, invasion, epithelial-mesenchymal transition, and signaling events downstream of the EGFR were investigated in 4 SCCHN cell lines. The in vivo efficacy of cetuximab was evaluated in a xenotransplant model. Results Cetuximab inhibited migration, invasion, epithelial-mesenchymal transition, and lymph node metastasis by suppressing EGFR-GEP100-Arf6-AMAP1 pathway, but it did not inhibit cancer cell proliferation. Conclusion The improved survival by the addition of cetuximab is likely to be attributable to the antiepithelial-mesenchymal transition action of cetuximab via inhibiting EGFR-GEP100-Arf6-AMAP1 pathway. © 2016 Wiley Periodicals, Inc. Head Neck 39: 476-485, 2017 [ABSTRACT FROM AUTHOR]

Aim Cetuximab is an anti-epidermal growth factor receptor antibody used for the treatment of metastatic colorectal cancer and head and neck cancer. Hypersensitivity reactions (HSRs) are associated with cetuximab use. The aim of the study was to evaluate the utility of anti-cetuximab immunoglobulin E (IgE) detection in order to identify patients at risk of HSR to cetuximab. Methods We included patients ready to receive a first cetuximab infusion in a prospective cohort carried out at nine French centres. Pretreatment anti-cetuximab IgE levels were measured. We compared the proportion of severe HSRs in the low anti-cetuximab IgE levels (≤29 IgE arbitrary units) subgroup with that in a historical cohort of 213 patients extracted from a previous study. Results Of the 301 assessable patients (mean age: 60.9 ± 9.3 years, head-and-neck cancer: 77%), 66 patients (22%) had high anti-cetuximab IgE levels, and 247 patients received cetuximab (including 38 with high anti-cetuximab levels). Severe HSRs occurred in eight patients (five grade 3 and three grade 4). The proportion of severe HSRs was lower in the low anti-cetuximab IgE levels subgroup vs. the historical cohort (3/209 [1.4%] vs. 11/213 [5.2%], odds ratio, 0.27, 95% confidence interval, 0.07-0.97), and higher in high vs. low anti-cetuximab IgE levels subgroup (5/38 [13.2%] vs. 3/209 [1.4%]; odds ratio, 10.4, 95% confidence interval, 2.4-45.6). Patients with severe HSRs had higher anti-cetuximab IgE levels than patients without reaction (median, 45 vs. 2 IgE arbitrary units, P = 0.006). Conclusions Detection of pretreatment anti-cetuximab IgE is feasible and helpful to identify patients at risk of severe cetuximab-induced HSRs. [ABSTRACT FROM AUTHOR]

Purpose: Skin toxicity (ST) and early tumor shrinkage (ETS) are early phenomenon during the anti-epidermal growth factor receptor (EGFR) monoclonal antibody (MoAb) treatment. We conducted a meta-analysis and included relevant studies that reported the impact of ST and ETS on survival- and life quality-based outcome of metastatic colorectal cancer (mCRC) patients treated with anti-EGFR MoAb.Methods: Relevant studies were identified from PubMed and Embase reporting the correlation of ST and ETS with the clinical outcome of mCRC patients treated with anti-EGFR MoAb. We also collected evidences on the impact of ST and ETS on absolute benefit acquired from additional anti-EGFR treatment and quality of life (ST only). Pooled hazard ratio and rate difference were all estimated by using random-effects model.Results: Pooled data revealed that the occurrence of ST and ETS ≥20% (v < 20%) during anti-EGFR MoAb treatment were both associated with better OS, PFS and ORR. This association could not be disturbed by KRAS status. Mean changes in safety follow-up life health state from baseline appeared unaffected by ST. Only mCRC patients with wild-type KRAS tumor who suffered grade 2+ ST could benefit from additional anti-EGFR treatment to chemotherapy or best supportive care (BSC) alone. ETS was also a predictor for absolute survival benefit acquired from additional anti-EGFR treatment for patients with wild-type KRAS tumors, and the more early shrinkage the tumor was, the much benefit was observed.Conclusion: ST and ETS are predictive of absolute benefit acquired from anti-EGFR treatment in mCRC patients with wild-type KRAS tumors. These two on-treatment markers can be used for clinical decision-making if no adequate biological markers from tissues are provided. [ABSTRACT FROM AUTHOR]

Limited data are available on the efficacy of anti-IGF-1R agents in KRAS mutant colorectal cancer (CRC). We analysed the outcome of 69 chemorefractory, KRAS exon 2 mutant CRC patients who were enrolled in a double-blind, randomised, phase II/III study of irinotecan and cetuximab plus dalotuzumab 10 mg/kg once weekly (arm A), dalotuzumab 7.5 mg/kg every second week (arm B) or placebo (arm C). Objective response rate (5.6% vs. 3.1% vs. 4.8%), median progression-free survival (2.7 vs. 2.6 vs. 1.4 months) and overall survival (7.8 vs. 10.3 vs. 7.8 months) were not statistically significantly different between treatment groups. Most common grade ≥3 treatment-related toxicities included neutropenia, diarrhoea, hyperglycaemia, fatigue and dermatitis acneiform. Expression of IGF-1R, IGF-1, IGF-2 and EREG by quantitative real-time polymerase chain reaction was assessed in 351 patients from the same study with available data on KRAS exon 2 mutational status. Median cycle threshold values for all biomarkers were significantly lower (i.e., higher expression, p < 0.05) among patients with KRAS wild-type compared to those with KRAS exon 2 mutant tumours. No significant changes were found according to location of the primary tumour with only a trend towards lower expression of IGF-1 in colon compared to rectal cancers ( p = 0.06). Albeit limited by the small sample size, this study does not appear to support a potential role for anti-IGF-1R agents in KRAS exon 2 mutant CRC. Data on IGF-1R, IGF-1 and IGF-2 expression here reported may be useful for patient stratification in future trials with inhibitors of the IGF pathway. [ABSTRACT FROM AUTHOR]

Purpose: This study investigated the efficacy and safety of cetuximab-based treatment in patients with chemotherapy-resistant refractory mCRC with KRAS G13D mutation.Patients and Methods: An assessment of the efficacy and safety of cetuximab-based treatment was performed in an observation-enriched randomized controlled study comparing the cetuximab alone group (Cet group) and the combination of cetuximab and irinotecan group (CetI group) for KRAS G13D-mutated mCRC in Japan. In this study, the patients received a biweekly (500 mg/m2 on day 1) or weekly (250 mg/m2) intravenous infusion of cetuximab in Cet group, or a biweekly (500 mg/m2 on day 1) or weekly (250 mg/m2) intravenous infusion of cetuximab followed by irinotecan (150 mg/m2) in CetI group. Propensity score adjustment was used to achieve balance in the observational arm.Results: Data from a total of 29 patients (10 in Cet group, 19 in CetI group) were analyzed. Crude median progression-free survival time was 2.9 months in the Cet group and 2.5 months in the CetI group. Crude disease control rates were 55.6% in the Cet group and 47.4% in the CetI group. After a median follow-up of 43 months, the crude median overall survival was 8.0 months in the Cet group and 7.6 months in the CetI group. Cetuximab-based treatment did not markedly increase any characteristic toxicity and was generally well tolerated. Propensity score analyses adjusted for performance status and number of metastases showed comparable results with the crude results.Conclusion: Cetuximab-based treatment seemed to benefit patients with chemotherapy-resistant, refractory KRAS G13D-mutated mCRC. Our results might support the administration of cetuximab-based treatment for KRAS-mutant mCRC and would be able to provide treatment flexibility in this setting. [ABSTRACT FROM AUTHOR]

Purpose: Cetuximab demonstrates improved efficacy outcomes in patients with metastatic colorectal cancer (mCRC) harboring wild-type KRAS exon 2. Resistance to cetuximab is mediated by activating less frequent mutations in the RAS genes beyond KRAS exon 2. We performed extended RASmutational analysis using a high -throughput genotyping platform (OncoMap) and evaluated extended RAS analysis for predicting cetuximab efficacy in patients harboring wild-type KRAS exon 2 tumors following Sanger sequencing. Materials and Methods: Extended RAS analysis was performed on 227 wild-type KRAS exon 2 mCRC patients who received cetuximab as salvage treatment using OncoMap ver. 4.0. Targeted genes included exon 2, exon 3, and exon 4, both in KRAS and NRAS, and included BRAF exon 15. We assessed efficacy by the new RAS mutation status. Results: The OncoMap detected 57 additional mutations (25.1%): 25 (11%) in KRAS exon 2 and 32 (14.1%) beyond KRAS exon 2. Survival differences were observed after dividing patients into the wild-type RAS group (n=170) and mutant RAS group (n=57) using OncoMap. Progression-free survival was 4.8 months versus 1.8 months (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.32 to 0.61), and overall survival was 11.9 months versus 8.4 months (HR, 0.65; 95% CI, 0.47 to 0.88). Conclusion: Sanger sequencing is not sufficient for selecting candidates for cetuximab treatment. High - throughput extended RAS genotyping is a feasible approach for this purpose and identifies patients who might benefit from cetuximab treatment. [ABSTRACT FROM AUTHOR]

Introduction. A KRAS mutation represented the first genomic biomarker to predict lack of benefit from anti-epidermal growth factor receptor (EGFR) antibody therapy in advanced colorectal cancer (CRC). Expanded RAS testing has further refined the treatment approach, but understanding of genomic alterations underlying primary and acquired resistance is limited and further study is needed. Materials and Methods. We prospectively analyzed 4,422 clinical samples from patients with advanced CRC, using hybrid- capture based comprehensive genomic profiling (CGP) at the request of the individual treating physicians. Comparison with prior molecular testing results, when available, was performed to assess concordance. Results. We identified a RAS/RAF pathway mutation or amplification in 62% of cases, including samples harboring KRAS mutations outside of the codon 12/13 hotspot region in 6.4% of cases. Among cases with KRAS non-codon 12/13 alterations for which prior test results were available, 79 of 90 (88%) were not identified by focused testing. Of 1,644 RAS/RAF wild-type cases analyzed by CGP, 31% harbored a genomic alteration (GA) associated with resistance to anti- EGFRtherapy in advanced CRC including mutations in PIK3CA, PTEN, EGFR, and ERBB2. We also identified other targetable GA, including novel kinase fusions, receptor tyrosine kinase amplification, activating point mutations, as well as micro-satellite instability. Conclusion. Extended genomic profiling reliably detects alterations associated with lack of benefit to anti-EGFR therapy in advanced CRC, while simultaneously identifying alterations potentially important in guiding treatment. The use of CGP during the course of clinical care allows for the refined selection of appropriate targeted therapies and clinical trials, increasing the chance of clinical benefit and avoiding therapeutic futility. [ABSTRACT FROM AUTHOR]

The clinical outcome of colorectal cancer (CRC) is associated with the immune response; thus, these tumors could be responsive to different immune therapy approaches. Natural killer (NK) cells are key antitumor primary effectors that can eliminate CRC cells without prior immunization. We previously determined that NK cells from the local tumor environment of CRC tumors display a profoundly altered phenotype compared with circulating NK cells from healthy donors (HD). In this study, we evaluated peripheral blood NK cells from untreated patients and their possible role in metastasis progression. We observed profound deregulation in receptor expression even in early stages of disease compared with HD. CRC-NK cells displayed underexpression of CD16, NKG2D, DNAM-1, CD161, NKp46, and NKp30 activating receptors, while inhibitory receptors CD85j and NKG2A were overexpressed. This inhibited phenotype affected cytotoxic functionality against CRC cells and interferon-γ production. We also determined that NKp30 and NKp46 are the key receptors involved in detriment of CRC-NK cells' antitumor activity. Moreover, NKp46 expression correlated with relapse-free survival of CRC patients with a maximum follow-up of 71 months. CRC-NK cells also exhibited altered antibody-dependent cellular cytotoxicity function responding poorly to cetuximab. IL-2 and IL-15 in combination with cetuximab stimulated NK cell, improving cytotoxicity. These results show potential strategies to enhance CRC-NK cell activity. [ABSTRACT FROM AUTHOR]

Purpose: Anti-epidermal growth factor receptor antibody therapy alone or in combination with irinotecan is recognized as a standard third-line treatment for KRAS wild-type unresectable metastatic colorectal cancer. However, in some cases, it is difficult to administer irinotecan after third-line treatment. Therefore, we examined the efficacy and safety of the combination of cetuximab and S-1 in patients with KRAS wild-type unresectable metastatic colorectal cancer who were previously treated with irinotecan, oxaliplatin, and fluoropyrimidines.Methods: The study was designed as a phase II, non-randomized, open-label, multicenter trial. Cetuximab was initially administered at 400 mg/m(2), followed by weekly infusion at 250 mg/m(2). S-1 was administered at a fixed dose of 80 mg/m(2) orally twice daily for 28 days followed by a 14-day break, resulting in a 6-week treatment course. The primary endpoint was progression-free survival (PFS). The secondary endpoints were the overall response rate (ORR), overall survival (OS), disease control rate (DCR), time to treatment failure, dose intensity, safety, and BRAF mutation status.Results: Thirty-seven patients were eligible. The median PFS was 5.5 months, the median OS was 13.5 months, the ORR was 29.7 %, and the DCR was 73.0 %. The relative dose intensity was 86.8 % for cetuximab and 88.1 % for S-1. Grade 3-4 adverse events that occurred in >10 % of the patient population included rash, dry skin, diarrhea, paronychia, anorexia, fatigue, mucositis, and neutropenia.Conclusions: Combination therapy with cetuximab and S-1 was effective and well tolerated in patients with irinotecan-, oxaliplatin-, and fluoropyrimidine-refractory metastatic colorectal cancer. [ABSTRACT FROM AUTHOR]

Introduction Left- and right-sided colon cancers were significantly different in epidemiologic, clinical and histological parameters. However, the impact of primary tumor location in metastatic colon cancer treated with front-line targeted triplet regimens is unclear, particularly in Asian populations. Methods A total of 121 patients with KRAS exon 2 codon 12/13 wild-type metastatic colon cancer were enrolled between January 2007 and December 2013. All patients received one target agent, such as cetuximab or bevacizumab, as a front-line targeted triplet regimen. The impact of primary tumor location for cetuximab and bevacizumab groups was analyzed, respectively. Results In cetuximab group, left-sided metastatic colon cancer was superior to right-sided metastatic colon cancer in objective response rate (70.1% vs 33.3%, P = 0.024), progression-free survival (15.0 vs 5.3 months, P < 0.001) and overall survival (35.8 vs 14.4 months, P = 0.031 ). Primary tumor location was an independent prognostic factor for progression-free survival (hazard ratio 0.240, 95% confidence interval 0.114-0.508, P < 0.001). However, in the bevacizumab group, there were no differences in outcomes for either side. Primary tumor location was insignificant for progression-free survival and overall survival in univariate analysis. Conclusion Left-sided primary tumors were favored in cetuximab-based front-line targeted triplet regimen for metastatic colon cancer. [ABSTRACT FROM AUTHOR]

Background: Since 2013, informative trials exploring the optimal use of available biologic agents in the first-line setting of metastatic colorectal cancer (mCRC) have been presented. These trials have opened a stimulating debate on the biological effect that first-line therapies may have on subsequent lines of treatment even long after the first-line progression.Materials and Methods: We reviewed available preclinical and clinical data on the effect of different sequences of the biological drugs approved for use in mCRC patients. The importance of molecular selection of patients based on RAS mutational status and toxicity and quality-of-life issues were also analyzed.Results: Convincing evidence exists on the optimal therapeutic effect obtained by using anti-EGFR agents in first-line treatment before anti-VEGF agents. On the contrary, up-front anti-VEGF agents' use seems to determine biological changes that increase the risk of acquired resistance to subsequent EGFR inhibitors. This hypothesis is confirmed by the scarce evidence of EGFR inhibitor activity in second-line treatment. Such a therapeutic optimum is subject to a fine molecular selection based on RAS mutational status.Conclusion: There is accumulating evidence suggesting that, after precise and well-established molecular selection, anti-EGFR agents deliver their maximum efficacy in mCRC patients when given early in the treatment strategy. Their toxicity profile seems manageable under the supervision of experienced physicians. Large randomized trials prospectively confirming the impact of different sequencing strategies are eagerly awaited. [ABSTRACT FROM AUTHOR]

Objective: We aimed to evaluate the effect of intraperitoneal cetuximab administration on the healing of anastomosis and development of early adhesion formation in a rat model. Materials and Methods: Twenty-four female rats were used. A colon segment was resected and end-to-end anastomosis was performed. The rats were randomized into three groups after the performance of colonic anastomosis and received 10 mL of intraperitoneal solution including study drugs after closure of abdominal cavity: normal saline was administered to the normal saline group (n=8), cetuximab (400 mg/m2) was administered to the postoperative 1 group (n=8) 1 day after surgery, and cetuximab (400 mg/m2) was administered to the peroperative group (n=8) during surgery. Results: The mean adhesion grade was 2.63±0.92, and 0.50±0.76 and 0.63±0.74 for control and test groups, respectively. Cetuximab reduced adhesion formation in test groups (p<0.05). When all groups were compared, it was found that vascular endothelial growth factor levels decreased significantly only in the abdomen (p<0.05). Hydroxyproline levels and anastomosis bursting pressure were examined, and a statistical difference was found between groups (hydroxyproline p<0.05, bursting pressure p<0.05). However, when postoperative 1 day group was compared with the control group, it was found that there was no difference between groups according to these parameters (p>0.05), but when peroperative group was compared with the control group a significant decrease was observed in both parameters. Histopathological healing score was also evaluated. No statistical difference between groups was found. Conclusion: Twenty-four hours later from the operation, intraperitoneal cetuximab therapy may be a safe and feasible treatment for metastatic colorectal patients. [ABSTRACT FROM AUTHOR]

Background: Cetuximab is a monoclonal antibody against epidermal growth factor receptor with activity against head and neck cancer and colorectal cancer. Anaphylaxis in response to cetuximab is a significant clinical problem in the Southeastern United States with a grade 3/4 infusion reaction rate of 14%. Previous retrospective data have suggested that the presence of preformed immunoglobulin E antibodies against galactose-α-1,3-galactose in serum can predict anaphylaxis in response to cetuximab.Methods: Sixty patients were prospectively screened as part of the entry criteria for a phase 2 study of neoadjuvant carboplatin, nab-paclitaxel, and cetuximab. Patients were recruited at 2 academic medical centers known to have high anaphylaxis rates: the University of North Carolina and Vanderbilt. Only patients with a negative laboratory result were treated on the clinical protocol.Results: No patient experienced anaphylaxis; the negative predictive value was thus 100%. Other than smoking history, the demographics were similar for assay-positive subjects and assay-negative subjects.Conclusions: Subjects with a negative test result can be safely treated with cetuximab. Further research is required regarding the optimal cutoff for positivity and the positive predictive value. Cancer 2016;122:1697-701. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Previous studies have shown left-sided colorectal cancer (LCRC) and right-sided colorectal cancer (RCRC) exhibit different molecular and clinicopathological features. We explored the association between the primary tumor site and cetuximab efficacy in KRAS wild-type colorectal cancer (CRC).Methods: This study enrolled a cohort of patients, who had received cetuximab treatment after two or more lines of chemotherapy for KRAS wild-type (exon 2 nonmutant) metastatic CRC, from the databases of Taiwan Cancer Registry (2004-2010) and National Health Insurance (2004-2011). Survival data were obtained from the National Death Registry. Time to treatment discontinuation (TTD) and overall survival (OS) after the start of cetuximab treatment were compared between patients with LCRC (splenic flexure to rectum) and RCRC (cecum to hepatic flexure).Results: A total of 969 CRC patients were enrolled. Among them, 765 (78.9 %) and 136 (14.0 %) patients had LCRC and RCRC, respectively. Patients with LCRC, compared to patients with RCRC, had longer TTD (median, 4.59 vs. 2.75 months, P = .0005) and OS (median, 12.62 vs. 8.07 months, P < .0001) after the start of cetuximab treatment. Multivariate analysis revealed a right-sided primary tumor site was an independent predictor of shorter TTD (adjusted hazard ratio [HR] = 1.32, using the LCRC group as a reference, 95 % confidence interval: 1.08-1.61, P = .0072) and OS (adjusted HR = 1.45, 95 % CI: 1.18-1.78, P = .0003).Conclusion: Our findings demonstrate that a left-sided primary tumor site is a useful predictor of improved cetuximab efficacy in the third-line or salvage treatment of KRAS wild-type (exon 2 nonmutant) metastatic CRC. [ABSTRACT FROM AUTHOR]

Objective: The aim of this pilot study was to explore intrapatient mixed metabolic response and early 18F-FDG PET response evaluation using predefined quantification strategies in patients with advanced KRAS wild-type colorectal adenocarcinoma (mCRC) treated with cetuximab. Methods: A 18F-FDG PET was performed at baseline and after 2 cycles of cetuximab. Metabolic response was categorized using thresholds suggested in PERCIST. Quantitative analysis was done for the sum of all target lesions, ≤ 5 lesions and the metabolically most active lesion per PET. Quantitative data were correlated with clinical benefit, according to RECIST v1.1, after two months of treatment. Results: In nine evaluable patients the total number of target lesions was 34 (1–8 per patient). Mixed metabolic response was observed in three out of seven patients with multiple target lesions, using TLG. Dichotomised metabolic data of the sum of all or ≤ 5 lesions had a concordance with clinical benefit of 89% using SULmax or SULpeak, and 100% using TLG. Evaluating the metabolically most active lesion, concordance was 89% for all three units. Additionally, the decrease in TLG was significantly correlated with PFS for all three quantification strategies. Conclusion: Mixed metabolic response was observed in nearly half of the patients with advanced KRAS wild-type mCRC treated with cetuximab. If ≤ 5 target lesions were evaluated using TLG clinical benefit was predicted correctly for all patients. Moreover, decrease in TLG is significantly correlated with the duration of PFS. Validation of these promising preliminary results in a larger cohort is currently on-going. Trial Registration: ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

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Targeted molecular therapy is an effective anticancer strategy. Anti-EGFR monoclonal antibodies such as cetuximab (CTX) have been approved for the treatment of various malignancies, including colorectal cancer (CRC) with wild-type KRAS. However, their efficacy in patients with KRAS mutations has not been established. Therefore, we investigated whether CTX treatment was effective as a single agent or in combination with zoledronic acid (ZOL) in human CRC cell lines with different KRAS status. CRC cell lines SW48 (wild-type KRAS) and LS174T (mutant KRAS) were treated with ZOL, CTX and a combination of both drugs. Cytotoxicity was measured using the MTT assay. Changes in the levels of intracellular signaling proteins were evaluated using western blot analysis. Finally, we evaluated the efficacy of the combination treatment in an in vivo xenograft model. We observed that ZOL apparently inhibited growth in both cell lines, whereas CTX showed little effect. ZOL also increased the levels of unprenylated RAS. Combined ZOL and CTX treatment was synergistic in both cell lines and was associated with inhibition of the RAS-MAPK and AKT-mTOR signaling pathways. Furthermore, the combination treatment was more effective in suppressing the growth of xenografts derived from both SW48 and LS174T cells; this effect was associated with increased apoptosis. These results demonstrate that ZOL inhibits the growth of colon cancer cells regardless of KRAS status, and combination therapy using ZOL and CTX enhances this growth suppression. These findings suggest a novel strategy for the treatment of CRC independent of KRAS mutational status. [ABSTRACT FROM AUTHOR]

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EGFR pathway is an important therapeutic target in human tumors, including metastatic colorectal cancer (mCRC). The advent of EGFR-targeted monoclonal antibodies panitumumab and cetuximab has generated promise for the treatment of mCRC and has largely improved patients' progression-free survival (PFS) and overall survival (OS). However, treatment with anti-EGFR monoclonal antibodies is only effective in a subset of mCRC patients with wild-type KRAS. This indicates that there are other factors affecting the efficacy of anti-EGFR monoclonal antibodies. Existing studies have demonstrated that among colorectal cancer patients with wild-type KRAS, harboring mutations of BRAF, PIK3CA, NRAS, or PTENnull may demonstrate resistance to anti-EGFR-targeted therapy, and biomarkers detection can provide better-personalized treatment for mCRC patients. How to identify and reverse the secondary resistance to anti-EGFR monoclonal antibody therapy is also another great challenge to improve the anti-EGFR efficacy in wild-type KRAS mCRC patients. Finally, both of the molecular mechanisms of response and acquired resistance would be important for the directions of future research. This review focuses on how to further improve the predictive value of anti-EGFR therapies and how to also try and avoid futile treatment for wild-type KRAS colorectal cancer patients. [ABSTRACT FROM AUTHOR]

Currently, there are a few systemic treatment options for patients with metastatic colorectal cancer (mCRC). Targeted therapy used in this setting includes the use of monoclonal antibodies, such as cetuximab or panitumumab, directed against epidermal growth factor receptor. The aim of the present study was to estimate the frequency and severity of hypomagnesemia among patients with mCRC treated with cetuximab. The data from the Department of Clinical Oncology, University Hospital of Krakow (Krakow, Poland), concerning 52 patients treated between 2009 and 2013 were collected. Of these, 27 patients fulfilled the inclusion criteria to enter this retrospective study. The National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 were used to grade the level of hypomagnesemia. In total, 29.6% of all patients experienced hypomagnesemia during treatment, and the majority of cases were grade 1 (22.2%). There was no statistically significant correlation between magnesium (Mg) level and patient age, duration of treatment, localization of primary tumor or metastases, and the number of metastases. However, there was an upward trend in a logistic regression model showing that the risk of developing hypomagnesemia increases with age. Hypomagnesemia is a frequent problem among mCRC patients receiving cetuximab. It is essential to introduce guidelines regarding the monitoring of the Mg level and its supplementation in this group of patients. [ABSTRACT FROM AUTHOR]

Background: Amphiregulin, a ligand of the epidermal growth factor receptor (EGFR), is associated with the efficacy of cetuximab, an antibody against EGFR, as treatment for colorectal cancer (CRC). In contrast, the HER3 ligand heregulin correlates with cetuximab resistance. In this study, we evaluated how the combined levels of circulating amphiregulin and heregulin affect clinical outcomes in patients who receive cetuximab as therapy against advanced CRC. Methods: Plasma levels of amphiregulin and heregulin were measured by enzyme-linked immunosorbent assay in 50 patients with CRC in a training cohort, and in 10 patients in a validation cohort. The combined expression was then assessed with clinical outcome after receiver operating characteristics analysis. Results: Overall response rate was 26%, and median progression-free survival was 110 days in the training cohort. Patients with high amphiregulin and low heregulin had significantly higher objective response rate at 58% and significantly longer progression-free survival of 216 days. This result was confirmed in the validation cohort. Conclusion: A subgroup of CRC patients with high amphiregulin and low heregulin respond to cetuximab therapy better than other patients. [ABSTRACT FROM AUTHOR]

Circulating forms of the urokinase plasminogen activator receptor (uPAR) are associated with prognosis in patients with colorectal cancer. Preclinical studies have shown that uPAR can influence the state of phosphorylation and signalling activity of the epidermal growth factor receptor (EGFR) in a ligand-independent manner. The purpose of the study was to evaluate whether plasma soluble intact and cleaved uPAR(I-III)+(II-III) levels could identify a subpopulation of patients with metastatic colorectal cancer (mCRC) where treatment with cetuximab would have a beneficial effect. Plasma samples were available from 453 patients treated in the NORDIC VII study. Patients were randomized between FLOX and FLOX + cetuximab. The levels of uPAR(I-III)+(II-III) were determined by time-resolved fluorescence immunoassay. We demonstrated that higher baseline plasma uPAR(I-III)+(II-III) levels were significantly associated with shorter progression-free survival (PFS) (HR = 1.30, 1.14-1.48, p = 0.0001) and overall survival (OS) (HR = 1.75, 1.52-2.02, p < 0.0001). Multivariate Cox analysis showed that plasma uPAR(I-III)+(II-III) was an independent biomarker of short OS (HR = 1.45, 1.20-1.75, p = 0.0001). There were no significant interactions between plasma uPAR(I-III)+(II-III) levels, KRAS mutational status and treatment either PFS ( p = 0.43) or OS ( p = 0.095). However, further explorative analyses indicated that patients with low levels of circulating suPAR and a KRAS wild-type tumor have improved effect from treatment with FLOX + cetuximab as compared to patients with KRAS wild-type and high levels of suPAR. These results thus support the preclinical findings and should be further tested in an independent clinical data set. [ABSTRACT FROM AUTHOR]

The advances made in the therapeutic management of colorectal cancer (CRC) over recent years with the addition of therapies targeting angiogenesis or cell proliferation have positioned bevacizumab, cetuximab, and panitumumab as accepted first-line treatments when combined with FOLFOX or FOLFIRI for RAS wild-type (WT) metastatic CRC. The question has been raised as to the choice of targeted therapy to maximize chances of an optimal outcome. Three studies, the phase III FIRE-3 (AIO KRK-0306), the phase II PEAK, and the recently presented phase III CALGB/SWOG 80405 trial, have addressed this issue face-on, directly comparing the addition of bevacizumab versus cetuximab or panitumumab to FOLFOX/FOLFIRI in terms of efficacy outcomes. None of these studies met their primary endpoint (response rate, progression-free survival or overall survival respectively), meaning we are no closer to being able to categorically define an optimal targeted treatment in the first-line setting for patients with advanced CRC. This led to reflection over study design and further analyses, raising a number of important issues. High-sensitivity analysis of the mutational status of exons identified a population with a "pure" non-RAS-mutated profile showing benefit with anti-epidermal growth factor receptor (anti-EGFR) combinations, particularly in the context of early and greater depth of response. Coherent with a personalized therapeutic approach, the importance of performing individual high-sensitivity extended RAS testing is unequivocal and is currently a requirement in many countries to identify this all-RAS WT population, thus limiting unnecessary exposure and expense in patients unlikely to respond. These three studies, particularly the CALGB/SWOG 80405 trial, mark an important milestone in the roadmap of metastatic CRC treatment, highlighting the need for close analysis to fully exploit the available data. [ABSTRACT FROM AUTHOR]

Mammalian target of rapamycin (mTOR) has been shown to be overactive in human colorectal cancer, but the first-generation mTOR inhibitor, rapamycin, has failed to show clinical efficacy against colorectal cancer. On the other hand, although the secondgeneration mTOR inhibitor, PP242, has exerted substantial efficacy, it was revealed that independent inhibition by PP242 was transient, which could lead to positive-feedback loop to EGFR. Using wild-type KRAS colorectal cancer cells as models, we investigate the treatment efficacy of a widely used anti-EGFR monoclonal antibody, cetuximab, and PP242, alone or in combination in vitro and in vivo. Results of cell viability assays confirmed the synergistic inhibitory effect of PP242 and cetuximab on the survival of Caco-2 and HT-29 cells. Moreover, the ability of cancer-cell invasion and proliferation was also significantly inhibited by the combination therapy when compared with cetuximab or PP242 alone. Interestingly, the percentage of CD44-positive cancer cells was substantially decreased by the combination therapy in comparison with PP242 alone through fluorescence-activated cell sorting. The growth of cancer stem-like cell spheres in vitro was also maximally inhibited by combination therapy, in terms of either diameter or number. More importantly, the efficacy of combination therapy was more prominent than either drug alone in established tumor xenografts. These findings supported the potential use of combination therapy of PP242 and cetuximab against wild-type KRAS colorectal carcinomas. [ABSTRACT FROM AUTHOR]

A still relevant number of patients with RAS-BRAF wild-type colorectal cancer (CRC) do not respond to treatment with antiepidermal growth factor receptor (EGFR) monoclonal antibodies cetuximab and panitumumab, suggesting that additional biomarkers to guide patient selection are urgently needed. Circulating tumor cells (CTCs) may represent such a biomarker. In this prospective study, 38 patients with advanced RAS-BRAF-wild-type CRC received third-line therapy with cetuximab-irinotecan or panitumumab. Peripheral blood samples for CTC status determination were collected at baseline, during treatment at early (2-4 weeks) and at later (8-10 weeks) times. CTC enrichment was done with the AdnaTest ColonCancerSelect kit, whereas CTC detection was done with the AdnaTest ColonCancerDetect kit. CTC status positivity was defined according to the kit manufacturer's thresholds. Fifty percent of patients were defined as CTC positive at baseline and the overall RECIST response rate was 26%. CTC baseline status was not associated with treatment response, whereas early CTC status and CTC status changes during treatment were significantly associated with tumor response. Kaplan-Meier analysis showed a significantly shorter progression-free survival (median, 2.0 versus 4.0 months, p = 0.004) and overall survival (4.7 versus11.4, p = 0.039) in patients with early CTC + status compared with CTC - ones. In multivariable analysis including classical prognostic factors, the CTC status changes profile during treatment was an independent predictor of both progression-free survival ( p < 0.001) and overall-survival ( p = 0.001). CTC status assessed early during treatment with anti-EGFR monoclonal antibodies may predict treatment failure in advance compared to imaging-based tools. [ABSTRACT FROM AUTHOR]

A number of previous studies have reported that 30-50% of patients with colorectal cancer (CRC) harbor Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations, which is a major predictive biomarker of resistance to epidermal growth factor (EGFR)-targeted therapy. Treatment with an anti-EGFR inhibitor is recommended for patients with KRAS wild-type metastatic colorectal cancer (mCRC). A recent retrospective study of cetuximab reported that patients with KRAS p.G13D mutations had better outcomes compared with those with other mutations. The aim of this retrospective study was to assess the prevalence of KRAS p.G13D mutations and evaluate the effectiveness of cetuximab in mCRC patients with KRAS p.G13D or other KRAS mutations. We reviewed the clinical records of 98 mCRC patients with KRAS mutations who were treated between August, 2004 and January, 2011 in four hospitals located in Tokyo and Kyushu Island. We also investigated KRAS mutation subtypes and patient characteristics. In the patients who received cetuximab, univariate and multivariate analyses were performed to assess the effect of KRAS p.G13D mutations on progression-free survival (PFS) and overall survival (OS). Of the 98 patients, 23 (23.5%) had KRAS p.G13D-mutated tumors, whereas 75 (76.5%) had tumors harboring other mutations. Of the 31 patients who received cetuximab, 9 (29.0%) had KRAS p.G13D mutations and 22 (71.0%) had other mutations. There were no significant differences in age, gender, primary site, pathological type, history of chemotherapy, or the combined use of irinotecan between either of the patient subgroups. The univariate analysis revealed no significant difference in PFS or OS between the patients with KRAS p.G13D mutations and those with other mutations (median PFS, 4.5 vs. 2.8 months, respectively; P=0.65; and median OS, 15.3 vs. 8.9 months, respectively; P=0.51). However, the multivariate analysis revealed a trend toward better PFS among patients harboring p.G13D mutations (PFS: HR=0.29; 95% CI: 0.08-1.10; P=0.07; OS: HR=0.23; 95% CI: 0.04-1.54; P=0.13). In conclusion, treatment with cetuximab may be more clinically beneficial in mCRC patients with a KRAS p.G13D mutation, compared with those harboring other mutations. However, further investigation is required to clearly determine the benefits of cetuximab treatment in patients with KRAS p.G13D mutation-positive mCRC. [ABSTRACT FROM AUTHOR]