Anti-epidermal Growth Factor Receptor Therapy Research Articles

Anti-epidermal growth factor receptor therapy for glioblastoma in adults

Anti-epidermal growth factor receptor therapy for glioblastoma in adults

Contemporary best practice in the management of urothelial carcinomas of the renal pelvis and ureter.

Upper tract urothelial carcinoma (UTUC) accounts for 5% of urothelial carcinomas (UCs), the estimated annual incidence being 1–2 cases per 100,000 inhabitants. Similarly to bladder UC, divergent differentiations and histologic variants confer an adverse risk factor in comparison with pure UTUC. Molecular and genomic characterization studies on UTUC have shown changes occurring at differing frequencies from bladder cancer, with unique molecular and clinical subtypes, potentially with different responses to treatment. Systemic chemotherapy is the standard approach for patients with inoperable locally advanced or metastatic UCs. Although initial response rates are high, the median survival with combination chemotherapy is about 15 months. In first-line chemotherapy several cisplatin-based regimens have been proposed. For patients with advanced UC who progress to first-line treatment, the only product licensed in Europe is vinflunine, a third-generation, semisynthetic, vinca alkaloid. Better response rates (15–60%), with higher toxicity rates and no overall survival (OS) benefit, are generally achieved in multidrug combinations, which often include taxanes and gemcitabine. The US FDA has recently approved five agents targeting the programmed death-1 and programmed death ligand-1 pathway as a second-line therapy in patients with locally advanced or metastatic UC with disease progression during or following platinum-containing chemotherapy. Potential therapeutic targets are present in 69% of tumours analyzed. Specific molecular alterations include those involved in the RTK/Ras/PI(3)K, cell-cycle regulation and chromatin-remodeling pathways, many of them have either targeted therapies approved or under investigation. Angiogenic agents, anti-epidermal growth factor receptor therapy, phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) pathway inhibitors and immunotherapeutic drugs are being successfully investigated.

Update review of skin adverse events during treatment of lung cancer and colorectal carcinoma with epidermal growth receptor factor inhibitors.

The past decades have witnessed a rapid increase in the use of molecularly targeted therapies. One class of agents includes the epidermal growth factor receptor inhibitors (EGFRIs), which afford patients longer progression-free survival (PFS) times, especially among non-small cell lung cancer (NSCLC) and metastatic colorectal carcinoma (mCRC). Certain adverse effects, particularly skin toxicity, are mainly manifested as rash, xerosis, pruritus, nails changes, hair changes and mucositis. Previous studies reported the adverse events occurred based on the cutaneous inflammation reaction. Treatment recommended glucocorticoids and antibiotics. It is suggested that skin toxicity is an important issue because it usually affects patients' quality of life (QoL) and still causes dose reduction or discontinuation of targeted therapies. For these reasons, more and more oncologists and dermatologists recognize the importance of recognition and management of skin toxicities with the expansion in availability of EGFRIs. In this review, we conducted a systematic review of recent data to examine the types and frequencies of dermatologic toxicities associated with anti-epidermal growth factor receptor (EGFR) therapies in NSCLC and mCRC. In addition, we would like to explore the management and treatment options currently used by clinicians based on the possible mechanism.

Meta-analysis of the effects of anti-epidermal growth factor receptor on recurrent/metastatic head and neck squamous cell carcinoma.

Background:We performed a meta-analysis to compare the efficacy and safety of anti-epidermal growth factor receptor (EGFR) therapy and non-anti-EGFR therapy in recurrent/metastatic (RM) head and neck squamous cell carcinoma (HNSCC).Methods:The Cochrane library, WanFang Data, PubMed, Medline, VIP, CBM, and EBSCO databases were searched for relevant studies. The objective response rate (ORR, defined as complete response or partial response according to RECTST version 1.1) and grade 3 to 4 adverse effects were used.Results:Ten studies involving 2260 patients were included. Primary meta-analysis showed that anti-EGFR therapy improved the ORR [odds ratio (OR): 1.79, 95% confidence interval 1.44–2.21, P <.00001]. Subgroup analyses revealed that the ORR of patients with RM HNSCC could be improved by monoclonal antibodies (OR: 1.89, 1.46–2.45, P <.00001) and tyrosine kinase inhibitors (OR: 1.57, 1.07–2.31, P = .02). Analysis of grade 3 to 4 adverse effects demonstrated that diarrhea (3.15, [1.90, 5.20]), rash/desquamation (13.66, [6.86, 27.20]), hypomagnesemia (1.83, [1.28, 2.62]), vomiting (1.99, [1.00, 3.95]), anorexia (3.34, [1.45, 7.73]), dehydration (2.22, [1.19, 4.12]), and hypokalemia (1.63, [1.09, 2.42]) were significantly associated with anti-EGFR therapy.Conclusion:Anti-EGFR therapy is recommended for patients with RM HNSCC. Adverse effects, such as diarrhea, anorexia, hypomagnesemia, and hypokalemia, should be carefully monitored during anti-EGFR therapy.

A Novel Multiplex Droplet Digital PCR Assay to Identify and Quantify KRAS Mutations in Clinical Specimens

Recurrent activating point mutations in KRAS are critical drivers in pancreatic cancer and have been attributed to resistance to anti-epidermal growth factor receptor therapy in colorectal cancer. Although KRAS genotyping provides limited clinical utility in the diagnosis and management of pancreatic cancer patients at present, inferences about the fractional abundance of KRAS mutations may inform on tumor purity in traditionally challenging clinical specimens and their potential use in precision medicine. KRAS genetic testing has indeed become an essential tool to guide treatment decisions in colorectal cancer, but an unmet need for methods standardization exists. Here, we present a unique droplet digital PCR method that enables the simultaneous detection and quantification of KRAS exon 2, 3, and 4 point mutations and copy number alterations. We have validated 13 mutations (G12S, G12R, G12D, G12A, G12V, G12C, G13D, G60V, Q61H, Q61L, A146V, A146T, and A146P) and focal KRAS amplifications by conducting this assay in a cohort of 100 DNA samples extracted from fresh frozen tumor biopsies, formaldehyde-fixed, paraffin-embedded tissue, and liquid biopsy specimens. Despite its modest lower limit of detection (approximately 1%), this assay will be a rapid cost-effective means to infer the purity of biopsy specimens carrying KRAS mutations and can be used in noninvasive serial monitoring of circulating tumor DNA to evaluate clinical response and/or detect early signs of relapse.

The low prevalence of colonic serrated adenocarcinoma with high KRAS mutational status at Cipto Mangunkusumo Hospital, Indonesia

Background: Serrated adenocarcinoma (SA), a subtype of colorectal carcinoma, and the KRAS mutation, a strong marker for the patient’s response to anti-epidermal growth factor receptor therapy, have a clinical importance because of its progressive nature and tendency for chemoresistance. The purposes of this study were to (1) determine the prevalence of SA, (2) evaluate the histomorphological characteristics of SA and classical adenocarcinoma based on its prognostic factors, (3) determine the prevalence of the KRAS mutation in SA cases, and (4) identify the main characteristics of SA cases and classical adenocarcinoma with a KRAS mutation.Methods: This study was conducted by reviewing hematoxylin-eosin-stained slides of colorectal carcinoma (CRC) cases from January 2013 to July 2015 at the Department of Anatomical Pathology Cipto Mangunkusumo General Hospital. The final diagnosis of SA was based on the Tuppurainen et al criteria and the KRAS mutation was evaluated using real-time polymerase chain reaction.Results: Among the 117 adenocarcinoma cases, there were 41 unequivocal SA, 11 equivocal SA, and 65 classical adenocarcinoma. The prevalence rates of unequivocal and equivocal SA among all CRC cases were 7.7% and 2.1%, respectively. There were 11 (28.2%) cases of wild-type KRAS and 28 (71.7%) cases of mutated KRAS among all unequivocal SA cases. Tumor budding (TB) was the predominant prognostic factor.Conclusion: The prevalence of SA among all CRC cases was 7.7%. The KRAS mutation was found in almost three-quarters of all SA cases.

Analysis of KRAS, NRAS, BRAF, and PIK3CA mutations could predict metastases in colorectal cancer: A preliminary study.

Colorectal cancer (CRC) is usually diagnosed in the metastatic stage, when chemotherapy and molecularly-targeted therapies, instead of surgery, play the most important therapeutic role. Application of anti-epidermal growth factor receptor (EGFR) therapy requires the analysis of RAS mutation status and only RAS wild-type (wt) patients are qualified for the therapy. The objective of this study was to analyze driver mutations in KRAS, NRAS, BRAF, and PIK3CA genes in CRC patients. We assessed the KRAS, NRAS, BRAF, and PIK3CA genes in 102 inoperable, locally advanced and advanced CRC patients. Real-time polymerase chain reaction (RT-PCR) and high resolution melt PCR (HRM-PCR) techniques with DNA intercalating dye were applied in the study. Forty-six patients demonstrated the presence of examined mutations (45.1%). No significant differences in driver mutation occurrence between men and women, as well as between younger (<65 years) and older (≥65 years) patients were found. The mutations were present significantly more frequently in metastatic than in primary tumors (p = 0.039) due to the high incidence of KRAS gene mutations in metastatic tissue. BRAF and PIK3CA mutations were found only in primary tumors. The incidence of PIK3CA mutations was significantly higher (11.77%) in early than in advanced stages of the disease (1.96%; p = 0.05); NRAS mutations were found only in metastatic cancer (7.85%; p = 0.041). Only a single mutation of the PIK3CA and no mutations of NRAS were found in rectal cancer. Our results have shown low occurrence of driver mutations in Polish CRC patients, involving also mutations in rarely tested genes. The extent of the research panel of additional mutations could contribute to creating a better method of qualifying patients for molecularly targeted therapies and obtaining a better outcome for these therapeutic strategies.

Clinical update on K-Ras targeted therapy in gastrointestinal cancers.

KRAS mutations are common in pancreatic and colorectal cancers and are associated with lack of response to anti-epidermal growth factor receptor therapy. Ras is an established therapeutic target that has long eluded efforts to develop specific inhibitors, while targeting downstream signaling pathways has proven largely ineffective, highlighting a need for rational combination strategies to overcome resistance. Recently, renewed interest in directly targeting Ras has led to the development of several small-molecule inhibitors that bind directly to K-Ras or its effector proteins, downregulation of K-Ras expression using therapeutic antisense oligonucleotides or siRNAs, and targeting scaffold proteins such as kinase suppressor of Ras. Indirect approaches to inhibiting K-Ras include combining inhibitors of the mitogen-activated protein kinase pathway with novel targeted agents. Immunotherapy in early studies has also shown clinical promise. This review summarizes the current evidence for each of these approaches.

Efficacy of bevacizumab versus epidermal growth factor receptor inhibitors for wild-type RAS metastatic colorectal cancer: a meta-analysis.

BackgroundResults from several prospective clinical trials comparing anti-epidermal growth factor receptor (EGFR) therapy and anti-vascular endothelial growth factor (VEGF) therapy plus chemotherapy for wild-type RAS metastatic colorectal cancer (mCRC) have been inconsistent. This meta-analysis aims to investigate the optimal choice for these target agents.MethodsWe searched for clinical trials in both electronic databases from inception until January 2018 and recent conference abstracts to identify prospective clinical studies comparing the efficacy of a VEGF inhibitor (bevacizumab) versus EGFR inhibitors (cetuximab or panitumumab) on wild-type RAS (including its subset KRAS) mCRC. All analyses were conducted using RevMan 5.3 software.ResultsA total of 5 studies were included. EGFR inhibitors were associated with a significant benefit in terms of overall survival (OS) compared with VEGF inhibitors in wild-type KRAS or wild-type RAS populations, with hazard ratios (HRs) equal to 0.86 (95% CI: 0.78, 0.95; p=0.003) and 0.83 (95% CI: 0.72, 0.95; p=0.007), respectively. This survival benefit was limited to the first-line setting. No difference was found for progression-free survival (PFS), whereas the objective response rate (ORR) was significantly increased in the wild-type RAS population (OR: 0.64; 95% CI: 0.50, 0.82; p=0.0004). No difference in OS was noted between EGFR inhibitors versus a VEGF inhibitor plus the FOLFIRI regimen, whereas superior survival was noted for EGFR inhibitors plus the mFOLFOX6 regimen versus a VEGF inhibitor (HR: 0.75; 95% CI: 0.57, 0.98; p=0.04). PFS was significantly prolonged (HR: 1.48; 95% CI: 1.14, 1.92; p=0.003), whereas a trend favoring OS (HR: 1.23; 95% CI: 0.93, 1.63; p=0.14) was noted for a VEGF inhibitor in patients with right-sided tumors, with no difference in the ORR (OR: 0.85; 95% CI: 0.52, 1.38; p=0.51). However, left-sided tumors exhibited superior OS (HR: 0.71; 95% CI: 0.59, 0.85; p=0.0002), PFS (HR: 0.84; 95% CI: 0.72, 0.98; p=0.03), and ORR (OR: 0.66; 95% CI: 0.48, 0.92; p=0.01) for EGFR inhibitors.ConclusionThis meta-analysis suggests the superiority of anti-EGFR therapy compared with anti-VEGF therapy for mCRC with wild-type RAS. Primary tumor location should be taken into account in target drug selection. Further research is still needed to confirm which inhibitor may be a better choice when combined with different chemotherapy regimens.

The safety of trifluridine and tipiracil for the treatment of metastatic colorectal cancer

ABSTRACTIntroduction: TAS102 is an oral thymidine-based nucleoside analog that has been approved for the treatment of patients with metastatic colorectal cancer (mCRC) previously treated with, or not candidates for, available therapies including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapies, anti-vascular endothelial growth factor (VEGF) agents and, if RAS wild-type, anti-epidermal growth factor receptor (EGFR) therapy. The pivotal RECOURSE phase III trial demonstrated a significant improvement in disease control rate, progression-free survival (PFS), and overall survival (OS) as compared with placebo in patients with refractory mCRC.Areas covered: This manuscript aims to review the clinical development of TAS102 in CRC, with a particular focus on safety, and to provide some perspective regarding its role in clinical practice. A literature search was conducted of MEDLINE and EMBASE databases for published studies (January 2004–December 2016) using the search terms TAS102, trifluridine–tipiracil, metastatic or advanced CRC, clinical trial, toxicity, safety, pharmacology, pharmacokinetics, and therapy.Expert opinion: TAS102 significantly improves survival of patients with refractory mCRC and has manageable toxicity. An expanding role in the treatment of CRC is expected for TAS102 in the near future, as its favorable safety profile makes TAS102 a suitable drug to be combined with other cytotoxic and targeted agents.

Colorectal Cancer: Why Does Side Matter?

Colorectal cancer (CRC) is a heterogeneous disease, and the search for clinical and molecular prognostic and predictive factors is thus necessary to better tailor each individual patient's management. Primary tumor location (PTL) seems to act as a master prognostic factor pooling different clinical, pathological, and molecular poor prognostic factors. In fact, right-sided (RS) CRC patients are more frequently femaleand elderly with microsatellite unstable, BRAF mutated, CpG island methylator phenotype (CIMP)-high, poorly differentiated tumors, compared to left-sided (LS) CRC patients. PTL does not seem to clearly influence disease-free survival (DFS) in localised colon cancer even though the opposite prognostic value of RS tumors on DFS depending on RAS/BRAF mutational status has been recently suggested in these patients. In metastatic CRC (mCRC), the poor prognosis associated with RS tumors is confirmed in the most recent publications in the era of double and triple chemotherapeutic regimens and targeted agents. Concerning the predictive value of PTL, in patients with RAS wild-type mCRC in the first-line setting, anti-epidermal growth factor receptor (EGFR) therapy combined with chemotherapy appears to be more effective than bevacizumab in LS CRC, while patients with RS CRC benefit less from anti-EGFR therapy, and intensive chemotherapy plus bevacizumab may be more appropriate but EGFR antibodies remain an option if objective response is needed. Due to the limitation of the current data (unplanned and retrospective analyses), these conclusions must be interpreted with caution. Clinical trials in RS CRC may be of interest to clarify what is the best treatment strategy in these patients.

Clinical Utility of Analyzing Circulating Tumor DNA in Patients with Metastatic Colorectal Cancer.

Multiple genomic changes caused by clonal evolution induced by therapeutic pressure and corresponding intratumoral heterogeneity have posed great challenges for personalized therapy against metastatic colorectal cancer (mCRC) in the past decade. Liquid biopsy has emerged as an excellent molecular diagnostic tool for assessing predominant spatial and temporal intratumoral heterogeneity with minimal invasiveness.Previous studies have revealed that genomic alterations in RAS, BRAF, ERBB2, and MET, as well as other cancer-related genes associated with resistance to anti-epidermal growth factor receptor (EGFR) therapy, can be analyzed with high diagnostic accuracy by circulating tumor DNA (ctDNA) analysis. Furthermore, by longitudinally monitoring ctDNAs during anti-EGFR therapy, the emergence of genomic alterations can be detected as acquired resistance mechanisms in specific genes, mainly those associated with the mitogen-activated protein kinase signaling pathway. Analysis of ctDNA can also identify predictive biomarkers to immune checkpoint inhibitors, such as mutations in mismatch repair genes, microsatellite instability-high phenotype, and tumor mutation burden. Some prospective clinical trials evaluating targeted agents for genomic alterations in ctDNA or exploring resistance biomarkers by monitoring of ctDNA are ongoing.To determine the value of ctDNA analysis for decision-making by more accurate molecular marker-based selection of patients and identification of resistance mechanisms to targeted therapies or sensitive biomarkers for immune checkpoint inhibitors, clinical trials must be refined to evaluate the efficacy of study treatment in patients with targetable genomic alterations confirmed by ctDNA analysis, and resistance biomarkers should be explored by monitoring ctDNA in large-scale clinical trials. In the near future, ctDNA analysis will play an important role in precision medicine for mCRC. IMPLICATIONS FOR PRACTICE: Treatment strategies for metastatic colorectal cancer (mCRC) are determined according to the molecular profile, which is confirmed by analyzing tumor tissue. Analysis of circulating tumor DNA (ctDNA) may overcome the limitations of tissue-based analysis by capturing spatial and temporal intratumoral heterogeneity of mCRC. Clinical trials must be refined to test the value of ctDNA analysis in patient selection and identification of biomarkers. This review describes ctDNA analysis, which will have an important role in precision medicine for mCRC.

Targeted data-independent acquisition for mass spectrometric detection of RAS mutations in formalin-fixed, paraffin-embedded tumor biopsies

Genomic testing for KRAS and NRAS mutations in clinical biopsies of various cancers is routinely performed to predict futility of anti-epidermal growth factor receptor (anti-EGFR) therapies. We hypothesized that RAS mutations could be detected and quantified at the protein level for diagnostic purposes using data-independent acquisition (DIA)-based mass spectrometry in formalin-fixed, paraffin-embedded (FFPE) tumor samples. We developed a targeted DIA assay that surveys the specific mass range of all possible peptides harboring activating mutations in KRAS exon 2. When the assay was applied to tumor samples with known KRAS or NRAS mutations (G12A, G12D, G12V, and G13D), RAS-mutant and wild-type peptides were successfully detected in 11 of 13 biopsy samples. Mutation statuses obtained by DIA were concordant with those obtained by DNA sequencing, and yields of mutant peptide (mutant peptide/[mutant + wild-type peptides]) exhibited linear correlation with yields of RAS-mutant mRNA. When applied to biopsy samples with failed DNA testing results, the DIA assay identified an additional RAS-mutated sample. SignificanceProteomic detection of RAS mutations by DIA in tumor biopsies can provide solid evidence of mutant RAS protein regardless of the mutation types and sites in exon 2. This robust method could rescue samples that fail genomic testing due to insufficient tumor tissue or lack of sequenceable DNA. It can be used to explore the relationship between protein expression level of mutant RAS and therapeutic outcome.

Anti-epidermal growth factor receptor therapy concurrently with induction chemotherapy in locoregionally advanced nasopharyngeal carcinoma.

Little is known about the efficacy and toxicity of anti‐epidermal growth factor receptor therapy concurrently with induction chemotherapy (IC) in locoregionally advanced nasopharyngeal carcinoma (LA‐NPC). The present study aimed to address this question. We identified 2848 patients with newly diagnosed LA‐NPC receiving IC between January 2012 and May 2015. The propensity score matching (PSM) method was used to balance various factors and to match patients. Survival outcomes and toxicities between different groups were compared. In total, 596 patients were selected at a 1:3 ratio, with 149 in the IC + CTX/NTZ group and 447 in the IC alone group. The 3‐year disease‐free survival, overall survival, distant metastasis‐free survival and locoregional relapse‐free survival rates for IC + CTX/NTZ vs IC alone were 84.3% vs 75.2% (P = .059), 94.0% vs 87.9% (P = .053), 88.0% vs 84.9% (P = .412) and 93.3% vs 88.2% (P = .242). Multivariate analysis established a treatment group (IC vs IC + CTX/NTZ) as a prognostic predictor for DFS (hazard ratio [HR], 1.497; 95% confidence interval [CI], 1.016‐2.206; P = .041) and OS (HR, 1.984; 95%, CI, 1.023‐3.848; P = .043). Grade 3‐4 skin reaction (15.4% vs 0.4%, P < .001) and mucositis (10.1% vs 2.7%, P < .001) were more common in the IC + CTX/NTZ group than that in the IC alone group. Our findings suggested that CTX/NTZ in combination with IC may be a more effective and promising strategy for patients with LA‐NPC treated with intensity‐modulated radiotherapy.

Consensus molecular subtypes classification of colorectal cancer as a predictive factor for chemotherapeutic efficacy against metastatic colorectal cancer.

The consensus molecular subtypes (CMS) classification is one of the most robust colorectal cancer (CRC) classifications based on comprehensive gene expression profiles. This study aimed to clarify whether the CMS is a predictive factor for therapeutic effects of standard chemotherapies for metastatic CRC (mCRC). We retrospectively enrolled 193 patients with mCRCs, and using comprehensive gene expression data, classified them into 4 subtypes: CMS1–CMS4. The associations between the subtypes and treatment outcomes were analyzed. Regarding first-line chemotherapy, irinotecan (IRI)-based chemotherapy was significantly superior to oxaliplatin (OX)-based chemotherapy for progression-free survival (PFS; hazard ratio [HR] = 0.31, 95% confidence interval [CI] 0.13–0.64) and overall survival (OS; HR = 0.45, 95% CI 0.19–0.99) in CMS4. Regarding the anti-epidermal growth factor receptor (anti-EGFR) therapy, CMS1 showed particularly worse PFS (HR = 2.50, 95% CI 1.31–4.39) and OS (HR = 4.23, 95% CI 1.83–9.04), and CMS2 showed particularly good PFS (HR = 0.67, 95% CI 0.44–1.01) and OS (HR = 0.49, 95% CI 0.27–0.87) compared with the other subtypes. The biological characteristics of CMS may influence the efficacy of chemotherapy. CMS might be a new predictive factor for the efficacy of chemotherapy against mCRCs.

Final Analysis of Outcomes and RAS/BRAF Status in a Randomized Phase 3 Study of Panitumumab and Best Supportive Care in Chemorefractory Wild Type KRAS Metastatic Colorectal Cancer

IntroductionTumor rat sarcoma gene (RAS) status is a negative predictive biomarker for anti-epidermal growth factor receptor (EGFR) therapy in metastatic colorectal cancer (mCRC). We analyzed outcomes according to RAS and v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutational status, and evaluated early tumor shrinkage (ETS) and depth of response (DpR) for patients with wild type RAS. Patients and MethodsPatients with confirmed metastatic colon or rectum adenocarcinoma, wild type Kristen rat sarcoma gene tumor exon 2 status, clinical/radiologic disease progression or toxicity during irinotecan or oxaliplatin treatment, and no previous anti-EGFR therapy were randomized 1:1 to receive best supportive care (BSC) with or without panitumumab (6.0 mg/kg, intravenously, on day 1 of each 14-day cycle) in this open-label, multicenter, phase III study (20100007). RAS and BRAF mutation status were determined using Sanger sequencing. ETS was evaluated as maximum percentage change from baseline to week 8; DpR was calculated as the percentage change for tumor shrinkage at nadir versus baseline. ResultsOverall, 270 patients had RAS wild type mCRC (panitumumab with BSC, n = 142; BSC, n = 128). For patients with wild type RAS tumors, median overall survival (OS; hazard ratio [HR], 0.72; P = .015) and progression-free survival (PFS; HR, 0.45; P < .0001) were improved with panitumumab with BSC versus BSC. Similar improvements were seen for patients with wild type RAS, and wild type BRAF tumors (OS: HR, 0.75; P = .04; PFS: HR, 0.45; P < .0001). Median DpR was 16.9% for the evaluable panitumumab with BSC wild type RAS population. Overall, 69.5% experienced any type of tumor shrinkage at week 8; 38.2% experienced ≥ 20% shrinkage. Similar improvements in OS and PFS were seen with stratification according to ETS. ConclusionThis analysis showed that panitumumab improved outcomes in wild type RAS mCRC and indicated that ETS and DpR could be used as additional efficacy markers.

Mutant allele-specific imbalance in patients with metastatic colorectal cancer.

706 Background: Patients with colorectal cancer(CRC) harboring RAS mutations do not respond to antiepidermal growth factor receptor (anti-EGFR) therapy. Next generation sequencing (NGS) identifies and quantifies mutant and wild type alleles as seen on the sequencing electropherograms. RAS mutant allele-specific imbalance (MASI) occurs when the mutant allele peak is higher than the wild type one. The aims of this study were to verify the rate and tissue distribution of RAS MASI as well as its clinical relevance. Methods: Results of NGS study of patients with metastatic colorectal cancer were collected retrospectively. The clinical charts of patients with RAS mutations were reviewed by the investigators who were blinded to the MASI results. Results: Between August 2014 and Jan 2016, 26 out of 52 (50%)patients tested, were found to harbor RAS mutations. Among them, 11 patients were detected with KRAS MASI(42.3%) Table 1 shows the different characteristics. 6 out of 11 patients presented with synchronous metastatic disease. This correlated with a statistically significant difference in the mean disease free survival that was 9 months in the KRAS MASI group compared with 27.5 months in the non MASI group. A few patients had more than one mutation. ie KRAS Ex2- G12D, 62.3%, PKI3CA Ex9-E545K, 24.6%, Ex20-H1047Y, 0.6% in the MASI group and KRAS Ex2-G12C+G12V - 10.85%, KRAS Ex4-A146T - 10.3%, NRAS gene Ex2-G12D - 1.1%, in non MASI group. Patients in the MASI group had a different clinical profile. (See Table 1) The overall survival of patients was calculated from diagnosis of metastatic disease, till death, 24 months-this was not significantly nor statistically different amongst groups. Conclusions: With the caveat of a small study and a retrospective analysis we showed that patients with MASI have worse characteristics that were translated to a significant shorter disease free survival. OS was not different amongst the groups. [Table: see text]

Prolonged survival with anti-epidermal growth factor receptor therapy in head and neck squamous cell carcinoma: A case series

Head and neck cancer (HNC) is the sixth most common cancer worldwide, with approximately 650,000 patients newly diagnosed annually. In the late 1990s, surgery followed by postoperative radiotherapy (RT) or RT alone was the standard therapeutic modality for locoregionally advanced head and neck squamous cell carcinoma (LA-HNSCC). As chemotherapeutic agents were identified to have additional effects when combined with RT, chemoradiotherapy has become the standard treatment over the last decade for patients with LA-HNSCC who were not candidates for surgery. Despite the heterogeneity of both tumor location and genetic aberrations, 90% of HNCs are histologically squamous cell carcinomas. Hereby, we present a case series of patients with HNSCC who were benefited with anti-epidermal growth factor receptor therapy with a prolonged survival.

Expression of epidermal growth factor receptor in advance stage nonkeratinizing nasopharyngeal carcinoma in west Sumatra, Indonesia

Introduction: Nasopharyngeal carcinoma is a head and neck cancer with a unique geographic distribution. Indonesia is one of the countries with an intermediate incidence of nasopharyngeal carcinoma where 13,000 new cases are found every year or 6.2 cases/100,000 in population per year. The subcellular mechanism of the nasopharyngeal carcinoma has not been clearly confirmed, but in several studies overexpression of the epidermal growth factor receptor was found. Based on histopathological classification, nonkeratinizing subtypes consisting of differentiated (WHO II) and undifferentiated (WHO III) are the most frequent types in endemic areas, whereas in non-endemic areas the majority of cases are keratinizing subtype (WHO I). The objective of this study was to evaluate the expression of epidermal growth factor receptor in advanced stage nonkeratinizing nasopharyngeal carcinoma as well as to evaluate difference in the expression between differentiated nonkeratinizing (WHO II) and undifferentiated (WHO III) nasopharyngeal carcinoma that may affect the anti-epidermal growth factor receptor therapy for nasopharyngeal carcinoma. Methods: Biopsies from 34 advance stage (stage III and stage IV) nonkeratinizing nasopharyngeal carcinoma consisting of 17 differentiated nonkeratinizing and 17 undifferentiated carcinomas were included in the study. Expression of epidermal growth factor receptor in tumor tissues was investigated by immunohistochemistry (IHC). Results: Our results demonstrated that epidermal growth factor receptor was expressed in 23 out of 34 subjects (67.65%). Expression in differentiated nonkeratinizing nasopharyngeal carcinoma was 76.47% (13 out of 17), and it was higher than in undifferentiated carcinoma (58.82%), but there was no statistically significant difference between the two histopathological subtypes (p=0.465). Conclusions: The epidermal growth factor receptor was expressed in most cases of advance stage nonkeratinizing nasopharyngeal carcinoma, and there was no difference in the expression between differentiated nonkeratinizing (WHO II) and undifferentiated nonkeratinizing nasopharyngeal carcinoma (WHO III).

A survey of patient and physician acceptance of skin toxicities from anti-epidermal growth factor receptor therapies

BackgroundInhibition of the epidermal growth factor receptor (EGFR) extends patient survival in multiple tumor types. Skin toxicities are the most common adverse event (AE) elicited by EGFR inhibitors. Here, we provide deeper insights into patients’ and physicians’ acceptance of the risk/benefit trade-offs of skin toxicities during cancer therapy, including comparison of their perceptions and experiences with dermatologic AEs.MethodsA multinational survey of 195 patients and 120 physicians was conducted to gauge attitudes regarding skin toxicities as an AE during cancer therapy.ResultsSkin toxicities were identified by patients and physicians as the AE that is most discouraging to patients when undergoing cancer therapies. Skin toxicities were cited as causing pain, impairing quality of life, and proving difficult to manage. Despite these negative influences, the majority of patients (71%) indicated they were willing to accept skin toxicities as an AE of an effective therapy. Indeed, the majority of patients and physicians preferred a more effective therapy that induces more severe skin toxicities than a less efficacious therapy that induces less severe skin toxicities; interestingly, patients were willing to accept a higher likelihood of severe skin toxicities than physicians.ConclusionIn this examination of patients’ perspectives, we found that patients were willing to accept skin toxicities if they were the anticipated byproduct of a more effective therapeutic regimen. Important differences were observed between patients’ and physicians’ attitudes regarding risk/benefit trade-offs during cancer therapy, suggesting that patient’s considerations and shared decision-making are key to cancer care.