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Pre-emptive Low-dose Doxycycline During Anti-EGFR Treatment

ABSTRACT: Up to 60% of patients with metastatic colorectal cancer can be treated with one of monoclonal antibodies targeted against epidermal growth factor receptor (EGFR). This treatment is associated with a specific spectrum of toxicity: acne-like rash from limited up to erythema, often with severe pruritus, sometimes combined with other types of skin toxicities (hair and nail changes). Previously in STEPP study investigators shown that pre-emptive treatment with oral doxycycline (200 mg daily), topical steroids and sun blockers reduces the number of more severe skin side effects of panitumumab. The study is designed to described the profile of skin toxicity of EGFR blocking drugs combined with low-dose doxycycline (100 mg daily) used in the pre-emptive manner.

DISEASE(S): Skin Toxicities,Colorectal Cancer,Colorectal Neoplasms

PROVIDER: 2108692 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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A randomised phase II study evaluating Dual inhibition of epidermal growth factor receptor (EGFR) signalling using CetUXimab and Erlotinib or dose escalated Cetuximab in patients with chemotherapy refractory KRAS wild-type metastatic colorectal cancer

Project description:Interventions: Patients randomised to treatment Arm B will receive dual EGFR inhibition, consisting of Cetuximab 400mg/m2 (initial dose), then 250mg/m2 via intravenous infusion each week, plus Erlotinib 100mg via oral tablet(s) daily continuously. Patients randomised to treatment Arm C will receive high-dose Cetuximab, 500mg/m2 via intravenous infusion each week. Treatment will continue until disease progression, unacceptable toxicity (as defined in the protocol), patient and/or clinician preference, or patient death. Patients participating in the optional skin management study randomised to Group 1 will commence pre-emptive skin side effect treatments the day before starting study Cetuximab, and will continue until study treatment is ceased. Patients will be required to adhere to: daily use of moisturiser and topical 1% hydrocortisone (steroid) applied to face, hands, feet, neck, back each day; use of sunscreen before sun exposure; and taking doxycycline (antibiotic) 100mg via oral tablet(s) twice each day. Primary outcome(s): Tumour response rate, as assessed by RECIST v.1.1 using chest, abdomen and pelvis CT.[Baseline, 6-weekly while on treatment then 3-monthly for 12 months of follow-up. RECIST assessments cease for completion of follow-up, study withdrawal, progressive disease, new anti-cancer therapy or patient death.] Study Design: Purpose: Treatment; Allocation: Randomised controlled trial; Masking: Open (masking not used);Assignment: Parallel;Type of endpoint: Safety/efficacy

| 2457580 | ecrin-mdr-crc

Adverse Events of anti-EGFR Therapy are Triggered by Hair Eruption and Commensal Skin Microbiota

Project description:EGFR targeted anti-cancer therapy induces severe skin toxicities, which affect life quality in patients. The lack of mechanistic details underlying these adverse events hampers their effective management. Here we identified EGFR as the epidermal master-regulator of the ERK pathway, which secures skin barrier integrity upon hair eruption. EGFR deficient epidermis displays a Th2-dominated expression signature and is permissive for excessive microbiota outgrowth. In the absence of EGFR, opening of the follicular ostia during hair eruption allows invasion of commensal microbiota aggravating barrier disruption and initiating an additional Th1 and Th17 response. Chronic folliculitis leads to Staphylococcus aureus dominated dysbiosis, further exacerbating inflammation and expanding barrier defects. Restoration of epidermal ERK signaling via therapeutic FGF7 treatment or transgenic SOS expression rescues skin barrier integrity in the absence of EGFR. These data reveal a gatekeeper function of the EGFR/ERK cascade in hair follicles securing the epidermal barrier around the erupting hair shaft.

2019-12-31 | GSE119376 | GEO

Skin Toxicity in Patients With Metastatic Colorectal Cancer Treated With Anti-EGFR and Chemotherapy (DERMIA)

Project description:Clinical evidence has suggested that sub-antimicrobial doses of doxycycline may have the potential to treat inflammatory lesions of acne. The efficacy of doses below 100 mg/day of doxycycline in the prevention of skin toxicity in patients with treated with Epidermal Growth Factor Receptor (EGFR)-targeted therapies has never been studied. Therefore, the aim of the present study is to describe the efficacy of doxycycline 50 or 100 mg per day in the prevention of skin toxicity in patients with metastatic Colorectal cancer (mCRC) treated with anti-EGFR in combination with chemotherapy.

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TRANSCRIPTIONAL EFFECTS OF INHIBITING EGFR IN KERATINOCYTES

Project description:EGFR activation is important in human epithelial malignancies, including cutaneous squamous cell carcinoma, lung, colon, pancreatic and other cancers. Therapies targeting EGFR are currently used to treat such cancers, but one significant drawback to EGFR inhibitor therapies is the associated skin toxicity. This toxicity usually presents as papular or pustular folliculitis, dry skin with pruritus and hair and nails abnormalities. The side effects often limit the usefulness of EGFR inhibitors in cancer treatment. The transcriptional changes caused by EGFR inhibition in epidermal keratinocytes have not been extensively explored. To define the transcriptional changes caused by inhibition of EGFR in primary human epidermal keratinocytes, we treated these cells with Tyrphostin and compared treated and control cultures in parallel, using Affymetrix microarrays. Using metaanalysis approaches, we integrated the observed changes with a large set of already existing data on transcriptional profiling in epidermal keratinocytes. We found that EGFR inhibition suppresses expression of genes associated with keratinocyte proliferation, attachment and motility. Apoptosis is facilitated by both induction of proapoptotic and suppression of antiapoptotic genes. Surprisingly, EGFR inhibition induces expression of markers of epidermal differentiation. Time course of human epidermal keratinocytes treated with Tyrphostin (AG1478) and untreated controls

2012-10-19 | E-GEOD-41680 | biostudies-arrayexpress

EGFR and hair shaft differentiation

Project description:EGFR signaling controls skin development and homeostasis in mice and humans and its deficiency causes severe skin inflammation, which might affect epidermal stem cell behaviour. Here, we describe the inflammation-independent effects of EGFR-deficiency during skin morphogenesis and in adult HFSCs. Expression and alternative splicing analysis of RNAseq data from interfollicular epidermis and outer root sheath indicate that EGFR controls genes involved in epidermal differentiation, but also in centrosome function, DNA damage, cell cycle and apoptosis. Genetic experiments employing p53-deletion in EGFR–deficient epidermis reveal that EGFR signalling exhibits p53-dependent functions in proliferative epidermal compartments, as well as p53–independent functions in differentiated hair shaft keratinocytes. Loss of EGFR leads to absence of Lef1 protein specifically in the innermost epithelial hair layers, resulting in disorganization of medulla cells. Thus, our results uncover important spatial and temporal features of cell-autonomous EGFR functions in the epidermis.

2019-07-23 | GSE128436 | GEO

TRANSCRIPTIONAL EFFECTS OF INHIBITING EGFR IN KERATINOCYTES

2012-10-19 | GSE41680 | GEO

Comparison of Two Preemptive Treatment Strategies of Panitumumab Mediated Skin Toxicity and Assessment of QoL in Patient With Ras-wt Colorectal Cancer

Project description:80 - 90 % of the patients treated with anti-EGFR antibodies (panitumumab or cetuximab) experience skin toxicity, mostly acne like skin rash. A standardized treatment of skin rash is neither established as standard arm for clinical trials nor as guideline for the treatment of skin toxicity in clinical practice. While an improvement of QoL has been demonstrated for panitumumab and cetuximab in comparison to best supportive care the data basis for patient related outcomes regarding skin toxicity deriving from randomized trials is still small. Recent surveys among German oncologist revealed that physicians are reluctant to use oral antibiotics as preemptive treatment . Only 19 out of 110 oncologists stated that they are thinking about using preemptive treatment in patients with acne-like skin rash. Thus, in the present trial two main questions will be addressed: (i) Can preemptive treatment with oral doxycycline be replaced by a sequential skin treatment strategy (i.e. local treatment with erythromycin followed by doxycycline in case of inefficacy = development of acne) without compromising treatment efficacy of skin toxicity treatment? (ii) Comparison of general and skin related QoL between both treatment arms.

| 2130638 | ecrin-mdr-crc

Whole genome expression data from pre-auricular and post-auricular skin tissues

Project description:Photoaging is cumulative damage that is caused by chronic, repeated solar radiation exposure to skin. Its molecular mechanisms are poorly understood at the level of global gene expression.This study set out to uncover genes and functional modules involved in photoaging at the level of transcription, with the use of skin samples from Chinese women.Using the Illumina microarray platform, we compared the genome-wide expression profiles of 21 pairs of sun-exposed pre-auricular and sun-protected post-auricular skin samples from northern Chinese women.In total, 1,621 significantly regulated genes were identified from skin due to photoaging by microarray analysis. These genes were subjected to functional enrichment analyses with both the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) annotation databases. As revealed by the functional analyses, the up-regulated functional modules in sun-exposed pre-auricular skin were related to various cellular activities in regulation of the skin homeostasis (e.g., the KEGG pathways TGF-beta signaling pathway and ECM-receptor interaction ), whereas the down-regulated functional modules were mostly metabolic-related. Additionally, five selected genes (HOXA5, LEPR, CLDN5, LAMC3, and CGA) identified as differentially-expressed were further confirmed on their expression by quantitative real-time PCR (Q-RT-PCR). Our findings suggest that damage from skin homeostasis and down-regulation of skin metabolism may play important roles in the process of photoaging. We compared the genome-wide expression profiles of 21 pairs of sun-exposed pre-auricular and sun-protected post-auricular skin samples from northern Chinese women by using the Illumina microarray platform.

2014-02-07 | E-GEOD-38308 | biostudies-arrayexpress

A phase 2 study, investigating prevention and treatment algorism of the skin toxicity related with Panitumumab treatment in patients with unresectable and/or metastatic CRC with KRAS wild type refractory to 5-FU containing chemotherapy

Project description:Interventions: pre-emptive administration of minocycline hydrochloride 100mg twice per day and consistent heparinoid containing skin moisturizer, which are started at panitumumab contained chemotherapy started. And reactive treatment of topical steroid; Hydrocortisone butyrate cream 0.1% apply to face, diflupredonate ointment 0.05% apply to the other part. Primary outcome(s): incidence rates and timing of grade two or more skin toxicity during 6 weeks from Panitumumab contained chemotherapy started. Study Design: Single arm Non-randomized

| 2621298 | ecrin-mdr-crc

A Double-blind Placebo-controlled Randomized Multicenter Phase II Trial of Skin Toxicity Treatment in Subjects with Metastatic Colorectal Carcinoma Receiving Panitumumab

Project description:Primary objectives: To compare the patient rated efficacy of preemptive basic skin treatment with or without doxycycline on the occurrence and grade of panitumumab induced skin toxicities and resulting in the end of study treatment Primary endpoints: Time until unblinding of skin therapy allocation (basic skin treatment with or without doxycycline) due to insufficient efficacy (i.e. unbearable skin toxicity, measured by patient’s allocating point 6 through 10 on a visual analogue scale)

| 2527993 | ecrin-mdr-crc

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