Inhibition of the BRAF(V600E) oncoprotein by the small-molecule drug PLX4032 (vemurafenib) is highly effective in the treatment of melanoma. However, colon cancer patients harbouring the same BRAF(V600E) oncogenic lesion have poor prognosis and show only a very limited response to this drug. To investigate the cause of the limited therapeutic effect of PLX4032 in BRAF(V600E) mutant colon tumours, here we performed an RNA-interference-based genetic screen in human cells to search for kinases whose knockdown synergizes with BRAF(V600E) inhibition. We report that blockade of the epidermal growth factor receptor (EGFR) shows strong synergy with BRAF(V600E) inhibition. We find in multiple BRAF(V600E) mutant colon cancers that inhibition of EGFR by the antibody drug cetuximab or the small-molecule drugs gefitinib or erlotinib is strongly synergistic with BRAF(V600E) inhibition, both in vitro and in vivo. Mechanistically, we find that BRAF(V600E) inhibition causes a rapid feedback activation of EGFR, which supports continued proliferation in the presence of BRAF(V600E) inhibition. Melanoma cells express low levels of EGFR and are therefore not subject to this feedback activation. Consistent with this, we find that ectopic expression of EGFR in melanoma cells is sufficient to cause resistance to PLX4032. Our data suggest that BRAF(V600E) mutant colon cancers (approximately 8-10% of all colon cancers), for which there are currently no targeted treatment options available, might benefit from combination therapy consisting of BRAF and EGFR inhibitors.

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Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR

Ductal carcinoma in situ (DCIS) of the breast represents a heterogeneous group of neoplastic lesions in the breast ducts. The goal for management of DCIS is to prevent the development of invasive breast cancer. This manuscript focuses on the NCCN Guidelines Panel recommendations for the workup, primary treatment, risk reduction strategies, and surveillance specific to DCIS.

https://www.unitypoint.org/desmoines/filesimages/Cancer%20Education/Oncology%20Nursing%20Conference/2015/2014%20NCCN%20Clin%20Pract%20Guidelines%20Male%20Sex%20Dysf.pdf

Clinical practice guidelines in oncology

Similar to embryonic development, changes in cell phenotypes defined as an epithelial to mesenchymal transition (EMT) have been shown to play a role in the tumorigenic process. Although the first description of EMT in cancer was in cell cultures, evidence for its role in vivo is now widely reported but also actively debated. Moreover, current research has exemplified just how complex this phenomenon is in cancer, leaving many exciting, open questions for researchers to answer in the future. With these points in mind, we asked four scientists for their opinions on the role of EMT in cancer and the challenges faced by scientists working in this fast-moving field.

EMT in cancer

UV radiation (UV) is classified as a "complete carcinogen" because it is both a mutagen and a non-specific damaging agent and has properties of both a tumor initiator and a tumor promoter. In environmental abundance, UV is the most important modifiable risk factor for skin cancer and many other environmentally-influenced skin disorders. However, UV also benefits human health by mediating natural synthesis of vitamin D and endorphins in the skin, therefore UV has complex and mixed effects on human health. Nonetheless, excessive exposure to UV carries profound health risks, including atrophy, pigmentary changes, wrinkling and malignancy. UV is epidemiologically and molecularly linked to the three most common types of skin cancer, basal cell carcinoma, squamous cell carcinoma and malignant melanoma, which together affect more than a million Americans annually. Genetic factors also influence risk of UV-mediated skin disease. Polymorphisms of the melanocortin 1 receptor (MC1R) gene, in particular, correlate with fairness of skin, UV sensitivity, and enhanced cancer risk. We are interested in developing UV-protective approaches based on a detailed understanding of molecular events that occur after UV exposure, focusing particularly on epidermal melanization and the role of the MC1R in genome maintenance.

/pdf/uv-radiation-and-the-skin-2ub2qrbyk1.pdf

UV Radiation and the Skin

From bench to bedside

Incidence rates reported by the National Cancer Registry were low compared to other European countries. Over the period 1989-1994 a decrease in reported melanoma incidence was observed, which was not reported in any other country and is most probably artificial. A melanoma registration programme in East-Flanders obtained a higher registration compared to the National Cancer Registry in females, especially in the age group < 50. In these younger females, 6 of 22 (27%) melanomas were in situ compared to 5 in 29 (17%) in the other group (p = 0.39). Additionally thinner invasive melanomas (median Breslow thickness 0.94mm versus 1.56mm, p = 0.019) were reported in this group compared to females aged over 50. Such early-stage melanomas are more likely to be treated on an outpatient basis. These data suggest that the lower registration by the National Cancer Registry is most probably related to its hospital-based reporting system. Incorporation of registration procedures including pathology laboratories and the direct reporting by treating physicians, are currently being investigated in a cancer registration network in Flanders.

Cancer registration in Belgium : experience from a melanoma registration programma in the province of East-Flanders

Background Early detection of skin cancer is still a major challenge in dermatology practice today. While surveillance programs are offered to high-risk patients, systematic total-body examination (TBE) in the general population is not cost-effective. In the past, we demonstrated that a lesion-directed screening (LDS) in the general population delivered similar detection rates to TBE and was less time-consuming.

Objectives To study whether a lesion-directed early-access consultation can optimize skin cancer detection in dermatology practice.

Methods In this observational study, we offered an early-access consultation in patients contacting the dermatology department concerning 1 or 2 lesions of concern meeting predefined criteria.

Results 342 persons were seen at the dermatology department after triage by phone. Skin cancer detection rate was 13.2% (4.1% for melanoma). If advised/referred by a doctor skin cancer detection rate was 23.6% (9% for melanoma). With a history of skin cancer, detection rate was 24.3% (4.3% for melanoma). In patients with no referral and a negative history of skin cancer, detection rate was 7.7% (1.7% for melanoma), which is at least triple the rates reported by population-based screening programs. In patients in whom the index lesion was benign, worry of having skin cancer had decreased significantly by the end of the consultation. Additional total-body examination in these patients had low additional detection rate (0.5%) and a high number of unnecessary excisions (number needed to excise 13).

Conclusions An early-access dermatology consultation for LDS after triage by phone resulted in high overall skin cancer and melanoma detection rates. Our data indicate that performing TBE is especially useful if the index lesion is suspicious. In addition to surveillance programs in high-risk patients, LDS may be a way to optimize skin cancer detection in the general population and use available time more efficiently in daily dermatology practice.

https://biblio.ugent.be/publication/8701240/file/8708042.pdf

Lesion-directed screening to optimize skin cancer detection in dermatology practice: an observational study

20TiPPhase I trial of stereotactic body radiotherapy with concurrent fixed dose ipilimumab in metastatic melanoma: Dose limiting toxicity and abscopal effect

Editor, Skin cancer is currently the most frequent cancer worldwide, and its incidence is rising dramatically. Our group found in the previous work that the prevalence of keratinocyte cancers will triple in the next 20 years in Belgium with associated increases in treatment costs. Keratinocyte skin cancer (KC) is known to influence the health-related quality of life (HRQoL) in a specific way, and it is currently considered to be a chronic disease with often multiple tumours, treatment and follow-up. Utility values are needed for cost-effectiveness analyses of new interventions; however, we have no data on which instrument is most fit. The most common approach is the EQ-5D instrument. In case of KC, we know, based on unpublished previous work, that these dimensions of health are unsatisfactory to capture the true impact on a patient daily life and the EQ-5D is prone to a «ceiling effect», meaning that a substantial proportion of the patients would report full health with an EQ-5D value at 1. The main objective is to measure the exact HRQoL in patients with actinic keratosis or KC using the generic EQ-5D-5L questionnaire, as well as the time trade-off method (TTO), 15 dimensions questionnaire (15D) and a visual analogue scale (VAS) in relation to their Charlson Comorbidity Index (CCI). For all instruments, we evaluated ceiling effects, the convergent and construct validity. Patients aged ≥18 years consulting a dermatologist at Ghent University Hospital, Belgium, and the Erasmus University Medical Centre Rotterdam, the Netherlands, were questioned via email (189 or 78.1% patients) or by phone (53 or 21.9% patients) depending on their preference. We recruited a total of 242 patients with KC and/or actinic keratosis in both centres. One hundred and thirteen of them were female (46.7%), and the mean age was 67.6 (SD 11.03) years. Demographics and clinical data can be found in Table 1. A clear ceiling effect was observed in health utility (HU) scores derived by TTO and 15D but less for the VAS as well as absent for the EQ-5D-5L HU scores. The 15D showed a strong correlation with EQ-5D-5L (q = 0.706, P < 0.001), but construct validity was not confirmed in the present study for the 4 generic instruments in this population. There was no correlation between the clinical indices of disease (tumour location, diagnosis and type of treatment) and the utility; however, CCI score did impact utilities significantly. Only EQ-5D-5L seemed to have some validity in a low comorbid population (CCI < 5) as a result of treatment impact (Table 2, surgical vs. non-surgical, b 0.162, P < 0.05). The method of

Health state utility instruments in patients with keratinocyte cancer and actinic keratosis: a cross‐sectional study

/pdf/erratum-to-chronic-and-invasive-fungal-infections-in-a-5dnoc32rsp.pdf

Lieve Brochez

Papers

Cancer registration in Belgium : experience from a melanoma registration programma in the province of East-Flanders

Lesion-directed screening to optimize skin cancer detection in dermatology practice: an observational study

20TiPPhase I trial of stereotactic body radiotherapy with concurrent fixed dose ipilimumab in metastatic melanoma: Dose limiting toxicity and abscopal effect

Health state utility instruments in patients with keratinocyte cancer and actinic keratosis: a cross‐sectional study

Erratum to: Chronic and Invasive Fungal Infections in a Family with CARD9 Deficiency