Merkel Cell Carcinoma with a Suppressor of Fused (SUFU) Mutation: Case Report and Potential Therapeutic Implications

The Author(s) 2015. This article is published with open access at Springerlink.com Introduction: Merkel cell carcinoma is a neuroendocrine malignancy. Suppressor of fused (SUFU) is a tumor suppressor oncogene that participates in the Hedgehog (Hh) signaling pathway. The aim of the study wa

Warning signal: Unaware of an in absentia conviction, South African cancer specialist jailed on return to the United Arab Emirates.

In 2002, Dr. Cyril Karabus, a specialist in pediatric cancers and retired head of the Oncology and Hematology Unit of Red Cross Children\u27s Hospital in Capetown, South Africa, spent a brief locum at Sheikh Khalifa Medical City, a hospital in Abu Dhabi in the United Arab Emirates (UAE). He was there for only 5 weeks, during which time he treated a young girl who died of acute myeloblastic leukemia. After Karabus returned home, the girl\u27s father complained to police about his daughter\u27s death, and Karabus was convicted of murder in absentia. Karabus knew nothing of the charges or of the conviction. Widely respected for his expertise and compassion, Karabus had dedicated his life to treating children with malignancies. In South Africa, he was especially well known for his commitment to saving the lives of black children with cancer during the apartheid era.

Level of evidence used in recommendations by the National Comprehensive Cancer Network (NCCN) guidelines beyond Food and Drug Administration approvals.

BackgroundA previous analysis of 113 National Comprehensive Cancer Network® (NCCN®) recommendations reported that NCCN frequently recommends beyond Food and Drug Administration (FDA)-approved indications (44 off-label recommendations) and claimed that the evidence for these recommendations was weak.MethodsIn order to determine the strength of the evidence, we carried out an in-depth re-analysis of the 44 off-label recommendations listed in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®).ResultsOf the 44 off-label recommendations, 14 were later approved by the FDA and/or are supported by randomized controlled trial (RCT) data. In addition, 13 recommendations were either very minor extrapolations from the FDA label (n = 8) or were actually on-label (n = 5). Of the 17 remaining extrapolations, 8 were for mechanism-based agents applied in rare cancers or subsets with few available treatment options (median response rate = 43%), 7 were based on non-RCT data showing significant efficacy (>50% response rates), and 2 were later removed from the NCCN Guidelines because newer therapies with better activity and/or safety became available.ConclusionOff-label drug use is a frequent component of care for patients with cancer in the United States. Our findings indicate that when the NCCN recommends beyond the FDA-approved indications, the strength of the evidence supporting such recommendations is robust, with a significant subset of these drugs later becoming FDA approved or supported by RCT. Recommendations without RCT data are often for mechanism-based drugs with high response rates in rare cancers or subsets without effective therapies

Characteristics and survival of patients with advanced cancer and p53 mutations.

P53 mutations are associated with invasive tumors in mouse models. We assessed the p53mutations and survival in patients with advanced cancer treated in the Phase I Program. Of 691 tested patients, 273 (39.5%) had p53 mutations. Patients with p53 mutations were older (p<.0001) and had higher numbers of liver metastases (p=.005). P53 mutations were associated with higher numbers of other aberrations; PTEN (p=.0005) and HER2 (p=.003)aberrations were more common in the p53 mutation group. No survival difference was observed between patients with p53 mutations and those with wild-type p53. In patients with wild-type p53 and other aberrations, patients treated with matched-therapy against the additional aberrations had longer survival compared to those treated with non-matched-therapy or those who received no therapy (median survival, 26.0 vs. 11.8 vs. 9.8 months, respectively; p= .0007). Results were confirmed in a multivariate analysis (p= .0002). In the p53 mutation group with additional aberrations, those who received matched-therapy against the additional aberrations had survival similar to those treated with non-matched-therapy or those who received no therapy (p=.15). In conclusion, our results demonstrated resistance to matched-targeted therapy to the other aberrations in patients with p53 mutations and emphasize the need to overcome this resistance

BRAF V600E mutations in urine and plasma cell-free DNA from patients with Erdheim-Chester disease.

Erdheim-Chester disease (ECD) is a rare histiocytosis with a high prevalence of BRAF V600E mutation (>50% of patients). Patients with BRAF-mutant ECD can respond to BRAF inhibitors. Unfortunately, the lack of adequate archival tissue often precludes BRAF testing. We hypothesized that cell-free DNA (cfDNA) from plasma or urine can offer an alternative source of biologic material for testing. We tested for BRAF V600E mutation in cfDNA from the plasma and urine of 6 ECD patients. In patients with available archival tissue, the result of BRAF mutation analysis was concordant with plasma and urine cfDNA results in all 3 patients (100% agreement, kappa 1.00). In all 6 patients, BRAF mutation analysis of plasma and urine cfDNA was concordant in 5 of 6 patients (83% agreement, kappa 0.67). Testing for BRAF V600E mutation in plasma and urine cfDNA should be further investigated as an alternative to archival tissue mutation analysis

Outcomes of patients with advanced cancer and KRAS mutations in phase I clinical trials.

BackgroundKRAS mutation is common in human cancer. We assessed the clinical factors, including type of KRAS mutation and treatment, of patients with advanced cancer and tumor KRAS mutations and their association with treatment outcomes.MethodsPatients referred to the Phase I Clinic for treatment who underwent testing for KRAS mutations were analyzed.ResultsOf 1,781 patients, 365 (21%) had a KRAS mutation. The G12D mutation was the most common mutation (29%). PIK3CA mutations were found in 24% and 10% of patients with and without KRAS mutations (p<0.0001). Of 223 patients with a KRAS mutation who were evaluable for response, 56 were treated with a MEK inhibitor-containing therapy and 167 with other therapies. The clinical benefit (partial response and stable disease lasting ≥6 months) rates were 23% and 9%, respectively, for the MEK inhibitor versus other therapies (p=0.005). The median progression-free survival (PFS) was 3.3 and 2.2 months, respectively (p=0.09). The respective median overall survival was 8.4 and 7.0 months (p=0.38). Of 66 patients with a KRAS mutation and additional alterations, higher rates of clinical benefit (p=0.04), PFS (p=0.045), and overall survival (p=0.02) were noted in patients treated with MEK inhibitor-containing therapy (n=9) compared to those treated with targeted therapy matched to the additional alterations (n=24) or other therapy (n=33).ConclusionsMEK inhibitors in patients with KRAS-mutated advanced cancer were associated with higher clinical benefit rates compared to other therapies. Therapeutic strategies that include MEK inhibitors or novel agents combined with other targeted therapies or chemotherapy need further investigation