Melanoma brain metastases harboring BRAF V600K or NRAS mutations are associated with an increased local failure rate following conventional therapy.

Studies on melanoma brain metastases (MBM) with regard to mutational status are lacking. We investigated the outcomes of MBM in molecularly characterized patients for BRAF and NRAS mutations receiving conventional treatment. We investigated associations between outcomes [competing risk of local and distant brain failure (LF, DF) and overall survival (OS)] and clinical/pathological features of patients with known mutation status following initial treatment of MBM. Competing risk analysis was performed using the methods of Fine and Gray. We identified 235 patients with MBM diagnosed from 2005 to 2011. Mutation prevalence was BRAF non-V600K 98 (42%), BRAF V600K 34 (14%), NRAS 43 (18%), and wild-type for both genes (WT) 60 (26%) patients. Six month cumulative incidence LF rates were 3% for combined SRS or surgery with adjuvant radiation, 18% for surgery, 18% for SRS, 60% for WBRT, and 67% for systemic therapy. On multivariate analysis, only mutation status and initial treatment type were found to be independent predictors of local control. As compared to WT, NRAS (HR 2.58, 95% CI 1.18-5.67, p = 0.02) and BRAF V600K (HR 2.83, 95% CI 1.23-6.47, p = 0.01) mutational status were statistically significant while BRAF non-V600K status was not statistically significant (p = 0.23). Mutation status was not associated with DF or OS. BRAF V600K and NRAS mutation status predict increased LF following conventional treatments for MBM. These data can inform the design and interpretation of future MBM trials.

Clinical characteristics and outcomes with specific BRAF and NRAS mutations in patients with metastatic melanoma.

BACKGROUND: Hotspot mutations in BRAF and NRAS are the most common somatic events in patients with melanoma. These mutations occur at highly conserved residues, but include several different substitutions. To determine whether specific mutations are clinically important to differentiate, tumor characteristics and clinical outcomes were compared among patients with advanced melanoma with 1) BRAF V600E versus V600K mutations and 2) NRAS exon 1 versus exon 2 mutations. METHODS: Retrospective clinical and pathologic data were collected for patients with advanced melanoma with BRAF or NRAS mutations. The demographics, tumor characteristics, and clinical outcomes of the patients were compared to identify significant mutation-specific associations. RESULTS: Among 302 patients with activating BRAF mutations, 76% had BRAF V600E and 24% had V600K substitutions. Compared with V600E, the presence of a V600K mutation was significantly associated with older age (median, 60.0 years vs 44.7 years; P < .001), male sex (80% vs 59%; P = .001), head/neck primary tumor location (30% vs 15%; P = .0026), shorter interval to stage IV disease (0.98 years vs 2.8 years; P = .015), and a shorter overall survival from the time of diagnosis of stage IV disease (median, 2.44 years vs 1.25 years; hazards ratio, 1.68 [P = .014]). Comparison of 136 patients with NRAS exon 1 (18%) and exon 2 (82%) mutations found an association with primary tumor histology (P = .0096) only. CONCLUSIONS: The presence of different substitutions at BRAF V600 correlates with patient demographics, tumor characteristics, and prognosis. These findings demonstrate the presence of mutation-specific clinical differences between different BRAF genotypes in patients with melanoma, and support the incorporation of this information in patient evaluation and clinical trial design.

NRAS mutation status is an independent prognostic factor in metastatic melanoma.

BACKGROUND: There is a need for improved prognostic markers in melanoma. In this study, the authors tested the prognostic significance and clinicopathologic correlations of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) and neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS) mutations in patients with metastatic melanoma. METHODS: Clinical and pathologic data were collected retrospectively on melanoma patients who were clinically tested for BRAF (exon 15) and NRAS (exons 1 and 2) mutations at The University of Texas M. D. Anderson Cancer Center. Analyses were performed to identify significant associations of mutations with tumor and patient characteristics and with survival from the diagnosis of stage IV disease. RESULTS: The genotypes of the full cohort (n = 677) were 47% BRAF mutation, 20% NRAS mutation, and 32% wild-type for BRAF and NRAS ("WT"). Tumor mutation status was associated (P = .008) with the risk of central nervous system involvement at the diagnosis of stage IV disease, with a higher prevalence observed in BRAF-mutant (24%) and NRAS-mutant (23%) patients than in WT patients (12%). Among patients with nonuveal melanoma who underwent mutation testing within 6 months of stage IV diagnosis (n = 313), patients with NRAS mutations had a median survival of 8.2 months from stage IV diagnosis, which was shorter than the median survival of WT patients (15.1 months; P = .004). Multivariate analysis of this population incorporating age, sex, metastases (M1) category, serum lactate dehydrogenase level, and mutation status confirmed that NRAS mutations are associated independently with decreased overall survival (vs WT; P = .005; hazard ratio, 2.05). CONCLUSIONS: Patients with BRAF or NRAS mutations were more likely than WT patients to have central nervous system involvement at the time they were diagnosed with distant metastatic disease. NRAS mutation status was identified as an independent predictor of shorter survival after a diagnosis of stage IV melanoma.

A Rare Case of Simultaneous Evans Syndrome and Primary Antiphospholipid Syndrome.

Evans Syndrome (ES) is a rare autoimmune disorder that presents with simultaneous or sequential development of autoimmune hemolytic anemia (AIHA), thrombocytopenia, and/or neutropenia. This disease may occur in conjunction with other autoimmune disorders. Primary antiphospholipid syndrome (APS) is a disorder characterized by thrombosis, which can cause life-threatening complications such as fetal demise, strokes, or deep vein thrombosis. A 67-year-old male with type 2 diabetes mellitus, hypertension, and renal insufficiency presented with concomitant ES and APS. His hematological abnormalities began in 2013 after a deep vein thrombosis of the left lower extremity led to a diagnosis of APS and was started on chronic warfarin. In 2014, he was found to have immune thrombocytopenia (ITP) with relapses the following year. Several months later, he was hospitalized and diagnosed with AIHA. In the setting of his previous episodes of ITP and current AIHA, the diagnosis of ES was made. The initial treatment was 100 mg prednisone taper, but rituximab was required to make complete platelet recovery. The severe deterioration and rapid recovery with proper treatment of the patient highlights the importance of a timely diagnosis of ES. Mild thrombocytopenia can be associated with APS; however; severe thrombocytopenia may warrant further investigation for other possible causes. Maintaining ES on the differential diagnosis of patients with APS and thrombocytopenia could enhance health outcomes.

Phase II study of gefitinib in patients with advanced salivary gland cancers.

BACKGROUND: The purpose of this study was to determine the antitumor activity of the epidermal growth factor receptor (EGFR) inhibitor gefitinib in patients with recurrent/metastatic salivary gland cancer. METHODS: We conducted a phase II study in adenoid cystic carcinoma (ACC) and non-ACC. Gefitinib was administered 250 mg orally daily. The primary endpoint was tumor response. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and disease control rates. EGFR and human epidermal growth factor receptor 2 (HER2) expression were evaluated and correlated with outcomes. RESULTS: Thirty-seven patients were enrolled in this study, and 36 were evaluable (18 with ACC and 18 with non-ACC). No responses were observed. Median PFS was 4.3 months and 2.1 months, and median OS was 25.9 months and 16 months for patients with ACC and non-ACC, respectively. The disease control rate at 8 weeks was higher in patients with ACC. No unexpected toxicities occurred. EGFR and HER2 overexpression did not correlate with outcomes. CONCLUSION: We did not observe significant clinical activity of gefitinib in advanced salivary gland cancer. NCT00509002.

Characterizing the clinical benefit of ipilimumab in patients who progressed on high-dose IL-2.

Ipilimumab improves overall survival (OS) in patients with metastatic melanoma including those previously treated with high-dose interleukin-2 (HD IL-2). The primary objective of this study was to determine if clinical response or progression-free survival (PFS) to HD IL-2 could predict benefit to subsequent ipilimumab. The secondary objective was to further characterize the clinical benefit of ipilimumab in patients who have progressed on HD IL-2. We reviewed the records of all patients with metastatic melanoma who received HD IL-2 at MD Anderson Cancer Center or Beth Israel Deaconess Medical Center from 2003 to 2009 and further identified patients who also received ipilimumab after progressing on HD IL-2. OS to ipilimumab was calculated from the first dose of ipilimumab, determined by Kaplan-Meier analysis, and was compared in patients based on their prior clinical response and PFS to HD IL-2 using the log-rank test. Patients were grouped based on their prior response to HD IL-2 as follows: complete response and partial response, stable disease, and progressive disease. Patients were also grouped and compared by prior PFS to HD IL-2 in >60 days versus ≤60 days. A total of 208 patients with melanoma were treated with HD IL-2, 130 (63%) received additional systemic therapy after confirmed disease progression, and 48 (23%) received ipilimumab. The clinical benefit of ipilimumab was similar to previously published results (OS, 12.0 mo; PFS, 2.5 mo; response rate, 16.7%). Prior clinical response or PFS to HD IL-2 did not predict benefit to subsequent ipilimumab. Prospective trials of HD IL-2 followed by ipilimumab could potentially identify patients most likely to benefit from a sequential approach of HD IL-2 followed by ipilimumab.

Two somatic biallelic lesions within and near SMAD4 in a human breast cancer cell line.

Loss of chromosome arm 18q is a common event in human pancreatic, colon, and breast cancers and is often interpreted as representing loss of one or more tumor-suppressor genes. In this article, we describe two novel biallelic deletions at chromosome band 18q21.1 in a recently characterized human breast cancer cell line, HCC-1428. One lesion deletes a fragment of approximately 300 kb between SMAD4 and DCC that encodes no known genes. The second lesion is an in-frame SMAD4 deletion (amino acids 49-51) that affects the level of SMAD4 protein but not the SMAD4 message. This change accelerates 26S proteasome-mediated degradation of both endogenous and exogenous mutant SMAD4. Examination of normal DNA from the same patient demonstrated that both lesions are somatic and associated with loss of both normal alleles. These data support the concept that two independent tumor-suppressor loci exist at chromosome segment 18q21.1, one at SMAD4 and the other potentially at an enhancer of DCC or an unrelated novel gene.