There is a critical need to improve our understanding of the pathogenesis of melanoma brain metastases (MBM). Thus, we performed RNA sequencing on 88 resected MBMs and 42 patient-matched extracranial metastases; tumors with sufficient tissue also underwent whole-exome sequencing, T-cell receptor sequencing, and IHC. MBMs demonstrated heterogeneity of immune infiltrates that correlated with prior radiation and post-craniotomy survival. Comparison with patient-matched extracranial metastases identified significant immunosuppression and enrichment of oxidative phosphorylation (OXPHOS) in MBMs. Gene-expression analysis of intracranial and subcutaneous xenografts, and a spontaneous MBM model, confirmed increased OXPHOS gene expression in MBMs, which was also detected by direct metabolite profiling and [U-13C]-glucose tracing in vivo. IACS-010759, an OXPHOS inhibitor currently in early-phase clinical trials, improved survival of mice bearing MAPK inhibitor–resistant intracranial melanoma xenografts and inhibited MBM formation in the spontaneous MBM model. The results provide new insights into the pathogenesis and therapeutic resistance of MBMs. Significance: Improving our understanding of the pathogenesis of MBMs will facilitate the rational development and prioritization of new therapeutic strategies. This study reports the most comprehensive molecular profiling of patient-matched MBMs and extracranial metastases to date. The data provide new insights into MBM biology and therapeutic resistance. See related commentary by Egelston and Margolin, p. 581. This article is highlighted in the In This Issue feature, p. 565

Purpose: Given the limited sensitivity and specificity of prostate-specific antigen (PSA), its widespread use as a screening tool has raised concerns for the overdiagnosis of low-risk and the underdiagnosis of high-grade prostate cancer. To improve early-detection biopsy decisions, the National Cancer Institute conducted a prospective validation trial to assess the diagnostic performance of the prostate cancer antigen 3 (PCA3) urinary assay for the detection of prostate cancer among men screened with PSA. Patients and Methods: In all, 859 men (mean age, 62 years) from 11 centers scheduled for a diagnostic prostate biopsy between December 2009 and June 2011 were enrolled. The primary outcomes were to assess whether PCA3 could improve the positive predictive value (PPV) for an initial biopsy (at a score > 60) and the negative predictive value (NPV) for a repeat biopsy (at a score < 20). Results: For the detection of any cancer, PPV was 80% (95% CI, 72% to 86%) in the initial biopsy group, and NPV was 88% (95% CI, 81% to 93%) in the repeat biopsy group. The addition of PCA3 to individual risk estimation models (which included age, race/ethnicity, prior biopsy, PSA, and digital rectal examination) improved the stratification of cancer and of high-grade cancer. Conclusion: These data independently support the role of PCA3 in reducing the burden of prostate biopsies among men undergoing a repeat prostate biopsy. For biopsy-naive patients, a high PCA3 score (> 60) significantly increases the probability that an initial prostate biopsy will identify cancer.

Rationale: Constitutive activation of the epidermal growth factor receptor (EGFR) is prevalent in epithelial cancers, particularly in non-small cell lung carcinoma (NSCLC). Mutations identified in EGFR predict the sensitivity to EGFR-targeted therapy. Detection of these mutations is mainly based on tissue biopsy, which is invasive, expensive, and time consuming. Objectives: Noninvasive, real-time, inexpensive detection and monitoring of EGFR mutations in patients with NSCLC is highly desirable. Methods: We developed a novel core technology, electric field–induced release and measurement (EFIRM), which relies on a multiplexible electrochemical sensor that can detect EGFR mutations directly in bodily fluids. Measurements and Main Results: We established EFIRM for the detection of the EGFR mutations in vitro and correlated the results with tumor size from xenografted mice. In clinical application, we demonstrated that EFIRM could detect EGFR mutations in the saliva and plasma of 22 patients with NSCLC. Finally, a blinded test was performed on saliva samples from 40 patients with NSCLC. The receiver operating characteristic analysis indicated that EFIRM detected the exon 19 deletion with an area under the curve of 0.94 and the L858R mutation with an area under the curve of 0.96. Conclusions: Our data indicate that EFIRM is effective, accurate, rapid, user-friendly, and cost effective for the detection of EGFR mutations in the saliva of patients with NSCLC. We termed this saliva-based EGFR mutation detection (SABER).

Ample evidence has shown survival benefits associated with treatment of intermediate- and high-risk, early-stage prostate cancer.^1-4 Low specificity of tests for serum levels of prostate-specific antigen (PSA), however, has limited its utility for prostate cancer screening.^5-7 Strategies are needed for detecting cancers with more aggressive features (Gleason score, ≥7) to enable survival benefits from treatment while limiting unnecessary biopsies and overdetection of indolent disease.

While clinical outcomes following immunotherapy have shown an association with tumor mutation load using whole exome sequencing (WES), its clinical applicability is currently limited by cost and bioinformatics requirements. We developed a method to accurately derive the predicted total mutation load (PTML) within individual tumors from a small set of genes that can be used in clinical next generation sequencing (NGS) panels. PTML was derived from the actual total mutation load (ATML) of 575 distinct melanoma and lung cancer samples and validated using independent melanoma (n = 312) and lung cancer (n = 217) cohorts. The correlation of PTML status with clinical outcome, following distinct immunotherapies, was assessed using the Kaplan–Meier method. PTML (derived from 170 genes) was highly correlated with ATML in cutaneous melanoma and lung adenocarcinoma validation cohorts (R2 = 0.73 and R2 = 0.82, respectively). PTML was strongly associated with clinical outcome to ipilimumab (anti-CTLA-4, three cohorts) and adoptive T-cell therapy (1 cohort) clinical outcome in melanoma. Clinical benefit from pembrolizumab (anti-PD-1) in lung cancer was also shown to significantly correlate with PTML status (log rank P value < 0.05 in all cohorts). The approach of using small NGS gene panels, already applied to guide employment of targeted therapies, may have utility in the personalized use of immunotherapy in cancer.