Transcriptional Profiling of Malignant Melanoma Reveals Novel and Potentially Targetable Gene Fusions.

Invasive melanoma is the deadliest type of skin cancer, with 101,110 expected cases to be diagnosed in 2021. Recurrent BRAF and NRAS mutations are well documented in melanoma. Biologic implications of gene fusions and the efficacy of therapeutically targeting them remains unknown. Retrospective review of patient samples that underwent next-generation sequencing of the exons of 592 cancer-relevant genes and whole transcriptome sequencing for the detection of gene fusion events and gene expression profiling. Expression of PDL1 and ERK1/2 was assessed by immunohistochemistry (IHC). There were 33 (2.6%) cases with oncogenic fusions (14 novel), involving BRAF, RAF1, PRKCA, TERT, AXL, and FGFR3. MAPK pathway-associated genes were over-expressed in BRAF and RAF1 fusion-positive tumors in absence of other driver alterations. Increased expression in tumors with PRKCA and TERT fusions was concurrent with MAPK pathway alterations. For a subset of samples with available tissue, increased phosphorylation of ERK1/2 was observed in BRAF, RAF1, and PRKCA fusion-positive tumors. Oncogenic gene fusions are associated with transcriptional activation of the MAPK pathway, suggesting they could be therapeutic targets with available inhibitors. Additional analyses to fully characterize the oncogenic effects of these fusions may support biomarker driven clinical trials.

Population bias in somatic measurement of microsatellite instability status.

Microsatellite instability (MSI) is a key secondary effect of a defective DNA mismatch repair mechanism resulting in incorrectly replicated microsatellites in many malignant tumors. Historically, MSI detection has been performed by fragment analysis (FA) on a panel of representative genomic markers. More recently, using next-generation sequencing (NGS) to analyze thousands of microsatellites has been shown to improve the robustness and sensitivity of MSI detection. However, NGS-based MSI tests can be prone to population biases if NGS results are aligned to a reference genome instead of patient-matched normal tissue. We observed an increased rate of false positives in patients of African ancestry with an NGS-based diagnostic for MSI status utilizing 7317 microsatellite loci. We then minimized this bias by training a modified calling model that utilized 2011 microsatellite loci. With these adjustments 100% (95% CI: 89.1% to 100%) of African ancestry patients in an independent validation test were called correctly using the updated model. This poses not only a significant technical improvement but also has an important clinical impact on directing immune checkpoint inhibitor therapy.

Detection of NRG1 Gene Fusions in Solid Tumors.

PURPOSE: NRG1 gene fusions are rare but potentially actionable oncogenic drivers that are present in some solid tumors. Details regarding the incidence of these gene rearrangements are lacking. Here, we assessed the incidence of NRG1 fusions across multiple tumor types and described fusion partners. EXPERIMENTAL DESIGN: Tumor specimens submitted for molecular profiling at a Clinical Laboratory Improvement Amendments (CLIA)-certified genomics laboratory and that underwent fusion testing by anchored multiplex PCR for targeted RNA sequencing were retrospectively identified. The overall and tumor-specific incidence was noted, as was the specific fusion partner. RESULTS: Out of 21,858 tumor specimens profiled from September 2015 to December 2018, 41 cases (0.2%) harbored an NRG1 fusion. Multiple fusion partners were identified. Fusion events were seen across tumor types. The greatest incidence was in non-small cell lung cancer (NSCLC, 25), though this represented only 0.3% of NSCLC cases tested. Other tumor types harboring an NRG1 fusion included gallbladder cancer, renal cell carcinoma, bladder cancer, ovarian cancer, pancreatic cancer, breast cancer, neuroendocrine tumor, sarcoma, and colorectal cancer. CONCLUSIONS: NRG1 fusions can be detected at a low incidence across multiple tumor types with significant heterogeneity in fusion partner.See related commentary by Dimou and Camidge, p. 4865.

A phase I study of a 2-day lapatinib chemosensitization pulse preceding nanoparticle albumin-bound Paclitaxel for advanced solid malignancies.

PURPOSE: Systemic chemotherapy fails to access much of the tumor burden in patients with advanced cancer, significantly limiting its efficacy. In preclinical studies, brief high doses of tyrosine kinase inhibitors (TKI) targeting the human epidermal growth factor receptor (HER) family can prime tumor vasculature for optimal chemotherapeutic delivery and efficacy. This study investigates the clinical relevance of this approach. EXPERIMENTAL DESIGN: A phase I clinical study of escalating doses of the HER TKI lapatinib given as a 2-day pulse before a weekly infusion of nab-paclitaxel (100 mg/m(2)) was conducted in patients with advanced solid tumors. RESULTS: Twenty-five patients were treated. Treatment was associated with grade 1 to 2 toxicities including diarrhea, nausea, rash, neutropenia, neuropathy, fatigue, alopecia, and anemia. The two dose-limiting toxicities were grade 3 vomiting and grade 4 neutropenia, and the maximum tolerated dose of lapatinib was defined as 5250 mg/day in divided doses. Lapatinib concentrations increased with increasing dose. Dynamic Contrast Enhanced Magnetic Resonance Imaging studies in a subset of patients confirmed a decrease in tumor vascular permeability immediately following a lapatinib pulse. Sixty-five percent of evaluable patients experienced a partial or stable response on this therapy, 72% of whom were previously taxane-refractory. CONCLUSION: A 2-day pulse of high-dose lapatinib given before weekly nab-paclitaxel is a feasible and tolerable clinical regimen, suitable for testing this novel vascular-priming chemosensitization hypothesis developed in preclinical models.