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

AimsMetaplastic breast carcinoma (MBC) is a rare subtype of breast carcinoma less responsive to conventional chemotherapy than ductal carcinoma. In molecular terms, MBCs usually cluster with triple-negative breast cancers (TNBCs), but have a worse prognosis than TNBCs. Studies investigating MBCs for specific biomarkers of therapy response are rare and limited by the methodological approaches. The aim of the present study was to characterise MBCs on a molecular level and test programmed death-ligand 1 (PD-L1) biomarker expression in MBCs for future therapeutic interventions.MethodsWe profiled 297 samples (MBC (n=75), TNBC (n=106), human epidermal growth factor receptor 2 (HER2)-positive breast cancers (n=32) and hormone-positive breast cancers (n=84)) by next-generation sequencing. Immunohistochemistry for PD-L1 and programmed cell death 1 (PD-1) expression was performed using automated procedures.ResultsThe most commonly mutated genes in MBCs included TP53 (56%) and PIK3CA (23%). Pathogenic mutations in other genes, including HRAS, FBXW7, PTEN, AKT1 and SMAD4, were rare. PD-L1 expression was detected in a significantly higher proportion of MBCs (46%) than in other subtypes (6% each in hormone-positive and HER2-positive breast cancers, and 9% in TNBC, not otherwise specified, p<0.001). PD-1-positive tumour infiltrating lymphocytes (TILs) varied greatly in MBCs.ConclusionsComprehensive profiling of a large cohort of this rare subtype of breast carcinoma highlighted the predominance of TP53 mutation and increased PD-L1 expression in carcinoma cells. These results can be exploited in clinical trials using immune checkpoint inhibitors.

The unique molecular features of VVM render this disease a distinct subtype of melanoma. Gene-based molecular therapy and immunotherapies may be promising and should be evaluated in clinical trials. Cancer 2017;123:1333-1344. © 2016 American Cancer Society.

BackgroundHead and neck squamous cell carcinoma (HNSCC) exhibits high rates of recurrence, and with few approved targeted agents, novel treatments are needed. We analyzed a molecular profiling database for the distribution of biomarkers predictive of chemotherapies and targeted agents.MethodsSeven hundred thirty‐five patients with advanced HNSCC (88 with known human papillomavirus [HPV] status), were profiled using multiple platforms (gene sequencing, gene copy number, and protein expression).ResultsAmong the entire patient population studied, epidermal growth factor receptor (EGFR) was the protein most often overexpressed (90%), TP53 gene most often mutated (41%), and phosphatidylinositol 3‐kinase (PIK3CA) most often amplified (40%; n = 5). With the exception of TP53 mutation, other biomarker frequencies were not significantly different among HPV‐positive or HPV‐negative patients. PIK3CA mutations and phosphatase and tensin homolog (PTEN) loss are frequent events, independent of HPV status. The immune response‐modulating programmed cell death 1 (PD1) and programmed cell death ligand 1 (PDL1) axis was active across sites, stages, and HPV status.ConclusionMolecular profiling utilizing multiple platforms provides a range of therapy options beyond standard of care. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1625–E1638, 2016

Our species is routinely depicted as unique in its ability to achieve cooperation, whereas our closest relative, the chimpanzee (Pan troglodytes), is often characterized as overly competitive. Human cooperation is assisted by the cost attached to competitive tendencies through enforcement mechanisms, such as punishment and partner choice. To examine if chimpanzees possess the same ability to mitigate competition, we set up a cooperative task in the presence of the entire group of 11 adults, which required two or three individuals to pull jointly to receive rewards. This opengroup set-up provided ample opportunity for competition (e.g., freeloading, displacements) and aggression. Despite this unique set-up and initial competitiveness, cooperation prevailed in the end, being at least five times as common as competition. The chimpanzees performed 3,565 cooperative acts while using a variety of enforcement mechanisms to overcome competition and freeloading, as measured by (attempted) thefts of rewards. These mechanisms included direct protest by the target, third-party punishment in which dominant individuals intervened against freeloaders, and partner choice. There was a marked difference between freeloading and displacement; freeloading tended to elicit withdrawal and third-party interventions, whereas displacements were met with a higher rate of direct retaliation. Humans have shown similar responses in controlled experiments, suggesting shared mechanisms across the primates to mitigate competition for the sake of cooperation.Pan troglodytes | freeloading | enforcement | punishment | partner choice