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Alvarez-Breckenridge, Christopher

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Alvarez-Breckenridge

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Christopher

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Alvarez-Breckenridge, Christopher

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2017 - 201912020 - 20211

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    Evolution of Delayed Resistance to Immunotherapy in a Melanoma Responder
    (Springer Nature, 2021-05-03) Liu, David; Lin, Jia-Ren; Robitschek, Emily; Kasumova, Gyulnara; Heyde, Alexander; Shi, Alvin; Kraya, Adam; Zhang, Gao; Moll, Tabea; Frederick, Dennie; Chen, Yu-An; Schapiro, Denis; Ho, Li-Lun; Bi, Kevin; Sahu, Avinash; Mei, Shaolin; Miao, Benchun; Sharova, Tatyana; Alvarez-Breckenridge, Christopher; Stocking, Jackson; Kim, Tommy; Fadden, Riley; Lawrence, Donald; Hoang, Mai; Cahill, Daniel; Maleh Mir, Mohsen; Nowak, Martin; Brastianos, Priscilla; Lian, Christine; Ruppin, Eytan; Izar, Benjamin; Herlyn, Meenhard; Van Allen, Eliezer; Nathanson, Katherine; Flaherty, Keith; Sullivan, Ryan; Kellis, Manolis; Sorger, Peter; Boland, Genevieve
    Despite initial responses, most melanoma patients develop resistance to immune checkpoint blockade (ICB). To understand the evolution of resistance, we studied 37 tumor samples over 9 years from a metastatic melanoma patient with exceptional response followed by delayed recurrence and death. Phylogenetic analysis revealed co-evolution of 7 lineages with multiple convergent, but independent resistance-associated alterations (RAAs). All recurrent tumors emerged from a lineage characterized by loss of chromosome 15q, with post-treatment clones acquiring additional genomic driver events. Deconvolution of bulk RNAseq and highly-multiplexed immunofluorescence (t-CyCIF) revealed differences in immune composition amongst different lineages. Imaging revealed a vasculogenic mimicry phenotype in NGFR-High tumor cells with high PD-L1 expression in close proximity to immune cells. Rapid autopsy demonstrated 2 distinct NGFR spatial patterns with high polarity and proximity to immune cells in subcutaneous tumors versus a diffuse spatial pattern in lung tumors, suggesting different roles of this neural crest-like program in different tumor microenvironments. Broadly, this study establishes a high-resolution map of the evolutionary dynamics of resistance to ICB, characterizes a de-differentiated, neural crest tumor population in melanoma immunotherapy resistance, and describes site specific differences in tumor-immune interactions via longitudinal analysis of a melanoma patient with an unusual clinical course.
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    Clinical and radiographic response following targeting of BCAN-NTRK1 fusion in glioneuronal tumor
    (Nature Publishing Group UK, 2017) Alvarez-Breckenridge, Christopher; Miller, Julie; Nayyar, Naema; Gill, Corey M.; Kaneb, Andrew; D’Andrea, Megan; Le, Long P.; Lee, Jesse; Cheng, Ju; Zheng, Zongli; Butler, William; Multani, Pratik; Chow Maneval, Edna; Ha Paek, Sun; Toyota, Brian D.; Dias-Santagata, Dora; Santagata, Sandro; Romero, Javier; Shaw, Alice; Farago, Anna; Yip, Stephen; Cahill, Daniel; Batchelor, Tracy; Iafrate, A. John; Brastianos, Priscilla
    Glioneuronal tumors constitute a histologically diverse group of primary central nervous system neoplasms that are typically slow-growing and managed conservatively. Genetic alterations associated with glioneuronal tumors include BRAF mutations and oncogenic fusions. To further characterize this group of tumors, we collected a cohort of 26 glioneuronal tumors and performed in-depth genomic analysis. We identified mutations in BRAF (34%) and oncogenic fusions (30%), consistent with previously published reports. In addition, we discovered novel oncogenic fusions involving members of the NTRK gene family in a subset of our cohort. One-patient with BCAN exon 13 fused to NTRK1 exon 11 initially underwent a subtotal resection for a 4th ventricular glioneuronal tumor but ultimately required additional therapy due to progressive, symptomatic disease. Given the patient’s targetable fusion, the patient was enrolled on a clinical trial with entrectinib, a pan-Trk, ROS1, and ALK (anaplastic lymphoma kinase) inhibitor. The patient was treated for 11 months and during this time volumetric analysis of the lesion demonstrated a maximum reduction of 60% in the contrast-enhancing tumor compared to his pre-treatment magnetic resonance imaging study. The radiologic response was associated with resolution of his clinical symptoms and was maintained for 11 months on treatment. This report of a BCAN-NTRK1 fusion in glioneuronal tumors highlights its clinical importance as a novel, targetable alteration.