Abstract B085: High mutation burden and response to immune checkpoint inhibitors in angiosarcomas of the scalp and face
Authors: Painter Corrie , Jain Esha , Dunphy Michael , Anastasio Elana , McGillicuddy Mary , Stoddard Rachel , Thomas Beena , Balch Sara , Anderka Kristin , Larkin Katie , Lennon Niall , Chen Yen-Lin , Zimmer Andrew , Baker Esme O. , Maiwald Simone , Lapan Jen , Hornick Jason L. , Raut Chandrajit , Demetri George , Lander Eric S. , Golub Todd 
Published: February 2019

Abstract
Objective: Angiosarcoma (AS) is a rare soft tissue sarcoma, with an incidence of 300 cases/yr and a 5-year DSS of 30%. The low incidence has impeded large-scale research efforts. To address this, we launched a patient-partnered genomics study which seeks to empower patients to accelerate research by remotely sharing their samples and clinical information. Methods: We developed a website (ASCproject.org) to allow remote acquisition of medical records (MR), saliva, blood, and archival tissue from patients in the US and Canada. Whole-exome sequencing (WES) of ~20,000 genes is performed on tumor and matched germline DNA. Transcriptome analysis is performed on tumor RNA. Ultra-low pass whole-genome sequencing (ULP-WGS) and in some cases WES is performed on cell free DNA (cfDNA) obtained from blood samples. Clinical data including information about demographics, diagnosis, treatments, and responses are obtained via patient-reported data (PRD) and through MR abstraction. The resulting clinically annotated genomic database is shared widely to identify genomic drivers and mechanisms of response and resistance to therapies. Results: Since launch on March 13 2017, 321 patients with AS have registered. The average age of patients is 56 yrs (range 22-89). Primary locations of AS were primary breast (24%), breast with prior radiation (20%), head/face/neck/scalp (HFNS) (21%), bone/limb (9%), abdominal (3%), heart (3%), lung (1%), liver (1%), lymph (0.5%), multiple locations (11%), and other locations (5%). 142 (48%) reported being disease free at the time of enrollment. To date, 153 saliva kits, 167 MRs, 43 blood samples, and 97 tissue samples have been obtained. WES analysis is complete for 14 samples.ULP-WGS is complete for 10 cfDNA samples, and WES on 4 cfDNA samples. Transcriptome sequencing is complete for 9 tumor samples. We identified several previously described genes known to be altered in AS, including recurrent alterations in KDR and TP53. Tumor mutational burden (TMB) and mutational signature activities were quantified for each tumor sample. All three of the AS from the HFNS in the initial cohort exhibited a high TMB (&gt;150 mutations) and dominant UV light signature (COSMIC Signature 7). Based on this, we hypothesized that HFNS AS might respond well to immune checkpoint inhibitors. We identified through PRD 56 patients with HFNS AS who reported what medications they received. Of these, 2 reported receiving immune checkpoint inhibitors for the treatment of metastatic disease. Both patients had refractory metastatic HFNS AS and reported receiving off-label anti-PD1 therapy. Both had complete or near-complete responses following immunotherapy, and currently report having no evidence of disease. Clinical responses were confirmed through review of MRs. Sequencing is currently being performed on tumor samples from both patients. Conclusion: A patient-partnered approach enabled rapid identification and enrollment of over 300 patients with AS, an exceedingly rare cancer, in 15 months. We were able to obtain tumor, blood, saliva samples to perform genomic analyses, which were then merged with detailed clinical information. PRD, clinical, and genomic data generated from the first 12 patients and 14 samples have been released on cbioportal.org. Additional data will be released in six-month intervals. Initial results show high TMB and a UV signature in 3 out of 3 patients with HFNS AS. In addition, we identified 2 patients with HFNS AS who had extraordinary responses to immunotherapy. These findings suggest a common genomic basis for HFNS AS and could provide rationale for clinical interventions using checkpoint inhibitors for these AS. Analyses of additional samples are under way to further characterize mutational signatures in HFNS AS and implications for patient care. This study serves as proof of principle that patient-partnered genomics efforts can democratize cancer research for exceedingly rare cancers.
Citation Format: Corrie Painter, Esha Jain, Michael Dunphy, Elana Anastasio, Mary McGillicuddy, Rachel Stoddard, Beena Thomas, Sara Balch, Kristin Anderka, Katie Larkin, Niall Lennon, Yen-Lin Chen, Andrew Zimmer, Esme O. Baker, Simone Maiwald, Jen Lapan, Jason L. Hornick, Chandrajit Raut, George Demetri, Eric S. Lander, Todd Golub. High mutation burden and response to immune checkpoint inhibitors in angiosarcomas of the scalp and face [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B085.