Search

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 (>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.

Angiosarcoma (AS) is an exceedingly rare soft tissue sarcoma, with an incidence of 300 cases/yr and a 5-year disease-specific survival of 30%. The low incidence has impeded large-scale research efforts that may lead to improved clinical outcomes. To address this, we launched a nationwide clinical-genomics study in order to empower patients to accelerate research by sharing their normal and tumor samples and clinical information remotely. Patients can access the study through an online portal (ASCproject.org). Enrolled patients are mailed saliva and blood draw kits. The study team obtains medical records and stored FFPE tumor samples. All received FFPE samples are examined by an expert pathologist to confirm a diagnosis of angiosarcoma. In order to validate that our processes would enable the generation of a robust dataset from tissues acquired from multiple institutions, we sought to characterize previously described genes known to be altered in angiosarcoma (e.g., TP53, NF1, KDR, BRCA2, MET, ARID1A, POT1, BRCA1, ASXL1, KDM6A, BRAF, SETD2, PTPRB, NRAS). A total of 251 patients have enrolled since the project launched in March of 2017. Primary locations of AS are primary breast 59 (25%), breast with prior radiation 45 (19%), head/face/neck/scalp 52 (22%), bone/limb 26 (11%), abdomen 5 (2%), heart 5 (2%), lung 2 (1%), liver 1 (1%), lymph 1 (0.4%), multiple locations 25 (11%), and other locations 12 (5%); 107 (52%) reported being disease free at the time of enrollment. To date, we have received 129 saliva kits, 106 medical records, 19 blood samples, and 36 tissue samples. Whole-exome sequencing (WES) was performed on 21 FFPE/saliva matched pairs with a goal mean target coverage of 150x for tumors. Ultra-low pass whole-genome sequencing (0.1x) was performed on cell free DNA (cfDNA) from plasma in order to determine tumor fraction. Of 10 cfDNA samples sequenced, 4 samples met criteria to perform WES. Additionally, transcriptome sequencing was performed on 9 FFPE samples. Sequence data processing and analysis has been completed on the first 10 samples and is in progress for the subsequent samples. Alterations were detected in genes previously described to be affected in angiosarcoma. Recurrent mutations in TP53 were detected in 50% (5/10) of analyzed samples, comprising 3 missense mutations, 1 frameshift deletion, and 1 frameshift insertion. Alterations were seen in at least one sample in all other genes selected for this initial analysis. This initiative demonstrates the feasibility of studying tissues from geographically dispersed patients and serves as proof of concept that patient-driven genomics efforts can democratize research for exceedingly rare cancers. Enrollment is still in progress, and additional samples will be sequenced and analyzed at scale. The data generated from these studies will be deposited into the public domain in six-month intervals. Citation Format: Michael Dunphy, Esha Jain, 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 Hendrey Lapan, Jason Hornick, Chandrajit Raut, George Demetri, Eric Lander, Todd Golub, Nikhil Wagle, Corrie Painter. The Angiosarcoma Project: Generating the genomic landscape of an exceedingly rare cancer through a nationwide patient-driven initiative [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5384.

The Metastatic Breast Cancer Project (MBCproject) is a research study that directly engages patients (pts) through social media and advocacy groups, and empowers them to share samples, clinical data, and experiences. The goal is to create a publicly available database of genomic, molecular, clinical, and patient-reported data to enable research. Working with pts and advocates, a website (MBCproject.org) was developed that allows pts with metastatic breast cancer (MBC) to register. Registered pts are sent an online consent form that asks for permission to obtain and analyze their medical records and samples. Once enrolled, pts are sent a saliva kit and asked to mail back a saliva sample, which is used to extract germline DNA. We contact participants' medical providers and obtain medical records and a portion of their stored tumor biopsies. Pts may be asked to mail in a blood sample, which is used to extract cell free DNA (cfDNA). Whole-exome sequencing (WES) is performed on tumor DNA, germline DNA, and cfNDA; transcriptome sequencing is performed on tumor RNA. Clinically annotated genomic data are used to study specific pt cohorts (including outliers) and to identify mechanisms of response and resistance to therapies. All de-identified data are shared via public databases. Study updates are shared with participants regularly. From 10/2015-11/2017, 4237 MBC pts registered, representing over 1,000 institutions. 95% answered the 16-question survey about their cancer, treatments, and demographic information. 2471 (58%) completed the consent form. 2,136 saliva kits were mailed to pts and 1,523 saliva samples were sent in (71%). 408 blood kits were mailed to pts and 175 blood samples have been received for cfDNA analysis. To date, we have obtained medical records from 311 pts and 190 tumors from 127 pts. In 10/2017, all data generated so far were publicly released on cbioportal.org, including WES for 103 tumors from 78 pts linked to clinical data including pathology (22 elements), medical record abstraction including all treatments and timelines/durations (67 elements), and patient-reported data (11 elements). 81% of biopsies included in this release were from the breast and 19% from metastatic sites. 75% were obtained prior to any therapy, 24% following therapy. New data will be released 4/2018 and every six months thereafter, as they are generated. Additional patient-reported data, including treatments, side effects, quality of life, family history, pregnancies, and sites of metastasis, will also be collected and shared. In summary, a patient-driven approach enabled rapid identification of thousands of MBC pts willing to share samples and clinical data. Remote acquisition of medical records, saliva, blood, and tumor tissue for pts across the U.S. is feasible. This shared clinico-genomic database should enable research in MBC and may serve as a model for patient-driven research in other cancers. Citation Format: Nikhil Wagle, Corrie Painter, Elana Anastasio, Michael Dunphy, Mary McGillicuddy, Rachel Stoddard, Esha Jain, Dewey Kim, Simona Di Lascio, Brett N. Tompson, Sara Balch, Beena Thomas, Priti Kumari, Shawn Johnson, Jamie Holloway, Ofir Cohen, Erik H. Knelson, Katie Larkin, Sam Pollock, Alicia Wong, Samira Bahl, Simone Maiwald, Andrew Zimmer, Esme O. Baker, Jen Hendry Lapan, Scott Sutherland, Scott Sassone, Viktor Adalsteinsson, Eric S. Lander, Todd R. Golub. The Metastatic Breast Cancer Project: Partnering with patients to accelerate progress in cancer research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5371.