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Despite rare cancers accounting for 25% of adult tumors1, they are difficult to study due to the low disease incidence and geographically dispersed patient populations, which has resulted in significant unmet clinical needs for patients with rare cancers. We assessed whether a patient-partnered research approach using online engagement can overcome these challenges, focusing on angiosarcoma, a sarcoma with an annual incidence of 300 cases in the United States. Here we describe the development of the Angiosarcoma Project (ASCproject), an initiative enabling US and Canadian patients to remotely share their clinical information and biospecimens for research. The project generates and publicly releases clinically annotated genomic data on tumor and germline specimens on an ongoing basis. Over 18 months, 338 patients registered for the ASCproject, which comprises a large proportion of all patients with angiosarcoma. Whole-exome sequencing (WES) of 47 tumors revealed recurrently mutated genes that included KDR, TP53, and PIK3CA. PIK3CA-activating mutations were observed predominantly in primary breast angiosarcoma, which suggested a therapeutic rationale. Angiosarcoma of the head, neck, face and scalp (HNFS) was associated with a high tumor mutation burden (TMB) and a dominant ultraviolet damage mutational signature, which suggested that for the subset of patients with angiosarcoma of HNFS, ultraviolet damage may be a causative factor and that immune checkpoint inhibition may be beneficial. Medical record review revealed that two patients with HNFS angiosarcoma had received off-label therapeutic use of antibody to the programmed death-1 protein (anti-PD-1) and had experienced exceptional responses, which highlights immune checkpoint inhibition as a therapeutic avenue for HNFS angiosarcoma. This patient-partnered approach has catalyzed an opportunity to discover the etiology and potential therapies for patients with angiosarcoma. Collectively, this proof-of-concept study demonstrates that empowering patients to directly participate in research can overcome barriers in rare diseases and can enable discoveries. A framework of patient-partnered research allows patients with angiosarcoma to share their samples and clinical records securely to accelerate molecular characterization of tumors and identification of therapeutic approaches.

Molecular profiling studies have enabled numerous discoveries for metastatic prostate cancer (MPC), but they have mostly occurred in academic medical institutions focused on select patient populations. We developed the Metastatic Prostate Cancer Project (MPCproject, mpcproject.org), a patient-partnered initiative to empower MPC patients living anywhere in the U.S. and Canada to participate in molecular research and contribute directly to translational discovery. Here we present clinicogenomic results from our partnership with the first 706 MPCproject participants. We found that a patient-centered and remote research strategy enhanced engagement with patients in rural and medically underserved areas. Furthermore, patient-reported data achieved 90% consistency with abstracted health records for therapies and provided a mechanism for patient-partners to share information about their cancer experience not documented in medical records. Among the molecular profiling data from 333 patient-partners (n = 573 samples), whole exome sequencing of 63 tumor samples obtained from hospitals across the U.S. and Canada and 19 plasma cell-free DNA (cfDNA) samples from blood donated remotely recapitulated known findings in MPC and enabled longitudinal study of prostate cancer evolution. Inexpensive ultra-low coverage whole genome sequencing of 318 cfDNA samples from donated blood revealed clinically relevant genomic changes like AR amplification, even in the context of low tumor burden. Collectively, this study illustrates the power of a longitudinal partnership with patients to generate a more representative clinical and molecular understanding of MPC.NoteTo assist our patient-partners and the wider MPC community interpret the results of this study, we have included a glossary of terms in the Supplementary Materials.

Background: 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 their samples, clinical information, and experiences. The goal is to create a publicly available dataset of linked genomic, clinical, and pt-reported data to enable research. Methods: In collaboration with pts, advocates, and advocacy groups, a website (MBCproject.org) was developed that allows pts with metastatic breast cancer (MBC) anywhere in the U.S. or Canada 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 a blood kit and asked to mail back a saliva sample, which is used to extract germline DNA, and/or a blood sample, which is used to extract germline DNA and cell free DNA (cfDNA). We contact participants’ medical providers and obtain medical records and a portion of their stored tumor biopsies. Whole exome sequencing (WES) is performed on tumor DNA, germline DNA, and cfDNA; transcriptome sequencing (RNA-seq) is performed on tumor RNA. Medical records and pt-reported data are abstracted to create a detailed clinical record for each pt. All de-identified data are shared regularly via public databases (cbioportal.org, mbcproject.org, dbGaP, NCI Genomic Data Commons) without restrictions. Study updates are shared with participants regularly. Results: From 10/20/15-7/8/19, 5357 women and men with MBC registered. 3290 pts receiving care at over 1700 different institutions consented to share medical records and tumor/saliva/blood samples, and to have genomic analysis performed. Details of clinical data collection, biospecimen acquisition, and genomic data generation to date are outlined in the Table. WES from 463 tumors obtained from 326 pts have been generated (with matched germline WES), including 61 pts with 2 timepoints, 19 pts w 3 timepoints, and 11 pts w 4+ timepoints. 278 tumor exomes were from the breast/regional lymph nodes, 63 from distant metastatic sites and 122 from cfDNA. 110 tumor exomes were from samples obtained before the diagnosis of MBC, 258 from after the diagnosis of MBC, and 95 to be determined (TBD). 161 tumor exomes were obtained prior to any therapy, 204 following some therapy, and 98 TBD. Clinically annotated genomic data are used to study specific pt cohorts (including rare subsets and outliers) and to identify mechanisms of response and resistance to therapies. Examples of the clinical and genomic analyses that will be presented include: - Pts diagnosed 5 yrs after diagnosis (830 pts enrolled; 77 with tumor WES) - Long-term survivors, >10 yrs with MBC (159 pts enrolled; 11 with tumor WES) - Resistance to CDK4/6 inhibitors (709 pts enrolled; 148 with tumor WES) Conclusions: Partnering directly with pts enables rapid identification of thousands of pts willing to share tumors, blood, saliva, and medical records to accelerate research. This approach allows for identification of patients with specific phenotypes, who have been challenging to identify with traditional approaches. Remote acquisition of medical records and saliva/blood/tumor samples is feasible. This clinically annotated dataset is a shared resource for the research community. Table 1Clinical data collection, biospecimen acquisition, and genomic data generation:NumberConsent signed3290 ptsSurvey #1 submitted3290 pts(demographics, diagnosis details, receptor status, clinical experiences)Survey #2 submitted1435 pts(pathology details, sites of metastasis, treatments with start and stop dates)Medical record received1307 ptsSaliva sample received1976 ptsBlood sample received1121 ptsTumor samples received482 tumor samples from 346 ptsDigital image of tumor slide H&E generated482 tumor samplesWES from germline complete310 germline samplesWES from tumor sample complete341 tumor samplesRNA-seq from tumor sample complete229 tumor samplesULP-WGS from cfDNA complete947 blood samplesWES from circulating tumor DNA complete122 blood samples Citation Format: Nikhil Wagle, Corrie Painter, Elana Anastasio, Michael Dunphy, Mary McGillicuddy, Esha Jain, Tania G Hernandez, Sara Balch, Beena Thomas, Dewey Kim, Alyssa L. Damon, Shahrayz Shah, Brett N. Tomson, Rachel Stoddard, Colleen Nguyen, Jorge Buendia-Buendia, Ofir Cohen, Jorge Gomez Tejeda Zanudo, Netsanet Tsegai, Lauren Sterlin, Ulcha Fergie Ulysse, Kathryn Sine, Oyin Alao, Jacqueline Lucia, Eric S. Lander, Todd R. Golub. The metastatic breast cancer project: Generating the clinical and genomic landscape of metastatic breast cancer through patient-partnered research [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD8-01.